Autonomic epileptic seizures, autonomic effects of seizures, and SUDEP.

Many generalized tonic-clonic seizures are accompanied by profound autonomic changes. However, autonomic seizures and autonomic status epilepticus can also be seen with specific electroclinical syndromes (Panayiotopoulos syndrome), etiologies, and localizations. Such autonomic symptoms may impact cardiorespiratory function. While it is likely that several factors contribute to SUDEP, further study of both ictal respiratory and cardiac changes and underlying neuroanatomical mechanisms involved in autonomic seizure semiology are likely to provide important data to improve our understanding of the pathophysiology of this devastating condition. This paper will review the association between autonomic symptoms and epileptic seizures and will highlight the work of three young investigators. Drs. Lisa Bateman and Brian Moseley will review their work on cardiorespiratory effects of recorded seizures and how this assists in our understanding of SUDEP. Dr. John Millichap will review autonomic seizures and autonomic dysfunctions related to childhood epilepsy and will discuss the importance of expanded research efforts in this field.

The new ILAE report on terminology and concepts for the organization of epilepsies: critical review and contribution.

This critical review refers to the new report on terminology and concepts for the organization of epilepsies by the Commission of the International League Against Epilepsy (ILAE). It is unfortunate that most of the proposals in the Commission's report are modified interpretations and nomenclature of previous ILAE classifications; new terms are not better than the old ones, and recent advances have not been incorporated. Hence, the new ILAE report met with considerable dissatisfaction from several expert epileptologists. The Commission abandoned (1) the disease-syndrome distinction, although "disease" is generally differentiated from "syndrome" in most medical texts as well as in the ILAE classification itself; (2) the distinction of "generalized" and "focal" for epileptic syndromes, despite maintaining this distinction for epileptic seizures and despite the fact that most epileptic syndromes manifest exclusively either with generalized or focal epileptic seizures; (4) the terms "idiopathic,""symptomatic," and "cryptogenic," although these terms have been well defined in the previous ILAE classifications; reiterating their true meaning would be sufficient. Genetic epilepsy could be a new category and (5) the designation of "benign" epilepsies, despite the recommendations of experts at the Monreale workshop. In addition, the Commission proposed that "age at onset" be used as a primary dimension for organizing the epilepsies. However, (a) this runs counter to classification efforts of other diseases in medicine and neurology; (b) syndromes that are likely to be linked together on the basis of electroclinical (and often genetic) evidence are now separated and intermixed with a number of heterogeneous epilepsies; and (c) a considerable number of epileptic syndromes have a wide range of age at onset from childhood to adulthood. Furthermore, epilepsy syndromes were given by name only, without definition; thus we remain dependent on previous ILAE definitions, which are often broad and imprecise. The ILAE should commission consensus of opinion from experts in specific fields in order to define each syndrome. Areas of certainties and uncertainties and of agreements and disagreements should be identified and explained. This approach may be the only way toward achieving a scientifically sound and clinically meaningful organizational system for the epileptic seizures and the epilepsies-a process that would incorporate the tremendous advances in our field and would be accepted by the wider community of clinicians and scientists.

Video-EEG documented lengthy seizure in Panayiotopoulos syndrome: clinical manifestations may be inconspicuous.

A 4-year-old boy had an autonomic seizure of Panayiotopoulos syndrome during video-EEG recording. Interictal EEG showed multifocal spikes in the centrotemporal and left posterior regions. Ictal electrographic onset included fast rhythms in the left posterior regions progressing to a mixture of high-amplitude spikes and fast and slow rhythms, bilaterally. The clinical symptoms (sighing, arousal with eyes opening, eye-deviation, and emesis with possible alteration of consciousness) started two minutes after the electrographic onset. These symptoms were mild and their characterisation as epileptic seizure behaviour would have been difficult without the ictal EEG documentation. The clinical manifestations of the child's previous epileptic seizures were mainly from the Rolandic area. [Published with video sequences].

The new ILAE report on terminology and concepts for organization of epileptic seizures: a clinician's critical view and contribution.

