Clinical manifestations

Presentation and course

The clinical manifestations of epileptic myoclonus vary significantly between syndromes and diseases manifesting with this type of seizure, and it is often associated with other seizures and neurologic and cognitive symptoms (see, for example, MedLink clinical summaries Juvenile myoclonic epilepsy, Dravet syndrome, Unverricht-Lundborg disease, and Lafora disease).

Myoclonic jerks are shock-like, irregular, and often arrhythmic, unidirectional clonic-twitching movements that are singular or repetitive. They are of variable amplitude, force, location, duration, and circadian distribution, and have a number of precipitating factors.

Epileptic myoclonus is commonly accompanied by generalized EEG discharges of mainly polyspikes, as in generalized epilepsies (15). However, the ictal EEG may show focal abnormalities only (idiopathic reading epilepsy), be entirely normal, or require processing using jerk-locked back-averaging techniques.

The myoclonic jerks may be:

The clinical manifestations of myoclonic seizures show significant differences between idiopathic generalized epilepsy, such as juvenile myoclonic epilepsy, and progressive myoclonic epilepsies, such Lafora disease.

Juvenile myoclonic epilepsy. In juvenile myoclonic epilepsy, the myoclonic jerks are shock-like, irregular, and arrhythmic clonic movements of proximal and distal muscles, mainly of the upper extremities. They are of variable amplitude and force. They are often mild, restricted in the fingers or hands, making the patient prone to drop things unexpectedly or look clumsy. They are sufficiently violent to cause falls in more than half of the patients. The same patient usually experiences mild and violent jerks. One-fifth of the patients describe their jerks as unilateral, probably because jerks of the dominant hand become more apparent. Video-EEG studies on these patients show that the jerks affect both sides.

Consciousness is not impaired during the jerks. However, patients with pronounced myoclonic jerks and myoclonic status epilepticus may complain of lack of awareness. This may be due either to the distress caused by the continuous jerks or, most likely, to mild absences interspersed with jerks.

The myoclonic jerks of juvenile myoclonic epilepsy generally appear when the patient reaches their mid-teens, usually preceding the appearance of generalized tonic-clonic seizures by a few months. Some patients (less than 10%) with mild forms of juvenile myoclonic epilepsy never develop generalized tonic-clonic seizures, probably as the result of early diagnosis and treatment. Myoclonic jerks characteristically occur after awakening, particularly after sleep deprivation and excessive alcohol consumption. Patients who do not demonstrate this circadian pattern probably do not belong to juvenile myoclonic epilepsy but to other syndromes such as juvenile absence epilepsy. Myoclonic jerks are independent of typical absences and do not occur during the absence ictus. A series of myoclonic jerks often heralds generalized tonic-clonic seizures (clonic-tonic-clonic generalized convulsions).

Lafora disease. In Lafora disease, the jerks are massive and synchronous bilateral myoclonic jerks of brief duration, usually limited to 1 or more muscle groups. The myoclonic jerks are not associated with loss of consciousness and are usually triggered by visual stimulation or proprioceptive impulses. Epileptic visual seizures with elementary visual hallucinations may be an early sign of the disease. With progression, myoclonus increases in intensity and becomes severe and multifocal, precipitated by posture or action. At this point, intellectual deterioration occurs rapidly. A terminal stage of severe dementia, spastic quadriparesis, and almost constant myoclonic seizures is reached within 2 to 10 years after the onset of symptoms.

Jerks of massive bilateral myoclonus mainly involve the upper limbs, with elevation of the shoulders producing slight contraction of the trunk. Massive bilateral myoclonus can be asymmetrical, and it is a challenge in clinical practice to distinguish within asymmetrical jerks those that correspond to focal jerk with secondary generalization and those that correspond to generalized although asymmetrical jerks. The pathophysiologic and etiologic significance and, therefore, the therapeutic decisions are different. Jerks are clearly increased by waking up and falling asleep; a child with massive bilateral myoclonus may have sleep difficulties caused by jerks that wake the child up each time he or she starts to fall asleep. Jerks may also be precipitated by photic stimulation.

