Tremor, Chorea, and Other Movement Disorders¶

Chapter 447 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 447

Key Clinical Points¶

Essential tremor (ET) is the most common movement disorder, affecting ~1% of the general population and 5% of those >60 years.
Dystonic tremor is distinguished from ET by occurring in the direction of the dystonic contraction and disappearing when the dystonia is relieved.
Huntington's disease (HD) is characterized by caudate nucleus atrophy visible on MRI and shows anticipation (earlier onset in subsequent generations).
A levodopa trial is mandatory in all cases of childhood-onset dystonia to exclude dopa-responsive dystonia (DRD).
Dystonic storm is a rare, potentially fatal condition characterized by acute generalized dystonic contractions, often triggered by stress or infection.
Deep brain stimulation (DBS) of the globus pallinus internus (GPi) is effective for generalized dystonia, while STN stimulation may cause dyskinesia.
Beta-blockers (e.g., propranolol) are contraindicated in patients with bradycardia or asthma.
Alcohol typically improves essential tremor but is not recommended as a long-term treatment due to risks of dependence.
Tetrabenazine (or deuterated tetrabenazine) is used to treat chorea in Huntington's disease, with dosing starting at 12.5 mg/d and titrating to 25–75 mg/d.
Dystonia pathophysiology involves co-contracting synchronous bursts of agonist and antagonist muscles and loss of surround inhibition.

DEFINITION & OVERVIEW¶

• Hyperkinetic Movement Disorders: Involuntary movements unaccompanied by weakness. • Tremor: • Definition: Rhythmic oscillation of a body part due to intermittent muscle contractions. • Characteristics: Alternating contraction of agonist and antagonist muscles. • Classification (Two Axes): • Axis 1: Clinical characteristics, history (age at onset, family history), complications, and associated signs. • Axis 2: Etiology (genetic, secondary, or idiopathic). • Types by Timing: • Rest tremor • Postural tremor • Kinetic or intention tremor • Action tremor • Dystonia: • Definition: Involuntary, patterned, sustained, or repeated muscle contractions often associated with twisting movements and abnormal posture. • Athetosis: • Definition: Slow, distal, writhing, involuntary movements with a propensity to affect the arms and hands (a form of dystonia with increased mobility). • Chorea: • Definition: Rapid, semi-purposeful, graceful, dance-like nonpatterned involuntary movements involving distal or proximal muscle groups. • Note: If movements are large amplitude and predominantly proximal, the term ballism is used. • Myoclonus: • Definition: Sudden, brief (<100 ms), jerk-like, arrhythmic muscle twitches. • Tic: • Definition: Brief, repeated, stereotyped muscle contractions that can often be suppressed for a short time. Can be simple (single muscle group) or complex (range of motor activities).

EPIDEMIOLOGY¶

• Essential Tremor (ET): • Most common movement disorder. • Prevalence: ~1% of general population; 5% in those >60 years. • Estimated 5–10 million cases in US or Western Europe. • Huntington's Disease (HD): • Prevalence: 2–8 cases per 100,000. • Geographic Distribution: Common in Europe, North America, South America, and Australia; rare in African blacks and Asians. • Focal Dystonia: • Frequency: ~30 per 100,000 (likely higher due to underdiagnosis). • Gendered Prevalence: Women affected ≈ 2x more often than men (Exception: writer's cramp is more frequent in men). • Subtype Distribution: • Cervical dystonia: ~40% • Blepharospasm: ~15% • Focal hand or leg dystonia: ~10% • Musician's dystonia: ~3% • Spasmodic dysphonia: ~2% • Oromandibular dystonia (OMD): ~1%

