Gastaut classification
Etiology
Exemplary condition
Mental status
EEG background
Typical duration of MSE
Clinical characteristics of myoclonus
Frequency of myoclonus
Stimulus-sensitive
EEG correlate
Time-locked EEG
Location of presumed physiologic disturbance
Primary MSE
Idiopathic generalized epilepsy
Juvenile myoclonic epilepsy
Alert
Normal
Hours
Synchronous
Large amplitude
Arms
Irregular
Every few seconds, sometimes in clusters of 3–5 jerks
Some photosensitive
3–5 Hz generalized polyspike-wave
+
Thalamocortical
Secondary MSE
Symptomatic generalized epilepsy
Myoclonic-astatic epilepsy (of Doose)
Alert to stupor
Diffuse slowing, disorganized; slow spike-wave
Days to weeks
Asynchronous
Fluctuating amplitude (small > large)
Distal muscles
Irregular intervals
Often nearly continuous
−/+
2–3 Hz generalized spike-wave or polyspike-wave complexes
+/−
Thalamocortical or cortical
Dravet Syndrome (SMEI)
Stupor
Diffuse slowing, disorganized
Hours to days
Two forms:
Isolated MSE—deltoid
Obtundation status—face and limbs
−
Fast spike and wave
+
Cortical
Symptomatic focal epilepsy
EPC
Alert
Regional slowing
Persistent, intractable
Unilateral, rhythmic, distal, arms
Regular, asynchronous,
Around 1 Hz
+/−
Somato-sensory
PLEDs/LPDs or no correlate
+ PLEDs (LPDs)
Cortical
Symptomatic MSE
Neurodegenerative
Progressive Myoclonic Epilepsies
Alert to lethargic
Background slowing; generalized spike-and-wave and focal spikes
Hours to days
Bilateral or multifocal
Trunk, limb and facial muscles
Irregular intervals.
Often nearly continuous, debilitating
+/−
Photo-sensitive, startle, sound
Bilateral myoclonus with correlate.
Multifocal jerks often without
+
Cortical
Toxic-Metabolic
Renal failure
Lethargy to coma
Moderate background slowing
Variable
Asynchronous
Variable amplitude
Irregular intervals
−/+
Multifocal spikes or slow spike-wave
+/−
Cortical and reticular
Silver toxicity
Coma
Moderate slowing, then alpha coma
Variable
*
*
+/−
14–18-Hz electropositive central-frontal polyspikes
*
Cortical
Fig. 12.1
Classification of myoclonic status epilepticus. Gastaut’s proposed classification system divides myoclonic status epilepticus (MSE) into “true MSE”, which occurs in patients with epilepsy, and “symptomatic MSE,” which occurs as a result of another disease process. True MSE is further divided into primary and secondary forms of MSE. Adapted from Gerard and Hirsch [3], with permission
According to Gastaut’s classification system, acquired or symptomatic MSE is a term used for persistent myoclonic seizures in patients with no history of epilepsy, seen in the context of infectious, inflammatory, neurodegenerative, toxic-metabolic, or anoxic brain disease. MSE occurring in patients with progressive myoclonus epilepsies (PME) is classified among the symptomatic forms of MSE. For the purpose of this chapter, we will defer details on anoxic status epilepticus and “subtle” myoclonic status after generalized convulsions which are covered elsewhere in this book (see also Chap. 13, “Anoxic Myoclonic Status Epilepticus,” and Chap. 17, “Treatment of Refractory and Super-Refractory Status Epilepticus”).
Pathophysiology
Neuroanatomically, myoclonus can be classified into cortical, subcortical, spinal, and peripheral myoclonus. Epileptic myoclonus can be a cortical or thalamocortical phenomenon.
