Parkinson's Disease Center and Movement Disorders Clinic

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1 Parkinson's Disease Center and Movement Disorders Clinic 7200 Cambridge Street, 9th Floor, Suite 9A Houston, Texas phone Myoclonus Diagnosis Myoclonus is the medical term for sudden, rapid, brief, involuntary jerking of a muscle or group of muscles. These shock-like movements may be caused by sudden muscle contractions (positive myoclonus) or sudden losses of muscle tone (negative myoclonus). Many different neurological disorders can cause myoclonus; therefore, neurologists consider it a symptom of disease rather than a specific diagnosis. Indeed, everyone experiences myoclonus on occasion. For example, "sleep starts," also known as hypnic jerks, are the shock-like twitches that some people experience while drifting off to sleep. This is a form of myoclonus that occurs in normal, healthy individuals. Pathological myoclonus, however, may be extremely disabling. Myoclonus may affect a small region (focal or segmental myoclonus), such as one hand, or may produce violent jerks over the entire body (generalized myoclonus). Myoclonic jerks may occur alone or in sequence, either in a pattern or randomly. When patterned, they sometimes resemble more common forms of tremor. They may occur infrequently or many times each minute. All types of myoclonus are similar insofar as the movement cannot be controlled by the person who is experiencing it and, in contrast to a tic, there is no warning or premonitory sensation. In more severe cases, myoclonus can distort movement and severely limit a person s ability to walk, talk, and eat. These types of myoclonus may indicate that an underlying condition of the brain or nerves is causing the myoclonus. Classifying the many different kinds of myoclonus is difficult, as the causes, clinical effects, and responses to treatment vary greatly. It can be classified in a number of ways. By distribution (body parts affected), myoclonus can be classified as focal,

2 multifocal, or generalized and by provoking factors as spontaneous and reflex. Myoclonus can also be classified on physiology, meaning, the presumed source of its origin in the nervous system: cortical (brain), subcortical (between the brain and spinal cord), spinal, or peripheral (nerves outside of the central nervous system). It is useful for physicians to classify myoclonus by physiology because the presumed source of myoclonus (cortical, subcortical, spinal, or peripheral) helps guide the physician towards the most effective treatment. Myoclonus can occur at rest, when maintaining posture, or during action. Stimulus sensitive myoclonus is a type of myoclonus triggered by outside stimuli such as lights, noise, or movement. It can be brought on by surprise as well. Myoclonus can also be classified by etiology (the underlying cause), which is described in more detail below. 1. Physiologic myoclonus This type of myoclonus occurs in healthy people and rarely requires treatment. Examples include hiccups, sudden jerk when someone is startled, or twitching of the arm or leg when beginning to fall asleep. Sleep myoclonus occurs during the initial phases of sleep, especially at the moment of dropping off to sleep. Some forms appear to be stimulus-sensitive. Persons with sleep myoclonus are rarely troubled by, or need treatment for, the condition. However, myoclonus may be a symptom in more complex and disturbing sleep disorders, such as restless legs syndrome, and may require treatment by a doctor. 2. Essential myoclonus This type of myoclonus occurs on its own without an underlying medical condition. Essential myoclonus is sometimes an inherited disorder but can also arise in people with no family history of neurological disease. Essential myoclonus tends not to worsen over time and cognition remains normal. Hereditary essential myoclonus is synonymous with myoclonus-dystonia syndrome. Approximately 30-50% of cases are due to mutations of the epsilon- 3

3 sarcoglycan gene, but other genes have also been identified. It is typically inherited from the father. When the mutated gene is inherited from the mother, it has a much lower likelihood of causing the disease. It typically starts in childhood with myoclonic jerks and usually is seen in combination with mild dystonia (abnormal postures). Psychiatric features such as depression, anxiety, and obsessive-compulsive disorder may also be a part of the clinical picture. The myoclonus in myoclonus-dystonia syndrome is often improved with alcohol. 3. Epileptic myoclonus This term is used to denote conditions in which myoclonus occurs in the setting of epilepsy (seizure disorders). Myoclonus can occur in the setting of primary generalized epilepsy syndromes such as juvenile myoclonic epilepsy (JME) or in the secondary (symptomatic) generalized epilepsy syndromes, such as the progressive myoclonic epilepsies. Progressive myoclonic epilepsy (PME) PME is a group of diseases characterized by myoclonus, epileptic seizures, and other serious symptoms such as trouble walking or speaking. PME tends to arise during childhood or adolescence. The rare disorders that comprise PME often get worse over time and are sometimes are fatal. There are several forms of PME. a. Lafora body disease (PME type 2) is inherited as an autosomal recessive disorder, meaning that the disease occurs only when a child inherits two copies of a defective gene, one from each parent. Lafora body disease is characterized by myoclonus, epileptic seizures, and dementia (progressive loss of memory and other intellectual functions). b. Unverricht-Lundborg disease, also called Baltic Myoclonic Epilepsy (PME type 1), is another form of PME that is also inherited as an autosomal recessive fashion. Its symptoms are similar to Lafora body disease but often worsen less rapidly. 4