ETIOLOGY & PATHOPHYSIOLOGY¶

• Essential Tremor (ET): • Etiology unknown; ≈ 50% have positive family history (autosomal dominant). • Genetics: NOTCH2NLC gene (GGC repeat expansion) associated, but no confirmed causative gene. • Potential Sites: Cerebellum and inferior olives (10% of patients show cerebellar signs). • Pathology: Loss of Purkinje cells and axonal torpedoes (controversial). • Dystonia: • Mechanism: Co-contracting synchronous bursts of agonist/antagonist muscles; recruitment of muscle groups not required for a given movement (overflow). • Underlying Defect: Derangement of action selection; loss of surround inhibition at multiple levels (cortex, brainstem, spinal cord) with increased cortical excitability. • Basal Ganglia Role: Primary site of origin; lesions in putamen can induce dystonia. • Dopamine System: Involved as dopaminergic therapies can both induce and treat forms of dystonia. • Huntington's Disease (HD): • Cause: Mutations in Huntingtin gene (HTT). • Mechanism: Mutant HTT RNA is toxic, disrupts transcription, impairs immune/mitochondrial function; fragments may interfere with transcriptional regulation. • Anticipation: Expansion of repeat length (especially in males) leads to earlier onset in subsequent generations. • Genetic Modifiers: FAN1 and MSH3 genes. • Dopa-responsive Dystonia (DRD): • Cause: Mutations in GCH1 gene (GTP cyclohydrolase-1). • Clinical: Childhood-onset with diurnal fluctuations. • Monogenic Dystonias: • TOR1A: Most common cause of early-onset generalized dystonia (3-bp deletion). • ATP1A3: Sudden-onset, triggered by fever/stress; often in adolescence. • SGCE: Myoclonic-dystonia; alcohol-responsive jerks; requires paternal inheritance due to maternal imprinting.

CLINICAL FEATURES¶

• Tremor Characteristics: • ET: High-frequency (6–10 Hz); postural or action tremor; bilateral/symmetric; improved by alcohol, worsened by stress. • Comparison to PD: PD is primarily rest tremor; ET is postural/action. • Severity: Severe ET may show intention tremor with overshoot and mild ataxia. • Involvement: Head (30%), voice (20%), tongue (20%), face/jaw (10%), lower limbs (10%). • Dystonia Characteristics: • Range: Focal (single muscle group) to generalized (multiple groups). • Features: Pain, depression, anxiety; often brought out by voluntary movement (action dystonia); attenuated by relaxation or sensory tricks (geste antagoniste). • Cervical Dystonia: Laterocollis, torticollis, anterocollis, retrocollis. • Blepharospasm: Eyelid contraction; can cause functional blindness. • Oromandibular Dystonia (OMD): Lower face, lips, tongue, jaw. • Meige's Syndrome: Combination of OMD and blepharospasm (mostly women >60). • Spasmodic Dysphonia: Vocal cord contraction; adductor (choking/strained) or abductor (breathy/whispering) involvement. • Limb Dystonias: Writer's cramp, musician's cramp, the yips. • Huntington's Disease (HD): • Early stage: Focal/segmental chorea; progresses to dystonia, rigidity, bradykinesia, myoclonus. • Progression: Functional decline predicted by weight loss; progression to dementia. • Westphal Variant: Akinetic-rigid parkinsonian syndrome in ≈ 10% of younger patients. • Nonmotor features: Weight loss, neuroendocrine abnormalities (e.g., hypothalamic dysfunction), psychiatric issues (suicidal behavior, aggression). • Eye movements: Early signs include slowed/reduced amplitude saccades and impaired convergence.

DIFFERENTIAL DIAGNOSIS¶

• ET vs. Parkinson's Disease (PD): • Timing: PD is rest tremor; ET is postural/action. • Associated features: PD has bradykinesia, rigidity, and gait issues; ET does not. • Handwriting: PD shows micrographia; ET shows larger handwriting with visible tremor. • Dystonic Tremor vs. Essential Tremor: • Direction: Dystonic tremor occurs in the direction of contraction and stops when dystonia is relieved (e.g., turning head away). • Frequency: Focal dystonias often have high-frequency tremors resembling ET. • Drug-induced vs. Primary Dystonia: • Drug-induced: Often acute/chronic following neuroleptics or long-term levodopa in PD. • Psychogenic Dystonia: • Presentation: Fixed, immobile dystonic postures.

