See page 1245 or

slreuglhoevideuce
labels.
Jhe ouliueouly versiou o
lhis arlicle, which oers
uore delailed iuorualiou
ou addilioual selecled
causes o uuscle weak
uess, is available al.
hllp.//www.aap.org/
ap/uRL.
M
uscle weakness is a common
complaint among patients
presenting to the family phy-
sician`s office. Although the
cause of weakness occasionally may be appar-
ent, often it is unclear, puzzling the physician
and frustrating the patient. A comprehen-
sive evaluation of these patients includes a
thorough examination and coordination of
appropriate laboratory, radiologic, electro-
diagnostic, and pathologic studies.
DefiniIions
Determining the cause of muscle weakness
involves distinguishing primary weakness
from fatigue or asthenia, common condi-
tions that differ from, but often overlap
with, muscle weakness.
1
Fatigue describes the
inability to continue performing a task after
multiple repetitions; in contrast, a patient
with primary weakness is unable to perform
the first repetition of the task. Asthenia is
a sense of weariness or exhaustion in the
absence of muscle weakness. This condi-
tion is common in people who have chronic
fatigue syndrome, sleep disorders, depres-
sion, or chronic heart, lung, and kidney
disease.
1
Because these conditions are preva-
lent in the ambulatory population, family
physicians can expect to encounter patients
with asthenia and fatigue more frequently
than those with intrinsic muscle weakness.
1
Selected causes of asthenia and fatigue are
listed in Table 1.
1
Unfortunately, the distinction between
asthenia, fatigue, and primary weakness
often is unclear. Patients frequently con-
fuse the terms, and the medical literature
sometimes uses them interchangeably.
2
In
addition, a patient`s condition may cause
progression from one syndrome to another;
for example, asthenia in a patient with
heart failure may progress to true muscle
weakness through deconditioning. Further,
asthenia and fatigue can coexist with weak-
ness, such as in patients with multiple scle-
rosis and concomitant depression. Because
depression is so prevalent, it is essential to
consider it as a possible cause of a patient`s
symptoms; diagnosis can be facilitated by
using one of the several validated screening
tools designed for the outpatient setting.
3,4
This article discusses only intrinsic muscle
weakness in adults.
Muscle weakness is a common complaint among patients presenting to family physicians. Diagnosis begins with a patient
history distinguishing weakness from fatigue or asthenia, separate conditions with different etiologies that can coexist
with, or be confused for, weakness. The pattern and severity of weakness, associated symptoms, medication use, and fam-
ily history help the physician determine whether the cause of a patient's weakness is infectious, neurologic, endocrine,
inflammatory, rheumatologic, genetic, metabolic, electrolyte-induced, or drug-induced. In the physical examination, the
physician should objectively document the patient's loss of strength, conduct a neurologic survey, and search for patterns
of weakness and extramuscular involvement. If a specific cause of weakness is suspected, the appropriate laboratory or
radiologic studies should be performed. Otherwise, electromyography is indicated to confirmthe presence of a myopathy
or to evaluate for a neuropathy or a disease of the neuromuscular junction. If the diagnosis remains unclear, the examiner
should pursue a tiered progression of laboratory studies. Physicians should begin with blood chemistries and a thy-
roid-stimulating hormone assay to evaluate for electrolyte and endocrine causes, then progress to creatine kinase level,
erythrocyte sedimentation rate, and antinuclear antibody assays to evaluate for rheumatologic, inflammatory, genetic,
and metabolic causes. Finally, many myopathies require a biopsy for diagnosis. Pathologic evaluation of the muscle tissue
specimen focuses on histologic, histochemical, electron microscopic, biochemical, and genetic analyses; advances in tech-
nique have made a definitive diagnosis possible for many myopathies. (Am Fam Physician 2003;71:1327-36. Copyright
2003 American Academy of Family Physicians.)
Evaluation of the Patient with
Muscle Weakness
AARON SAGUIL, CPT (P), MC, USA, Madigan Army Medical Center, Taccma, \ashingtcn
April 1, 2005
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1328 !MERICAN &AMILY 0HYSICIAN www.aafp.org/afp Vclume 71, Number 7
U
April 1, 2005
DifferenIiaI Diagnosis
Conditions that result in intrinsic weakness
can be divided into several main categories:
infectious, neurologic, endocrine, inflam-
matory, rheumatologic, genetic, metabolic,
electrolyte-induced, or drug-induced.
In adults, medications (Table 2
5,6
), infec-
tions, and neurologic disorders are common
causes of muscle weakness. The use of alco-
hol or steroids can cause proximal weakness
with characteristic physical and laboratory
findings.
5,7,8
Infectious agents that are most
commonly associated with muscle weakness
include influenza and Epstein-Barr virus
(Table 3
6,9-12
). Human immunodeficiency
virus (HIV) is a less common cause of
muscle weakness but should be considered
in patients with associated risk factors or
symptoms.
6,9
Neurologic conditions that can
cause weakness include cerebrovascular dis-
ease (i.e., stroke, subdural/epidural hemato-
mas), demyelinating disorders (i.e., multiple
sclerosis, Guillain-Barr syndrome), and
neuromuscular disorders (i.e., myasthenia
gravis, botulism). Localizing neurologic
deficits can help the physician focus the
diagnostic work-up
6,10-12
(Table 3
6,9-12
).
