Idiopathic focal epilepsies

Handbook of Clinical Neurology, Vol. 111 (3rd series) Pediatric Neurology Part I O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 61

Idiopathic focal epilepsies FEDERICO VIGEVANO1*, NICOLA SPECCHIO1, AND NATALIO FEJERMAN2 Department of Neuroscience, Bambino Gesu` Children’s Hospital, IRCCS, Rome, Italy

1 2

Department of Neurology, Hospital de Pediatrıþ Prof. Dr. Juan P Garrahan, Buenos Aires, Argentina

INTRODUCTION In the 1960s the hypothesis regarding the existence of nonsymptomatic focal epilepsies with idiopathic etiology was put forward. The original description of benign epilepsy with centro-temporal spikes or rolandic spikes was attributed to Nayrac and Beaussart (1958). Since then other conditions with idiopathic focal epilepsy have been described that share common features in addition to focal seizures: onset in pediatric age, normal psychomotor development, and benign course related to the spontaneous remission of seizures. Based on genetic assessment idiopathic focal epilepsies can be divided into two groups: nonautosomal dominant and autosomal dominant idiopathic focal epilepsies. The nonautosomal dominant entities are characterized by: 1. 2. 3. 4.

5. 6.

7. 8.

Onset during childhood Absence of neurological and intellectual deficit Family history of epilepsy in a third of patients Sporadic focal seizures, with motor and vegetative component, sometimes prolonged; sleep-related polymorphous seizures Benign evolution with disappearance of seizures before puberty Peculiar EEG paroxysmal abnormalities as focal negative diphasic slow spike followed by a slow wave, increasing in frequency during sleep; the slow spikes tend to migrate throughout the course of the disease and disappear at different ages Ictal EEG characterized by focal rhythmic sharp waves or spikes, rarely with secondary generalization Age-dependent extreme somatosensory evoked potentials

In this group we include benign epilepsy with centrotemporal spikes (BECTS), Panayiotopoulos syndrome (PS), and idiopathic childhood occipital epilepsy, as described by Gastaut (ICOE-G), and benign idiopathic midline spikes epilepsy (BIMSE) (syndrome in development). The autosomal dominant entities are characterized by: 1. 2. 3.

Autosomal dominant mode of inheritance Absence of other etiological factors Occurrence of seizures in a brief self-limited period during the first months of life 4. Partial seizures in clusters, with variable site of onset 5. Seizures with or without secondary generalization 6. Absence of typical interictal EEG trait 7. Normal development 8. Association with nonepileptic paroxysmal disorders In this group we include benign familial infantile seizures (BFIS) and benign familial neonatal–infantile seizures (BFNIS).

THE NONAUTOSOMAL DOMINANT ENTITIES Table 61.1 summarizes the main features of these entities.

Benign childhood epilepsy with centro-temporal spikes Benign childhood epilepsy with centro-temporal spikes (BCECTS) is the most frequent among the benign focal epilepsies in childhood and accounts for about 15 to 25% of all epileptic syndromes in children aged between 4 and 12 years (Dalla Bernardina et al., 2005). The annual

*Correspondence to: Federico Vigevano, Director of Neuroscience Department, Bambino Gesu` Children’s Hospital, Piazza S. Onofrio, 4 - 00165 Rome, Italy. Tel: þ390668592262, Fax: þ390668592463, E-mail: [email protected]

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Table 61.1 Main features of nonautosomal dominant idiopathic focal epilepsy during childhood

Onset –typical –range Type of seizures

Occurrence Other type of seizures Other clinical features Interictal EEG

Treatment Prognosis Chromosomal loci

BECTS

PS

ICOE-G

BIMSE

7 years 4–10 years Orofacial motor signs Speech arrest Sialorrhea Somatosensory symptoms

4.5 years 1–14 years Autonomic symptoms with emesis, loss of consciousness, head and/or eyes deviation Sleep Hemiclonic Generalized seizures Normal IQ Minor lower scores in comprehension Repetitive highamplitude multifocal spikes, 10% normal EEG

8 years 3–16 years Visual seizures with elementary visual hallucinations, blindness

17 months 4–30 months Focal, with loss of responsiveness and mild cyanosis

Daytime Hemiclonic Generalized seizures Postictal headache

Daytime –

Sleep Hemiclonic Generalized seizures Transient “sectorial” cognitive impairment CTSW: diphasic, high-voltage (100–300 microvolts) sharps, with a transverse dipole, often followed by a slow wave Not necessary Excellent 15q14 (not confirmed)