DIAGNOSTIC APPROACH¶

Huntington's Disease (HD) Confirmation:
Clinical suspicion of chorea with positive family history → Genetic testing (with counseling) → Confirmed diagnosis.
Neuroimaging: MRI (Axial FLAIR) to identify high signal in caudate/putamen and enlarged lateral ventricles.
Dopa-responsive Dystonia (DRD) Identification:
Clinical finding of childhood-onset dystonia → Levodopa trial → Improvement confirms DRD.
General Dystonia Workup:
Rule out drug-induced causes (neuroleptics, levodopa).
Rule out secondary causes (lesions in striatum/globus pallidus, toxins like manganese or CO).
Evaluate for other syndromes (Wilson's disease, Lesch-Nyhan, etc.).

MANAGEMENT & TREATMENT¶

Pharmacologic Therapy: • Chorea in HD: • Medication: Tetrabenazine or deuterated tetrabenazine. • Dosing: Start 12.5 mg/d → Titrate to 25–75 mg/d. • Essential Tremor (ET): • Medication: Beta-blockers (e.g., propranolol). • Contraindications: Bradycardia or asthma. • Dystonia: • Note: Dopa-responsive dystonias are treated with levodopa.
Surgical Therapy: • Generalized Dystonia: • Primary Option: Deep brain stimulation (DBS) of the globus pallidus internus (GPi). • Alternative: STN stimulation (Note: may cause dyskinesia).
Supportive/Other: • Alcohol: May improve ET but not recommended for long-term use due to addiction risk.

PROGNOSIS & COMPLICATIONS¶

• Huntington's Disease (HD): • Progression: Leads to significant functional decline, weight loss, and eventually dementia. • Psychiatric risks: Depression with suicidal tendencies, aggression, and psychosis. • Dystonic Storm: • Risk: Rare but potentially fatal acute generalized dystonic contractions triggered by stress or infection. • Surgical Risks: • STN stimulation for dystonia may lead to dyskinesia.

SPECIAL CONSIDERATIONS¶

• Pediatric Patients: • Childhood-onset dystonia requires levodopa trial to rule out DRD. • Genetic testing in children must be accompanied by counseling due to risk of depression/suicide. • Elderly Patients: • Essential tremor prevalence increases significantly (5%) in those >60 years. • Meige's syndrome predominantly affects women aged >60 years. • Specific Ethnic Groups: • X-linked dystonia-parkinsonism (Lubag) found exclusively in patients of Filipino origin due to founder effect.

KEY PEARLS & CLINICAL TRAPS¶

• Dystonic Tremor vs. ET: Dystonic tremor is directional and disappears when the underlying dystonia is relieved. • Huntington's Imaging: Look for caudate/putamen atrophy (high signal on axial FLAIR) and enlarged lateral ventricles. • Monogenic Dystonias: Over 200 genes linked; use 'DYT' prefix (e.g., DYT-TOR1A). - TOR1A: Most common cause of early-onset generalized dystonia. - GCH1: Dopa-responsive. - SGCE: Alcohol responsive myoclonic-dystonia. • Dystonias & Drugs: Drug-induced dystonia is commonly seen with neuroleptics or chronic levodopa in PD patients.

FLOWCHARTS¶

Management of Parkinson's Disease (PD)¶

Neuroprotective Therapy
Current Status: No drug approved for neuroprotection/modification.
Potential Agents: e.g., rasagiline 1 mg/d.
Timing of Symptomatic Therapy
Option A: Initiate at diagnosis/early course → Goal: Preserve beneficial compensatory mechanisms.
Option B: Wait until functional disability → Preferred by some experts.
Selection of Initial Therapy
For Elderly or Advanced Disease → Start with low doses of levodopa.
For Mildly Affected Patients → MAO-B inhibitor (preferred for safety and potential disease-modifying effect).
For Younger Patients with Significant Disability → Dopamine agonists.

