Management of Movement disorders other than Parkinson

Mohammed AlkuwaitiR2 Neurology

Content:Hyperkinetic movement disorders- Tremors- Dystonia- Tic- Chorea- Hemifacial spams

Tremors:Tremor is an involuntary, rhythmic, oscillatory movement, which can present as a resting tremor, action tremor, or intention tremor.

Essential tremorsEssential Tremors: most common movement disorder

Occurs at a rate of 5% in the general population.

Frequency increases with age

In many families, ET is inherited in an autosomally dominant pattern. In 30 to 50% of cases.

It’s a Postural +/- Kinetic tremors- typically an alternating flexion-extension movement- Faster (7 to 10 Hz) than the PD tremor (4 to 7 Hz), - Usually involves the head, neck, and voice. - Tremor often interferes with handwriting, drawing, holding a spoon, using a drinking cup, and manipulating tools.

Other tremors:Task specific tremors:

- Orthostatic tremor : when asked to stand in place for several seconds, they develop hard and cramping calves and thighs that shake uncontrollably. Although considered by- Primary writer’s tremor only while writing. The handwriting becomes sloppy, shaky, and large.

Cerebellar kinetic tremor “Intentional tremors”- Apparent during a goal-directed limb movement, e.g. finger-to-nose or- Patient’s greatest disability occurs at the “endpoint- Usually caused by a lesion in the cerebellar outflow (dentatorubral) tracts- Seen most typically in patients with multiple sclerosis, CVAs, or primary cerebellar disorders.

Rubral tremor: - Mixes rest/postural/ kinetic- induced by structural disease in the midbrain or fiber pathways connecting this region with the cerebellar and thalamic nuclei.

Palatal tremor, also termed “palatal myoclonus”,- Is characterized by continuous and synchronous contractions of the soft palate that occur at frequencies of 100 to 150 per minute. - Maybe accompanied by persistent ear clicks caused by the repetitive opening and closing of the eustachian tubes. - Concomitant contractions of other muscles, including the larynx, extraocular muscles, neck, diaphragm, tongue, and face, may be observed. - generally persist throughout life with infrequent remissions, may be idiopathic or due to brain stem or cerebellar disease.

Other tremors:

Essential Tremors therapeutic options:• Life style• Medical management• Botilinum toxin• Surgical option

Lifestyle:

• Avoid or minimize exacerbating factors (e.g. stress, tremogenic drugs).

• Limit Caffeine-containing beverages (although no clear convincing evidence)

• Alcohol reduce the ampl of ET in 2/3 of pts. – Effective alcohol level can be as low as 0.03%– Possible prophylactic treatment

Alcohol and Tremors

• The evidence concerning the risk of alcholism amont ET patients is contradictory.– Some investigators suggested that alcohol is a risk

factor for ET.– The regular use of alcohol to treat essential tremors

is inadvisable.–Mechanism of action is thought to be centrally by

potentiating GABA receptor-mediated chloride influx and stabilizing neuronal membranes.

Medical Management

- Indication: When tremor causes enough disability or social embarrassment to justify pharmacologic intervention.

- The choice of medication must balance efficacy in reducing tremor with avoidance of intolerable side effects.

- In general, arm/hand tremor is more effectively treated by medications than is head or voice tremor.

Medical management:“Popranolol” (Inderal) non-selective.

- most well-studied beta-blocker used in the treatment of ET. - 45% and 75% will show improvement in arm tremor compared with placebo.- Dosing “Standard” or “Long-acting” formulation- Initiated with 20 mg/d.- Titrated weekly to an effective dosage, typically 120 mg/d - as 320 mg/d.

Side effects: - Elderly: may experience symptomatic hypotension or bradycardia. - Other side effects include impotence, drowsiness, confusion, headache, depression and exercise intolerance. (Benito-Leon et al, 2007b).

If side effects develop, patients do not usually develop tolerance.

Contraindicated: Asthma, COPD, 2nd degree heart block and Insulin dependent DM.

Medical Management:Mechanism of action:

- Central mechanism of action has been suggested for β-adrenergic blockers, but they are not lipid soluble and hence do not cross the blood–brain barrier. -- This suggests that the therapeutic effect of β-adrenergic blockers might be mediated, at least in part, by the peripheral β-adrenergic receptors.

Other selective beta-antagonists such as nadolol also appear to be effective but have not been as well studied compared with the nonselective beta-antagonist.

Medical Managment“Primidone” Anticonvulsant,

- A structural analog of phenobarbital- It has similar efficacy to propranolol

Dosing: - The typical starting dose is 25 mg nightly. - Titrated slowly to avoid side effect- It may take 6 to 8 weeks for patients to achieve an effective dose (average 750 mg/d divided into three doses a day)

Side effects:- Most bothersome: Somnolence and fatigue- 20% may develop: nausea, drowsiness, and unsteadiness, even when starting at very low doses - Unlike propranolol, the early mild side effects of primidone are habituating and, therefore, may be tolerated with slow upward titration in dose.

