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Katie Connolly, Melanie Ostrekher and EliAa Rennert-May, chapter editors Doreen Ezeife and Nigel Tan, associate editors Steven Wong, EBM editor Dr. Ramesh Prasad, Dr. Martin Sc:hreiber and Dr. Gemini Tanna, staff editors
Basic Anatomy Review ................... 2 Anatomy of the Kidney Renal Structure and Function Renal Hemodynamics Differential Diagnoses of Common Presentations . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Azotemia Proteinuria Hematuria Assessment of Renal Function ............. 6 Measurement of Renal Function Urinalysis Urine Microscopy Urine Electrolytes Electrolyte Disorders. . . . . . . . . . . . . . . . . . . . . 9 Sodium Homeostasis Hyponatremia Hypernatremia Potassium Homeostasis Hypokalemia Hyperkalemia Acid-Base Disorders .................... 16 Metabolic Acidosis Metabolic Alkalosis Renal Failure .......................... 19 Presentation of Renal Failure Acute Kidney Injury (AKI) ................ 20 Approach to AKI Chronic Kidney Disease (CKD) . 21 Management of Chronic Kidney Disease Renal Replacement Therapy ............. 22 Dialysis Renal Transplantation Glomerular Disease .................... 23 Terminology of Glomerular Changes Presentation of Glomerular Disease Investigations for Glomerular Disease Secondary Causes of Glomerular Disease Infections and Glomerular Disease Tubulointerstitial Disease ............... 27 Tubulointerstitial Nephritis (TIN) Acute Tubular Necrosis (ATN) Analgesic Nephropathies Vascular Diseases of the Kidney .......... 30 Large Vessel Disease Small Vessel Disease Systemic Diseases and the Kidney ........ 32 Hypertension (HTN) Hypertensive Nephrosclerosis Renovascular Hypertension Renal Parenchymal Hypertension Multiple Myeloma Malignancy Diabetes and the Kidney ................ 34 Cystic Diseases of the Kidney ............ 36 Adult Polycystic Kidney Disease Medullary Sponge Kidney Autosomal Recessive Polycystic Kidney Disease Common Medications .. 38 Landmark Nephrology Trials .. 39 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Toronto Notes 2011

Nephrology NPI

NPl Nephrology



Basic Anatomy Review

Anatomy of the Kidney

Renal Structure and Function

The Nephron basic structural and functional unit ofthe kidney, approximately I million per kidney 2 main components: glomerulus and attached renal tubule (Figure I) direction of blood flow: afferent arteriole -+ glomerular capillaries -+ efferent artuiale -+ vasa recta (the capil.laries surrounding the tubules) -+renal venules

Osmatic diuratics liEzide diu191ics K+ Sparing diantics

o.-.lingII!Dolloop .

( ) L.oapdiul'ltics


! :z:

i ;a

N1+-K- 2CI-

H,D -



0 [



1. N1p1Jnm Compa1ants
Tlble 1. MaJor Fu1dons of the Kidneys
1. Willa EKrltiGn

Ghmarular fi1nl1ion
Tubailr secretion Tub.-r calllxllism Tubailr tllaCI and Wllllr rubsGiptilll Tubaar Kseaetion Tub.-r HaecratiCII HCO, synlheais ..:1 rBaa!ption Tubular Ca, Mg. P04 lnllspart
Elytlqail!lil pracb:lian lcorttxl Vitamin Ddvation [25[0H)D 1,25(0HJDI Ranil praductian (JG applfiiUi)

(urea, Cl)

Eiu:mian of nitragnJUs prDib:ls of pratailrnelllbalism

Excretion af organic (!Ne) and Dfllllnic bases (Cr) llnllkdawn end ucratian af drugs {..tDalicl, diul'llicll) end peplida hlmlanes (mast pituillry harmCIIIIS, ilsUin.
Clllllds vduma s1a1us and osmolar balance Clllllds pllillssium cai!CI!nlnllian Al:id-basa balance Al:id-basa balance .Min Ca. Ma-1'04 harnaastasis Calcium hiDII!IISialis

Red lilad eel proU;Iian

Allin VIICUI.-ra&i&Wlcellllaldastlmle sacratian Allin ECF Allin VIICUiar rnista1ce

Glucose !llp!iY lllllintailed in prnlanged staiYIIIion

....aod ............... Na IIKL18tian Ranil praductian

Gluconeogereis tfmm lacbde, py!\MII8 end smila acids)

'IbroDlo Nota 2011

Buic Anatomy Review

Nephrology NP3

The Glomerulus site where blood constituents are filtered through to the kidney tubules fur excretion or reabsorption consistB of following cell types 1. capillary endotbelial cells and podocytes support the glomerular basement membrane (GBM) and furm the plasma filtration apparatus 2.mesangialcells have contractile properties and produce substances to help control blood flow 3. parietal epithelium covers the interior of Bowman's capsule filtration occurs aaoss the GBM Into Bowman's space (Figure 2) filtration barrier: conaists ofcapillary endothelium, GBM. podocyte filtration alit& particles are selectively filtered by size (<60 kDa) and charge (negatlve charge repelled)

I!J---Aifanllnt artariola

I. Bowman's Cllpde 4. M111111111ium


z. Bawmln'SipiiCI

(pari81111 &pilhtllium) 5. Mlllllllllill calla

6. CIIPiiiiY 7. EndGihalilll cell

8. Glomerular BM

Figure 2. The Glamerjjus The Renal Tubules reabsorption and seaetion occur between the renal tubules and vasa recta untll tubular fluid is transfurmed Into urine for excretion each anatDmic segment of the nephron has unique characteristics and specialized functions that enable selective transport of solutes and water proximal tubule responsible for reabsorbing -60% offiltered NaCl and water, as well as -90% offiltered bicarbonate and most critical nutrients !II1Cb. as glucose and amino acids loop ofHenle consists of three major segments by cellular morphology and location: descending thin limb, ascending thin l.!.mb. and ascending thick limb important role in urinary concentrating ability by contributing to the generation ofa hypertonic medullary interstitium contributes to reabsorption ofcalcium and magnesium ions distal comrol.uted tubule reabsorbs -596 of the filtered NaCl composed of a tight epithelium with llttl.e water permeab:llity regulates pH by absorbing bicarbonate and secreting H reabsorbs caldum In response to parathyroid hormone collecting duct regulates the final composition of the urine important fur hormonal regulation of salt and water balance (water reabsorption governed by antidiuretic hormone) reabsorption ofsodium and secretion of potassium at cortical collecting duct regulated by aldosterone

Renal Hemodynamics
Renal Blood Flow (RBF) of Renal Plasma Flow (RPF): 2096 ofcardiac output= 1000 mlJmin Glomerular Filtration Rate (GFR) the rate of fl.uJ.d transfer between glomerular capillaries and Bowman's space 120 ml/min in healthy adult= 173 IJday, of which 99% is reabsorbed, giving a daily urine
output ofl.0-1.5 L
GIDmrulu fillmiDn 11m!

highest in early adulthood, decreasing thereafter

GFR - K, 1M' - Alii r, = ultnlillndion caallicilnt AP = hylhstJdic pnmnn All = DlmotiC PIIIISUIII
Nit ouMwd pr811Uf8

NP4 Nephrology

Buic Anatomy Rniew/Differentlal Dlagnoses of Common PruentalioDI



renal autoregulation maJntains a constant GFR over a range of mean arterial pressures (70 to 180 m.mHg). 2 mechanisms of autoregulatl.on: myogenic mechanism: release of vasoactive factors in response to alterations in perfusion

pressure. E.g. rise ln perfusion pressure causes afferent arteriolar coll8trlctl.on, leading to a decrease in GFR tubuloglomerular feedback: changes in [Na] delivery to macula densa lead to afferent arteriolar tone (increased delivery Cllll8e8 afferent constriction) Filtration Fraction (FF) percentage of RPF filtered across the glomeruli expressed as a ratio: FF = GFRJRPF, normal = 0.2 or 20% angiotensin II (An) causes constrktion of renal efferent arterioles which increases FF thereby
malnta!DingGFR renin is released from Juxtaglomerular apparatus in response to decreased RPF

1. .1- iutre!J;II ar!Briala 2. JG eel belllsym!lllhBtic narva IIM!u!Eon

B_ ,r .- .. .



I ro

0 --o



.. ..-.. . ) -.

Hillin _

I ..
I. VuoCGIIIbictian 2. 1' vasc1*nmoo1h mulda IJliWih 3. 1' Nl reablorplion 4. 1' lldoataruna

AngiDIInlill - - - -- Angiulenlin II

Adnml cortax Stinullllian of Na 6\ . . nrllnlian illha - - AldOSielone -4--


5. 1' bie1nbo11118

Differential Diagnoses of Common Presentations

Definition higher urea and Cr are usually caused by inability of the kidney to excrete urea. Cr and other compounds in the blood
1 Azcaml


llfrpovallnlil) IUd lou8l (hamorrhaae. Gl, lkin. lrilll .1- ECV aapsis)
Hapat011111lll synlhme

1 llrlnaiM!

l'osklnrllt/C lllllllructial Anattlmic (1hirt. entire GU net

e.g. slllnBI, tumau; BPH)




Al:uiiii!Djar nKilllil ,IJt


Acutllllllergiej inlllrllitill neplriil A

A-ICIIIIIAI!ing C-dnnic181ting

12" .-111111 ARF/Iaxi11

llanaiii1Bry obllruclian A/C

Chronic IUUainlllrBiiiB nephritis C Pyalal'lllplriis

llanBI vain Dllslructian AIC

!thrombosis, embcilc, aartic dissactian, campn181ian YIICUilil. polllbda tr.Jmt. ar;aryJ

NC {llPAlUS, DIC, zm lml crisis)

F"11111r1 4. a.ssificltian af AzatBIIH

Toronto Notes 2011

Differential Diagnosis of Common Presentationa

Nephrology NPS

24-hour urine protein: gold standard to assess degree of proteinuria (see Table 2) urine albumin-to-creatinine ratio (ACR): used to screen for diabetic nephropathy Microalbwninuria defined as ACR mglmmol (female) or mg/mmol (male) marker of vascular endothelial function an important prognostic marker for kidney disease in diabetes and hypertension (see Diabetes and Kidney, NP34) an elevated ACR or 2.8 mglmmol is the earliest sign of diabetic nephropathy composition of normal total urine protein 60% filtered plasma protein: 50% albumin, 15% Ig, 25% other 40% Tamm-Horsfall mucoprotein secreted from tubular cells




I Proteinuria I
Physiologic Orthostlllic Absence of protainuria overnight Usually resolves spontaneously (exercise, fever, CHF}


+ htllaiDail:

Tubulaintamitial {impairud resorption! <2 gfday e.g. Fanconi"s IJY!ldrome

I Doss of large protains (albuminII I Glan.rr


{Ovarprocklction of LMW protainsl e.g. multiple myeloma, amyloidosis, Waldensbllm'a macroglobulinemia

t Tulluloiraratitill Nonndy low molacular waight {LMWI proteins i <60 kD) pus through glomerular filtnltion blrriar and ana raabsolbad in proximaltmule Proximal1ubule dysfunction causes impan.d l'labsorplion and incraased exJ:relion af LMW proteins Albumin {>60 kDI is NOT affected Thus, edema is partly secondary to salt and Wlll8r l'lltllntion
2.Giom.-r No111111lly, the 111ntion barrier is selectively penneable to SIZE {<60 kDI and CHARGE {repels nagativa particles). Thus, albtnin is NOT filtarud through a nonmlll giDIJIIIIIIuS Damage to any component of tha QIDIIIIIIIIar filtration barriar mulls in loss of albumin and other high MW proteins. Thus. edema is secondary to hypoalbuminemia {low oncDtic but also due to enhanced renal tubular reabsorption af filtered sodium and water (mechanism uncer111inl


Minimal Change GN Membranous GN Focal segmental glomeruloaclerosis {FSGSI Membrano-prolif. GN Post-strap. GN lgA nephropBihy

LMW -low molecular GN - glom1111lonephri1is


Second1ry SystEmic disease Sl.E, diabetes, vasculitis Infectious disease HIV, Hap Band C, bllctarial endocarditis Hlllditary/Jnelllbolic Alport's, Fabry's, sickle cell, polycystic kidney disease Medications NSAIOs, gold, heavy melllls Cancer {carcinoma,lymphomal Lymphom1, solid tumour Others Cryoglobulinemia, hypertansiva nephrosclerosis

Figure 5. Classification of Proteinuria Table 2. Daily Excretion of Protein

Daily Elu:nrtion

<150 mg tollll protein (and < 30 mg albumil) 30-300 mg albumin >3500 mg total protein
Variable llllount of proteinuria

MiCIDIIIbwninuria Nephrotic range proteinuria

3.11vartlaw production of LMW proteins which axceeds the reabsorptive capacity of the proximal 1ub\Q Plasma cllll dyscmiu: produce light chain lg myeloma, W.ldanstrom'a macroglobulinemia, monoclonl gammopathy of undanninad significiii'ICII

C111 be seen with glornerulll' clsease; i.e. mild glomerular disease can lead to a
mild dagrae of proteinuria, prolifllllltive lasioos may also be associlllad with scrne

degree of proteinuria

Up to 2000 mg pll' day

Possible tubular disease because of failure to reabsorb filtered proteins

urine R&M, C&S, urea, Cr further workup (if degree of proteinuria >0.5 glday, casts and/or hematuria) CBC, glucose, electrolytes, 24-hr urine protein and Cr urine and serum immunoelectrophoresis, abdominal!pelvic ultrasound serology: ANA, RF, p-ANCA, c-ANCA, Hep B, Hep C, HIY, ASOT indications for nephrology referral ACR >30-1000 mglmmol nephrotic syndrome: marked proteinuria >3.5 g/1.73m2/daywith hypoalbuminemia (<35 giL)

NP6 Nephrology

DUferential Diagnosea of Common Preaentatiom/.Aneasment of Renal Function

Toronto Notes 2011

Definition presence ofblood or RBCs in urine gross hematuria: pink, red, or tea-coloured urine in gross hematuria, the urine should be centrifuged it is hematuria only if the sediment is red. If the supernatant is red. test for heme with a dipstick - if +ve for heme: myoglobinuria or hemoglobinuria - if -ve for heme: pseudohematuria. Consider medications (e.g. rifampin), food dyes (e.g. beets) or metabolites (e.g. porphyria) microscopic hematuria: normal coloured urine, >2-3 RBCs/HPF on microscopy

-ve dipstick. no RBCI

Pseudohematurill Food (basts), dyes, madicati011 (rifampin)


+ve dipsticll.- +ve RBCs

Hematological Coaguloplllhy, sickle cell


[1rue hematuria) Hemoglobin (hemolysis)

+ve dipllick, no RBCI
Myoglobin (rhabdomyolysis)



Urologic Nephrolithiasis, 1rauma, tumour. pro.tatitis, urethritis Dysuria or flank pain common Isomorphic RBCs, no casts Blood at beginning (lni!Yitis) or end [prostate, bladder) of stre1111




GN Post-51rap. GN Rapidly-progressive GN nephritis (ICuta and chronic) Papillary necrosis lgA naphroplllhy

Comective tissue diseases (CTDJ Waganar's, Goodpastura's, SLE, Ct.Jrg-Stnluss, HSP Infection Pyelonephritis Heneditary AIport's, polycystic kidnsy disaasa (PCKD)

Figura 6. An Approach to Hamll'lllria

Investigations for Hematuria Hx and Px: family history of nephrolithiasis, hearing loss (Alpert's), cerebral aneurysm (PCKD), diet, recent URTI, irritative and obstructive urinary symptoms (UTI) urine R&M, C&S, urea, Cr 24-hr urine stone workup: calcium, oxalate, citrate, magnesium, uric acid, cysteine further workup (if casts and/or proteinuria): CBC, electrolytes, 24-hr urine protein and Cr, serology (.ANA, RF, C3, C4, p-ANC.A, c-.ANCA, .ASOT), abdo/pelvic ultrasound, cystoscopy urology consult

Assessment of Renal Function

[Cr),.,,.. x GFR = [CrJ..t..., x urin flow ms(ml/min) GFR - ICrJ.m. x urjne !low r11!: [Cr)-

Measurement of Renal Function

Glomerular Filtration Rate (GFR) = rate of filtration of plasma by the glomeruli most renal functions decline in parallel with a decrease in GFR GFR is often estimated using serum creatinine concentrations [ Cr] creatinine (Cr) is a metabolite of creatine (intermediate in muscle energy metabolism) Cr is freely filtered at the glomerulus with no tubular reabsorption and minimal secretion (10%) rate of production determined by muscle mass Cr excreted= Cr filtered (at steady state)



There is an inverse relati011ship between sarum Cr concentration and CrCI at steady state.

Ways to Estimate GFR I. Calculate creatinine clearance (CrCl) calculation provides reasonable estimate of GFR measure plasma [Cr], 24-hr urine volume and urine [ Cr] GFR= (urine [Cr] xurinevolumeinmL)/(plasma [Cr] xdurationofurine collection in minutes) two major errors limiting the accuracy of CrCl increasing Cr secretion can overestimate true GFR, particularly in azotem.ic patients incomplete urine collection can underestimate true GFR; over-collection of urine overestimates it

Toronto Notes 2011

Assessment of Renal Function

Nephrology NP7

2. Cockcroft-Gault formula serum Cr used along with age, gender and weight (kg) to estimate GFR (see sidebar) nonnal range is >90 ml/min (> 1.5 ml/s) 3. MDRD (Modification of Diet in Renal Disease) formula most common way in which GFR is estimated complex formula incorporating age, gender, serum Cr, Mrican descent GFR is reported as ml/min/L73m2 body surface area Limitations of Using Serum Cr Measurements I. must be in steady state constant GFR and rate of production of Cr from muscles sudden injury may reduce GFR substantially, but it takes time for Cr to accumulate and then re-establish steady state 2. GFR must fall substantially before plasma [CrI rises above normal laboratory range with progressive renal failure, remaining nephrons compensate with hyperfiltration GFR is relatively preserved despite significant structural damage 3.plasma [CrI is influenced by the rate of Cr production lower production with smaller muscle mass (ie. female, elderly, low weight) e.g. consider plasma [Crl oflOO f!InOl!L (1.13 mgldL) in both of these patients 20 year-old man who weighs 100 kg, GFR = 144 mUmin 80 year-old woman who weighs 50 kg, GFR = 30.6 mUmin 4. contribution of tubular secretion to Cr excretion is increased when GFR is low CrCl overestimates GFR certain drugs (cimetidine, trimethoprim) interfere with Cr secretion 5. errors in Cr measurement very high bilirubin level causes [Cr] to be falsely low acetoacetate (a ketone body) and certain drugs (cefoxitin) create falsely high [Cr] Measurement of Urea Concentration urea is the m.aj or end product of protein metabolism plasma urea concentration is a measurement of renal function but should not be use alone as it is modified by a variety of factors urea production reflects dietary intake of protein and catabolic rate; increased protein intake or catabolism (sepsis, trauma, GI bleed) causes urea level to rise ECF volume depletion causes a rise in urea independent of GFR or plasma [CrI in addition to filtration, a significant amount of urea is reabsorbed along the tubule reabsorption is increased in sodium-avid states such as ECF volume depletion typical ratio of urea to [Cr] in serum is 1:12 in Canadian units (using mmol/L for urea and !llllol!L for Cr), and 14:1 in US units (urea expressed as BUN in mgldl and Cr in mgldL)


CrCI (mVmin] = I11!H!!fll X wt (kg) X 12 I X 0.85 in W0111111] (Crl,.... (umol!ll

Cockcroft-Gault Fonnlll



C&nical Settings in which Urw. Lenl Ia MfKt.d lndaptlmlont llf Rn..

incruH in Urwa Volume depletion (prarenalezotemial Gl hemonllage High protlin diet

Celllbolic lllrt8 with tilsuu bnlakdown Cortic:osteroid or cytotoldc agents

In lira
Low protein diet
Livar disalsa

use dipstick in freshly voided urine specimen to assess the following:
1. Specific Gravity ratio of the mass of equal volumes of urine/H 20 normal range is 1.001 to 1.030 values <1.010 reflect dilute urine, values >1.020 reflect concentrated urine value usually 1.010 in end stage renal disease (isosthenuria)
2. pH urine pH is normally between 4.5-7.0; if persistently alkaline, consider: renal tubular acidosis UTI with urease-producing bacteria (e.g. Proteus)


Z4 hour Urinll Callectian 1. lliscllld first morning $JI&Cim&n 2. Collect all subsequent urina for lila
next24 hi"$ 3. IWripra.. bltwnn voids 4. Collect second morning CIIJIIy: Cloudilass may indicate infection Colour: usually pllla yallow or lllllbar. but may be colourtess (dillllellls insipidus, excess Wlt8r intalal], bright yallow (due to ribofiiMn ingestion or vitamin ..bllllll). or dlllt yaUow (conciiTII'IDd urina in inlnMiscu!er volume depletion]

3. Glucose freely filtered at glomerulus and reabsorbed in proximal tubule causes of glucosuria include 1. hyperglycemia >9-11 mmol/L (>160-200 mg!dl) leads to filtration that exceeds tubular resorption capacity 2. increased GFR (e.g. pregnancy) 3. proximal tubule dysfunction (e.g. Fanconi's syndrome) 4. Protein dipstick only detects albumin; other proteins (e.g. Bence-Janes, lg, Tamm-Horsfall) may be missed microalbuminuria (defined as 30-300 mglday) is not detected by standard dipstick (see Diabetes and the Kidney, NP34) sulfosalicylic acid detects all protein in urine by precipitation gold standard: 24-hr urine collection for total protein


Eslinwting Urillll DIIIIDI..ity Lut 2 digits of lila specific g111Yity x 30 = urine osmolality approximatEly e.g. specific gravity of 1.020

= 600m0sm

NP8 Nephrology

Assessment of Renal Function

Toronto Notes 2011

5o Leukocyte Esterase
enzyme found in WBC and detected by dipstick presence ofWBCs indicates infection (e.g. UTI) or inflammation (e.g. AIN) nitrates in urine are converted by bacteria to nitrites high specificity, low sensitivity for UTI +ve dipstick for leukocyte esterase and nitrites is 94% specific for diagnosing a UTI

6. Nitrites


.. ,

7. Ketones
positive in alcoholic/diabetic ketoacidosis, prolonged starvation, fasting


B. Hemoglobin
Red 1)111 calls WlitiCIIcasts


Aly 111 or


... lllllwilfl

<21111 eels per <4v.liit8CIIs

positive in hemoglobinuria (hemolysis), myoglobinuria (rhabdomyolysis) and true hematuria (RBCs seen on microscopy)

Urine Microscopy
centrifuge urine specimen for 3-5 minutes, discard supernatant, resuspend sediment and plate on slide shaking tube vigorously may disrupt casts

oSmllli >211dcellslll afCI'/Iflll powarfilll o Smahmollltcl tiiPf) hcleria >4vAilecells perhpf


,.._. Hlltf IIQI8Itive

pdhclogy,clllll pdhclogy


lblhocllaf sii;JIIi:n ILtnotrmediU

normal range = 2-3 RBCs per high power field (HPF) hematuria = greater than 2-3 RBCs/HPF dysmorphic RBCs and/ or RBC casts suggest glomerular bleeding (e.g. proliferative glomerulonephritis) isomorphic RBCs, no casts suggest extraglomerular bleeding (e.g. bladder Ca)

normal range = up to 3 WBCs/HPF pyuria = greater than 3 WBCs/HPF indicates inflammation or infection if persistent sterile pyuria present (i.e. negative culture), consider: chronic urethritis, prostatitis, interstitial nephritis, calculi, papillary necrosis, renal TB, viral infections

detected using Wright's or Hansel's stain (not affected by urine pH) consider allergic interstitial nephritis, atheroembolic disease

Oval Fat Bodies renal tubular cells filled with lipid droplets seen in heavy proteinuria (e.g. nephrotic syndrome) 2. CASTS cylindrical structures formed by intratubular precipitation of Tamm-Horsfall mucoprotein; cells may be trapped within the matrix of protein
Table 3. Interpretation of Casts

Hyaline casls
Red blood cell casts White blood call casls

Physiologic (concenlnrted urile, fever, exercise] Glomerulll' bleedilg (glomerulonephritis, vasculitis} lnfeclian (pyelaneplritis] lnllanmrtion (interstitial nephritis} Acute tubulll" necrosis Glomerulonephritis, interslitial nelllritis Heavy proteiruria (>3.51fday]

Pigmented gnmlar casts (heme grarular casls, muddy brown] Fatty casts

uric acid- consider acid urine, hyperuricosuria (e.g. gout) calcium phosphate - alkaline urine calcium oxalate - consider hyperoxaluria. ethylene glycol poisoning sulfur - sulfa-containing antibiotics

Toronto Notes 2011

.Assetl8lllent of Renal Function/Electrolyte Disorders

Nephrology NP9

Urine Electrolytes
can use to evaluate the source of an electrolyte abnormality or grossly assess tubular function commonly measure: Na, K. Cl. osmolality and pH no 'normal' values; electrolyte excretion depends on intake and current physiological state therefore results must be interpreted in the context of a patient's current state, e.g. 1. ECF volume depletion: expect low urine [Na] (kidneys should be retaining Na) a high urine [Na] in this setting suggests a renal problem or the action of a diuretic urine [Na] <10 mmolJL suggests the patient is pre-renal 2. daily urinary potassium excretion rate should be decreased (<20 mmolJd) in the setting of hypokalemia if higher than 20 mmolJd, suggests renal etiology osmolality is useful to estimate the kidney's concentrating ability refers to the fractional excretion ofNa FENa =Urine [Na] xPlasma [Cr]/ (Plasma [Na] xUrine [Cr]) <1% suggests the pathology is prerenal


INal"'- x [Crlurilo

Fractional Excrwlion of Sodium FEti, = .. X ICrl- X 1DO Many fonnuills uud in nephrology 11111 derived from 1he division of two frllctiDRI, each of which urine and plasma concentmian (e.g. U,IP, + Wl'2l In 1he cqe of it is UNJPNo + UcJPc. which 1hln givls the above equation.

Examples of Common Urine Electrolyte Abnormalities high urine Na (>20 mmolJL) in the setting of acute renal failure: indicates renal disease vs. pre-renal high urine Na (>40 mmolJL) in the setting of hyponatremia: generally from causes such as diuretics, tubular disease (e.g. Bartter's syndrome), SIADH additionally, urine pH is useful to grossly assess renal acidification "low" pH (<5.5) in the presence oflow serum pH is an appropriate renal response a high pH in this setting might indicate a renal acidification defect (e.g. RTA)

Electrolyte Disorders
Sodium Homeostasis
Introduction hyponatremia and hypernatremia are disorders of water balance hyponatremia suggests too much water in the extracel.l.ular fluid relative to Na hypernatremia is too little water in the extracel.l.ular fluid relative to Na both can be associated with normal, decreased or increased total body Na solutes (such as Na, glucose, or urea) that cannot freely traverse the plasma membrane contribute to effective osmolality and induce transcellular shifts of water water moves out of cells in response to increased ECF osmolality water moves into cells in response to decreased ECF osmolality physiologically, ECF volume is determined by Na content, not Na concentration Na deficiency leads to ECF volume contraction Na excess leads to ECF volume expansion clinical signs and symptoms of hyponatremia and hypernatremia are secondary to cells (especially in the brain) shrinking (hypematremia) or swelling (hyponatremia) Tabla 4. Clinical Assessment of ECF Volume (Total Body Na)
Fllid Campartmall: Hypovolllllic Decreased Orlho6tatic op

..... ,
Sodium [Na) 135145 mmaVL (K) 3.S.5 mmoVL
Chloride (CI) 95-105 mmoVL Bicarbonall (HC01) I 8-23 mmoVL

Increased Nonnal to increased SJ lnspira!DfY Clllcldes NonnaVincreased Present Variable Increased DecntaSed

BloDd prassura Ausculllltioo CJf hBBrt Allsculllltioo CJf lungs lntenlitial Skin tull!Dr Edema (dependent)

Nonnal Decreased Absent Decreased Decreased Increased

Urine output Body weight Hct. serum pruteil

NP10 Nephrology

mectrotyte Disorders

Toronto Notes 2011

hyponatremia: serum [Na] <136 mmol!L can be associated with increased, normal or decreased (most common) serum osmolality

Mechanisms of Hyponatremia
1. Hyponatremia despite dilute urine (U0 ..,.<100) expect urine to be dilute with hyponatremia (ADH should be suppressed) due to excessive water intake that overwhelms the kidneys' normal water excretion capacity psychogenic polydipsia in psychiatric patients (e.g. schizophrenia) ability to excrete water is compromised in people with low solute excretion (particularly urea) e.g. elderly women with "tea and toast" diet low protein intake, low urea excretion

2. Hyponatremia with concentated urine (Uoam>200) if urine remains concentrated. ADH is acting when it should not be may be physiological (due to volume stimulus) or pathological (other reasons)
volume mediated ADH release can be due to true or effective volume depletion causes of true volume depletion: losses from skin, GI, urine, blood or 3rd spacing effective volume depletion: CHF and cirrhosis pathological ADH release: SIADH and endocrine deficiency SIADH - many causes including medications, lung disease, neurological disease, ectopic production, stress (pain, nausea, surgery); see Table 5 adrenal insufficiency (decreased volume and co-secretion ofADH and CRH) hypothyroidism (decreased cardiac output, decreased GFR)


, ...-----------------.

3. Hyponatremia with no (or minimal) urine advanced renal failure with oliguria may be associated with hyponatremia if the patient ingests even a moderate amount of dilute fluids

If 1111 urin8 osmolality is unknown. BUUIII81he urine is hypoolill101ar/dilu1e.

Hypo-Osmol (dilutionall Most common cause of hyponatremia Excess water in relidion to sodium stores which can be decreased, nonnal or increased Categorized by volume 5brtus as datannined by clinical assessment

I Hyponatremia
I10-011111olu RIJIIIntion in ECF of larae volumes of isotonic fluids that do not contain 10dium (e.g. 11111nnitoll Pseudohyponatramia -lab artnct seen with severe hyperlipidemia or panaprotainamia (e.g multiple myelomaI

HypaP.OIIIIIolar (transloc:ati-11 Extra osmol us in ECF <h.w watEr out of cells diluting the Na in ECF Usually glucose (nanaly hypertonic mannitol) Evary I 0 mmoVL incraua in blood glucose results in 3 mmoVL dacraaS8 in Na

ltyp!lrwlemic: u..<2Q/anuric CHF Cirrhosis and ascites Pregnancy

Euvulemic u_>1DD SIADH [normlll U.J Altalal insufficiency Hypothyroidism U_<10D "-Ychogenic polydipsia Traat1111nt Tnaat with water restriction Tnaat with salt and wlllllr (i.a. nonmal salina)

Hypovulemic U,..>20 lliurelics Salt-wasting nephropathy U..<10 Diarrhea Excessive sweating Third spacing (e.g. pancnaatitis, bum1) Treat11111nt Treatment goal is to replenish lost Na AND water Treat with nonmal or {rarely) hypertonic saline For faster treatment usa nonmiiiiRIIine + furo&emide

u >2D ..


TrNtmlllt Treatment golll is Naloss with ralatively mora water loss Treat with sahnd water restriction and sometimes diurelics

Figure 1. An Approach to Hyponatremia

Signa and Symptoms

depend on degree of hyponatremia and more importantly, velocity of progression from onset acute hyponatremia (<24-48 hours) more likely to be symptomatic chronic hyponatremia (>24-48 hours) less likely to be symptomatic due to adaptation adaptation: normalization of brain volume through loss of cellular electrolytes (within hours) and organic osmolytes (within days) adaptation is responsible for the risks associated with overly rapid correction neurologic symptoms predominate (secondary to cerebral edema) -headache, nausea, malaise, lethargy, weakness, muscle cramps, anorexia, somnolence, disorientation, personality changes, depressed reflexes, decreased level of consciousness (LOC)

Toronto Notes 2011

mectrolyte Disorders

Nephrology NP11

seizures, coma, respiratory arrest, pennanent brain damage, brainstem herniation, death risk of brain cell shrinkage with rapid correction of hyponatremia can develop osmotic demyelination of pontine and extrapontine neurons, which may be irreversible (e.g. central pontine myelinolysis: cranial nerve palsies, quadriplegia, decreased LOC)

Risk Fac:tors for Osmotic Demyelination rise in serum [Na] with correction >8 mmolJL/d if chronic hyponatremia
associated hypokalemia and/or malnutrition if patient with hyponatremia and hypovolemia is given large volume of isotonic fluid (ADH is stimulated by hypovolemia; when hypovolemia is corrected, the ADH level falls suddenly causing sudden brisk water diuresis, and therefore rapid rise in serum Nalevel) patient with psychogenic polydipsia, deprived of water

Investigations ECF volume status assessment

serum electrolytes, glucose, Cr serum osmolality, urine osmolality urine Na <10-20 mmolJL suggests volume depletion as the cause of hyponatremia assess for causes of SIADH (see Table 5) TSH, free T4, and cortisol levels consider CT chest if suspect pulmonary cause of SIADH consider CT head if suspect CNS cause

Treatment of Hyponatremia
general measures for all patients water restrict (1 Uday) treat underlying cause monitor serum Na frequently to ensure correction is not occurring too rapidly monitor urine output frequently: high output of dilute urine is the first sign of dangerously rapid correction of hyponatremia A. Definitely Arote (known to have developed over <24-48 hours) commonly occurs in hospital (dilute IV fluid+ reason for ADH excess e.g. post-operative) less risk from rapid correction since adaptation has not fully occurred if symptomatic correct rapidly with 3% NaCll-2 cc/kglh up to serum Na=125-130 mmolJL may need furosemide to address volume overload if asymptomatic, treatment depends on severity if marked fall in plasma [Na], treat as symptomatic B. Chronic or Unknown 1. if severe symptoms (seizures or decreased LOC) must partially correct acutely aim for increase ofNa by 1-2 mmol/L/hr for 4-6 hrs limit total rise to 8 mmol/L in 24 hrs IV 3% NaCl at 1-2 cc/kg/hr may need furosemide 2. if asymptomatic water restrict to< 1 Uday fluid intake consider IV 0.9% normal saline (NS) + furosemide (reduces urine osmolality, augments excretion of electrolyte-free Hp) consider NaCl tablet or Oxocubes as a source ofNa 3. refractory furosemide and IV NS demeclocyline 300-600 mg PO bid (antagonizes effect of ADH on collecting duct; avoid if cirrhosis or congestive heart failure as nephrotoxic in these settings) extra osmoles- give oral urea (increases loss ofwater without Na; 30-60 g/day) slow rate of IV 3% NaCI (e.g. 10 cclhr = 120 mmol/day of sodium which will increase serum [Na] by about 3 mmol/Uday)

'a.... of Rlpld Conallan of


lnadvart8nt rapid c011'8ction of

hyponatremia can eiiSily occur e.g. patient with hypol18ln!mil dua to SIADH from nausea G ravofll' givan for lllliaf of hypo1111nmia induced nausaa ADH quickly turned off in tha lbunC8 of 01111181. 1111 kidnl'fS rapidly excrete the excess free water, and lhe serum [Na+] rises

rapidly Plltill'lt at risk of osmotic

d1111'(11inlllion High output dilute urine (> 100 cc,lhr, < 1DD mOsmiL) in lha sstting of hyponalr8mia is u.uaUy thefi!$1: sign of dangerously rapid C01111Ction of serum &Odium

... ' .-----------------. ,

Conection of Na in hyponab8mia should dlfinitlly known to t. <24-48 hrs dumion. Frequent moniiDring at 5e111111 Na and urine output il essential.

not exteed BmmoVI/24 hrs Ldess



ea-ntratlon of Na in Common
lnfuut.Na in 0.45% NaCI = 77 mmoi/L Na in O.K NaCI = 154 mmoi/L Na in 3'11. NeCI = 513 mmaVL Na in 5% NeCI - 855 mmaVL Na in Ringer's = 130 mmolll Na inD5W = 0

C. Options jf overly rapid correction occurs

give water (i.e. switch to IV D5W) give ADH to stop water diuresis (DDAVP 1-2



Impact of IV Solution on Plasma Na

funnula to estimate the change in serum Na caused by retention of 1 L of any infusate [TBW = (for men) 0.6 x wt(kg); (for women) 0.5 x wt(kg)] change in serum Na = infusate [Nal - serum !Nal TBW+lL this formula assumes there are no losses of water or electrolytes

,..__________________ ,

HzO Dlllcit 1nd TBW Eqllllti1.1BW = O.Bxwt (kg) man; TBW = 0.5 x wt (kg) women

2. H10 deficit = TBW x ([Na]plllsma140)/140

NP12 Nephrology

mectrotyte Disorders

Toronto Notes 2011

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SlADH} 1. urine that is inappropriately concentrated for the serum osmolality 2. high urine sodium (>20-40 mmol/L) 3.highFENa
Table 5. Disorders Associated with SIADH
Small ceiiCa Bronchog111ic Ca AdenoCa of panCI'I!IIS disease

Pneumonia Lung abscess

CNS Mass lesion Encephalitis Subaraclnlid hemorrhage

Acute psychosis Acute intermittent poqilyria




TB Acute respiratory failure S1roke Positive pressure ventiation Head trauma

Antidepressants TCAs SSRis


sllrte Pain Severe nausea HIV

Oxytocin Nicotine

Cllb1111BZ8pi'le Barbiturates Chlorpropamide

hypernatremia: serum [Na] >145 mmol/L too little water relative to total body Na; always a hyperosmolar state usually due to net water loss, rarely due to hypertonic Na gain results from problems with water intake (access, thirst) and/or site of increased water loss (renal or extrarenal) less common than hyponatremia because patients are protected against hypernatremia by thirst and release of ADH

I Hypemmamia I

HypiMIIImic (raN) IIII'O!renic [hypertonic salina or NaHCO,) Cushing's syndrorna Hyparald01111ronism Traat wi1h salt restriction, diuretics, wmer replacement Dialysis if ranal failure



Is patient putting out a small volume [500 mlJd) of miXimaly [ > 8DD mOsnv\u) Ll'ina?