Cortical myoclonus is the consequence of an epileptic impulse that activates the sensorimotor cortex leading to myoclonic seizures. The neurons in the sensorimotor cortex may be the primary generator, or myoclonus can be driven by abnormal epileptic inputs propagating from other parts of the brain. Cortical myoclonus affects mainly the distal upper limbs and face. Cortical myoclonus often has multifocal generators, e.g., in patients with LGS or PME. It can have a single cortical generator, but the epileptic activation may spread through transcallosal or intrahemispheric cortico-cortical pathways, producing generalized or bilateral myoclonus [4]. Patients with focal or multifocal epileptic myoclonus may not have an EEG correlate on routine scalp recording. The neurophysiologic correlate of the myoclonus may only be detectable by using jerk-locked EEG or magnetoencephalograhy (MEG) averaging, or coherence analysis methods [5]. In jerk-locked back-averaging, EEGs spikes are averaged, time-locked with respect to the EMG onset to reduce the non–time-locked background EEG activities. A positive peak of the EEG spikes is expected to occur 15–20 ms prior to the myoclonus for the upper limbs, and 25–40 ms for the lower limbs. Spikes are located near the contralateral primary motor cortex. Cortical reflex myoclonus is considered a fragment of a focal or multifocal epilepsy and involves a few adjacent muscles; it is often brought on by action or by sensory stimulation involving hyperexcitability of the sensorimotor cortex [1]. Cortical reflex myoclonus can be associated with giant somatosensory evoked potentials (SSEP) responses. For continuous muscle jerks from a focal cortical origin, the term epilepsia partialis continua (EPC) is used [6].
Myoclonic seizures associated with primary generalized epilepsies are considered a form of thalamocortical myoclonus which originates from ascending subcortical inputs that stimulate a hyperexcitable cortex diffusely and synchronously [6, 7]. Muscles are usually activated bilaterally. Muscles innervated by cranial nerves are activated rostrocaudally. Myoclonus is usually spontaneous, arrhythmic, and affecting mainly axial muscles. The myoclonus always has an EEG correlate of a generalized spike or polyspike-and-wave discharge. The negative peak of the generalized spike (which lasts 30–100 ms in duration) precedes the jerk (<100 ms duration) by 20–75 ms. Compared to cortical myoclonus, spikes are less strictly time-locked to the EMG jerk. Thalamocortical myoclonus is observed in JME, benign myoclonic epilepsy of infancy, and myoclonic-astatic epilepsy.
Reticular reflex myoclonus is seen in patients with metabolic abnormalities such as renal failure or anoxic brain injury and can be associated with cortical myoclonus. In those circumstances, the EEG shows generalized spikes, maximal over the vertex, usually not time-locked to the jerks. Giant SSEPs are not observed. Myoclonus can be spontaneous or stimulus-induced (although the temporal relationship to stimuli can be variable).
Negative myoclonus (NM) is characterized by a brief interruption of tonic muscular contraction for <500 ms, without evidence of preceding myoclonia [8]. NM is typically non-epileptic, e.g., the asterixis in hepatic encephalopathy. In specific conditions, the negative myoclonus can be associated with an epileptiform discharge and presents as epileptic negative myoclonus (ENM) [8–10]. Tassinari demonstrated that the onset of the EMG silent period was related to the negative component of the spike on the EEG, occurring before the slow wave [11]. ENM can be seen frequently in patients with the PMEs and in electrical status epilepticus during sleep (ESES syndrome) but is rarely considered a form of MSE.
Primary Myoclonic Status Epilepticus
Genetic Generalized Epilepsies
Genetic generalized epilepsies (GGE) are a subgroup of epilepsies with a presumed genetic etiology and usually without structural or anatomic abnormalities [12].
Based on associated seizure types, three forms of MSE can be distinguished in GGE patients:
Type 1, also called “typical MSE” is seen in patients with bilateral myoclonic jerks synchronous with generalized polyspike-wave discharges on EEG and without impairment of consciousness [13, 14].
Type 2 is defined by continuous myoclonic jerks preceded, followed, or interrupted by a generalized tonic–clonic seizure (GTCS). Consciousness is impaired in these patients during and after the GTCS but not during the buildup of myoclonic jerks preceding the convulsion.