Polygraphy recording shows that during a jerk there is a spike or a polyspike of a spike-wave complex. Video alone is not precise enough to show this evidence. This kind of jerk can occur in juvenile myoclonic epilepsy and in myoclonic epilepsy in infancy (19).

Myoclonic status epilepticus. Generalized myoclonic status epilepticus usually results from lack of avoidance of precipitating factors and/or inappropriate use of antiepileptic drugs (35). In idiopathic generalized epilepsy, it is more common in juvenile myoclonic epilepsy (mainly limb jerks), and consciousness may be unaffected. Myoclonic status epilepticus of perioral, eyelid, myoclonic absence epilepsy, and Doose syndrome usually manifests with myoclonus intermixed with or superimposed on absence seizures. Myoclonic status epilepticus often terminates with generalized tonic-clonic seizures.

Myoclonic status epilepticus is commonly encountered in progressive myoclonic epilepsies, Dravet syndrome, and myoclonic encephalopathy in nonprogressive disorders of mainly chromosomal disorders such as Angelman syndrome, prenatal brain anoxia-ischemia, and congenital abnormalities. In the latter syndrome, myoclonic jerks are predominantly asymmetrical and asynchronous, consciousness is often severely affected, and the condition lasts for weeks, months, or even years, with persistent deterioration of mental function. This type of myoclonic status epilepticus usually starts insidiously with progressive deterioration of consciousness and drooling, and the patient becomes more and more ataxic (08; 21). The EEG shows continuous generalized asynchronous slow-wave activity intermingled with multifocal spikes, occasionally resulting in spike-wave complexes.

Acute symptomatic myoclonic status epilepticus after prolonged anoxia or other severe metabolic insults consists of very brief, sudden movements of restricted parts of the body that may be triggered by external stimuli, such as mechanical ventilation. Myoclonic status epilepticus of nearly continuous myoclonus may appear several hours after cardiac arrest and lasts for many days (45).

Negative myoclonic status epilepticus has been reported with subcontinuous negative myoclonus manifesting with segmental or axial loss of muscle tone. This condition may persist for days or months. Failing attempts to oppose gravity during the episodes of loss of tone produces jerk-like negative motor effects, which do not occur when the patient lies down. There is no positive myoclonus. The EEG shows continuous spike-waves during slow-wave sleep.

Prognosis and complications

Prognosis varies significantly depending on etiology and the type of epilepsy. It is relatively good in juvenile myoclonic epilepsy, poor in Dravet syndrome, and desperate in Lafora disease.

Clinical vignette

Case 1. Juvenile myoclonic epilepsy. A 38-year-old woman with juvenile myoclonic epilepsy experienced the onset of myoclonic jerks and generalized tonic-clonic seizures beginning in her mid-teens. She also had minor absences of which she was not aware, although these were documented with video EEG. She had frequent violent myoclonic jerks in the morning, which often ended with generalized tonic-clonic seizures. She had been treated with the inappropriate medications phenytoin and carbamazepine up to the age of 33 years, when she was referred for an EEG. EEG documented myoclonic status epilepticus with repetitive myoclonic jerks interspersed with mild absences. Subsequently, she remained free of generalized tonic-clonic seizures for 5 years of follow-up on valproate monotherapy. Myoclonic jerks occurred only occasionally on awakening after sleep deprivation.

Case 2. Myoclonic epilepsy in infancy. At 3 years of age, an otherwise normal girl developed frequent and violent myoclonic jerks, mainly in the head and shoulders, with grunting noises but no impairment of consciousness. These were spontaneous and occurred day and night. Routine EEG 6 weeks from the onset of the jerks documented forceful jerks. The seizures stopped only when clonazepam was added to valproate (valproate was probably not needed). At 6 years of age, she was no longer on medication, had developed well, was free of seizures, and had a normal EEG.