Medical ManagmentPropranolol and primidone Combination therapyGreater relief in some patients

Other less well-studied oral agents may be used to treat ET, includingbenzodiazepines, topiramate, and gabapentin.

These medications have varying effectiveness.

Medical Managment“Topiramate” Topamax, Anticonvulsant - Shown effective anti-tremor drug in a multicentre, double-blind, placebo controlled trial of 208 patients with essential tremor. (Ondo WG et al, neurology 2006)

- Addition to a significant decrease in the Fahn–Tolosa–Marin tremor rating scale scores.

- Topiramate was associated with a greater improvement in function and disability than did placebo. Most common Side effects:• paraesthesias (58 [28%]), weight loss (46 [22%]), and taste perversion (40

[19%]); other side-effects included nausea, difficulties in concentration and attention, and somnolence.

Medical Managment

Gabapentin: Neurontin, anticonvulsant• Mixed results from double-blind, placebo controlled studies in essential

tremor have been reported. (Lyons KE et al, CNS drugs 2008)

Levetiracetam, ‘Keppra” anticonvulsant• Had a significant anti-tremor effect in one double-blind, placebo-

controlled trial at a single dose of 1000 mg. (Bushara KO, Neurology 2005).

• Was not found to be effective in other studies. (Elble RJ, Clin Neuropharmacol 2007).

Medical Managment

Diazepam, lorazepam, clonazepam, alprazolam,

• Ameliorating effects on essential tremors. (Lyons KE, CNS Drugs 2008).

Botulinum toxin therapy: Level C

Muscles that are involved in the production of the oscillatory movement- Forearm wrist (and finger) flexors (eg, flexor carpi radialis and ulnaris)- Head and voice tremors (inj to neck and vocal cords)- Primary writing tremor

3 months improvement in amplitude

The challenge:- Appropriately target the muscles- Inject the appropriate amount of toxin for clinical effect

Surgical therapy: Level C1> Deep brain stimulation (DBS)

- Ventral intermediate (Vim) nucleus of the thalamus- possibly other nuclei, e.g subthalamic nucleus and caudal zona incerta

Single side Vim DBS mainly:- Reduces contralateral, but to a lesser extent also ipsilateral tremor: head, rest, task-specific hand tremors and cerebellar-outfl ow tremors

bilateral Vim DBS is often associated:- Dysarthria, loss of balance, and loss of coordination.

2>Thalamotomy (lesioning of the thalamus)-Very effective approach. However, thalamotomy has increasingly been replaced by DBS of the ventralis intermedius nucleus.

3> Vagal Nerve stimulation: No meaningful benefit

DystoniaDefinition:

- Dystonia is a neurologic disorder dominated by involuntary, stereotyped, patterned (sustained or spasmodic) contractions of muscles. These movements frequently cause twisting and other abnormal movements or postures.

- Causes involuntary simultaneous co-contraction of both agonist and antagonist muscles, resulting in the ‘‘twisted’’ Movements. - Dystonic contractions are usually sustained at the peak of the movement, differentiating dystonic contractions from the brief contractions seen in chorea or myoclonus.

- In addition, dystonic contractions involve the same pattern of muscles, where as in chorea the involved muscles are more random.

- Dystonic movements may be slow or fast and can be associated with tremor (dystonic tremor).

- Dystonic movements typically worsen with action and can be very task specific in some patients.

- Overflow dystonia: As the dystonic syndrome progresses, actions in one body region can induce dystonic movements in another region

Sensory trick: (geste antagoniste) - In which a specific touch to an affected body part can help improve the dystonia.

Dystonia

Classification of Dystonia:

Primary dystonia• Childhood-/Adolescent-Onset

- The average age of onset is around 9 years.- A GAG deletion mution in DYT1 gene in Chromosome 9q lead to failure of

protein torsin A production. - Autosomal dominant condition has only a 30% penetration rate- More common among Ashkenazi Jews- Usually begins with symptoms in a limb, most commonly a leg, during

activities such as running or walking.- The dystonia often spreads to other body regions, including the other leg,

trunk, and arms within 5 years.

Primary dystonia• Adult onset

- Prevalence 3.4 to 6.2 per 100,000. - Commonly 4th – 5th decade of life- Women: Men 3 : 1- It often begins as a focal dystonia in the upper body, Symptoms may

worsen over time and spread segmental rarely generalize.

Dystonia plus syndromes:In general, these are rare disorders that are different from heredodegenerative disorders or other

secondary dystonias since they are not associated with known neuropathologic findings (Fahn et al, 1998).