TABLES & FIGURES¶

• Table 447-1: Hyperkinetic Movement Disorders - Tremor: Rhythmic oscillation of a body part due to intermittent muscle contractions. - Dystonia: Involuntary, patterned, sustained, or repeated muscle contractions often associated with twisting movements and abnormal posture. - Athetosis: Slow, distal, writhing, involuntary movements with a propensity to affect the arms and hands (this represents a form of dystonia with increased mobility). - Chorea: Rapid, semi-purposeful, graceful, dance-like nonpatterned involuntary movements involving distal or proximal muscle groups. When the movements are of large amplitude and predominant proximal distribution, the term ballism is used. - Myoclonus: Sudden, brief (<100 ms), jerk-like, arrhythmic muscle twitches. - Tic: Brief, repeated, stereotyped muscle contractions that can often be suppressed for a short time. • Table 447-2: Monogenic Forms of Isolated and Combined Dystonia - DYT-TOR1A: Childhood or adolescent onset, generalized (AD). - DYT-KMT2B: Early onset, generalized, mild syndromic features (AD). - DYT-THAP1: Adolescent onset, cranial or generalized (AD). - DYT-ANO3: Adult onset, focal or segmental (AD). - DYT-GNAL: Mostly adult onset, focal or segmental (AD). - DYT-VPS16: Frequent cervical and laryngeal dystonia (AD or AR). - DYT-EIF2AK2: Childhood or adolescent onset, focal to generalized (AD or AR). - DYT-PRKRA: Generalized (AR). - DYT-HPCA: Childhood onset (AR). - DYT-AOPEP: Frequent cervical and laryngeal dystonia (AR). - DYT-GCH1: Dystonia plus parkinsonism, Dopa-responsive (AD). - DYT-TAF1: Dystonia plus parkinsonism, Neurodegeneration (XL). - DYT-ATP1A3: Dystonia plus parkinsonism, Rapid onset (AD). - DYT-SGCE: Dystonia plus myoclonus, Alcohol responsive (AD). - DYT-KCTD17: Dystonia plus myoclonus, Childhood onset (AD).

Reference Tables¶

TABLE 447-1 Hyperkinetic Movement Disorders Tremor Dystonia¶

Harrison's 22e, p.3509

Tremor	Rhythmic oscillation of a body part due to intermittent muscle contractions
Dystonia	Involuntary, patterned, sustained, or repeated muscle contractions often associated with twisting movements and abnormal posture
Athetosis	Slow, distal, writhing, involuntary movements with a propensity to affect the arms and hands (this represents a form of dystonia with increased mobility)
Chorea	Rapid, semi-purposeful, graceful, dance-like nonpatterned involuntary movements involving distal or proximal muscle groups. When the movements are of large amplitude and predominant proximal distribution, the term ballism is used.
Myoclonus	Sudden, brief (<100 ms), jerk-like, arrhythmic muscle twitches
Tic	Brief, repeated, stereotyped muscle contractions that can often be suppressed for a short time. These can be simple and involve a single muscle group or complex and affect a range of motor activities.

TABLE 447-2 Monogenic Forms of Isolated and Combined Dystonia¶

Harrison's 22e, p.3510

FORM OF DYSTONIA		GENE	DESIGNATION AND PHENOTYPIC SUBGROUP	ADDITIONAL DISTINGUISHING FEATURES	MODE OF INHERITANCE
Isolateda		TOR1A	DYT-TOR1A	Childhood or adolescent onset, generalized	AD
		KMT2B	DYT-KMT2B	Early onset, generalized, mild syndromic features	AD
		THAP1	DYT-THAP1	Adolescent onset, cranial or generalized	AD
		ANO3	DYT-ANO3	Adult onset, focal or segmental	AD
		GNAL	DYT-GNAL	Mostly adult onset, focal or segmental	AD
		VPS16	DYT-VPS16	Frequent cervical and laryngeal dystonia	AD or AR
		EIF2AK2	DYT-EIF2AK2	Childhood or adolescent onset, focal to generalized	AD or AR
		PRKRA	DYT-PRKRA	Generalized	AR
		HPCA	DYT-HPCA	Childhood onset	AR
		AOPEP	DYT-AOPEP	Frequent cervical and laryngeal dystonia	AR
	Dystonia plus parkinsonism	GCH1	DYT-GCH1	Dopa-responsive
		TAF1	DYT-TAF1	Neurodegeneration
		ATP1A3	DYT-ATP1A3	Rapid onset
	Dystonia plus myoclonus	SGCE	DYT-SGCE	Alcohol responsive
		KCTD17	DYT-KCTD17	Childhood onset