The International League Against Epilepsy (ILAE) standardized classification and terminology for "epileptic seizures" of 1981 and "epilepsies and epileptic syndromes" of 1989 provide a fundamental framework for organizing and differentiating the epilepsies. However, a revision of these classifications is mandated by recent major technologic and scientific advances. Since 1997, the relevant ILAE Commissions have made significant efforts to achieve better and internationally uniform classifications as reflected in their reports of 2001, 2006, and 2010. Their initial aim to construct a "new scientific classification from application of methods used in biology that determines separate species and natural classes" proved elusive and, therefore, the last Commission in their report of 2010 confined their revisions to "new terminology and concepts" instead of "proposing a new classification (in the sense of organization) of epilepsies." It is unfortunate that most of the proposals in this report are modified interpretations and nomenclature of previous ILAE classifications; new terms are not better than the old ones, and recent advances have not been incorporated. Hence, the new ILAE report met with considerable protest from several expert epileptologists. This critical review refers mainly to the epileptic seizures, the classification of which may be an easier and less controversial task in the ILAE revisions. A revised classification should incorporate advanced knowledge of seizure pathophysiology, and clinical, interictal, and ictal manifestations. Such an attempt was made and detailed in the 2006 report of the ILAE Classification Core Group. However, these changes were largely discarded in the new ILAE report of 2010, without justification. This is inexplicable considering that the scientific advances that were available to the two Commissions were the same or had improved between 2006 and 2010. Of major concern is that "No specific classification is recommended for focal seizures which should be described according to their manifestations." Such a proposition defies the essence and the principle of any classification that requires an organization and a common language for communication. Free text descriptions are fine in a manual of differential diagnosis but not as a classification system. Another striking weakness is that even the accepted types of epileptic seizure are listed by name only, without defining them. The result is avoidable confusion. Furthermore, the report fails to consider reflex epileptic seizures. Status epilepticus is the most conspicuous omission despite immense advances of our understanding of it and its relevance on the classification. It appears that the new ILAE report does not fulfill its intent to improve the previous classifications and it may be premature to submit anything similar to this for approval by the ILAE General Assembly. The ILAE Commission could benefit by asking experts in basic and clinical science to provide a concise statement in their field of expertise as, for example, what are focal, myoclonic, or absence seizures, and their subtypes, their manifestations, and their possible pathophysiology. Areas of certainties and uncertainties, agreements and disagreements should be identified and stated clearly, with documentation of the reasons for it. Probably this is the only way forward for a truly scientific, sound, and clinically meaningful organizational system for the epileptic seizures and the epilepsies.

Benign childhood focal epilepsies: assessment of established and newly recognized syndromes.

A big advance in epileptology has been the recognition of syndromes with distinct aetiology, clinical and EEG features, treatment and prognosis. A prime and common example of this is rolandic epilepsy that is well known by the general paediatricians for over 50 years, thus allowing a precise diagnosis that predicts an excellent prognosis. However, rolandic is not the only benign childhood epileptic syndrome. Converging evidence from multiple and independent clinical, EEG and magnetoencephalographic studies has documented Panayiotopoulos syndrome (PS) as a model of childhood autonomic epilepsy, which is also common and benign. Despite high prevalence, lengthy and dramatic features, PS as well as autonomic status epilepticus had eluded recognition because emetic and other ictal autonomic manifestations were dismissed as non-epileptic events of other diseases. Furthermore, PS because of frequent EEG occipital spikes has been erroneously considered as occipital epilepsy and thus confused with the idiopathic childhood occipital epilepsy of Gastaut (ICOE-G), which is another age-related but rarer and of unpredictable prognosis syndrome. Encephalitis is a common misdiagnosis for PS and migraine with visual aura for ICOE-G. Pathophysiologically, the symptomatogenic zone appears to correspond to the epileptogenic zone in rolandic epilepsy (sensory-motor symptomatology of the rolandic cortex) and the ICOE-G (occipital lobe symptomatology), while the autonomic clinical manifestations of PS are likely to be generated by variable and widely spread epileptogenic foci acting upon a temporarily hyperexcitable central autonomic network. Rolandic epilepsy, PS, ICOE-G and other possible clinical phenotypes of benign childhood focal seizures are likely to be linked together by a genetically determined, functional derangement of the systemic brain maturation that is age related (benign childhood seizure susceptibility syndrome). This is usually mild but exceptionally it may diverge to serious epileptic disorders such as epileptic encephalopathy with continuous spike and wave during sleep. Links with other benign and age-related seizures in early life such as febrile seizures, benign focal neonatal and infantile seizures is possible. Overlap with idiopathic generalized epilepsies is limited and of uncertain genetic significance. Taking all these into account, benign childhood focal seizures and related epileptic syndromes would need proper multi-disciplinary re-assessment in an evidence-based manner.