4 c. Lysosomal storage diseases are a third form of PME and include neuronal ceroid lipofuscinoses and sialidosis, which are disorders of lysosomes, the small compartments within cells that digest unneeded debris. The lysosomal storage diseases are also autosomal recessive and usually cause visual problems, dementia and dystonia (sustained muscle contractions that cause twisting movements or abnormal postures) in addition to myoclonus. d. Mitochondrial Diseases: Disorders of another cellular compartment, mitochondria, may also cause PME. Mitochondria are needed to produce energy for nerve cell growth and function. Mitochondrial diseases, such as myoclonic epilepsy with ragged-red fibers (MERRF), cause action myoclonus, seizures, muscle disease and problems with balance and walking. Some mitochondrial diseases, like MERRF, are usually inherited from one's mother because mitochondria have their own DNA that is passed unchanged from a mother to her children. 4. Secondary myoclonus This type of myoclonus occurs in the context of an underlying disorder (neurological or non-neurological). There are many potential causes of myoclonus. Myoclonus can occur by itself, but most often it is one of several symptoms associated with a wide variety of nervous system disorders and other diseases. Listed below are some of the causes of myoclonus: Infection Head or spinal cord injury Stroke Brain tumors Kidney or liver failure Inherited metabolic diseases Chemical or drug poisoning Prolonged oxygen deprivation to the brain (hypoxia) 5

5 Examples of neurologic diseases that can be accompanied by myoclonus are listed below: Multiple sclerosis Parkinson's disease Dementia with Lewy bodies Corticobasal degeneration Multiple system atrophy Frontotemporal dementia Alzheimer's disease Creutzfeldt-Jakob disease Stiff-person syndrome Autoimmune encephalitis Celiac Disease Several types of secondary myoclonus are described in further detail below: Post-hypoxic myoclonus (Lance-Adams syndrome) Lance-Adams syndrome occurs in patients who have undergone cardiorespiratory arrest (the heart stops beating) and later regain consciousness. Lack of blood flow to the brain starves it of oxygen and causes damage to the brain. With recovery from this severe episode, myoclonus may develop days or weeks after the event. It is usually an action myoclonus that stops when the patient is at rest. Opsoclonus-Myoclonus Syndrome This is a rare condition in which there are brief, sudden muscle spasms in addition to irregular eye movements called opsoclonus. It appears between 6 and 18 months of age and often responds quite effectively to steroid or ACTH treatment. About one-half of children have an underlying brain tumor, a neuroblastoma, thus all children with this syndrome should be evaluated with brain imaging. In adults, 6

6 this syndrome may be associated with other malignancies such as lung cancer, thus a rigorous evaluation for an underlying malignancy should be considered. Palatal myoclonus, Now called palatal tremor, this is a regular, rhythmic contraction of one or both sides of the rear of the roof of the mouth, called the soft palate. These contractions may be accompanied by myoclonus in other muscles, including those in the face, tongue, throat, and diaphragm. The contractions are very rapid, occurring as often as 150 times a minute, and may persist during sleep. This condition usually appears in adults and can last indefinitely. People with palatal myoclonus usually regard it as a minor problem, although some occasionally complain of a clicking sound in the ear from the noise made as the tensor veli palatini muscle in the soft palate contracts. Many neurologists now classify this condition as a type of tremor rather than myoclonus. Peripheral myoclonus This type of myoclonus occurs when the signal triggering the myoclonus originates in the peripheral nerves (nerves located outside of the brain and spinal cord). The most common example of peripheral myoclonus is hemifacial spasm. Hemifacial spasm is manifested by twitching jerks on one side of the face due to involuntary contractions of the eyelid and other facial muscles, which may impact vision due to brief episodes of eye closure. Hemifacial spasm may be caused by blood vessels or tumors pushing against the seventh cranial nerve, thus brain imaging is usually warranted for further evaluation. Further information on hemifacial spasm may be found in the link entitled, Hemifacial spasm, in the Conditions section of the PDCMDC website. The diagnostic approach to a patient with myoclonus has two objectives: (1) identifying what part of the nervous system is producing myoclonus and (2) establishing the cause. Clinicians are able to categorize myoclonus on the basis of 7

