Myoclonus
Etiologic Classification
The most commonly used classification of myoclonus is based upon etiology. This scheme includes physiologic myoclonus, essential myoclonus, myoclonic epilepsy, and secondary or symptomatic myoclonus.
Physiologic myoclonus
Physiologic myoclonus is a normal phenomenon with little or no associated disability. Examples of physiologic myoclonus include hypnic jerks, otherwise known as sleep starts, that occasionally occur at the onset of sleep. Singultus results from the rhythmic contraction of the diaphragm and rarely requires intervention. The final form of physiologic myoclonus is benign sleep myoclonus of infancy, which usually occurs in the immediate postpartum period and is often mistaken for epilepsy. The inappropriate treatment of this disorder with anticonvulsant drugs may lead to increased sedation and more myoclonic jerks. The key feature of benign sleep myoclonus of infancy is the temporal relationship with the onset of sleep.
Essential
The second category of myoclonus, based on etiology, is essential myoclonus. By definition, essential myoclonus is idiopathic, although it can occur spontaneously or in association with a positive family history, likely in an autosomal dominant pattern of inheritance. Diagnostic criteria for essential myoclonus have been established. When genetically transmitted, essential myoclonus usually occurs in conjunction with tremor or dystonia, with a locus identified on chromosome 7q21-q31; the gene for chromosome 7-linked essential myoclonus is ε-sarcoglycan (SCGE). The disease course of essential myoclonus is either nonprogressive or only minimally progressive. The anatomic distribution is typically multifocal.
Progressive Myoclonic Epilepsy
The third category of myoclonus, based on etiology, is PME. Myoclonus varies in its predominance in these conditions, from being the only seizure manifestation, to one of multiple seizure types within the epileptic syndrome, to seizures rather than myoclonus dominating the clinical picture.
The lysosomal lipid storage diseases, neuronal ceroid lipofuscinoses, and sialidosis; the mitochondrial disorder, MERFF; the cystatin B deficiency, Unverricht-Lundborg disease; and the glycogen-storage disease, Lafora disease, comprise the PME.
Cognitive Involvement
Myoclonic epilepsy can be categorized based on cognitive involvement. Disorders that typically involve cognitive decline include Lafora disease, neuronal ceroid lipofuscinosis, MERRF, and sialidosis. Patients with Unverricht-Lundborg disease, an autosomal-recessive disorder, usually have mild dementia but little cognitive decline. Severe stimulus-sensitive myoclonus occurs in conjunction with generalized tonic-clonic seizures.
Age of Onset
Myoclonic epilepsy can also be categorized based on age of onset. In PME, myoclonic epilepsy is the defining symptom. Dementia and ataxia develop rapidly, typically beginning at age 6 to 15 years, and a lifespan of 10 to 20 years after onset is common. Giant SEP can be elicited by mixed and digital nerve stimulation. Transcranial magnetic stimulation shows a decrease in intracortical inhibition in the motor cortex. Juvenile myoclonic epilepsy, with a manifestation of myoclonic jerks upon awakening, has its onset in early adolescence, with a nondegenerative disease course. Familial adult myoclonic epilepsy, as can be surmised from its name, has an onset of symptoms in adulthood. This disorder is not associated with a degenerative disease course. The myoclonus is typically seen as generalized jerks of the limbs and tremulous movements of the fingers, with rare generalized tonic-clonic seizures. The genetic transmission is autosomal dominant, with a locus identified at 8q24.
- Predominance of myoclonus
- Cognitive involvement
- Age of onset
Secondary Myoclonus
Secondary, or symptomatic, myoclonus accounts for the vast majority of cases of myoclonus. The list of associated conditions is extensive and includes inborn errors of metabolism, trauma, neurodegenerative diseases, viral or mitochondrial encephalopathies, metabolic derangements, drug-induced syndromes, toxin exposure, and celiac disease.
Secondary Myoclonus: Inborn Errors of Metabolism
Myoclonus occurs in specific inherited metabolic diseases of childhood and adolescence, such as lysosomal storage diseases, including type 2 or 3 Gaucher disease, Tay-Sachs disease, Sandhoff disease, and sialidosis type II. The manifestation of the myoclonus varies from one condition to another, as well as over the course of a single metabolic disease.
Secondary Myoclonus: Trauma
Trauma occurring at the level of the brain, spinal cord, or peripheral nervous system can result in myoclonic movements. Brain trauma can include injury, infectious agents (e.g., Creutzfeldt-Jakob disease), neoplasm, inflammation, or hypoxia (Lance Adams syndrome); spinal-cord trauma can be the result of injury, inflammation, infection, or a lesion.
Secondary Myoclonus: Neurodegenerative Diseases
Neurodegenerative diseases that often have myoclonus as a component include the spinocerebellar ataxias (SCAs), multiple system atrophy, corticobasal ganglionic degeneration, Huntington disease, Parkinson's disease, Lewy body dementia, subacute sclerosing panencephalitis, and Alzheimer's disease. MERRF and a condition of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) fall under the rubric of mitochondrial conditions. Metabolic entities can be inherited, such as those associated with the previously mentioned PMEs or progressive myoclonic ataxia, or can be sporadic, such as those related to uremia, hepatic failure, hypercapnia, hyperglycemia, and metabolic alkalosis.
