Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Ohtahara syndrome is one of the earliest developing forms of epileptic encephalopathy. The syndrome is characterized by tonic spasms, focal seizures, a specific pattern of suppression bursts in EEG, and poor prognosis. In this article, the clinical, genetic, neurophysiologic, and etiologic data related to Ohtahara syndrome are reviewed. The condition is classically thought to be mainly secondary to cerebral malformations. A variety of genetic mutations have increasingly been identified in subjects with Ohtahara syndrome. Metabolic disorders also have been reported as causes of the syndrome.
Ohtahara syndrome is one of the earliest developing forms of epileptic encephalopathy.
The main characteristics of the syndrome are tonic seizures and a suppression-burst pattern on EEG.
Although the condition was classically attributed to structural brain damage, it has increasingly been associated with a variety of genetic mutations as well, most prominently involving the STXBP1, SCN2A, ARX, and KCNQ2 genes, though multiple other associations have been made.
Prognosis is very poor.
Early infantile epileptic encephalopathy with suppression bursts was first described by Ohtahara and colleagues in 1976 (41) and is considered one of the earliest forms of epileptic encephalopathy, the other being early myoclonic epilepsy of infancy. The 1989 revised classification by the International League Against Epilepsy placed the syndrome under "symptomatic generalized epilepsies and syndromes with nonspecific etiology" (08).
In 2001, the International League Against Epilepsy Task Force on Classification and Terminology proposed to include Ohtahara syndrome in the list of epileptic encephalopathies (11). These are conditions in which not only epileptic activity but also the epileptiform EEG abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function. This group also includes early myoclonic encephalopathy, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and electrical status epilepticus during sleep.
In 2010, the proposed organization presented by the Classification Commission of the International League Against Epilepsy included Ohtahara syndrome as an electroclinical syndrome, characterized by its clinical and EEG characteristics (04). The term early infantile epileptic encephalopathy is still used as well, referring either to Ohtahara syndrome specifically or to a spectrum of epileptic encephalopathy syndromes occurring during infancy, of which Ohtahara syndrome is one. This ambiguous terminology highlights the difficulty that can sometimes occur in distinguishing Ohtahara syndrome from other related syndromes such as early myoclonic encephalopathy.
In 2002, Aicardi and Ohtahara summarized the characteristics of the syndrome (01):
(1) Onset is in early infancy, within the first 3 months, and often within the first 10 days of life.
(2) The main seizure type is tonic spasms.
(3) Other seizures can be present, including focal seizures and, rarely, myoclonic seizures.
(4) The EEG is characterized by suppression bursts, during both waking and sleeping states.
(5) The prognosis is poor, marked by severe psychomotor retardation, often with death during infancy.
(6) The seizures are intractable and frequently progress to West syndrome.
(7) There are multiple etiologies: the majority of cases are associated with structural brain malformations, whereas a subset is associated with specific genetic mutations or metabolic abnormalities.
The seizures in Ohtahara syndrome develop within the first 10 days of life in the majority of reported cases and may occur as early as the first hour after delivery (40; 07). Onset is acute in a previously normal infant.
The primary seizures seen in Ohtahara syndrome are tonic spasms, occurring both singly and in clusters. They may be either generalized and symmetrical or lateralized, and occur both during wakefulness and during sleep. The duration of spasms is up to 10 seconds, and the interval between spasms within a cluster ranges from 9 to 15 seconds. The seizures are very frequent, with affected patients experiencing as many as 100 to 300 isolated seizures or 10 to 20 clusters of seizures per day (43). Status epilepticus consisting of continuous epileptic spasms has been described (30). In one third of cases, other seizure types, including focal motor seizures, hemiconvulsions, or generalized tonic-clonic seizures, are observed (63). Massive or segmentary myoclonic jerks are rarely present (01).
The characteristic EEG feature is the suppression-burst pattern: discharges of wide amplitude spikes and polyspikes alternating with suppression of electric activity at a regular rate. The suppression-burst pattern occurs both while awake and during sleep without differentiation. The pattern can be widespread and synchronous, asynchronous over both hemispheres, or limited to 1 side, as observed in hemimegalencephaly. In a study of the video-EEG aspects of the syndrome, Fusco and colleagues demonstrated the coincidence between tonic spasms and burst EEG (13).
Over time, Ohtahara syndrome may evolve into West syndrome and, subsequently, into Lennox Gastaut syndrome. The transition to West syndrome occurred in 12 out of the 16 cases (75%) in 1 series (63). This transition occurred between 2 and 6 months of age. Two of these 12 West syndrome cases later evolved into Lennox-Gastaut syndrome. Accordingly, the suppression-burst pattern often evolves into hypsarrhythmia and later to a diffuse slow spike-wave pattern. In other patients, the interictal EEG shows multiple independent spike foci.