No Is urine osmole excretion rme > 750 mOsm/d 1


No Positive renlll re..,onse to DDAVP 511% increasa in urina osmolality?


Diuretics [loop) Osmotic diurasis Hyparglycamia Endoganous[uraa with axcass NG protein faads)

\W Insensible water loss Respinrtory, skin Gl [dianhaa) Osmotic (lactulosa, malabsorption) Remota renal loss



Figura I. An Approach ta Hyparnatramia

Signs and Symptoms

with acute hypc:matrcmia no time for adaptation, therefore more likely to be symptomatic adaptive response: cells import and generate new osmotically active particles to normalize size due to brain cell shrinkage: altered mental status. weakness, neuromuscular irritability, focal neurologic deficits, seizures, coma, death polyuria, thirst. signs ofhypovolcmia

increased risk of vascular rupture resulting in intracranial hemorrhage rapid correction may lead to cerebral edema due to ongoing brain hyperosmolarity

Toronto Notes 2011

Treatment of Hypovolemic Hypernatremia

mectrolyte Disorders

Nephrology NP13

general measures for all patients give free water (oral or IV) treat underlying cause monitor serum Na frequently to ensure correction is not occurring too rapidly if evidence of hemodynamic instability, must first correct volume depletion with NS bolus loss of water is often accompanied by loss of Na but a proportionately larger water loss in patients with presumed normal total body Na content, use formula to calculate water deficit: H20 deficit= TBW x (serum rNa! - 140) [TBW = 0.6 x wt(kg) for men, 0.5 x wt(kg) for women] 140 replace free water deficit; "free water" is water without sodium encourage patient to drink pure water, as oral route is preferred for fluid administration if unable to replace PO or NG, correct H2 0 deficit with hypotonic IV solution lL DSW approximately equals 1 L free water 11 0.45% NS approximately equals 500 mL free water use formula (see Hyponatremia, NP 11) to estimate expected change in serum Na with 1 Linfusate aim to to lower [Na] by no more than 12 mmolJL in 24 hours (0.5 mmol/L/hr) must also provide maintenance fluids and replace ongoing losses rule of thumb: give 2 cc/kglhour of free water to correct serum [Na] by about 0.5 mmol/Uhour or 12 mmol/Uday
Treatment of Hyparvolemic Hyparnatramia general measures as above hypervolemic hypematremia: remove excess total body Na with diuresis or dialysis (if renal failure present), then replace water deficit using D5W DIABETES INSIPIDUS (DI}



COIT8Ction of 181\1111 INal in

hypernalremia snould not exceed 12 mmoVl/241n.

collecting tubule is impermeable to water due to absence of ADH or impaired response to ADH central defect in release of ADH (central DI) or renal response to ADH (nephrogenic DI)

central Dl: neurosurgery, granulomatous diseases, trauma, vascular events, and malignancy nephrogenic DI: lithium (most common), hypokalemia. hypercalcemia. and congenital

urine osmolality inappropriately low in patient with hypematremia (UDIIn <300 mOsm!kg) serum vasopressin concentration may be absent or low (central), or elevated (nephrogenic) dehydration test: HzO deprivation until loss of 3% of body weight or until urine osmolarity rises above plasma osmolarity; if fails to concentrate urine, most likely Dl administer DDAVP (exogenous ADH) (10 fig intranasally or 2 fig SC): central Dl: diagnosed ifthere is rise in urine osmolality, fall in urine volume treat with DDAVP nephrogenic Dl: exogenous ADH fails to concentrate urine as kidneys do not respond treat with water (IV D5W or PO water), thiazides may help as well (reduced ECF volume stimulates proximal tubular reabsorption of sodium and water, leading to less delivery of glomerular filtrate to ADH sensitive parts of renal tubule, and therefore lower urine volume: results)

Potassium Homeostasis
approximately 98% of total body K stores are intracellular normal serum K ranges from 3.5-5.0 mEq/L in response to K load, rapid removal from ECF is necessary to prevent life-threatening hyperkalemia insulin, catecholaminc:s and acid-base status influence K movement into cells aldosterone has a minor effect potassium excretion is regulated at the distal nephron K excretion = urine flow rate x urine [K]
Factors which Increase Renal K Loss

hyperkalemia increased distal tubular urine flow rate and Na delivery (thiazides and loop diuretics) increased aldosterone activates epithelial sodium channel (eNa C) in cortical collecting duct, causing Na reabsorption and K excretion metabolic alkalosis hypomagnesemia increased non-reabsorbablc: anions in tubule: lumen: HC03, penicillin, salicylate

NP14 Nephrology

mectrotyte Disorders

Toronto Notes 2011

serum [K] <3.5 mEq/L

Approach to Hypokalemia 1. emergency measures: obtain ECG; if potentially life threatening. begin treatment immediately 2. rule out transcellular shifts ofK as cause ofhypokalemia 3. assess contribution of dietary K intake 4. 24-hr K excretion or spot urine K 5. TTKG =transtubular potassium gradient =(UJJPJ/(Uoom/PomJ 6. if renal K loss, check BP and acid-base status 7. may also assess plasma renin and aldosterone levels, serum [Mg]
DICQIIsedlnhlq Limited diatary in!Bb Cll.y ingll&lion

lnc..-ldlou {1rue hemll1llria) Hemoglobin {hemolyiil)

U. <25 mEq/day


Gllo- Diarrhea L.martives Vilous adenoma

u. >30 mEq/day TTKG >7

IIBnallaaaa CheckBP

into C.lls Mlllllbolic alkalosis {IQH axchanqa across call mambrana) I111LJin {llimulatus NII/I( AlPBse) Catacholaminas, Ji1-egonills {v.ntolin ), thaophylline (stimulllle Na/K All'ase} Tocolytic agents Uptake into newly forming cells -Vitamin 811 injections i1 pernicious anemia Colony stimulating factors 'I' WBC production



Hypo- or -motaivl

Check acid bll$8 sbdus



llyparlllni11 1" hyperakloslllrnnism {e.g Conn's syndrome) 2 (renovascular disease, reni1 tumour} Non.,aldoslllrnne mineralocorticoid [Cushing's, exogenous)

Alhlemic Diurulics (furosemide, hydrnchloruthilllide) ranall01111 duatll hyparaldoslllrnnism and mlllllbolic alkalosis) Inherited renal tubular lesions - Bartter's {loop of Henle dyafunction: furosemide-lib effect) - Gitelman's (disbl convoluted tlb.lle


Variable HypoMg Vomiting/NG

TTl(G =

Trant-Tubolllr KGraclent

Figura 9. An Approach to Hypaklllamia

Signs and Symptoms usually asymptomatic, particularly when mild (3.0-3.5 mmol/L) nausea, vomiting, fatigue, generalized weakness, myalgia, muscle cramps, and constipation if severe: arrhythmias, muscle necrosis, and rarely paralysis with eventual respiratory impairment arrhythmias occur at variable levels of K; more likely if digoxin use, hypomagnesemia, or CAD ECG changes are more predictive of clinical picture than serum [K] U waves most important (low amplitude wave following aT wave) flattened or inverted T waves depressed ST segment prolongation of Q-T interval with severe hypokalemia: P-R prolongation, wide QRS, arrhytlmtias; increases risk of digitalis toxicity

Figura 10. ECG Changes in Hypokalemia

Toronto Notes 2011

mectrolyte Disorders

Nephrology NP15

Treatment treat underlying cause if urine output and renal function are impaired, correct with extreme caution risk of hyperkalemia with potassium replacement especially high in elderly, diabetics, and patients with decreased renal function beware of excessive potassium repletion, especially if transcellular shift caused hypokalemia if true K deficit, potassium repletion (decrease in serum [K] of 1 mEq is very roughly 100-200 mEq of total body loss) oral sources- food, tablets (K-Dur-), KClliquid solutions IV - usually KCl in saline solutions, avoid dextrose solutions (may exacerbate hypokalemia via insulin release) max. 40 mmol/L via peripheral vein, 60 mmolJL via central vein, max. infusion 20 mmo!Jhr o K-sparing diuretics (triamterene, spironolactone, amiloride) can prevent renal Kloss restore Mg if necessary

serum [K] >5.0 mEq!L
Approach to Hyperkalemia 1. emergency measures: obtain ECG, if life threatening begin treatment inunediately 2. rule out factitious hyperkalemia; repeat blood test 3. hold exogenous K, and any K retaining medications 4. assess potential causes of transcellular shift 5. estimate GFR (calculate CrCl using Cockcroft-Gault) 6. if normal GFR, calculate TTKG = (Uk/PJ<)/(U0 om/P01111) TTKG <7 = decreased effective aldosterone function TTKG >7 = normal aldosterone function
Table 6. Causes of Hyperkalemia
hctitious lntaq

Cellular Releue
Intravascular hemolysis Rhabdomyolysis Insulin deficiency Hyperosmolar states (e.g. hyperglycemia) Matabolic acidosis (axcaptfor katD-and lactic acidosis) Tumour lysis syndrome Drugs o Beta-blockers Digitalis avardase (blocks NII/XATPase) Succinylcholine Decreased GFR o RIJ1al failure Law effectiw circulating volume NSAIDs in renal insufficiency Nonnal GFR but hypoaldasteronism (saaTable7)

Sample hemolysis* Sample taken from vein whera IV KCI is ruming Prolonged use af tourniquet Leukocytosis (eldreme) ThrombocytDsis (extreme)




'Most camman

Tabla 7. Causes of Hyperkalemia with normal GFR

Dacrusad Aldostarona Sti11U. (low renin, low aldollerone) Decrusad Aldllltlrona Praductian (nonnal aldolterone) ldecraued tubular raspol K-sparing diuretics o Spironolactone Amiloride Tri1111terene

Hyporeninemic, hypaaldosteranism o Associated with DM2, NSAIDs, chronic interstitial nephritis, HIV

Adrenal insufficiency ol any cause (e.g. Addison's diseasa, AIDS, metastatic can car) ACE inhibitors o AngiotEnsin II receptor blockers Heparin Congenital adranal hyperplasia with 21-bydroxylase deficiency

Other K-splling drugs Pantamidi'la Trimethaprim o Cyclasparine, tacrolimus o Pseudohypoaldosteronism (rare inherited tubular disardnl

Signs and Symptoms usually asymptomatic but may develop nausea. palpitations, muscle weakness, muscle stiffness, paresthesias, areflexia, ascending paralysis, and hypoventilation impaired renal ammoniagenesis and metabolic acidosis ECG changes and cardiotoxidty (do not correlate well with serum [K]) peaked and narrow T waves decreased amplitude and eventual loss of P waves prolonged PR interval

NP16 Nephrology

mectrolyte Disorders/Add-Base Disorders

widening of QRS and eventual merging with T wave (sine-wave pattern) AVblock ventricular fibrillation, asystole

Toronto Notes 2011


.. ,

In patients with dilbetes and increued [K+] and hypervfycamia, often jUI! giving insulin to mtore euglycamia is sufficient to correct the hyperkalemia.


T W11W


T W11W


1 g

Figura 11. ECG Changes in Hyperkalemia

acute therapy is warranted ifECG changes are present, or if patient is symptomatic tailor therapy to severity ofincrease in [K] and ECG changes [K] <6.5 and normal ECG tn:at underlying cause, stop K intake, increase the loss ofK via urine and/or GI tract (see below) [K] between 6.5 and 7.0, no ECG changes: add insulin to above n:gimen [K] >7.0 and/or ECG changes: first priority is to protect the heart, add Ca gluconate to above

Tnilllllenl of Hypllllcelemll
SEE BIG KDROP SEE - Calcium gluconata
BIG- BIIQDnist. Bicllb, Insulin, Glucosa

I- Ka.,.xaim11
DIOP- Diuretics, Dialysis

1. Protect the Heart Ca gluconate 1-2 amps (10 mL of10% solution} IV antagonizes cardiac toxicity of hyperkalemia, protects cardiac conduction system, no effect on serum [K] onset within minutes, lasts 30-60 minutes

2. Shift K into Cells regular insulin (Insulin R) 10-20 units IV; with 1-2 amp DSOW (give DSOWbefon:insulin) onset of action 15-30 min, lasts 1-2 h monitor capillary blood glucose q lh because of risk of hypoglycemia can n:peat every 4-6 hours NaHC03 1-3 amps (given as 3 amps of7.5% or 8.4% NaHC03 in lL D5W) onset of action 15-30 min, transient effect, drives K into cells in exchange for H (Ventolin) in nebulized form (dose= 2 cc or 10 mg inhaled) or 0.5 mg IV onset of action 30-90 min, stimulates Na/K ATPase caution if patient has heart disease as tachycardia may result from this high dose ofbeta2 agonist 3. Enhance K Removal from Body
via urine (prefern:d approach) furosemide mg IV), may need IV NS to avoid hypovolemia fludrocortisone (synthetic mineralocorticoid} if suspect aldosterone deficiency via gastrointestinal tract cation-exchange n:sins: calcium resonium or Kayexalate (increasingly falling out of favor as they bind Na in exchange for K, and controversial how much K is actually n:moved - main benefit may be the diarrhea it causes) plus sorbitol PO to avoid constipation (must ensure that patient has a bowel movement after resin is administen:d ) Kayexalate enemas with tap water (not sorbitol enemas as they can cause colonic necrosis) dialysis (renal failun:, life threatening hyperkalemia unn:sponsive to therapy)

Acid-Base Disorders
acid-base homeostasis influences protein function and can critically affect tissue and organ function with consequences to cardiovascular, n:spiratory, metabolic and CNS function see Respirolo!O" R5 for mon: information on respiratory acidosis/alkalosis normal concentration ofHC03 = 24 mEq!L normal pC02 = 40 mmHg each add base disorder has an appropriate compensation inadequate compensation or overcompensation indicates the presence of a second acid-base disorder e.g. in metabolic acidosis, inadequate compensation means there is also respiratory acidosis; overcompensation means there is also respiratory alkalosis

Toronto Notes 2011

Acid-Due Disorders

Nephrology NP17

Reepiratury acidoi Acute: 1' 10 PCO, = 1' 1 HCO, Chronic: 1' 10 PCO, = 1' 3 HCO,

a.piratury alludosi Acute: "- 10 PCO, = "- 2 HCO, Qlranic: "- 10 PCO, = "- 5 HCO,

Figure 12. An Approach to Acid-Baaa Disordars

Metabolic Acidosis
Identify Main Disturbanc), then:
1. Evaluate compensation (Figure 12)


.. "

2. Calculate plasma anion gap (PAG) PAG = Na- (HC03 + Cl) baseline= 12, range 10-14 PAG can be altered by plasma albumin level: for each 10 giL fall in albumin, lower baseline PAG by 3 (e.g. is plasma [albumin]= 20 giL, expect PAG = 6)
3. If PAG elevated. compare increase in PAG with decrease in HC03 if increase in PAG < decrease in HC03, there is a coexisting non-AG metabolic acidosis if increase in PAG > decrease HC03, there is a coexisting metabolic alkalosis 4. Calculate osmolar gap osmolar gap = measured osmolality- calculated osmolality calculated osmolality= (2 x Na) + urea+ glucose (all units are in mmolJL) normal osmolar gap < 10 if gap> 10, consider: methanol poisoning, ethylene glycol poisoning, OR another cause of acidosis plus ethanol ingestion

UHful EqudDn 1. PAG = [Na] - [CI] - [HC01-l (nonnal range = 10141

2. Olmoillr Gap = mea&ured OIITiolality - calculided osmolality (normal < 1Dl 3. Calculated Osmolality = 2[Na]

IUreal + (Glucose]

Etiology and Pathophysiology 1. lncreaJed PAG Metabolk Acidosis (4 types) 1. Lactic acidosis (2 types)
L-lactic acid - Type A: due to tissue hypoperfusion (any cause of shock), ischemic bowel, profound hypoxemia - Type B: failure to metabolize normally produced lactic acid in the liver due to severe liver disease, excessive alcohol intake, thiamine deficiency, or metfonnin accumulation (metformin interferes with electron transport chain) D-lactic add: rare syndrome characterized by episodes of encephalopathy and metabolic acidosis, requires carbohydrate malabsorption (e.g. short bowel syndrome), colonic bacteria that produce D-lactic acid. a carbohydrate load, diminished colonic motility and impaired D-lactate metabolism 2. Ketoacidosis diabetic starvation alcoholic (decreased carbohydrate intake and vomiting) 3. Toxins methanol (toxic to brain and retina, can cause blindness and brain death)- metabolized to formic acid ethylene glycol (toxic to brain and kidneys)- metabolized to oxalic acid (envelope shaped crystals in urine) salicylate 4. Advanced renal failure (i.e. serum Cr increased at least Sx above baseline - a very low GFR causes anion retention, and renal disease leads to impaired bicarbonate production)


C.n of lncrnMd Anian Glp M.mlllolic Aeidoli

MUDPILES Metlllnol Uremia Dillbetic/alcoholic/llarvation katuacidosis PII'Bidehyde lsopropylalcohoV11011 Lactic scidosis Ethyl- glycol



ICARMEL Ketoacidosis

lllnal Failur. Metlllnol Ethyl- Glycol Lactic Acidosis

NP18 Nephrology

Add-Due Disorders

Toronto Notes 2011

c - of Non-Anian Glp Mmba6c



Diarrhea* Urehlroenteric fi5tulll Pancreaticoduodenal fistulil increased *Most Common

2. Normal PAG Metabolic Acidosis (Hyperc.hlorem.ic Acidosis) diarrhea (HC03 loss from GI tract) RTA (renal tubular acidosis) type I RTA (distal): inability to fully excrete H load as Nl4 therefore accumulates type II RTA (proximal): impaired HCO, reabsorption type IV RTA: defective ammoniagenesis due to decreased aldosterone, hyporesponsiveness or hyperkalemia to help distinguish renal causes from non-renal causes, use Urine Anion Gap= (Na + K) - Cl calculation establishes the presence or absence of unmeasured +ve ions (e.g. NH 4) in urine if <0, suggests adequate Nlf.t in urine (likely nonrenal cause: diarrhea) if >0, suggests problem is lack ofNlf.t in urine (e.g. distal RTA)


,...----------------. ,

Treatment of Metabolic Acidosis

treat underlying caus insulin for DKA restore tissue perfusion for 'l}rpe A lactic acidosis ethanol + dialysis for methanol or ethylene glycol poisoning alkaline diuresis dialysis ifASA overdose correct coexisting disorders ofK (see Hyperkalemia, NP15) consider treatment with exogenous alkali (e.g. NaHCO,) if: severe reduction in [HC03 ] e.g. <8 mmol/L, especially with very low pH (<7) no metabolizable anion (e.g. salicylate, formate, oxalate, sulphate) note: lactate and ketoacid anions can be metabolized to HC03 risks of sodium bicarbonate therapy hypokalemia: causes K to shift into cells (correct K deficit first) ECF volume overload: Na load given with NaHC03 , can exacerbate pulmonary edema overshoot alkalosis: abrupt, poorly tolerated transition from overly aggressive alkali loading, partial conversion of accumulated organic anions to HC03 and persisting hyperventilation

3 Clinical Sc-rlosdml'roll- a Mi1111d Dilar*rwlth NRr Narmal pH

(i.e. incraesad PAG metabolic acidosis + resp.llkalosisl Cirrhosis ASA overdcn;e Sepsia

Metabolic Alkalosis
requires initiating event and maintenance factors initiating event GI (vomiting. NG tube) or renal loss ofH exogenous alkali (oral or parenteral administration), milk alkali syndrome diuretics (contraction alkalosis): decreased excretion ofHC03, decreased ECF volume, therefore increased [HC03 ] post-hypercapnia: renal compensation for respiratory acidosis is HC03 retention, rapid correction of respiratory disorder results in transient excess of HC03 maintenance factors volume depletion: increased proximal reabsorption ofNaHC03 and increased aldosterone hyperaldosteronism (1 o or 2): distal Na reabsorption in exchange forK and H excretion leads to HC03 generation, aldosterone also promotes hypokalemia hypokalemia: transcellular K/H exchange, stimulus for ammoniagenesis and HC03 generation

I Metabolic alkalolis (1' pH, 1' HCD,I I I I

U0 <20 mEq/1.. Salina 1111ponsiva



U >20 mElJIL 0

IAssess volume atatus

Gil Vomiting NGtube



Pilar dlulllllcl 11 Post-hypercapnia Volume depleted

I I Volume depleted I I Normal ECF vohne I

Diundic . .

II +

Salina resislllnt

ICheck blood
Hyperten.ivll 1 hyperaldosteronism 2 hyperaldosteronism Cushing's syndrome

+ +


Nllllllllnllin Exogenous alkali S8\111'8 hypokalemia Bartter's, Gilelm1111's

Nate: cannot use

tD assess volume st11t11s i1 presenoe of alkalemia:

1' HCO, lll<CI'IItion, drag Na -+ 1' Nil exctlltion

Figure 13. An Approach to Metabolic Alkalosis

Toronto Notes 2011

Add-Base Disorders/Renal Failure

Nephrology NP19

Evaluate compensation (identify co-existing respiratory acid-base disorders)

hypoventilation (an upper limit to compensation exists- breathing cannot be stopped; see Figure 12)

treat underlying cause correct underlying disease, replenish K and Mg deficits, and possibly K-sparing diuretic saline sensitive metabolic alkalosis (most common) treabnent: volume repletion carbonic anhydrase inhibitor (e.g. acetazolamide) to facilitate loss ofHC03 in urine saline resistant metabolic alkalosis ECF volume normal or high usually aldosterone or glucocorticoid excess remove source of aldosterone or glucocorticoid spironolactone

Renal Failure
Presentation of Renal Failure
signs and symptoms depend on acuity of onset, severity of insult, adaptation to nephron loss/ dysfunction, treatment of reversible disease process

1. Volume Overload
due to increase in total body Na content signs: weight gain, H1N, pulmonary or peripheml edema

2. Electrolyte Abnormalities
high K (decreased renal excretion, increased tissue breakdown) P04 (decreased renal excretion, increased tissue breakdown) Ca (rare; happens during recovery phase after rhabdomyolysis-induced acute kidney injury or in settings where hypercalcemia contributes to renal failure, such as in multiple myeloma or sarcoidosis) uricacid low Na (failure to excrete excessive water intake) Ca (decreased Vit D activation, hyperphosphatemia, hypoalbuminemia) HC03 (especially with sepsis or severe heart failure)

3. Uremic Syndrome
retention of urea and other metabolites as well as deficiencies of hormones, causing the manifestations of uremic syndrome

Signs and Symptoms of Renal Failure

CNS: headache, lethargy, somnolence, confusion, asterixis, hyporeflexia PNS: "glove and stocking" type sensory neuropathy, wrist or foot drop CVS: shortness of breath, pleuritic chest pain, pericardia! friction rub GI: anorexia, nausea and vomiting, decreased taste GU: irritative and/or obstructive urinary tract symptoms (e.g. frequency, urgency, straining, nocturia), hematuria, palpable bladder (if bladder problem has contributed to renal failure) endocrine: weight loss, amenorrhea, decreased libido MSK: nocturnal muscle cramps, muscle weakness skin: pruritus, pallor, yellow discolouration

CNS: decreased LOC, stupor, seizure CVS: cardiomyopathy, CHF, arrhythmia, pericarditis, atherosclerosis GI: peptic ulcer disease, gastroduodenitis, AVM hematologic: anemia, bleeding tendency (platelet dysfunction), infections endocrine: decreased testosterone, estrogen, progesterone increased FSH, LH metabolic: renal osteodystrophy: secondary increased PTH due to decreased Ca, high P04 and low active vitamin D osteitis fibrosa cystica hypertriglyceridemia, accelerated atherogenesis decreased insulin requirements, increased insulin resistance dermatologic: pruritus, ecchymosis, hematoma, calciphylaxis (vascular Ca deposition)

NP20 Nephrology

Acute Kidney Injury (AKI)

Toronto Notes 2011

Acute Kidney Injury (AKI)

)-----------------, Definition
Thu 2 mOll: common CIIUIIIII of acute kidney injury in hospilllized patients 1111 prerenal1120hlmia and acubl tubular IIICrosis. lllrn.mber that p111rt1nal fliiUrtl Cllrll&ad to ATN.

abrupt decline in renal function leading to increased nitrogenous waste products formerly known as Acute Renal Failure (ARF)

Clinical Features
azotemia (increased BUN, Cr) abnormal urine volume (anuria, oliguria, polyuria)

, ..)-----------------.
CI111111D Pn_.lllll Elialllgy Clinical: Dlc111uad BP, incrtuad HR, lrld orthostatic HR and BP chlngas I11C11181ad [u11a] > > lncraaad [Cr] Urine [Na] <10-20 mmoVI. Urina ollllllllllli1y >500 mOsmfkv Fractional uxcrvtion af Na <1'lr. Cllllll to Rlnal Etiology Appropriate dinical contaxt Urinalysis positive for casts: Pigmented g111nular- ATN WBC-AIN RBC-GN Cl11111 to PDit-B-1 EtiDIIIIIt' Known solitary kidney Olderman Rucunt retroperito1181111 surgury Anuria Palpablubladder Ultrasound shows hydronephrosis




I PDitrlllll [aspac:ly if solitary kidney) I I I Neurogenic I

Diaordared Autoregulation ACEVARBs Calcinuurin ilhibitors [cydosporina, tacrolimus) Hypen:lllcemill


Absalubl Humorrlulgu Glloss Skin loss Ranalloss


I'N-nlll rN
Normal RBC, pigmenlld

'lllacull.r Vasculitis Malignant HTN Thrombotic microangiopatily Cholastarolamboli Large vessel disease

Effective Low cardiac output Sapsis 3rdspacing

Allltomic Uratar Bladder U1'8111111


IGiomll.r lllnt1111titial I I Tuular I GN AIN ATN

. ..

Dllfwentl..... Pra-rnll fro11 Ani

Figure 14. An Appro1ch tD Acute Kidney Injury

llri1l (NI]

<2ll >40 <I

>40 IIi <2ll


Approach to AKI


llrileiCTWAI FeNa

llrileOSIIIIIIIily >500

blood: CBC, electrolytes, Cr, urea (think prerenal if increase in urea is relatively greater than increase in Cr), Ca, P04 urine volume, C&S, R&M: sediment, casts, crystals urinary indices Foley catheterization (rule out bladder outlet obstruction) fluid challenge (ie. fluid bolus to rule out most pre-renal causes) imaging: abdo U/S (assess kidney size, hydronephr06is, post-nmal obstruction) indications for renal biopsy diagnosis is not certain prerenal azotemia or ATN is unlikely oliguria persists >4 weeks

1. preliminary measures pre-renal correct prerenal factors: optimize volume status and cardiac performance, hold ACEI/ARB renal exclude reversible renal causes: die nephrotoxic drugs, treat infection, and optimize electrolytes post-renal consider obstruction: structural (stones, strictures) vs. functional (neuropathy) treat with Foley catheter, indwelling bladder catheter, nephrostomy, stenting 2. treat complications fluid overload NaCl restriction high dose loop diuretics hyperkalemia (refer to Treatment of Hyperkalemia, NP16) adjust dosages of medications cleared by kidney 3. definitive therapy depends on etiology note: renal transplant is not a therapy for AKI

Toronto Notes 2011

.Acute Kidney Injury/Chronic Kidney Disease (CKD)

Nephrology NP21

high morbidity and mortality in patients with sustained AKI and multi-organ failure

Chronic Kidney Disease (CKD)

abnormal markers (Cr, urea) GFR <60 ml/min for >3 months or kidney pathology seen on biopsy or decreased renal size on U/S (kidneys <9 em) clinical features of chronic kidney disease volume overload and hypertension electrolyte and acid-base balance disorders (e.g. metabolic acidosis) uremia



lncidenc1 llf Etlalagilla llf Chronic Kidney Dii-ICm)


Interstitial nephriti&'
Cystir/HirediiB!y/Congenital SecondllfY GNI\Iasculitis

GlomenJonephrilis OtharJ\!nknown

4.Dl(, 3.1% 2.4%

Table 8. Stages of Chronic Kidney Disease IKIDOQI, 2002)



Ncrmal or increased Gm
Mild decrease in Gm Modaral9 decrease in GFR Moderate decrease in GFR
S8\111'8 decr88SB in GFR


60-89 45-59


Manqlllllld llf Complicllti- llf em



End &!age renal di&ea&e

< 15 (or dialy&i&l

N - Low-nitrogen diet E - Electrolytes: monitDr K P- pH: mebbolil: acidosis H - Hypertansion


II - RBCs: m1111111ge anemia with

arythropoiatin D - Dstaodystrophy: giva calci.lm

Management of Chronic Kidney Disease

diet protein restriction with adequate caloric intake limits endogenous protein catabolism K restriction (40 mmol/day) Na and water restriction P04 restriction (1 gld) avoid extra-dietary Mg (i.e. antacids) medical treatment of secondary hyperparathyroidism calcium supplements (e.g. TUMS) treats hypocalcemia when given between meals and binds phosphate when given with meals consider calcitriol (1,25-dibydroxy-vitamin D) if hypocalcemic sevelamer (phosphate binder) if both hypercalcemic and hyperphosphatemic vitamin D analogues are being introduced in the near future cinacalcet for hyperparathyroidism (sensitizes parathyroid to Ca, decreasing PTH) sodium bicarbonate for metabolic acidosis erythropoietin injections (Hct <30%) for anemia; target Hct 33-36% DDAVP for prolonged bleeding time if patient has clinical bleeding or invasive procedures ACEI for hypertension (target 130/80 or less), loop diuretics when GFR <25 rnUmin statins for dyslipidemia adjust dosages for renally excreted medications (avoid nephrotoxic medications) dialysis (hemodialysis, peritoneal dialysis) renal transplantation

between meals Ito increased Cal and with mills (1D bind and decreased POJ
N - NIJihrotoxins: IMiid IIIPhnrtaxic drugs [ASA, gentamicin) end adjust doses of renally excreted


AmllettrJZ118; 155:791-1!5 ....,._: To Multi th1 roll alllrin IIQiallnlin

s,ys1lm (liAS] bDcUde in ClnliJvuaHr cv IIUb:llrlll in pllilnbi with c:lmlnil; ijdnly



il,._ . . . . . . l'llillllwith a..i: lliUir ma.. .. l'lllbilllil: A

sa.dy . . . .: Rlndomillld I:GIIbGied lrilll111d llllly!ld CV CIUII:omll il pDIIII Mdl cllanic ijctluy diMIIIICXIIVprgOOJril lllllad with RAS

blockll$i.llerin lfiQiallnlil IIWiflm bb:kldt-buld 1hlllpyMil pllceba lllllllllllfnll (bell-lllocklr, Cltill!lchlnnal bbclan 11111 ot111r ll'llillyparllllsNe-bllld thenvfl theavt illhe slid\'. llllldti:Twanty-!Mirilll{N = 457!iiiWIIII incblld. Can1llrld ID plabo, liAS blacbdl raOOcad IIIII rilk al hllllllai1111 in peliellts with diablli: Pllilnls with no!Miilbelic CKD, liAS bloc:bde dectelsed CV oulcGme CGirj1llld ID llllllfnll111npy. C...._: RAS blocbde llduced CV aull:omes in dilbatic nepllropllhv Will u no!Miilbelic


NP22 Nephrology

Renal Replacem.ent Therapy

Toronto Notes 2011

Renal Replacement Therapy

lndlc:llliDna fvr Dilllyaia Hypl!blemia lrafractoryl
Acidosis lrulnctoryl VoiU11111 OVIIrkllld 1111fractory)
Elevated urea (>35-50 mM)


or Acidosis (rulnctory)
Eleclrolylll imbalance lrefractoryl

Intoxication (e.g. methanol I Overtoad (rulnctory volume ovarkllld) Pulm-rv edema

Encephl.lopaltly, pericarditis,



,.-----------------. .,
Type (e.g. FBDI



length le.g. 4h 3 1irnaflwk or 2h daly) Q Blood Flow (Max 4011 cc/min) Ultnlfitration (e.g. 2L or to target dry
weightI Na 140 lean budjusted by stilling II: 155 and "rampilg" down to
Serum K Dilllysllhl 4-6 1.5

minimize cmnpingl K (based an serum (KJI

3.S.4 Z.5

<3.5 Ca I.Z5
HC!la 40


Indications for Dialysis in Chronic Renal Failure absolute indications volume overload unresponsive to medication hyperkalemia unresponsive to medication severe metabolic acidosis unresponsive to medication neurologic signs or symptoms of uremia (encephalopathy, neuropathy, seizures) uremic pericarditis refractory accelerated hypertension clinically significant bleeding diathesis persistent severe nausea and vomiting plasma Cr >1060 IUDOl!L (12 mg!d.L) or BUN >36 mmol/L (100 mg/dL; clinical picture also important) relative indications anorexia decreased cognitive functioning profound fatigue and weakness severe anemia unresponsive to erythropoietin persistent severe pruritus restless leg syndrome hemodialysis: blood is filtered across a semipermeable membrane removing accumulated toxic waste products, solutes, excess fluid (ultrafiltration), and restoring buffering agents to the bloodstream available as intermittent (e.g. three times per week), continuous {CVVHD) or sustained low efficiency (SLED) peritoneal dialysis: peritoneum acts as a semipermeable membrane similar to hemodialysis filter advantages: independence, fewer stringent dietary restrictions, better rehabilitation rates available as continuous ambulatory (CAPD; four exchanges per day) or cyclic (CCPD; machine carries out exchanges overnight) patients with chronic kidney disease should be referred for surgery to attempt construction of a primary AV fistula when their eGFR is <20 mL/min, the serum Cr level quoted as >350 IUDoliL (>4.0 mg!d.L), or within 1 year of an anticipated need refer patients with chronic renal disease to a nephrologist early on to facilitate treatment and plan in advance for RRT
Tabla 9. Peritoneal Dialysis VI. Hemodialysis

Heparin [none, tight [500 Ullil

,,., .-----------------.
Whta lnitiltll DIALYSIS

or full [1 DOD Ulh]) IV fluid to support BP {e.q. IWSI



Hospital (usually)

OsmDiic IJI!SSUre via dextrose dialysate Concentration gradient and convection Peritoneum Indwelling catheter il peritoneal cavity lnfactian at cathatur sita Bacterial peritonitis Melabolic effects of glucose Difficult to achieva ade!J!ata clearance il patients with large body mass

CrCI <ZO ml/rnin Educat8 patient regarding dialysis; if not acandidll:e far diaysis, makllamngamiiiD far AV fillula CrCI <15 ml/min Waigh risk lll1d banafill for initialing dialysis CrCI < 1Dml/rnin
Dialysis should be initiated

Solule Remcml

Hythlstatic pressure
Concentration gradient llld convection Semi-permeable artificial membrane Line from vessel to artificial kidney



Vasculll" accll88 (c!DII, collapse)

Bactenmia Bleeding due to hepain Hemodynamic rtrass of axtracorporaal circuit Disequi!ibrilm syndrome (headache, ce111bral adama, hypotensian, nausea. muscle cramps rellll!d to soluWwaterflux over short time)

Cockcroft-Gault equation (or

Modification of Diet in Renal Disaequatianl should ba used to measure

Monitor far ul"llllic complications Significant benefits in qllllity of Iife can occur if dialysis started before CrCI <15 mVmin It is unclaar whether patients who s111rt dialysis early hive inc1111sed survival A praamptive transplant can ba c0111idarad patient is ttabla, in order to avoid dialysis

kidney func:tion

Young, ligh functioning. residual renal functian Bed-bound, co-morbidities, no renal function Success depends on presence of residual renal function Residual renal function not as important

Ftom: Nlllionll


Toronto Notes 2011

Renal Replacement Therapy/Glomerular Diseue


Renal Transplantation
preferred modality of RRT, best way to reverse uremic signs and symptoms provides maximum replacement of GFR only therapy shown to improve survival in patients with ESRD native kidneys usually left in situ 2 types: deceased donor, living donor (related or unrelated) kidney transplanted into iliac fossa, transplant renal artery anastomosed to external iliac artery of recipient 1 year renal allograft survival rates

,,.-----------------, '

Nephrology NP23

CD1111110Diy IJud lmmunDSupprauin Drup

Calcinelllin inllillilors Cyclosporine Tacrolimus

Antiprvlifwmivlt 11111dic.tio
Mycophenolate Mofetil Azathioprine

Other qlllts
Sirolimus Pnldnisone

Complications leading causes oflate allograft loss: chronic rejection and death with functioning graft #1 cause of mortality in transplanted patients is cardiovascular disease immunosuppressant drug therapy: side effects include infections, malignancy (skin, Kaposi's sarcoma, post-transplant lymphoproliferative disorder) acute rejection: graft site tenderness, rise in Cr, oliguria, fever de novo glomerulonephritis (usually membranous) new-onset diabetes mellitus (often due to prednisone use) cyclosporine or tacrolimus nephropathy (refer to Small Vessel Disease, NP32) chronic allograft nephropathy early allograft damage caused by episodes of acute rejection and acute peritransplant injuries immunologic and nonimmunologic factors (HTN, hyperlipidemia, age of donor, quality of graft, new onset diabetes) CMV (cytomegalovirus) infection and other opportunistic infections usually occur between 1 and 6 months post-transplant BK virus (polyoma virus) nephropathy can result from over-immunosuppresion and lead to graft loss

Anti-lymphocyt antiiiiDdi

Ntplru/IJill Tlllfl/llt 20f, 24:2915-2918 S1udy: illlrolplctiw, llllldlld cola! with Yll'l MIIQII fulluw 141


c.n.n ....,.lnnlt*nt

Nacfllnll " -. . . . . . .

pdenls 46. 6ftwhile Iwere llllll:l!ed tD 533 dlcnlld daacr lrlnlpiMt (D1X) patilllll ..t 5331ive damr lllXJ 1rlnsplad patieals

m IIDCbJnll homa dialysis {NHDj


or d-.ed donor1lllll!ilrt
!Maam: l'lirBy aull:anw

Noctmll homecliysisverulille

Glomerular Disease
Terminology of Glomerular Changes
terms applying to a population of glomeruli in the kidney diffuse: majority ofglomeruli abnormal (>50%) focal: some glomeruli affected terms applying to an indMdual glomerulus global: entire glomerulus abnormal segmental: only part of the glomerulus abnormal Types of Changes proliferation: hyperplasia of one ofthe glomerular cell types (mesangial. endothelial, parietal epithelial), with or without inflammatory cell infiltration membranous changes: capillary wall thickening due to immune deposits or alterations in basement membrane crescent formation: parietal epithelial cell proliferation and mononuclear cell infiltration from crescent-shape in Bowman's space

bltdll: No sigricanl dillerence il uvivll hmrd NHD 11111 DlX. Significlri survinl blllefitlor pllierQ _.dergoing LlX venus NHD. Signliclnt rnonalty hmnllllia l'llll:tian willlllX 10.511MilllllllfliRe in hllll1l ratialor D1X Vlnlll NHD ralnlce. Cancbin: lflllu mlllty1D DlX.
lit is iriaricr1D llX.


