Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of Panayiotopoulos syndrome, benign childhood partial seizures with ictal vomiting and extraoccipital spikes, benign nocturnal childhood occipital epilepsy, early onset benign childhood epilepsy with occipital paroxysms, early onset benign childhood occipital epilepsy (Panayiotopoulos type), early onset benign childhood occipital seizures, early onset benign childhood seizure susceptibility syndrome with occipital and extraoccipital spikes, early onset benign childhood susceptibility to autonomic seizures and autonomic status epilepticus, early onset benign occipital seizure susceptibility syndrome, early onset childhood epilepsy with occipital paroxysms (Panayiotopoulos type), and Panayiotopoulos type benign childhood occipital epilepsy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Panayiotopoulos syndrome is a common idiopathic, age- and self-limited, childhood-related, benign susceptibility to focal autonomic seizures and autonomic status epilepticus specific to childhood. It affects around 6% of children with nonfebrile seizures. Seizures manifest with a wide spectrum of ictal autonomic manifestations, mainly emesis, syncope-like epileptic seizures (ictal syncope), mydriasis, incontinence, and thermoregulatory and cardiorespiratory irregularities. Half of the seizures last for more than 60 minutes, often two to three hours, and, thus, constitute autonomic status epilepticus. There is marked variability of interictal EEG findings, from normal to multifocal spikes that also vary in serial EEGs. Ictal EEG onset is from the frontal or posterior regions. Seizures are infrequent in most patients; one third have a single seizure only, and half of them have two to five seizures. The remaining third of patients may have more than five seizures, and these may be frequent. Panayiotopoulos syndrome is a remarkably benign condition despite high incidence of autonomic status epilepticus. Seizures are self-limiting, with remission typically occurring within a few years from onset but probably 10% of patients may have more protracted active seizure periods. Prophylactic antiepileptic drug treatment may not be needed for most of the patients. Autonomic status epilepticus in the acute stage needs thorough evaluation, benzodiazepines intravenously, in rectal or buccal preparations, are commonly used to terminate this nonconvulsive status epilepticus. Aggressive treatment should be avoided because of the risk of iatrogenic complications, including cardiorespiratory arrest. Panayiotopoulos syndrome is frequently misdiagnosed as encephalitis, atypical migraine, syncope, cyclic vomiting syndrome, and other epileptic or nonepileptic disorders. The result of this erroneous diagnosis is avoidable mismanagement, high morbidity, and costly hospital admissions. In this article, the author details the clinical and laboratory findings of the syndrome that he described and provides practical guidance for appropriate diagnosis and management.
• Panayiotopoulos syndrome is a common self-limited childhood-related syndrome manifesting with infrequent autonomic seizures that often last for hours (autonomic status epilepticus).
• It is frequently unrecognized or misdiagnosed as encephalitis and other nonepileptic or epileptic disorders, which may result in avoidable morbidity and costly hospital admissions.
• EEG shows marked variability in the localization of spikes and may also be normal.
• Prophylactic antiepileptic treatment may not be needed.
• Out-of-hospital termination of impending autonomic status epilepticus, mainly with buccal midazolam, is highly recommended.
• Parental education is an integral and important part of management.
Panayiotopoulos syndrome is best described as early-onset benign childhood seizure susceptibility syndrome with mainly autonomic seizures and autonomic status epilepticus. An expert consensus defines Panayiotopoulos syndrome "as a benign age-related focal seizure disorder occurring in early and mid-childhood. It is characterized by seizures, often prolonged, with predominantly autonomic symptoms, and by an EEG that shows shifting and/or multiple foci, often with occipital predominance" (28).
“Panayiotopoulos syndrome” is now the formally approved term for this syndrome in the new ILAE report on classification (06; 15) and in the National Institute of Health and Care Excellence (NICE) Guidelines (National Institute of Health and Care Excellence 2012). A number of previously used descriptive synonyms for Panayiotopoulos syndrome have been rightly abandoned, such as “early onset benign childhood epilepsy with occipital paroxysms,” “early onset benign childhood occipital epilepsy,” “nocturnal childhood occipital epilepsy.” The reason for this is that these descriptive terms are incorrect (17; 28; 10; 53; 66; 87; 86; 68; 99; 100; 111) because:
(1) Onset of seizures is mainly with autonomic symptoms, which are not occipital lobe manifestations.