Type 3 is observed in patients with absence status with superimposed myoclonic jerks prominent in the eyelids, with variable involvement of the upper extremities. Consciousness is moderately impaired in these patients. A combination of types 2 and 3 can be observed and has been referred to as “atypical MSE”.
The occurrence of MSE associated with GGE (or true primary MSE, according to Gastaut) is rare and seen mostly in JME [15]. JME is one of the most frequent types of GGE and is characterized by myoclonic seizures, tonic–clonic seizures, and absence seizures. The reported incidence is 3.2/1000 patient years [16]. In JME, the myoclonic jerks are bilateral, repetitive but arrhythmic, and predominantly involving the arms, sometimes trunk and legs, and rarely the face. Milder jerks produce more distal movements which can be asymmetric or focal based on report, direct observation or both. In MSE, the repetitive contractions and inhibitions produce a myoclonic tremor which can be disabling and interfere with ambulation. Consciousness is typically preserved. The myoclonus is invariably associated with an electrographic spike or polyspike-and-wave discharge (Fig. 12.2). In a study evaluating JME patients who were treated between 1994 and 1999, the authors found a prevalence of MSE of 1.4% [13]. A higher prevalence has been reported in studies based on patient reports without requiring EEG documentation [17, 18].
Fig. 12.2
Myoclonic status epilepticus in idiopathic generalized epilepsy. A 13-year-old girl with juvenile myoclonic epilepsy presented with frequent myoclonic jerks at age 12. Her mother also had myoclonus and seizures. She was unable to tolerate valproic acid due to weight gain and raised liver enzymes. On lamotrigine monotherapy she experienced an increase in the frequency and severity of morning myoclonus, which kept her from getting out of bed in the morning. During elective video-EEG monitoring, she had a cluster of myoclonic jerks recurring every 10–30 s for 40 min. Sample EEG demonstrates a drowsy background with frequent 3–4 Hz bifrontally predominant generalized polyspike-wave discharges. Myoclonic jerks involving the trunk, arms and legs occur in a sequence of 3–4 jerks with each polyspike-wave run lasting longer than 2 s. From Gerard and Hirsch [3], with permission
MSE in JME is frequently triggered by poor anti-seizure drug (ASD) compliance or inappropriate choice of ASD excessive alcohol intake, or sleep deprivation. MSE observed after inappropriate ASD use, is usually seen when narrow spectrum ASDs, such as carbamazepine, phenytoin, vigabatrin, or oxcarbazepine are used [14, 19]. This most commonly occurs when JME remains unrecognized or is mistaken for a focal epilepsy. Clinically, aside from the sometimes subtle and localized myoclonus, prominent asymmetric features in JME are seen in more than 10% of patients and described as lateralized myoclonic jerks or generalized convulsions preceded by a noticeable head version [20, 21]. Misinterpretation of EEG findings such as frontal or frontotemporal fragments of generalized discharges, asymmetric maxima of generalized epileptiform activity, or over interpretation of physiologic focal sharp transients may delay the diagnosis [22]. MSE in JME is typically easy to treat and resolves after the administration of a benzodiazepine (e.g., lorazepam or diazepam), valproic acid, or levetiracetam [23]. In cases caused by inappropriate ASDs, stopping the drug in question is paramount to prevent recurrence.
The pathophysiologic mechanism behind this drug-induced seizure aggravation is thought to involve the thalamocortical network, and in particular, the ventrobasal complex of the thalamus (VB), which enhances GABAergic action [24, 25]. Its activity is usually inhibited by the GABA-mediated activity of the reticular nucleus of the thalamus. Drugs such as oxcarbazepine or carbamazepine are presumed to enhance GABA-A transmission of the VB nucleus [26]. The increase in VB activity is not sufficiently opposed by the inhibitory action of the reticular nucleus, resulting in enhanced oscillatory thalamocortical activity, leading to more prominent and sustained sharp wave discharges [27]. Additionally, it has been demonstrated that ASDs that act mainly as voltage-dependent sodium channel blockers (such as carbamazepine and phenytoin) enhance membrane stabilization, leading to increased hypersynchronization of neuronal discharges. Lamotrigine, even though usually classified among the wider spectrum ASDs and effective against generalized seizures, may also worsen myoclonic seizures in some patients [26, 28].