CIUII mlllbllty

Presentation of Glomerular Disease

Important Points To Remember each glomerulopathy presents as one of 4 major glomerular syndromes acute nephritic nephrotic rapidly progressive glomerulonephritis asymptomatic urinary abnormalities each glomerulopathy can be caused by a primary disease OR can occur secondary to a systemic disease some glomerulopathy can present as more than one syndrome at different times

Clinical/Lab Features proteinuria (but <3.5 g/1.73 m 2 /day) abrupt onset hematuria (microscopic or macroscopic) azotemia (increased Cr and urea)

NP24 Nephrology

Glomerular Disease
RBC casts and/or dysmorphic RBCs in urine oliguria HTN (due to salt and water retention)

Toronto Notes 2011

F...,_ -' Ntphrilie Syndrume



smoky urine


Azutemil RBC euts

Oliguria Hypertension

etiology can be divided into low and normal complement levels (Table 10) frequently immune-mediated, with Ig and C3 deposits found in GBM outcome dependent on etiology
Table 10. Etiology of Nephritic Syndrome

Low Complement Laval

Postinfectious GN Mambranoprolifarativa GN Secondary Cues

Nonnll Camplamant Lartl lgA nephropathy Anti.{iBM disaasa PolyariErilis nodosa Wegener's granulomatosis Henoch.Schonlein pLrpura Goodpasue's synrtome

Endocarditis Abscess or shunt neplritis Cryoglobulinemia


, ...----------------.

Clinical/Lab Features heavy proteinuria (>3.5 g/1.73m2/d) hypoalbuminemia edema hyperlipidemia (elevated LDL cholesterol),lipiduria (fatty casts and oval fat bodies on microscopy) hypercoagulable state (due to antithrombin III, Protein C and ProteinS urinary losses) patient may report frothy urine glomerular pathology on renal biopsy: minimal change disease (or minimal lesion disease or nil disease) - i.e. glomeruli appear normal on light microscopy membranous glomerulopathy focal segmental glomerulosclerosis (FSGS) membranoproliferative glomerulonephritis nodular glomerulosclerosis each can be idiopathic or secondary to a systemic disease or drug (sirolimus can cause proteinuria without obvious glomerular pathology) Tabla 11. Naphrotic Syndroma Minimal

Prwentation -' Nepllratie Syndnlme 1. Sevn proteinuria (>3.5 Qfdl 2. Hypollbumilemia 3. Edama 4. Hyperlipidemia, lipiduria 5. Oval fat bodies (microscopy( 6. Hypereoag!Jahle stile (antithrombin Ill, protein Cand pnrtein S lost in urineI


Membranous Glomeruloplllly HBV, SLE, solid breast. Gil

Focal S..-nlll Mambranoprolifaratiwe Glomeeulosderosis Glomeeulonephrilil

Nodular Diabetes mellitus, amyloidosis


Th. .py

Hodgkin's lymphoma

Reflux ne(h'opathy, HIV; HBV, obe&ity

HCV, malaria. SLE, leukemia, lymphoma, inlecl8d &hunt

Gold, penicillamine Heroin Recllce BP, ACB, &teroids Steroids, ACEVARB fur proiBinuria Aspirin, ACEI, dipyridamole Treat undBriying controversial cause


The Nephritic-Nephrotic Spectrum

glomerular pathology can present with a clinical picture anywhere on a spectrum with pure nephritic and pure nephrotic syndromes at the extremes (see Figure 15)
Naphratic lntarmadiate

Hamatu.ria, "-

[ Protainara
FSGS Membranous gtomarulopathy
Minimal change Membranoproliferative GN Focal proliferative GN lgA nephropllhy ldioplllhic membranoprolifenrtive GN

Diffuse prolifen.tive GN Crescentic GN



Figura 15. Tha Spectrum of Glomerular Pathology

Toronto Notes 2011

Glomerular Disease

Nephrology NP25


Clinical/Lab Features a subset of nephritic syndrome in which renal failure progresses in weeks to months crescent formation usually seen on renal biopsy RBC casts and/or dysmorphic RBCs in urine classified by immunofluorescence staining (see Table 12) treatment: underlying cause for postinfectious; corticosteroids + cyclophosphamide or other cytotoxic agent + plasmapheresis in select cases prognosis: 50% recovery with early treatment, depends on underlying cause
Tabla 12. RPGN Classification

RPGNTpl: AJrti.GBM m iltld .. %111RPGNC. 15% of cases lmmuno.ftuorncence Linear pattern due to lgG 111d SUing Pattem C3 deposition along capillary loops
Antibodies against type IV collagen in GBM

RPGN Type II: Immune Complex miltlll

24% of cases Granular pattern due to subendlllhelial or subepithelial deposits DllgG and C3 Most often di&sa&e

RPGN Type Ill: Non-immUDI lllldillld (i.e. piuci-immune)

60'J(, of cases

No immune stailing
Vasculitis of glomerular capillaries Idiopathic Wegener's {c-ANCA +vel Microscopic polyangiitis (p-ANCA +vel Cilurv-Stn!uss (ANCA -vel

z to systemic

Idiopathic anti.{lBM disease Goodpasture's disease

lgA nephropathy Post-infectious GN, SLE, Cryoglobulinemia, Henoch-Sclxlnleil pLrpura



Clinical/Lab Features isolated proteinuria (usually <2 glday) and/or isolated microscopic or macroscopic hematuria isolated proteinuria can be postural occasionally can signal beginning of more serious GN (e.g. FSGS, IgA nephropathy, amyloid, diabetic nephropathy) hematuria with or without proteinuria IgA nephropathy (Berger's disease): most common type of primary glomerular disease worldwide, usually presents after viral URTI hereditary nephritis (Alport's disease): X-linked nephritis often associated with sensorineural hearing loss; proteinuria <2 glday thin basement membrane disease: usually autosomal dominant, without proteinuria; benign benign recurrent hematuria: hematuria associated with febrile illness, exercise or immunization; a diagnosis of exclusion after other possibilities are ruled out

Investigations for Glomerular Disease

blood work first presentation: electrolytes, Cr, urea, albumin, fasting lipids determining etiology: CBC, ESR, serum immunoelectrophoresis, C3, C4, ANA, p-ANCA, c-ANCA, cryoglobulins, HBV and HCV serology, ASOT (anti-streptolysin titres), VDRL,


urinalysis: RBCs, WBCs, casts, protein 24-hr urine for protein and CrCl radiology CXR (infiltrates, CHF, pleural effusion) renal ultrasound renal biopsy (percutaneous or open) ifheavyproteinuria or renal insufficiency, and cause not obviously diabetic nephropathy urine immunoelectrophoresis for Bence-Jones protein if proteinuria present

NP26 Nephrology

Glomerular Disease

Toronto Notes 2011

Secondary Causes of Glomerular Disease

!flyalic (Sill AmlillluD Oir 2008; 67:1115-B

............ ..._..

Mllillnll: 1181111 urila !llftilllriB.IIId -b1dionnybM i11lependent plldic!Nit lbiilyfur cliic:ll M:GmB in 1lllrlpy al nllpllilis 1111 nlld 10 ba inlllplltld in cunjundiln. Ch1191 in imiTM1ilgicl111111 (lllli-dsDNA, senrn C3111M only imit8d lbity 10 llflldictllle 1t1P01111i ID IJealmentllld ny be Ullid



Amyloidosis nodular deposits of amyloid in mesangium, usually related to amyloid light chain (AL) presents as nephrotic range proteinuria with progressive renal insufficiency can be primary or secondary secondary causes: multiple myeloma, TB, rheumatoid arthritis, malignancy Systemic Lupus Erythematosus (Figure 16) lupus nephritis can present as any of the glomerular syndromes nephrotic syndrome with an active sediment is most common presentation glomerulonephritis caused by immune complex deposition in capillary loops and mesangium with resulting renal injury serum complement levels are usually low during periods of active renal disease children and males with SLE are more likely to develop nephritis
SLE Claaificatian I

....._.:In pltienlsMII pralflnM 1up.ll neplrii1, gkJcacolticuids in cumbinltian with

IAinQIImllliclcy Ia blln dlmlll'lllrltld on fur c;ydaphosphm!Haied reQimllll. v.tich
11'8 h - IIIOCillld with considlrlbil


advene l.h:ts.ln short 1111 medium-term

It Ieist lillilll emcy llllll'fll!d wi1h pulse cyclgpholpluidullld um 1axicny pofile: faiUitu NSpond b, I month! lhUd Mb


fallllwing 11111iaian .. nat oocammon IIIII fiiJill

Minimal meungilll lupus nephritis

dillale: lialrsilllld Rl!llllmlltion in Slf 11M niles far ior9-111nn plliert ll1d !lllftuvMI complllb1l Mll1boee obleMd in IIIJIHjiabetc 11011-SI.E patients, Mil Rlspmtltionl*ng thl melhod al choict.

Class I and II do nat need lriiBtmant direcllld Ill renal lesions






Mesangial proliferative lupus nephritis

Focal lupus nephritis

Diffuse lupus nephritis



Lowest possible


dose of steroids 1111d obsei'VIIIion

cytotoxic drugs (consider dialysis or renal 1ransplant with severe disease!



Membranous lupus nephritis

Steroids (corrtrovarsiall

l l


Advanced sclerotic lupus nephritis


ESRil Planning

Figure 16. International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis 2003 HIV-Assoc:iated Renal Disease 1. direct nephrotoxic effect ofHIV infection, antiretroviral drugs (e.g. tenofovir, indinavir) and other drugs used to treat HIV-assodated infections 2.HIV-assodated nephropathy histology: focal and segmental glomerular collapse with mesangial sclerosis, "collapsing FSGS" tubular cystic dilation and tubule-reticular inclusions clinical features: predominant in black men, heavy proteinuria, progressive renal insufficiency prognosis: kidney failure within one year without treatment therapy: short-term, high dose steroids, ACEI, HAART Henoch-Schonlein Purpura (HSP) seen more commonly in children purpura on buttocks and legs, abdominal pain, arthralgia and fever glomeruli show varying degrees of mesangial hypercellularity IgA and C3 staining of mesangiwn usually benign, self-limiting course; 10% progress to CRF

Goodpasture's Disease
antibodies against type IV collagen present in lungs and GBM more common in 3rd and 6th decades of life, men slightly more affected than females present with RPGN type I and hemoptysis/dyspnea pulmonary hemorrhage more common in smokers and males treat with plasma exchange, cyclophosphamide, prednisone

Wegener's Granulomatosis 80% of patients have renal involvement focal segmental necrotizing RPGN with no immune staining majority of patients with renal disease are c-ANCA positive may be indolent or fulminant in progression vasculitis and granulomas rarely seen on renal biopsy treating with cyclophosphamide, prednisone or sulfa may prevent recurrence

Toronto Notes 2011

Glomerular Diaeaae/Tubulointerstitial Diaease

Nephrology NP27

Cryoglobulinemia cryoglobulin&: monoclonal IgM and polyclonal IgG presents as purpura, fever, Raynaud's phenomenon and arthralgias at least 50% of patients have hepatitis C renal disease seen in 40% of patients (isolated proteinuria/hematuria progressing to nephritic syndrome) most patients have decreased serum complement (C4 initially) treat hepatitis C. plasmapheresis overall prognosis: 75% renal recovery

Infections and Glomerular Disease

Shunt Nephritis immune-complex mediated nephritis associated with chronically infected ventriculoatrial shunts inserted for treatment of hydrocephalus presents as acute nephritic syndrome with decreased serum complement nephrotic range proteinuria in 25% of patients Infective Endocarditis manifests as mild form of acute nephritic syndrome with decreased serum complement S. aureus is most common infecting agent treatment with appropriate antibiotics usually resolves GN Hepatitis B membranous GN, polyarteritis nodosa, membranoproliferative GN Hepatitis C membranoproliferative GN, cryoglobulinemia Syphilis membranous GN Malaria variable glomerular involvement

Tubulointerstitial Disease
Tubulointerstitial Nephritis (TIN)
Definition cellular infiltrates affecting primarily the renal interstitium and tubular cells functional tubule defects are disproportionately greater than the decrease in GFR classified as acute or chronic Signs and Symptoms manifestation of disease depends on site of tubule affected 1. proximal tubule (e.g. multiple myeloma, heavy metals) Fanconi syndrome: decreased reabsorption in proximal tubule causing glycosuria, aminoaciduria, phosphaturia, hypouricemia proximal RTA (decreased bicarbonate absorption): Type II RTA 2. distal tubule (e.g. amyloidosis, obstruction) distal RTA (Type I RTA) Na-wasting nephropathy hyperkalemia. type N RTA 3. collecting duct (e.g. sickle cell anemia. analgesics, PCKD) urine concentrating defect polyuria (nephrogenic DI)

Definition rapid (days to weeks) decline in renal function 10-20% of all acute kidney injury

NP28 Nephrology

'IUbulointerstitial Diseaae

Toronto Notes 2011

Etiology hypersensitivity I. antibiotics: beta-lactams, sulfonamides, rifampin, quinolones, cephalosporins 2. other: NSAIDs, allopurinol, furosemide infections bacterial pyelonephritis, Streptococcus, brucellosis, Legionella, CMY, EBV, toxoplasmosis, leptospirosis immune SLE, acute allograft rejection,Sjogren'ssyndrome,sarcoidosis,mixedessentialcryoglobulinemia idiopathic Pathophysiology acute inflammatory cell infiltrates into renal interstitium

Signs and Symptoms

acute renal failure if hypersensitivity reaction: may see fever, skin rash, arthralgia, serum sickness-like syndrome if pyelonephritis: flank pain and costo-vertebral angle (CVA) tenderness other signs and symptoms based on underlying etiology hypertension and edema are uncommon

Investigations urine sterile pyuria, WBC casts, mild proteinuria, hematuria eosinophils if allergic interstitial nephritis blood increased Cr and urea eosinophilia if drug reaction normal PAG metabolic acidosis (renal tubular acidosis) hypophosphatemia, hyperkalemia, hyponatremia gallium scan shows intense signal due to inflammatory infiltrate renal biopsy definitive Treatment treat underlying cause (e.g. stop offending medications, antibiotics if pyelonephritis) corticosteroids (may be indicated in allergic or immune disease) Prognosis recovery within 2 weeks if underlying insult can be eliminated

2. CHRONIC TUBULOINTERSTrTIAL NEPHRITIS Definition characterized by slowly progressive renal failure, moderate proteinuria and signs of abnormal tubule function Etiology persistence or progression of acute TIN urinary tract obstruction: most important cause of chronic TIN chronic pyelonephritis: due to vesicoureteral reflux or UTI with obstruction nephrotoxins exogenous analgesics: NSAIDs (common), acetaminophen cisplatin, lithium, cyclosporine, tacrolimus heavy metals (lead, cadmium, copper), lithium, mercury, arsenic radiation chinese herbs endogenous hypercalcemia, hypokalemia, oxalate, uric acid nephropathy vascular disease: ischemic nephrosclerosis, atheroembolic disease malignancies: multiple myeloma granulomatous: TB, sarcoidosis, Wegener's granulomatosis immune: SLE, Sjogren's, cryoglobulinemia, Goodpasture's, amyloidosis, renal graft rejection hereditary: cystic diseases of the kidney, sickle cell disease others: radiation, Balkan (endemic) nephropathy

Toronto Notes 2011

Tubulointeratitial DiAease

Nephrology NP29

Pathophysiology fibrosis of interstitium with atrophy of tubules, mononuclear cell inflammation Signs and Symptoms tubular dysfunction (e.g. acidosis, electrolyte disturbances) progressive renal failure with azotemia and uremia dependent on underlying etiology Treatment stop offending agent or treat underlying disease supportive measures: correct metabolic disorders (Ca, P04) and anemia Findings which Suggest Chronic Tubulointerstitial Nephritis normal PAG metabolic acidosis hyperkalemia (out of proportion to degree of renal insufficiency) polyuria, nocturia partial or complete Fanconi's syndrome urine: mild proteinuria, few RBCs and WBCs, no RBC casts ultrasound: shrunken kidneys with irregular contours

Acute Tubular Necrosis (ATN)


Definition abrupt and sustained decline in GFR within minutes to days after lschemidnephrotoxic insult GFR shuts down to avoid life-threatening loss of electrolytes from non-functioning tubules Etiology see Figure 17 Clinical Presentation typically presents as an abrupt rise in urea and Cr after a hypotensive episode. sepsis, rhabdomyolysis, or administration of nephrotoxic drug urine: high FEN., pigmented-granular casts Complications hyperkalemia: can occur rapidly and cause serious arrhythmia metabolic acidosis, decreased Ca, increased P04> hypoalbuminemia Investigations blood: CBC, eletrolytes, Cr, urea, Ca, P04> blood gases urine: R&M, electrolytes, osmolality ECG abdominal ultrasound
[ Acute Tubular Nacrosis [

Exogenous Antibiotics - Aminoglycosides - Caphalosporins - Amphotericin B Antiviral {cidofovir) Antinaoplastics - Cisplatin



Endogenous Endotoxins (bacterial) Myoglobin Hemoglobin


Clrculldlng Valuma Hemorrhage ilcl. post surgical Skin l011es Gllosses Ranalloues EffvctNII cculating Valuma Haart failure Uver failure Sepsis Anaphylaxis

- Methotrexate
Conti'IISt madill Haavymlltals Other - Fluorinated anaesthstic - E1ilylena glvcol

YIIMI Dcclulion large or smal renal artery involvement

Figure 17. Etiology of ATN

NP30 Nephrology

Tubulointerstitial DiaeaseNuc:ular Diseases of the Kidney


Toronto Notes 2011

AmlnlrriiMid2011; 11;148:214-84 ..,...:Todlnna1beelftctive11811al

........ c...ra......- Nlplnfllhy

feaoklopam dopmill, iiDJIIII, 11111ii,llnutridl, ar ll'lll1liiDl on nephropattlf. SIUy 0.., rudomillld, conlnlllad

largely supportive once underlying problem is corrected loop diuretics may help manage volume overload and reduce tubular metabolic requirements to allow for recovery (controversial) consider early dialysis in severe/rapidly progressing cases to prevent uremic syndrome

1lills tl1lt used these


il para

correct fluid balance before surgical procedures for patients with chronic renal disease requiring radiographic contrast: giveN-acetylcysteine 600-1200 mg PO bid day before and day of procedure use renal-adjusted doses of nephrotoxic drugs in patients with renal insufficiency isotonic NaHC03 at 3 mlJkg over lh before procedure and 1 ml/kglh for 6h post-procedure if not contraindicated avoid giving diuretics, ACE inhibitors, cyclosporine on morning of procedure if possible

.....:ln111141 (RR = 0.62 IOA4o.B8]) llld Thllop1i111 (RR = 0.49 (0.23-1.06]) !Wad thl risk llliiPhroplthy more thin saline IIane. Furoserride increesed the risk (RR = lZ1 (1.48-716]). DlhlriiJIIIIIdilnat lflect risk nep/lruplthy. Ca:llaon: foi.IC8lytcyslain8 il mGI9 IH!Ir;dnltion dlnr.

Analgesic Nephropathies
1. Vasomotor Acute Kidney Injury (AKI)
normally prostaglandins vasodilate renal arterioles to maintain blood flow NSAIDs act by blocking cycloo.xygenase enzyme, thereby preventing prostaglandin synthesis and causing renal ischemia more common in elderly, underlying renal disease, hypovolemia (diuretics, CHF, cirrhosis, nephrotic syndrome) clinically: develop prerenal azotemia within a few days of starting NSAID treatment: discontinue NSAID, dialysis rarely needed

2. Acute Interstitial Nephritis (AIN)

majority due to fenoprofen (60%), ibuprofen, naproxen may be associated with minimal change glomerulopathy and nephrotic range proteinuria resolves eventually with discontinuation ofNSAID, may require interval dialysis short term high dose steroids ( 1 mglkg/day of prednisone) may hasten recovery

3. Chronic Interstitial Nephritis

due to excessive consumption of antipyretics (phenacetin or acetaminophen} in combination withNSAIDs associated with emotional stress, psychiatric symptoms and Gl disturbance papillary necrosis gross hematuria, flank pain, declining renal function calyceal filling defect seen with IVP - "ring sign" increased risk of transitional cell carcinoma of renal pelvis good prognosis if discontinue analgesics

4. Acute Tubular Necrosis (ATN)

incidence of renal dysfunction is related to the severity of acetaminophen ingestion vascular endothelial damage can also occur both direct toxicity and ischemia contribute to the tubular damage renal function spontaneously returns to baseline within 1-4 weeks dialysis may be required during the acute episode of ingestion

5. Other Effects of NSAIDs

sodium retention (2 to reduced GFR} hyperkalemia, HTN (2 to hyporeninemic hypoaldosteronism) excess water retention (due to elimination of ADH- antagonistic effect of prostaglandins}

Vascular Diseases of the Kidney

Large Vessel Disease
important, potentially reversible cause of renal failure

abdominal trauma, surgery, embolism, vasculitis, extrarenal compression, hypercoaguable state, aortic dissection kidney transplant more vulnerable

Toronto Notes 2011

Vascular Diseasea of the Kidney

Nephrology NP31

Signs and Symptoms {depend on presence of collateral circulation}

fever, nausea, vomiting, :flank pain leukocytosis, elevated AST, LDH, ALP acute onset hypertension (activation ofRAAS) or sudden worsening oflong-standing hypertension renal dysfunction (if bilateral, or solitary functioning kidney)

renal arteriography (more reliable but risk of contrast-mediated ATN, atheroembolic renal disease) contrast-enhanced CT or magnetic resonance angiography, duplex Doppler studies (operator dependent)

prompt localization of occlusion and restoration of blood flow anticoagulation, thrombolysis, percutaneous angioplasty or clot extraction, surgical thrombectomy
llruculn6n-llllllll:ll n.n,rtar llaoArllly S11101il

2. ISCHEMIC RENAL DISEASE (RENAL ARTERY STENOSIS) chronic renal impairment secondary to hemodynamically significant renal artery stenosis or microvascular disease significant cause ofESRD: 15% in patients over 50 years old (higher prevalence if significant vascular disease) usually associated with large vessel disease elsewhere causes 1. atherosclerosis - more common in elderly 2. fibromuscular dysplasia - more common in females, age 30-50

NE/Af21J09; 361:1953-62
S1udy: WIH:arUt 111-bildllll RCT.Iftldilll falaw. !4)af34mantlls

l'lliiiii:DpltiiiiiiSinuiiQIJOiwilll l1hllusdllulic Ulosis in lllaut onellflllllllely llld benefit af -ulndion. lrDwntion: I'IR:ullnlaus JMialllrilltion &IIID!gl with 11111i:ll1hiiiiP'f [l.a.lllllils.eooplatalat. BP Clllb'GQ versus mml
lkiiDamu: Prny CIIJbDTIII- chqll in mel fln:tion af ClllltiJine c:oncermtion _. timel. Sewndery IUI:1111111 inc:lJde liP, ti11111Dfim mil ewnt. time 111111 C'l Mil. IIIII natally. blulll: No PCIIII dil\lrence il ci1119 af -1 fln:tian inllrwntion lll1d rnedicll1hnpv t:anlral No &igniicant diflaranc:n in IllY HCalldll'( were fOIIId bltweln l'l'mCUirizltio llld medical1hellpy cDIII!ul. 31 pltiea111911 llplria:ld 1 plriplac:ldullli:IIJ1IIclllion, nd 55 patients 120') BlqE!irmc:ed I pasl-pmcedlllll


Risk Factors >50 years old

smoking other atherosclerotic disease severe/refractory HTN and/or hypertensive crises asymmetrical renal size increasing Cr with ACEUARB flash pulmonary edema with normal LV function must establish presence of renal vessel stenosis and prove it is responsible for renal dysfunction duplex Doppler U/S (kidney size, blood flow): good screening test (operator dependent) CT or MR angiography (effective noninvasive tests to establish presence of stenosis) ACE inhibitor renography (ie. captopril renal scan) renal arteriography (gold standard)



Cancbin: llenllftly lt'I'IKIArizlti carries 5ignificlnt ri5b Mhoullll'( beneil Ill nnl fln:tian oriiCOIIdlly11111:c1n1 cam!Bid1D


medical therapy, percutaneous angioplasty + stent, surgical revascularization little or no benefit if therapy is late Le. kidney is already shrunken. However, therapy can be considered to save the opposite kidney if normal


hypercoagulable states (e.g. nephrotic syndrome, especially membranous), ECF volume depletion, extrinsic compression of renal vein, significant trauma, malignancy (e.g. RCC), sickle cell clinical presentation determined by rapidity of occlusion and formation of collateral circulation acute: nausea/vomiting, flank pain, hematuria, elevated plasma LDH, rise in Cr, sudden rise in

chronic: increasing proteinuria and/or tubule dysfunction

renal venography (gold standard), CI' or MR angiography, duplex Doppler U/S

anticoagulation with heparin then warfarin (1 yr or indefinitely, depending on risk factors)

NP32 Nephrology

Vascular Diseasea of the Kidney/Systemic Diseases and the Kidney

Toronto Notes 2011

Small Vessel Disease

see Hypertension, NP32
....... 1:11111 ..W*'ilm.Mid2lXXl; 17;133:600-3 cohort-wMII follow " of 5-I 0years. Pllilnll: 145 paliiJU w iducilnxllnnlllllll crisis w11a inl6im111d li&2paaMh IICiari*w. wllo did 11111 hm ranll crilil. need fordBy$is IIIII Ill\' dalllllllllllg paliiJU Mil nlllli crilil . . . .: Six!y-0111 J*CII1I ol ptltilutlwitl-1 crilil good outx:ons (55 hid 110 diltflis 111d 3418C8ivld 11mPQIIIY dilllvsist onlv 4 rl 1bese pllierQ chronic rellll fliUe 111d .-m-t dilllysil. Gllltlrlllln 50'1. ol .. patiarG wllo inibllv dilllysi5 3'II I Bmon1hs 1111r. Farrt.nt dilytisw .t, dBIIII occ:uned in 31% ollhB plllilds. c.Jailn: llllnllcrisis Cll1 M1111111Q11dwhn llypWnliol contraiiiiiMIII ACE illlibibn


progressive renal insufficiency due to embolic obstruction of small and medium-sized renal vessels by atheromatous emboli spontaneous or after renal artery manipulation (surgery, angiography, percutaneous angioplasty) anticoagulants and thrombolytics interfere with ulcerated plaque healing and can worsen disease presentation: acute or chronic, progressive renal dysfunction, labile hypertension, extrarenal atheroembolic disease support diagnosis (livedo reticularis is a classic sign) pathology: needle-shaped cholesterol clefts (due to tissue-processing artifacts) with surrounding tissue reaction in small/medium-sized vessels no effective treatment; avoid angiographic and surgical procedures in patients with diffuse atherosclerosis

a spectrum which includes HUS, TTP, DIC, post-partum renal failure renal involvement more common in HUS than TTP renal involvement characterized by fibrin thrombi in glomerular capillary loops arterioles treatment depends on cause supportive therapy TTP: plasma exchange, corticosteroids (splenectomy and rituximab if refractory) avoid platelet transfusions and ASA

.... ..........

NEJM mrl; 251:2562-75 s.dJ; rftorrimd controlled iill will IZIIIOIIIIfolcJw.q). l'llilnla: 1645 p!lients scheduled ta receilt 1

.........: NJrcoplalollfe COrticollaroidiiMd ailher.l) lillndl'd dose cyct)IJIQ!ila; dlcianb iniLoction; 3) dBcianb iniLoction; 4) low doll illlhls Mil

50% scleroderma patients have renal involvement (mild proteinuria, high Cr, HTN) histology: media thickened, "onion skin hypertrophy of small renal arteries, fibrinoid necrosis of afferent arterioles and glomeruli 10-15% scleroderma patients have a "scleroderma renal crisis": malignant liTN (usually within the first few years), ARF, microangiopathy, volume overload, visual changes, HTN encephalopathy renal involvement usually occurs early in the course of illness treatment BP control with ACEI slows progression of renal disease

Eslinalld Coc:tr.llft-Gd GfR 12 mollllulllrbnplllllllion. ....:1111 TICIGiilllllllm llllowllllignific:lndv hifi!BJ IGI'R It 12IIU!Ihl COIIfllld 111111 111111' M111 (65.4 mVmin VI. 51.1, 51.4, 56.7for IIIIlS I, 2. 4 reepeciMiy. lie TIICIIhlsn llso I'-d dlclllllld IIIII riiCID 11jel:tion Ill 6 n.dls ll1d 12111111111svs. II M111 (p<O.OOI iqJITiild dole cydolporile Md *oirus; llld dea!iaed ..,_!lin IIQiinlt 11 olher 1rms. Thn110 iiiRicl in Mill pllilnt lllrviwl.._, P"- SidrM hlllhB higlat incidaiiCI of dlll,ad-..1 IIIII sericu lllvene MID; llc!Girooslln sbliliclnllv
Ill r.-onlllllililllls; IIIII regimes hild 1lle liMist ill:idea ol dill1helllut



cyclosporine and tacrolimus causes both acute reversible and chronic, largely irreversible nephrotoxicity major cause of kidney failure in other solid organ transplant (e.g. heart) acute: due to afferent and efferent glomerular capillary constriction leading to decreased GFR (tubular vacuolization) pre-renal azotemia treatment calcium channel blockers or prostaglandin analogs, reduce dose of cyclosporine or switch to another immunosuppressive drug chronic: result of obliterative arteriolopathy causing interstitial nephritis and CRF (striped :fibrosis),less frequent now due to lower doses of calcineurin inhibitors

hifl181t OJIIIIIrUiillie mctiullllas.


llwdosB 11croiinls IIIII

using ildldion

1llmpNi: in!IJIIO!Uppllllion iiiiiJII111111Jl11111

Systemic Diseases and the Kidney

Hypertension (HTN)
HTN occurs in about 20% of population etiology classified as primary ("essential; makes up 90% of cases) or secondary diseases of renal parenchyma or renal vasculature can cause secondary hypertension conversely, hypertension due to other factors can cause renal disease (hypertensive nephrosclerosis) or worsen pre-existing renal disease

Toronto Notes 2011

Systemic Diseases and the Kidney

Nephrology NP33

Hypertensive Nephrosclerosis
Tabla 13. Chronic vs. Malignant Nephrosclerosis
Mlllipnt Nephl"llld_. Slow vascular sclerosis with ischemic changes affacting Fibrinoid namsis of arterioles, disn.,tion of vascular intralobular and all&rent arterioles endothelium Clinil:<ll Pll:lure African American, undllllyilg chronic kidllll'f disease, chronic hypertensive disease Uri111lpia Mid pnrtainuria. normal urine sedinant

Acute aiBVillion in BP (dBP > 120 rrrnHg) HTN encephalopathy

Protainuria and hematuria (RBC casts)


Blood pr8S$U18 control, frequent follow-up Can progress to renal fllilure despite patient adherence

Lower dBP tu 1Q0.1 10mmHg within &-24 hour& More aggressive treatment can cause ischemic event Identify and treat underlying cause of HTN Lower survival renal insufficiency develops


Renovascular Hypertension

HTN caused by renovascular disease 1-2% of all hypertensive patients, most common cause of secondary hypertension suspect if negative family history of HTN sudden onset or exacerbation of HTN difficult to control with antihypertensive therapy epigastric or flank bruit spontaneous hypokalemia (renin activation from underperfused kidney) history of diffuse atherosclerosis

Etiology and Classification

decreased renal perfusion of one or both kidneys leads to increased renin release and subsequent angiotensin production increased angiotensin raises blood pressure in 2 ways 1. causes generalized arteriolar constriction 2. release of aldosterone increases Na and water retention elevated blood pressure can in turn lead to further damage of kidneys and worsening HTN 2 types of renovascular HTN (RAS) atherosclerotic plaques: proximall/3 renal artery, usually males >55 years, smokers fibromuscular hyperplasia: dista12/3 renal artery or segmental branches, usually young females patients with bilateral renal artery stenosis are at risk of ARF with ACEI or NSAIDs when there is decreased renal blood flow (RBF), GFR is dependent on A11-induced efferent arteriolar constriction which raises filtration fraction (GFR/RBF)

renal U/S and Dopplers digital subtraction angiography (risk of contrast nephropathy) renal scan before and after ACEI (accentuates difference in GFR) MR angiography (avoid gadolinium contrast if eGFR <30 ml/min because of risk of systemic dermal fibrosis) gold standard is arterial angiography

BP lowering medications (ACEI is drug of choice if unilateral renal artery disease but contraindicated ifbilateral renal artery disease) angioplasty stent angioplasty for simple fibromuscular dysplasia lesion in young patients occasionally surgical bypass

Renal Parenchymal Hypertension

HTN caused secondary to GN, AIN, diabetic nephropathy, or any other chronic renal disease mechanism of HTN not fully understood but may include excess renin-angiotensin-aldosterone system activation due to inflammation and fibrosis in multiple small intra-renal vessels production of unknown vasopressors, lack of production of unknown vasodilators, or lack of clearance of endogenous vasopressor ineffective sodium excretion with fluid overload

NP34 Nephrology

Systemic Diseasea and the Kidney/Diabetea and the Kidney


Toronto Notes 2011

as well as investigations for renovascular HTN, additional tests may include 24-hour urinary estimations of Cr clearance and protein excretion imaging {U/S, CT, radionuclide scan) serology for collagen-vascular disease renal biopsy

most chronic renal disease is irreversible, but treatment of HTN can slow the progression of renal insufficiency control ECF volume: Na restriction (88 mmol/day intake), diuretic, dialysis with end-stage disease ACE inhibitor and/or ARB may provide added benefit (monitor K and Cr)

Multiple Myeloma
futuiW of Mulliplll ,.,.._.