Secondary Myoclonus: Drugs
Drugs that are associated with myoclonic movements include anesthetic agents such as etomidate and propofol; serotonergic drugs, which can cause a serotonergic syndrome when used in patients who are elderly, in patients who have hepatic disease, or in combination with other serotonergic drugs; opiates, the influence of which is presumably due to antalgesic effects of the metabolite morphine-3-glucuronide; and a wide variety of other drugs, including anticonvulsants (carbamazepine9, phenytoin, lamotrigine, vigabatrin), mefloquine, gatifloxacin, tranexamic acid, Γ-hydroxybutyrate, antineoplastic agents, contrast agents, and dopamine agonists and antagonists. The diagnosis of drug-induced myoclonus is typically one of exclusion.
Secondary Myoclonus: Toxins
Exposure to a wide range of toxins, including gases, metals, organic solvents, and pesticides, can result in myoclonus. A few of the more common toxins that may cause myoclonus are lithium, bismuth, aluminum (particularly in patients with renal failure), methyl bromide intoxication, tetanus, lead, mercury, enteropathogenic toxin, acetone, toluene, strychnine, carbon monoxide, organophosphate compounds, and baking soda.
Secondary Myoclonus: Celiac Disease
Many people with celiac disease have myoclonic movements. Although commonly thought to be related to the malabsorption, particularly of vitamin B12, that frequently occurs in people with celiac disease, the pathogenesis may instead derive from an immunoinflammatory process. Typically, myoclonus does not respond well to the removal of gluten from the diet.
Other Forms of Myoclonus: Nocturnal Myoclonus
Symonds coined the term nocturnal myoclonus in 1953; using electromyography, Lugaresi first recorded the movements of the disorder—typically an extension of the great toe associated with flexion at the ankle, knee, and hip—and published the findings in 1965. The repetitive, almost stereotyped, movements usually occur at 15- to 40-second intervals during non-rapid eye movement sleep; due to the slow speed of the movements, they are technically not myoclonic, and the preferred term used today is periodic limb movements of sleep (PLMS). PLMS can be a primary or secondary condition. If sleep is recorded for multiple nights, more than 90% of patients with restless legs syndrome are found to have PLMS. Conversely, only 30% of people with PLMS also have restless legs. The prevalence of PLMS increases with advancing age, with more than 30% of people over the age of 65 having PLMS. The primary treatment is with dopaminergic agents and benzodiazepines (particularly clonazepam). Because of the potential development of vasovagal syncope, caution is urged in using dopaminergic agents in patients with postpolio syndrome, a group who commonly have PLMS.
Other Forms of Myoclonus: Psychogenic Myoclonus
Psychogenic myoclonus has a psychological rather than a physiologic basis. This disorder is more common in women than in men and is usually worsened with exposure to stress or anxiety. The typical movements are segmental or generalized but can be focal. The diagnosis of psychogenic myoclonus often requires electrophysiologic testing, including EMG, EEG, and back-averaging EEG-EMG to rule out physiologic causes. Typical findings include Bereitschaftspotential (a movement-related cognitive potential indicative of motor preparation) without stimulus, and the recordings may not show potential with stimulus. Jerks lasting more than 70 milliseconds are usually psychogenic and show a triphasic pattern of activation of agonist and antagonist muscles. Reflex psychogenic myoclonus typically has a latency of more than 100 milliseconds, lacks giant potentials on SEP, has long-duration bursts on EMG, and variable activation patterns.
Other Forms of Myoclonus: Myoclonus Dystonia
In myoclonus dystonia, upper-extremity involvement predominates, and the legs are usually spared. The cardinal diagnostic criteria include an onset of symptoms within the first or second decade of life; myoclonus occurs in all cases, with dystonia in half; males and females are equally affected; the disease course is relatively benign but does vary; the mode of inheritance is autosomal-dominant with variable severity and incomplete penetrance, dependent upon parental origin of the allele; reduced penetrance occurs upon maternal inheritance, indicating genomic imprinting; seizures, dementia, ataxia, and other neurologic deficits are absent.
Optional diagnostic criteria include responsiveness to ethanol ingestion and personality and psychiatric disturbances. Genetic testing typically shows a mutation in the SCGE. The finding of an SCGE mutation is confirmatory of diagnosis; however, the lack of an SCGE mutation does not preclude the diagnosis of myoclonic epilepsy.
Given the variable expressivity, genetic heterogeneity, probable nongenetic phenocopies, and anticipation (particularly with paternal transmission), careful genetic counseling is very important.
- Onset in first or second decade
- Myoclonus in all; dystonia in half
- Males and females equally affected
- Relatively benign but variable course
- Autosomal-dominant mode of inheritance
- Other neurologic deficits absent
Other Forms of Myoclonus: Opsoclonus-Myoclonus
Opsoclonus-myoclonus, also known as Kinsbourne syndrome, is the dancing eyes syndrome or myoclonic encephalopathy of infants. The primary features of the disorder include the saccadic eye movements—which are involuntary, irregular, conjugate, either multidirectional or horizontal ocular flutters that are precipitated by change of fixation—and action myoclonus, which typically involves the face, limbs, fingers, and trunk. The age of symptom onset is usually less than 2 years in children and can be any age in adults. Therapy is aimed at treating the underlying cause, including excision of the neoplasm (usually neuroblastoma) or antiviral therapy, as indicated.