Less common myopathies include those
caused by endocrine, inflammatory, rheu-
matologic, and electrolyte syndromes
(Tables 4
5-8,13-26
and 5
6,8,15,16,18,20,24-38
). Of
the endocrine diseases, thyroid disease is
common, but thyroid-related myopathy is
uncommon; parathyroid-related myopathy
should be suspected in a patient with muscle
weakness and chronic renal failure.
14,15,32
Inflammatory diseases typically affect older
adults and include both proximal (poly-
myositis and dermatomyositis) and dis-
tal myopathies (inclusion body myositis);
the proximal inf lammatory myopathies
respond to steroids.
21-23
Rheumatologic dis-
orders causing weakness, such as systemic
lupus and rheumatoid arthritis, can occur
in young and elderly persons.
17,18
Disorders
of potassium balance are among the more
common electrolyte myopathies and may be
primary (such as in hypokalemic or hyper-
5IrengIh of ecommendaIions
rey c||n|ca| recommenda||on |abe| |e|erence:
ll is essenlial lo consider depression as a possible diagnosis, several screening
lools lor depression have been validaled lor use in oulpalienl sellings.
A 3,4
Primary muscle weakness musl be dislinguished lrom lhe more common
condilions ol laligue and aslhenia.
C !
ll lhe diagnosis is slill inconclusive aller lhe hislory, physical examinalion, and
laboralory, radiologic, and eleclromyographic evalualion, a muscle biopsy is
required lor palienls who have a suspecled myopalhy.
C 4!
A = con:|:|en|, ood-qua|||y pa||en|-or|en|ed ev|dence, b = |ncon:|:|en| or ||m||ed-qua|||y pa||en|-or|en|ed ev|dence,
C = con:en:u:, d|:ea:e-or|en|ed ev|dence, u:ua| prac||ce, op|n|on, or ca:e :er|e:. 5ee pae 124 |or more |n|orma||on.
1A8LL 1
Causes of AsIhenia and faIigue
Addison's disease
Anemia
Anxiely
Chemolherapy
Chronic laligue syndrome
Chronic pain
Decondilioning/sedenlary
lileslyle
Dehydralion and eleclrolyle
disorders
Depression
Diabeles
libromyalgia
Hearl disease
Hypolhyroidism
lnleclions (such as inlluenza,
Lpslein-8arr virus, HlV, hepalilis C,
luberculosis)
Medicalions
Narcolics
Paraneoplaslic syndrome
Pregnancy/poslparlum
Pulmonary disease
Penal disease
Sleep disorders
||v = human |mmunode||c|ency v|ru:.
Adap|ed w||h perm|::|on |rom ||n:haw |b, Carnahan I|, Iohn:on ||. |epre::|on,
anx|e|y, and a:|hen|a |n advanced |||ne::. I Am Co|| 5ur 2002,19.276.
April 1, 2005
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Vclume 71, Number 7 www.aafp.org/afp !MERICAN &AMILY 0HYSICIAN 1329
MuscIe Weakness
kalemic periodic paralysis) or secondary
(such as in renal disease or angiotensin-
converting enzyme inhibitor toxicity).
Patients in whom these disturbances are
suspected should have electrocardiography
to screen for cardiac sequelae.
13,27-30
Rare causes of muscle weakness include
genetic (muscular and myotonic dystro-
phies), metabolic (glycogenoses, lipidoses,
and mitochondrial defects), and sarcoid-
and amyloid-associated myopathies
24-26,34-38
(Tables 4
5-8,13-26
and 5
6,8,15,16,18,20,24-38
).
HisIory
Once muscle weakness has been differenti-
ated from asthenia and fatigue, the physi-
cian should ask the patient about disease
onset and progression. Acute onset may
indicate infection or stroke. Subacute onset
may implicate drugs, electrolytes, or inflam-
matory or rheumatologic disease. Chronic
progressive weakness is the classic presenta-
tion in genetic and metabolic myopathies.
Despite these generalizations, there is consid-
erable variation in the time courses of differ-
ent classes of myopathy, and even within the
individual disorders. For instance, although
typically subacute, myasthenia gravis may
present with rapid, generalized weakness or
remain confined to a single muscle group for
years (as in ocular myasthenia).
12
Because of this variability, the pattern of
muscle weakness is crucial in differentiating
the etiology. The physician should estab-
lish whether the loss of strength is global
(e.g., bilateral; may be proxi-
mal, distal, or both) or focal.
Focal processes (those that are
unilateral or involve specific
nerve distributions or intra-
cranial vascular areas) tend to
be neurologic-although not
all neurologic processes are
focal-and may require a different approach
than that used with global strength loss.
In patients with diffuse weakness, the
physician should determine whether the loss
of function is proximal or distal by noting
which physical activities muscle weakness
limits. If the patient has difficulty rising from
a chair (hip muscles) or combing his or her
hair (shoulder girdle), the weakness is proxi-
mal; if the patient has difficulty standing
on his or her toes (gastrocnemius/soleus) or
1A8LL 2
MedicaIions and NarcoIics
IhaI Can Cause MuscIe Weakness
Amiodarone (Cordarone)
Anlilhyroid agenls. melhimazole (Tapazole),
propyllhiouracil
Anlirelroviral medicalions. zidovudine
(Pelrovir), lamivudine (Lpivir)
Chemolherapeulic agenls
Cimelidine (Tagamel)
Cocaine
Corlicosleroids
libric acid derivalives. gemlibrozil (Lopid)
lnlerleron
Leuprolide acelale (Lupron)
Nonsleroidal anli-inllammalory drugs
Penicillin
Sullonamides
Slalins
|n|orma||on |rom re|erence: and 6.