Calcium (elevated) Anemia llanlll Failure Lytic Bon l.Hions


malignant proliferation of plasma cells in the bone marrow with the production of immunoglobulins patients may present with severe bone disease and renal failure light chains are filtered at the glomerulus and appear as Bence-Jones proteins in the urine (monoclonal light chains) kidney damage can occur by several mechanisms: hypen:al.cemia light chain cast nephropathy (LCCN) or "myeloma kidney" hyperuricemia infection secondary amyloidosis monoclonal Ig deposition disease {MIDD) diffuse tubular obstruction LCCN large tubular casts in urine sediment (light chains+ Tamm-Horsfall protein) proteinuria and renal insufficiency, can progress rapidly to kidney failure

deposits of monoclonal Ig in kidney, liver, heart and other organs mostly light chains (85-90%) causes nodular glomerulosclerosis (similar to diabetic nephropathy) lab features: increased BUN, increased Cr, urine protein immunoelectrophoresis positive for Bence-Jones protein (not detected on urine dipstick) poor candidates for kidney transplantation

cancer can have many different nephrological manifestations kidney transplantation cannot be performed unless malignancy is cured solid tumours: mild proteinuria or membranous GN lymphoma: minimal change GN {Hodgkin's) or membranous GN {non-Hodgkin's) renal cell carcinoma tumour lysis syndrome: hyperuricemia, diffuse tubular obstruction chemotherapy (especially cisplatin): ATN or chronic TIN pelvic tumours/mets: post-renal failure secondary to obstruction 2 amyloidosis radiotherapy (radiation nephritis)


, ...----------------.

Diabetes and the Kidney

diabetic nephropathy: presence of microalbuminuria or overt nephropathy in patients with DM who lack indicators of other renal diseases most common cause of end-stage renal failure in North America 35-50% ofType 1 will develop nephropathy, unknown percentage ofType2 at diagnosis up to 30% of Type 2 have albuminuria (75% mkroalbuminuria, 25% overt nephropathy) microalbuminuria is a risk factor for progression to overt nephropathy and cardiovascular disease once proteinuria is established, renal function declines, 50% patients reach ESRD within 7-10 years

OM i& 11118 of the caulilli of ESRD that

doas not resuk in smaUkidneys at

of ESRD. The othen; 1118 amyloidosia. HIV nephropathy, PCKD and multipl1 rn'(llollll.

..... , .----------------.
Abnonnll Urine ACR Values from 20D8 Canadian Diabetes Association CPG > 2.0 m!Vmmol in males > Z.B m!Vmmol in f811111es

Toronto Notes 2011

Diabetes and the Kidney

Nephrology NP35

associated with liTN and diabetic retinopathy (especially Type 1 diabetes) and/or neuropathy (especially Type 2 diabetes) indication of possible nondiabetic renal disease in diabetic patients rising Cr with little/no proteinuria lack of retinopathy or neuropathy (microvascular complications) persistent hematuria (microscopic or macroscopic) signs or symptoms of systemic disease inappropriate time course; rapidly rising Cr, short duration ofDM family history of nondiabetic renal disease (e.g. PCKD, Alpert's) DIABETIC RENAL COMPLICATIONS

(Urine Prolllin)

0 ---



Figure 18. GFR and Urine Protein ovar Time in Diabetes

1. Progressive Glomerulosclerosis
classic diabetic glomerular lesion: Kimmelstiel-WII.son nodular glomerulosclerosis (15-20%) more common lesion is diffuse glomerulosclerosis with a uniform increase in mesangial matrix stage 1 increased GFR (120-150%) -compensatory hyperfiltration of remaining nephrons slightly increased mesangial matrix stage2 detectable mlcroalbuminuria (between 0-300 mg/24 hours) Albumin-Creatinine ratio (ACR) 2.0-20 mg/mmol in men (18-180 mgld), 2.8-28 mglmmol in women (25-250 mg/d) increased mesangial matrix stage 3 macroalbuminuria (>300 mgl24h); ACR in men >20 mglmmol, (> 180 mg/d); in women, ACR is >28 mg/mmol (>250 mg/d) clinically detectable proteinuria, +ve urine dipstick normalGFR very expanded mesangial matrix stage4 increased proteinuria (>500 mgl24hr) decreased GFR <20% glomerular filtration surface area present sclerosed glomeruli



ACEI c.. catJse hyperkalemia. Therefore, be ISUre to wmch serum K.

especially if patient hu DM 111d renal in&Ufficiency.

2. Accelerated Atherosclerosis
common finding decreased GFR may increase Angiotensin II production resulting in increased BP increased risk of ATN secondary to contrast media

3. Autonomic Neuropathy
affects bladder leading to functional obstruction and urinary retention residual urine promotes infection obstructive nephropathy
111111 o.t-wD TthUtln. ldl il ...ll It Hijl Yucllil' IIIII (tlfTAII6ET S1udy)

4. Papillary Necrosis
Type 1 DM susceptible to ischemic necrosis of medullary papillae sloughed papillae may obstruct ureter can present as renal colic or with obstructive features hydronephrosis

2008 Canadian Diabetics Association Clinical Practice Guidelines on Chronic Kidney Disease in Diabetes screen for microalbuminuria with a random urine test for albumin to Cr ratio (ACR) and eGFR
with a serum creatinine (e.g. using MDRD equation) Type 1 DM: annually in adults after 5 years with diagnosis Type 2 DM: at diagnosis then annually must have at least 2/3 abnormal ACRs to diagnose nephropathy with DM and CKD: urine ACR and serum Cr (for eGFR) every 6 months delay screening if transient cause of albuminuria or low eGFR evaluate for other causes of proteinuria, rule out nondiabetic renal disease avoid unnecessary potential nephrotoxins (NSAIDs, aminoglycosides, dye studies)

S1udy: l'rDip8ctiw. ndiclabl. daublt-llild. !llllbniz8d oontnJied bill. Pri:iplll: 25.620 pllilllls will! median b'low141 of 5& moadts. llllrllnllll: fllilllll NCM eh rmnipril (10 mw'd; N=85761.1JDWn (80 ll9'd; N=85421 a t:ai!Dalltian of both Mluyo.-: alalyU. cloubq II Clllllinine IMland d11t1. llultl: Thllllllllllr of aull:llmiiMIIIIIIimi'-lar111miartln ranipril (1150; IIR 1.00. a 0.121.01).10- inCIIIIIIdMII coriinltionthenlpv(1233; 1111.01, 1.01-1.18, p=0.037). The need lor dilt,'sis or of - Clll1iWia. Will limilrwith 1llrrillf1an
(189) IIIII 11milcil (174; HR 1.09, O.BS-1.34111'111 men fllqUBrtwilll canminllion 111arapy 1212; HR 1.Z4, 1.01-1.51, p=D.038). Ea.tud Gfll dlcliwd lent with 11nq,rillllllqlllred Mil 1elmitlllln or

2008; 372:547-553

llilwy albumin IIXCratian -lea willllllnillr1ln (p=O.OIM)IIIII carnbinllian lhnpr (p=0.001l

coriinltion1lillllll\'(p<O.C011.1111 n- in

Cancbin: Renll oulcomes IWit simillr in both IIIINsatllli 111d CombinlliDn u.ap, llda PRltliNiria11 Qflllll ax11nt U. nadllarapy, but -IIIOCiltld willl JXIGIIIr

NP36 Nephrology

Diabetes and the Kidney/Cystic Diseases ofthe Kidney

Toronto Notes 2011

O.....ill'llilawilb'l'yJIIIZDIIIId Naplnp6f NEJM 2Dl1; 345:881-869 ... Rilldornillld. iblbiHfm, pilcebf. cortrolld trill Ylitll m1111 fulliJw.iJp o/3.4 Yll'l l'llilnll: 1513 Jllllients!1111111age60, m 1111ie, lllllli-attmil:ily) with NIB1111d napbrvpl1hy [llillry lllurii:Cr lid senl11 Cr , ,

dillllicl, ClrmlyiiCtirG IIQIIIISI. lhllrndlln: t.llln 50 mg 1'0 OO(t:Ud Ill doubled lflll4 Mlks) VI. pllcaho. a....: l'rinlly endpoilts ilcUied iblbli'G rl swn Ct ESRil, 01 dllth. S.Candlly lllldpoinll ilcbled IIIJIIIidily llld lllllltllj;yfmm CW CIUIBS. .....: incillnct rl doublng rl swn Cr {IUIZS\IIIId ESRD !RR but hid 110 1111 rilkof dlllll. Harllit IICIIIdllllt.t lllll'llullbil b BP cliqn abiL Slcoadlly 11'111 poi'dl- similr,lllhlllqlllt8 of hDijlitlilltion for hllrtfliU. WIS tignificlnttv lowarv.illl



c:.lllian: LDIIflln carllfTid rnl benelils in patients will!. 2dilllleles 1111 118pi'Riplllly, IIIII was Qllllllll'{ WIII1Diarat8d.

Priorities in the Management of Patients with DM 1. vascular protection for all patients with diabetes ACEI, antiplatelet therapy (as indicated) BP control, glycemic control, lifestyle modification, lipid control 2. optimization ofBP in patients who are hypertensive treat according to hypertension guidelines 3. renal protection for DM patients with nephropathy (even in absence ofliTN) Type 1 DM: ACEI 2 DM: CrCl >60 mL/min: ACEI or ARB- CrCl <60 mL/min: ARB 2 line agents: nondihydropyridine calcium channel blockers (diltiazem, verapamil) ACEI and ARB can be safely used together if needed for control of significant proteinuria (monitor for hyperkalemia and acute rise in creatinine) check serum Cr and K levels within 1 week of initiating ACEI or ARB and at time of acute illness serum Cr can safely be allowed to rise up to 30% with initiation of ACEI or ARB, usually stabilizes after 2-4 weeks, monitor for significant worsening of renal function or h!ferkalemia if >30% rise in serum Cr or hyperkalemia, discontinue medication and consider 2 line agent consider holding ACEI, ARB and/or diuretic with acute illness and in women before becoming pregnant consider referral to nephrologist if ACR >60 mg/mmol, eGFR <30 mUmin, progressive kidney function loss, unable to achieve BP targets or unable to stay on ACEI or ARB

l'nllliiiiiAII:tiDn llr llllllli: 111111 D-. Codltn l.llti!Ju$jtltllsv 2007; (4):Cil002181

_ . . on111e progqanoftilbllic Dlpi'Riplllly. IIUy sn.:tial: Rlld01nised carmlled 1rial (IItTs) IIIII behn ad lfla' SUiits of thlllllcts rl mlriclld prollin diet on renll flllction in Uljecls will! cilbltll. 12 lluciii-IIVi-. .....: The riskrlendsll;em'li cl- 01 delllll was luwlr in pitieD on III'A'jJIOIBil da

Cystic Diseases of the Kidney

characterized by epithelium-lined cavities filled with fluid or semisolid debris within the kidneys includes: simple cysts (present in SO% of population over SO), medullary cystic kidney, medullary sponge kidney, polycystic kidney disease (autosomal dominant and recessive) and acquired cystic kidney disease (in chronic hemodialysis patients)

........: To review


Adult Polycystic Kidney Disease

PKD1 (1:400), PKD2 (1:1,000), accounts for about 10% of cases of renal failure autosomal dominant; at least 3 genes: PKD1 (chr 16p), PKD2 (chr 4q), PKD3 (location not yet determined) polycystin protein from PKD1 responsible for cell-cell and cell-matrix interaction defect can lead to abnormal cell growth and cyst formation extrarenal manifestations; most common; multiple asymptomatic hepatic cysts (33%), cerebral aneurysm (10%), diverticulosis and mitral valve prolapse (25%) polycystic liver disease rarely causes liver failure less common: cysts in pancreas, spleen, thyroid, ovary, seminal vesicles, and aorta

llllierU willl Type I cilbetes no eftect on Gill was IMQd il the bNrmin diet group.

Signa and Symptoms often asymptomatic; discovered incidentally on imaging or by screening those with FHx acute abdominal flank pain/dull lumbar back pain hematuria (microscopic frequently initial sign, gross) nocturia (urinary concentrating defect) rarely extra-renal presentation (e.g. ruptured berry aneurysm, diverticulitis) HTN (increased renin due to focal compression ofintrarenal arteries by cysts) (60-75%) palpable kidneys Common Complications

urinary tract and cyst infections, HTN, CRF, nephrolithiasis (5-15%), flank and chronic back

Clinical Course polycystic changes are always bilateral and can present at any age clinical manifestations rare before age 20-25 kidneys are normal at birth but may enlarge to 10 times normal size variable progression to renal functional impairment (ESRD in up to 50% by age 60) Investigations radiographic diagnosis- best accomplished by renal U/S (enlarged kidneys, multiple cysts throughout renal parenchyma, increased cortical thickness, splaying of renal calyces) cr abdo with contrast (for equivocal cases, occasionally reveals more cystic involvement) gene linkage analysis for PKD1 for asymptomatic carriers Cr, BUN, urine R&M (to assess for hematuria)

Toronto Notes 2011

Cystic Diseues of the Kidney

Nephrology NP37

Treatment goal: to preserve renal function by prevention and treatment of complications educate patient and family about disease, its manifestations and inheritance pattern genetic counselling: transmission rate 50% from affected parent prevention and early treatment of urinary tract and cyst infections (avoid instrumentation of GUtract) TMP /SMX, ciprofloxacin: able to penetrate cyst walls, achieve therapeutic levels adequate hydration to prevent stone formation avoid contact sports due to greater risk of injury to enlarged kidneys screen for cerebral aneurysms if family history of aneurysmal hemorrhages monitor blood pressure and treat hypertension with ACEI dialysis or transplant for ESRD (disease does not recur in transplanted kidney) may require nephrectomy to create room for renal transplant

Medullary Sponge Kidney

common, autosomal dominant, usually diagnosed in 4th-5th decades multiple cystic dilatations in the collecting ducts of the medulla renal stones, hematuria and recurrent UTis are common features an estimated 10% of patients who present with renal stones have medullary sponge kidney nephrocalcinosis on abdominal x-ray in 50% patients, often detect asymptomatic patients incidentally diagnosis: contrast filled medullary cysts on IVP, characteristic radial pattern ("bouquet of flowers"), "swiss cheese" appearance on morphology treat UTis and stone formation as indicated does not result in renal failure

Autosomal Recessive Polycystic Kidney Disease

1:20,000 incidence prenatal diagnosis by enlarged kidneys perinatal death from respiratory failure patients who survive perinatal period develop CHF, HTN, chronic kidney disease treated with kidney and/or liver transplant

Table 14. Drugs In Nephrology


Sita Dl Acciol
llick Df Loop Df Han Ia

Mecllanism If AICial (Secondary Bllc1j



Advana EfllcCs


bumllllnida (Bumaellluinaxe) ethlcrynlbl (Edecrin., lllnemidl (Dernadat')

Nl!ii(I2CI1Tinsport renal and VIISDdilltary lllhlc1s (Kloss; 1' Hsacretion; 1' Casxmdion)

lA ad111111 secandllry tD CHF, fu1111amida: Allarw in sLMB-1111siiMI individuals naplrrutic synd111ma, cinliDtic ascites; ada11111- IVJIM/PD q&-Sh Elactrolytl abniiiTTIIIIitia; lrfpok*ni11, hyponatnmia, 1' fnle Wltar claarance in SIAIJIJ.induced (ITIIX 600 mlfd) until dsii!ld rtllipon118 lrfpocalcemi11, hypemllciLI'ia (with i1llne furmation) lrfponatremia), BP (less affiCtiv8 due tD Valuma deplltion with matabolic abiosis lfTN - 20-80 rngld PO 00/hid nrtaction) Pracipitmas ldtacks



Tliazide Diurllica

hydrochloruthiazida (HCTZ) chlaruthillzide (Dilliltj (Lozule, Lozideltj matDiaz!llla (Zir=lyn., chlorthalidona (fWvton8) spi!IIRolllctona(AidiC!Dne] triamtlnlna([)yrlnium) amiloride (MUnorS)

Disbll convolutlld tuoole


Nt/CIIIInsportar (K lost; 1' H Ca uaation)

1st lila fur eaantillllfTN Treatment Df edema Idiopathic hypert:alciuriaand stonea [ia.bataslnsipidus RII!Wcas K caused by other loss

HCTZ: ede11111- 25-100 00 lfTN -12.5-25 PO DO (m11X 50 rngld) 2&-200 mlfday Oil/bid dosing lfTN: 50-200 mlfday Oil/bid doling Hyparaldosteronism- 10[1.400 mlfday Oil/bid amilorida: &-10 DO

Hypok*nia I11C1181ed serum lillie levels PracipitDs gooty idtacks, hypacllllcenia EIMtdlipids Gklc011eintuiiJiliiCI Hyperkalemia (elUtion with ACE irilibi!Dr) TriamiiAinl can ba naphru!Dxic (rn) Neplrlllijhia Gyna1111111ia (IIS!rDgllic efltct Df spironollclonl)


Cortical duct Na llabsorption)

antagonist Clo111 apiclll Na chann

SMni CHF.IICitea [iipironra:tuna), cystic fibrosis (amiIoride vilco&ity of secretions) Combina ACE-irilibitar fDr syrJIIII,jistiC elfecl 1hiazide Conan lrfpokalemia
drug with 1hiazidatallduc1

CollbiaaliP All* Dyazida tlriamterene + HClZ) Aldlctllid8 8 (spironDIIClona + HClZ) Mloduratic(amilmida + HClZ) Vasntic8 (nlapril + HClZ) Zlisllntic Pisinopril + HCTZ)


Ran II tubules (proximal n


To "- intnacrenial or jllii'IOcQjillr prassu111 NOIHillbsorilabla solutn incriiiSil osmDtic prassUrl Df filtratl MobilizllliDnDIIIKCISSfllid - irilibits reabsorption DfWIIIrand 1' adam!lllus stale$ urinary IIXI:IIIion Df1Dxic matarials II wsoconlllricting lfTN net CardioprDiecliVII ellicta I wsodilation -> BP RllnoprotactiVIIIfflcts l'revel1ts II mediated aldolllrtlnl nlll1111 fnlm adrlnal cor11x n action on praximal Rillll111bules 1' Na and H0 exallion -> BP 1 Redul:es fibrosis and athenlgenesis
VIISCUill' &moolh muscilll

manritDI: oJ. ICP: 0.25-2 w\IIIV- 3[1.60 min

Transiant110luma axpansion Elactrolytl abnormlllitias [

Na, oJ./1' IQ


rurnipril [Allee., enlllapril lisinoprii(Prinivir') tnmdolapril [MII'ik., caplopril (CapDtanltj

Tissuas dillull81r


11mipril: HTN- 2.5-20


Astllna Hyperkalamia A!pnulocyiDsis (captapril) Acute kidney injny

us1- 1D PO OD mg tnnlolapril: HTN-1-4 OD

t ..


IOII8rtln (Comare) candasartan (AtiCind<tj irbesrrtan [Avap111., valsarttll(Diovan") !Wnisartan (ro.tcardisiiJ eprusartan (TMten., olmasartan [0.-runaciiJ aliskimn (llasitaze]

Vascular smoolh mllll:kl, adrenal inhiMor at1he qiotnin lfTN cortax, praximalllJJulls II AICiplor: II CardioprullcliVII ellicta (111 action on vasculrr Renopratective etfecta smoolh ITIJida BP l'revel1ts anlliDiensin II mediated aldolllrtlnlllllllla fnlm adrlnal corllx and action on proximal Rilllll111bules 1' Na .,d H0 exallion 1

lfTN: lllllllll12&-100 PO 00 cnesartan 8-32 PO oo irt:Jesartan 150-300 PO OD wlsarbln DO telni$8111n 2HO PO OD 400-800 PO DD 26-40 mg PO OD

Hyperkalemia CIU!ion - m!Wca dOII8 in hapatic impeirmant Acute kidney injny

Rlllin Altlpisa


Inhibits mnin plllductiDn and activity Cardioprotactivl and renoprutactive IMIIuatsd


llliskimn 15!l-JOD



... ...

Toronto Notes 2011

Landmark Nephrology Triala

Nephrology NP39

Landmark Nephrology Trials

Trill ACEI and Diabetic


NEJM 1993; 329:1456-62

Captapril protscts against deterioration in ranal function in insulin-dependent diabetic nephropathy and is more effecti\le than blood-pressure control alone Treatment with ACEitrandolapril alone or trandolapril combined with Vlllllp8mil d11C1811sed the incidence of microalbuminuria in patients with type Zdiabetes and hypertension with nonnoalbumiooria Renal artery revascularization compared to medical therapy does not improve 11!11111 function, BP, renal or cardiovascular events, or mortality and carries significant operative risks The ARB telrniser1lln and the ACEI enalaprilare etJllllly effective in slowing ranal function delarioralion in type 2 diabatas with mild to moderate hyp811Bnsion and aar1y naptropathy S1lnlard irrmunosuppresion therapy in ranal tnn;plant patients low dosetacrolimus is superior to cyclosporina and sirolifllls in reduction of acute rejection, rnainll!nance of ranallunction, 111d allograft survival Use of high dose dialysis or high flux memblllll!s versus standard dose or low flux in thrice-weekly dialysis does not improve survival or outcomes. Possible benefit in cardiac-related outcomes with high flux membranes Treetment with irbesartan reduced the risk of developing end-stage renal disaase and worsening renal function lrbes811Bn is ranoprotective independently of its blood-fJII!SSure lowering effect in patients with type 2 diabetes and microalbuminuria Telmisartan and ramipril monotherapy reduced proteillria and rise in creatinina in patients with high vascular risk In non-diabetic nephropathy, ACEI were renoprotective iJ patients with nonnephrotic range proteinuria Losartan conferred significant renal benefits in patients with type 2 diabetes and napiJapathy and was ganeraly well-tolerated High intensity continuous renal-replacement therapy in acute kidney iljury does not inprove survival or outcomes compared to low intensity treatment. and is essociated with higher rates of hypophosphatemia Uptitration of either ACEI Benazepril or ARB Losartan to optinal antiproteinuria doses conferred benefit on renal outcome in patients without diabetes and had proteinuria and ranal ilsulliciency Daclizumab induction, MMF, steroids and low-dose tacrolifllls effectively maintail stable renal function following renal transplantation, without the nagativa Blfacts on renal function commonly reported for standard CNI regimens


NEJM2004; 351:1941-1951


NEJM2009; 361:1953-62


NEJMZ004; 351:1952-61


NEJM 2007; 257:2562-75


NEJM2002; 347:2010-19


NEJM2001; 345:851-&D NEJM 2001; 345:870-8

lMicet 2008; 372:547-33

iimctJt 1999; 354:359-64

NEJM2001; 345:861-9 NEJM2009; 361:1627-38


JASN2001; 18:1889-1898


NEJMZ001; 357:2562-75

NP40 Nephrology


Toronto Notes 2011

Adler SG, S.hmt DJ.(2003I. An au1tn8 aiSAIIItiiiiDpiCi in gtlmarullr 111d lr8llrrrmt for naphrology1Rina&L Amaril:ln Jaulllli of Killll'f lise-, Val 42: 3!5-418. Andreoli TE at Cecil Essentials of Medicine, 6111 ad. Saundlr Publisq Philllllllphia. Andi'D!Iue HJ. Mlliu NM. (1999]. Ma1111gement of ife threlterirG acid-base disorders pill I. WM. Vol. 338 !11: 2&-33. Andi'D!Iua HJ. Mllias NM. (1 999]. Mallllgamant of ill thraatarirQ acid-bela disordara pill II. NEJM. Val 338(21: 107-11. Andi'D!JU8 HJ. Mllias NE.(2Wll. HypoMtremia. Vol 342(201: 1483-1499, 1581-1589. 1lndl All, Bain SC,IIau1iir P, Klrllerv B. Madsllld S. Jerwll J. et II. AJ9o1nin-lleceplor Blockllde VIISU5 Converting.fnzyme Wilition in Type 2Diabe11s and Naplnap11hy, NEJM. Vol. 351(1t,1952-61. Bramar BM, Caopar ME, da Zaluw D. Kaine WF. Mitch WE, Blli.{2001l. Effac:tJ of IDArlln anlilnll Crial'lscul in l'ltiants with Type 21ilbatas111d

Nephropathy, NEJM, Vol. 345(121; 861-861. Churchill DN,Iilllcka PG, Jindal KK. TDII*lira EB, Gold ate in MB. (19991 CiMca1 pnctic8 tuillllilas lor initiatian al dialysis. Canadian Society of Nephrabgy. JAm SGc Nephrol; Vol. 10 S231H1. DanadioJII. GrandeJP.(2ll02). Medi:al J1119111: lgAnephropathy. NEJM. Vol. 347:738-748. Gabow PA. (1 9931. Aullllomal domin1nt di- NEJM. Vol. 329(51:332-342. Grerierg. Artlv. Primer on Kidney liseues. 3rd ed. San llego: Academic Pless, 2001. Hakim R.Limus M (1995].1niliBiion DfDi.._ JAm Soc NlplrGI, Vol&, 131S.13Z8. Hliperin Ml. GDidatain MB, KatsayR, llll (198111. Fluid, alactmlyla,and scidblsa pllysiDiogy: I problam.JIIsad IPJIRIICh, lrd ad. HarcourtBlaca & Co.: New Yort. Halperin M. Kimel K. (1998].1'atJssirm. The Lancet, Vol352: 13HO. Hns SB. MIIIIDr SJ. 2l111111n 8.(19981. NIW 1hl m111111g1m11nt of diab111s: aphysicilll's tuida. St.ring CormiUII for thllilvision Dfthl Ham ph ill RR at II. Rll\'iiW ai!IQQ !IRIII fliU.. http;l/lw.w.embblfcl)lllicr/Jflrf.html. Hudson BG. Trwii\Uon K, SundUimoorthy M. Nei111111 EG.(2ll031. Mechllilms of Disease: Alport's Synd!ame, Goodpaslire's Syndrome, lAd Type NCollagen. NEJM, Vol. 348: 2543-2556. John lUll CA. L8vey AS, Cor.h J, Levin A, Lau J, llcnoyln. G.(2ll041. CiMca1 pmcb clnrie di&eue in adults: Pill l Gbmarul fittmion rata, prulli11ria, ud ather rrartn. American Familyl'hysicillls. Johnson RJ. Ftahally Comprallnivl clinical naphrology. Mosby: Naw Yort. 100001 clinicallfiCiice Quidelnes lor clllanic disease: evalurlion, clmification, ud stRtlication: 2ll00 wcutive updale.http;lfwww. dDGVtdo!lilloc.htm Kalina WF. Gnllled E. (19991. Protairama. alilllrruril, rist USIISII!IInt, dBIIctian, elimination (I'ARA!lE): 1 pOiition pepar altha Nltio1llll Kidney Famdltion. A J mar Killis, Vol. 33[51: 1004-1010. Llwis EJ. Hunsicbl LG, l!llin RP. Rohda Tha Elllcts of AngiJtlnsii-Corrnrting Enl'l"la ..libition on liabatic NIJRapethy. NEJM. Vol. Mcfarllna P. lalla S. Houldan R, Hams S.(2ll031. Napllapalhy: Canadi1n Dilllllll Allocillian clinical prlctica tuidalinll axpart commit!IL Mtp//lw.w.diabltll.ct/ Mallzar, Sat al. (19!181. Clinicall'rlctice Guidalinll fol tha Managamant of Dilllllll in Canida. CMAJ.
Myn, A. Madici111141h ld. Baltimora: Wililma & 21)01. ONTARGET m.tigi!Dn. (2ll081 T*isnn, or bath in patients 111igh risk lomsculu IMII1li. NEJM, 358, 1547-59. Slbltina M.(2ll041. Pucket Melil;ina: Tba Ganaralllolpital Handbook of hlamal Madicina. 2nd ad. CllajQr 4. 1-21).

LippincllttWillau. &

Wlins. Schiftl H,Lang SM. Fischer R.(2ll021. Daily Hamodialysis and 1hl Outcome of Aaa Renal FaiU.. NEJM. Vol. 346{5t3DS.1D. Schreiber M. Samnara lor 3 clinical clsrkllan medicine: hyponatremia and hypamatramia. Dclallar 29, 2ll02. Smith, Kinsey. Renal Diseese: AConcl!plual ApJiroach. New Ywk: Cland1ill.ivingstone, 1987. Thldhani R,l'llscual M,llonwntra.Jil (1 9961. kuteranal fliU.. NEJM. Vol. 334(221:14481460.

Mina Atia, Tara Rutin and Courtney Scott, chapter editors Doreen Ezeife and Nigel Tan, associate editors Steven Wong, EBM editor Dr. David Chan, staff editor

The Neurological Exam ................... 2 General Exam and Mental Status Cranial Nerves Exam Motor Exam Sensory Exam Coordination Exam and Gait Basic Anatomy Review ................... 4 Lumbar Puncture ........................ 7 Seizure Disorders and Epilepsy . . . . . . . . . . . . 8 Seizure Status Epilepticus Behavioural Neurology .................. 10 Acute Confusional State/Delirium Dementia Alzheimer's Disease (AD) lewy Body Disease (LBD) Frontotemporal Dementia (FTD) Creutzfeldt-Jakob Disease (CJD) Normal Pressure Hydrocephalus (NPH) Aphasia Apraxia Agnosia Cranial Nerve Deficits . . . . . . . . . . . . . . . . . . . 17 NEURO-OPHTHALMOLOGY Abnormalities of Vision .. 20 Acute Visual Loss Optic Neuritis Anterior Ischemic Optic Neuropathy Amaurosis Fugax Central Retinal Vein Occlusion (CRVO) Optic Disc Edema Optic Disc Atrophy Abnormalities of Visual Field ............. 21 Abnormalities of Eye Movements ......... 22 Disorders of Lateral Gaze Internuclear Ophthalmoplegia (I NO) Diplopia Nystagmus Abnormalities of Pupils .. 23 Relative Afferent Pupillary Defect (RAPD) Horner's Syndrome Anisocoria Movement Disorders .................... 25 Overview of Movement Disorders Function of the Basal Ganglia Approach to Movements Disorders Parkinson's Disease (PD) Other Parkinsonian Disorders Huntington's Disease Dystonia Tic Disorders Tourette's Syndrome Motor Neuron Disease .................. 29 Amyotrophic Lateral Sclerosis (ALS) Other Motor Neuron Diseases
Toronto Notes 2011

Peripheral Neuropathies . . . . . . . . . . . . . . . . . 30 Neuro-oncology ....................... 32 Paraneoplastic Syndrome Tumours of the Nervous System Neuromuscular Junction Diseases ......... 32 Clinical Approach Myasthenia Gravis (MG) Lambert-Eaton Myasthenic Syndrome (LEMS) Myopathies............................ 34 Clinical Approach Polymyositis/Dermatomyositis Myotonic Dystrophy Duchenne and Becker Muscular Dystrophy Cerebellar Disorders . . . . . . . . . . . . . . . . . . . . 35 Wernicke-Korsakoff Syndrome Cerebellar Ataxias Vertigo ............................... 36 Galt Disturbances ...................... 36 Pain Syndromes ........................ 36 Approach to Pain Syndromes Neuropathic Pain Tic Douloureux Postherpetic Neuralgia (PHN) Complex Regional Pain Syndromes (CRPS) Thalamic Pain (Dejerine Roussy Syndrome) Headache ............................. 39 Clinical Approach to Headaches Migraine Headaches Episodic Tension-Type Headache Chronic Tension-Type Headache Cluster Headache Sleep Disorders ........................ 42 Overview of Sleep Disturbances of Alertness and Sleep CNS Infections ......................... 44 Spinal Cord Syndromes ................. 44 Stroke ................................ 44 Terminology Approach to Stroke Stroke Syndromes Ischemic Stroke Hemorrhagic Stroke Hypertensive Stroke Global Cerebral Ischemia Treatment of Stroke Primary and Secondary Prevention Stroke Rehabilitation Multiple Sclerosis (MS) .. 49 Common Medications ................... 51 Landmark Neurology Trials............... 52 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Neurology Nl

N2 Neurology

The Neurological Exam

Toronto Notes 2011

The Neurological Exam

General Exam and Mental Status
vitals: pulse (especially rhythm), BP, temperature H&N: meningismus, head injury/bruises (battle sign, raccoon eyes), tongue biting CVS: carotid bruits, heart murmurs

mental status: WC (AVPU scale, Glasgow Coma Scale) cognition: Folstcin Mini-Mental Status Exam (MMSE), clock drawing, frontal lobe testing (for perserveration) clock drawing: give patient a blank piece of paper and tell them to draw the face of a clock. put in all the numbers, and set the hands to 'ten after eleven'.

T1ble 1. Mini-Mentll Status Exam (MMSEI

D111111in Orillllltian Regiltration

Score Task /5 Time: Ye.-, Season, Month, Day, Date

Attlnlian and CanCIDiration

Recall Lan,.age

/5 /3 /5 /3 /2 /1 /3

Place: Counlly, Province, City, Building. Floor lmmediilte Recall: 3 wnlated items
Spell 'WORLD' backwards or do Sarial7s

Delayed recall af previous 3 items Naming: Pen, Watch Repetition: 'No ifs, ands, or buts' 3-Step Command: "take this paper in your left hand, fuld it in half, and place it on the floor with your right hand." Read and obey: 'CLOSE YOUR EYES' Writing: Write afull sentence Copy:



/1 /30

Pentagons (1 0


Cognitive impaiment if <24/30


Cranial Nerves Exam

Olfactory (CNI): test each nostril separately to identify common odours Optic (CNII) a. VISual Acuity: test each eye individually using best corrected vision b. VISual Fields: test all4 quadrants for each eye individually c. Pupil: direct and consensual pupillary reaction (afferent limb), accommodation, swinging flashlight test (for RAPD) d. Fundoscopy; optic disc edema, optic disc pallor, venous pulsations, hemorrhages Extra Ocular Movements (EOM) a. Oculomotor (CNIII): levator palpebrae superioris, medial rectus, superior rectus, nrreriorrectus,nrrerioroblique b. Trochlear (CNlV): superior oblique c. Abducens (CNVI):lateralrectus Trigeminal (CNV) a. Sensory: Vl-V3, corneal reflex (afferent) b. Motor: temporalis, masseter, pterygoids, jaw jerk reflex Facial (CNVII) a. Sensorimotor: muscles offacial expression, hyperacussis (stapedius), corneal reflex (efferent) b. VISceral sensory: taste of anterior 2/3 oftongue c. VISceral motor: salivary and lacrimal glands Vestibulocochlear (CNVIII) a. Vestibular: nystagmus (described based on fast phase), caloric reflexes b. Cochlear: test each ear masking the other with white noise, Rinne, Weber Glossopharyngeal (CNIX) and Vagus (CNX): palatal elevation, gag reflex, vocal cord function, swallowing Accessory (CNXI): trapezius and sternocleidomastoid Hypoglossal (CNXII): tongue muscle bulk, fasdculations, strength

If patient has not brought their glasses.

best CDITBCIIId vision.

havalhem look through a pinhole for

CNIII with pupil1paring -Think vascular caus1s likl diabetic ophthalmoplagia CNIII with pupil involvement- Think

compressive lesions.