Case 3. Epilepsia partialis continua of unknown cause. An intelligent 12-year-old girl had epilepsia partialis continua, which started at 4 years of age and continued to the present with increasing frequency and duration. Fast (3 to 10 Hz) twitching of the left eyelid occurred simultaneously with the left rectus abdominis (she pointed close to the midline by the umbilicus) and a muscle in the armpit (probably the latissimus dorsi). This lasted from hours to 2 to 3 days and was continuous day and night. It was interspersed with ipsilateral left-sided, focal tonic-clonic motor seizures mainly affecting the face and upper limb. Additionally, there was postictal, and probably ictal, left hemiparesis, mainly of the upper limb. She did not lose consciousness during these attacks and communicated well. She was also able to understand, but could not speak, during the focal motor seizures. She had never had a full-blown generalized tonic-clonic seizure.

Initially, the seizures occurred once or twice per year but presently occurred every 2 weeks. Neurologic and mental status was normal. High-resolution brain MRI was normal. All appropriate tests for metabolic or other diseases associated with epilepsia partialis continua were normal. Drug treatments have failed; only rectal diazepam has provided temporary relief during the attacks.

Biological basis

Localization

Myoclonic seizures can arise from either neocortical or subcortical structures and may often be the result of abnormal interactions and connectivity of cortical-subcortical circuits (56; 38; 06; 82; 11; 77; 49). Jerks predominate in the extremities, often causing the patient to drop objects; this indicates that the motor strip is affected. However, the rhythmicity of the spike-wave complex suggests that the reticular structure of the thalamus is also involved and that there is, in fact, a loop between the motor strip and the thalamus. The jerks do not, therefore, constitute a generalized seizure because they predominate in 1 neurophysiological pathway. Rather, they are usually called “generalized myoclonus” because no site of onset can be identified, and the whole motor structure seems to be hyperexcitable.

Hyperexcitability in the motor pathways permits synchronization in the rolandic and thalamic structures, the discharge in 1 structure triggering the discharge in the other structure, and the cycle is closed. The discharge then goes along the pyramidal pathway. Polygraphy recording of several muscles, including the eyelid, neck, and upper and lower limbs, shows that the contraction reaches the eyelid before continuing to the upper limb and then the lower limb, demonstrating that the discharge is produced in the brain cortex.

Pathophysiological hypotheses on the origin of negative myoclonus involve subcortical as well as cortical mechanisms. Neuroimaging and neurophysiologic investigations, including intracerebral recordings and electrical stimulation procedures in epilepsy, suggest the participation of premotor, primary motor, primary sensory, and supplementary motor areas in the genesis of negative myoclonus (70; 71).

Pathophysiology

The pathophysiology of myoclonus is complex. There are several genetic, chemical, and electrical stimulation models in animals that have provided significant insights on the basic circuitry and neurochemistry of myoclonus, though much additional work is needed.

The pathophysiology of myoclonic seizures depends on whether these are cortical or thalamocortical (cortical-subcortical) (56; 38; 06; 11; 77).

Cortical epileptic myoclonus is generated by a focal cortical discharge as demonstrated by a focal EEG transient back-averaged before the myoclonus EMG burst.

The myoclonus is focal or multifocal with frequent spreading. Examples include cortical reflex posthypoxic myoclonus, many instances of progressive myoclonic epilepsy, and epilepsia partialis continua.

Cortical-subcortical myoclonus of generalized epilepsies arises from paroxysmal, abnormal, and excessive oscillation in bidirectional connections between cortical and subcortical sites. This is associated with generalized polyspike EEG discharge (4 to 6 Hz for juvenile myoclonic epilepsy, slow spike-wave for epileptic encephalopathies).

Myoclonic seizures can be induced by photic stimulation in baboons, such as Papio papio, and are associated with dysfunction of GABAergic and monoaminergic neurotransmission (58). Seizures in this model appear to originate in the cerebral cortex.

In the tottering mouse, myoclonic seizures are also associated with abnormal monoaminergic circuits. The Otx1-/- mouse and flathead mutant rat both exhibit myoclonic seizures, which may be related mainly to loss of GABAergic interneurons. Myoclonic seizures can be induced in rats by a number of chemoconvulsant agents, including pentylenetetrazol, bicuculline, picrotoxin, flurothyl, and other compounds; all of these reduce neurotransmission at GABAA receptors, among other actions. In these models, isolated myoclonic seizures typically lead to and precede full-blown tonic-clonic seizures and, in this respect, may differ from human-isolated myoclonus (06).

