Miscellaneous Movement Disorders

Essential tremor (ET) is a common movement disorders, of which 50% of cases are inherited as an autosomal
dominant trait. It most often affects the hands and symptoms may be aggravated by stress, fatigue, caffeine
and temperature extremes.

(+) Family History - dominant gene; one affected parent = 50% chance child will have it

Age > 40 years old

Albuterol
Alcohol withdrawal
Amiodarone
Antidepressants
Cocaine
Corticosteroids
Cyclosporine
Lithium
Metoclopramide
Nicotine
Phenytoin
Procainamide
Pseudoephedrine

Symptoms worsen over time
Can cause difficulty with activities of daily living:
Holding a cup/glass without spilling liquids
Eating normally
Putting on make-up or shaving
Talking
Writing legibly

Increased risk for psychosocial disability, anxiety, depression

Behavioral Techniques and Physical Therapy
Relaxation therapy
Wrist weights
Minimizing exposure to agents that worsen tremor

Pharmacotherapy

Surgical Treatment
Unilateral thalamotomy
Deep brain stimulation (BDS of the ventral intermediate
(VIM) nucleus of the thalamus

Usual effective dose: 20-120 mg/day
Effectiveness: Hand Tremor > Head Tremor

Tolerance:10-15% of responders develop tolerance after 1 year:
Dose increase
Switch to primidone
Add primidone

Common ADRs: light headedness, fatigue, impotence, bradycardia, reduced blood pressure
CIs: cardiogenic shock; uncompensated heart failure; sick sinus syndrome; severe sinus bradycardia; > 1st
degree heart block; bronchial asthma
Precautions: depression; diabetes; abrupt withdrawal

Dosing: requires gradual titration from low doses (12.5 mg) to usual dose of 125–250 mg TID
Effectiveness: like propranolol
Common ADRs: sedation, drowsiness, nausea, vomiting, dizziness, ataxia, confusion, vertigo, and acute toxic
reaction.
CIs: porphyria; hypersensitivity to phenobarbital; pregnancy; breast-feeding
Precautions: abrupt withdrawal; suicidal ideation; blood dyscrasia
Monitoring: Complete blood count at baseline and every 6-12 months

Tics are fast, repetitive muscle movements that result in sudden and difficult to control body jolts or sounds. TS is a condition diagnosed in patients who have two or more motor tics and at least one vocal tic and in whom tics have lasted for more than one year and started to occur before age 18 years old. There is no cure for TS, but treatment can help to control symptoms.

Brief, rapid, recurrent, and seemingly purposeless stereotyped motor contraction

Characterized by multiple motor tics often accompanied by phonic tics
Waxing and waning course
Predominantly affects males

Associated behavioral disturbances:
Anxiety
Depression
Attention deficit hyperactivity disorder (ADHD)
Obsessive-compulsive disorder (OCD)

Four likely risk genes with multiple de novo damaging variants include:
WWC1
CELSR3
NIPBL
FN1

The risk of a family with one affected child having a second is about 25%

Overall, pathophysiology of TS is unknown:
Dopamine neurotransmission
Disinhibition of cortical-striatal-thalamic motor loop
Various second-messenger systems

Education and counseling
Pharmacotherapy - Indicated when the tics are disabling and interfere with quality of life

Options:
α-2 agonists
Neuroleptics

Other options:
Clonazepam
Tetrabenazine
Botulinum toxin injections

Moderate efficacy

Agents
Clonidine 0.5-5 mg/day
Guanfacine 0.5-4 mg/day

Common ADRs:
Sedation
Headache
Dizziness
Irritability
Dry mouth

Particularly helpful in comorbid ADHD

Improved efficacy compared to α-2 agonists

Agents
Atypical:
Aripiprazole 5-30 mg/day
Risperidone 0.5-16 mg/day
Olanzapine 1.25-10 mg/day
Ziprasidone 5-40 mg/day

Conventional:
Haloperidol 0.5-20 mg/day
Fluphenazine 0.5-20 mg/day
Pimozide 0.5-10 mg/day