Eyelid myoclonia (also known as Jeavons Syndrome) is a photosensitive epilepsy which starts in childhood and can persist into adulthood. Seizures consist of twitching of the eyelids, often associated with jerky upward deviation of the eyeballs and retropulsion of the head. Seizures can be frequent, often multiple in a day, and are usually triggered by eye closure in an illuminated room. The photosensitivity tends to decline with age. Eyelid myoclonic status, characterized by prolonged episodes of eyelid myoclonia, persisting at eye closure, has been described in a high percentage of patients (72%), more commonly during late childhood [29]. The ictal EEG is characterized by generalized polyspikes concomitant with the eyelid myoclonia.
Secondary Myoclonic Status Epilepticus
Symptomatic Generalized Epilepsies
Dravet Syndrome. Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is an epileptic encephalopathy that typically presents with prolonged febrile seizures in the first year of life followed by a variable course that includes different seizure types, developmental regression, and seizure intractability [30]. Most cases result from a de novo mutation of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1 [31]. Myoclonic jerks are divided into myoclonic seizures and non-epileptic myoclonus based on the presence of an epileptiform EEG correlate [32]. Myoclonic seizures can be dramatic in DS, involving the axial muscles, often causing the child to fall. The massive jerks are frequently mixed with numerous asynchronous and arrhythmic distal myoclonic jerks, often without a clear epileptiform EEG correlate and difficult to differentiate polygraphically from non-epileptic myoclonus.
The occurrence of MSE in DS is rare; this group of patients usually presents with convulsive status epilepticus, which can occur in up to 75% of patients within the first years [33, 34]. Yakoub and colleagues reported the occurrence of MSE in 3 out of 17 patients with a diagnosis of DS [35]. In these 3 patients MSE lasted, respectively, 3, 24, and 36 h and occurred at the ages of 14 months, and 4 and 5 years. The EEG correlate of MSE was characterized by rapid high voltage arrhythmic generalized fast spike waves (3–5 Hz) accompanied by myoclonic jerks (mostly in deltoid muscles), at times associated with tonic contractions.
Patients with DS often present with “obtundation status” which can occur in up to 40% of patients and consists of fluctuating alteration of consciousness with slight increased postural tone and fragmentary and segmental, erratic myoclonus of low amplitude, involving the limbs and the face [33, 36]. It can last for several hours or even several days and it can be interrupted by strong sensory stimuli. The EEG is characterized by diffuse slow waves intermixed with focal and diffuse spikes, sharp waves, and spike and waves, of higher voltage over the anterior regions and the vertex without correspondence between the spikes and the myoclonic jerks. Even though myoclonic jerks seem to be frequent in this clinical manifestation, given the absence of a true relationship between the myoclonus and the spikes, it is usually not classified as a MSE but as a form of atypical absence status.
Lennox-Gastaut Syndrome. Lennox-Gastaut syndrome (LGS) is a severe childhood epileptic encephalopathy characterized by frequent seizures, progressive cognitive impairment, drug resistance, and typically a characteristic EEG pattern with slow spike and slow wave pattern and runs of polyspikes during sleep. Different seizure types may coexist: tonic seizures, atypical absence, GTC, and myoclonic seizures. Myoclonus in LGS is seen in 10–30% of patients and can range from brief jerks of the face and head to massive bilateral myoclonus and falls, arising spontaneously. Consciousness is usually intact unless the seizures cluster. The myoclonic seizures are associated with brief bursts of 3–3.5 Hz generalized spike or spike-and-wave activity. At least one or more episodes of status epilepticus have been reported in most patients (about 90%) [37]. The most frequent form of status epilepticus is absence status. MSE is extremely rare in this group of patients and if present is suggestive of a diagnosis of MAE. One case report of MSE in LGS described MSE due to lamotrigine treatment [38, 39].