7 its distribution over the body, its electrophysiological characteristics, and its etiology (cause). Physicians may order certain tests to learn what is causing the myoclonus. These may include: Electroencephalogram (EEG): a record of the brain s electrical activity. Electromyography (EMG): measures muscle activity and the electoral signals associated with myoclonus. Imaging tests including MRI, CT scan, or PET scan to look for abnormalities such as lesions or tumors. Blood tests to see if there any medical conditions that could be causing the myoclonus. Cause Although some cases of myoclonus are caused by an injury to the peripheral nerves (defined as the nerves outside the brain and spinal cord), most forms of myoclonus are caused by a disturbance of the central nervous system (the brain and spinal cord). Studies suggest that several locations in the brain are involved in myoclonus. One such location is in the area of the brainstem located close to structures that are responsible for the startle response, an automatic reaction to an unexpected stimulus involving rapid muscle contraction. The specific mechanisms underlying myoclonus are not yet fully understood. Scientists believe that some types of stimulus-sensitive myoclonus may involve over excitability of the parts of the brain that control movement. These parts are interconnected in a series of feedback loops called motor pathways. These pathways facilitate and modulate communication between the brain and muscles. Key elements of this communication are chemicals known as neurotransmitters, which carry messages from one nerve cell, or neuron, to another by binding to a receptor. Laboratory studies suggest that an imbalance between these chemicals may underlie myoclonus. Receptors that appear to be related to myoclonus include 8

8 those for two important inhibitory neurotransmitters: serotonin, which constricts blood vessels and promotes sleep, and gamma-aminobutyric acid (GABA), which helps the brain maintain muscle control. Treatment If possible, the underlying cause of myoclonus should be corrected, but this is not always possible. If the myoclonus is due to a medication side effect, then the myoclonus usually resolves with discontinuation of that medication. If myoclonus persists despite eliminating treatable causes, then the treatment of myoclonus otherwise focuses on medications help reduce symptoms. The drugs used to treat myoclonus usually possess anti-seizure properties. Epileptic myoclonus and cortical (arising from the brain s cerebral hemispheres) myoclonus respond best to clonazepam and sodium valproate, which may be used alone or in combination. Clonazepam is a tranquilizer and is commonly used to treat myoclonus. Dosages of clonazepam are usually increased gradually until the patient improves or side effects become bothersome. Drowsiness and loss of coordination are common side effects. The beneficial effects of clonazepam may diminish over time if the patient develops a tolerance for the medication. If disability from the myoclonus is not adequately improved on either or both of these medications, then medications such as levetiracetam (Keppra) can be added, which is also very effective in treating myoclonus. Levetiracetam has also been shown to be effective in posthypoxic myoclonus. Primidone may also be of value was an additional drug, as well as clobazam and acetazolamide in severely effected patients. Often, a single drug is not effective by itself, and combinations of medications are frequently required. When medications fail, botulinum toxin can be used. In certain types of myoclonus, such as palatal myoclonus and hemifacial spasm, botulinum toxin (BoNT) injections 9

9 can be very effective. This medication is directly injected into the muscles causing the involuntary jerks at relatively low doses, allowing for relaxation of the muscles, thus preventing the spasms. Rarely, surgical intervention known as deep brain stimulation (DBS) is considered as a last resort for certain forms of myoclonus. Further studies are needed to evaluate the effectiveness of such treatment. Tumors that cause myoclonus in children with opsoclonus-myoclonus may need to be surgically removed and/or treated with chemotherapy and radiation. Selected References Baizabal-Carvallo JF, Jankovic J. Distinguishing features of psychogenic (functional) versus organic hemifacial spasm. J Neurol. 2017;264(2): Baizabal-Carvallo JF, Jankovic J. Movement disorders in autoimmune diseases. Mov Disord. 2012;27(8): Baizabal-Carvallo JF, Jankovic J. Parkinsonism, movement disorders and genetics in frontotemporal dementia. Nat Rev Neurol. 2016;12(3): Baizabal-Carvallo JF, Jankovic J. Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatry. 2015;86(8): Borg M. Symptomatic myoclonus. Neurophysiol Clin. 2006;36: Browner N, Azher SN, Jankovic J. Botulinum toxin treatment of facial myoclonus in suspected Rasmussen encephalitis. Mov Disord. 2006;21: Caviness JN, Brown P. Myoclonus: current concepts and recent advances. Lancet Neurol. 2004;3: Caviness JN. Treatment of Myoclonus. Neurotherapeutics. 2014;11(1): Erro R. The importance of electrophysiological assessment of myoclonus. Clin Neurophysiol. 2017;128(1): Espay AJ, Chen R. Myoclonus. Continuum (Minneap Minn). 2013;19(5 Movement Disorders):

