Myoclonus
Treatment
The most important step in treating myoclonus is to first identify and appropriately classify the subtype of the disorder because the pathology—and, therefore, treatments and outcomes—are cause specific in many cases. Before proceeding to therapy, it is essential to treat any underlying conditions, such as metabolic derangements and toxin or drug exposures that have led to the disorder. In many cases, treatment is not necessary; however, when myoclonus interferes with quality of life and activities of daily living, a number of therapies are available. The mainstay of treatment is with pharmacologic agents, but in specific circumstances, chemodenervation with botulinum toxin injection therapy, immunomodulatory therapy, and surgical interventions are warranted.
Pharmacologic Agents
Few randomized, double-blind, placebo-controlled trials have been conducted on the effects of antimyoclonic drugs, and although clonazepam and valproic acid are often used in the treatment of myoclonus, they have never been formally studied for this use. Expert opinion forms the basis for the use of most drugs in treating myoclonus. The guiding principles in the pharmacologic treatment of myoclonus are (1) to recognize that therapy is empiric, targeted at symptom relief, and (2) that, although polytherapy is often required, treatment should be instituted with a single drug. The choice of drugs is based upon the answers to questions identified in the diagnostic approach—the fundamental cause and origin of the movements—and the side-effect profile of the agents. The primary drugs used to treat myoclonus include levetiracetam (Keppra®), clonazepam (Klonopin®), valproic acid (Depakote®, Depakene®), primidone (Myidone®, Mysoline®), piracetam (Nootrypl®), and acetazolamide (AK-Zol®, Diamox®).
Primary Pharmacologic Agents: Levetiracetam
Levetiracetam (Keppra®), a pyrrolidone derivative, has been shown in open-label trials and multiple case reports to have antimyoclonic activity. Because this drug is well tolerated, has no interaction with other drugs, does not require titration, and is not metabolized but is excreted unchanged in the urine, a trial is warranted in most patients with myoclonus, particularly those with proven posthypoxic cortical myoclonus.
Types of myoclonus in which levetiracetam may be useful
- Cortical
- Lance Adams syndrome
- Postencephalitic myoclonus
- PME,
- Creutzfeldt-Jakob disease
- Paraneoplastic
- Negative
- Spinal
Mechanism of action
- Unknown, but does not appear to derive its benefit from any interaction with known mechanisms involved in inhibitory and excitatory neurotransmission.
Adverse reactions
- Asthenia
- Headache
- Somnolence
- Dizziness
Cautions
- Dosage should be adjusted based on renal function
- Should be used with caution in the elderly
| Dosage |
Adults |
Children |
| Initial |
250 to 500 mg per day |
|
| Maintenance |
Increase by 500 mg per week up to a maximum of 3000 mg per day |
|
| Usual |
|
20 to 40 mg per kg per day |
Primary Pharmacologic Agents: Clonazepam
Types of myoclonus in which clonazepam may be useful
- Essential and other types of myoclonus
- Lance Adams syndrome
- Subcortical action myoclonus
- Spinal myoclonus, nocturnal myoclonus (PLMS)
- Opsoclonus-myoclonus
- Myoclonus that occurs secondary to tetanus toxin and opiate therapy
Mechanism of action
- Unknown, but believed to suppress the propagation of activity produced by foci in the cortex, thalamus, and limbic areas through effects on the GABA and serotonin systems
Adverse effects
- Sedation, including excessive sedation in the elderly
- Vertigo
- Behavioral changes
- Tolerance
Contraindications and cautions
- Acute narrow-angle glaucoma
- Hepatic insufficiency
- In children, should be used with caution, may cause paradoxical hyperactivity
- Adverse events often limit the use of this drug in the treatment of myoclonus
| Dosage |
Adults |
Children |
| Initial |
0.5 mg per day, with slow upward titration |
0.1 to .03 mg per kg per day |
| Maintenance |
4 to 10 mg per day |
0.5 mg per kg per day maximum |
Primary Pharmacologic Agents: Valproic Acid
Types of myoclonus in which valproic acid may be useful
- Cortical myoclonus
- Subcortical myoclonus
- Opsoclonus-myoclonus
- Juvenile myoclonic epilepsy
- Other forms of myoclonus
Mechanism of action
- Unknown, but probably works by affecting the metabolism of GABA. There is evidence that valproic acid acts at multiple levels of GABA synthesis, degradation, and competitive inhibition, preventing the uptake of GABA by glial cells and axonal terminals; its effects are not related to GABA transaminase inhibition.