Fixation-off sensitivity in epilepsies other than the idiopathic epilepsies of childhood with occipital paroxysms: a 12-year clinical-video EEG study.

PURPOSE: To define the spectrum of the epileptic syndromes and epilepsies (other than the idiopathic epilepsies of childhood with occipital paroxysms) that can be associated with fixation-off sensitivity (FOS), delineate the electrographic types of FOS abnormalities and identify the patterns that can be associated with clinical seizures, and examine whether there may be a pure form of fixation-off sensitive epilepsy. METHODS: We reviewed the clinical and video EEG data of all our patients with FOS over the last 12 years. Children with idiopathic focal epilepsies and occipital EEG paroxysms were excluded. RESULTS: From January 1995 to December 2006, 19 of about 8,500 patients had had one or more video-EEGs with FOS, yielding an approximate incidence of 0.2%. From the 14 patients with full clinical and EEG data available, 12 had various epilepsies that included IGE phenotypes (7), symptomatic or probably symptomatic focal (3), cryptogenic generalised (1), and adult onset idiopathic photosensitive occipital (1), and two had no seizures. Seven patients (50%) were photosensitive. FOS EEG abnormalities were occipital in six patients, generalised in eight, and generalised with posterior emphasis in two patients. Seven of these patterns were associated with habitual seizures in seven patients, but actual FOS-induced seizures (absences) were documented with video EEG in only one patient; three others had some historical evidence suggesting that, under some circumstances, their FOS EEG abnormalities might generate clinical seizures. CONCLUSIONS: Despite the association of FOS with generalised and focal, symptomatic and cryptogenic and mild or pharmaco-resistant epilepsies, closer analysis of our data, and supportive evidence from functional imaging and physiological observations on alpha rhythm generation, disclose a prominent role of the occipital areas, even when FOS EEG abnormalities and seizures are ostensibly generalised. Although FOS appears to be of relatively low epileptogenicity, an electroclinical profile of pure FOS epilepsy may exist [Published with video sequences].

Idiopathic epilepsy with generalized tonic-clonic seizures only versus idiopathic epilepsy with phantom absences and generalized tonic-clonic seizures: one or two syndromes?

PURPOSE: To define the relationship between two syndromes of idiopathic generalized epilepsy (IGE) with apparently similar phenotypes: The form with generalized tonic-clonic seizures only (IGE-GTCS) and that with phantom absences (IGE-PA). METHODS: We compared the electroclinical features of 33 consecutive patients with GTCS and generalized spike wave (GSW); 18 had only GTCS and were diagnosed as IGE-GTCS, and 15 had hitherto unnoticed mild absences on the electroencephalography (EEG) and were diagnosed as IGE-PA. All patients were subjected to the same diagnostic workout, including video EEG during hyperventilation with breath counting (HBC). Patients with a clinical history of absences or myoclonic seizures were excluded. RESULTS: PA were easily identified with the first or second EEG in 14 of 15 patients with IGE-PA and always with sleep-deprived EEGs; conversely, PA did not occur in the IGE-GTCS patients despite using more EEGs. GTCS were twice as frequent in the IGE-GTCS group and tended to occur on awakening, whereas episodes of absence status affected twice as many patients with IGE-PA. The hereditary risk was 30% in the IGE-GTCS and 6.7% in IGE-PA. GSW had a strong polyspike component in IGE-PA and were briefer in IGE-GTCS. There is no evidence for a maturational influence on the duration of GSW in either syndrome. CONCLUSION: Our findings clearly indicate that IGE-GTCS and IGE-PA are two distinct IGE syndromes and emphasize the role of PA for patients' diagnosis and management and for syndromic classification. They also appear to validate HBC as a simple, sensitive, and pragmatic method for the clinical identification of typical absences.

Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14.

A previous study of 34 nuclear pedigrees segregating juvenile myoclonic epilepsy (JME) gave significant evidence of linkage with heterogeneity to marker loci on chromosome 15q13-14 close to the candidate gene CHRNA7 (Hum. Mol. Genet. 6 (1997) 1329). The aim of this work was to further evaluate the putative aetiological role of CHRNA7 in JME within the 34 families originally described, and to assess the contribution of this locus to a broader phenotype of idiopathic generalised epilepsy (IGE). Multipoint linkage analysis and intrafamilial association studies were performed with microsatellite markers that encompass both CHRNA7 and its partial duplication (CHRFAM7A). A maximum HLOD of 3.45 [alpha=0.58; (Zall=2.88, P=0.0008)] was observed 8 cM distal to D15S1360, a CHRNA7 intragenic marker. Significant exclusion lod scores were obtained across the region in 12 mixed phenotype JME/IGE families. Mutation screening of the CHRNA7 gene (and consequently exons 5-10 of CHRFAM7A) and its putative promoter sequence identified a total of 13 sequence variants across 23 of 34 JME-affected families. Two variants (c.1354G>A and c.1466C>T) are predicted to result in amino acid changes and one (IVS9+5G>A) is predicted to result in aberrant transcript splicing. However, none of the variants alone appeared either necessary or sufficient to cause JME in the families in which they occurred. In conclusion, linkage analyses continue to support the existence of a locus on chromosome 15q13-14 that confers susceptibility to JME but not to a broader IGE phenotype. Causal sequence variants in the positional candidate CHRNA7 have not been identified but the presence of multiple segmental duplications in this region raises the possibility of undetected disease-causing genomic rearrangements.

Occipital lobe seizures and epilepsies.

Occipital lobe epilepsies (OLEs) manifest with occipital seizures from an epileptic focus within the occipital lobes. Ictal clinical symptoms are mainly visual and oculomotor. Elementary visual hallucinations are common and characteristic. Postictal headache occurs in more than half of patients (epilepsy-migraine sequence). Electroencephalography (EEG) is of significant diagnostic value, but certain limitations should be recognized. Occipital spikes and/or occipital paroxysms either spontaneous or photically induced are the main interictal EEG abnormalities in idiopathic OLE. However, occipital epileptiform abnormalities may also occur without clinical relationship to seizures particularly in children. In cryptogenic/symptomatic OLE, unilateral posterior EEG slowing is more common than occipital spikes. In neurosurgical series of symptomatic OLE, interictal EEG abnormalities are rarely strictly occipital. The most common localization is in the posterior temporal regions and less than one-fifth show occipital spikes. In photosensitive OLE, intermittent photic stimulation elicits (1) spikes/polyspikes confined in the occipital regions or (2) generalized spikes/polyspikes with posterior emphasis. In ictal EEG, a well-localized unifocal rhythmic ictal discharge during occipital seizures is infrequent. A bioccipital field spread to the temporal regions is common. Frequency, severity, and response to treatment vary considerably from good to intractable and progressive mainly depending on underlying causes.

Syncope-like epileptic seizures in Panayiotopoulos syndrome.