Not necessary Excellent –

–

Occipital spikes (fixation off sensitivity)

Midline spikes during sleep

Frequently necessary Uncertain –

Not necessary Excellent –

BECTS, benign epilepsy with centro-temporal spikes; PS, Panayiotopoulos syndrome; ICEO-G, idiopathic childhood occipital epilepsy – Gastaut type; BIMSE, benign infantile midline spikes epilepsy; CTSW, centro-temporal spikes and waves.

incidence ranges between 7.1 and 21 per 100 000 in children under age 15 (Heijbel et al., 1975) with a slight male predominance. Absence of neurological and intellectual deficits is part of the definition, even though BCECTS has also been reported in patients with neuroradiologically documented cerebral lesions (Santanelli et al., 1989). Genetic factors play an important etiological role, as corroborated by the higher incidence of positive family history for epilepsy and focal EEG abnormalities. Linkage to chromosome 15q14 was pointed out (Neubauer et al., 1998), but not confirmed by later studies.

CLINICAL FEATURES Age at onset ranges between 4 and 10 years in 90% of patients, with a peak around 7 years. Seizures occur during sleep in 80% to 90% of patients, and only while awake in less than 10%. Seizure frequency is usually low with 10% of patients experiencing one seizure only (Dalla Bernardina et al., 2005). Duration of seizures commonly ranges from 30 seconds up to no more than

2–3 minutes. Major clinical findings include: (1) orofacial motor signs, especially tonic or clonic contractions of one side of the face with predilection of the labial commissure; (2) speech arrest; (3) sialorrhea, which is not clear whether it is related to increased salivation, swallowing disturbance, or both; and (4) somatosensory symptoms, represented by unilateral numbness or paresthesia of the tongue, lips, gums, and inner cheek. Less frequently ictal manifestations include: (1) clonic jerks involving the arm and the leg of one side, with postictal paresis; and (2) generalized seizures which are not infrequently observed in younger children and probably related to rapid generalization of focal seizures. The benign character of rolandic spikes was recognized in the 1950s (Bancaud et al., 1958). Several longterm follow-up studies confirmed the good prognosis (Loiseau et al., 1988), and over 90% of the cases are in remission by 12 years of age. The prognosis is favorable even for those whose seizures are difficult to control, and seizures almost always remit spontaneously in adolescence. No differences in seizure frequency, seizure

IDIOPATHIC FOCAL EPILEPSIES relapsing, duration of active period of epilepsy, and social adjustments have been found between BCECTS patients receiving an antiepileptic drug (AED) and those left “untreated” (Ambrosetto and Tassinari, 1990). The only predictor of short-term prognosis is the age at BETCS onset: the earlier the onset of seizures, the longer the active period. The occurrence of GTCS seizures after recovery from BCECTS is a rare event, involving approximately 2% of subjects, the same range as relapse with partial seizures (Loiseau and Duche´, 1989). Children with BCECTS are classically considered as free of neuropsychological impairments. However, learning, language, and behavioral disabilities are thought to affect these patients, although much less frequently than in those affected by other forms of childhood epilepsy. We have reviewed a large list of transient neuropsychological impairments seen in children with atypical features of BCECTS (Fejerman, 2009). It is interesting to note that in a study investigating the influence of cognition on the quality of life of 30 children with BCECTS, parental emotional impact was considered the major independent predictor of quality of life (Connolly et al., 2006). On the other hand, even when children with BCECTS show some learning difficulties, the intellectual abilities or behavior disorders did not differ from the healthy children, and a vast majority of the patients are able to attend normal schools. In adolescents and young adults in complete remission from BCECTS there were no significant differences compared with controls in cognitive functions.

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These transient “sectorial” cognitive impairments tend to occur in the active phase of the disease, and seem to be more correlated with the ongoing epileptiform activity in the awake state and particularly during nonREM sleep than with seizure frequency (Deonna, 2000).