Myoclonic-Astatic Epilepsy (of Doose). Myoclonic-astatic epilepsy (MAE) is a generalized epilepsy syndrome characterized by different seizure types (myoclonic, myoclonic-astatic, and generalized tonic–clonic seizures), typically with onset between 7 months and 6 years of age. In contrast to LGS, MAE initially presents with a normal development and has often a more benign course, with at least half of the patients entering remission. In the majority of patients, febrile and nonfebrile tonic–clonic seizures precede the onset of the myoclonic and myoclonic-astatic seizures [40, 41]. Thirty-six percent of patients develop status epilepticus, with features of atypical absences and myoclonus lasting hours or even a few days [39, 42]. The episodes of MSE are described as loss of contact, alteration of vigilance, drooling, speech disorders, and erratic myoclonus. The myoclonus is predominantly seen in the face, extremities of upper limbs, eyelids, mouth, tongue, and finger. The EEG is characterized by 2–3 Hz spike-and-wave activity, and irregular polymorphous hypersynchronous activity (Fig. 12.3).
Fig. 12.3
Myoclonic status epilepticus in myoclonic-astatic epilepsy. A 65-year-old woman had mild mental retardation and myoclonic-astatic epilepsy since childhood. Seizures had been infrequent for many years. In the setting of withdrawing levetiracetam she developed frequent myoclonic jerks characterized by sudden flexion of her trunk and neck with elevation and extension of both her arms. At their most frequent, these jerks occurred twice a minute for 15 min. The patient was able to talk and interact with examiners between jerks. The EEG background shows mild diffuse slowing with a 10 Hz alpha rhythm and frequent 4–5 Hz bifrontally predominant polyspike-wave discharges corresponding to the myoclonus. Myoclonic jerks continued frequently (10–25/h) for 24 h. This improved dramatically with reinstitution of levetiracetam. From Gerard and Hirsch [3], with permission
MSE tends to occur in MAE patients with unfavorable outcome and accelerated mental deterioration. As described for JME, cases of MSE in MAE can be triggered by ASDs, specifically carbamazepine, vigabatrin, and levetiracetam [6, 40, 43]. Treatment consists of benzodiazepines and valproate or ethosuximide. Patients usually respond to treatment, but MSE may recur.
Epilepsy With Myoclonic Absences. Epilepsy with myoclonic absences was first described by Tassinari and colleagues in 1969 [44]. The syndrome is rare, with onset between 2 and 12 years of age, more frequently seen in boys and characterized by absence seizures associated with rhythmic myoclonic jerks, and in about half the patients, GTCs as well. The EEG shows bilateral synchronous and symmetric 3 Hz spike-and-wave discharges. In Tassinaris’s case series, only 1 patient out of 36 presented with MSE, which was interrupted after the administration of IV diazepam.
Myoclonic Status in Non-Progressive Encephalopathies. Myoclonic status in non-progressive encephalopathies (MSNE) was first described in 1980 by Dalla Bernardina and colleagues after observing seven children with cerebral palsy due to severe prenatal or neonatal cerebral damage, presenting with recurrent long-lasting myoclonic status [36]. The same electroclinical picture was later described by others [45, 46]. Based on electroclinical characteristics, three types of MSNE can be identified:
The first group is characterized by absences associated with almost continuous jerks (rhythmic or arrhythmic) and positive brief myoclonic absences and hypnagogic startles. This subgroup includes: Angelman syndrome (AS), Prader–Willi syndrome, and Rett syndrome [47, 48]. No neuroradiologic abnormalities are usually observed. The EEG is characterized by high amplitude slow waves with superimposed spikes involving the posterior regions, associated with rhythmic myoclonias observed on the EMG record. Subcontinuous delta-theta activity involving the central areas is seen, as well. These patients are usually refractory to treatment; benzodiazepines and ACTH generally have a transitory effect. Improvements have been observed with ethosuximide, associated with valproic acid treatment, or levetiracetam [47].