N4 Neurology

The Neurological Exam/Basic Anatomy Review

Toronto Notes 2011

Sensory Exam
primary sensation spinothalamic tract: pain and temperature dorsal column: proprioception and vibration cortical sensation graphesthesia, stereognosis, extinction, 2 point discrimination

Romberg Stable with eyes open and closed = normal Stable with eyes open, falls with eyes closed = +ve Romberg, suggesting loss of joint position sense Falls with eyes open and closed = cerebellar or vestibular syndromes

Coordination Exam and Gait

coordination exam finger-to-nose, heel-to-shin, rapid alternating movement stance and gait gait: antalgic, hemiplegic, ataxic, apraxic, festination, foot drop, broad-based tandem gait heel-to-toe walking Romberg pull test for retropulsion

See Functional Neuroanatomy software

Basic Anatomy Review

see also Neurosurgery. NS24 for Dermatome/Myotome information

1. Corticospinal tract 2. Lateral spinothalamic tract and spinotectal fibres 3. Decussation of medial lemniscus 4. Reticular fonnation 5. Nucleus of spinal tract of trigeminal (V) nerve (descending) 6. Spinal tract of trigeminal (V) nerve 7. Nucleus cuneatus B. Fasciculus cuneatus 9. Nucleus gracilis 1D. Fasciculus gracilis 11. Central canal 12. Arcuate fibres

1. Pontine nucleus 2. Abducens nerve fibres 3. Corticospinal tract and corticonuclear fibres 4. Medial lemniscus 5. Nucleus of facial (VII) nerve (motor) 6. Facial (VII) nerve fibres 7. Trigeminal (V) nerve fibres B. Nucleus of abducens (VI) nerve 9. Nucleus of spinal tract of trigeminal (V) nerve 1D. Lateral vestibular nucleus 11. Middle cerebellar peduncle 12. IV ventricle

1. Interpeduncular fossa 2. Occulomotor (1111 nerve fibres 3. Cerebral peduncle 4. Substantia nigra 5. Red nucleus 6. Edinger-westphal nuclei 7. Occulomotor (Ill) nucleus complex (motor) B. Medial lemniscus 9. Spinothalamic tract 1D. Central canal 11. Superior colliculus


Figure 1. Brainstem

Cerebrocerebellum Spinocerebellum _ Vestibulocerebellum


Saggital section through brainstem and cerebellum

Flocculus Tonsils


Anterior view Figure 2. Cerebellum

'IbroDlo Nota 2011

Buic Anatomy Review

Neurology NS

il matar cariJDI:


\1 }

Axial muld"

Figun 3. Discriminatin Touch Patlway

Column) fra111 BadJ

4. Spi1Dihlllmic Tnct

Triguminal ganglion

. ]f0/-\ l
Thelanu \ ,

- \ It

lntamel ''\ capaule '

[ .....

from fac:e .__..


J face




1 Mediallemniscus


I 'f, Chillf
Figun 5. Discriminatin Touch Pltlway


T of thupinal nM:t: trigeminaloocleus

Spinal triguminalrM:Iu



Column) fra111 Face

Figun li. Spinlllllllamic Pain Pltlway fra111 Face

Uppar mlllllr mu111111 in mamr car!IIX

Axial muld" l

. IJj

Alcill m111cl88

Figun 7. CalticaiiJinal Malar Patlway

N6 Neurology





Flg1re 1. Sympathellc Md Parympatludlc Pathway

Toronto Notes 2011

Lumbar Puncture

Neurology N7

Lumbar Puncture
Indications diagnostic: CNS infection (meningitis, encephalitis), inflammatory disorder (MS, Guillain-Barre, vasculitis), subarachnoid hemorrhage (CT negative), CNS neoplasm (neoplastic meningitis) therapeutic: to administer anesthesia, chemotherapy, contrast media; to decrease intracranial pressure (pseudotwnour cerebri, nonnal pressure hydrocephalus) Contraindication& increased intracranial pressure (ICP) - could lead to cerebral herniation CT first if immunocompromised, possible CNS disease, new-onset seizures, papilledema, altered LOC, focal neurologic findings, >60 years old infection over lumbar puncture (LP) site uncooperative patient Complications tonsillar herniation post-LP headache (5-40%) -clear pattern: worse when upright, better supine; generally onset within 24 hrs prevention: smaller gauge (ie. 22) needle, reinsert stylet prior to needle removal, blunt ended



The needle for a lumbar punclin is insertBcl into one of L34, L4-5, or L5.S1

The volume of CSF removed during a lurnb11r puncture i& ruplsni&hed within
one hour.



symptomatic treatment: caffeine and sodium benzoate injection corrective treatment: blood patch spinal epidural hematoma infection What to send LP for Tube #I: Cell Count and Differential: RBCs and WBCs and differential xanthochromia [yellow bilirubin pigmentation) implies recent bleed into cerebrospinal fluid (CSF)I Tube #2: Chemistry: Glucose (compare to serum glucose) and protein Tube #3: Microbiology: Gram stain and C&S specific tests depending on clinical situation/suspicion viral: PCR for herpes simplex virus (HSV) bacterial: polysaccharide antigens of H. injluenzae, N. meningitidis, S. pneumococcus fungal: Cryptococcal antigen, India ink stain (cryptococcus), culture TB: Acid-Fast stain, TB culture, TB PCR Tube #4: Cytology (for evidence of malignant cells) Tube #5: RBCs: compare RBC cell count to that of tube #l
Tabla 5. Lumbar Puncture lntarpral:ltion (Normal vs. Various Infectious Causes)

Do nat delay antibiotics while waiting

fer alumb11r puncture if suspicion of


RBC in tuba #1 > >#5 -1r8umatic tap RBC in tube #1




<0.45 gil

60% of serum glc >3.0mmoL'l Normal

Cells O..SWBC, DRBC 0 neutrophills <100Dx1D'/l. Lymphocytes mostly, somePMNs >11XX!x1o'/l. PMNs

Cle.- or opaiBSCent

Normal or slightly increased <0.45-IIJI\. > 11Ji\.


Opalescent yellow, may clot Clear or opaiBSCent

Decreased ( < 25% serum glc or <2.0 mmoi/L) llecraasad (usually <2.0-4.0 mmoi/L)

Granulomatoullnlection fun;jal)

ncraased but usually <51Jil

<11XXlx1o'!L Lymphocyllls

N8 Neurology

Seizure Disorders and Epilepsy

Toronto Notes 2011

Seizure Disorders and Epilepsy


Mldlcll EmetgiiiCyl S1atus Epilepticus can cause irmtanible brain damage without traatmant

seizure - transient neurological dysfunction caused by excessive activity of cortical neurons, resulting in paroxysmal alteration of behaviour and/or EEG changes epilepsy - chronic condition characterized by two or more unprovoked seizures ictal- during seizure post-ictal- period following a seizure when there may be a state of confusion/somnolence inter-ictal- period between seizures during which epileptic discharges may be seen on EEG status epUepticus- seizure lasting >30 minutes without spontaneous cessation or recurrent seizures without full return to consciousness inter-ictally





+'. Panial- Simpla

can secondarily become - - - - - - - - - - - - - - - - - Generahzad





Abet nee

Motor Sensory






Fevar Metabolic Trauma


Figura 1D. Classification of Saizuras

Stroke is the most common cause of late-onset (>50 'f8lll' of age) seizures,
accounting for 53-BO'K. of c__


+ +



+ ...


idiopathic identifiable etiology: vascular, congenital, neurodegenerative or other neurologic disorders, neoplasm, trauma, childhood epilepsy syndromes, infection, metabolic, toxins, genetic cryptogenic

Signs and Symptoms generalized seizures

tonic-clonic (grand mal): prodrome of unease or irritability hours to days before the attack tonic ictal phase: tonic muscle contractions, arm flexion and adduction, leg extension, 'cry' as respiratory muscle spasm and air is expelled; lasts 10-30 seconds clonic ictal phase: clonus involving violent jerking of face and limbs, tongue biting, incontinence; <90 seconds post-ictal: decreased WC, flaccid limb and jaw, extensor plantar reflexes, loss of corneal reflexes lasting hours, headache, confusion, aching muscles, sore tongue, amnesia, elevated serum CK lasting hours absence (petit mal): usually only seen in children, unresponsive for 5-10 seconds with arrest of activity, staring, blinking or eye-rolling, no post-ictal confusion; 3Hz spike and slow wave activity on EEG tonic: decreased LOC with muscle contraction in flexion or extension drop attack, arrest of respiration causing cyanosis clonic: decreased LOC with repetitive clonic jerks myoclonic: brief contractions localized to muscle groups of one or more extremities or more generalized atonic: loss of postural tone leading to drop attack

partial seizures
simple (no change in level of consciousness): motor: rhythmic jerking or sustained spasm oflocalized muscles forceful turning of eyes and head to side contralateral to focal discharge (adversive seizure); may start in one location and spread to another (Jacksonian March); possible post-ictal hemiparesis (Todd's paralysis) sensory: numbness/tingling/"electric" sensation of affected parts that may spread to other locations; other forms include visual, auditory, olfactory, gustatory, vertiginous autonomic: epigastric discomfort. pallor, sweating, flushing, piloerection, papillary dilatation psychiatric: symptoms rarely occur without impairment of consciousness and are more commonly complex partial

Toronto Notes 2011

Seizure Diaorders and Epilepllf

Neurology N9

complex (alteration of mood, memory, perception) forms: dJ5phasic, dysmnesic (deja vu), cognitive (disorientation of time sense), affective (fear, anger), illusions, structure hallucinations (music, scenes, taste, smells), epigastric fullness automatism (chewing, swallowing, lip-smacking, scratching, fumbling, running, disrobing, continuation of actions prior to decreased LOC) followed by distant staring unresponsiveness
Table &. Classic Factors Differentiating Seizure versa Syncope

Complex partial s!ll1us can resemble ll:hizophnmia or pl'jl:hotic daprvuion.


Tempo111llobe eplepsy is suggestad by

an 1110 of fvar, olfactury or gumtory

Chomu:llri.tic: lima af Onset


Seizure Day or niltrt

Sudden or brief Possibla spscific aura Normal or cyanotic Uncommon outside of ictus

Upright, not recuntent Gradual

hellucinationt; visceral. or d6jl w sen1lllions.

Frontoparietal cortex seizures are auggested by contndllhnl facal118nsory

or motor plwnam111.

Colaur Duration lncoll:inanca

Dizzy, blurring, lighth88dad

Pallor Common; diaphoresis Brief Possible but rare Rare Occasionel brief jerks Rare unless from fall None No111111l

Dllfwentill DiltP*il of Connlslons Syncope, pseudoll8izurv,
hyperv8ntilatian. panic disordlr. 11A, hypoglycemia, movement disorder, alcoholic blackouts, mig111inn !confusional, verlebrabesilarl, narcolepsy (r;alapi8X'fl

Briuf or prolonged
Common Occurs in tonic-clonic or co1J111ex partial Common Common. tongue biting Common i1 absence or conlJiex partial Normal or Abnonnal

Motllr ActMty Injury



Nota thllt frontal saiZIDI (raral can look. lib a puudasG!n WilD odd mo1Dr activity that may occur.

Tabla 7. Classic Factors Differentiating Seizure versa Pseudosaizures (Conversion Disorder)

Trigg en Duration


Emotionel disturbance

Brief or prolonged
Synchronous. S181'8Dlypic. automatisms

May be prolonged
Opisthotonos, rigidity, forced eye closure, irragular axtnmity moVIITI8nts, shakilg heed, pelvic thrust crying

Motllr ActMty

l'ngncy I MUll TIIBIIIQIInicity of anticonwlunts due 1D increased risk of open neural tuba dafvct. Advisa patient pregnancy 1D take 5 mgfday of folic acid. Consider switching medicatio111.


Day or Night
May occur May occur
Spontaneous Dftan intsr-iclill di&chqas Increased

Day; other people present

Rare Rare Suggestion ::!: stinulus Nonnal Nonnal

lncoll:inanca llepraduction af Attac:k



MinistJy of T111nsportation must be conllcted by law far Ill patients who have had auizurl. Patients will hiM
license suspended Llltil seizure free for


'l'wloleiBJres do IIIII


"* out teillm IIIli YM:0111110111D present with boll!I


.... ,l------------------, ;
Antic--Ill Mlldi:ltiBraad spectrum (germalized from onsll and partial onset seizures): felb.mate, lamolrigina,lavelinlcebrm, nlfinamida, topinsmate, Wl)roate, zonisamide


evaluation of new onset seizures: history and physical, complete neurologic exam, CBC, electrolytes, FBG, calcium, magnesium, ESR, creatinine, urea, liver function tests, EEG, MRI (if suggestion of focal deficit, progression or >25 years of age)

anticonvulsant& psychosocial issues: stigma of seizures, educate patient and family, advise of dangerous activities including driving, pregnancy issues surgical treatment if focal

Narrow spectrum {simple partial, complex partial and secondarily u-ndized 118izurl: clllbarnllz8pine, gabapenlin. laco11mide, oxcarblmpine, phanob.tlillll, ph1111ytuin. PfliUIIbelin,
primidone, tiagabine, vigabatrin
Abnncasaizurn (a type of gan8111lizad seizure): ethosuximide

Status Epilepticus
initial measures: ABCs, vitals, ECG, nasal 0 2, IV with NS, glucose 50 ml IY, thiamine 100 mg IY.EEG bloodwork: electrolytes, calcium, magnesium glucose, CBC, toxicology screen and alcohol level, anticonvulsant levels focused history general physical exam (once seizures controlled): LOC, vital signs, HEENT (tongue biting, papilledema), neck stiffness, signs of neurocutaneous disorders, decreased breath sounds, cardiac murmurs or arrhythmias, urinary incontinence, aphasia, motor exam

NIO Neurolo8Y

Seizure Disorders and EpUepayJBehavioural Neurology

Toronto Notes 2011

Reflex asymmeby or unilatel'll Babinski aign may bs indicativa of afuc:all85ion.

Convulsive Seizure

Stllbll Epileptic




EEG findings suggIM of Epilepsy:

lbnonnalspikas, polyspika discharges,

2. Vrtlllsigns 3. Laboratory investigations

Kfvwr or meningismus

spib.wave compiiXIS.

4. Glucose 50 mliV
5. lor'IIZapam 0.1-2 (or Diazepam 10 mg IV over 2 mini

Lumbar Punc:ture with Gram stain and Treat pl'llllmptivllly with anliliotics


,.Jr-----------------, ,

20-59% of first EEG are positive in epilepsy, 59-92% of epilepsy is picked wilh repeated EEGs.

Fosphanytoin 1OOG-1500 mg IV at 150 m!Vmin or Phanytoill OOG-1500 mg IV at a max of 50 mG"min Another 10 mWkg of F08phanytoin or Phunytoin Phalobarbital 1OOG-1500 mg IV tlowly
12h (Tihctay SE)

l.ICU 2. Continuous infusion of MidiiZIJIIIriV' propuloVpun1Dbarbitlll 3. Burst suppression (on EEGI

Figura 11. Smtus Epilapticus

Behavioural Neurology

Delirium is a medical emergency CBrT'finU significant risk of morbidity and mortality.

see Psychiatry. PS17

Acute Confusional State/Delirium

Table 8. Selected Intracranial Causes of Acute Confusion Etialllgy


Dulirium is characterized by awte



IC8v' Clilicel Fallllnls

Thunderclap headache Increased ICP Meningisrrus Focal neurological signs Fever, headache, nausea, pholophobia Meningisrrus Focal neurological signs Fever, headache, :t seizure Increased ICP Focal neurological signs Trauma Hx Increased ICP Focal n1111rological signs Skin r.&l. actiw joinhi

1-'igllions CT (non-contrast) lP Angiogra(tly CT,LP negative CT (non-contrast)


Subarachnoid hemormage

marbd variability,

fluctuating level of consciousness, poor

attention, and marbd psychomotor

Menilgitis Encephalitis Abscess TI'IUIIIIIic Difluse axonal shear, epidural hematoma, subdural hematoma

LP;MRI CT wilh contrast (often ring enhancing lesion) CT (non-contrast) MRI ANA; ANCA; RF MRI Angiography CT (non-contrast) MRI


Visual hallucilations more indicate organic diseas1.

Etiology of Delirium I WATCH DEATH lnfuctious Withdrawal from drugs Acute matabolic: dilllnlar Trauma
CNS pdlology Hypoxia


Acuta CNS Vll&culiti&


Mass eh:t/edema, hemorrhage, seizure Status epilepticus Todd's phenornanon Psychotic disorder, mood disorder, IIIXiaty disorder

Increased ICP Focal neurological signs Papiladema See Seizure Disorders andEpilepsy, NB No organic signs or svn.rtoms

Deficiencies in vitamins Endocrinopatllias Acute vascular insults

Toxins HIIV'( millis

PriiiiiiiY Psychilbic

No specific tests

Toronto Notes 2011

Behavioural Neurology

Neurology Nil

Management of Acute Confusion - General Measures

see Psychiatr:y. PSIS well-lit room hearing aids and glasses orienting stimuli (clocks, calendars) avoid restraints or catheters stop all unnecessary medications treat underlying cause, antipsychotics

see Psychiatry. PSIS

an acquired, generalized and (usually) progressive impairment of cognitive function (i.e. memory, recall, orientation, language, abstraction, etc.) affects content. but not level of consciousness

15% ofthose >65 years of age have dementia common etiologies: 60-SO% Alzheimer's Disease (AD); 10-20% vascular dementia <5% reversible: hypothyroid, normal pressure hydrocephalus (NPH), nutritional deficiencies, depression and infection

see Table 9 for common causes of dementia see Table 10 for acquired causes of dementia reversible causes: Wernicke-Korsakoft medication (benzodiazepines, beta-blockers, anticholinergics), heavy metals, hepatic or renal failure, Wilson's Disease, B12 deficiency, 1'/-.l.- glucose, 1'/.J.. cortisol, thyroid dysfunction, NPH, depression (pseudodementia), brain tumour, subdural hematoma must rule out delirium

geriatric giants incontinence/falls/polypharmacy memory and safety (wandering, leaving doors unlocked, leaving stove on, losing objects) behavioural (mood, anxiety, psychosis, suicidal ideation, personality changes, aggression) ADLs and IADLs cardiovascular, endocrine, neoplastic, renal alcohol, smoking OTCs, herbal remedies, medications (sedative hypnotics, antipsychotics, antidepressants, anticholinergics), compliance, accessibility history of vascular disease, history of head trauma collateral history is usually very helpful



Ambulating Toileting Hygiene

Acc:ountilg Food preparation


Physical Examination
blood pressure hearing and vision neurological exam as directed depending on risk factors and history MMSE or MOCA + clock drawing +frontal lobe testing (go/no-go, word lists, similarities, proverb) + Baycrest Neurocognitive Assessment

depends on suspected etiologies (see Tables 9 and 10) CBC (note MCV for evidence of alcohol use), glucose, TSH, B12o RBC folate electrolytes, LFTs, renal function, lipids, serum calcium CThead MRI as indicated as clinically indicated- VDRL, HIY, ANA, anti-dsDNA, ANCA, ceruloplasmin, copper, cortisol, toxicology, heavy metals issues to consider failure to cope fitness to drive caregiver education and stress respite services and day programs power of attorney

Villlmin 112 Deficiency Symp1D1111 Mllcroqlic llnemia Confusion or change in men1111 sta1111 {if lldwnced)
Dlcreaud vibnrtion

Oistal numbnllill and parlllllmia Weakness with UMN findings Dianhea. anorexia, pallor, SOB


advanced directives (DNR)

N12 Neurolo8Y

Behavioural Neurolo8Y

Toronto Notes 2011

Teble 9. Common Ceuses of Dementi

It' Dtmentill DDx

Primuy llegananrliVB

Key Cli1icll Fellures

Allheiner's disease
Lewy body disease

VITAMIN D VEST V"rtamin deficiency (812. folatll, thiamine) lntnlcranilll tumour


Memory impairment Aphasia, apraxia, agnosia Hallucinations Parkinsonism Fluctuating Disinhibition, parsiMIIiltion Decreased social Progressive non-fluent aphasia Memory relatively spared Chorea Abrupt onset StEpwise de!Eiionrtion Dysexecutive syndrome Focal neurological findings Systemic S&S Dl vasculitis


(hulld injury)

Anoxia Metabolic (diabetes) fnflclion (pollti11C8p/llllitis, HIV) Nonnll pressure hydrocephalus

Duganendive (Aizhuirne(s,

d11111Bntia (e.g. Pick's disease)


Huntington's, CJDJ


Endocrine (hypathyruid)
Space occupying lesion (chronic

Huntington's disease Multi-infarct d11111Bntia

Molecular testing MRI,SPECT


Toxic (alcohol)

eNS vasculitis

ANA; ANCA; RF MRI AngiJgraphy

Teble 10. Acquired Causes of Dementia

Etiology Key Clinical Features
Fever, headache, nausea Localizing neum Chronic Chronic abscess HIV Creutzfelt.Jacob disease Syphilis FIMII", headache Increased ICP Localizing nauro signs See Dil!!!ll, 1029 Rapidly progressive, myoclonus Ataxia, myoclonus Trauma llx Increased ICP, papilledema Localizing naum signs See Rheumatoloov, RH9 lncreaed ICP Localizing neum signs Systemic S&S of cancer LP;MRI CT contrast


Chronic meningitis

LP + investigetions

HIV serology EEG LP WRL CT (non-contrast)


Diffuse axonal shear, epidural hematoma, &Ubdural hematoma SlE Mass effect/edema, hemorrhage, seillft Paraneoplastic

MRI; ANA, anli-dsllNA CT contrast MRI Ani).Hu antibodies


Alzheimer's Disease (AD)

see P&ycbiatcy. PSIS
Definition progressive cognitive decline interfering with social and occupational functioning characterized by the following 1. anterograde amnesia - impaired ability to learn new information 2. one of the following cognitive disturbance a. Aphasia -language disturbance b. Apraxia - impaired ability to carry out motor activities despite intact motor function c. Agnosia - failure to recognize or identify objects despite intact sensory function d. Disturbance in executive function - planning, m:ganizing, sequencing, abstracting Pathophysiology genetic factors a minority (<7%) ofAD cases are familial, autosomal dominant 3 major genes for autosomal dominant AD have been identified: amyloid precursor protein (chromosome 21) presenilin 1 (chromosome 14) presenilin 2 (chromosome 1) the E4 polymorphism of apolipoprotein E is a susceptibility genotype (E2 is protective)

4 A"lllllf IIIII D If AD

Anterograde amnesia
Aphasia ApiiiXil

Disturbance in uecutiva function

Toronto Notes 2011

Behavioural Neurology

Neurology N13

pathology (although not necessarily specific for AD) gross pathology diffuse cortical atrophy, especially frontal, parietal, and temporal lobes microscopic pathology senile plaques (extracellular deposits of amyloid in the gray matter of the brain) neurofibrillary tangles (intracytoplasmic paired helical filaments with beta-amyloid and hyperphosphorylated Tau protein) biochemical pathology 50-90% reduction in action of choline acetyltransferase

1/12 of population 65-75 years of age l/3 of population >85 years of age accounts for 60-80% of all dementias
Risk Factors

family history of AD
head injury

low education level

smoking aluminum (controversial) Down's syndrome
Signs and Symptoms

cognitiveimpairment memory impairment for newly acquired information (early) deficits in language, abstract reasoning, and executive function psychiatric manifestations major depressive disorder {5-896) psychosis (20%) motor manifestations {late) parkinsonism (consider Lewy body disease)

perform investigations to rule out other causes of dementia as necessary EEG: generalized slowing (nonspecific) MRI: dilatation oflateral ventricles; widening of cortical sulci SPECT: hypometabolism in temporal and parietal lobes


acetylcholinesterase inhibitors have been shown to improve cognitive function donepezil rivastigmine (Exelon), galantamine (Reminyl) relative contraindications: bradycardia, arrhythmia, CHF, CAD, asthma, COPD, ulcers, or increased risk of ulcers and GI bleeding galantamine is contraindicated in patients with hepatic/renal impairment memantine (Ebixa) is an NMDA-receptor antagonist that has some benefits in later stage AD other - although efficacy not proven ginkgo biloba Vit E (caution: >400 IU/day associated with excess mortality; Ievell evidence) symptomatic management low dose neuroleptic trazodone for sleep disturbance antidepressants

progressive mean duration of disease 10 years

Lewy Body Disease (LBD)


progressive cognitive decline interfering with social or occupational function; memory loss may or may not be an early feature one {possible LBD) or two {probable LBD) of the following: fluctuating cognition with pronounced variation in attention and alertness recurrent visual hallucinations parkinsonism

Nl4 Neurolo8Y

Behavioural Neurolo8Y

Toronto Notes 2011

Etiology and Pathogenesis Lewy bodies (eosinophilic cytoplasmic inclusions) found in both cortical and subcortical structures Epidemiology 15-25% of all dementias Signs and Symptoms :O.uctuation in cognition with progressive decline visual hallucinations parkinsonism repeated falls sensitivity to neuroleptic medications (develop rigidity, neuroleptic malignant syndrome, extrapyramidal symptoms) REM sleep disorder Treatment acetylcholinesterase inhibitors (e.g. donepezil) Prognosis typical survival3-6 years

Frontotemporal Dementia (FTD)

Definition progressive dementia characterized by core symptoms of either disinhibition and emotional lability or of apathy and detachment Etiology and Pathogenesis gross pathology atrophy of frontal and temporal poles microscopic pathology Pick bodies (intraneuronal inclusions containing abnormal Tau proteins) Epidemiology 10% of all dementias Signs and Symptoms core features behavioural disorder impairment of personal conduct and of regulation of social interactions decline in personal hygiene and grooming mental rigidity/inflexibility perseverative and stereotyped behaviour speech and language altered speech output (economy or pressure of speech) echolalialperseveration physical signs primitive reflexes (ie. pout, grasp, palmomental, glabellar) parkinsonism Investigations MRI/SPECT - frontotemporal atrophy/hypometabolism

Creutzfeldt-Jakob Disease (CJD)

Definition rare degenerative fatal brain disorder Pathophysiology prion proteins causing alterations in the brain such as spongiform changes, astrocytosis and neuronal loss Epidemiology rare (1 in a million), peak incidence between 50-70 years old

Toronto Nota 2011

Neurology NlS

Clinical Presentation sparadk CJD: rapidly progressive demenling illness causing death within months, associated
with myoclonus

cerebellar ataxia cxtrapyramidsl signs aldnelk mutism and cortical bUndness sometimes occur
fatalwlthinlyear EEG: triphasic compleus

rule out treatable dementia, neurologic exam, EEG, MRI only wsr.y to confirm diagnosis is brain biopsy/autopsy


sparadk CJD: most common form (8596), no risk facmrs hereditary CJD: family history or tests positive fur genetic mutation (5-10%) acquired CJD: transmitted via exporure to prion in nervous system tissue (<1%) Iatrogenic CJD transmitted In organ transplants, InJections (human growth hormone
products), electrodes
variant: earlier onset, more psychiatric symptoms, Longer duration, ab&ence of triphasic

Prion prollins have 11 normll fonn and 111 irnc:lioua form. The inflctio1111orm iJ aln:nmally fDided and leads tD abnormal fDidina af no11111l prian pra1Ji111. Thae
aln:lrmally fDided prgteinIIVIII'8glllll

compleus on EEG (Le. Mad Cow disease) kuru: historically due to cannabalism in Papua New Guinea

laadilll tD nUGnll loa.

panencephalopathic form: primarily seen in Japan, progresses over years Histopathology sponglform changes, astrocytosls and neuronal. loss occur sporadically Treatment no known treatment

Normal Pressure Hydrocephalus

see NeuJ'OS11IFI'.Y. NS7

NPH Prog-bl llf Cl-11: Triad


A11DciWA!nxil af Damantia




Th&laft: han. . . ia domir-.ntftw

an acquired disturbance of language characterized by errom in speech production, writing, comprehension. or reading

IIIIICJUIIII in Iimas! Ill riF!-Mnded

people and 70% of lllfi-Mnded PIIOP'--

Neuroanatomy of Aphasia Broca's area (posterior inferior frontal lobe) involved in speech production (expressive) Wemick.e's area (posterior superior temporal. lobe) used for annprehension oflanguage (receptive) angular gyrus is responsible fur relaying written visual stimuli to Wernicke's area fur reading
comprehension the arcuate fascl.culus association bundle connects Wernicke's and Broca's areas >9996 of right-banded people have left hemisphere language representation 7096 ofleft-handed people have left hemisphere language representation, 1596 have right hemisphere representation, and 15% have bilateral representation
Assessment of Language asseaament ofcontext handedness (writing, drawing, toothbrush. sdsllors) education level native language learning difficulties assessment for aphasia 1. spontaneous speech fluency paraphasia&: semantic ("cbm for "tablej, or phonemic ('"clable" for "table") 2. repetition 3.namlng 4. comprehension (auditory and reading) 5. writing 6. neologism&
W.micb's area: poetllrior apect af 1" tampan! IJYIUII

Figure 12. Broca's and Wemlcb's Ar...

Nl6 Neurolo8Y

Behavioural Neurolo8Y

Toronto Notes 2011


Apbasilllocalizes 111e lesion to the dominant cerabral bemllpbare.

Table 11. Approach to Aphasias


Good Good Poor Good

Naning POor POor

Llsian l.oclizllian I'Dsterior irmor frontal lobe


No...ftuent No...nuent


1. Fronlllllobe watershed between MCA and ACA territories 2. \1\otita matter lesions deep to (1)
Combined sensory and motor tllnscortical Posterior infaior frontal lobe AND posterior superior temporal lobe


No...nuent No...ftuent Fluent Fluent Fluent

Poor Poor Poor Good Poor

Good Poor Poor Poor Good



Canduc:tion Scn.aryTCA

Relatively Spared POor Relatively Spared Poor

Posterior superior len1Jmllobe Arcuate fasciculus

1. Subcortical temporopilistal 2. Temporoparietal watershed between MCA and PCA taritories

Numerous possible locations






II"B typicllly ISIOCilted Mil carablllllllllllil (a.g. post-MI, CO poilonif'G, hypabrllliln)

most recovery from stroke-related aphasia occurs in first three months, but may continue for >1 year with recovery, the type of aphasia may evolve poor prognosis: global aphasia

inability to perform skilled voluntary motor sequences that cannot be accounted for by weakness, ataxia, sensory loss, impaired comprehension, or inattention

Clin icopathologic:al Correlations

Table 12. Apraxia

Hemi1pheres Lalt
Right and left Right and left Right
!Ill merely tile illlbiily Ia canstruct. cRw, dresl.

Ideomotor ldelliOIIII
Canlbuctianal Dressing

Inability to parforrn skilled laamed motor sequencas Inability to sequence actions Inability to draw or consbuct Inability to dress

Blowing out a mall:h; combing one's hair Preparilg and mailing an envalope Copying afigure Dressing

specilil:llyla the inllbily Ia c.ryoutthe lelmed ..-nts iMJiwd in conslnrjjon, drMing, M11yskilll uida from plllliln naedad to canyiMthesaiiSb.

disorder in the recognition of the significance of sensory stimuli in the presence of intact sensation and naming

'IbroDlo Nota 2011

Bebaivoaral. Nearology/Craaial Nerve Defi.dh

Neurology Nl7

Clinicopethologic:l Correl.tions
Tillie 13. AaDiils
Apen:apiM VIIUII Aplla Aaacillila \'111111 Apllil

lnaiJiity to l1lllle or demanslrale 1he use mill object jJ'BIIIIIIad vilully zt to dilllarled visual pan:aptian Recognilian by tiU:h 181011ils intllc:l

Lisian BIBIBal


... ' ,
Pariml '-ii!M Lssians of1he dominant Pllrietalloba n chnctlrizBd by Gamnlll!"a Syndro1111: acak:ulia, agraphia,. m;.r agnDBia, and lsft-right llsarianbdiDR. l.eliOM of1ha pwillll IDIIe are clwBI:IIrized by 11111111et. .,D81Jt1naaia. and cartical 1111n111ry lOIS.


lnalility Ill ranun abjact prann18d vi&ualy 2"to disCIIIIBct batws111 viul CDitax 111d III!PgB li8IIS Viul JIIIC8pliorr is inlllct 111 dllmoiiiba18d by viul matching lnaiJiity to ra:ognize firnililrrfaces iJ the pesen:e of Biatenrl accpjal!lqJonrlanm or r9i iiaior
inllct vi...l pen:eptian and inllct auditory IIICO(Jitian

tampa10-accipitll ragian
Anlaillr pll'ietal llbe in 1he llmsphere app01ita tha lffactad hind

CabJr . . . . . lnaiJiily to pan:aive cHI'

Figar Aplasia

lnaiJiily to idediy objects by touch lnaiJiily to racagniza, 11111111, and pailt to Dial filga!s

llaminant hemisphara

Cranial Nerve Deficits

CN 1: Anosmia
Cllnlc:al Features absence ofsense ofsmell associated with a lo98 of taste usually not recognized by patient ifit is uni1atera1 Classification
D8l8l: odours do not reach olfactory receptors because of physical obstrudion heavy smoking, chronl.c .rbinitts, sinusltis olfadory neuroepithelial: destruction of receptors or their axon filaments intluenza, herpes simplex, intm"eron treatment of hepatitis C virus, atrophic rhinitis (leprosy) c:entral: lesion of olfactory pathway Kallman syndrome, albinism, head injury, cranial surgery, SAH, chronic meningeal inflammation, meningioma, aneuryam. Parkinson's diaease

msta. considrr rnailglring.
If 1111111mill il nlll: UlociiiiBd wi1h loa af

lf.lllmanrflsyndrorne ila conganitll dilordrr of ..,..,. and
hypoganiiiiDinlpil: hypogan..ilm.

CN II: Optic Nerve

see Neuro-Ophthalmology. N20






\ JR



..... SO
0 Shiny H. Lai Zllll&

CN Ill: Oculomotor Nerve

Clinic:al Features E.lci!Macle ptosis, resting eye position is down s.nd out'" (depressed s.nd abducted), pupil dilated (mydriasis)

Figun 13. Dilgnastic PasitiDns Df GilD 1D lsola1B Primary Ac:tio uf

Common Lealona

midbrain: bilateral with contralateral pyramidal signs mydrlasls posterior commwlicating artery aneurysm: early mydrlasis then CNm palsy cavernous sinus (internal carotid aneurysm, meningioma, slnua thrombosis) ischemia ofCNIII (DM, temporal arteritis, HTN, atherosclerosis): pupil sparing

Pupry cOMiril:blrfibiVII&re on lha par1ohalllllllpiCI: af CNIII au cornprlllion of the neml... to mydriQia while infan:lion (mr.cting canlnl of CIIUIII pupilllry



:mwr-----IV , __ _ _ 1/1 C31llid .tary r----lnt.nlll




L.eeions iRVGivilg tha C'8V8111DU8 liar1 111M pallliea of Ill. 1\f. Ill. V1 and V2 as Wflllas pain and proptosis.
IBid 1o


Figun 14. Canrnaus SEa

Nl8 Neurolo8Y

Cranial Nerve Deficits

Toronto Notes 2011

CN IV is the only mnill nerve that exits pcmaio!ly 111d cro111111 thu midlinu. A CN IV lesion may cause a con1nllateral

CN IV: Trochlear Nerve

Clinical Features diplopia (with downward and inward gaze), minimized with head tilt to opposite side patient may complain of difficulty going down stairs or reading Lesions common: ischemic (DM, HTN), idiopathic, trauma (TBI or surgical), congenital other: cavernous sinus lesion, orbital fissure (tumour, granuloma)


..... ,
CN IV is at ri&k of 1rlluma during

neurosurgical procedures ilvalving the midbrain becausu of it$ long in1rllc11111illl


CN V: Trigeminal Nerve
Lesions trigeminal neuralgia, herpes zoster, cavernous sinus, orbital fissure, trauma. cerebellopontine angle tumours, demyelination, syringobulbia, metastatic infiltration of nerve, ipsilateral brainstem lesion, contralateral parietal lesion Trigeminal Neuralgia (Tic Douloureux) excruciating unilateral paroxysmal shooting "electricn pains in trigeminal root territory usually in V3 distribution V 1, V 2 normal sensory exam etiologies: idiopathic, compression by tortuous blood vessel (SCA), cerebellopontine angle tumour (5%), multiple sclerosis (5%) pain lasts seconds/minutes over days/weeks; remits for weeks/months triggers: touching face, eating, talking, cold wind, shaving, applying make-up F > M; usually middle-aged and elderly medical treatment carbamazepine; narcotics do not help if medical treatment fails (order increasingly invasive): gamma knife, invasive percutaneous denervation (radiofrequency/glycerol), percutaneous balloon microcompression, microvascular decompression rule out structural lesion, multiple sclerosis or vascular lesion with MRI

H1111 later of Tri111111inal Nem: typi:lllly illVIIMs Vl (opthalmic division].

Hutcbions Sign: tip of no.e involvllllllll; pr8dicts comul involvement.

CN VI: Abducens Nerve

Clinical Features inability to abduct the eye on the affected side patient complains ofhorizontal diplopia. worse on ipsilateral lateral gaze Common Lesions pons (infarction, hemorrhage, demyelination) - associated with facial weakness and contralateral pyramidal signs tentorial orifice (compression, meningioma) - false localizing sign ofincreased ICP cavernous sinus (carotid aneurysm, thrombosis) vascular- may be secondary to DM, HTN, or temporal arteritis congenital- Duane's syndrome

it''has 1h1 longast in1rllcrsnial couru CN VI

lDid is wlnerable to increased ICP, mating a1&111 localizing sign.


,,.)-----------------, ,

CN VII: Facial Nerve

Clinical Features ipsilateral facial weakness (involuntary and voluntary) impaired lacrimation, decreased salivation, numbness behind auricle, hyperacusis, taste d)15function of anterior 2/3 oftongue Investigations brainstem (LMN) versus cortical (UMN) symptoms and signs help localize lesion Differential Diagnosis idiopathic= Bell's Palsy, 80-90% of cases (see OT23) other: temporal bone fracture, EBV, Ramsay-Hunt (HSV), otitis media/mastoiditis, sarcoidosis, DM mononeuropathy, parotid gland disease

Forehlllld i15p11recl in a UMN CN VII lasion due to bilateral innervation from cerabral hemispheres.