EEG PATTERNS The cornerstone of the diagnosis of BCECTS lies in the characteristic interictal EEG pattern. Background EEG activity is normal both in the awake state and during sleep. Interictal epileptic discharges include typical sharp/spike-waves located in centro-temporal or rolandic areas (CTSW). CTSW are broad, diphasic, highvoltage (100–300 microvolts) sharps, with a transverse dipole, and they are often followed by a slow wave (Fig. 61.1A). The spikes may occur isolated or in clusters (Loiseau and Duche´, 1989), and focal rhythmic slow activity is occasionally observed in the same region as the spikes. The spikes may be seen in one or both hemispheres. Bilateral synchronous discharges or independent CTSW appear in wakefulness or sleep in about a third of cases (Engel and Fejerman, 2006) (Fig. 61.1B). A characteristic dipolar EEG pattern has been emphasized. An increase in discharge is observed in drowsiness and all stages of sleep. In about a third of children, the spikes appear only in sleep (Lombroso, 1967). Spikes in other areas, multifocal paroxysms, and spike-wave discharges at the onset or during evolution may also appear (Dalla Bernardina et al., 1991). In some cases, multifocal

Fp2 F4 F4 C4 C4 P4 P4 O2 Fp2 F8 F8 T4

Fp2 F4 F4 C4 C4 P4 P4 O2

T4 T6

Fp2 F8

T6 O2

F8 T4

Fp1 F3

T4 T6

F3 C3 C3 P3 P3 O1 Fp1 F7

T6 O2 Fp1 F3 F3 C3

=C3 P3

P3 O1

F7 T3

Fp1 F7

T3 T5

F7 T3

T5 O1 Fz Cz

T3 T5 T5 O1 Fz Cz

Cz Pz

Cz Pz

ECG1 + ECG1-

ECG1 + ECG1-

MKR + MKR-

MKR + MKR-

A

B

Fig. 61.1. Interictal EEG of a 7-year-old patient with benign epilepsy with centro-temporal spikes. (A) Spikes are evident over left centro-temporal area during wakefulness. (B) During sleep there is an increase in spikes-and-waves, which also involve the right hemisphere.

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paroxysms are especially evident during sleep. Generalized spike-wave discharges are rarely seen in the waking state, but are not infrequent during drowsiness and sleep. Cortical hyperexcitability has been documented also with somatosensory evoked potentials (SEPs): tapping of hands and/or feet or electrical stimulation of the fingers at 1 Hz elicited extreme SEPs on the contralateral hemisphere (De Marco and Tassinari, 1981). Ictal EEG pattern is generally characterized by a sequence of rhythmic spikes remaining quite monomorphous throughout the discharge.

Atypical BCECTS With the term “Atypical BCECTS” we intend to describe a subset of patients who present severe epileptic manifestations with marked language, and/or cognitive, and/or behavior impairments concomitant with severe changes in awake and sleep EEG patterns. Aicardi and Chevrie (1982) first described this condition in seven children with BCECTS presenting periods with new types of seizures, mainly atonic and myoclonic, associated with continuous spike-and-waves in slow-sleep EEG (CSWS/ESES), and transitory deterioration in school performance. They used the term “atypical benign partial epilepsy of childhood” (ABPE). This condition has also been named “pseudo-Lennox syndrome” (Hahn et al., 2004). Actually, ABPE (or pseudo-Lennox syndrome) may be found in both idiopathic and symptomatic cases. ABPE is a particularly severe epileptic condition especially regarding cognitive consequences. Patients with ABPE have significantly lower full-scale and verbal IQ than patients with typical BCECTS. Neuropsychological impairment, which may sometimes be present before the onset of the disease, is constantly present during the clinical course. Long-term follow-up studies showed that verbal deficit remains in all ABPE patients after the remission of the disease, and that the longer the duration of CSWS/ESES pattern the more severe the permanent cognitive impairments (Metz-Lutz and Filippini, 2006). However, in the experience of one of us (NF), in all of the 16 patients with ABPE, seizures remitted and EEG normalized, and none of them presented significant neurocognitive sequelae (Fejerman et al., 2007). Clinical semiology consists of focal motor seizures such as anarthria, dysarthria, sialorrhea, drooling, oromotor dyspraxia, swallowing difficulties, hemifacial contractions, and atonic head nods. Focal atonic events (epileptic negative myoclonus) may be frequent enough to cause limb deficit. Ictal EEG is characterized by bilateral or diffuse spike discharges dominant in the rolandic regions, which may be synchronous

with hemifacial twitching and may be inhibited by voluntary mouth and tongue movements. Interictal awake EEG shows bilateral sharp and sharp-slow wave complexes with higher amplitude in the rolandic area, which increases during sleep with bilateral synchronization.