The clinical progression of this condition is marked by severe psychomotor retardation, and death in infancy is common, often attributed to pneumonia/respiratory illness or sudden unexpected death in epilepsy (SUDEP) (63; 47). Those who survive are typically mentally and physically handicapped, even among those in whom seizures are eventually relatively well-controlled (42).
The seizures in Ohtahara syndrome are often intractable to currently available antiepileptic therapy. Severe psychomotor retardation is typical. With time, the disorder may evolve into West syndrome or focal epilepsy, and from there may evolve into Lennox-Gastaut syndrome. Psychomotor development may be slightly better if the infants do not develop West or Lennox-Gastaut syndrome (07).
The clinical progression of this condition is marked by severe psychomotor retardation, and death in infancy is common, often attributed to pneumonia/respiratory illness or sudden unexpected death in epilepsy (SUDEP) (63; 47). Those who survive are typically mentally and physically handicapped, even among those in whom seizures are eventually relatively well-controlled (42; 17).
A female patient was born from an uneventful pregnancy by cesarean section at 38 weeks of gestation. Apgar scores were 8 at 1 minute and 9 at 5 minutes. During the first day of the patients life, seizures began with bilateral clonic movements and oral automatisms. She had a mild right hemiparesis and visual inattention, with no dysmorphic features. She alternated between a state of wakefulness with eyes opened and with some response to environmental stimulation, and a state of apparent sleep with poor response to external stimuli. EEG showed a continuous pattern of suppression bursts during wakefulness and sleep; only during wakefulness was it associated with a bilateral brief tonic contraction, simultaneous with the burst. Brain MRI showed left hemimegalencephaly, with left cerebellar and basal ganglia enlargement. She was initially started on phenobarbital and vigabatrin. At 1 month old, she underwent adrenocorticotropic hormone therapy without success. A video-EEG examination recorded at 53 days of life showed tonic spasms, which were present continuously during wakefulness and were associated with ictal burst discharges. At the age of 2 months she began to develop more complex focal seizures. She subsequently developed breathing difficulty and high fever. She was hospitalized in another hospital, and after 10 days, she died of septic shock.
Ohtahara syndrome is classically attributed to structural abnormalities within the brain. Genetic etiologies have been increasingly identified.
The etiology of Ohtahara syndrome can be variable, though the condition has classically been thought to be related to structural brain abnormalities. Because of the close relationship between Ohtahara syndrome, West syndrome, and Lennox-Gastaut syndrome, it is suggested that these all represent age-specific responses of the brain at various developmental stages to heterogeneous, nonspecific exogenous factors (40).
In Ohtahara's original series of 10 cases, 2 infants had porencephaly, 1 had agenesis of the corpus callosum, and 1 had "subacute diffuse encephalopathy" (40). Subsequently, cases of Ohtahara syndrome were identified in association with several different metabolic abnormalities. Numerous genetic mutations have been identified, many of which are also associated with structural and/or metabolic abnormalities.
Pathology. Structural anomalies associated with Ohtahara syndrome include agenesis or dysgenesis of the corpus callosum, dentato-olivary dysplasia, cerebellar hypoplasia, pontine hypoplasia, delayed or abnormal myelination, cerebral atrophy, and focal polymicrogyria (07; 49; 57; 44; 51). There is a strong association between Ohtahara syndrome and hemimegalencephaly (13). Several studies discuss the role of cortical dysgenesis in relation to the early infantile encephalopathies (10; 54).
Metabolic disorders have occasionally been observed, including cases of nonketotic hyperglycinemia (07), Leigh encephalopathy (55), cytochrome c oxidase deficiency (60), molybdenum cofactor deficiency (17), pyridoxine dependency, and carnitine palmitoyltransferase deficiency (13). Cases of Ohtahara syndrome with mitochondrial respiratory chain complex I deficiency and familial complex IV deficiency have been described (05; 52; 17). Ohtahara syndrome has also been seen in the setting of pyridoxal-5′-phosphate oxidase deficiency (44).
Genetics. Genetic mutations have been increasingly recognized. Identifiable genetic abnormalities were detected in half of patients with Ohtahara syndrome in 1 study (26). The most common gene mutations associated with Ohtahara syndrome involve ARX (45), STXBP1 (58; 44; 28), KCNQ2 (44; 20), and SCN2A (32; 44; 35; 28). Less common genetic abnormalities associated with Ohtahara syndrome include aberrations involving AARS, ARX (02), BRAT1 (50), CASK (49; 28), DMXL2 (12), DEPDC5 (28), GABRA1 (23), GABRB2 (64), GNAO1 (15), KCNT1, LIS1 (28), KCNT2 (14), PIGQ (32), NECAP1 (37), PACS2 (62), SCN8A (36), SIK1 (48), SLC25A22 (29), and VOUS (28). Olson and colleagues described 1 patient each with mutations in PNPO, PIGA, and SEPSECS (44). Of note, mutations in SIK1, PIGA, SCN2A, PIGA, SLC25A22, PNPO, KCNQ2, KCNT1, GABRB2, and STXBP1 have also been associated with early myoclonic encephalopathy.