1A8LL 3
InfecIious and NeuroIogic Causes of MuscIe Weakness
InfecIious
Lpslein-8arr virus
Human immunodeliciency
virus
lnlluenza
Lyme disease
Meningilis (mulliple agenls)
Polio
Pabies
Syphilis
Toxoplasmosis
NeuroIogic
Amyolrophic laleral sclerosis
Cerebrovascular disease
Slroke
Subdural/epidural hemalomas
NeuroIogic (con||nued
Demyelinaling disorders
Cuillain-8arre syndrome
Mulliple sclerosis
Neoplasm
Neuromuscular disorders
8olulism
Lamberl-Lalon myaslhenic syndrome
Myaslhenia gravis
Organophosphale inloxicalion
Padiculopalhies
Cervical spondylosis
Degeneralive disc disease
Spinal cord injury
Spinal muscle alrophy
|n|orma||on |rom re|erence: 6 and 9 |hrouh 12.
The use of aIcohoI or sIe-
roids can cause proximaI
veakness viIh characIeris-
Iic physicaI and IaboraIory
findings.
1330 !MERICAN &AMILY 0HYSICIAN www.aafp.org/afp Vclume 71, Number 7
U
April 1, 2005
1A8LL 4
5eIecIed Causes of Primary MuscIe Weakness
Cau:e Wea|ne:: Ae o| on:e|/d|ano:|: 5y:|em|c :ymp|om: and ||nd|n: |abora|ory abnorma||||e: Crea||ne ||na:e ||ec|romyoram |u:c|e b|op:y
Drugs
Alcohol Proximal (may be dislal) Variable Change in menlal slalus, lelangieclasia,
peripheral neuropalhy
Llevaled lransaminase and CCT
levels, anemia, decreased
vilamin 8
!2
Normal lo elevaled Normal Myopalhic changes*, selecled alrophy
ol lype ll muscle libers
Endocrine
Adrenal insulliciency Ceneralized Variable Hypolension, hypoglycemia,
bronzing ol lhe skin
Hyponalremia, hyperkalemia, ACTH
assay, ACTH slimulalion lesl
Normal Myolonic dischargeso Diminished glycogen conlenl
Clucocorlicoid excess Proximal Variable 8ullalo hump, slriae, osleoporosis Llevaled urine-lree corlisol,
dexamelhasone suppression, or
corlicolropin-releasing hormone
slimulalion lesls
Normal Myopalhic MUAPsp Seleclive alrophy ol lype ll muscle
libers
Paralhyroid hormone (secondary
hyperparalhyroidism)
Proximal, lower exlremily
more lhan upper exlremily
Variable, older adull Usually has associaled comorbidilies
(cardiovascular disease, diabeles)
Hypocalcemia, uremia Normal Myopalhic MUAPsp Alrophy ol lype ll muscle libers,
increased lipoluscin benealh cell
membrane, calcium deposils in
muscle
Thyroid hormone
(hyperlhyroidism)
Proximal, bulbar 40 lo 49 years Weighl loss, lachycardia, increased
perspiralion, lremor
Llevaled T
4
and T
3
, TSH
variable, depending on cause
Normal or elevaled Myopalhic MUAPsp wilh or
wilhoul librillalion polenlials[[
Usually normal
Thyroid hormone
(hypolhyroidism)
Proximal 30 lo 49 years Menorrhagia, bradycardia, goiler, delayed
relaxalion ol deep lendon rellexes
TSH Llevaled Wilh or wilhoul myopalhic
MUAPsp and librillalion
polenlials[[
Myopalhic changes*, glycogen
accumulalion
InfIammaIory
Dermalomyosilis Proximal Variable, increased
incidence wilh age
Collron papules, heliolrope rash,
calcinosis, inlerslilial lung disease,
disordered Cl molilily
Llevaled myoglobin, ANA posilive,
myosilis auloanlibodies may be
presenl
Crealer lhan !0 limes
normal elevalions
Myopalhic MUAPsp wilh
librillalion polenlials[[
lnllammalory inlillrale wilh myopalhic
changes* and replacemenl by
adipose and collagen
lnclusion body myosilis Dislal, especially
lorearm and hand
Al leasl 50 years
(younger lhan
50 years. rare)
Dysphagia, exlramuscular involvemenl
nol as common
Llevaled myoglobin, posilive ANA
less common, myosilis
auloanlibodies may be presenl
Llevaled Myopalhic MUAPsp wilh
librillalion polenlials[[
lnllammalory inlillrale wilh vacuoles
conlaining eosinophilic inclusions
Polymyosilis Proximal Variable, increased
incidence wilh age
lnlerslilial lung disease, disordered Cl
molilily, overlap wilh rheumalologic
diseases more common
Llevaled myoglobin, ANA posilive,
myosilis auloanlibodies may be
presenl
Crealer lhan !0 limes
normal elevalions
Myopalhic MUAPsp wilh
librillalion polenlials[[
lnllammalory inlillrale wilh myopalhic
changes* and replacemenl by
adipose and collagen
heumaIoIogic
Pheumaloid arlhrilis local, periarlicular, or dilluse Adull Symmelric joinl inllammalion (especially
MCP, PlP joinls), dry eyes and moulh
Llevaled rheumaloid laclor Normal or elevaled No dala Alrophy ol lype ll muscle libers,
may have overlap syndrome wilh
polymyosilis
Syslemic lupus erylhemalosus Proximal Adull Malar rash, nephrilis, arlhrilis ANA, anli-DNA anlibodies,
depressed C3 and C4
Normal lo elevaled No dala Type ll liber alrophy, lymphocylic
vasculilis, myosilis
GeneIic
8ecker muscular
dyslrophy
Hip, proximal leg and arm Lale childhood lo
adullhood
Menlal relardalion, cardiomyopalhy None Llevaled Myopalhic MUAPsp wilh
librillalion polenlials[[
Myopalhic changes*, decreased and
palchy slaining ol dyslrophin
Limb-girdle muscular
dyslrophies**
Variable, usually proximal
limb, pelvic, and shoulder
girdle muscles
Variable Variable, may have cardiac abnormalilies None Variable, normal, or
elevaled
Myopalhic MUAPsp +/-
librillalion polenlials[[
Myopalhic changes*, may demonslrale
absence ol specilic prolein on
immunohislochemical slaining
Myolonic dyslrophy
lype !