'IbroDlo Nota 2011 A. Ftlcill n..,. llliDn (Balra 1118krl

Cranial Nerve Defidb

B. S.Uclaar llliDn

Neurology Nl9

Figure 15. UMN VL llt'IN fllcill N8M1 Palsy

CN VIII: Vestibulocochlear Nerve

CN IX: Glossopharyngeal Nerve
Clinical Features sharp paroxy8l1l8l pain of posterior pha.rynx radlating to ear. triggered by swallowing taste dysfunction in posterior 113 oftongue
absent gag re:flex (dysphagia)

wt.IICI'IIIIi!g for th8 Prlll8nce D1 and - i n g rillk fill' IIPildian. tha p181811CB rJ I gllg raftM ia illlll'icillnt llltlur. the cornet tilt il1o DIIIIMI tha plltillll Ginldng WIQr !rum a. c:up a.nd IDDting for coughing. choking. or "wtlness" Df vaice.

Treatment carbamazepine or surgical ablation of CN IX

D...ralllla.llll8g.... ri.._CniUI llarw dafi5b (CN IX, X,JO,JOI)

CN X: Vagus Nerve
Clinical Features
dysphagia (palatal and pharyngeal weakness) dysarthria (laryngeal weakness): inability to produce understandable speech due to impajred phonation (laryngeal sound production) and/or resonance (the alteration of sounds in the cavity between the larynx and the lips/nares) secondary to impaired motor control over peripheral speech organs

llllrlll:nniiVIIUIIIMe: mngioma.
I'IIIUrD!Inmll, miiBibllll,

IIIIBDrrrj!llilil, meningitis lniaiiMI: strDU, demy11inlltion. IYrinaotutil, poliomyelilit. llllroeytuma Nadc trau11111, .urgary, tumour11

Talala 14. Cllluilbtion af Dyar1fuill


NDITIIII is inilillhld when lh IDIIfJI 1h1'8W1a bolus blt:lt

Slured. indistinct speech

Plrlicul.- difticully Mill villltory "R" Dilliculty consiiiBlt& purilcad by tlllgus a1d l_.,ill CIIIIOIIIID pnub:sd by lips

Mo1Dr ne1.1111 (e.g. Al.S) f'a1Dnl niiVI (a.g. GBSI NIUUIII&CUIIr junction (8.11- MG) Myapathv (a.g. DMfMI

into the pa.lsbil8ldlwlly-tongue mowm111111ra innarwbld udllli....y

by CN XII. Tha bolus slimuiiiiBs tha 10ft palal8 to slsva18 llld the bolu is dlllldlld into 1ha Of1IPiwynx. tt.c1: the
phlryngalll conslric1Dn cunnct, tha

Slow 111d manu!GKius

Slllliled or

TIDID.. Demyelination DlgenaretiCII



llld the weal conls clo11. SWIIowing diiPBnda on liferent inlarmllion vii CN V, IX, and X and mo1or action via CN v; VIL IX. X. and XII.

rhythm lmprap.- s1111ss

Canballllr disease Canballar outflow tnlct diSIIIII

Connection& il the nucl- Df the

tralrtulsolm.ius i1 the meciiAI. in prtlxi'nily to the l'llpillloly l:lllntnl, u;l

the swallcrwi'lg centra. Swallowing 111d n coordinllecl1o prevent IIIJinllion.

N20 Neurolo8Y

Cranial Nerve Defu:its/Neuro-Ophthalmolo8f

Toronto Notes 2011

Table 14. Classification of Dysarthria (continued)



DealiSCendo volume

Parkinson's disease Other causes of parkinsonism (see Movement Disonlets)

llmtington's disease

Prolonged senlllnce segments intermixed with silences Variable, improper stn!ss

Dystonia muscuiCIUm deformans Other hyperkinetic extrapynrnidal disarders (see MavemenrDisonfets)

Bursting quality
Dystonic Slow speaking rate Prolonged individual phonemes
"Abbmiatians: ALS- amyrAJopliic lltllllscllrolis; GBS -Guillain-Bami l','lllroma; MG -llftllllhril gmis; IJ.l-dlnni!Dmyasitis; PM-polymyositis

CN XI: Accessory Nerve

Clinical Features
ipsilateral shoulder drop, weakness on turning head to contralateral side

CN XII: Hypoglossal Nerve

Clinical Features
tongue deviation toward side oflesion chronic LMN lesion: ipsilateral tongue atrophy and fasciculations

Abnormalities of Vision Acute Visual Loss
ophthalmologic: acute angle closure glaucoma, vitreous hemorrhage, retinal detachment optic nerve: optic neuritis, anterior ischemic optic neuropathy (arteritic, non-arteritic), compression by space occupying lesion (e.g. aneurysm) vascular: TWamaurosis fugax, central retinal artery or vein occlusion, carotid-cavernous sinus fistula CNS: stroke, optic tract/chiasm lesion, migraine infectioD}inflammation: endophthalmitis

Optic Neuritis

optic Disc Edema, N21, Multiple Sclerosis, N 49


Anterior Ischemic Optic Neuropathy


If you ill'll8Cl the diagnolis of qiant cen arteritis do not wait for biopsy rasLJts. Beqin treatment immediatelyl

see also Optic Disc Edema, N21 clinical presentation: painless vision loss over hours to days non-arterltic: (NAION): vision loss due to atherosclerosis arteritic (AION): normally due to giant cell arteritis (see RheumatoloGY. RH17)

Amaurosis Fugax
see Qphthalmology. OP37 and Stroke section, N44

Central Retinal Vein Occlusion (CRVO)

see Qphthalmology. OP24

'IbroDlo Nota 2011


Neurology N21

Optic Disc Edema

Tillie 15. Commo1 Causes of Opac Disc Edell
Optic Nlllllll




llld cohu vision Pail (esp with eye



Rapid Pf'OW888iv8 cemal le 'liullou visimllaa with .J, acuity

>50 Unillleralecuta field datact M1h .J, cokuvision

>50 IWIIteral Vllilllle vision lou

CardiDvascular risk !aetas

Heaclschl!, foil( hx:al neurologicll deficits NoRAPD

DiiC retiwl hemanllage, no VIllOUS jQsatians

taldam. jaw deucicetion

If GCA: headache,

. .I

if llllerior

RAPD No RAI'Il Pale llll!rnenllll diiC ad111111, Swollen diac, V8IIDUJ relilal Ct. flml 11191f98111R, retiMI hemanhages hlllllllhllge
Ghlll cell arteritis
Associated with vascUopathy


MS. vial




Calsidar ASA I non..taritic; optimim risk factors.l8duce mrnids I arteritic lOP. :t laser

Optic Disc Atrophy

etlologln; glaucoma, AION, compressive tumour, optic neuritis, Leber's hereditary optic neuropathy, congenital praartatioa: disc pallor, low visual acuity, peripheral vision defect. decreaeed colour vision treatment: none (irreversible), aim to prevent

Abnormalities of Visual Field

monocalar scotoma: an area ofabsent or diminished vision within an otherwise Intact visual field

hemianopsia: loss ofhalfof the visual field homonymoWI: loss of either the right or left half of the visual field in both eyes bitemporal: loss of both temporal visual fields (lesion ofclrlasm) quadr.mtanopsJa: loss ofone quarter of the visual :field

BrTEMPORAL HEMIANOPSIA chiasmallesion in clilldren: craniopharyngioma In middle aged: pituitary mass in elderly: meningioma

retrochiasmallesion the more congruent. the more porterior the lesion check all hemiplegic patients fur ipsilateral homonymous hemianopsia (e.g. left hemisphere -+right visual field defect)

i Q
Figun 1&. Cherlll:telistic Visl Field Dlfecbi with 1.81iaas Alal!g the Viull Plthvny

N22 Neurology


Toronto Notes 2011

Abnormalities of Eye Movements Disorders of Lateral Gaze

Etiology brainstem infarcts multiple sclerosis tumours Pathophysiology voluntary eye movements are triggered in the frontal eye fields, located anterior to the precentral gyrus, bilaterally in the frontal lobes each frontal eye field controls voluntary saccades to the contralateral side via connections to the contralateral paramedian pontine reticular formation (PPRF) a unilateral lesion in one frontal eye field: prevents voluntary saccades to the opposite side, eyes deviate toward the side of the lesion can be overcome with doll's eye maneuver a unilateral lesion in the PPRF in the pons: prevents voluntary saccades to the ipsilateral side, eyes deviate away from the lesion cannot be overcome with doll's eye maneuver seizure involving a frontal eye field: cause eye deviation towards the opposite side



A lesion in a cerebral hemisphere causes eyes to "look away" from the hemiplegia, and to look towards the lesion. A lesion in the brainstem causes the eyes to "look toward" the side of the hemiplegia, and to look away from the lesion.

Internuclear Ophthalmoplegia (INO)

Etiology MS (most common; see Multiple Sclerosis, N49) brain stem infarction neoplasm AV malformations Wernicke's encephalopathy Pathophysiology results from a lesion in medial longitudinal fasciculus (MLF) which disrupts coordination between CN VI nucleus in pons and the contralateral CNIII nucleus in midbrain -+ disrupts conjugate horizontal gaze
Standard {normal}

Right {normal}

Clinical Features on gaze away from the side of the lesion: I) adduction ofipsilateral eye is impaired; 2) full excursion of contralateral eye in abduction but with monocular abduction nystagmus cannot be overcome by caloric testing accommodation reflex intact may be bilateral upbeating nystagmus on upward gaze often present

Left {abnormal}

Monocular mostly due to relatively benign optical problems (refractive error, cataract, functional) Binocular cranial nerve palsy (see Cranial Nerves, N17) CN III (oculomotor) DM, aneurysm, tumour, trauma isolated CN III palsy with pupil sparing usually due to DM and most will resolve spontaneously in several months isolated CN III palsy with pupil involved usually indicates compressive lesion (especially posterior communicating artery aneurysm) CN IV (trochlear) DM,trauma CN VI (abducens) DM, tumour, trauma, raised ICP (false localizing sign) muscle Graves' ophthalmopathy neuromuscular junction myasthenia gravis (MG) (see Myasthenia Gravis, N32) other orbital trauma, tumour Wernicke's encephalopathy Miller-Fischer variant of GBS leptomeningial disease

Vergence {normal}
Shelley Wall 2003

Figure 17. Internuclear Ophthalmopliegia

Diplopia worse at end of the day suggests myasthenia gravis {e.g. fatiguable}.

If only diplopia on extremes of gaze, cover each eye in isolation during extremes of gaze. The covered eye that makes the outermost image disappear is the one with pathology.

Toronto Nota 2011


Neurology N23

definition: rapid. involuntary, small amplitude movements ofthe eyes that are rhythmic in nlrtnre direction of nystagmus is defined by the rapid component of the eye movement can be categorized by movement type (pendular, jerking, rotatory, coarse) or as normal vs.

Abnormalities of Pupils
Relative Afferent Pupillary Defect (RAPD) (Marcus-Gunn Pupil)
see also Ol!hthalmolop. OP33
Definition a fallure ofdirect pupillary responses to light. caused by a defect In the visual afferent pathway anterior to the optic chiasm clinical testing swinging llgbt test swing light from one eye ID the other, both pupils should constrict initially when normal side is illuminated. both pupils constrict

when damaged side is Illuminated, both pupils paradoxically dilate because the damaged
eye perceives less light relative to normal eye pupil reacts poorly to light. and better to accommodation

differential diagnosis

optic neuritis is the most common cause of RAPD other causes: optic nerve compression, large retinal detachment. central retinal artery/vein

occlusion, advanced glaucoma

PreC8atal nucleus ( 1 1 1 - - - - -+-.H-----"?'\


Namll ....... Dii'IICt raspons1 CGn18IIIIUII reapo!118


CGn81riction of

lllmulltad f10J8


COIIItriction of IDIIimulllllld f10J8

Figu.. 18. RAPD

N24 Neurology




Horner's Syndrome

..... '
H-' Sylllnne PIDIIil


a sympathetic defect clinical features: partial ptosis (drooping eyelid), miosis (conrtricted pupil), anhydrosis (lack of sweating), and apparent enophthalmos lesions occur anywhere along the sympathetic pathway on the affected side 1st-order neuron (central): hypothalamus, medulla (brainstem stroke), spinal tumcnu; MS, intracranial tumoUIS, syringomyelia 2nd-order neuron (preganglionic): apical lung cancer (Pancoast's tumour), paravertebral mass, carotid artery dissection 3rd-order neuron (postganglionic): cluster headache, cavernous sinus IIlllli8, trauma (lncluding surgical) clinical confirmation with cocaine test cocaine does not dilate a miotic Homer's pupiL Cocaine blocks the reuptake of nora.dtenaline. which dJlates a normal pupil central vs. pre-ganglionic vs. post-ganglionic paredrine (hydraxyamphetamlne. stimulates noradrenaline release) will not dilate in a case of post-ganglionic lesion, but will dilate ifthere is a pre-ganglionic or central lesion no test to di1ferentiate central from pre-ganglionic lesion

Short ciery


c.rvical u-I'Giion



F"IJirl 19. Sympatflatic

of Pupilary Dlatian

clefiDltion: unequal size of the pupJls see Qphtha1moloo OP31

Toronto Notes 2011

Movement Disorders

Neurology N25

Movement Disorders
Overview of Movement Disorders
Tabla , 6. Muvamant Disorder Definitions
Aladhisia Altlrilil
A1hltolis Subjective restlessness relieved by stereotypic movements (e.g. squinnilgl Loss of rruscle contraction (negative myodonusl Slow writhing movements, especially distally Slow ami/or small alflllilude movements Rapid jerky movarnentthat looks semipuposeful Excessive movements associated with neuroleptics Co-corrtnlction of and antagonists causing sustained twisting movements Episodes of halted mCJIDr action. aspacially cllrilg walking Unilateral violent flingir4 movement Briel muscle group contraction 1hat is either focal, segmental, or generalized Muscle quivering Acceleration of movements Stereotyped actions due to inner urge; can be suppressed Rhythmic alternating movements




Dysblnil Free.dng

DllllblngM-.nt IIVPerldnul: BXCess of movement (i.e. most movements sean in movarnent

[i.e. bradykinesia and freezingl

HvPokilllllia: reduction in movarnent

Myoclonus Myukimil





Soma myoclonus is rtim!Ws sensitive and can be induced by noise, movement, light, vi11UIIl1hreat, or

Function of the Basal Ganglia

the striatum (caudate and putamen) is the input of the basal ganglia. It receives input from the cortex and thalamus to inhibit the globus pallidus pars interns (GPi) and substantia nigra reticularis (SNr), promoting movement the GPi and SNr are the output of the basal ganglia. They project fibres to the cortical motor areas via the ventral thalamus (thalamocortical) to prevent excess movement using tonic inhibition (in particular the GPi) the cerebral cortex initiates movement via excitatory (glutamatergic) projections to the striatum, which then activate two pathways: direct and indirect indirect cortex striatum GPe STN GPi/SNr thalamus motor cortex activation ofthis pathway causes inhibition of the thalamus and ultimately prevents movement direct: cortex striatum -+ GPi/SNr -+ thalamus -+ motor cortex activation of this pathway removes the inhibitory effect of the GPi on the thalamus, thereby allowing movement




---- GABA ----- :

Excitatory connections connections

- --- -- --

Figure 20. Neural Connections Df the Basal Ganglia

N26 Neurology

Movement Disorders

Toronto Notes 2011

Splenium of corpus callosum

Lucy Zhang 2011

',.l-------------------, '
In a young patient ( <45) must do TSH (thyroid disease), ceruloplasmin (Wilson's disease), and CT/MRI (cerebellar disease) as indicated by type of tremor.

Figure 21. Horizontal Section of Basal Ganglia

Approach to Movements Disorders

1. Describe the movements. Classify each as hyperkinesias or hypokinesias 2. Name the movements (see Table 16) 3. Consider the differential diagnoses for the movements named

Alcohol dampens essential tremor. Alcohol potentiates intention tremor.

',..)-------------------. '
>90% of essential tremor does not need treatment.

Differential Diagnoses 1. Tremor: a. Postural: physiologic, anxiety, sedative/alcohol withdrawal, drug toxicity, heavy metal poisoning, carbon monoxide poisoning, thyrotoxicosis, benign essential tremor, cerebellar, Wilson's disease benign essential tremor is a common autosomal dominant trait that presents as a bilateral postural tremor of the vertical axis, especially in the upper extremities b. Intention: brainstem lesion, cerebellar lesion, alcohol, anticonvulsants, sedatives, Wilson's disease c. Resting: Parkinsonism, Wilson's disease, mercury poisoning
Table 17. Approach to Tremors
Resting Body Part Characteristics Worse with Associated Sx DDx Distal UE 3-7Hz pill rolling Rest while concentrating "TRAP" IPD, Parkinsonism, Wilson's disease Sinemet, anticholinergics, surgery, DBS Postural Uf/head/voice 612Hz fine tremor Sustained posture (outstretched arms}
Autosomal dominant FHX

Intention Anywhere <5Hz coarse tremor Finger to nose Cerebellar findings Cerebellar disorders, Wilson's disease, alcohol, MS Treat underlying cause

Physiologic, benign essential, drugs, hyperthyroid, hyperglycemic Propranolol, anticonwlsants, primidone

Most common cause of chorea is drug therapy for Parkinson's disease.


2.Chorea: Huntington's disease, neuroacanthocytosis, SLE, APLA syndrome, Wilson's disease, cerebrovascular disease, tardive dyskinesia, senile chorea, Syndenham's chorea, pregnancy chorea 3.Dystonia a. Primary dystonia: familial, sporadic (torticollis, blepharospasm, writer's cramp) b. Dystonia-plus syndromes: dopa-responsive dystonia, myoclonus-dystonia c. Secondary dystonia: thalamotomy, stroke, CNS tumour, demyelination, PNS injury, drugs/toxins (L-dopa, neuroleptics, anticonvulsants, Mn, CO, cyanide, methanol) d. Heterodegenerative dystonias: Parkinsonian disorders, Wilson's disease, Huntington's disease 4.Tics a. Primary tic disorders: transient tic disorder, chronic tic disorder, Gilles de la Tourette, adult onset or senile b. Secondary tic disorders: encephalitis, CJD, Syndenham's chorea, head trauma, drugs, mental retardation syndromes c. Association with OCD and ADHD

Toronto Notes 2011

Movement Disorders

Neurology N27

Parkinson's Disease (PD)


Etiology sporadic: combination of oxidative stress to dopaminergic neurons, environmental toxins (e.g. pesticides), accelerated aging, genetics famllial (10%): autosomal dominant a-synuclein mutations, autosomal recessive Parkin gene or DJ-1 gene mutation Ouvenile onset) .MPTP (neurotoxin) Pathophysiology loss of dopaminergic neurons in pars compacta of substantia nigra, thus reduced dopamine in striatum leading to disinhibition of the indirect pathway and decreased activation of the direct pathway causing increased inhibition of cortical motor areas a-synucleinopathy: a-synuclein accumulates in Lewy bodies and causes neuritis in substantia nigra Signs and Symptoms positive motor rest tremor: asymmetric 4-5Hz "pill-rolling" tremor, especially hands rigidity: lead-pipe hypertonus; cogwheeling due to superimposed tremor negative motor bradykinesia: slow small amplitude movements, difficulty initiating movement related findings: masked facies, hypophonia, aprosody (monotonous speech), dysarthria, micrographia, shuffling gait with decreased arm swing freezing: occurs with walking triggered by initiating stride or barriers/destinations, lasts seconds postural instability: late finding of falls, shuffling gait with acceleration and flexed body cognition: bradyphrenia (slow to think/respond), late finding of dementia behavioural: personality change, decreased spontaneous speech, depression, sleep disturbances,

ley Pukionim


lllJIIIor Rigidity

Aki1181ii-.'bmdykin81ia Postuml instability



Conlldw an Alterllldve Dilgnasis If Atypical Parlcirwo.U.m Poor ruponu to Ldopa Abrupt onset of symptmns
Rapid progression Earlylalls Early autonomic dysfunction

Symmllric symptoms It onut Early age of onset (<50)

Early cognitive impairment FHx of psydliabic/demenling

Re1:ent diagnosis af psychiabic dillllsa History of encephalitis UnUSUII toxin axpDSUI'B ExUnsiv. tlliVII histDry

autonomic: later findings of constipation, urinary retention, sexual dysfunction

Treatment pharmacologic (levodopa/carbidopa). Levodopa is a dopamine precursor, mainstay of treatment carbidopa decreases peripheral conversion to dopamine treatment of early PD: DA agonists, amantadine, MAOI adjuncts: DA agonists, MAOI, anticholinergics (especially ifprominent tremors), COMT inhibitors surgical: thalamotomy, pallidotomy, deep brain stimulation (thalamic, pallidal, subthalamic), embryonic dopaminergic stem cell transplantation levodopa related fluctuation: delayed onset of response (affected by mealtime), end-of-dose deterioration (i.e. "wearing-offu), random oscillations of on-off symptoms major complication oflevodopa therapy is dyskinesias psychiatric (see Ps_ychiatr:y)

Other Parkinsonian Disorders

parkinsonism: akinesia (bradykinesia and low amplitude) often accompanied by rigidity. Tremor is an optional feature, as is postural instability Lewy Body disease (see Behavioural Neurology, Nl3) progressive supranuclear palsy: tauopathy with limited vertical gaze (classically downgaze), early falls, axial rigidity and akinesia, dysarthia and dysphagia corticobasal degeneration: tauopathy with varied presentations but classically presents with unilateral parkinsonism, dystonia/myoclonus, apraxia "alien limbs" phenomenon multiple syatem atrophy: synucleinopathy presenting as either cerebellar predominant (previously olivo-ponto cerebellar atrophy or OPCA) or parkinsonism predominant (previously striato-nigral degeneration). Both are associated with early autonomic dysfunction (previously Shy-Drager syndrome) vascular parkinsonism: multi-infarct presentation with lower body parkinsonism

Huntington's Disease
Etiology and Pathogenesis genetics: autosomal dominant CAG repeat disorder with anticipation of Huntington gene on chromosome 4leading to accumulation of defective protein in neurons pathology: global cerebral atrophy; especially affects the striatum, leading to increased activity of the direct pathway and decreased activity of the indirect pathway

N28 Neurolo8Y

Movement Disorders

Toronto Notes 2011

North American prevalence 4-8/100,000 mean age of onset 35-44 years; but varies with degree of anticipation from 5-70
Signs and Symptoms

typical progression: insidious onset with clumsiness, fidgetiness, irritability progressing over 15 years to frank dementia, psychosis and chorea chorea: begins as movement of eyebrows and forehead, shrugging of shoulders, and parakinesia (pseudopurposeful movement to mask involuntary limb jerking) progresses to dance-like or ballism, and in late stage is replaced by dystonia and rigidity dementia: progressive memory impairment and loss of intellectual capacity mood changes: irritability, depression, anhedonia, impulsive, bouts of violence psychosis juvenile onset (Westphal variant): begins in adolesence with bradykinesia and rigidty with a severe progressive course spanning 5 to 10 years

MRI: enlarged ventricles, atrophy of cerebral cortex and caudate nucleus genetic testing

no disease altering treatment psychiatric symptoms: antidepressants and antipsychotics chorea: neuroleptics and benzodiazepines dystonia: botulinum toxin



most common movement disorder encountered in movement disorder clinics after parkinsonism

worse with fatigue, stress, emotions; relieved by sleep or specific tactile/proprioceptive stimuli ('geste antagoniste: e.g. place hand on face for cervical dystonia) more likely to be progressive and generalize ifyounger onset or if leg dystonia
Batulirun toxin {BOTOXI acts by preventing ACh the neuromuscular junction.

local medical: botulinum toxin systemic medical: anticholinergics, muscle relaxants (Baclofen), benzodiazepines, antidopaminergics (reserpine, neuroleptics); dopamine for dopa-responsive dystonia surgical: surgical denervation of affected muscle, stereotaxic thalamotomy (unilateral dystonia), posteroventral pallidotomy

Tic Disorders
Clinical Classification

motortics simple: blinking, head jerking dystonic: bruxism, grinding teeth, abdominal tension, sustained mouth opening complex: copropraxia (obscene gestures), echopraxia (imitate gestures), throwing, touching vocal tics simple: blowing, coughing, grunting, throat clearing complex: coprolalia (shout obscenities), echolalia (repeat others' phrases), palilalia (repeat own phrases)

dopamine blocker

Toronto Notes 2011

Movement Disorders/Motor Neuron Disease

Neurology N29

Tourette's Syndrome (aka Gilles de Ia Tourette's Syndrome)

Definition according to DSM IV 1. Presence of motor and vocal tic at some point during illness, not necessarily concurrently 2. Multiple tics a day nearly everyday or intermittently throughout 1 year with no tic-free periods greater than 3 months 3. Onset prior to 18 years of age 4. Not due to effect of a substance or general medical condition Epidemiology prevalence among adolescents 3-5/100,000; M>F Signs and Symptoms tics: wide variety that wax and wane in type and severity can be voluntarily suppressed for some time but are preceded by unpleasant sensation that is relieved once tic is carried out psychiatric: compulsive behaviours (associated with OCD and ADHD), hyperactive behaviour, 'rageS: sleep-wake disturbances, learning disabilities Treatment clonidine, clonazepam Prognosis Begins at 5 years progressively increasing until I 0 years; often improves in adolescence and 50% are tic-free by 18 years

Motor Neuron Disease

Amyotrophic Lateral Sclerosis (ALS) (aka Lou Gehrig's Disease)
Definition progressive degeneration of motor neurons causing UMN and LMN symptoms Etiology genetic (5-10% familial, especially SOD1 mutation), viral, autoimmune paraneoplastic, glutamate toxicity, idiopathic Pathology degeneration and loss of motor neurons with astrocytic gliosis bunina bodies (eosinophilic hyaline intracytoplasmic inclusions) in 7096 disorder of anterior horn cells of spinal cord, cranial nerve nuclei, and corticospinal tract Epidemiology 5/100,000 with onset between 40-60 (earlier if familial) Signs and Symptoms limb motor symptoms: segmental and asymmetrical UMN and LMN symptoms of limbs bulbar findings: dysarthria, dysphagia, tongue atrophy and fasciculations pseudobulbar affect or emotional lability sparing of ocular muscles and of sphincters Investigations EMG: denervation (3limbs + paraspinal), reinnervation, fasciculations muscle biopsy: small angulated fibres (ie. denervation), fibre-type grouping rule out cord disease/compression with CT or MR.I Management disease specific: riluzole muscle stiffness/spasticity: baclofen, tizanidine sialorrhea: TCA (e.g. amitriptyline), anticholinergics (e.g. scopolamine patch) pseudobulbar affect: dextromethorphan/quinidine, TCA, SSRI non-pharmacologic: ventilatory support (e.g. BiPAP), early nutritional support, rehabilitation (PT, OT, SLP), psychosocial support Prognosis median survival3 years (longer ifventilatory support), death due to respiratory failure

il'' inconllittlnt with ALS IW FilaSen110ry ax, predomirnnt p11in, bowel or bladder incontinence, cognitive
mllld& wallkm!H.

Denuvation on EMG Fibrillations, lhlrp wavas,

complax repllilive disc:tlarges; raimarvation11111pliluda and

duration of mlllllr units.

N30 Neurolo8Y

Motor Neuron Diseue/Perlpheral Neuropathies

Toronto Notes 2011

Other Motor Neuron Diseases

prograsive muscular atrophy (progras.ivt: bulbar pahy): only LMN symptoms with asymmetric weakness, later onset than ALS, 5-10% of patients in ALS centres primary lateral sclerosis (progressive pseudobulbar palsy): UMN symptoms, later onset, not futal with variable disability; 5-10% of patients in ALS centres spinal muscular atrophy: pediatric disease with symmetric LMN symptoms polll:-polio syndrome: residual asymmetric muscle weakness, atrophy multifocal motor neuropathy: conduction block on NCS, asymmetric LMN symptoms, anti-GM1 Ab, treatable with IVIg

,, ,
DDx of M-neuropltllr Mljlipllll Vasculitis (e.g. PAN), OM, leprosy, ureoidosis, HIV.Iymphoma. Lvm- diMUI, pr8SIIn palsy predisposition (herediWy), multifocal motor neuropathy (pun motor), chronic inflammatory demyeli111.1ing polynauropllhy (ClOP).

Peripheral Neuropathies
monoradiculopatby: dennatomal deficit due to single nerve root lesion due to disc herniation or root compression causing radicular pain polyradic:ulopathy: multiple dermatome deficits due to multiple nerve root lesions most common cauda equina syndrome (ie.lumbosacral roots) plempatby: deficit matching distribution of a nerve plexus brachial plexopathy upper (C5-C7}: LMN sx of shoulder and upper ann muscles (Erb's palsy) lower (C8-Tl): LMN sx and sensory sx of forearm and hand (Klumpke's palsy) DDx: trauma, idiopathic neuritis, tumour infiltration, radiation, thoracic outlet syndrome (i.e. cervical rib) lumbosacral plexopathy (rare, especially unilateral) DDx: idiopathic neuritis, infarction (i.e. diabetes), compression mononeuropatby: single nerve deficit carpal tunnel syndrome (most common): compression of median nerve at wrist symptoms: wrist pain, paresthesia first 3 digits, radiation to elbow, worse at night signs: Tinel's sign, thenar muscle wasting, sensory deficit EMG and NCS: slowing at wrist (both motor and sensory) Bell's Palsy (most common cranial neuropathy): see OtolaeyngolQg}'> OT23 other less common mononeuropathies due to entrapment/compression: ulnar (compression at elbow}, median (at pronator teres), Saturday night palsy (radial nerve entrapment at spiral groove of humerus), obturator (from childbirth), peroneal (due to crossing legs or surgical positioning), posterior tibial (tarsal canal) mononeuropatby multiplex: deficit affecting multiple discrete nerves (asymmetric) most commonly due to diabetes polyneuropathy: symmetrical distal stocking-glove pattern presentation: symmetrical distal sensorimotor deficit affecting longest fibres first (i.e. stocking-glove distribution}, hypotonia; progression of dysesthesia early, weakness later most polyneuropathies are due: to medical conditions like diabetes, renal disease:, substances, toxins, or are hereditary other important etiologies: SLE, mv; leprosy, alcohol, B12 deficiency, uremia chronic inflammatory demyelinating polyneuropathy (CIDP} chronic relapsing sensorimotor polyneuropathy with increase protein in CSF and demyelination (shown on EMG/NCS) course is fluctuating compared to acute onset of GBS treatment firstline is prednisone: alternatives are plasmapheresis, IVIg, and asathioprine critical illness polyneuropathy associated with sepsis and multisystem organ failure; severe sensorimotor axonal neuropathy
Table 18. Diffarential Diagnosis of Symmetric Polyneuropathy Etiology+ V.Cul

Dlabellc Neara,.dlles 1. Axonal (most common): pain> mDior 2. Autonomic: anhydrosis, onhcmatic hypotension, impotence, gaslroplnsis, bowel and blldd1r dysfunction 3. Mononeuropllthy multiplex: ll8MI
4. Cranial niURipelhy: CNIII (pupil sparing) > IV > VI

infarct or compression

..._', ..
DDx of o.r,.llnllting Ntluropllthy GBS, CIDP. paraprotBinemia. dipthlria, amiodarone, storage disaue.. prassura paiiJY predisposition. paraneoplaslic.

Axonal neuropatllies hiiVI decr.ased
amplitude on NCS; dlll'll'(llinlling neuroplllhin hiiVI dlc11111Sed velocity on NCS.


Ototoxic drugs (e.g. aminoglycosides)

should not be given to diabetic&. Sensory neuropattw of feet pr8Y8nt them from adequately compeiiSiting for lass of vestibular function.

Ischemic Ischemic Ischemic AxonaVdemyelination lnfillrative AxonaVdemyalination Demyelination Demyelination Clrunic Clrunic Ctronic Clrunic Clrunic Clrunic







RH17 RH&

sae BtlllliTIIIIIllagy. RH9 see HIV serology Laprosy serology Nerve biopsy Lyme serology LP (1' protsin; no 1' cells) LP (1' protein)


Lyme Immune




Toronto Notes 2011

Peripheral Neuropathies

Neurology N31

Table 18. Differential Diagnosis of Symmetric Polyneuropathy" (continued)


AxonaVdamyalination AxonaVdemyelination AxonaVdemyelination Axonal Demyelination Axonal Axonal Axonal lschemio'axanal Axonal Axonal Axonal Axonal Axonal

Chronic Chronic Chronic Chronic Chronic


lnvesligllions G811111ic testing Anti-Hu SPEP Skelellll bone survey SPEP





Myaloma Lymphoma Monoclonal gammapa1hy Taxin

Bone manow biopsy



SPEP Bone manow biopsy GGT Urile heavy metals

Heavy metals Medications

sw-acute sw-acute sw-acuta

Chronic Chronic Chronic

Drug levels


Hypothyroidism Ranal hlikuu

Fasting glucose, HbA1C, 2hr OGTT

TSH, T4 Lytes, Cr, BUN V'rtamin 812 Urile parphyrins biopsy


Brz deficiency


Porphyria Amyloid

Sw-acute sw-acute sw-acuta

GBS-Qilllin-Bant -polyuteritisnodosa; SLI-systemic ._ RA-me...r.tuid lllhritis; Cll' -IDmic nlmnltory polyrldiciD!aJruplthy; HMSN-hllldllry IRIIIIrsansary nauro]ll1hy; SPB' -sarum pnlblin allclrophDnllis; S- senscny; M- matDr; A-IUI!mnic +Mostcanvn!1VII'p)l1lrltatiologiasil illicstype

Guillain-Barre Syndrome (GBS) definition: acute rapidly evolving polyneuropathy risk factors and etiology pathophysiology suspected to be focal inflammation viral/bacterial infections and vaccinations, have been shown to predispose to GBS signs and symptolll8 sensory: distal and symmetric paresthesias, loss ofproprioception and vibration sense, pain motor: weakness starting distally in legs, areflexia autonomic: blood pressure dysregulation, arrhythmias, bladder dysfunction
investigationa CSF: albuminocytological dissociation (high protein, normal WBC) EMG/NCS: conduction block, differential or focal (motor>sensory) slowing, decreased

GBS is a neurological emergency due to risk of imminent raspinrtory failtn.



F-wave subtypes 1. Acute inflammatory demyelinating polyneuropathy (AIDP) 2. Acute motor-sensory axonal neuropathy (AMSAN) 3. Acute motor axonal neuropathy (AMAN) treatment disease specific: IVIg or plasmapheresis nonpharmacologic: admit and monitor vital signs and vital capacity due to risk of respiratory failure, manage dysautonomia, manage pain prognosis nadir of symptoms at 2-3 weeks, with resolution at 4-6 weeks 5% mortality (higher ifiCU), 7-15% permanent substantial deficits Diagnostic Approach to Peripheral Neuropathies 1. Differentiate: motor vs. sensory vs. autonomic l. Pattern of Deficit: symmetry, focal vs. diffuse, upper vs. lower limb, cranial nerve involment 3. Tempo: acute to chronic, relapsing remitting vs. constant 4. Good History: PMH, detailed family tree, exposures (e.g. insects, toxins, sex. travel), systemic symptoms 5. Detailed Peripheral Neuro Bum: LMN findings, differentiate between root and peripheral nerves, check cranial nerves, check respiratory status

Miller-RICIH!r Y11rimt af GBS - Triild 1. Ophthalmoploqill

2. Ataxia 3. Arvllexil



Mg and pi1Ui111apilemillalld tD morv rapid improvement, less intensive care

and less ventillllion, but do not change

mortality or ralaps1 ram.

N32 Neurolo8Y

Neuro-oncology/Neurom115Cular Junction Diseaaa

Toronto Notes 2011

Paraneoplastic Syndromes
uncommon complication of cancer; often is the presenting complaint

likely an autoimmune attack on the nervous sym:em by tumour antigens

Associated Neoplasms small cell lung cancer: cerebellar degeneration, encephalitis, opsoclonus-myoclonus,
retinopathy, neuropathy, Lambert-Eaton syndrome breast: cerebellar degeneration, encephalomyelitis, opsoclonus-myoclonus thymoma: myasthenia gravis other syndromes: necrotizing myelopathy, motor neuron syndrome, neuropathies, mononeuritis multiplex, polymyositis and dermatomyositis, encephalitis

antibodies commonly ordered include anti-Hu, anti-Ri and anti-Yo

unsatisfactory and often palliative. Options to consider are steroids, IVIg, plasmapheresis and treatment of malignancy

Tumours of the Nervous System

see NS9

Neuromuscular Junction Diseases

Clinical Approach to Disorders of the Neuromuscular Junction
Tabla 19. Common Disorders of the Neuromuscular Junction

OculluAiulblr pamis

+ +



', ..