The putative involvement of the cerebellum in the pathogenesis of cortical myoclonic syndromes has been long hypothesized, as neuropathological changes in patients with cortical myoclonus have most commonly been found in the cerebellum rather than in the suspected culprit, the primary somatosensory cortex. A model of increased cortical excitability due to loss of cerebellar inhibitory control via cerebello-thalamo-cortical connections has been proposed, though evidence remains equivocal (32). An important factor that may play a role in the expression of myoclonic/clonic seizures is the maturation of the endogenous brain mechanisms involved in seizure control (82). One of the structures involved in the regulation of the myoclonic seizures is the substantia nigra pars reticulata. The seizure-modulating effects are mediated chiefly via GABA A receptors. The substantia nigra pars reticulata has a strategic position in the brain influencing the output of the basal ganglia network--the thalamus, superior colliculus, and reticular formation, and back to the striatum. Disturbances in this network give rise to abnormal movements, including myoclonic seizures. There is evidence that substantia nigra pars reticulata-based seizure modulation has age-, sex-, and region-specific features that must be taken into account when novel treatments are contemplated (82; 37).

Several genes or loci have been associated with conditions manifesting myoclonic seizures, including GABA receptor, chloride or calcium channels, EF-hand domain containing protein 1 (EFHC1) for juvenile myoclonic epilepsy, cystitis B for Unverricht-Lundborg disease, EPM2A or EPM2B for Lafora disease, potassium channels (KCNC1 for myoclonus epilepsy and ataxia due to potassium channel mutation), battening and other genes linked to neuronal ceroid lipofuscinosis, sodium channels for Dravet syndrome, GABA transporter 1 (GAT1) for myoclonic-atonic epilepsy, kinesis family member 5A (KIF5A) for neonatal intractable myoclonus, and many others. Mitochondrial diseases can also manifest with myoclonus, such as myoclonus epilepsy with ragged-red fibers. Familial adult myoclonic epilepsy has been linked to chromosomal or genetic abnormalities, such as contactin-2 (CNTN2). Creutzfeldt-Jakob disease is a prion disease. For a more exhaustive list, please see (20). Autoimmune etiologies have also been reported.

Epidemiology

Epileptic myoclonus is the most common type of seizure. Depending on the syndrome, epileptic myoclonus may be the predominant or the only type of seizure or rare. See the following section on myoclonus and epileptic syndromes.

Differential diagnosis

Confusing conditions

There is a long list of epileptic and nonepileptic paroxysmal events that should be differentiated from myoclonic seizures (65; 14). This first requires skillful assessment of the clinical and family history of the patient, such as distribution, temporal profile, and activation characteristics of the myoclonic movement; age at onset and progression; other types of seizure; neurologic and cognitive state; and other family members with similar events. Neurophysiologic tests and, particularly, polygraphic recordings are often mandatory for the proper diagnosis.

Broadly, the differential diagnosis is to exclude nonepileptic myoclonus such as hyperekplexia and associated diseases, as well as normal events such as hypnagogic myoclonus, hiccups, benign myoclonus of sleep, and tics.

Once the epileptic nature of the symptoms has been established, the distinction should be made between myoclonic and other types of epileptic seizure. Myoclonic seizures are briefer than tonic seizures and epileptic spasms. Myoclonic seizures are single or irregularly recurrent events, as opposed to clonic seizures, which are rapid rhythmically recurrent myoclonic-like events. Clonic seizures are rhythmical, regular repetitive myoclonic jerks at 2 to 3 Hz (range 1 to 5 Hz). Tonic seizures comprising a sustained increase in muscle contraction usually last a few seconds (> 2 to 10 seconds), but occasionally last minutes. They may be segmental or axial, and of variable severity, from inconspicuous to violent. They are associated with EEG flattening or low-amplitude fast activity. Epileptic spasms are sudden and brief bilateral tonic contractions of the axial and proximal limb muscles with abrupt onset and termination. They usually last for 0.4 to 0.8 seconds (range 0.2 to 2 seconds).