Dislal grealer lhan proximal,
lool drop, lemporal and
masseler wasling
Adolescence lo
adullhood
Conduclion abnormalilies, menlal
relardalion, calaracls, insulin resislance
None Normal lo minimally
elevaled
Myopalhic MUAPsp,
myolonic discharges[[
Less necrosis and remodeling lhan in
muscular dyslrophies, alrophy ol
lype l muscle libers, ring libers
MeIaboIic
Clycogen and lipid slorage
diseases, milochondrial disease
Proximal Variable Variable, exercise inlolerance and
cardiomyopalhy more common
Some glycogenoses associaled
wilh abnormal llLToo
Variable, may increase
wilh exercise
Normal or myopalhic MUAPsp
+/- librillalion polenlials[[
Myopalhic changes* wilh glycogen
deposils, lipid deposils, or ragged
red libers (lor glycogen, lipid, or
milochondrial disease, respeclively)
CC1 = amma-|u|amy||ran:|era:e, AC1| = adrenocor||co|rop|n hormone, |UA|: = mo|or un|| ac||on po|en||a|:, 1

= |r||odo|hyron|ne, 1
4
= |hyrox|ne,
15| = |hyro|d-:||mu|a||n hormone, C| = a:|ro|n|e:||na|, ANA = an||nuc|ear an||bod|e:, |C| = me|acarpopha|anea|, ||| = prox|ma| |n|erpha|anea|,
||C = e|ec|romyoram, |||1 = |orearm |:chem|c exerc|:e |e:||n.
|yopa|h|c chane: are non:pec|||c and |nc|ude a|rophy, deenera||on, and reenera||on o| mu:c|e ||ber:.
o|yo|on|c d|:chare: are a |ype o| pro|oned bur:| o| ac||v||y :een on |n:er||on o| |he ||C need|e.
p|yopa|h|c |UA|: are :hor|er |n dura||on, |ower |n amp|||ude, and po|ypha:|c when compared |o |UA|: |rom norma| mu:c|e.
5econdary hyperpara|hyro|d|:m u:ua||y cau:ed by rena| |a||ure.
|n|orma||on |rom re|erence: |houh 3 and 1 |hrouh 26.