Post-exen:ile enhlncement Reflexes

ANS anti:hulin. .ic Sx

+ + + +

+ +

Dis1un of 1h1 niUilllllllscular junction typically feature prominent fatiguability.



Associated conditions
Rapatilivll EMG stimulatilll


Small cell carcinoma


1' (rapid sti'I'IJiation)

-.1- (slow

1' (rapid stimulation)

>lr (slow stimulation)

Myasthenia Gravis (MG)

Etiology and Pathophysiology
damage and blockade of post-synaptic acetylcholine receptors by specific antibodies 15% of patients with myasthenia gravis have associated thymic neoplasia, 85% have thymic

autoimmune disorder

bimodal age of onset - 20's (mostly women) and 60's (mostly men)

Toronto Notes 2011 Signs and Symptoms

Neuromusc:ula.r Junction Diseasea

Neurology N33

see also Table 19 fatiguability and weakness of skeletal muscles without reflex, sensory, or coordination abnormalities typically ocular (diplopia/ptosis) -+bulbar (dysarthria/dysphagia) -+ necldlexors/extensors -+ proximal limbs respiratory muscle weakness may lead to respiratory failure

Myasthenia Gravis is a neurological emergency due to 1he risk of imminent rnpillllory failure I


,, ,,

edrophonium (Tensilon) test -can result in respiratory difficulty so have crash cart nearby assess for improvement over 2 minutes following edrophonium injection EMG repetitive stimulation -+ decremental response single fibre electromyography shows increased jitter (80-10096 sensitivity) anti-acetylcholine receptor antibody assay (70-80% sensitivity) MUSK antibody may be used if seronegative for AChR antibody CT/MRI to screen for thymoma/thymic hyperplasia
Tensilon is a drug 1hat inhibit$ acltylcholinestlrllsl. It improvM mJscll function immadilltaly in my811henia

gravis, but not in cholinergic crisis.


thymectomy 8596 of patients show improvement or remission symptomatic relief acetylcholinesterase inhibitors (e.g. pyridostigmine) does not affect primary pathologic process -+ rarely result in control of disease when used alone immunosuppression steroids are mainstay oftreatment - 70-80% remission rate azathioprine, cyclophosphamide and mycophenolate as adjuncts to steroids or as steroid sparing therapy short-term immunomodulation (for crises) IVIg and plasmapheresis

zClinical Forms rrf Mpltllenil GriVis 1. Ocular [15"'} 2. Gene1111ized (85%1

3096 eventual spontaneous remission

Lambert-Eaton Myasthenic Syndrome (LEMS)

Etiology and Pathophysiology
downregulation of presynaptic voltage-gated Calcium channels 2 to specific channel binding antibody causing decreased amounts of ACb released into the synaptic cleft 50-6696 are ultimately associated with small cell carcinoma of the lung

Signs and Symptoms

weakness of skeletal muscles without sensory or coordination abnormalities reflexes are diminished or absent, but increase after active muscle contraction bulbar and ocular muscles affected in 25% prominent anticholinergic autonomic symptoms (dry mouth >impotence> constipation > blurred vision)



Lambert-Eaton myas1hanic syndrome can be differentiated from myasthenia Qlllvis, by 1ha phenomenon of postexercise facilitlltion.

edrophonium test (see Myasthenia Gravis) -+ no response EMG: rapid (> 10Hz) repetitive stimulation -+ incremental response screen for malignancy, especially small cell lung cancer post-exercise facilitation- an incremental response to repetitive stimulation due to presynaptic calcium accumulation

Treatment tumour removal

acetylcholine modulation increased acetylcholine release (3-4 diaminopyridine) decreased acetylcholine degradation (pyridostigmine) immunomodulation steroids, plasmapheresis, IVIg

N34 Neurolo8Y


Toronto Notes 2011

Clinical Approach to Muscle Diseases
Table 20. Myopathies
Etiology lnlllmmiiDry Polymyositis Mya[gies Pharyngeal involvement Mya[gias Similar to polymyositi& Characteri&tic r.&les Can be paraneoplastic

Ksr lnvatigations
1' CK Biopsy: endomesial Necrosis 1' CK Biopsy: parifasciculll' atrophy




lmporu,nt lnfanution to Reganllnf Myapllthilll Weakness: proximal > distal

Pain: myalgias, but no impaired

MyotDnil [difficulty with relaxldioo)

Sarcoido8is Inclusion body myositis

ACE IIMII Biopsy: IJliiUIOIIllls

Weak quads and deep finger flexors

See Endocrinology

1' CK Biopsy: ilclusion bodias TSH, serum cortisol, calcium panel Toxicology Biopsy: selective loss of thick Myosin filaments




Thyroid (1' or -1-) Cushing's syndrome Parathyroid (1' or -1-) Medication Critical illness myopathy

Myoplllllisl1118 chlllle1llrizad by prominent symmetric proximal

Medication or toxin history

weakness end lbsant SIIIIIO!'f chlngal.


Hereditary Dystrophy

ICU patient Hx steroid& and nondepolarizing palltfzing agents Faiure to ween from ventilation
Mya[gies Inflammatory myopathy onset {Duchenne and Becker) Prograssiw proxi11111l muscle -knass pseudohypertrophy Distal myopathy Myotonia Genetic anticipation Exercise-related rnyalgias, cramping, and myoglobumimria Episodic W8ilkness between attacks

Parasitic, bactErial, or vinll Duchenne

1' ITI'fl9obin Biopsy: abnormal dyttrophin Staining Genetic testing

Good Cll..ti- to Alina Proximal


Legs: climbing slllirl, stand from sit Anna: n111ch above hlllld, wash hair

Myotonic dystrophy



Hereditary Mltlbolic


Common Mellicalio1111bat Cauu Mpptllhy Steroids, mrtins and IIIT!mnmrBis

1' lactate 1' serurnturinary myoglobil Pllst-sxen:ise 1'cr-I-K Increased lactate Biopsy: ragged red fibres

Heredililry Periodic Parllylil Heredililry

Periodic paralysis MERRF MELAS ICI!ImsSayre


Ptosis, conmon Proximal > distal myopathy Exercise intolerance Rhabdomyolysis

Abbreviltion5: MBliiF -ITilochoncnl encephlllomyoplllhy slrulie-like episodes

rauged llld fibe11; MELAS- mitochondrial encepllllomyopathy, lactic I!Cifbis, and

see RH13

Myotonic Dystrophy
Etiology and Pathophysiology unstable trinucleotide repeat in DMK gene (protein kinase} at 19ql3.3 number of repeats correlates with severity of symptoms; autosomal dominant Epidemiology most common adult muscular dystrophy prevalence 3-5/100 000 Signs and Symptoms appearance: ptosis, bifacial weakness, frontal baldness {including women), triangular face giving a drooping/dull appearance

Toronto Notes 2011

Myopathies/Cerebellar Disorders

Neurology N35

physical exam distribution ofweakness: distal greater than proximal (in contrast to other myopathic disorders) myotonia: delayed relaxation of musclc:s after exertion (elicit by tapping on thenar muscles with hammer) cardiac: 90% have conduction defects ( 1 heart block; atrial arrhythmias) respiratory: hypoventilation 2 to muscle: weakness ocular: subcapsular cataracts, retinal degeneration, decreased intraocular pressure EMG: subclinical myotonia -long runs with declining frequency and amplitude

Treatment no cure management of myotonia: phenytoin

Duchenne and Becker Muscular Dystrophy

see Pediatrics, P46

Cerebellar Disorders
Clinico-Anatomic Correlations vermis: trunk/gait ataxia cerebellar lobe (i.e. lateral): tremor, rebound phenomenon, dysarthria, dysdiadochokinesis, nystagamus Symptoms and Signs of Cerebellar Dysfunction nystagmus: observe on extra-ocular movement testing (most common is gaze-evoked nystagmus) dysarthria (ataxic dysarthria): abnormal modulation of speech velocity and volume- elicit scanning/telegraphic/slurred speech on spontaneous speech (see Dysarthria, Nl9) ataxia: broad-based, uncoordinated, lurching gait dysmmetria: irregular placement ofvoluntary limb or ocular movement dysdiadochokinesis: unable to perform rapid alternating movements (e.g. pronationsupination task) postural instability: look for truncal ataxia on sitting (titubation =rhythmic rocking of trunk and head); look for difficult tandem gait and broad based gait intention tremor: elicit on finger-to-nose testing- typically orthogonal to intended movement, and increases as target is approached hypotonia: decreased resistance to passive muscular extension- occurs immediately after injury to lateral cerebellum pendular patellar reflex: knee reflex causes pendular motion ofleg occurs after injury to cerebellar hemispheres rebound phenomenon: overcorrection after displacement of a limb (with both arms extended --+ pushing both will cause one to rebound up if there is lesion on that side)

Wernicke-Korsakoff Syndrome
deficiency of thiamine due to alcohol abuse acute: apathy, confusion, decreased EOM, ataxia (truncal and gait) without treatment progresses to encephalopathy and ultimately death treatment: thiamine 100 mg Korsakoff's syndrome: progressive decline ofboth anterograde and retrograde memory note that alcohol can also cause a cerebellar ataxia separate from thiamine deficiency. The ataxia can be due to cerebellar atrophy or alcohol polyneuropathy

Cerebellar Ataxias
Congenital Ataxias early onset nonprogressive ataxias associated with various syndromes as well as development abnormalities (e.g. Arnold-Chiari malformation, Dandy-Walker cysts) Hereditary Ataxias autosomal recesaive: includes Friedreich's ataxia, ataxia telangiectasia, vitamin E deficiency Friedreich's ataxia: prevalence 2/100 000; onset between 8 and 15 years signs: gait and limb ataxia, weakness, areflexia, extensor plantar reflex, impaired proprioception and vibration death in 10-20 years from cardiomyopathy or kyphoscoliotic pulmonary restriction autosomal dominant: spinocerebellar ataxias (SCA.s) of which 30 exist, most are CAG repeats

N36 Neurolo8Y

Cerebellar Disorden/Vertigo/Gait Diaturbances/Pain Syndromes

Toronto Notes 2011

Acquired Ataxias neurodegeneration (e.g. multiple system atrophy) systemic: alcohol, celiac sprue, hypothyroidism, Wilson's, thiamine deficiency toxins: carbon monoxide, heavy metals, lithium, phenytonin, solvents vascular: infarct, bleed, basilar migraine autoimmune: MS, Miller-Fischer (GBS) children: tumours, post-viral

see Otolaryngology, OT12

Gait Disturbances
Approach to Gait Disturbances I. Length of stride if small paces - look at posture if stooped with no armswing- Parkinsonian gait look for other signs of extrapyramidal disorders if upright with exaggerated armswing - Marche a petit pas due to diffuse infarction of both cerebral hemispheres (lacunar)


CENTRAL MOTOR SYSTEMS 3 compnnb tu til cantrol af pit 1. Pyramidal: main ouUiow from cor1ex to spinal cord 2. Extrapyramidal: bani ganglia inhibita BJa:llll mCMimanb; 3. Clrlblllum: afflcts coordination of

2. If normal stride length, look at width between feet if wide-based- ataxia if high stepping and positive Romberg- sensory ataxia loss of joint position sense (+ve Romberg) if wide based without high stepping - cerebellar ataxia veers to side of the lesion if scissoring of legs or toe walking- spastic gait bilateral circumduction due to spastic paraparesis from cerebral palsy, multiple sclerosis or cord compression 3. If normal width, look for height of step if high stepping bilaterally- bilateral foot drop if feet barely leave ground or disjointed movement - magnetic/apraxic gait frontal lobe pathology due to normal pressure hydrocephalus or cerebrovascular disease
4. If no high stepping, lookfor stabllity of pelvis if rotation of pelvis - waddling gait

proximal muscle weakness due to congenital deformity or myopathy

5. If no waddling, look at symmetry if asymmetric - antalgic gait, deformity or hemiparetic gait antalgic gait is due to pain from an MSK problem hemiparetic gait involves a foot drop and circumduction of spastic leg due to UMN lesion

6. If movement is elaborate and inconsistent, especially when being observed. conaicler functional pit rule out an odd gait due to chorea from Huntington's disease

Pain Syndromes
Approach to Pain Syndromes

Pinprick CIIUUI sharpnns rnldimd byJIIJfibani Pain to damage is mediated by Cfibres

Definitions Nociceptive pain: pain arising from normal activation of peripheral nociceptors Neuropathic pain: pain arising from direct injury to neural tissue. bypassing nociceptive pathways Spontaneous pain: unprovoked burning, shooting, or lancinating pain Paresthesiae: spontaneous or evoked abnormal nonpainful sensations (e.g. tingling) Dysesthesiae: spontaneous or evoked pain with inappropriate quality or excessive quantity Allodynia: a dysesthetic response to a nonnoxious stimulus Hyperalgesia: an exaggerated pain response to a noxious stimulus

Toronto Notes 2011

Pain Syndromes

Neurology N37

Medical Pain Control

primary analgesics: OTCs, opiates adjuvants: antidepressants (TCAs, SSRis), anticonvulsants (gabapentin, carbamazepine), baclofen, sympatholytics (phenoxybenzamine), a2-adrenergic agonists (clonidine, pregabalin)

Surgical Pain Control direct delivery: implantable morphine pump

central ablation: stereotactic thalamotomy, spinal tractotomy or dorsal root entry lesion peripheral ablation: nerve blocks, facet joint denervation deep brain stimulation (DBS) or dorsal column stimulation

Neuropathic Pain
pain resulting from a disturbance of the central or peripheral nervous system

Symptoms and Signs

hyperalgesia/allodynia subjectively described as -burning, heat/cold, pricking, electric shock, perception of swelling, numbness (Le. stocking/sock distribution) can be spontaneous or stimulus evoked distribution may not fall along classical neuro-anatomicallines

Associated Issues
sleep difficulty anxiety/stress/mood alteration sexual dysfunction

Causes of Neuropathic: Pain

peripheral neuropathy systemic disease - diabetes, thyroid disease, renal disease, rheumatoid arthritis nutritional/toxicity- alcoholism, pernicious anemia, chemotherapy infectious - HN trauma - post surgical, nerve injury nerve root: post-herpetic neuralgia, cervical and lumbar radiculopathies, tic douloureux (see Trigeminal Nerve, Nl8), plexopathies central: MS, post-stroke, phantom limb, spinal cord injury Complex Regional Pain Syndromes (see N38) malignancy

Treatment pharmacotherapy: TCA. SNRI, anticonvulsant, long acting opiate, topical lidocaine, capsaicin
cream, intrathecal opioid or clonidine, Botox, nerve block surgical therapies: dorsal column neurostimulator, DBS (thalamus) other therapies: neuropsychiatry - cognitive behavioural theraphy, psychotherapy rehabilitation - physiotherapy CAM - acupuncture, meditation, massage therapy, TCM

Tic Douloureux (Trigeminal Neuralgia)

see Trigeminal Nerve, N18

Postherpetic Neuralgia (PHN)

pain persisting beyond 3 months in the region of a cutaneous outbreak ofherpes zoster

Etiology and Pathogenesis

destruction of the sensory ganglion neurons (e.g. dorsal root, trigeminal, or geniculate ganglia) secondary to reactivation of herpes zoster infection

10-15% of all patients with cutaneous herpes zoster >80% of herpes zoster infected patients >80 years old

N38 Neurolo8Y

Pain Syndromes

Toronto Notes 2011

Signs and Symptoms types of pain: constant deep ache or burning. intermittent spontaneous lancinating/jabbing pain, allodynia distribution: thoracic > trigeminal > cervical > lumbar > sacral Treatment acute herpes zoster early treatment with antiviral agents (acyclovir; longer-acting famciclovir and valaciclovir more effective) may prevent PHN in patients over 50 years PHN medical: TCA, pregabalin, gabapentin, opiate, lidocaine patch, intrathecal methylprednisolone surgical: spinal tractotomy, dorsal root entry zone lesion

Complex Regional Pain Syndromes (CRPS)

Definitions CRPS is a pain syndrome characterized by the following 1. presence of an initiating noxious event 2. continuing pain, allodyrua, or hyperalgesia with pain disproportionate to inciting event 3. evidence during the course of symptoms of edema, changes in skin blood flow, or abnormal vasomotor activity 4. absence of conditions that would otherwise account for degree of pain and dysfunction Classification CRPS type I (reflex sympathetic dystrophy): minor injuries of limb or lesions in remote body areas precede onset of symptoms CRPS type II (causalgia): injury of peripheral nerves precedes the onset of symptoms Signs and Symptoms stage I (acute) pain: burning or aching disproportionate to initial injury autonomic: edema and temperature inequality stage II (dystrophic) pain: constant and increased by stimulus to affected part autonomic: osteoporosis, cool hyperhydrotic skin, hair loss, cracked/brittle nails stage III (atrophic) pain: paroxysmal spread autonomic: thin, shiny skin, thickened fascia with contractures, bony demineralization Investigations diagnosis is clinical trial of differential neural blockade may be helpful Treatment medical: phenoxybenzamine (sympatholytic) surgical: paravertebral sympathetic ganglion blockade

Thalamic Pain (Dejerina Roussy Syndrome) - -Definition hypersensitivity to pain as a result of damage to the thalamus Etiology and Pathogenesis injury to ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei of the thalamus ischemic stroke hypertensive vascular hemorrhage Signs and Symptoms begins with hemianesthesia then persistent spontaneous burning contralateral to lesion altered response to light cutaneous and deep painful stimuli Treatment medical: amitriptyline, anti-convulsants surgical: stereotactic thalamic stimulation (may increase sensory deficit)

Toronto Notes 2011


Neurology N39
a.lllliaal cmc.J Eumilllllign: O.llil Pllilnt wilb 11Hdde .... a..,. Nllll
JWA 2006; 2!1&:1 274-83

Clinical Approach to Headaches
good history and physical to rule out serious causes of headache important aspects of neurologic exam: LOC and MSE, pupils (symmetry), fundi (papilledema, retinal hemorrhages), pronator drift, meningismus, deep tendon reflexes and Babinski, gait indications for a new-onset headache, worst headache of life, thunderclap headache, headache with worrisome symptoms (fever, meningismus, altered LOC, focal neurologic deficits, trauma, papilledema, morning headache) if CT is negative but suspicion of SAH or meningitis, perform a lumbar puncture

nnmanic: p-

Dnltlil!lllillllwilb ........... The most of..- for dilgnosing nipile i$ .urrrrm.d by 11-. P(Utling



a - 4inl1ion of 4-72



N - Nlu or-womiling D- Disllblingint!llsily

Table 21. Headaches- Primary

TCIIIioa-Typa Prevalence


ThaiR far dafiW or polllil1i n-i11111inl dill!jlllllii VlrillwM!I U.lllmblr rlfiiUM pr8I8IE Mdl 3111d feiW U.Llls ... 24 {1.5-3181. 3.5 {1.3-9.2111111 0.41 {0.32-0.521 TllpiC1ivltf. Dnlllil , . . .... h...... IIIII

Clustar <1%

15-40 F>M Nona Bilateral frontal MinLIII!s-days lndual; worse in PM Band-like; constant Mild-modarata Depression

12% 10-30 F>M

Aga of Ollllt
SexBia Family HistaiY


Uniateral>bilateral Fronto-tenwal Haurs-days Gradual; worse in PM Tlrobbing Modarata-severa Noise Light Strainilg Coujing Activity Rest Nausi!I1/VDmiting Photo/phonophobia Aura Muscle tension in scall)'neck Tandar scalp artaias AcuteRx MA NSAIDS Triptans Ergotamine Prophylaxis l'ropnllolol TCA Anticonvulsents

Retroorbilll 10mh-2. haurs

Dul'llion Onset/CGune

The prawlence rl ii'Uicllnill pllllology {!111111 problliiitylwrias lnlll011 v.1lh dlronic helldldle 1he plellllence is l.l'J. {0.77-1.11\).ln Ylll niglint-typl lllldlclw the prMiince is Howavll. inlhose prasal1ing wi1h new lllldlclw the prMiince is 32'Jo in 1hose jiiUidiiQ Ylilll t!UIIIarcllp hlllldlchl the prMimct is 43\ {211-611\). Ill th8le dilllrant popullbs. 110 clinical flllfln was found lo hlllllful inlllivJ imcrlrill pethoQ in a 1118111iniiUMYHawM!. -a indivi!UI c1inicll IIU.ns Will luund 1o 1xt ]IIICictive of lignili:lnt petholoQr.
c:QI8r-tp haadache

Daily headache for weeks, months, nocturnal

Constant, aching. stabbing S8\111'8 (waklls from sleep) Light

111ddneli-typl hlldlch1

Severity Pravoldng

10.7 {21-52) 5.3 {2.4-12) 3.8 {2.0-7.11


lllldlclwv.tiilllldlclw Mil wmiling

3.2 {1.66.61 2.3 {1.4-UI

1.8 {112.61


Noise Hunger Slaap deprivation Pallating Rest No vomiting No photophobia Muscle tension i'1 Non1)harmacological Psychological counseling Physical modalities (e.g. heat, massage) Phannacological Simple analgesics Tricyclic antidepressants

Walking around

ARoc:iltad Sx

Red watery eve Nasal congestion or rhinoi'Thea Unilateral Homer's Red watery eye, rhinorrhea Eyaid !hop
Acute Rx Oz Sumatriptan (IIIISII or injection) Prophylaxis Verapamil Lithium Methylsergide Pnmisolone

Six Dl Seria Halldac.._ lnaluda: 1. The lUdden onset Ill a savm


Pllysicll Signs

neurolovic deficibi; or 3. New headaches beginning after age 50.

2. AccomplfTYing impaired mental sbllus, uizul"ls, or focal


Table ZZ. Headaches- Serious

Meningllllrrilatilll Incidence Age of Onset SP:Bils Locetion Duration Onset/Coull8

...creased lllraa'anill Pressure

<1% Any age No bias Any location Chronic Gradual; worse in AM Unlike any previaus headache Severe

Te11poral Arteritis <<1% >60 No bias Ten'flOIBI Variable Variable Tt.-obbing Variable; can be severe


Any age
No bias Generalized; stiff neck Variable Meningitis: oours-days SAH: thunderclap onset Variable S8\111'8


N40 Neurolo8Y


Toronto Notes 2011

Table 22. Headaches - Seriouslcontinuedl

Meeinglll lniltion

Lying down Valsalva H81ldlow Exertion Standing/sitting


Tempol'll Arllrilis


Head movement

Associltld Sx

Rest and
Neck stiffness




Focal deficits (e.g. CN pelsi111) Kemig's sign Brudzinski's sign

Nausel/vomiling Focal neuro Sx DecriiiiSad lewl of consciousness Focal neuro Sx Pupilledeme CTJMRI and treat appropriatl!ly See also Neurosuroerv. NSS

Polymyalgia rheumatica

Jaw/tongue claucication
Visual loss
artery change&: Finn. nodular, incompressible Tender

Stluctur lnvalftd in Nacicllptian of


Larve in1rlcranial vessels



See also Rheumatology. RH17

Meningitis, SAH

Twnour, IIH, malignllll hypertension


SAH - 111blrachnaid hernarrlllge; IH - idiopathic iltrlcnlill hyperllnsiun; GCA- giant cellarllritis

Primary Headache disorders

tension-type, migraine, cluster, ice pick, exertional

Headaches with serious risk to life or function subarachnoid hemorrhage (SAH), meningitis, herniation (from space-occupying lesion),
temporal arteritis, venous sinus thrombosis

Secondary causes of headaches

SAH, intracranial hemorrhage, stroke, meningitis/encephalitis, sinusitis, trauma. increased intracranial pressure (space-occupying lesion, malignant HTN or pseudotumour cerebri), post lumbar puncture, temporal arteritis, drugs/toxins (in particular analgesia-induced/medication overuse)

Migraine Headaches
Definition (common migraine) <?:5 attacks fulfilling each of the following criteria
4-72 h duration 2 of the following: unilateral, pulsating, moderate-severe (interfers with daily activity), aggravated by routine phy5ical activity 1 of the following: nausea/vomiting, photophobia/phonophobia/osmophobia
1hB 01111 contracapliva pill il con1rlindicmd with complicat.d migraine due to risk of stroke.

18% females, 6% males; frequency decreases with age {especially at menopause)

Etiology and Pathophysiology



oftnnsient neurological dsficit8 (e.g. liAs and seizuras).

Migraina ra can mimic olhar causas

neurovascular theory of migraines (controversial) baseline state of neuron hyper-excitability during migraine: wave of neuronal excitation followed by wave of depression associated with vasoconstriction and dilation initiating event may occur in brainstem trigger: stress, sleep excess/deprivation, drugs (estrogen, nitroglycerin), hormonal changes, caffeine withdrawal, chocolate, tyramines (e.g. red wine), nitrites (e.g. processed meats) auras are felt to be due to a wave of excitation/depression leading to the symptoms experienced in an aura (e.g. visual symptoms due to wave through occipital cortex)

Signs and Symptoms

stages of uncomplicated migraine i. prodrome (hours to days before headache onset) ii aura iii. headache (see Table 21 for description oftypical headache) iv. postdrome aura fully reversible symptom of focal cerebral dysfunction lasting <60 minutes examples: homonymous visual disturbance (fortification spectra - zigzags; scintillating scotomata spots) unilateral paresthesiae and numbness or weakness aphasia prodrome/postdrome: appetite change, autonomic symptoms, altered mood, psychomotor agitation/retardation

Toronto Notes 2011


Neurology N41
Phi!R:IIIGgiell'h................ !'lin 2002; 91:241-51 lludr. dll!lbii-IJind, pilctillctanrollld IItTs of piwn'abgc 1nltment of lade mignrine rl1111de!ati.! to IIMII i1llnily {21,022 pllilla in 1111111. Dllllllhdilll: Nunarrl patients, iiDiirG, dutdl of lludy IIIII liming or \ypll rlresc:ue medication. M:omes inc:bled heldac:l!e ...Wat 111111 2holn, ITeedorn frgm plin II 2 tan, IJiflilld fllilffor 24 botn.llld lflm1l llffildJ will*l24 baurs. Mlin lids; Dill Will Millila for I Dill medicDns, 2ilbanml melbtions,llld IUbcullnlous FGr IIA 11lilf d 211. 111 intelwrmans wm ellectiw u:ept CftgG!4'. wi111NNTIIII1gi11Qfrom2.0for lll1lltripiM 6mg s.eto 5.41arnmiptM2.5 mg. The l:iwestlf for 0111 madi:atian -2.6 far UilripiM IIJl mg. For prilllll pain 1111111211. ttw lilwllt NNT 2.11ar IUI'I1atriplln 6 mg I.C, Mhlla IDMt NNT for 0111 madi:atian beilg 3.1 far RizlllriptJn 10 mg. For susllined 11!111- 24b NNT r111ged fTom U
ellec:ts cauld 1111 be 1111md IVSflntilaly. There W8l'll no drug-11Hirug complrilanl.
llffilctivt. Subcutnauslll11llriptln IIIII IIIII 1riptn- 1111111 llllctivt.

classification of migraines common migraine: no aura classic migraine: with aura (headache follows reversible aura in 60min) complicated migraine: with severe/persistent sensorimotor deficits examples: - basilar-type migraine (occipital headache with diplopia, vertigo, ataxia, and altered level of consciousness) - hemiplegiclhemisensory migraine - ophthalmoplegic migraine acephalgic migraine (aka migraine equivalent): aura without headache

avoid triggers mild to moderate migraine treatment 1st line treatment: NSAIDS - ASA, ibuprofen, naproxen moderate to severe migraine treatment triptans (most effective), ergots (dihydroergotamine, DHE), Tylenol #3 migraine prophylaxis: anticonvulsant& (divalproex, topiramate), TCA (amitryptiline, nortriptyline), propranolol, SHT antagonists (methylsergide), calcium channel blocker (verapamil)

Episodic Tension-Type Headache

Diagnostic Criteria
1. at least 10 previous headache episodes fulfilling criteria 2 through 4; number of days with such headaches: less than 180 days per year 2. headache lasting from 30 minutes to 7 days 3. at least two of the following pain characteristics: a. nonpulsatile (tightening) b. mild-moderate intensity c. bilateral d not aggravated by normal routine 4. both of the following (or only one is present): a. no nausea or vomiting b. no photophobia or phonophobia


!Mrl' most

lrellllnenl$ were

A prophylactic agll'll is 111Commlllldad Dilly if mignline attacks are severe enough ID C4US8 impairment af I patient's quality of life or Ha patient hat >3 mignill8f/month lhlrt have not responded 1natment. Su:a: SlivBrlllin SO at l.l'llc:tice p11111181ar:
{1111 evidence t.ed ,....,. Nartqy 200);


for m9lina llllllllchl


Chronic Tension-Type Headache


Diagnostic Criteria 1. average headache frequency of more than 15 days per month for more than 6 months fulfilling
the following criteria 2. at least 2 of the following pain characteristics a. pressing/tightening (nonpulsating) quality b. mild or moderate intensity (may inhibit but does not prohibit activities) c. bilateral location d no aggravation from climbing stairs or similar routine physical activity 3. both of the following a. no vomiting b. no more than one of the following: nausea, photophobia, or phonophobia 4. secondary headache types not suggested or confirmed

Cluster Headache
Diagnostic Criteria 1. at least five attacks fulfilling criteria 2 to 4 below
2. severe unilateral, supraorbital and/or temporal pain lasting 15 to 180 minutes (untreated) 3. headache associated with ipsilateral (to pain): conjunctival injection or lacrimation, nasal congestion or rhinorrhea, facial sweating, miosis or ptosis, eyelid edema, restlessness/agitation 4. not attributed to another disorder

N42 Neurolo8Y

Sleep Disorders

Toronto Notes 2011

Sleep Disorders

,, ,
1. Circadian rhythm: suprachiumalic
nucleus i1 hypolllalamus

Overview of Sleep
Definition sleep is a reversible state of unresponsiveness and lack of perceptual awareness of the environment Anatomy of Sleep the suprachiasmatic nucleus (SCN),located in the anterior hypothalamus, receives afferents from the retina and possibly from the lateral geniculate body; it projects not only to other hypothalamic nuclei, but also to the basal forebrain, thalamus, and periaquaductal gray Sleep Stages Stage 1: 50% of alpha waves get replaced by theta waves (4-7 Hz), slow rolling eye movements, high muscle tone Stage 2: vertex K complexes, beta waves (> 13 Hz), and high voltage (positive and negative) discharges with spindles on EEG; eye movement is still; high muscle tone Stage 3 and 4 (Delta sleep): slow wave (<2 Hz) but high voltage activity on EEG, still eye movements, low muscle tone, increased GH release, decrease in BP/HR/CO/RR Rapid Eye Movement (REM) sleep: mixed frequencies on EEG with low voltage and sawtooth waves, rapid eye movements, muscle paralysis, cholinergic brain state, dreaming

2. Slaap debt of somnogens {possibly adanosina) Iiiii wi1h tina spent awaka

Disturbances of Alertness and Sleep

,, ,
3 Cablgur!R of DyaDIIIJiilla 1. lnlrinsic sleep disorders 2. Exbinsic aeap disorde.-. 3. Circadian llllllllld disordn

Coma see




Alcohol shorten& llaap latency and promotes drowsiness. but I&ads to poor sleep mainteniiiCe duma second half olllnp.

Insomnia defi.oition: subjective complaint of poor sleep quality, non-restorative categoriea sleep onset: diffi.culty falling asleep; rule out disordered breathing, restless leg syndrome, and anxiety maintenance: waking up; rule out intrinsic sleep disorder with sleep study sleep offset: early morning awakening; rule out depression or disordered breathing non-restorative sleep differential diagnosis primary insomnia psychophysiologic hyperarousal from efforts to fall asleep - treatment: improve sleep hygiene sleep state misperception: normal sleep demonstrated despite complaint of poor sleep idiopathic insomnia - treatment: benzodiazepine receptor agonists or heterocyclic antidepressants sleep apnea - obstructive sleep apnea: refer to Respirology. R32 - central sleep apnea: no effort to breath over 10 seconds - DDx: heart failure, syringobulbia, lateral medullary syndrome, brainstem dysfunction restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) - RLS: unpleasant sensations creeping along leg leads to need to move legs leading to problems with sleep initiation - PLMD: repetitive leg movements in sleep, 90% of RLS - DDx: spasticity; radiculopathy. neuropathy. pregnancy; alcohol, iron deficiency - treatment: iron supplement. dopamine agonist l-2h prior to bed secondary insomnia poor sleep hygiene transient situation: associated with major life change or stressful event - resolves on its own secondary to psychiatric disorders (80% ofpsychiatric patients) - depression has been shown to be associated with short REM latency secondary to neurologic disorders - examples: dementia, Parkinson's disease, hemiballism, Huntington's disease, atlantoaxial subluxation, myotonic dystrophy secondary to drugs/toxins - examples: caffeine, alcohol, nicotine, amphetamines, cocaine, antidepressants, glucocorticoids, sedative (withdrawal of night), arsenic, copper, lead, mercury fatal familial insomnia: rare degenerative prion disease of increasing sleep - onset insomnia leading to death within 7 to 13 months - associated symptoms: fever, excess salivation, sweating others: environmental, altitude (lower FI02 )

Toronto Notes 2011

Sleep Disorders

Neurology N43

Narcolepsy irresistible desire to sleep in inappropriate circumstances and places clinical features: cataplexy, sleep paralysis (unable to move upon wakening for 2-3 minutes), hypnogogic/hypnopompic hallucinations (vivid dreams or hallucinations at sleep onset or at awakening) 10% of patients suffer all four symptoms (narcolepsy/cataplexy tetrad) epidemiology: M>F, prevalence 1:2000, onset in adolescence/early adult symptoms can become less troublesome with age but it is a life-long disorder etiology: post head injury, multiple sclerosis, hypothalamic tumours; rarely familial diagnosis: based on clinical history+ EEG findings of REM in <15 min of sleep onset; seen on 2/4 naps during a multiple sleep latency test


', ',

Cltlplexy: brief episodes of muscle p111111y$is in 181PDfll8 IXJ exceA emotion (l.g. lllll!lhDrl.



lifestyle modification ("cat naps) can occassionally be effective management on their own; certain activities are restricted (e.g. driving) modafinal (non-amphetamine stimulant) amphetamines avoided because of their propensity for habituation selegilene (metabolized in part to amphetamine), is a stimulant that also reduces cataplexy symptoms. others: moxindol, pemoline, and clomipramine are also effective
Parasomnias Associated with Slow Wave Sleep: Arousals occur in first 113 of sleep during stage 3 and 4 arousals associated with confusion/disorientation, amnesia treatment: self-limiting, diazepam confusional drunkneas: partial arousal from slow wave sleep associated with confusion and startling, resistance to being consoled, and appearance of being awake aggravated by napping in narcolepsy, stress/anxiety, fever, excess exercise, night terror predominantly in children somnambulism: sleep walking (ranges from sitting up in bed to violent sleep behaviour) 1-15% of population, with greatest frequency in childhood clinical presentation: agitation, automatisms, walkinglrunning, completion of complex tasks, verbalization, open eyes, choreiform movements, enuresis, difficult to arouse associated with fever, sleep deprivation, sleep apnea, urinary retention, external noise, medications increases the risk of psychoneurosis in adults, but not in children. night terror: abrupt awakening associated with fear and autonomic stimulation in children (ages 2 to 4), resolves by adolescence clinical presentation: child awakes suddenly, sits up in bed and screams, eyes open, dilated pupils, sympathetic activity, increased muscle tone, child is not consolable, agitation, vocalizations, enuresis different from other slow wave sleep arousals, night terrors can occur at any time of the night associated with fever, bladder distention, sleep deprivation, medications Circadian Abnormalities familial advanced sleep phase syndrome autosomal dominant condition of early morning awakening (i.e. "morning larksu) pathophysiology: codon mutation of Per gene leads to a 4 hours advance of sleep, temperature and melatonin rhythms shift work deep disorder: due to sleeping at times different than normal circadian rhythm delayed sleep phase syndrome: body's circadian rhythm is delayed compared to time displayed on clock time zone change syndrome Qet lag) REM Sleep Behaviour Disorder pathophysiology: loss of spinal inhibition that normally occurs in REM sleep leading to hyperpolarization of ventrolateral reticulospinal tract motor neurons of spinal cord diagnostic criteria (American Sleep Disorder Association): diagnosis requires at least #2 and 3 are fulfilled 1. injurious behaviour during sleep 2. movement associated with dreaming state 3. at least 1 of: potentially harmful behaviours in sleep acting out dreams disruption of sleep due to activities 4. polysomnograph shows: excess chin tone on EMG and/or excess chin or limb twitching on EMG 1 of: excess limb/body jerking, injurious behaviours, no epileptic activity rule out psychiatric or other sleep disorders

Nlln;olep-v- palienl$ have d11C1811$ed levels of hypacretin in CSF.