OTHER ATYPICAL EVOLUTIONS OF BCECTS Besides ABPE, evidence has been presented that patients with BCECTS may present clinical and EEG status lasting from hours to several days, with continuous drooling, and/or anarthria, and/or facial focal motor seizures. Moreover, several cases of Landau–Kleffner syndrome and CSWS syndrome had documented BCECTS before evolving into these epileptic encephalopathies (Fejerman et al., 2000, 2007).

DIAGNOSTIC CRITERIA Criteria for diagnosis include typical rolandic seizures especially during sleep, normal psychomotor and mental development, normal neurological examination, and characteristic awake and sleep EEG pattern, as described above. Awake and sleep EEG investigation is mandatory for diagnosis. A comprehensive neuropsychological assessment also has to be done at the onset of the disease. In fact, any sign of neuropsychological impairment or of learning disorders could be suggestive for atypical evolution. Structural neuroimaging studies, when the clinical and EEG features are typical, have been regarded as superfluous (Arzimanoglou et al., 2004). On the other hand, hippocampal asymmetries and white matter abnormalities on MRI have been reported in 33% of 18 children with BCECTS, even though their etiology was considered unclear (Lundberg et al., 1999). Actually, all the other benign idiopathic childhood focal epilepsies should be considered for differential diagnosis since the morphology of EEG abnormalities may overlap those of BCECTS, and their localization may change throughout the patient’s life. In this context, even though it is rare, the autosomal dominant rolandic epilepsy with speech dyspraxia (Scheffer et al., 1995) should also be considered in the differential diagnosis. Extremely difficult differential diagnosis is posed when the signs or symptoms arise from rolandic–sylvian areas. In the so-called “malignant rolandic–sylvian epilepsy” secondary to neuronal migration disorders and gliosis, in which clinical and EEG features may be similar to BCECTS, the role of magnetoencephalography in the differential diagnosis has been emphasized (Otsubo et al., 2001).

IDIOPATHIC FOCAL EPILEPSIES

TREATMENT When facing the decision whether to treat BCECTS or not, the natural course of the disease should be weighed against the efficacy and the risk of treatment (Bourgeois, 2000). Unfortunately, data available on the natural course of BCECTS are scarce. The active seizure period is less than 1 year in 50% of patients, whereas it lasts more than 6 years in 9.5% of subjects (Loiseau et al., 1988). Seizures are difficult to control with drugs in 40–50% of cases (Ambrosetto and Tassinari, 1990), and they appeared to be frequent in only 6% of patients (Loiseau et al., 1988). For these reasons, many authors suggest that drug treatment is not necessary in typical BCECTS (Dalla Bernardina et al., 2005). On the other hand, Loiseau and Duche (1989) pointed out that medication is advisable in about half the patients. Moreover the presence of neuropsychological impairments, either transitory or persistent must be considered. We believe that decisions about initiation of treatment or withholding therapy must be driven by patient individualization. Parents’ opinion about treatment must also be taken into account as the ictal events are disruptive to the patient or family, but on the other hand drugs may contribute to neuropsychological impairments. The choice of which drug is more suitable is not currently supported by definite evidence. In fact, although carbamazepine (CBZ) has been considered the drug of choice (Fejerman, 2008), class I and class II randomized controlled trials (RCTs) for children with BCECTS are lacking and no AED reaches the highest levels of evidence (level A or B) for efficacy for this population. According to Glauser et al. (2000), based on available efficacy and effectiveness evidence alone, for children with newly diagnosed BCECTS, CBZ and valproate (VPA) may be considered as candidates for initial monotherapy. No clear choice exists between these two AED candidates, for initial monotherapy for children with BCECTS based solely on efficacy or effectiveness. Selection of the initial AED therapy for a child with BCECTS requires integration of patient-specific, AED-specific, and nation-specific variables that can affect overall response to therapy (Glauser et al., 2000). Moreover, the possible worsening of EEG in rolandic epilepsy by some drugs and particularly CBZ, increasing epileptiform abnormalities during sleep and inducing epileptic negative myoclonus, must be taken into account (Parmeggiani et al., 2004). When the presence of ESES (associated or not with negative myoclonus, clinical status, or acquired aphasia) is detected in children with BCECTS, a change of antiepileptic drugs should be considered. Class IV studies suggest that sulthiame, benzodiazepines, ethosuximide, and, in most severe cases, corticosteroids might be

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useful (Fejerman et al., 2007). In all cases the appearance of ESES should increase the level of care in patients, and serial neuropsychological evaluations should be performed even if the continuous spike-and-waves do not reach 85% of the tracing study (Fejerman, 2009).