April 1, 2005
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Vclume 71, Number 7 www.aafp.org/afp !MERICAN &AMILY 0HYSICIAN 1331
1A8LL 4
5eIecIed Causes of Primary MuscIe Weakness
Cau:e Wea|ne:: Ae o| on:e|/d|ano:|: 5y:|em|c :ymp|om: and ||nd|n: |abora|ory abnorma||||e: Crea||ne ||na:e ||ec|romyoram |u:c|e b|op:y
Drugs
Alcohol Proximal (may be dislal) Variable Change in menlal slalus, lelangieclasia,
peripheral neuropalhy
Llevaled lransaminase and CCT
levels, anemia, decreased
vilamin 8
!2
Normal lo elevaled Normal Myopalhic changes*, selecled alrophy
ol lype ll muscle libers
Endocrine
Adrenal insulliciency Ceneralized Variable Hypolension, hypoglycemia,
bronzing ol lhe skin
Hyponalremia, hyperkalemia, ACTH
assay, ACTH slimulalion lesl
Normal Myolonic dischargeso Diminished glycogen conlenl
Clucocorlicoid excess Proximal Variable 8ullalo hump, slriae, osleoporosis Llevaled urine-lree corlisol,
dexamelhasone suppression, or
corlicolropin-releasing hormone
slimulalion lesls
Normal Myopalhic MUAPsp Seleclive alrophy ol lype ll muscle
libers
Paralhyroid hormone (secondary
hyperparalhyroidism)
Proximal, lower exlremily
more lhan upper exlremily
Variable, older adull Usually has associaled comorbidilies
(cardiovascular disease, diabeles)
Hypocalcemia, uremia Normal Myopalhic MUAPsp Alrophy ol lype ll muscle libers,
increased lipoluscin benealh cell
membrane, calcium deposils in
muscle
Thyroid hormone
(hyperlhyroidism)
Proximal, bulbar 40 lo 49 years Weighl loss, lachycardia, increased
perspiralion, lremor
Llevaled T
4
and T
3
, TSH
variable, depending on cause
Normal or elevaled Myopalhic MUAPsp wilh or
wilhoul librillalion polenlials[[
Usually normal
Thyroid hormone
(hypolhyroidism)
Proximal 30 lo 49 years Menorrhagia, bradycardia, goiler, delayed
relaxalion ol deep lendon rellexes
TSH Llevaled Wilh or wilhoul myopalhic
MUAPsp and librillalion
polenlials[[
Myopalhic changes*, glycogen
accumulalion
InfIammaIory
Dermalomyosilis Proximal Variable, increased
incidence wilh age
Collron papules, heliolrope rash,
calcinosis, inlerslilial lung disease,
disordered Cl molilily
Llevaled myoglobin, ANA posilive,
myosilis auloanlibodies may be
presenl
Crealer lhan !0 limes
normal elevalions
Myopalhic MUAPsp wilh
librillalion polenlials[[
lnllammalory inlillrale wilh myopalhic
changes* and replacemenl by
adipose and collagen
lnclusion body myosilis Dislal, especially
lorearm and hand
Al leasl 50 years
(younger lhan
50 years. rare)
Dysphagia, exlramuscular involvemenl
nol as common
Llevaled myoglobin, posilive ANA
less common, myosilis
auloanlibodies may be presenl
Llevaled Myopalhic MUAPsp wilh
librillalion polenlials[[
lnllammalory inlillrale wilh vacuoles
conlaining eosinophilic inclusions
Polymyosilis Proximal Variable, increased
incidence wilh age
lnlerslilial lung disease, disordered Cl
molilily, overlap wilh rheumalologic
diseases more common
Llevaled myoglobin, ANA posilive,
myosilis auloanlibodies may be
presenl
Crealer lhan !0 limes
normal elevalions
Myopalhic MUAPsp wilh
librillalion polenlials[[
lnllammalory inlillrale wilh myopalhic
changes* and replacemenl by
adipose and collagen
heumaIoIogic
Pheumaloid arlhrilis local, periarlicular, or dilluse Adull Symmelric joinl inllammalion (especially
MCP, PlP joinls), dry eyes and moulh
Llevaled rheumaloid laclor Normal or elevaled No dala Alrophy ol lype ll muscle libers,
may have overlap syndrome wilh
polymyosilis
Syslemic lupus erylhemalosus Proximal Adull Malar rash, nephrilis, arlhrilis ANA, anli-DNA anlibodies,
depressed C3 and C4
Normal lo elevaled No dala Type ll liber alrophy, lymphocylic
vasculilis, myosilis
GeneIic
8ecker muscular
dyslrophy
Hip, proximal leg and arm Lale childhood lo
adullhood
Menlal relardalion, cardiomyopalhy None Llevaled Myopalhic MUAPsp wilh
librillalion polenlials[[
Myopalhic changes*, decreased and
palchy slaining ol dyslrophin
Limb-girdle muscular
dyslrophies**
Variable, usually proximal
limb, pelvic, and shoulder
girdle muscles
Variable Variable, may have cardiac abnormalilies None Variable, normal, or
elevaled
Myopalhic MUAPsp +/-
librillalion polenlials[[
Myopalhic changes*, may demonslrale
absence ol specilic prolein on
immunohislochemical slaining
Myolonic dyslrophy
lype !
Dislal grealer lhan proximal,
lool drop, lemporal and
masseler wasling
Adolescence lo
adullhood
Conduclion abnormalilies, menlal
relardalion, calaracls, insulin resislance
None Normal lo minimally
elevaled
Myopalhic MUAPsp,
myolonic discharges[[
Less necrosis and remodeling lhan in
muscular dyslrophies, alrophy ol
lype l muscle libers, ring libers
MeIaboIic
Clycogen and lipid slorage
diseases, milochondrial disease
Proximal Variable Variable, exercise inlolerance and
cardiomyopalhy more common
Some glycogenoses associaled
wilh abnormal llLToo
Variable, may increase
wilh exercise
Normal or myopalhic MUAPsp
+/- librillalion polenlials[[
Myopalhic changes* wilh glycogen
deposils, lipid deposils, or ragged
red libers (lor glycogen, lipid, or
milochondrial disease, respeclively)
CC1 = amma-|u|amy||ran:|era:e, AC1| = adrenocor||co|rop|n hormone, |UA|: = mo|or un|| ac||on po|en||a|:, 1

= |r||odo|hyron|ne, 1
4
= |hyrox|ne,
15| = |hyro|d-:||mu|a||n hormone, C| = a:|ro|n|e:||na|, ANA = an||nuc|ear an||bod|e:, |C| = me|acarpopha|anea|, ||| = prox|ma| |n|erpha|anea|,
||C = e|ec|romyoram, |||1 = |orearm |:chem|c exerc|:e |e:||n.
|yopa|h|c chane: are non:pec|||c and |nc|ude a|rophy, deenera||on, and reenera||on o| mu:c|e ||ber:.
o|yo|on|c d|:chare: are a |ype o| pro|oned bur:| o| ac||v||y :een on |n:er||on o| |he ||C need|e.
p|yopa|h|c |UA|: are :hor|er |n dura||on, |ower |n amp|||ude, and po|ypha:|c when compared |o |UA|: |rom norma| mu:c|e.
