Movement Disorders

Ali Alrefai, M.D

Objectives
Anatomy Definitions Clinical evaluation of movement disorders ET & PD Huntingtons chorea Wilsons disease Drug-Induced movement disorders

Anatomy & Physiology of Basal Ganglia

Input zone (striatum: Putamen, caudate nucleus) Output zone (GPi, SNr) Intermediate zone (Gpe, STN) Input: Cerebral cortex, ventral midbrain Output: thalamusPremotor & prefrontal lobe; brainstem (SNr) Striatal neurons: 90% medium spiny neurons (GABA); Large spiny neurons (Ach); GABA interneurons

DA

GLU +

Cerebral Cortex
+ GLU

GABA D1>>D2

Striatum

GABA D1>>D2

SNC

GPi
GABA

GLU

SC

SNR

GABA

Ventrolateral Thalamus

Direct pathway: + & - signs indicates Excitatory or Inhibitory nature of NT. Activated pathways in large arrows. Inhibited pathways are shown in small arrows.

Cerebral Cortex
+GLU

DA

Striatum
GABA-

ENK/GABA D2>>D1 GLU

SNC

STN

GPe
GABA-

GLU+

SC

SNR

GLU

GPi

GABA

GABA

Ventrolateral Thalamus
Indirect pathway: + & - signs indicates Excitatory or Inhibitory nature of NT. Activated pathways in large arrows. Inhibited pathways are shown in small arrows.

Symptoms of Movement Disorders

Tremor: Rhythmic, mechanical oscillations Chorea: Abnormal involuntary purposeless brief dancing like movements, usually distal Dystonia: Involuntary sustained muscle contractions causing twisting movements or abnormal postures Ataxia: Disorganized poorly controlled movements Myoclonus; Tics; Ballism

Clinical Evaluation of Movement Disorders

History: Age of onset Mode of onset Course Drug history General medical background FH

Cont.
Examination: MME Eye Focal motor or sensory loss Hepatic, vascular Investigations: Copper Electrolytes,LFT,CBC,ESR,ANA,TSH Genetic testing Imaging

Tremor
Rest tremor
PD

Action tremor Postural

Physiologic ET PD

Kinetic
Midbrain Cerebellar

Task-Specific
Handwriting

Tardive dyskinesia
Severe ET

Essential Tremor
Bilateral action tremor of the hands and forearms Absence of other neurologic signs Long duration (>3 years) Family history Beneficial response to ethanol

Genetics of ET
FH of tremor in 17%-100% Bimodal distribution and autosomal dominant inheritance with nearly complete penetrance by the age of 65 FET1 on chromosome 3q13 in 16 Islandic families ETM on chromosome 2p22-p25 in a large Czech-American family

Treatment of ET
Beta-Blockers: Propranolol (Inderal) Primidone (Mysoline) Combination primidone/propranolol therapy Calcium channel blockers Carbonic anhydrase inhibitors Botulinum toxin type A Surgery: Ablative vs. DBS

Parkinsons Disease
Tremor, rigidity & bradykinesia Stooped posture Asymmetric onset Response (>70%) to pharmacologic Rx Dementia; Olfactory; Sleep; Autonomic; Depression

Pathological Findings
Neuronal loss: see figure Dopaminergic neurons in SNc

Presence of ubiquitin + neuronal processes (Lewy bodies)

Treatment of PD
Anticholinergics Amantadine Levodopa Dopamine agonists COMTi Selegiline Surgery Symptomatic therapy

Differential Diagnosis of PD
Parkinson plus syndromes: PSP, MSA, CBD, DLB HD Wilsons disease Toxins: MPTP, CO, Cyanide Trauma

Features suggestive of PD
Rest tremor Bradykinesia Rigidity Asymmetric onset

Huntingtons Disease

Clinical Presentation
3th-4th decade Chorea; Cognitive decline; Psychiatric sxs Sleep disturbance Duration: 15 years (10-30)

Juvenile HD:

10%<20 years Father inheritance parkinsonism, dystonia, dementia, ataxia, Myoclonus, seizures etc.

Genetics & Pathogenesis

Unstable enlargement of CAG repeat in 5 (1st exon) IT15 (4p16.3)Huntingtin (Htt) CAGGlu Polyglutamine 6-34); HD >40 Anticipation Htt widely distributed in CNS Function: ?

Management
Multidisciplinary approach Depression: SSRI, TCAetc. Mania: VPA, CBZ Chorea; Neuroleptics, Reserpine, Tetrabenazine Sleep: Trazodone; benzodiazepines Nutrition: Behavioral management of caregiver(s)

Wilsons disease
AR trait caused by mutation in coppertransporting P-type ATPase, causing abnormal copper accumulation in the liver, BG and other organs Liver disease (40%): Subclinical liver disease 95% under age 20 Acute hepatitis Fulminant hepatitis Cirrhosis Hemolysis

Neurological Manifestations
40% Invariably have liver dysfunction Isolated tremor (50%) Dysarthria Drooling Dysphagia Gait abnormality, parkinsonian syndrome, generalized dystonic syndrome

Cont.
Psychiatric (15%): Conduct disorder Cognitive impairment Psychosis Others (5%): Ocular: Kayser-Fleisher ring Renal: Aminoaciduria RTA Calculi Hematological Hemolytic anemia Skeletal: Osteomalacia and rickets

Dx & Rx
Diagnosis: 1. Low serum ceruloplasmin 2. Raised 24 hr urinary copper excretion 3. Raised liver copper concentration 4. Kayser-Fleisher ring in virtually all patients with neurological presentation 5. Brain MRI Treatment: 1. D-Penicillamine 2. Trientine 3. Zinc 4. Liver transplant

Idiopathic Torsion Dystonia (Oppenheims Dystonia)

8.2 years (6-9 years) Normal development, walk normally Symptoms start in legs in early onset and in arms and cranial structures in later onset Becomes generalized within one year of onset Intact mental function & no psychiatric illness + FH suggesting autosomal dominant inheritance Course is progressive in early stages followed by Spontaneous stabilization

Genetics
AD with reduced penetrance DYT1 gene is responsible for early-onset idiopathic torsion dystonia in Ashkenazi Jewish families, and in one large nonJewish family Gene is mapped to chromosome 9q32-34 Glycosaminoglycan (GAG) deletion Alteration of norepinephrine concentration in several areas of the brainstem

Diagnostic work up
Typical history and pattern of onset with a positive family Secondary dystonia should be suspected if: (1) Adult-onset (2) Early cranial or bulbar involvement before the lower limbs (3) Hemidystonia (4) Pyramidal tract signs (5) Cerebellar tract signs (6) Peripheral neuropathy (7) Dementia (8) Seizures (9) Abnormal eye signs such as optic atrophy, retinitis pigmentosa, and Kaiser-Fleischer rings

Treatment principles of dystonia

Physical and supportive therapy Therapeutic trial of levodopa in all childhood dystonia Anticholinergics: Most useful in Rx Benzodiazepines Oral baclofen Botulinum toxin particularly for cervical and facial dystonias Surgery for those with disabling symptoms despite optimal medical therapy

Drug-Induced Movement Disorders

Parkinsonism Acute dystonia Tardive dyskinesia Neuroleptic Malignant Syndrome Other drug-induced movement disorders