'..._---------------, ,

Slow WBVe sleep arousal is 11$50Cillted with confusion and amiiBiia; REM sleep aroUSBI is IISSIICimd wilh rapid awekanilg 111d vivid draam recan.

N44 Neurolo8Y

Sleep Disorden/CNS Infections/Spinal Cord Syndroma/Stroh

Toronto Notes 2011

Medical Disorder Affecting Sleep

nocturnal leg cramps: DM, exercise, pregnancy. metabolic, endocrine, Parkinson's disease, arthritis mood disorders alcohol abuse cerebral degenerative disorders trauma dementia: insomnia associated with wandering, aggression, verbalization, delirium during early evening ("sundowning") Parkinsonism: sleep onset and sleep maintenance insomnia sleep related epilepsy: brain synchronization is increased during sleep leading to an increased frequency of seizures during sleep, especially during non-REM sleep triggers: sleep deprivation treatment of sleep disorders decreases seizures, and treatment of epilepsy improves sleep astluna/COPD: lower airway obstruction, coughing, wheezing and SOB can interrupt sleep

fibromyalgia: associated with pain, nonrefreshing sleep, fatigue, muscle tenderness and trigger points

CNS Infections
see Infectious Diseases, ID6

Spinal Cord Syndromes

see Neurosu.meos NS28

Stroke: sudden onset neurological deficits of a vascular basis lasting longer than 24 hours
Transient Ischemic Attack (TIA): sudden onset neurological deficits of a vascular basis that resolve after a brief period (usually <30 min) Revenible Ischemic Neurological Deficit (RIND or minor stroh): sudden onset neurological deficits of a vascular basis lasting >24 hours that resolve completely or near completely within days Stroke in evolution or progressing stroke: stroke that is actively progressing due to propagation of underlying vascular etiology to include further vascular territory over hours






Figura 22. Classification of Stroke

Approach to Stroke
Initial AslleiSDleDt Goals 1. Has the patient had a stroke? 2. Is the patient a candidate for tPA? Onset: time when last known to be awake and symptoms free Mimics to rule out: post-ictal, hypoglycemia, systemic infection, tumours, conversion disorder

Toronto Notes 2011


Neurology N45

Assessment NIH Stroke Scale (NIHSS- see sidebar) applies mainly to MCA territory CT signs of acute stroke loss of cortical white-grey differentiation sulcal effacement (i.e. mass effect decreases sulci) hypodensity of parenchyma insular ribbon sign hyperdense MCA sign ASPECT score: where 10/10 is normal and <4/10 signifies high risk of bleed with tPA subtract 1 point for each of following structures if abnormal within the ischemic hemisphere: caudate, lentiform, insula, internal capsule, MCA 1, 2, 3, 4, 5, 6 Treatment if no hemorrhage on cr and there is a clinical indication, tPA may be offered to the patient within the appropriate time limits (see Emergency Medicine, ER38 for more tPA details)


,.l------------------, ,

The National lnstitul of Health Stnlb

Scale (NIHISI is a standardized clinicalaxaminatian that dlllllrmines the severity of an acute stroke. It can 11160 be Uied to monitor respolllill to treatment over time. The scale u.es11 items that evalullbJ: 11 1..8val of consciousness 21 V"11ual syR&m

31 Motor systam
41 Sensory system 5ll.angUIIge abiities Scoring (l!/421: O=no stroke H=mild stroke 5-15=moderate stroklil 1520=moderate to 111verutroke 21-42=18111118 stroke tPA should be considered if scoru 6 or greater.

Stroke Syndromes
Stroke Syndromes According to Vascular Territory ACA: contralateral paresis and sensory loss, loss of bladder control (hypertonic detrusor) MCA: proximal occlusion involves all of the below findings superior division: contralateral face and arm paresis and sensory loss, Broca's (expressive) aphasia (if in dominant hemisphere) inferior division: contralateral homonymous hemianopsia (esp. inferiorly), contralateral agraphesthesia and astereognosis, anosognosia, contralateral neglect, Wernicke's (receptive) aphasia (if in dominant hemisphere) Internal carotid: premonitory TIA or transient monocular blindness (amaurosis fugax), asymptomatic or similar to MCA occlusion PCA: contralateral homonymous hemianopsia (especially superiorly), midbrain findings (vertical gaze palsy, CN III palsy, INO), occipital findings (anomia, alexia without agraphia, visual agnosia) ifbilateral: cortical blindness or prosopagnosia Basilar artery proximal (usually thrombosis) occlusion: CN VI palsy, impaired horizontal EOM impairment, vertical nystagmus, reactive myosis, hemi- or quadriplegia, coma, locked-in syndrome distal (usually embolic) occlusion (aka Top of the Basilar Sydrome): decreased LOC, CN III palsy, decerebrate or decorticate posturing PICA (Lateral Medullary or Wallenburg Syndrome): ipsilateral ataxia, ipsilateral Homer's, ipsilateral facial sensory loss, contralateral limb impairment of pain and temperature, nystagmus, vertigo, NN, dysphagia, dysarthria, hiccup Lacunar Infarcts (basal ganglia, thalamus, posterior limb internal capsule) pure motor hemiparesis: contralateral arm, leg, and face pure sensory loss: hemisensory loss (usually thalamic) ataxic hemiparesis: ipsilateral ataxia and leg paresis dysarthria-clumsy hand syndrome: dysarthria, facial weakness, dysphagia, mild hand weakness and clumsiness


,_._________________ , thrombosis should be considered in the differential diagnosis of stroke and headache. It is an uncommon cause of either, but iSIIUOCiK!Bd with high morbidity and morllllity. Patients often present with headache alone, but can also have seizures, focal neurological deficits, or cranial narva plllsies. MRI with gadolinium is the bast diagnostic t11st. Treatment is typically anticoagulation with heparin initially, than llansition to


Ischemic Stroke
Etiology thrombosis: stepwise deficits, preceded by TIAs embolus: abrupt onset, no warning TIA, maximal at onset, multifocal if cardiac origin, seizure more likely Conditions Associated with Increased Risk of Cerebral Ischemia 'VUcular disorders: atherosclerosis, vasculitis, SLE, syphilis, AIDS, carotid or vertebral dissection, drug abuse (cocaine, amphetamines, heroin), migraines, venous or sinus thrombosis, lacunar infarcts (due to chronic HTN) cardiac disorders: mural thrombus, rheumatic heart disease, arrhythmia. endocarditis, mitral valve prolapse, prosthetic heart valves hematologic disorders: thrombocytosis, polycythemia. sickle cell disease, leukocytosis, hypercoagulable states


,_._________________, ,

If possibility of cardioembolic source,

look for arrhythmias likl atrial fibrillation.

N46 Neurolo8Y


Toronto Notes 2011




Hemorrhagic Stroke
intraurebral (ICH): hypertensive, amyloid angiopathy, or other cause subarachnoid (SAH): aneurysm, AVM, or other cause epidural/subdural hematoma

c.-llfiCH ffTN, 1rauma, AVM, hemorrhaoe

in cmlnl irfin:ll, drug HUH, carubllll amyloid angiopathy, lumoUili, coagulopathias, anticoagulation.



bloodwork: CBC, ESR, VDRL, serum glucose, cholesterol and lipids ECG Cf MRI lumbar puncture (rule out subarachnoid hemorrhage) intrarterial angiography or MRA (anterior circulation TIAs or dissection) carotid doppler or transcranial doppler echocardiography

SullaiiVian StNI Syndro11111

Vartabrobasilar insufficiency dua stenosis associated with left arm 1118 causing vertigo, headaches, left arm daudication.

Hypertensive Stroke
BP above upper limit of autoregulation of cerebral blood flow (normal is 150-200 mmHg), chronic HTN, acute HTN chronic HTN stimulates cerebral blood vessels causing adaptive changes like hyalinization and lipidosis to preserve the blood-brain barrier. This process affects mainly smaller penetrating arteries (<200 mm in diameter) leading to lacunar infarcts of the basal ganglia and thalamus acute HTN can cause hypertensive encephalopathy with dBP > 130 or sBP>200 assoc with findings on fundoscopy, focal neural Sx, NN, visual disturbances and change in WC due to microinfarctions and petechial hemorrhages pathology: hemorrhages occur from rupture of damaged blood vessels, likely at the site of Charcot-Bouchard aneurysms most common sites: putamen, thalamus, cerebellum, and pons


, ,t-----------------,

The classic sits of hypar111nsiva

hamorrhagn is 1h1 bual ganglia.

surgical: decompression to prevent herniation if cerebellar hematoma or superficial hemorrhage of cerebral white matter medical (controversial): antihypertensive to lower dBP to -100 mmHg (typically nitroglycerin or furosemide used cautiously), corticosteroids for vasogenic edema

Global Cerebral Ischemia

etiology: inadequate blood flow to brain to meet metabolic demands (e.g. cardiac arrest) when hypotension is less severe, the areas of the brain most severdy affected are the watershed areas between ACA, MCA and PCA

1-I'A in AMI Slniii-IINDS Tlilll

NULf 1995; 333:1581-7 Study: lllndanilld, d!IIHI-illnd, pabocunbaled lrill(3 month Pllilllt: &24 plli8llls (llllllllag& 76 y, 58'JI. man. 65\ v.tiltl Mill iscllenic: slrolce rl reced onset, IIIII IIIIINidlncB rl inlnlmllilll bllllliiiiNga an Cl Excmians inckllld hx rl racant linD or racant 11J'Q81r. SBP=1B5,1111'=110. DISAH, racant Gl or GU lllmorrhage, lliBifl v.rilli anlll rl

Treatment of Stroke
ensure medical stability limit or prevent neuronal death

linD, and llllrnlllial: IVt.fA (OJlllAI arpllcabaMhin

Mlin outcomll: NuW:Igic dllfili 1124 iiDin INI!SS sc*land functiansl oull:ome 1131111111hs
(CIIII'flllilllllllllj. a.ulll: l1wl wn na significlnt cltflnace 1124 hOUII. All rnri1l. lhelt were more !lllieniJ il the t.fA P41 Mill milnl or na dillebiily 38%, p=0.031. lntm:nblll hiii"IIIIIIIIQI- nm carrman in 1111 (p<O.OOII. Theru wu no ll9ifart dillaiiiiC8 in morllily. Clllllbia1: Nt.fA given Mhi13 hours of onset rl ICUll ilchlnic llrOiai lllll:tionllaub:oml 1113li'IJIIIIIL The riskrliml:nlnl il ilcrNied. Mlllndm: Whea IHSieSied It 12 months flumtile lima rJ ..... plliam. inthll3.
morll8y or rail rJ 11am111 strolrl 'IEJIJ 1 999;

Practical Guidelines general

ABC's, check glucose, urgent CT to rule out hemorrhage and assess infarct other labs and tests: CBC, PTT, INR, ECG

diagnosis make the correct etiological diagnosis so you have a rational approach for secondary
prevention of stroke consider transfer to stroke centre for neuroprotective or thrombolytic therapy if the patient is seen in first few hours (have been proven effective in clinical tests)

rt-PA (recombinant tissue plasminogen activator) within 3 hours of acute ischemic stroke onset (NINDS trial) treated patients were 30% more likely to have minimal or no disability at 3 months 6.4% of patients had a symptomatic intracerebral hemorrhage (0.6% in placebo group) treatment did not affect mortality compared to placebo but patients with severe strokes were more likely to have favourable outcomes if treated with rt-PA, benefits of rt-PA were sustained at 12 months

na dillebiily, willlll!llignifil:ant difln1ce in


Toronto Notes 2011 Anti-Platelet Therapy


Neurology N47

give ASA at presentation give antiplatelet agents if ASA not suitable or if already taking ASA clopidogrel (75 mg daily) ASA + dipyridamole (Aggrenox)



Table 23. Treatment

Condition Antiplatelet




Carotid Stanalis
TIA Cardiac Carotid or

noncamprauibla silll, sBP >185, dBP >110,aggressiveRx to d8CI'88Sa BP. uncontroUad serum glucose,1hrombacytopenia, PMH ICH, Sx of SAIVparicllldiliili/'MI, pregnant.

Alllollllll Cantraindicltio to tPA Improving Sx. minor Sx, hemorrhage or mns an CT. high INR or aPTT, uizln at &troks annt, 111cent ITllljar &llfllllry or tnluma, recent Gl or urinaty hamonhaga, recant LP or arterial punctu11111t

+ (carotidl



Cardiac Carotid or vertibmbasilar dipyramole, tidopidine, dopidagrel

+ (carotidl


Anticaagulllio1: Heparin IV to ll!liii'DPriate lllrget level then warfarin to INR 2-3 lbrombalrti:: 1h IV infusion of ll!Cambnmt tissue plasminogen activator (rt.PAI for ischemic stroke within 3h of stroke onset Get 24h CT to 1\10 ICH. Also aptian of intra-erterial tPA for specific dinical silliBtians

Rlllti11 contrlindicltion to tPA Early signs of I111Q8 cnbral inflllrc;tion, NIHSS >22. resistant HlN, >85, Hx AVM or ansury&m.

Carotid Endartereclllmy: 50-99% stenosis with law risk of periapellltive death or disabling strDks

Blood Pressure Control

do not lower the blood pressure unless the hypertension is severe antihypertensive therapy is withheld for at least 5 days after thromboembolic stroke unless there is acute MI. renal failure, aortic dissection, sBP above 220 mmHg. or dBP above 120 mmHg acutely elevated BP is necessary to maintain brain perfusion most patients with an acute cerebral infarct are initially hypertensive and their BP will fall spontaneously within 1-2 days IV labetalol is usually first line ifneeded
Blood Sugar



BP llllllt be lowered to sBP < 185 and dBP < 11 0 before IPA is given.

avoid hyperglycemia which will increase the infarct size


. . . . ..,.. . . . Sinllllrill I.MCtlt 1997; 341:15i..S1 lludy: llllndDniled, C11J1111rilh'lith 6munlll

IUipiiCtld ICUIII isclaric llnlial rl racaat onset

prevent complications NPO if swallowing difficulty DVT prophylaxis iflimb weakness initiate rehabilitation therapy (see also Primary and Secondary Prevention below) determine the vascular territory and etiology, then treat accordingly lower temperature if febrile

Primary and Secondary Prevention

Carotid Territory Event


carotid endarterectomy benefits those with symptomatic severe stenosis (70-99%), and is less beneficial for those with symptomatic moderate stenosis (50-69%), see Neurosw:w:y. NS21
Asymptomatic Carotid Bruit

suggests the presence of atherosclerotic stenosis and signifies increased risk for both cerebral and myocardial infarction modify risk factors, antiplatelet therapy if stenosis >60%, risk of stroke is 2% per year; carotid endarterectomy reduces the risk of stroke by 1% per year (but 5% risk of complications)
Hypertension primary prevention

'-dllge.111d 110 clair ildicllions lor, 111 CGIIIIU!dicdons ID, heparin 111 aspiin. lnl!rvenlion: Hlll111e patients- IIOI:IIed ldraclianlllcl hl,.m 15000 ar 12,500 Rl bidL IIJid hd- -lllaCitBd baplrin; Similllly, hill wn llloCIIBd :m mg daily. 1M pllilnls wn lllllomly ID riCIM apirin, hlplrin, halh, Cllllllilllar. Mthin IMYMb, ud dlltll ar deplndiiiC:y It 6manllll. blalll: FGr ba1ll hepllil vs. 110 heparin and aspiril vs.110 lll'iill. lher8 WISIIO 'aniiCIIt diffniCI in d8l1h Ill ZwnQ. or dNth dlpendlncy 116 manllll. Bath aspirin and bupuiHIIaCitBd pllilabi hid raaDII ilchumic lfnlbl \'lithil 14 days, aflsll byalimila'-lilld i.._. in hlllllllllllgic lllab il t!ae M,lrin. Afflr llljlltmeol fw prudielld ]RQIIIIIil, liltJ 8ipirin gnllp I decrelled list of delllll 01 depellllence d 6111rils 1141* 1000 18wir, p=D.ll31. Canlbin: TheiST IUIIQIIIJ thlt 11piin slaJid be lllftad inrnednly llftaollle onset rl ilch8mic

1Jm1111n 48 hL willl110 ll'idlnCI!i illnmnill


antihypertensives reduce the risk of ischemic stroke in elderly patient with isolated systolic hypertension (SHEP trial) ramiprillO mg OD is effective in patients at high risk for cardiovascular disease (HOPEStroke trial) ACEI reduce the risk of stroke beyond their antihypertensive effect secondary prevention ACEI and thiazide diuretics are useful in patients with a Hx of stroke/TIA (PROGRESS trial)

N48 Neurolo8Y


Toronto Notes 2011

Anti-Platelet Therapy primary prevention current evidence has not finnly established a protective role for antiplatelet agents for low-risk patients without a prior stroke/TIA secondary prevention generally ASA is chosen as the initial antiplatelet of choice for stroke prevention other agents (ASA + dipyridamole; clopidogrel) are reserved for those who suffer cerebrovascular symptoms while on ASA warfarin is generally reserved for specific indications in stroke prevention, dissection, cardiac!atrial fibrillation, venous thrombosis
CVmomity Al-c:IUIIII rn!ltlly

100 fC!]

S1roka 32\ (1 61u 441 67(431u 1451 ML slnlb, ar Z2\(141D3Ill Z6{191D431

16\ (5tu 251 56 {321u 1SSI


TNIImaotwMh llllliprillWdUCid the rill: of IIIW (3A piiRII'IIvs. 4.1 piii'CIIII; 11ft 0.&8; Clldlsla1: 1n lilts atliah rilkfor ClldwasaW mri1ri reU:ed !be risk rA slroke. as wd II oii'411W MID and 01'81111 mor111ty,

Hypercholesterolemia primary prevention statins reduce the risk of stroke in patients with CAD or at high risk for cardiovascular events, even with normal cholesterol (CARE study) secondary prevention more evidence is needed for high-risk patients with symptomatic cerebrovascular disease, but statins are generally used in these patients as well Atrial Fibrillation primary and secondary prevention warfarin is the first-line agent Smoking primary prevention smoking increases risk of stroke in a dose-dependent manner secondary prevention after smoking cessation, the risk of stroke decreases to baseline within 2-5 years Physical Activity regular physical activity is an important lifestyle measure in stroke prevention and this effect has a dose-response in terms ofboth intensity and duration of activity

S1llill il 511111 ,...._ ..RtiiiF Hurt

t.af21)02; 380:7-22 S1ully: llltldani1ld. diUIIII-illild, pllllllbocanballd trill Mil ... rA 5Ylll', . . . 20 538 plllienls aged 40 tl80 1811 (28\ rA 1Q8. 75\ l1lllll willl nomtlilg 111111 \'olio were CDIIIidenid 1D be IIIUbPnlillS.,., rill: rJ d81111 frlln CD101111Y MlllciualbecUirA dilllll, dilbetJs, 111 trOd hv1ftnllion. IK rJ pdlllll 1-.d kraw t:erebravlscullt diseue. Eldlsions ilcludld clmc lwr rA lllnornl lim 111 flllction. 1I'IISCie disuse.llld oO!ers. 1.-..-: RurHn1lllllm8nt 4wll8b rA piiCibo fallowld bv 4-6 Mlb rJ I ro.J dDsl rA 40 llrJ lirrwu11tii dUy. Pl&ra were111eri !lllbnimd 1D lm-tllin 40 II1IVd 01 pllcabo. Mlil Ou1amll: lnclJded lkuallld vacull Tnlltlly, llllj01 CDIDI1IIY events. 11d slnlb. IIIUII:

Stroke Rehabilitation
individualized based on severity and nature of impairment; may require inpatient program and continuation through home care or outpatient services multidisciplinary approach includes dysphagia assessment and dietary modifications communication rehabilitation cognitive and psychological assessments including screen for depression therapeutic exercise programs assessment of ambulation and evaluation of need for as&istive devices, splints or bracing vocational rehabilitation


RRR (MC!J NNT !CII S1roka M(151u34l 73(511D131I Major C11M111Y Z7\ (21 1D 331 33 (261u 461
13\ (61u 19) 58 (371D 128)

Al-c:ue rn!ltlly

CllldlliD1: SimWSIIIin llf8ly Nduced 1118 Iiiii: rA ltiGII,I1lljorC011111ryMIIIS,IIId lklusa Tnlltlly ill pelilnts llliPICUII5 yaw risk rJ CUftlllllryhelrtdi-e.

Toronto Notes 2011

Multiple Scleroais (MS)

Neurology N49

Multiple Sclerosis (MS)

Multiple Sclerosis: a chronic inflammatory disease of the CNS characterized by relapsing remitting, or progressive, neurologic symptoms due to demyelination and early relative sparing ofaxons
Relapsing Remitting

Clinical Patterns of MS (Figure 23)

relapsing remitting (RRMS) 85%, primary progressive (PPMS) 10%, progressive relapsing (PRMS) 5%, secondary progressive (SPMS) RRMS can become SPMS



I ,.


Prograsaiva Relapsing

Devic's =Neuromyelitis optica (NMO): severe optic neuritis and extensive transverse myelitis extending >3 vertebral segments Benign MS: RR without major disability by 10 yau-s CJinically Isolated Syndrome (CIS): single MS-like episode CJinically Absent MS: MRI disease only 'I\unefactive MS: solitary lesion >2 em mimicking neoplasms on MRI Fulminant MS (Marburg): rapidly progressive and fatal MS associated with severe axonal damage, inflammation, and necrosis Acute Disseminated Encephalomyelitis (ADEM): monophasic demyelinating disorder with multifocal neurologic symptoms seen mainly in children often following infection or vaccination

Figure 23. Clinical Patterns of MS

genetic polygenetic: the HLA-DR2 gene has been demonstrated to be a genetically susceptible area. 30% concordance for monozygotic twins, 2-4% risk in offspring of affected mother or father environmental MS is more common in region with less sun exposure and thus lower stores of vitamin D MS has also been linked to certain viruses, in particular an association with EBV has been found

onset 17-35, 3F:1M, except PPMS occurs in an older population with 1F:1M

Dissemination in Space and in Time as based on the revised McDonald criteria Dissemination in Time: 2 or more attacks, new gadolinium enhancing lesion 3 months later, or new T2lesions > 1 month after first attack Dissemination in Space: clinical evidence of 2 or more lesions; or three of [1 gadolinium enhancing or 9 T2lesions], [1 infratentoriallesion], [1 juxtacorticallesion], [3 periventricular lesions]

Features symptoms in order of frequency: fatigue, depression, numbness, weakness, visual disturbance, bladder dysfunction, spasticity, impaired gait, cognitive disturbance, pain Lhermitte's sign: flexion of neck causes electric shock sensation down back into limbs indicating cervical cord lesion Uhthoff's phenomenon: worsening of symptoms (classically optic neuritis) in heat SPMS: classically weakness oflegs in pyramidal distribution paired with cerebellar findings of arm (ie. intention tremor) symptoms not commonly found in MS: visual field defects, aphasia, apraxia, progressive hemiparesis



Mort aymptoms in MS n duiiD cont brainsbm and optic nerve lesions.

MRI: demyelinating plaques appear as hyperintense lesions on T2 weighted MRI, with active lesions showing enhancement with gadolinium typical locations: periventricular, corpus callosum, cerebellar peduncles, brainstem, juxta cortical region, and dorslateral spinal cord Dawson's fingers: periventricular lesions extending superiorly into corpus callosum CSF: oligoclonal bands in 90%, increased IgG concetration evoked potentials (visua1Jauditory/somatosensory): delayed but well-preserved wave forms

N50 Neurolo8Y

Multiple Sclerosis (MS)

Toronto Notes 2011


Aaltllllt. D.a,iq c-.ian llflbllftl E.-lllblliplllc:ln* Codnle Brtllllse Sytt Rer 2008; 2:Cil005218. SlUr. Coclme rjSllmltic !Miw. 2 RtT and qulli.ftct 1160 pilieals with fiest ridarnywlrm wilh lnin MRI (cliicllly ilolllled syndromes, CS).
plabo. (No IIIJpraprilll glllinrnlr ICitllllrilll W8llllaurJ).

COIM!rtiag 1D liliclly deliile t.IS, and .tvene lfllcts.

11116: Apooled odds 111iD (OR) rl 0.53 [(5\ Cl 0.10.71, p<D.Wll)forpatilllts an fNV811US It one M'O odds ndiowu 0.52 (95\, D.llll.71l, Tbara
1llllmlntCIIdlliy prog181si011

Treatment acute treatment: methylprednisolone 500-1000 mg IV daily X 3-7 days taper diseue modifying therapy (DMT): interferon-beta (Betaseron, Avonex, RebW), glatiramer acetate (Copaxone) and natalizumab (Tysabri) CIS: early treatment with Avonex may delay potential second attack RRMS: DMT reduces rate of relapse by 30%; attacks shorter and less severe SPMS: interferon-beta may slow progression PPMS: immusuppressant therapy (e.g. Methotrexate) symptomatic treabnent spasticity: baclofen, tizanidine, dantrolene, benzodiazepine bladder dysfunction: oxybutynin pain: TCA, carbamazepine, gabapentin fatigue: amantidine, modafinil, methylphenidate education and coUD8eling: MS society, support groups, psychosocial issues Prognosis good prognostic indicators: female, young, RRMS, presenting with optic neuritis, low burden of disease on initial MRI, low rate of relapse early in disease PPMS: poor prognosis, higher rates of disability, poor response to therapy

1D lilicdv delnile t.tS pllienls Mil em in _..,..limlfllml.

Tabla 24. Common Madications Medlanilm af


Gclllric Name kll'odupa + carbidupa


Carbidopa 25 ml)'levodopa 100 mg PO 1id Maxinum 200 mg carbidopa and 2000 mg levodupa per day

lllllcdons Partanson's Disease

N51UW-Ingle glaucoma. use of MAO inhibitor

Side Ellecll
Nausea, hypotension, hlllklcillllions, dyt;kinesias in last 14 days, hiSIOry of melanoma or undiagnosed skin lesions Hypotension. 1111usea. dizziness, constiplllion. diarrllea, vomiting, abdominal cramps, headache, nasal congestion, chwsiness, halklcinations Headache, insomnia, dizziness, nausea, dry mouth, hallucinlllions, confusion, orthostlllic hypotension, increased akinesia. risk of hypertensive crisis with tyramine-containing foods Nausea, diarrllea. abdominal cramps, increased periistalsis, increased salivation, increased bronchial seavtions, miosis, diaphoresis, muscle cRimps, fascicullllions, muscle weakness Dizziness, senurtion of hlllll. hypertllnsiva aisis, disease. peripheral vascular disease, coronary artery vasospasm, cardiac anest. nausea, vomHing, headache, hyposalivation, drowsiness Coronary artery vasospasm, transient myocardial ischemia, myocardial infarction. vtntricular tachyclldia, vantricU&r fibrilllllion. May caue significant rebound headache CNS disturbances (drowsiness, headache, unsteadiness, dizziness!, 1111usea/vomiting, skin rash, anamia Nausea, dianhea, insomnia, muscle cRimps, fillip, and anorexia Injection II!ICiions. injection site necrosis. flu-like symptoms (fever, chills, myalgia) tend to decrease overtime Transient drowsiness. daytime sedation, dizziness, Makness. fatip, convulsions, hypotonia, hypersensitivity to donepszil or to piperidine

Dupwine ptVCUr&llr

Dop511ine agonist



1.25 mg PO bid. increase by 2.5 mgld q2-4wks, up to 10-30 mg PO tid

Partanson's Disease

Concomitant use of potent inhibitors of CYP3A4, uncontrolled hypertension, ischemic heart disease, peripheral vascular disease. Caution with renal or hepatic diseil5e Concomitant use of meperidine or tricyclic IIIJiid8pniiiSanl8

... ...





Partanson's Disease




600 mlfd PO divided in 5-6 doses Range 6().1500 mlfd

Myastlllllia Gravis

Gl or GU obstruction



2ft.1DO mg PO pm, maximum 200 mlfd






Hemiplegiclbasilar migraine, ischemic heert disease; cnl!rovascdar disease. uncontroled hypertension. use of in past 24 hours, use of MAO inhibitor in last 14 days, SMre hepatic disease Hemiplegiclbasilar migraine, higiKiose ASA therapy, uncontrolled hypertension, ischemic heart disease, peripheral vascular disease, IIIMII8 hepatic or ranal dysfmction, use of triptans in last 24 hours; use of MAO inhibHors in last 14 days Hisllly d bone llllllllW depression, hepatic disease, hypersensitivity to the drug, or known sensitivity to tricyclic compounds such as Hypersensitivity to dunepezil or 1o piperidine derivatives Pregnancy, hypersensitivity to nllllnl or recombinant interferon beta Hypersensitivity 1o baclofen (Spinal Cord lnjlry)

Nasal spray 0.5 mglspray, maximum





EpitolinUSAI Cholinesterue lnhibHor donepszil

Start at 106-200 mg PO 0[).bid,

increase by 200 mgld up to 800-1200 mlfd (individual doses) needed

Epilepsy- partial :!: 2" generalillltion; ganeralizlld tonic-i:lonic Mild to moderatll Alzheimer's Oisease, Lewy Body Disease Relapsing.&mitting and Secondary Progressive Mulitple Sclerosis Spasticity (i.e. MS)


5mg PO OD, may increase to 10mg PO OD altar 4-6 Meks Betaseron111 0.25 mg (8 MU) SC every other day


interferon bet&-, b

Muscle RelaxantAnti spastic



Up to 20 mg PO qid. variable for intrathecal route

Antispasmodic Anticholingergic oxybutynin clbide Ditropen111 SmgPObid neurogeric bladder or reftex neurogenic bladder Glaucoma, Gl obstruction, megacolon, severe rnylsthenia pis, obstructive uroplllhy, hypersensitivity to Cllybutinin Headache, pain, dry mouth. constiplllion, urinllrV retention, diarrhea, nausea. dyspepsia, dizziness


N52 Neurolo8Y

Landmark Neurology Trials/References

Toronto Notes 2011

Landmark Neurology Trials


NEJM 1991; 7:445-53 NEJM 1995; 333:1581-7 NEJM 2008; 359:1317-29 NEJM 2008; 359:1238-51 NEJM 2006; 355:549-59 NEJM 2001; 345:311-8

Patienl1 with sy111:1tama1ic cellllid stenosis of 71}.9!1% benefited more from carotid endartarectomy 1han bast medical therapy


tPA reduces mortality llld long-tenn disability when ministered within 3 hours of aculll straka tPA improved clinical ouii:Qmas wla1 adminislllrad within 3to 4.5 hours of aculll ischemic strokB


Tempcnllobe epilepsy + surgery

ASA + dypiridamole and clopidop showed similar banslits in secondary

strokB prevention
The observed benefit of sllltins in patienl1 with a recent stroke or TIA disease is also axlllnded to

Surgery is superior to prolonged medical therapy in !Brqlorallobe epilepsy

Bnil Dlllh Wjdicu EF. Tha
Br11in Dallth. NFJM 2001; 344116): 1215-21.


Blidayasiri R, Waters MF. Gila CC 12005). Neurological dillarill dillgllOiis: a prioritized IPIIfDlCh. M1111clllletles: Blactwel Publisliing. pp.712. Kaaper II. hnvald E. lUi AS. HM1181 Sl. LDrQo DL. Jamalltlll JL.Ids 12005). Harrison's inlllmll medicioa, 16th ldition. TGIOI11D: McGtaw-Hill pp. 162&-30. C1111111an Prasanting !'.on1111illll Blidayasiri R, Waters MF. Gila CC 12005). Neurological dillarill dillgllOiis: a prioritized ljlpiOICh. MISSicl'llletles: Blactwel Publisliing, pp. 12-13,


Amblti BK. Slmh WT, Azer-Benlsilnov MT 120011. Residents manull of medicine. Hamilton: BC Declalr, pp. 211-13. Carpenter CCJ, Gri!IIIS RC. Losc:alill J. eds 120011. Cecil Essentials ci metile. 5th edition. Viii! Saunders Ca. pp. 97U. FeTri FF 12001 1'rlelical to lila c1111 medical plllient St Mabsy Inc. pp. 654-656. NOKWOrlllv Jlll!Jcdinetli C. Rodri!Ja M. Weilshe!U BG. t.Uiiple sclerosis. NEJM 2000; 343l131: 938-52. Dlak MJ, ad (2005). t.Uiipluclerosis: lllialagy, dilgnasis, and newtrt811Nnt 111111gits. New Jersev: Humana Prea Inc, 3640, 57, 131, 22223. Slllllllls MA. Feslil SK. eds DHice ]IIICiice of niiiiUIDgy. 2nd dian. Plillldei!Da: Else\lier Sc:iell:e. pp. 410-11. Palmln CH, ltlinglil SC. dan ll. Filippi M. Harlq HP, Kappas I, IIIII. Dilgnasli: critmia far multiple sclllr111is: 2005 ravilianstothe "Mcllanlld Crilaril". Ann Naurol 2005 Dac;58t6l:840-6. Parsistant V8ga1ativa State II. hnvald E. Fu:i AS, HIUSel' Sl. lDrQo DL. Jamelltlll JL. eds 12005). Harrison's rl internal medil:ine, 16th edition. TGIOI11D: McGtaw-Hill pp. 1625.


Claaificatian Subcammitlee rl the 24IS11:9-160. http;l/

Headadle Society. The 1nllmatimal Claaificatian rl Headadle Disoolen, 2nd edition.



llizlnlallld Efilaply Amblti BK. Slri1h WT, MT 12001). Rlllidilnts manull of medicine. Hamilton: BC Declalr, pp. 203mi. Ferri FF 1200n 1'rlelical !ollie care lithe medical plllient St Mobiy Inc. pp. 617-9. Carpen!Br CCJ, Gri!IIIS RC. Losc:alill J. ads (2001). Cacil Essentials ci rnlliciie. 5th edition. Viii! Saundln Co, pp. 95U4. Griggs RC Cecil EsSIIIIials of Mldicine7th Edition Andraall CaTpenr. Griggs, Barjllrjn. Saundi!S EI18Vill pp 1120-41.
IMitul E,ilptic lcMtanstlii Dll Ailrldgl BK. Statuupllplicus. NEJM 1998;338114):970-6. Spinal CGrd .,.._ W.Ur R, Jarjodll A. Naurulogie Spill! t:Qid l'j!JIIllllllll. Enlll'g Med Cfric North Arraica1897; I513): 69&-711.
S1llb lildsay K. Bane L. 2003 Neu10bgy and 1Jstr1ted. Cluchii.Ningstone p. 244. Fnmllnl W, Silver J. (20021 Eslllnlills of Physical Mliiciia and lllhebililllian. Philldllphia: Hlriay and Beluslnc., p. 171-782. Drganimd Qatiellllstroke 111i1j care lor stroke (Stroke Unnrialis11' Colllbora1ian). The Coclme Da!Bbne ci Systematic Reviews2001; IBie 3. Johnston SC, RIIIIIMII PM, MN, Gills MF. Bkins JS, Bamrlllin Allll al. Validlliln IIIII raiDrnant of scarasto p!lldict vary 111rt, stroke risk llftar


lrMsienl ischlemic lllllck. Lancet2001;368:283-92. M1m11s, D.


Cllvnic Pain- APrimary Guile to l'nlctical Mlnag...rt. Nlw JllrWf. llnna111 Praa. p. 111-28.


Aminal! MJ. Graenb1111 1:\\ Simon RP.I.ai9: Clnical 61h lditian. TGIOI11D: Mcllllw-llill Campania, Inc. pp. 254-56. 1ilardars Motor Syslam Marshlll FJ. Cecil Essentials ol Medicine 7111 &ltianAndreoli, Carpenter, Griggs, Benjanin. Salrlders BseWer pp 1090-100. Dlllllllil Patler1011 C. Feighlner JW, Garcia A, GY. MacKnight C, Sadolmick AD. Diagnosis and 1relllmelll ol dementia: 1. Risk assessment and primary prevention ci Alzhllimardil8u8. CMAJ. 2008 Fab 26;178151:548-S&.Reviaw. Feldman Hll Jacava C. Robilard A. Garcil A. Chow t Berrie M, et al and 1relllmelll rl dementia: 2. Diagnosis. CMAJ. 2008 Mardi 25; 118(7):825-36.

and l'rMIIilll....,.lltiC Nualgia: An CIINII rilk llcl1n ullfll il ciical 'ractil:l? CD811 PG. Sc:utt F, Lllldlllm-Gr&llll Mlit al. Chi]J!er 24 Nuak9:11sarders Yamada KA. AMdlllll S. The Washington Mlnualci Madi:al Tharspllllics, 3111 Edition. UppincDI rnl WAins J1P 531534.