Panayiotopoulos syndrome Panayiotopoulos syndrome (PS) is a significant childhood epilepsy because of high prevalence, unusual clinical features disguised as nonepileptic events, and overall excellent prognosis despite the frequent occurrence of autonomic status epilepticus (ASE). The clinical, EEG, magnetoencephalographic features, and long-term outcome of Panayiotopoulos syndrome have been confirmed through numerous and independent studies of more than 500 patients mainly from Europe, Argentine, and Japan (Ferrie et al., 2006, 2007; Panayiotopoulos et al., 2008; Michael et al., 2010). PS is a model of autonomic epilepsy specific to childhood characterized by infrequent epileptic seizures manifesting mainly and sometimes exclusively with autonomic symptoms, peak age at onset in early childhood, and an EEG with marked variability of spike localization. Because of its unusual ictal autonomic symptoms, misdiagnosis of PS as encephalitis and other nonepileptic paroxysmal disorders is a problem that raises significant clinical and management implications. Despite converging and multiple sources of evidence of what PS is, there are some recent reports doubting its prevalence, clinical features, localization of epileptogenicity, and differentiation from other epileptic syndromes (Taylor et al., 2008). One source of misunderstanding is that initially PS has been considered to be occipital epilepsy because of interictal EEG features overlapping with the idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) (Panayiotopoulos et al., 2008; Michael et al., 2010). However, these two syndromes have markedly different clinical features. Seizures in PS are infrequent, start with autonomic manifestations, and are long-lasting while seizures in ICOE-G are frequent, start with visual and other symptoms of occipital lobe origin, and are brief. Recognizing that occipital spikes and occipital symptomatology do not define PS, the recent ILAE report on classification and terminology has now discarded the descriptive terminology “early onset occipital epilepsy” in favor of the eponym characterization of PS (Berg et al., 2010). What is also significant is that PS has common links with rolandic epilepsy and ICOE-G, which may be unified under a broader category of “benign childhood seizure susceptibility syndrome,” which is an age-limited idiopathic predisposition to focal seizures and/or EEG abnormalities (Panayiotopoulos et al., 2008;

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Panayiotopoulos, 2010). This condition is attributed to a common, mild, and reversible functional derangement of the brain cortical maturational process, which is probably genetically determined. Genetic contributions are indicated by a 7–30% (10.8% in our study) incidence of epilepsy in first-degree relatives of individuals with PS (Ferrie et al., 1997; Caraballo et al., 2007; Dura´-Trave´ et al., 2008), relatively high prevalence of febrile seizures, and case reports of siblings with PS or PS and rolandic epilepsy (Ferrie et al., 1997; Caraballo et al., 2007; Livingston et al., 2009; Taylor et al., 2008). Cumulative results indicate a high prevalence of febrile seizures (about 17%) (Panayiotopoulos, 2002) in comparison to only 6.5% in our cohort (Specchio et al., 2010). Similar relatively low figures of febrile seizures were also found in other reports, for example Lada and colleagues (2003) reported 4.4%. According to Taylor et al. (2008), PS, like rolandic epilepsy, is probably genetically determined though conventional genetic influences may be less important than other mechanisms. SCN1A mutations have been recently reported in a child and two siblings (Livingston et al., 2009) with a more severe type of PS and strong association with febrile precipitants even after the age of 5 years. This may indicate that SCN1A mutations contribute to a more severe phenotype of PS; no SCN1A mutations were found in two sisters with typical PS, infrequent autonomic seizures, and no febrile precipitants (Panayiotopoulos, 2010).