(2) Of occipital symptoms, only deviation of the eyes may originate from the occipital regions, but this rarely occurs at onset. Visual symptoms are rare and not consistent in recurrent seizures.
(3) Interictal occipital spikes may never occur.
(4) Magnetoencephalography may show equivalent current dipoles clustering in the frontal areas (96) or other extraoccipital areas (46).
(5) Ictal EEG has documented variable onset from the posterior or anterior regions (04; 73; 110; 23; 56; 88; 44; 99; 100; 98).
As Martinovic pointed out, “insisting on the descriptive name ‘occipital epilepsy’ is misleading for electroencephalographers (who would seek occipital spikes that do not exist in 30% of the cases), clinicians (who would seek the conventional focal occipital seizure manifestations that do not exist in over 80% of the cases), and researchers on autonomic nervous system (who would be misinformed that the occipital lobes are the primary centers of the generations of autonomic manifestations)” (66).
Panayiotopoulos described this syndrome and autonomic status epilepticus particular to childhood through a 30-year prospective study that started in 1973 (83; 84). Initial publications included patients with EEG occipital paroxysms or occipital spikes that attracted the main attention (79; 81), but later it became apparent that the same clinical manifestations, and mainly ictal vomiting, could occur in children with EEG extraoccipital spikes or normal EEG (82).
In Panayiotopoulos’ original study, ictal vomiting occurred in only 24 children out of 900 patients of all ages with epileptic seizures (80). Twenty-one were otherwise normal children (idiopathic cases constituting what is now considered Panayiotopoulos syndrome), and 3 had symptomatic epilepsies. Half of the seizures were lengthy, lasting for hours (autonomic status epilepticus). The EEGs of the 21 idiopathic cases showed great variations: 12 had occipital paroxysms or occipital spikes alone or with extraoccipital spikes; two had central spikes and giant somatosensory evoked spikes; two had midline spikes; one had frontal spikes; one had brief generalized discharges; and three had consistently normal EEG.
Subsequent attention was focused on the predominant group with occipital spikes, which was established as “early onset benign childhood epilepsy with occipital paroxysms” (81). The other group of nine children with extraoccipital spikes or normal EEGs was reevaluated much later (82); their clinical manifestations and outcome were similar to those patients with occipital spikes. Based on these results, it has been concluded that these 21 children, despite different EEG manifestations, suffered from the same disease, which is now designated as Panayiotopoulos syndrome to incorporate all cases irrespective of EEG localizations (32; 52; 53; 83; 84; 58; 74; 75; 19; 17; 18; 28; 66; 90; 87; 86; 99; 100; 69; 111; 22; 109; 67).
However, there was initial skepticism and resistance to these findings, including from influential epileptologists, for many reasons, as explained by Ferrie and Livingston (29):
• Ictal vomiting had been considered as extremely rare and hitherto had been mainly described in neurosurgical series of adult patients. In children, it was generally not considered as having an epileptic origin.
• Autonomic status epilepticus was not recognized as a diagnostic entity; the proposition that it might be a common occurrence in a benign seizure disorder challenged orthodox concepts of status epilepticus.
• It implied that pediatricians had been failing to diagnose significant numbers of children with epilepsy, instead erroneously labelling then as having diverse nonepileptic disorders such as encephalitis, syncope, migraine, cyclic vomiting syndrome, and gastroenteritis.
• The characteristic EEG findings suggested alternative diagnoses. Occipital spikes suggested childhood epilepsy with occipital paroxysms of Gastaut; multifocal spikes suggested symptomatic epilepsies with poor prognosis.
“The veracity of Panayiotopoulos’s initial descriptions has, over the last 2 decades, been confirmed in large and long term studies from Europe, Japan and South America. The published database on which our knowledge of Panayiotopoulos syndrome is now based includes over 500 cases (68); there are few epilepsy syndromes that are better characterized. What emerge are a remarkably uniform clinical picture and a diagnosis which is strikingly useful in helping predict prognosis and dictate management” (29).