OBJECTIVE: To describe the clinical features of syncope-like epileptic seizures (SLES) and their frequency in Panayiotopoulos syndrome (PS). METHODS: This was a 6-year prospective study of all children aged 1-15 years referred for an EEG. PS was defined by the occurrence of at least one autonomic seizure (AS) in a neurodevelopmentally normal child and at least one EEG with focal spikes. SLES were defined as self-terminating events of sudden loss of postural tone and unresponsiveness, occurring either concurrently with other ictal autonomic symptoms and signs that characterize PS (AS + SLES) or on their own (pure SLES). RESULTS: PS was diagnosed in 33 of 394 consecutive children with at least one afebrile seizure (8.4%). SLES occurred at least once in 17 of 33 children (51.5%); 12 presented SLES in all their AS, and 5 had also AS without SLES. Overall, 53 of 74 AS manifested with SLES (71.6%); 25 were AS + SLES and 28 were pure SLES. The latter occurred in 7 children suddenly and without premonition or obvious triggers while standing, sitting, lying down, or asleep, did not resolve in the horizontal position, and were not associated with stiffening or any involuntary movements, even when longer than a few minutes. Concurrent autonomic symptoms during AS + SLES included emesis, incontinence, mydriasis, miosis, and cardiorespiratory abnormalities. CONCLUSIONS: SLES is a common ictal manifestation of PS and should be considered in the differential diagnosis of suspected syncope, particularly when clinical signs are atypical for neurocardiogenic syncope and the EEG shows focal spikes.

Multifocal spatiotemporal distribution of interictal spikes in Panayiotopoulos syndrome.

OBJECTIVE: To investigate the spatiotemporal course of interictal spikes in Panayiotopoulos syndrome (PS), and in particular whether seemingly independent extra-occipital spikes are truly autonomous or secondary, triggered by occipital spikes. METHODS: Seven children with the most representative interictal spike patterns on visual analysis were studied. Five had a single focus (occipital in two, suggestive of posterior to anterior spike propagation in two, and frontal) and two had two foci over the posterior and the anterior areas independently. Spikes were marked, clustered and waveform - averaged, and mapped on electrode space. RESULTS: The patterns of spatial and temporal dynamics of the interictal spikes were not stereotypical for any brain area, including the occipital lobe. Some of the anterior and the posterior spikes remained focal or showed little spread, but others appeared to propagate to the opposite direction (occipital to frontal and vice versa). CONCLUSIONS: In PS all cerebral locations are able to spontaneously and independently generate and propagate interictal spikes, indicating that PS is a multifocal epileptic syndrome. SIGNIFICANCE: Confirmation of the multifocal character of PS improves clinical diagnosis and challenges our current taxonomic concepts by expanding the anatomical boundaries of a distinct focal epilepsy phenotype from lobar to system.

Idiopathic childhood occipital epilepsy of Gastaut: a review and differentiation from migraine and other epilepsies.

The purpose of this review is to provide guidance for appropriate diagnosis and management of idiopathic childhood occipital epilepsy of Gastaut. The typical clinical features are visual seizures that typically consist of brief elementary visual hallucinations, which are mainly multicolored and circular. Ictal blindness and deviation of the eyes are also common symptoms. The seizures are usually frequent and diurnal. The electroencephalography is the only investigation with abnormal results, showing occipital spikes and often occipital paroxysms demonstrating fixation-off sensitivity. Brain magnetic resonance imaging is used to exclude symptomatic occipital epilepsy. Patients usually respond well to antiepileptic medication and about two-thirds remit by the age of 16 years. Idiopathic childhood occipital epilepsy of Gastaut is frequently misdiagnosed as migraine with visual aura, acephalgic, or basilar migraine. Differentiation from symptomatic occipital epilepsy, particularly when children are otherwise normal, can be difficult. Most children need prophylactic antiepileptic medication.

Autonomic status epilepticus in Panayiotopoulos syndrome and other childhood and adult epilepsies: a consensus view.