Monitor for metabolic syndrome (atypical agents) and worsening movement disorders (conventional agents)

Clonazepam
Modest tic-suppressing effects when used BID to TID
Useful in patients with comorbid anxiety disorder
Common ADRs: sedation, unsteadiness

Tetrabenazine
Shown to reduce the number of motor and vocal tics and severity of symptoms
Children may tolerate higher doses than adults
Common ADRs: as noted under HD

Botulinum toxin injections
Consider when tics $\rightarrow$ social distress, discomfort, or self injury
May be preferred if tics have dystonic feature
Common ADRs: weakness, pain

Myoclonus is a brief, rapid (<100 ms), shock-like, jerky movement consisting of single or repetitive muscle jerks. Myoclonus be focus, multifocal, segmental, or generalized. It can occur spontaneously, in associated with voluntary movement, or in response to external stimulus. Negative myoclonus consists of brief loss of muscle activity. Myoclonus can be severe and interfere with normal movement

Not typically repetitive
Not suppressible
Can severely interfere with normal voluntary movement

Common associated features:
Nearly all cases (+) an additional movement disorder (e.g., ataxia, dystonia)
Majority of cases (+) cognitive decline and epilepsy

Association with abnormal neuronal discharges in cortical, subcortical, brainstem, or spinal cord regions, particularly in association with hypoxemia encephalopathy, and neurodegeneration

Hereditary myoclonus

Reversible myoclonus can be seen with metabolic disturbances (renal failure, electrolyte imbalance,
hypocalcemia), toxins, and medications (e.g., serotonin syndrome)

Opiates
Antidepressants
Buspirone
Lithium
Antipsychotics
Antibiotics (β-lactam, quinolones, sulfonamides, aminoglycosides)
N-methyl-D-aspartate (NMDA) receptor antagonists (rare)

Manage underlying condition/remove offending agent

DBS in myoclonus dystonia

Pharmacotherapy:
≥1 GABAergic agents:
valproic acid (800–3000 mg/d)
piracetam (8–20 g/d)
clonazepam (2–15 mg/d)
levetiracetam (1000–3000 mg/d)
primidone (500–1000 mg/d)

Postanoxic myoclonus: 5-HTP + carbidopa

RLS is often considered a sleep-wake disorder and is associated with 4 core symptoms:
1. An urge to move the legs usually caused or accompanied by unpleasant sensation in the legs
2. Symptoms that begin or worse with rest
3. Partial or complete relief by movement
4. Worsening during the evening or night

Primary RLS: familial association

Secondary RLS:
Pregnancy
Neuropathy
End-stage renal disease
Iron deficiency

Lifestyle modifications: avoid caffeine, alcohol, and nicotine

Non-pharmacologic treatment:
Pneumatic compression devices (AAN level B evidence)
Alternative options: mental alerting activities, vibrating pads underneath the legs, acupuncture, near-infrared spectroscopy, and repetitive transcranial magnetic stimulation

Pharmacologic treatment:
Iron supplementation in cases of deficiency
Alpha2-delta calcium channel ligands, dopamine agonists, carbidopa/levodopa, benzodiazepines, opioids

Intermittent: as needed administration of levodopa/carbidopa, low-potency opioids, or benzodiazepines

Chronic Persistent: alpha2-delta calcium channel ligands (first line), dopamine agonists (second line)

Refractory: combination therapy with alpha2-delta calcium channel ligands, dopamine agonists, or benzodiazepines, or monotherapy with an opioid

Most common complication and reason for discontinuing dopaminergics in RLS

Characterized by symptoms beginning earlier in the day and/or symptom location spreading to the
upper extremities

Prevention:
Avoid dopaminergics
Use the lowest effective dopaminergic dose

Huntington’s disease (HD) is a rare, incurable, neurodegenerative disorder of the central nervous system characterized by progressive worsening of motor, cognitive, psychiatric, and behavioral symptoms.

Huntington’s disease is inherited in an autosomal dominant fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of gender.