5econdary hyperpara|hyro|d|:m u:ua||y cau:ed by rena| |a||ure.
|n|orma||on |rom re|erence: |houh 3 and 1 |hrouh 26.
[[||br|||a||on po|en||a|: repre:en| :pon|aneou: ac||v||y on |he par| o| :|n|e mu:c|e ||ber: (no| u:ua||y no|ed w||h nond|:ea:ed mu:c|e.
C and C4 are comp|emen| componen|:.
|nc|ud|n |ac|o:capu|ohumera| dy:|rophy.
oo|||1 eva|ua|e: |he r|:e o| ammon|a and |ac|a|e |n |he |orearm dur|n exer||on.
1332 !MERICAN &AMILY 0HYSICIAN www.aafp.org/afp Vclume 71, Number 7
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April 1, 2005
doing fine work with the hands
(intrinsics), the muscle weak-
ness is distal. Although many
myopathies are associated with
proximal weakness, a small
number are associated predom-
inantly with distal weakness;
these include myotonic dystro-
phy, inclusion body myositis, and the genetic
distal myopathies.
21,34
Patients with statin
or alcohol toxicity can present with either
proximal or distal weakness.
5,7,39
Other areas to address in the patient`s
history are associated symptoms, family
history, and pharmaceutical use. Common
drugs associated with muscle weakness are
listed in Table 2.
5,6
Associated symptoms are
found in many myopathies and can be espe-
cially helpful in narrowing the differential
diagnosis among endocrine, rheumatologic,
and inflammatory disorders. For example,
dysphagia may accompany weakness in
inclusion body myositis and systemic scle-
rosis, whereas menorrhagia may attend the
weakness that occurs in hypothyroidism. A
family history, which almost always is pres-
ent in genetic myopathies, may also be pres-
ent in other causes of weakness, including
lupus, rheumatoid arthritis, dermatomyo-
sitis, polymyositis, andthe potassium-related
paralyses
27
(Table o
5,7-15,17,18,21,24-27,34,36,38
).
PhysicaI ExaminaIion
The physical examination begins with an
objective confirmation of the subjective
severity and distribution of muscle weak-
ness. In addition to individual muscles, the
physician should survey functional activities
such as standing and writing to determine
whether the weakness is proximal, distal, or
both.
Next, a thorough neurologic survey should
accompany motor testing. The physician
should note patterns and relations among
defects and narrow the differential by deter-
mining whether the deficits are referable to
the central or peripheral nervous system. The
pattern is important. A neurologic examina-
tion that shows deficits in a single nerve or
radicular distribution indicates a possible
mononeuritis, entrapment neuropathy, or
radiculopathy, and calls for a different work-
up than that required for a limb paresis in a
patient with cerebrovascular risk factors.
If the neurologic examination is unreveal-
ing, a more general physical examination,
searching for extramuscular signs, is war-
ranted (Table o
5,7-15,17,18,21,24-27,34,36,38
). Mental
status testing may reveal changes suggestive
of a myopathy-inducing electrolyte disorder
(calcium or magnesium) or an arrest of
1A8LL 5
AddiIionaI 5eIecIed Causes
of MuscIe Weakness
EIecIroIyIe
Hypercalcemia
Hyperkalemia/hypokalemia
Hypermagnesemia/hypomagnesemia
Endocrine
Acromegaly
Primary hyperparalhyroidism
Hypopiluilarism
Vilamin D deliciency (osleomalacia)
heumaIoIogic
Polymyalgia rheumalica
Syslemic sclerosis/scleroderma
GeneIic
Dislal myopalhies
Oculopharyngeal muscular dyslrophy
Myolonic dyslrophy lype 2 (proximal myolonic
myopalhy)
MeIaboIic
Clycogenoses
Acid mallase deliciency
Aldolase A deliciency
8rancher enzyme deliciency
Myophosphorylase deliciency
Phospholruclokinase deliciency
Lipidoses
Carniline deliciency
Carniline palmiloyllranslerase ll deliciency
Trilunclional prolein deliciency
Milochondrial delecls
MisceIIaneous
Amyloidosis
Sarcoidosis
|n|orma||on |rom re|erence: 6, 3, 1, 16, 13, 20, and
24 |hrouh 3.
focaI processes Iend Io be
neuroIogic and may require
a differenI approach Ihan
IhaI used in paIienIs viIh
gIobaI sIrengIh Ioss.
April 1, 2005
U
Vclume 71, Number 7 www.aafp.org/afp !MERICAN &AMILY 0HYSICIAN 1333
MuscIe Weakness
mental development as occurs in genetic
myopathies.
25,29
The cardiovascular assess-
ment may elicit changes consistent with
a cardiomyopathy-a nonspecific conse-
quence of many myopathy-inducing disor-
ders-or a pericarditis, as occurs with some
of the infectious and rheumatologic causes
of muscle weakness.