Adverse effects
- Rare idiosyncratic hepatotoxicity
- Rare fatal pancreatitis
- Nausea and vomiting
- Weight gain
- Increased appetite
- Sedation
- Drowsiness
- Tremor
- Alopecia
Contraindications and cautions
- Contraindicated in patients with hepatic insufficiency or failure.
- Used with extreme caution in children younger than 2 years of age, who are at risk for developing life-threatening hepatotoxicity with the use of this drug
- Teratogenic
- Hepatic function must be monitored
- Gastrointestinal side effects, sedation, and the rare but life-threatening hepatic toxicity and pancreatitis may limit the use of this drug
| Dosage |
Adults |
Children over the age of 10 years |
| Initial |
15 mg per kg per day |
15 mg per kg per day |
| Maximum |
60 mg per kg per day up to 4500 mg per day |
60 mg per kg per day |
| Usual |
250 to 1000 mg per day, given in 3 equal doses |
|
Primary Pharmacologic Agents: Piracetam
Types of myoclonus in which piracetam may be useful
- Posthypoxic myoclonus (Lance Adams syndrome)
- PME
- Other forms of cortical myoclonus
Mechanism of action
- A pyrrolidone derivative and a nootropic, piracetam stimulates mental activity; has mild effects on GABA and monoaminergic activity, increases adenosine metabolism, modulates acetylcholine levels, and affects energy metabolism
Adverse effects
- Gastrointestinal discomfort
- Thrombocytopenia
- Euphoria
- Mania
Contraindications
- Renal insufficiency
- Hepatic dysfunction
Notes of interest
- Not available in the United States
- Typically used as add-on therapy
| Dosage |
Adults |
Children |
| Initial |
7.2 grams per day |
80 to 130 mg per kg per day |
| Maintenance |
16 to 24 grams per day |
400 mg per kg per day* |
*Has not been proven to be efficacious in treating opsoclonus-myoclonus at these doses.
Primary Pharmacologic Agents: Primidone
Types of myoclonus in which primidone may be useful
Mechanism of action
- Unknown, but has no affinity for known neurotransmitter receptors
Adverse effects
- Ataxia
- Vertigo
- Drowsiness
- Irritability
- Cognitive impairment
| Dosage |
Adults |
Children |
| Initial |
25 mg per day increasing slowly by 25 to 50 mg per week |
No prescribing information is available for the treatment of myoclonus in children |
| Maintenance |
500 to 750 mg per day |
|
Primary Pharmacologic Agents: Acetazolamide
Types of myoclonus in which acetazolamide may be useful
Mechanism of action
- Acts through inhibition of carbonic anhydrase
Adverse effects
- Dyspnea
- Seizures
- Vertigo
- Lightheadedness
- Anorexia
- Nausea
- Pruritis
- Headache
Caution
- Potassium levels should be carefully monitored
| Dosage |
Adults |
Children |
| Initial |
8 to 30 mg per kg |
No prescribing information is available for the treatment of myoclonus in children |
| Maintenance |
375 to 1000 mg per day |
|
Other Pharmacologic Agents
Additional drugs that have been used in the treatment of myoclonus include a variety of anticonvulsants, including zonisamide (Zonegran®), phenobarbital (Solfoton®), and lamotrigine (Lamictal®); serotonergic agents such as 5-hydroxytryptophan (which is not available in the United States), sumatriptan (Imitrex®), and fluoxetine (Prozac®, Sarafem®); and other agents such as tetrabenazine (Nitoman®, Xenazine®), trihexyphenidyl (Artane®, Trihexane®, Trihexy®), sumatriptan (Imitrex®), and melatonin. Caution is urged with the use of these drugs because many may exacerbate or cause myoclonus in some patients.