The second subgroup is characterized by the association of absence status and a negative, continuous, and semirhythmic myoclonus, mixed with sudden uncontrolled continuous dyskinetic movements, leading to a clinical picture of hyperkinetic loss of posture [48]. Patients are typically females with developmental cortical malformations. The EEG is characterized by continuous slow spike-wave associated with continuous rhythmic jerks with long-lasting inhibitory phenomena or alternating bilateral positive myoclonic jerks and prolonged negative myoclonus. These seizures are usually refractory to treatment.
The third group is characterized clinically by rhythmic myoclonia of the face and limbs. As the disease progresses, the clinical picture worsens with the appearance of pyramidal tract signs and intention tremors, as well as myoclonus followed by muscle inhibition. This subgroup is characterized mainly by progressive neuromuscular deterioration. A frequent finding in these patients is cortical dysplasia involving the motor area. The EEG is characterized by continuous spike activity in the rolandic region, accompanied by bilateral rhythmic myoclonia followed by prominent periods of inhibition. The EEG shows a subcontinuous series of generalized spike-wave type paroxysms, or bilateral continuous slow wave with notched delta appearance with corresponding rhythmic myoclonia of the face and limbs. This activity changes with time, and the paroxysms become sharp theta waves with very slow semirhythmic continuous spikes over the central regions and vertex.
These cases of subtle myoclonic status can go unrecognized clinically because of the mental retardation and concomitant continuous abnormal movements. Polygraphic recordings with EMG leads are very useful for recognizing these syndromes. Early recognition is important in order to start adequate treatment with the hope of preventing neuropsychologic deterioration.
Symptomatic Focal Epilepsy
Epilepsia Partialis Continua. Epilepsia partialis continua (EPC) has been defined as irregular myoclonic or regular clonic muscle twitches affecting a limited part of the body, occurring for a minimum of one hour, and recurring at intervals of no more than 10 s [49]. The underlying etiology is variable, from static insults to progressive disorders such as Rasmussen’s syndrome or other forms of autoimmune epilepsy, vasculitis, nonketotic hyperglycemia, or encephalitis.
The jerks are typically highly variable in duration, rate, intensity, and distribution and can be rhythmic and arrhythmic, typically spontaneous but also triggered by somatosensory stimulation. The clonic or myoclonic seizures are often associated with other seizure types. The EEG typically shows repetitive spikes or periodic lateralized epileptiform discharges (PLEDs), although the relationship to the jerk can be complex, and the absence of EEG findings does not exclude the diagnosis (Fig. 12.4). Based on jerk duration, EMG is helpful in distinguishing cortical vs subcortical types of myoclonic jerks. Cortical myoclonic jerks usually last <100 ms, and subcortical-based myoclonic jerks > 100 ms. The muscle jerks involve agonistic and antagonistic muscles simultaneously [50, 51].
Fig. 12.4
Epilepsia partialis continua (EPC). A 28-year-old right-handed woman presented with confusion, speech difficulty, and right arm numbness. During admission she started presenting right hand middle finger twitching. Continuous video-EEG monitoring showed continuous focal slowing over the left hemisphere. No interictal epileptiform discharges were seen. Electromyogram leads were placed on the right hand and demonstrated rhythmic clonic and myoclonic activity of 1 Hz, consistent with epilepsia partialis continua. The patient’s cerebral imaging was normal. Autoimmune work-up on serum and cerebrospinal fluid showed NMDA and serum N-type calcium channel antibodies
Treatment of EPC depends on the underlying cause. Levetiracetam, valproate, and benzodiazepines are commonly used ASDs. Despite medications, the continued focal jerking in EPC is often refractory to ASDs, which nevertheless are indicated to prevent secondarily generalized seizures [52]. When EPC is seen in autoimmune forms, high dose steroids, intravenous immunoglobulin (IVIG), and plasma exchange are used. Surgery is a therapeutic option when focal lesions are the cause of EPC. If the epileptogenic region involves the primary motor cortex, multiple subpial transection is a possibility [51]. Functional hemispherectomy is indicated for Rasmussen patients with progressive deterioration unresponsive to immunotherapy. Transcranial magnetic stimulation has been tried in patients with refractory EPC [53].
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