5,7,8,9,18,21,24,25,29,36,38
1A8LL 6
DiagnosIic CIues for MuscIe Weakness
||nd|n 5ue:|ed d|ano:e:
HisIory
Abdominal pain, excessive urinalion, renal slones Hypercalcemia, hyperparalhyroidism
Acule weakness wilh neurologic delicil(s) Spinal cord injury, slroke
Arlhralgia, malaise, myalgia, respiralory symploms Lpslein-8arr virus, HlV, inlluenza
Chronic neck or back pain, wilh or wilhoul sharp
shooling pains
Cervical spondylosis, degeneralive disc disease
Dislal weakness Cenelic dislal myopalhies, inclusion body
myosilis
Dysphagia, rash around eyelids, shorlness ol
brealh
Dermalomyosilis
Lasy bruising, emolional labilily, obesily Clucocorlicoid excess, sleroid-induced myopalhy
Lxercise-provoked weakness Clycogen and lipid slorage diseases,
milochondrial myopalhies, myaslhenia gravis
lamily hislory ol myopalhy Hyper- or hypokalemic periodic paralysis,
inllammalory disease, muscular dyslrophies,
rheumalologic disease
Heal-induced symploms, mulliple neurologic
delicils spread over space and lime
Mulliple sclerosis
Legal problems, memory loss, repealed lrauma,
sexual dyslunclion
Alcoholism
Posilive medicalion hislory Medicalion-induced myopalhy (esp.
anli-relrovirals, slalins, sleroids)
Sexually lransmilled disease HlV, syphilis
PhysicaI examinaIion
Arlhrilis, malar rash, nephrilis Syslemic lupus erylhemalosus
Cardiomyopalhy Alcohol, amyloid, glycogen slorage disease,
inllammalory myopalhies, muscular
dyslrophies, sarcoid
Dry eyes and moulh, joinl inllammalion
(especially MCP, PlP joinls)
Pheumaloid arlhrilis
lacial weakness, laligable weakness, plosis Myaslhenia gravis
Neurologic delicils
local
Cenlral Mulliple sclerosis, slroke
Peripheral Peripheral neuropalhy, radiculopalhy
Dilluse
Cenlral Amyolrophic laleral sclerosis
Peripheral Cuillain-8arre syndrome, polyneuropalhy
Orlhoslalic hypolension, skin bronzing Hypoadrenalism
||v = human |mmunode||c|ency v|ru:, |C| = me|acarpopha|anea|, ||| = prox|ma| |n|erpha|anea|.
|n|orma||on |rom re|erence: , 7 |hrouh 1, 17, 13, 21, 24 |hrouh 27, 4, 6, and 3.
1334 !MERICAN &AMILY 0HYSICIAN www.aafp.org/afp Vclume 71, Number 7
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April 1, 2005
Pulmonary testing may reveal the crackles
of a restrictive lung defect, found in some
inflammatory and rheumatologic myopa-
thies.
17,21
Gastrointestinal examination may
reveal hepatomegaly, associated
with metabolic storage diseases
and amyloidosis.
24,38
Skin find-
ings are possible in multiple
categories of disease (e.g., skin
bronzing in adrenal insuffi-
ciency; Gottron`s papules and
heliotrope rash in dermatomyo-
sitis; and erythema nodosum
in sarcoidosis). The skeletal
examination may reveal the leg
bowing and pseudofractures of
osteomalacia or the symmetric joint swelling
of lupus and rheumatoid arthritis.
8,17,18,21,25,35
LaboraIory and adioIogic EvaIuaIion
The sequence and timing of the ancillary
investigations varies with the clinical sce-
nario. In a patient whose muscle weak-
ness is suggestive of neurologic disease, early
neuroimaging (for suspected cerebrovascular
disease) or lumbar puncture (for possible
meningitis, encephalitis, or multiple sclero-
sis) is indicated. If infectious disease is sus-
pected, appropriate titers or cultures should
be obtained. When a specific class or type of
myopathy is suspected, appropriate testing
should be performed.
If the cause of muscle weakness is unclear,
serum chemistries (electrolytes, calcium,
phosphate, magnesium, glucose) should be
obtained, as well as a thyroid-stimulating
hormone assay to evaluate for electrolyte
and endocrine myopathies. If an endocri-
nopathy is suspected, more specific assays
can be performed based on clinical suspi-
cion (e.g., 24-hour urine cortisol testing
to rule out Cushing`s disease; oral glucose
load/growth hormone assay to rule out
acromegaly; vitamin D assay to rule out
osteomalacia).
8,13-15,28,29,32
Next, investigations looking for inflam-
matory, rheumatologic, or genetic myop-
athies can be performed sequentially or
concurrently. Although nonspecific, the cre-
atine kinase (CK) level usually is normal in
the electrolyte and endocrine myopathies
(notable exceptions are thyroid and potas-
sium disorder myopathies).
8,16,28,29
However,
the CK level may be highly elevated (10 to
100 times normal) in the inf lammatory
myopathies and can be moderately to highly
elevated in the muscular dystrophies.
16,23,25
Other conditions that can be associated with
elevated CK levels include sarcoidosis, infec-
tions, alcoholism, and adverse reactions to
medications. Metabolic (storage) myopa-
thies tend to be associated with only mild to
moderate elevations in CK levels.