Other Pharmacologic Agents: Zonisamide
Types of myoclonus in which zonisamide may be useful
- Lafora body disease
- Unverricht-Lundborg disease
Mechanism of action
- Unknown, but may produce anticonvulsant effects through actions on the ion channels, reducing voltage-dependent, transient inward currents (T-type calcium currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization
Adverse effects
- Headache
- Vertigo
- Irritability
- Anorexia
- Mood changes
- Ataxia
- Tremor
- Somnolence
Adverse effects in children
- Oligohydrosis
- Hyperthermia
Cautions
- Hepatic disease
- Renal disease
- Teratogenic
| Dosage |
Adults |
Children |
| Initial |
100 mg per day, gradually increasing by 100 mg per day over a 2-week period |
Not approved for use in children |
| Maintenance |
200 to 300 mg per day or 400 to 600 mg per day in patients with PME |
|
Other Pharmacologic Agents: Phenobarbital
Types of myoclonus in which phenobarbital may be useful
Mechanism of action
- Elevation of the seizure threshold of the motor cortex to electrical or chemical stimulation, likely related to the potentiation of GABA inhibition in the central nervous system; antagonizes glutamate excitation
Adverse effects, which often limit the use of phenobarbital in the treatment of myoclonus
- Sedation
- Ataxia
- Drowsiness
- Headache
- Depression
- Nausea
- Vomiting
- Tolerance
| Dosage |
Adults |
Children |
| Usual |
60 to 200 mg |
3 to 6 mg per kg per day |
Other Pharmacologic Agents: Lamotrigine
Types of myoclonus in which lamotrigine may be useful
Mechanism of action
- Blocks sodium channels, and its mechanism of action, thus, is likely based on its ability to block excitatory neurotransmission
Adverse effects
- Toxic epidermal necrolysis in children
Notes of interest
- Antifolate
- May cause myoclonus in some individuals
- Slow titration schedule that is required to avert side effects may limit compliance with this drug
| Dosage |
Adults |
Children |
| Usual |
200 to 400 mg per day given in 1 to 2 doses |
No prescribing information is available for the treatment of myoclonus in children |
Other Pharmacologic Agents: 5-hydroxytryptophan
Types of myoclonus in which 5-hydroxytryptophan may be useful
- Cortical myoclonus
- Posthypoxic myoclonus (Lance Adams syndrome)
- Subcortical action
- Palatal myoclonus
Mechanism of action
Adverse effects
- Anorexia
- Diarrhea
- Nausea
- Mood alteration
Notes of interest
- Only available as an experimental protocol after being removed from the pharmaceutical market in the United States (it is available from healthfood stores) and is usually used as a last resort because of often intolerable gastrointestinal side effects and the need for Institutional Review Board approval and signed informed consent
- Always given with carbidopa to limit peripheral metabolism
- May worsen myoclonus in some patients
| Dosage |
Adults |
Children |
| Initial |
No prescribing information is available for the treatment of myoclonus in adults |
No prescribing information is available for the treatment of myoclonus in children |
Other Pharmacologic Agents: Fluoxetine hydrochloride
Types of myoclonus in which fluoxetine hydrochloride may be useful
- Cortical myoclonus
- Posthypoxic myoclonus (Lance Adams syndrome)
- Subcortical action myoclonus
Mechanism of action
- Blocks the uptake of serotonin into human platelets
Adverse effects
- Urticaria
- Headache
- Asthenia
- Nausea
- Diarrhea
- Insomnia
- Nervousness
Cautions
- Caution is urged with rapid dose escalation and polypharmaceutical therapy, as these may result in serotonin syndrome
| Dosage |
Adults |
Children |
| |
Prescribing information is not available for myoclonus |
No prescribing information is available for the treatment of myoclonus in children |
Other Pharmacologic Agents: Sumatriptan
Types of myoclonus in which sumatriptan may be useful
Mechanism of action
- Through activation of 5-HT1 receptors on peripheral terminals of the trigeminal nerve, thereby innervating cranial blood vessels
Adverse effects
- Paresthesia
- Pain or pressure sensations
Contraindications
| Dosage |
Adults |
Children |
| |
Prescribing information is not available for myoclonus |
No prescribing information is available for the treatment of myoclonus in children |
Other Pharmacologic Agents: Tetrabenazine
Types of myoclonus in which tetrabenazine may be useful
Mechanism of action
- Occurs through the interference with vesicular storage of biogenic amines, including dopamine, serotonin, and norepinephrine; antagonizes dopaminergic postsynaptic receptors
Adverse effects
- Drowsiness
- Fatigue
- Weakness
- Depression
- Orthostatic hypotension