The specific etiology and epileptic syndrome should then be established, with particular emphasis between nonprogressive syndromes (eg, juvenile myoclonic epilepsy and myoclonic epilepsy in infancy), epileptic encephalopathies (eg, Dravet syndrome), progressive myoclonic epilepsies (eg, Unverricht-Lundborg and Lafora disease), and glucose transporter 1 deficiency syndrome (03).

Iatrogenic and drug-induced myoclonus may also need to be differentiated from other forms of nonepileptic or epileptic myoclonus. Serotonin syndrome, for example, may present with myoclonic jerks. Myoclonus can also be seen in older populations with neurodegenerative disorders, including Alzheimer disease, certain forms of Parkinson disease, Huntington disease, and, more classically, Creutzfeldt-Jakob disease. In Creutzfeldt-Jakob disease, myoclonus can be associated with the characteristic periodic discharges that can be detected by EEG studies; however, myoclonus can be seen in the absence of these discharges, suggesting subcortical generators.

Myoclonus can also be seen in certain forms of autoimmune disorders, including Isaac syndrome (neuromyotonia), although stiffness (neuromyotonia) and fasciculations or cramps are more characteristic. EMG is characteristic with neuromyotonic discharges and fibrillation potentials and fasciculations. Autoimmune workup may reveal autoantibodies, such as anti-GAD, anti-Caspr2, and others.

Post-hypoxic myoclonus can also be in the differential in the right setting (40). It manifests within hours from severe hypoxia, can be stimulus-induced, and may sometimes last even after mental status is improved, as described in 1963 for Lance-Adams syndrome. It can be multifocal.

Associated and underlying disorders

Myoclonus and epilepsy syndromes. Epileptic myoclonus is a common symptom in epileptic syndromes.

Idiopathic generalized epilepsies (63; 64; 65). The main and pure forms of myoclonic idiopathic generalized epilepsy in which all patients have myoclonic jerks include the following:

Myoclonic seizures occur in a significant number of patients with juvenile absence epilepsy (severe absences are the main type of seizure, but 30% may also have random myoclonic jerks) and idiopathic generalized epilepsy with photosensitivity. In all these syndromes, myoclonic jerks are generalized and manifest in the EEG with generalized spike-waves or polyspike-waves. Myoclonic jerks occur independently and often precede other types of seizure, such as generalized tonic-clonic seizures and absences.

In a number of other generalized epilepsies of unknown etiology, myoclonic jerks are a component of complex seizures combined with absences or other types of seizure. In epilepsy with myoclonic absences, a combination of positive and negative myoclonus often exists. The positive muscle jerk is associated with the positive component of a spike that precedes its negative transient. The negative myoclonus follows the spike by 100 msec, and its onset occurs before that of the slow-wave. In epilepsy with myoclonic-atonic seizures (Doose syndrome), loss of muscle tone (postmyoclonic atonia) immediately follows the myoclonic jerks. Eyelid myoclonia with absences (Jeavons syndrome) is a reflex syndrome of idiopathic generalized epilepsy with predominant eyelid myoclonia alone or followed by a brief and mild absence. Myoclonic absences, myoclonic-atonic seizures, and eyelid myoclonia may often occur in structural etiology generalized epilepsies. In all types of generalized epilepsy of unknown etiology, the myoclonic jerks are probably of cortical-subcortical origin.

Idiopathic focal epilepsies. Idiopathic reading epilepsy is a characteristic syndrome with focal jaw myoclonus. In idiopathic focal epilepsies, such as Rolandic epilepsy and Panayiotopoulos syndrome, positive and negative myoclonus may occur in atypical evolutions or they may be induced by carbamazepine. EEG shows continuous spike-waves during slow-wave sleep. In these situations, atypical myoclonic status epilepticus may occur. This manifests with continuous unilateral or bilateral contractions of the mouth, tongue, or eyelids; positive or negative subtle perioral or other myoclonia; dysarthria, anarthria, or speech arrest; difficulties in swallowing; buccofacial apraxia; and hypersalivation.