Huntington's disease (HD) is a genetic disorder caused by an expansion of CAG (cytosine-adenine-guanine) trinucleotide repeats in the huntingtin (HTT) gene, located on chromosome 4.

Normally, the HTT gene contains a repeating sequence of CAG, but in people with HD, the number of CAG repeats in this region is expanded beyond a certain threshold. The size of the CAG repeat expansion determines when and how severe the symptoms of HD will appear.

HD affects the whole brain, but certain areas are more vulnerable than others. Specifically, the basal ganglia – a group of nerves cell clusters, called nuclei. These nuclei play a key role in movement and behavior control and are the parts of the brain most prominently affected in early HD.

Unified Huntington’s Disease Rating Scale (UHDRS)
Gold-standard for evaluation of HD
Motor, cognitive, behavioral abnormalities, functional capacity

Motor symptoms are assessed using Total Motor Scale (TMS)

TMS Diagnostic Confidence Level (DCL) used to assess clinician’s confidence that symptoms represent HD
0 = normal
1 = nonspecific motor abnormalities
2 = motor abnormalities that may be signs of HD (50-89%)
3 = motor abnormalities that are likely signs of HD (90-98%)
4 = motor abnormalities that are unequivocal signs of HD (99%)

Diagnosis = Chorea + DCL 4

• < 5% at-risk individuals choose to pursue predictive genetic testing
• Current guidelines recommend against genetic testing to predict diagnosis age
• High rate of completed suicide attempts amongst individuals with HD

Consider drug therapy if chorea $\rightarrow$ distress or discomfort
Monotherapy preferred
First line: tetrabenazine (Xenazine)
Alternatives: reserpine, neuroleptics (e.g.,
haloperidol, fluphenazine, risperidone, olanzapine)

MOA: reversible inhibitor of VMAT2 $\rightarrow$ depletion of dopamine release by presynaptic striatal neurons

Genotyping for CYP2D6 is recommended when doses > 50mg/day are needed

Boxed Warning: increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with HD

CI: hepatic function impairment; active suicidality or untreated or inadequately treated depression; coadministration of monoamine oxidase inhibitors (MAOIs) or use of tetrabenazine within 2 weeks of discontinuation of MAOI therapy; coadministration with reserpine (≥20 days should pass after discontinuing reserpine before initiating tetrabenazine therapy) coadministration with deutetrabenazine or valbenazine

Common ADRs: sedation, depression, akathisia, worsening of voluntary motor control, QTc prolongation

Description: increase in muscle tone leading to a resistance to passive
movement $\rightarrow$ limited range of motion
More common in juvenile onset
May be induced by tetrabenazine or neuroleptics

Recommended agents:
 First line: levodopa (lower doses than in Parkinson’s disease)
 Alternative: DA agonists

CAUTION: increased risk of psychosis with DA agonists

Description: brief, involuntary and sudden muscle contractions

Recommended agents:
First line: clonazepam or valproic acid (as monotherapy or in combination)
Alternative: levetiracetam

CAUTION: increased fall risk and somnolence with benzodiazepines

Studied agents: fluoxetine, carbamazepine

Recommended agents:
First line: selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs)

If sleep disturbance: mirtazapine
If recurrent depression: carbamazepine (adjunctively)

CAUTION: anticholinergic effects of antidepressants

Recommended agents:
First line: SSRIs
Second line: SSRI + mirtazapine
If overt aggression: sedating antidepressant + neuroleptic

CAUTION: anticholinergic effects of antidepressants and neuroleptics

Recommended agents:
First line: SSRI or SNRI
If breakthrough anxiety: as needed low-dose benzodiazepines
If treatment resistant: antidepressant + neuroleptic

CAUTION: anticholinergic effects of antidepressants and neuroleptics, increased fall risk and somnolence with benzodiazepines

Recommended agents:
First line: low-dose antipsychotics
If rigid HD: clozapine, quetiapine, carbamazepine

CAUTION: reduced cognitive function and mobility