10 Fahn S, Jankovic J. Principles and Practice of Movement Disorders, Churchill Livingstone, Elsevier, Philadelphia, PA, 2007: Galstyan A, Wilbur C, Selby K, Hukin J. Opsoclonus-myoclonus syndrome: a new era of improved prognosis? Pediatr Neurol. 2017;72: Jankovic, J. Therapeutic developments for tics and myoclonus. Mov Disord. 2015;30(11): 8. Jankovic J, Shannon KM. Movement disorders. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice, 5th ed., Butterworth- Heinemann (Elsevier), Philadelphia, PA, Janssen S, Bloem BR, van de Warrenburg BP. The clinical heterogeneity of druginduced myoclonus: an illustrated review. J Neurol. 2017;264(8): Kluger B, Triolo P, Jones W, Jankovic J. The therapeutic potential of cannabinoids for movement disorders. Mov Disord. 2015;30(3): Lizuka T, Sakai F, Ide T, Jankovic J, Tolosa E, eds. Parkinson's Disease and Movement Disorders, 5th ed., Lippincott Williams and Wilkins, Philadelphia, PA, 2007: Lohi H, Turnbull J, Zhao XC, et al. Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology. 2007;68: Magaudda A, Ferlazzo E, Nguyen VH, Genton P. Unverricht-Lundborg disease, a condition with self-limited progression: long-term follow-up of 20 patients. Epilepsia. 2006;47:860. Mehanna R, Jankovic J. Movement disorders in cerebrovascular disease. Lancet Neurol. 2013;12(6): Mehanna R, Jankovic J. Movement disorders in multiple sclerosis and other demyelinating diseases. J Neurol Sci. 2013;328(1-2):1-8. Ross S, Jankovic J. Palatal myoclonus: An unusual presentation. Mov Disord. 2005;20: Rothenberg AB, Berdon WE, D'Angio GJ, Yamashiro DJ, Cowles RA. The association between neuroblastoma and opsoclonus-myoclonus syndrome: a historical review. Pediatr Radiol. 2009;39:

11 Roze E, Bounolleau P, Ducreux D, Cochen V, Leu-Semenescu S, et al. Propriospinal myoclonus revisited: Clinical, neurophysiologic, and neuroradiologic findings. Neurology. 2009;72: Shibasaki, H., Thompson, PD. Milestones in myoclonus. Mov Disord. 2011;26: Tai KK, Bhidayasiri R, Truong DD. Post-hypoxic animal model of myoclonus. Parkinsonism Relat Disord. 2007;13: Thomas M, Jankovic J. Tics, myoclonus, stiff person syndrome, gait freezing and rigidity. In: Moore P, Naumann M, eds. Handbook of Botulinum Toxin Treatment, 2nd ed., Blackwell Science, London, UK, 2003: Tyvaert L, Krystkowiak P, Cassim F, Houdayer E, Kreisler A, et al. Myoclonus of peripheral origin: two case reports. Mov Disord. 2009;24: Vercueil L. Myoclonus and movement disorders. Neurophysiol Clin. 2006;36: Yaltho TC, Jankovic J. The many faces of hemifacial spasm: Differential diagnosis of unilateral facial spasms. Mov Disord. 2011;26(9): Zutt R, van Egmond ME, Elting JW, et al. A novel diagnostic approach to patients with myoclonus. Nat Rev Neurol. 2015;11(12): Support Organizations Brain Resources and Information Network (BRAIN) National Institute of Neurological Disorders & Stroke P.O. Box 5801 Bethesda, MD Toll free: (800) Fax: (301) Website: braininfo@ninds.nih.gov 12

12 National Organization for Rare Disorders (NORD) 55 Kenosia Avenue Danbury, CT Phone: (203) Toll free: (800) Fax: (203) Website: Joseph Jankovic, M.D. 13