Panayiotopoulos syndrome

C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Jerome Engel Jr MD PhD, editor. (Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.)
Originally released January 11, 1999; last updated October 7, 2017; expires October 7, 2020

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.

Overview

Panayiotopoulos syndrome is a common idiopathic, 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 or cardiorespiratory irregularities. Half of the seizures last for more than 60 minutes, often 2 to 3 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. Panayiotopoulos syndrome is frequently misdiagnosed as encephalitis, atypical migraine, syncope, cyclic vomiting syndrome, and other epileptic or nonepileptic disorders. The result 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.

Key points

 

• 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.

Historical note and terminology

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" (Ferrie et al 2006).

“Panayiotopoulos syndrome” is now the formally approved term for this syndrome in the new ILAE report on classification (Berg et al 2010; Commission on Classification and Terminology of the International League Against Epilepsy 2014) 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 (Covanis 2006; Ferrie et al 2006; Caraballo et al 2007; Koutroumanidis 2007; Martinovic 2007; Panayiotopoulos et al 2008; Panayiotopoulos et al 2012; Michael et al 2010; Specchio et al 2010a; Specchio et al 2010b; Vigevano et al 2013) 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 (Saitoh et al 2007) or other extraoccipital areas (Kanazawa 2005a) Magnetoencephalography may show equivalent current dipoles clustering in the frontal areas (Saitoh et al 2007) or other extraoccipital areas (Kanazawa 2005a).

Image: Frontal origin in a child with Panayiotopoulos syndrome (MEG)
Image: Two patients with rolandic epilepsy and a patient with Panayiotopoulos syndrome (MEG)

(5) Ictal EEG has documented variable onset from the posterior or anterior regions (Beaumanoir 1993; Oguni et al 1999; Vigevano et al 2000; Demirbilek and Dervent 2004; Koutroumanidis et al 2005; Parisi et al 2005; Iannetti et al 2009; Specchio et al 2010a; Specchio et al 2010b; Schmidt et al 2012).

Image: Autonomic status epilepticus in a child with Panayiotopoulos syndrome (video-EEG)
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)” (Martinovic 2007).

Panayiotopoulos described this syndrome and autonomic status epilepticus particular to childhood through a 30-year prospective study that started in 1973 (Panayiotopoulos 2002; Panayiotopoulos 2007). Initial publications included patients with EEG occipital paroxysms or occipital spikes that attracted the main attention (Panayiotopoulos 1981; Panayiotopoulos 1989), 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 (Panayiotopoulos 1999).

Image: Occipital paroxysms in 4 children with epileptic seizures (EEG)

In Panayiotopoulos' original study, ictal vomiting occurred in only 24 children out of 900 patients of all ages with epileptic seizures (Panayiotopoulos 1988). 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; 2 had central spikes and giant somatosensory evoked spikes; 2 had midline spikes; 1 had frontal spikes; 1 had brief generalized discharges; and 3 had consistently normal EEG.

Image: Extraoccipital spikes only or brief generalized discharges in 3 children (EEG)
Subsequent attention was focused on the predominant group with occipital spikes, which was established as “early onset benign childhood epilepsy with occipital paroxysms” (Panayiotopoulos 1989). The other group of 9 children with extraoccipital spikes or normal EEGs was reevaluated much later (Panayiotopoulos 1999); 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 (Ferrie and Grunewald 2001; Koutroumanidis 2002; Koutroumanidis 2007; Panayiotopoulos 2002; Panayiotopoulos 2007; Lada et al 2003; Ohtsu et al 2003; Ohtsu et al 2008; Covanis et al 2005; Covanis 2006; Covanis 2010; Ferrie et al 2006; Martinovic 2007; Parisi et al 2007; Panayiotopoulos et al 2008; Panayiotopoulos et al 2012; Specchio et al 2010a; Specchio et al 2010b; Moseley et al 2013; Vigevano et al 2013; Degerliyurt et al 2014; Verrotti et al 2014; Mellish et al 2015).

However, there was initial skepticism and resistance to these findings, including from influential epileptologists, for many reasons, as explained by Ferrie and Livingston (Ferrie and Livingston 2010):

 

• 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 (ICOE-G); 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 (Michael et al 2010); 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” (Ferrie and Livingston 2010).

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 (Caraballo et al 2007; Ferrie et al 2007; Koutroumanidis 2007; Leal et al 2007; Martinovic 2007; Panayiotopoulos 2007).

Autonomic status epilepticus, the more common type of nonfebrile status epilepticus in normal children (Okanishi et al 2008), has been properly assessed in a consensus statement (Ferrie et al 2007; Ferrie 2010).

Panayiotopoulos syndrome is detailed in the ILAE “epilepsy diagnosis” manual of the Commission and described as follows (Commission on Classification and Terminology of the International League Against Epilepsy 2014):

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 6 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 1 and 14 years of age (majority between 3 and 6 years). Seizures are infrequent in most patients, with 25% having a single seizure (which may be autonomic status epilepticus) and 50% having 6 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 1 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.

Differential diagnoses.

 

Familial focal epilepsy with variable foci
• Childhood epilepsy with centrotemporal spikes - if seizures have prominent frontoparietal opercular features
• Celiac disease, epilepsy, and cerebral calcification syndrome
• Focal seizures due to structural brain abnormality
• Migraine associated disorders including benign paroxysmal vertigo
• Syncope
• Disorders associated with intermittent encephalopathy (eg, metabolic disorders, especially mitochondrial)
• Disorders associated with intermittent vomiting (eg, gastrointestinal disorders)

Adapted from (Commission on Classification and Terminology of the International League Against Epilepsy 2014).

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