Epileptic encephalopathies and congenital nonprogressive encephalopathies. Examples of epileptic encephalopathies with myoclonus include the following:

Progressive myoclonic epilepsies. Progressive myoclonic epilepsies comprise a group of rare heterogeneous genetic (mainly autosomal recessive) disorders (30; 48). They are characterized by myoclonus, other types of epileptic seizures and progressive neurocognitive impairment. The most common and classical forms include the following:

However, these are not progressive disorders, though epileptic cortical myoclonus may be a prominent and severe symptom.

Other syndromes or diseases included by some authors in progressive myoclonic epilepsies are Krabbe leukodystrophy, myoclonic encephalopathy and macular degeneration, atypical inclusion body disease, pantothenate-kinase-associated neurodegeneration (formerly Hallervorden-Spatz disease), infantile neuroaxonal dystrophy (Seitelberger disease), coeliac disease, GM2 gangliosidosis (Tay-Sachs disease), and early-onset Alzheimer disease (30 to 40 years of age). However, either these disorders are extremely rare, or epileptic myoclonus, when it occurs, is an occasional and exceptional clinical feature.

Myoclonic occipital photosensitive epilepsy with dystonia. This is a newly described epilepsy syndrome of autosomal dominant inheritance that involves a spectrum of phenotypes from juvenile myoclonic epilepsy, sometimes with an idiopathic occipital photosensitive epilepsy overlap, to progressive myoclonus epilepsy with paroxysmal dystonia (72).

Diagnostic workup

A comprehensive history of the illness, personal history, and family history, and a thorough clinical examination, are imperative and often sufficient to make a correct diagnosis of myoclonus. Important diagnostic clues for myoclonus include the following:

Following the clinical assessment, there may be a need for certain diagnostic procedures, which are determined by the type, duration of, and possible etiology of myoclonus, as well as the age and neurologic and general physical status of the patient (13; 74; 54). They may include the following:

Electrophysiological studies provide useful information for the diagnosis and classification of myoclonus (74; 10; 84). Routine and follow-up EEG is useful in determining the following:

For the pathophysiologic categorization of myoclonus (cortical, thalamocortical), the following neurophysiological techniques are used:

Polygraphic monitoring is essential for the diagnosis of negative epileptic myoclonus, allowing the demonstration of brief interruptions of a tonic EMG activity, not preceded by a positive myoclonus in the agonist and antagonist muscles of the affected limb. Simultaneous EEG-EMG monitoring demonstrating the association of negative myoclonus with an epileptic potential is consistent with the diagnosis of epileptic negative myoclonus (71).

Transcranial magnetic stimulation may represent a valuable tool for investigating important neurophysiological and pathophysiological aspects of myoclonus (61). According to 1 review, transcranial magnetic stimulation studies have detected abnormalities in motor cortex excitability and sensorimotor plasticity. Well-defined motor cortical excitability patterns can be identified in the different disorders characterized by myoclonus. The most consistent finding is a decrease in intracortical inhibition. Short-interval intracortical inhibition is reduced in myoclonic epilepsies. Unlike the juvenile and the benign myoclonus epilepsy, long-interval intracortical inhibition, interhemispheric inhibition, and sensorimotor integration were altered in patients with progressive myoclonic epilepsies. Furthermore, repetitive transcranial magnetic stimulation might have therapeutic potential at least in some patients with myoclonus (61).

A novel diagnostic approach to patients with myoclonus has been described (85). The initial step is to confirm whether the movement disorder phenotype is consistent with myoclonus and to define its anatomical subtype. The next steps are aimed at identification of both treatable acquired causes and those genetic causes of myoclonus that require a diagnostic approach other than next-generation sequencing. Finally, other genetic diseases that could cause myoclonus can be investigated simultaneously by next-generation sequencing techniques. To facilitate next-generation sequencing diagnostics, the authors provide a comprehensive list of genes associated with myoclonus (85).