Notes of interest
- Not currently available in the United States
| Dosage |
Adults |
Children |
| Initial |
12.5 mg 2 to 3 times a day, increased by 12.5 mg per day every 3 to 5 days |
No prescribing information is available for the treatment of myoclonus in children |
| Maintenance |
25 mg three times a day |
|
Other Pharmacologic Agents: Trihexyphenidyl
Types of myoclonus in which trihexyphenidyl may be useful
Mechanism of action
- Acetylcholine-receptor antagonist, exerts a direct inhibitory effect upon the parasympathetic nervous system; also has relaxing effect on smooth musculature
Adverse effects
- Dry mouth
- Blurred vision
- Constipation
- Urinary retention
- Tachycardia
Contraindications
| Dosage |
Adults |
Children |
| Initial |
1 mg per day |
|
| Maintenance |
6 to 80 mg per day given every 12 hours as a sustained-release capsule |
No prescribing information is available for the treatment of myoclonus in children |
Other Pharmacologic Agents: Melatonin
A small open-label study showed melatonin to be effective in treating children with myoclonus associated with sleep onset that caused delayed sleep onset and severely fragmented sleep. This substance induces sleep by inhibiting the wake-generating system. The typical dose is 3 to 5 mg in the FR form and 4 mg in the controlled-release form.
Immunosuppression
Immunosuppression, used in treating opsoclonus-myoclonus in children, may be achieved with the use of adrenocorticotropic hormone (ACTH), azathioprine (Imuran®), corticosteroids, and immunoglobulin therapy (IVIg). The mechanism of action occurs through suppression of lymphocytes and antibodies and restoration of neurotransmitter balance. Adverse reactions with the use of ACTH include cushingoid features, fluid retention, psychological effects, cardiovascular effects, gastric ulcers, skin changes, osteoporosis, infection, diabetes mellitus, and growth suppression. ACTH is typically administered as intramuscular injections for 2 months, beginning twice a day, with slow downward tapering. Adverse reactions with the use of azathioprine and corticosteroids include leucopenia, thrombocytopenia, nausea, and vomiting. Prescribing information is not available for myoclonus.
IVIg may be effective in treating parainfectious opsoclonus-myoclonus and idiopathic opsoclonus-myoclonus. Adverse reactions with the use of IVIg include headache, fever, and flu-like symptoms. The typical dosage is 1 to 2 grams per kg per day for 1 or more days.
Chemodenervation
Chemodenervation with the use of botulinum toxin type A injection therapy may be effective in treating focal myoclonus, particularly hemifacial spasm and palatal myoclonus, but chemodenervation may also be of benefit in treating myoclonus of a spinal origin. In the Hsiung et al. review, the typical dose of botulinum toxin type A used for treating hemifacial spasm in 70 patients over 630 treatment cycles was 12.5 U to 70 U, with 96% of patients reporting at least a 50% improvement in symptoms at 2 years, and 88% at 5 years; Deuschl et al. used 4 U to 10 U of botulinum toxin type A to treat two patients with palatal myoclonus, with the dose and dosing interval determined by the patients' symptoms. Lagueny et al. achieved successful remission of a case of action-induced spinal myoclonus with a single injection of 100 U of botulinum toxin type A (Botox®).
Surgical Techniques
Surgical techniques that have been employed in the treatment of myoclonus include decompression of a peripheral injury in peripheral myoclonus, removal of the compression lesion in spinal myoclonus, thalamic stimulation for medically intractable inherited myoclonus-dystonia syndrome, and excision of neoplasms in opsoclonus-myoclonus. This latter technique has a better outcome in children than in adults.
Summary
In summary, an improved quality of life and an enhanced ability to perform activities of daily living are possible for many people with myoclonus. Appropriate therapy yielding the best outcomes can be achieved when an accurate diagnosis is made, including identifying and treating any specific causal factors and related conditions. New pharmacologic agents hold promise in alleviating the disabling movements of myoclonus, and randomized, double-blind, placebo-controlled studies of these drugs are warranted. Challenges remain in identifying the mechanisms responsible for myoclonic movements, the reasons why some patients and not others develop posthypoxic myoclonus, the genetics involved in inherited myoclonus, and effective treatments for those patients whose myoclonus is not alleviated by currently available therapies.