1) Myoclonus-dystonia, 2) Rapid-onset dystonia-parkinsonism3) Dopa-responsive dystonia (DRD, DYT5, Segawa disease)

- Presents in normal children- Typically begins with foot dystonia, gait abnormalities, and hyperreflexia, progressing to

generalized dystonia.- Maybe confused with the distonia seen in cerebral palsy.- A unique feature of DRD is its diurnal fluctuation, with worsening of symptoms late in the

day.- autosomal dominant (“point” mutation in the gene for GTP cyclohydrolase 1

“GCH1”(synthesis of tetrahydrobiopterin, a cofactor in dopamine synthesis). May also occur in autosomal recessive forms due to a mutation in the tyrosine hydroxylase gene.

- DRD is extremely sensitive to treatment with levodopa, and the effect is sustained over time. - Most reliable diagnostic test is: response to dopamine

Dystonia therapeutic options:

• Medical management• Botilinum toxin• Surgical option

Medical Therapy:Primary dystonia:

- Is only symptomatic, not neuroprotective, with the goal to: - relieve involuntary movements, - correct abnormal posture, - prevent contracture, - reduce pain and embarrassment, and improve function.

Secondary dystonia with an identifiable etiology- respond to specific treatments,e.g.:- Levodopa in dopa-responsive dystonia- Withdrawal of the causative treatment in drug-induced- Copper chelation in Wilson’s disease.

All children or adolescents who present with dystonia- Trial of levodopa - Carbidopa/levodopa at 300mg/d will improve symptoms of DRD, - Dose should be titrated up to 1000 mg/d for 1 month to r/o DRD

If ineffective, the next to be tried is:- an anticholinergic medication.

- Trihexyphenidyl (Artane) is the best studied- Young-onset generalized dystonia have the most benefit

from this class of agents.- Sided effects: drowsiness, confusion, memory difficulty,

blurring of vision, hallucinations, and urinary retention might limit its usefulness.- Slow titration to avoid AE- Symptomatic AE management:

Pyridostigmine for constipationPilocarpine eye drops blurring of vision, Cholinergic drugs urinary retentionSynthetic saliva dry mouth.

Medical Therapy:

TicsTics are sudden, repetitive, rapid, involuntary movements or vocalizations with

differing degrees of intensity and frequency and unpredictable durations. They usually involve the eyes, face, shoulders, neck, and vocal apparatus more than the rest of the body.

Motor tics:- Simple: brief, sudden, meaningless movements such as eye blinking, shoulder shrugging, and head turning. - Complex: involve a variety of muscle groups, can appear to be purposeful(touching, jumping, body contortions, copropraxia), or involve the prolonged maintenance of a posture (dystonic tic).

Vocal (Phonic)- Simple: e.g. throat clearing, grunting, barking, or sniffing- complex: the use of words—ie, echolalia, palilalia, or coprolalia. It is important to note, that coprolalia occurs in only about 10–19% of patients.

Common Characteristics - Onset at approx 5–7 years of age. - waxing and waning course; - Exacerbation in stress, anxiety, excitement, anger, or fatigue - Reduction during periods of concentration or active engagement - Absence during sleep.

A premonitory sensation (an urge, impulse, tension, pressure, itch, or tingle) often occurs before a motor or phonic tic.

Diagnosis: based on historical features and a clinical examination.

the Yale Global Tic Severity Scale (YGTSS)

Tics Classification:Transient tic disorder:

-motor or vocal or both, occurring <12 months.

Chronic tic disorder:- solely motor or less commonly, only vocal in nature. >12 months.

Tourette syndrome/disorder - Onset prior to age 21, boys > girls- Multiple motor tics and at least one vocal tic at some time, though not necessarily concurrently- Waxing and waning course with progressive evolution- Presence of tics for greater than 12 months- Absence of precipitating illness (eg, encephalitis, stroke or degenerative disease) or association with potential tic-inducing medication- Observation by a knowledgeable individual

Tic disorder, not otherwise specified

Associated problems:Attention deficit hyperactivity disorder ADHD

- Occurring in about 50% (range 21–90%). - age 4–5 years and often precedes the onset of tics

Obsessive-compulsive disorder - Incidence between 20% and 89%.- Manifest several years after the onset of tics.

Anxiety and depression: - Depression has ranged from 13% to 76% in different studies.

Episodic outbursts and self-injurious behavior- Rage attacks (screaming, threatening behaviors, stomping,

kicking, destroying objects, punching holes in walls, etc.) - Self-injurious behaviors

Academic difficulties despite normal intellectual functioning.