CLINICAL FEATURES In a recent series (Specchio et al., 2010) prevalence was 5.2% amongst children aged between 1 and 14 years with a first afebrile focal seizure. There were slightly more girls (55.9%) than boys (44.1%) in the study. Age at onset ranged between 1.1 and 8.6 years with a mean of 4.4 (1.6) years, three-quarters (71%) presenting between 3 and 6 years of age. Though cumulative results indicate that both sexes are probably equally affected, a female preponderance of around 56–60% was found in some series (Lada et al., 2003; Dura´-Trave´ et al., 2008; Specchio et al., 2010). There has been a significant debate on the exact prevalence of PS that may reflect awareness and diagnostic precision between authors (Panayiotopoulos et al., 2008; Taylor et al., 2008). In the original cohort of Panayiotopoulos, prevalence was around 13% in children aged 3–6 years with one or more nonfebrile seizures, and 6% in the age group 1–15 years (Panayiotopoulos, 1988). A prevalence of 5% for PS is also indirectly estimated from comparisons with rolandic epilepsy (approximate prevalence of 12%) with a rolandic/PS ratio ranging from 2.1 to 2.9

(median 2.4) in various studies (Panayiotopoulos, 2002; Michael et al., 2010). PS is the most common specific cause of afebrile nonconvulsive status epilepticus in childhood (Okanishi et al., 2008). These figures may be higher when including in the syndrome children who are currently considered to have atypical clinical presentation (Panayiotopoulos, 2002). PS is paradoxically not mentioned in designed controlled epidemiological studies, probably because this syndrome was only recently formally recognized, its features resemble many other conditions, and it often comprises a single seizure only (Panayiotopoulos et al., 2008). All patients with PS have autonomic seizures. Autonomic signs such as malaise, nausea, retching, pallor, or flushing are almost always the first ictal symptoms with children complaining of “feeling sick,” “I want to throw up,” or “tummy-ache.” Vomiting is the most frequent autonomic manifestation. Consciousness at seizure onset is usually intact, becoming gradually impaired during the course of the seizure, with severity fluctuating from mild confusion to total unresponsiveness in most patients. Eyes and/or head deviation, generalized hypotonia, and hemi- or generalized convulsions are the most common nonautonomic symptoms. Syncope-like attacks with the child becoming flaccid and unresponsive are also reported. In others, generalized hypotonia was concomitant with malaise and pallor. Most seizures occur while the child is asleep. Seizure duration is usually long (range 5–90 minutes). Most seizures last more than 30 minutes, meeting the time criterion for status epilepticus. “An autonomic seizure is an epileptic seizure characterized by 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. The altered autonomic function may be objective or subjective or both” (Ferrie et al., 2007). Pure autonomic seizures consist solely of altered autonomic function from onset to the end. In PS, autonomic seizures follow a rather stereotypical pattern in which emesis predominates (Panayiotopoulos, 2002, 2010; Ferrie et al., 2006, 2007). Seizures start while the child is fully conscious and able to speak: he complains of feeling unwell and of nausea prior to the development of more salient autonomic symptoms followed by impairment of consciousness and other nonautonomic seizure manifestations, which may end with generalized convulsions. When seizures occur in sleep, the child either wakes up with similar manifestations, or is found in the middle of a seizure.

IDIOPATHIC FOCAL EPILEPSIES Ictal syncope-like attacks or ictal syncope is another intriguing clinical manifestation of PS (Panayiotopoulos, 2002; Caraballo et al., 2007; Ferrie et al., 2007). The child becomes “completely unresponsive and flaccid like a rag doll,” which may precede or be concurrent with other seizure symptoms or be the sole manifestation of a seizure. They may occur while the patient is standing, sitting, lying down, or asleep and last from 1–2 minutes to half an hour. Relative to the debate on the differential diagnosis between PS and ICOE-G (Panayiotopoulos et al., 2008; Taylor et al., 2008) is the finding that visual symptoms rarely occur in PS (4.3%) (Specchio et al., 2010), they always happen after the onset of autonomic symptoms and they are not consistent in all seizures of the same patient.

EEG PATTERNS Interictal spikes are typically repetitive with high amplitude and their morphology is identical to that of centrotemporal spikes of benign rolandic epilepsy or the occipital paroxysms of the ICOE-G. However, small and single spikes are often seen. Although spikes are most often occipital, they may also be temporal, parietal, central, and frontal, alone or in various combinations (Fig. 61.2). Generalized discharges have also been recorded. Photoparoxysmal abnormalities are reported although rarely. In serial follow-up EEGs, a certain percentage of patients showed shift from the occipital to centro-temporal areas and to frontal areas (Specchio et al., 2010). Ictal EEG is characterized mainly by rhythmic theta activity at onset followed by spikes, poly-spikes, and spike-and-waves with diffusion to both hemispheres.