Panayiotopoulos syndrome has been confirmed worldwide with a unique uniformity in all races and was the core theme of the June 2007 issue of Epilepsia (10; 31; 53; 61; 66; 84).
Autonomic status epilepticus, the more common type of nonfebrile status epilepticus in otherwise normal children (77), has been properly assessed in a consensus statement (31; 29).
Panayiotopoulos syndrome is detailed in the ILAE “epilepsy diagnosis” manual of the Commission and described as follows (15):
Overview. Panayiotopoulos syndrome is characterized by the onset of autonomic seizures in early childhood that are often prolonged. The EEG commonly shows high amplitude focal spikes and may be activated by sleep. Seizures are infrequent in most patients, with 25% only having a single seizure (which may be autonomic status epilepticus) and 50% having six seizures or less. Seizures are self-limiting, with remission typically occurring within a few years from onset.
Note. Self-limiting refers to there being a high likelihood of seizures spontaneously remitting at a predictable age.
Clinical context. Panayiotopoulos syndrome is characterized by onset of seizures between one and 14 years of age (majority between three and six years). Seizures are infrequent in most patients, with 25% having a single seizure (which may be autonomic status epilepticus) and 50% having six seizures or less. Frequent seizures can occur in some patients. Seizures usually resolve by 11 to 13 years of age. Both sexes are affected equally. Antecedent and birth history is normal. Head size and neurologic examination are usually normal. Development and cognition are normal. However, during active seizure periods, subtle neuropsychological deficits in language and executive functioning have been reported. A history of febrile seizures is seen in 5% to 17% of patients.
Mandatory seizures. The mandatory seizure type for this syndrome is the presence of seizures with prominent autonomic features mainly emetic (nausea, retching, vomiting), but pupillary (mydriasis), circulatory (pallor, cyanosis), thermoregulatory, and cardiorespiratory (heart and respiratory rate disturbances) changes also occur. There may be incontinence and excessive salivation. Headache or cephalic auras may occur at onset. Apnea and cardia asystole can occur, but only exceptionally are these severe. Two thirds of seizures start in sleep. Seizures are often prolonged (minutes to hours), constituting autonomic status epilepticus; however, the child recovers without residual neurologic or cognitive deficits. As the seizure evolves, loss of responsiveness, head and eye deviation, and hemiclonic activity (often with a Jacksonian march) may develop. Some seizures may have prominent fronto-parietal opercular features.
EEG background. The background EEG is normal.
Caution. If focal slowing consistently over one area is not seen, consider structural brain abnormality.
Caution. Generalized slowing is not seen except in postictal periods.
Interictal EEG. A single routine EEG is normal in 10% of patients. Multifocal high voltage repetitive spikes or sharp and slow-waves are seen in 90% of patients; these often are present in different focal areas on sequential EEGs. All focal brain regions may be affected, but abnormality in posterior regions is common, with occipital spikes seen on EEG in 60% of patients. Low voltage spikes and generalized discharges may be seen in a minority of cases.
Activation. Eye closure (elimination of central vision and fixation off sensitivity) may activate occipital spikes. EEG abnormality is enhanced by sleep deprivation and by sleep, when discharges often have a wilder field and may be bilaterally synchronous.
Ictal. Ictal patterns are unilateral, often having posterior onset, with rhythmic slow (theta or delta) activity intermixed with small spikes.
Imaging. Neuroimaging is normal. If the electroclinical diagnosis of Panayiotopoulos syndrome has been made and there are no atypical features, neuroimaging is not mandatory.
Genetics. There are reports of Panayiotopoulos syndrome or other epilepsy syndromes in siblings and in families, suggesting that there are genetic influences that are likely complex (polygenic). There are no known genes.
Family history of seizures/epilepsy. There is usually no family history of epilepsy or febrile seizures; however, rare cases are reported with family members with epilepsy or febrile seizures.
• Familial focal epilepsy with variable foci
Adapted from (15).
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