Management

Good management of myoclonic seizures demands a thorough clinical and investigative approach in order to identify their cause and the needs of the patient (53; 76). Myoclonic seizures will usually resolve if the offending agent is withdrawn (drug- or toxin-induced myoclonus), if the metabolic disturbance is corrected (eg, hyponatremia or nonketotic hyperglycemia), or the treatment of the underlying disease is effective. Management also depends on whether the myoclonic seizures are severe or mild, static or progressive, and occur alone or in combination with other types of seizure (focal or generalized, convulsive or nonconvulsive). It should also be emphasized that current management is not limited to seizure control but includes measures to achieve optimal health-related quality of life with regard to the physical, mental, and psychological functioning of the patient within his/her family, and educational and social environment (80; 81).

Antiseizure medications are the basis of the symptomatic treatment of epileptic myoclonus (83; 67; 57; 73; 50; 12; 76). However, the selection of an antiseizure medication and its dosage is demanding. The antiseizure medication chosen should possess true antimyoclonic efficacy and should also be beneficial for any other types of coexisting seizure. The antiseizure medication safety profile is of paramount importance and may vary significantly depending on the patient's neurocognitive stage, age, and sex. Monotherapy is preferred, but polytherapy is often unavoidable, particularly in patients with progressive myoclonic epilepsy, either because of worsening myoclonus with the progression of the disease or the presence of multiple types of seizure. More than half of the current antiseizure medications make myoclonus worse or do not treat it effectively.

Currently, there is no preventive or curative treatment for most progressive myoclonic epilepsy. Despite significant advances in the management of some aspects of progressive myoclonic epilepsy, the neurologic manifestations are resistant to any treatment. For example, bone marrow transplantation may be curative for Gaucher disease type 1 and enzyme replacement therapy may be successful in reversing systemic manifestations, but neither of these has proven beneficial in the neurodevelopment of Gaucher disease type 3 or myoclonus. Management of progressive myoclonic epilepsy is, therefore, often only supportive and palliative (62). It includes the following:

Patients and their families have immense needs from the time that progressive myoclonic epilepsy (even 1 of the mildest forms) is first diagnosed. Medical therapeutic support is important but alone is not sufficient to achieve an acceptable quality of life. This requires a coordinated approach involving a wide range of healthcare professionals, including physicians, specialist nurses, psychologists, psychotherapists, and pharmacists (81).

Symptomatic treatment of myoclonus usually starts with a single appropriate antimyoclonic antiseizure medication, but this is often effective only in the initial stages of the disease and only for a few months. As the disease progresses, the myoclonus becomes relentlessly worse and requires multiple combinations and high doses of antiseizure medications. This may, in turn, increase the number of adverse effects and worsen the already disturbed neurologic and mental state of the patient.

Clonazepam, valproate, levetiracetam, topiramate, and zonisamide are antiseizure medications with antimyoclonic efficacy (65; 24; 12; 76). Piracetam is specifically effective against cortical myoclonus of progressive myoclonic epilepsy and myoclonus of hypoxic encephalopathy. Ethosuximide is mainly effective in negative myoclonus. Clobazam and phenobarbitone are secondary options. Lamotrigine is often a promyoclonic drug (65; 02). Lamotrigine monotherapy often worsens myoclonus but may be used in combination with another antimyoclonic antiseizure medication for the control of other types of coexisting seizure.

Fast-acting benzodiazepines are used by some patients to overcome temporarily disabling myoclonus during social events and the treatment of myoclonic status epilepticus. Chloral hydrate can be used to control daytime myoclonic exacerbations (68). A ketogenic diet should be considered for patients with severe myoclonic epilepsies such as Dravet syndrome (09). Carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin, tiagabine, and vigabatrin may worsen myoclonus and should be avoided.