Pathophysiology. Despite the presence of various neuropathologic pictures, Ohtahara syndrome is typically believed to be mainly secondary to structural brain abnormalities, in particular, disorders of neuronal migration and differentiation (03). Even in some cases in which the syndrome is related to metabolic disorders, there may be associated structural malformations. Glutaric aciduria and mitochondrial disorders, for example, can produce cerebral malformations. A patient with mitochondrial respiratory chain complex I deficiency had cortical atrophy and a thin corpus callosum (05), and it has been hypothesized that complex I deficiency may lead to abnormal neuronal migration during brain development (38).
Structural brain malformations have also been associated with many of the genetic abnormalities identified in patients with Ohtahara syndrome. Specifically, defects of the cavum septum pellucidum, hypoplastic corpus callosum, cerebral atrophy, and hydranencephaly and lissencephaly have all been described in patients with mutations of the ARX gene (19). Cerebral atrophy, thinning of the corpus callosum, and delayed myelination have been reported in patients with STXBP1 mutations (44; 28). Cerebral atrophy and signal abnormalities in the deep gray matter have been reported in patients with KCNQ2 mutation (44; 20; 28). SCN2A mutations have been associated with dentato-olivary dysplasia (57), polymicrogyria (59), and cerebral atrophy (44; 28). Cerebral atrophy and thinning of the corpus callosum are also associated with GNAO1 mutations (15) and DMXL2 mutations (12). Cortical dysplasias have been described in conjunction with both DEPDC5 and VOUS mutations (28). Two patients with Ohtahara syndrome and CASK mutations had cerebellar hypoplasia (49). One reported patient with PACS2 mutation had cerebellar dysplasia involving the hemispheres and vermis (62). The siblings with BRAT1 mutations and Ohtahara syndrome both had progressive microcephaly (50). The patient with PIGA mutation had dysgenesis of the corpus callosum (44).
The prominence of tonic seizures in Ohtahara syndrome may be an indication of brainstem dysfunction. Reviewing 12 published autopsy cases, Djukic and colleagues found that all 12 had brainstem and cerebellar abnormalities, the majority of which were thought to be congenital (09). It has been shown that the bursts in the suppression burst EEG pattern may be associated with the brainstem, thalamus, and cortex, and the periods of suppression only with the cortex, suggesting a deafferentation between cortical and subcortical structures (18). Brainstem dysfunction is also thought to contribute to the development of hypsarrhythmia in infantile spasms (27) and may play a role in the transition from Ohtahara syndrome to West syndrome.
Ohtahara syndrome is rare, with a prevalence between 0.04% and 0.2% of childhood epilepsies (42). It may be slightly more common in males, with a male to female ratio of 1.3:1 in 1 review (09). An Australian study found that Ohtahara syndrome accounted for 8 of 114 patients (7%) with severe infantile epilepsies identified over a 2-year period (17).
Early myoclonic encephalopathy is also associated with onset in early infancy, a suppression-burst pattern in EEG, a variety of seizure types, and poor psychomotor outcome.
Classically, the major differences between the 2 syndromes are as follows: (1) metabolic pathologies dominate in early myoclonic encephalopathy, and brain malformations in Ohtahara syndrome, though a variety of genetic abnormalities are increasingly being recognized in both conditions; (2) tonic spasms in Ohtahara syndrome versus focal seizures and erratic myoclonias in early myoclonic encephalopathy; (3) continuous suppression-burst pattern in both waking and sleeping states in Ohtahara syndrome, whereas this EEG pattern is supposed to be limited to sleep in early myoclonic encephalopathy; (4) different evolutional pattern with age: Ohtahara syndrome often evolves into West syndrome and, further, to Lennox-Gastaut syndrome with age, but early myoclonic encephalopathy demonstrates no unique evolution; it continues as such for a long time or changes into focal epilepsy or severe epilepsy with multiple independent spike foci (43). Differentiation between the 2 syndromes may be difficult, especially early on when both myoclonus and tonic seizures may coexist. There is considerable clinical overlap between the 2 conditions, with wide variations in underlying pathophysiology as well as phenotype. Therefore, they are conceptualized by many as part of a continuum of disease, with various underlying etiologies leading to a common phenotypic spectrum (09; 03; 44).
It is important to note that the nonreactive suppression-burst EEG pattern may be found not only in patients with Ohtahara syndrome or early myoclonic encephalopathy, but also in newborns with hypoxic-ischemic encephalopathy. Seizure types and evolution allow for a correct diagnosis.