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Ictal discharge could by occipital, but also frontal and fronto-temporal areas seem to be involved. There is no specific EEG pattern for PS; PS current appears as a multifocal epileptic syndrome with significant EEG variability within given patients and between patients (see discussion in EEG). Historically, of the 21 patients of Panayiotopoulos (1988) with identical clinical manifestations and prognosis only 12 had occipital spikes while the other nine had extra-occipital spikes, brief generalized discharges, and even normal EEG. It is because occipital spikes predominated that subsequent reports emphasized this subset of patients with PS, discounting the other significant group of PS without occipital spikes. It is now well documented that the EEG of PS shows marked variability in terms of localization of focal spikes in one given record and in serial tracings, and that there may be generalized discharges and indeed normal EEGs (Panayiotopoulos, 2002, 2010; Lada et al., 2003; Ferrie et al., 2006, 2007; Caraballo et al., 2007). In about 90% of cases, the EEG reveals mainly multifocal, highamplitude, sharp-slow wave complexes that may appear in any area, often shifting from one region to another in the same or the contralateral hemisphere in sequential EEGs of the same child. Occipital spikes predominate but they do not occur in a third of the patients. Occipital paroxysms in their classical form with fixation-off sensitivity are even rarer. A single routine EEG may be normal in 10% of patients, and a few children have consistently normal EEG. Sleep typically accentuates the spike abnormalities, and photosensitivity is minimal and not clinically relevant. Interictal spikes are typically of high voltage and morphologically identical to the centro-temporal spikes of benign rolandic epilepsy but smaller spikes may occur. Furthermore, EEG foci are not restricted to the occipital

Fp2 F4 F4 C4 C4 P4 P4 O2 Fp2 F8 F8 T4 T4 T6 T6 O2 Fp1 F3 F3 C3 C3 P3 P3 O1 Fp1 F7 F7 T3 T3 T5 T5 O1 Fz Cz Cz Pz ECG1 - ECG1+ MKR + MKR-

Fig. 61.2. Interictal EEG of a 5-year-old patient with Panayiotopoulos syndrome showing bilateral occipital spikes-and-waves.

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regions but frequently shift, multiply, and propagate diffusely with age-related changes, in particular the migration of the EEG focus from the occipital region to the fronto-centro-temporal areas. EEG does not have any prognostic value in PS (Specchio et al., 2010).

Currently, there is no strong evidence indicating the optimal AED in PS, though CBZ appears to be preferred (Ferrie et al., 2006, 2007)

PROGNOSIS AND TREATMENT

Idiopathic childhood occipital epilepsy Gastaut type (ICOE-G) was described by Gastaut who retrospectively identified 36 patients with occipital paroxysms and widely reported them as “a new type of epilepsy: benign partial epilepsy of childhood with occipital spike-waves” (Gastaut, 1982). Fejerman and Caraballo and colleagues proposed the term of late onset childhood occipital epilepsy as the “Gastaut type of benign childhood occipital epilepsy” in order to distinguish it from the “Panayiotopoulos type of early onset benign childhood occipital epilepsy” (Caraballo et al., 2000). The new classification scheme of the ILAE Task Force recognizes this syndrome as “late onset childhood occipital epilepsy (Gastaut type)” (Engel, 2001).

Our findings from the neuropsychological assessment of children with PS revealed normal intelligence quotient (IQ) in all patients (median Full IQ 103, Verbal IQ 102, Performance IQ 104) (Specchio et al., 2010). These findings are particularly important in view of the increasing number of reports emphasizing cognitive, linguistic, and behavioral abnormalities of children with rolandic epilepsy that has significant links with PS (see review in Panayiotopoulos et al., 2008). Compared to matched control children, patients with PS had normal IQ. Also, all patients had normal values in all subtests of WISC-R, which explore attention, shortterm memory, and visual perception functions. However, patients show minor but statistically significant lower scores (always within normal limits) in arithmetic, comprehension, and picture arrangement sub-tests in comparison with controls. These minor deviations are much milder than anticipated considering that 76.5% of patients were on chronic AED treatment, which has a known adverse effect on cognitive functions. The overall conclusions of all reported studies on PS are that IQ is normal in all patients; the most frequent deficit has been found in visual and visuo-perceptual functions. Less frequently some minor attention and memory disturbances have been reported. PS is one of the most benign epilepsy syndromes in terms of seizure frequency and remission. Cumulative results indicate that 40% (range 18–83%) have a single seizure, 48% (41–58%) have 2–5 seizures, and only 5% (3–6%) have more than 10 seizures (Panayiotopoulos, 2002, 2010; Michael et al., 2010). Ninety percent of patients go into complete remission within 1–2 years of onset; the others may have frequent seizures, a protracted active seizure period, and may develop rolandic and less often occipital or other seizures but these are also agerelated and remit. The low frequency of seizures makes it difficult to draw any conclusion about the therapeutic superiority of the AEDs administered. Most children with PS might not need medication as the natural course of PS may only include one seizure. Treatment is suggested for children in whom seizures are frequent or interfere significantly with their quality of life. However, most parents usually request treatment because of the dramatic impact of the semiology of PS and the duration of seizures (Valeta, 2005; Panayiotopoulos et al., 2008).