PURPOSE: To discuss and propose a definition of autonomic status epilepticus (SE), describe its clinical and EEG features, and review what is known about its epidemiology, pathophysiology, differential diagnosis, and management. METHODS: An international consortium of established researchers in the field was identified from their published work, agreed the purpose of the project, searched the literature, and, by use of e-mail communication, agreed the consensus document. RESULTS: Autonomic SE is a condition lasting at least 30 min and characterized by epileptic activity causing altered autonomic function of any type at seizure onset or in which manifestations consistent with altered autonomic function are prominent (quantitatively dominant or clinically important) even if not present at seizure onset. It is best described, and probably most commonly encountered in children, with Panayiotopoulos syndrome. However, it also occurs in children with symptomatic epilepsies and, exceptionally, in adults. Its pathogenesis and most appropriate management are poorly understood. CONCLUSIONS: It is hoped that this document will help clinical recognition of Autonomic SE, reduce misdiagnosis, and promote further interest and studies into what has been a relatively neglected area.

Syndromes of idiopathic generalized epilepsies not recognized by the International League Against Epilepsy.

This chapter assesses probable epileptic syndromes within the idiopathic generalized epilepsies (IGE) that have not yet been recognized by the International League Against Epilepsy (ILAE). Jeavons syndrome, a purely reflex IGE that predominantly manifests with eyelid myoclonia and electroencephalogram (EEG) abnormalities on eye closure, is the most distinct and undisputed of the syndromes. Another is autosomal-dominant cortical tremor, myoclonus, and epilepsy, a purely monogenic disorder that has been documented in numerous reports, mainly from Japan and Italy. Perioral myclonia with absences is certainly a seizure type that may constitute an IGE syndrome when it is associated with a number of other clinical and EEG manifestations. Similarly, many patients suffer for years from phantom absences, a type of mild absence, before a first generalized tonic-clonic seizure that usually occurs in adulthood. Both perioral myoclonia with absences and phantom absences are clinically significant because they are probably lifelong and are associated with a very high incidence (around 50%) of absence status epilepticus that may escape diagnosis and appropriate treatment. The position of early childhood IGE, which manifests mainly with typical absence seizures that are distinctly different from childhood absence epilepsy and other recognized IGE syndromes, is less clear. The prevalence of these syndromes is significant. Their identification allows better clinical management and is important for genetic research and counselling. In addition, their recognition permits application of exclusion criteria for a more purified definition and a better understanding of the true boundaries of the other IGE syndromes already accepted by the ILAE.

Autonomic seizures and autonomic status epilepticus peculiar to childhood: diagnosis and management.

Autonomic seizures and autonomic status epilepticus in children have a high prevalence, manifest with dramatic clinical symptoms, and have important clinical and management implications. They probably affect approximately 13% of children aged 3-6 years with one or more nonfebrile seizures, or 6% in the age group 1-15. The primary cause is an idiopathic age-dependent epileptogenic susceptibility (Panayiotopoulos syndrome), but 10-20% are due to cerebral pathology. Autonomic seizures and autonomic status epilepticus have been best studied in Panayiotopoulos syndrome, which has been confirmed worldwide in more than 800 cases and recently recognized in the new classification scheme of the International League Against Epilepsy. Seizures start with autonomic symptoms, mainly emesis, while the child is usually fully conscious. Other more conventional seizure manifestations often ensue, but autonomic manifestations commonly predominate to the end of the seizure. Ictal syncope (transient loss of consciousness and postural tone) is an intriguing common symptom. Half of the seizures last longer than 30 minutes, constituting autonomic status epilepticus. Prognosis is invariably excellent except for the symptomatic cases. The interictal EEG shows great variability from normal to severely epileptogenic, often with multifocal spikes. Pathophysiology of Panayiotopoulos syndrome is unknown, but it is likely that they are due to diffuse maturation-related epileptogenicity activating susceptible-for-children emetic centers and the hypothalamus. Thus, Panayiotopoulos syndrome is not occipital epilepsy, with which it is often erroneously equated. Autonomic seizures and autonomic status epilepticus are frequently misdiagnosed and often treated as encephalitis, atypical migraine, cardiogenic syncope, or other unrelated medical conditions such as gastroenteritis. This review examines the existing evidence, provides a means of improving diagnostic yield, and proposes practice parameters and guidelines for the diagnosis and management of autonomic seizures and autonomic status epilepticus in children.