7,16
In addition to CK, an erythrocyte sedi-
mentation rate (ESR) and an antinuclear
antibody assay (ANA) may help determine
if a rheumatologic myopathy exists. If either
ESR or ANA assay is positive, additional
studies may be obtained, including rheuma-
toid factor (rheumatoid arthritis); anti-
double-stranded DNA or antiphospholipid
antibodies (lupus); or anticentromere anti-
bodies (scleroderma).
17-19
Patients with idio-
pathic inflammatory myopathies also tend
to have elevated ESR and ANA levels; many
of these same patients have overlap syn-
dromes, in which an inflammatory myopa-
thy and a rheumatologic disease coexist. An
antisynthetase antibody, when positive, may
help confirm the presence of an inflamma-
tory myopathy.
23
EIecIromyography
If the presence of myopathy is uncer-
tain, electromyography may be indicated.
Although changes seen on electromyography
are not pathognomonic for any specific dis-
ease process, an abnormal electromyogram
can indicate if a neuropathy or neuromuscu-
lar disease is present or can help solidify the
diagnosis of a primary myopathy.
The AuIhor
AAPON SACUlL, CPT (P), MC, USA, is a lacully developmenl lellow in lhe
Deparlmenl ol lamily Medicine al lhe Madigan Army Medical Cenler, Tacoma,
Wash. Dr. Saguil received his medical degree lrom lhe Universily ol llorida
College ol Medicine, Cainesville. He compleled a lamily praclice residency al
DeWill Army Communily Hospilal, lorl 8elvoir, Va.
Addre:: corre:pondence |o Aaron 5au||, C|1 (|, |C, U5A, |epar|men| o|
|am||y |ed|c|ne, |ad|an Army |ed|ca| Cen|er, 1acoma, WA 9341 (e-ma||.
aaron.:au||@u:.army.m||. |epr|n|: are no| ava||ab|e |rom |he au|hor.
In a paIienI vhose muscIe
veakness is suggesIive
of neuroIogic disease,
earIy neuroimaging (for
suspecIed cerebrovascuIar
disease) or Iumbar puncIure
(for possibIe meningiIis,
encephaIiIis, or muIIipIe
scIerosis) is indicaIed.
April 1, 2005
U
Vclume 71, Number 7 www.aafp.org/afp !MERICAN &AMILY 0HYSICIAN 1335
MuscIe Weakness
Electromyography assesses several com-
ponents of muscle electrical activity: the
muscle`s spontaneous activity; its response
to the insertion of a probe; the character of
the muscle`s individual motor unit action
potentials; and the rapidity with which addi-
tional motor units are recruited in response
to an electrical signal. Muscle inflammation,
atrophy, necrosis, denervation, or neuromus-
cular disease can alter these components,
giving rise to patterns that may help illu-
minate the underlying pathology. Although
the procedure can cause minor discomfort,
most patients tolerate it well.
16,24,40
MuscIe iopsy
If the diagnosis is still inconclusive after the
history, physical examination, andlaboratory,
radiologic, and electromyographic evalua-
tions, a muscle biopsy is required for patients
who have a suspected myopathy.
41
The tech-
nology of this method, especially regarding
the use of genetic markers, is advancing rap-
idly, making a definitive diagnosis possible
for a wider range of myopathies.
24,25
The biopsy site should be an affected mus-
cle that is not diseased to the point of necro-
sis. Common biopsy sites are the vastus
lateralis of the quadriceps for proximal
myopathies and the gastrocnemius for distal
myopathies; in patients without involve-
ment of these muscles, an affected group is
chosen.
24
The muscle biopsy can be accom-
plished as an outpatient procedure and car-
ries the attendant risks of pain, bleeding,
infection, and sensory loss. As with elec-
tromyography, patients should avoid using
anticoagulants before the procedure, and
the site chosen for biopsy should be free of
overlying infection.
The pathologic analysis of biopsy spec-
imens focuses on the histologic, histo-
chemical, electron microscopic, genetic,
and biochemical changes that are found in
the affected muscle. Histology may show
atrophic, degenerating, and regenerating
muscle fibers (general findings referred
to as myopathic changes), or it may show
more specific findings such as accumula-
tions of glycogen (glycogen storage dis-
eases), ragged red fibers (mitochondrial
myopathies), noncaseating granulomas
(sarcoidosis), and amyloid deposits (amy-
loidosis). Histochemical techniques assay
for specific enzymes and proteins, and
may reveal deficiencies as in disorders of
carbohydrate or fatty acid metabolism
or the muscular dystrophies. Electron
microscopy and biochemical assays may
help to uncover subtle changes not detect-
able by other techniques, further aiding
in the diagnosis of metabolic and protein-
deficiency myopathies.
7,18-20,21,24,25,27,28,35,37
Jhe opiuious aud asserlious coulaiued hereiu are lhe
privale views o lhe aulhors aud are uol lo be couslrued
as oicial or as relecliug lhe views o lhe u.S. ^ruy
Medical 0eparlueul or lhe u.S. ^ruy Service al large.
Jhe aulhor does uol have auy coulicls o iuleresl.
Sources o uudiug. uoue reporled.
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MuscIe Weakness