Clonazepam is probably the most effective antimyoclonic drug for any type of epileptic myoclonus of any cause (65). However, it has a narrow spectrum and, for this reason, is usually prescribed in polytherapy. Clonazepam monotherapy may be the first choice in myoclonic epilepsies in which other types of seizure do not occur or emerge from clusters of myoclonic jerks, such as reading epilepsy, benign myoclonic epilepsy in infancy, and mild forms of juvenile myoclonic epilepsy. Clonazepam alone may not suppress and may even precipitate generalized tonic-clonic seizures. Furthermore, clonazepam may deprive patients of the warning of impending generalized tonic-clonic seizures provided by the myoclonic jerks.

Small doses of clonazepam (0.5 to 2 mg at night) are usually sufficient in most patients with myoclonic jerks due to idiopathic generalized epilepsy. However, in progressive myoclonic epilepsy, doses of 20 to 30 mg/day are often required with the worsening of the disease or the development of tolerance to the drug.

Valproate has been recognized as the most effective drug to treat generalized epileptic seizures of all types and of all causes (65). In juvenile myoclonic epilepsy, for example, valproate monotherapy controls absence seizures in around 75%, generalized tonic-clonic seizures in 70%, and myoclonic jerks in 75% of patients. Its efficacy in focal epilepsies is less impressive and is inferior to carbamazepine. The broad-spectrum efficacy of valproate is ideal for patients with multiple types of seizure.

The major concern with valproate is that it is undesirable in women because of its teratogenic effects and its tendency to cause weight gain and polycystic ovary syndrome. The risk of major congenital malformations with valproate monotherapy is 5% to 8% compared with a background risk of 1.6% to 2.5%. This is higher with increasing doses of valproate and is double or more when given in combination with other antiseizure medications, particularly lamotrigine.

Hepatic failure resulting in fatalities occurs mainly in children receiving polypharmacy and with organic brain disease; the risk is 1/600 before the age of 3 years. Acute hemorrhagic pancreatitis is another rare, but serious, adverse effect of valproate in children and is seen particularly with polytherapy (see package insert for valproate).

Levetiracetam is probably the preferred newer antiseizure medication for the treatment of myoclonus (24; 12). It is the likely alternative to replace valproate in the treatment of epileptic myoclonic disorders and, particularly, juvenile myoclonic epilepsy (65).

Despite the lack of randomized trials, it is suggested that levetiracetam appears most effective in patients with cortical myoclonus, whereas clonazepam remains the only first-line therapeutic option in subcortical and spinal myoclonus (24; 12). However, this view may be challenged by the results of numerous studies showing that both of these drugs are effective in all types of epileptic myoclonus (65). For example, clonazepam has been suggested as the preferred antimyoclonic drug for juvenile myoclonic epilepsy and reading epilepsy with jaw myoclonus.

Ethosuximide is as effective as valproate in the treatment of absence seizures. It is also a useful adjunct for the treatment of negative myoclonus, certain types of myoclonic epilepsy, and drop attacks. It does not control generalized tonic-clonic seizures that, from anecdotal reports, may become worse.

Phenobarbital has moderate efficacy in controlling generalized tonic-clonic seizures and myoclonic jerks but may exacerbate absences.

Piracetam has an antimyoclonic efficacy in cortical myoclonus and progressive myoclonic epilepsy.

Perampanel may be effective as an add-on medication in drug-resistant epilepsies with myoclonic seizures (36).

In a case report lacosamide produced a progressive antiseizure effect on Jacksonian motor seizures and subsequently on positive myoclonus, which developed into negative myoclonus before complete resolution (75).

Ketogenic diet is the main treatment of patients with glucose transporter 1 deficiency syndrome (03).

There is a growing interest in the use of cannabidiol for the treatment of severe epilepsies in children, such as Dravet syndrome (17). In June 2018, Epidiolex^® (cannabidiol oral formulation) from GW Pharmaceuticals obtained marketing authorization by the U.S. Food and Drug Administration, becoming the first drug to be approved for the treatment of Dravet syndrome in the United States market.

New therapies for refractory myoclonus, including sodium oxybate and even deep brain stimulation, are also being explored with increasing enthusiasm (59; 18).