Tic therapeutic options:

• Medical management• Botilinum toxin• Surgical option

Tic therapy

• First step is “education”• Most patients do not require pharmacological therapy.• Councilling, Relaxation training, Cognitive behavioral therapy and Habit reversal training might be enough.

Medical Therapy:• Neuroleptic drugs– Dopamine receptor blocker• Fluphenazine “less sedating”• Resperidone• Pimozide Less sedating (FDA approved)• Haloperidol (FDA approved)

Side effects: sedation, depression, weight gain, and school phobia (separation anxiety), tardive stereotype and tardive dystonia. Prololned QT interval, Neuroleptic malignant syndrome, Akathisia

Medical managment

• Neuroleptic drugs–Monoamine-depleting drug• Tetrabenazine (Nitoman)Side effect: Dizziness, Depression, Akathisia and

parkinsonism, not known for Tardive dyskinesia, less wt gain.

• Topiramate

Botulinum toxin therapy

• Localized motor tics• Life threatening tics e.g. dystonic cervical tics

Deep brain stimulation:

• Pt with disabling TS• Targeting thalamus, globus pallidus internal

and anterior limb of internal canpsule

ChoreaChorea consists of irregular, purposeless, abrupt, rapid, brief, jerky,

unsustained movements that flow randomly from one part of the body to another.

The term “choreoathetosis” describes the combination of chorea and athetosis, a slow form of chorea manifested by writhing movements predominantly involving distal extremities.

Ballism, a severe form of chorea, comprises wide amplitude, flinging movements, usually involves the proximal limbs and most often affects only one side of the body (hemiballism).

Ballism is typically caused by a lesion in the contralateral subthalamic nucleus

Etiological classification of Chorea

Huntington disease• A primary neurodegenerative disease• Autosomal dominant• Mutation in Chromosome 4, causing between 37 and 86 CAG

repeats. Leading to intranuclear inclusions.• Prevalence 5 to 10 per 100,000 in the US• Gradual onset of chorea, dementia, and behavioral

abnormalities in a young or middle-aged adult should suggest the possibility of HD

• In the terminal phases of HD, dysarthria, dysphagia, and respiratory difficulties become the most disabling and life-threatening problems

Management:• Targeting the chorea1) DA receptor-blocking agents

– e.g., haloperidol and fluphenazine– Side effects

2) Dopamine-depleting agents (less side effects)– e.g., tetrabenazineSide effect: Dizziness, Depression, Akathisia and parkinsonism, not

known for Tardive dyskinesia, less wt gain.

- Introduced for the treatment of chorea in the UK in 1971

- FDA approval 2008

- First drug for the treatment of chorea associated with HD

- A potent and selective depletor of dopamine from nerve terminals, and, to a lesser extent norepinephrine and serotonin.

- By inhibiting the brain synaptic vesicular monoamine transporter type 2 (VMAT2), impairs uptake of monoamines into synaptic vesicles, causing them to remain in the cytoplasm, where they are rapidly degraded by monoamine oxidases.

Tetrabenazine “Nitoman”

Approach to Huntington management

Approach to Huntington management

Prognosis

• Despite advances in treatment, this disorder results in progressive functional decline and eventual death, usually within 12 to 15 years of onset.

• Neural transplantation with fetal striatal or other cell sources may become experimental options in the future.

Hemifacial spams

Definition: intermittent twitching of the muscles supplied by one facial nerve.

Incidence 0.78 per 100,000, F : M 2 : 1Average age at onset being 45 to 51 years. Etiology: compression of the facial nerve at its

junction with the brain stem by an aberrant or ectopic posterior fossa artery. 90% of cases; other: tumors and bony or other abnormalities.

Clinical Features• Begin in the periorbital region and spread to the

ipsilateral facial muscles during the next few months.

• Spasm occurs spontaneously, is almost always unilateral, and is exacerbated by voluntary facial movements such as lip pursing, stress, fatigue, anxiety, or a change in head position.

• The movements often persist during sleep.• Ipsilateral tinnitus Stapedius muscle contraction

Management

• Clonazepam• botulinum toxin injection to the involved

muscles is now the treatment of choice• Endoscopic surgical correction may offer a

permanent treatment.

Refernces1. Bhidayasiri R. Differential diagnosis of common tremor

syndromes. Postgrad Med J. 2005 Dec;81(962):756-62.2. Joseph Jankovic, Treatment oh hyperkinetic movement

disorders. Lancet Neurol 2009; 8: 844–563. Harvey S.Singer, Treatment of Tics and Tourette Syndrome.

Current Treatment Options in Neurology (2010) 12:539–5614. Jill L. Ostrem, Nicholas B. Galifianakis, Overview of common

movement disorders. Continuum Lifelong Learning Neurol 2010;16(1):13–48.

5. Joseph Jankovic, Chapter 30 “Movement disorders”

Thanks for you attention