West syndrome can occur as a primary syndrome without being preceded by Ohtahara syndrome. The differential diagnosis is based on age at onset, which is earlier in Ohtahara syndrome; on interictal EEG because hypsarrhythmia is not present in Ohtahara syndrome; and on seizure type. The diagnosis of Ohtahara syndrome does not preclude a later diagnosis of West syndrome as the former often evolves into the latter.
EEG is a key test in confirming the clinical diagnosis.
Follow up testing, including brain imaging, metabolic testing, and genetic testing can help to identify underlying etiologies and may help guide treatment.
In the initial stage of Ohtahara syndrome, interictal EEG shows a suppression burst pattern characterized by high-voltage paroxysmal discharges separated by periods of nearly flat tracing at a nearly regular rate. The suppression-burst pattern may be predominant or asynchronous over 1 hemisphere. It is present in both wakefulness and sleep. Ictal EEG shows the coincidence of the burst and tonic spasms (13). High frequency EEG activity between 80 and 150 Hz has also been identified in patients with Ohtahara syndrome and suppression burst; this was not identified in normal controls (56). Though the clinical significance of this finding remains unclear, it may be more commonly observed in those with structural brain lesions (22).
As the typical etiology of Ohtahara syndrome is structural brain damage, neuroimaging may provide valuable diagnostic information. CT and MRI may reveal specific findings consistent with the malformative etiologies described previously. Metabolic and genetic investigations are suggested in cases considered as cryptogenic or with normal or nonspecific imaging abnormalities. It has been suggested that patients with Ohtahara syndrome should be screened for underlying vitamin responsive disorders, including pyridoxine deficiency, biotinidase deficiency, folinic acid responsiveness, GLUT-1 deficiency, pyridoxamine phosphate oxidase deficiency, thiamine transporter deficiency, riboflavin transporter deficiency, and hyperinsulinemia hyperammonemia syndrome in addition to those mentioned above (46; 53).
Brainstem evoked potentials may demonstrate dysfunction in some patients (24). However, data are limited, and the presence or absence of brainstem evoked potential abnormalities does not contribute to or exclude a diagnosis (09).
No definitive treatments exist.
Antiseizure medications are inconsistent and generally have poor efficacy.
If an underlying metabolic disorder is identified, appropriate treatment may be available.
Appropriate patients may benefit from surgical interventions.
Drug treatment. Evidence for the use of specific antiseizure medications in Ohtahara syndrome is anecdotal. Phenobarbital, valproate, pyridoxine, zonisamide, topiramate, levetiracetam, and benzodiazepines have been used with limited effectiveness to control seizures (63; 61; 28; 39). Sodium channel agents were reported to control seizures in several patients with Ohtahara syndrome and KCNQ2 mutations, but did not improve long-term outcome (20). Adrenocorticotropic hormone therapy has also had limited efficacy and may be beneficial in cases that progress to West syndrome (07; 43; 61; 21). Vigabatrin was found to be effective at controlling seizures in a few case reports (06; 25). The ketogenic diet has been reported to have a beneficial effect in some cases (07; 21). Medicinal cannabis and cannabinoid derivatives have not been well studied in this condition. No medications are effective in treating the developmental disability and progressive decline that are typical of this condition.
Metabolic abnormalities. Cases in which a metabolic disorder is identified and corrected may have a better outcome and improved psychomotor development. In particular, favorable outcomes have been reported after correction of underlying pyridoxine deficiency (13). Folinic acid was reported to dramatically reduce seizures and improve the EEG in 1 patient with STXBP1 mutation (58). Supplementation of pyridoxal 5′-phosphate can lead to substantial improvements in patients with pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency (16).
Surgery. Cases with hemimegalencephaly or cortical dysplasia can benefit from neurosurgical treatment with hemispherectomy or focal resection (24). Appropriately chosen patients who are treated surgically may have a favorable outcome in terms of seizure control and development (31).
Other treatment. High-definition transcranial direct current stimulation treatment has been reported in 2 patients with Ohtahara syndrome: interictal epileptiform discharges were significantly decreased in both after treatment; the frequency of tonic spasms, but not other seizure types, was significantly decreased in 1 patient, whereas the other showed no significant reduction in seizure frequency (33; 34).
The seizures in Ohtahara syndrome are often intractable to currently available antiepileptic therapy. As many as half of infants with this condition may die in the first 2 years of life (17). Severe psychomotor retardation is almost universal in survivors, even among those in whom seizures are eventually relatively well controlled (42; 17). Correction of underlying metabolic disorder, if identified, can improve prognosis.
Jules C Beal MD
Dr. Beal of Weill Cornell Medicine and New York-Presbyterian Queens Hospital received honorariums from Neurelis as a speaker.See Profile
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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