Idiopathic childhood occipital epilepsy of Gastaut

CLINICAL FEATURES The main features of late onset childhood occipital epilepsy are visual seizures predominantly characterized by elementary visual hallucinations, blindness, or both (Gastaut and Zifkin, 1987). They are usually frequent and diurnal, and they usually last from seconds to 1 to 3 minutes. Elementary visual hallucinations are the most common and most characteristic ictal symptom. They are often the first, and frequently the only, seizure clinical manifestation, which may progress and coexist with other occipital symptoms such as sensory illusions of ocular movements and ocular pain, tonic deviation of the eyes, eyelid fluttering, or repetitive eye closures. Seizures may terminate with hemiconvulsions or generalized convulsions. Ictal blindness usually lasts for 3 to 5 minutes. Deviation of the eyes, usually following elementary visual hallucinations and often associated with ipsilateral turning of the head, is the most common (around 70%) nonvisual symptom (Gastaut, 1982; Gastaut and Zifkin, 1987). Consciousness is preserved during the visual symptoms but may be lost if the seizures progress to other symptoms and convulsions. Postictal headache, sometimes indistinguishable from migraine headache, often occurs in one-third of the patients. Headache, mainly orbital, may occasionally be ictal. Visual seizures are predominantly diurnal and occur at any time of the day. The mean age at onset is 8 years with a range from 3 years to 16 years. Seizures are frequent, occurring at a frequency of several per day or weekly. Late onset childhood occipital epilepsy is rare, with a probable prevalence of 0.2 to 0.9% of all epilepsies, 2 to 7% of benign childhood focal

IDIOPATHIC FOCAL EPILEPSIES seizures, and 10 to 20% of all benign childhood occipital seizures (Panayiotopoulos, 2000). There may be an increased family history of epilepsies or migraine in late onset childhood occipital epilepsy (Gastaut and Zifkin, 1987).

EEG PATTERNS The EEG shows occipital spikes or occipital paroxysms, with or without fixation-off sensitivity. Occipital paroxysms, in routine recordings, occur when the eyes are closed, because of fixation-off sensitivity. Occipital paroxysms occur as soon as and last as long as fixation and central vision are eliminated by several means (Fig. 61.3). These may be (a) eyes closed in a lit room, (b) covering eyes with ordinary commercial underwater goggles with semitransparent tape, and (c) glasses with lenses that prevent fixation.

PROGNOSIS AND TREATMENT Prognosis is unclear, though available data may indicate that remission occurs in more than 60% of patients (Gibbs et al., 1954; Gastaut and Zifkin, 1987). Gulgonen et al. (2000) tested intellectual functioning, attention, memory, academic achievement, visual-motor functioning, and executive functioning in 21 patients with Gastaut type idiopathic occipital lobe epilepsy. There were no significant differences in basic neurophysiological functions between the patients and control groups, although patients’ performance scores were lower in attention (less than 0.01) and memory (less than 0.01), as well as in intellectual functioning (less than 0.05) (Gulgonen et al., 2000). Childhood occipital epilepsy Gastaut type should be treated because seizures, though brief and mild, are frequent. Secondary generalization is probably unavoidable without medication.

Benign infantile focal epilepsy with midline spikes and waves during sleep First Bureau and Maton (1998) and later Capovilla and Beccaria (2000) and Capovilla et al. (2006) described a peculiar form of epilepsy in children, with homogeneous electroclinical features and a benign course. The authors therefore hypothesized that it was a new form of benign focal epilepsy. A distinctive aspect of this condition was that all of the described children presented peculiar interictal EEG abnormalities detectable during sleep and characterized by isolated or grouped spikes and waves ranging from the midline to the central regions. The authors pointed out that the above abnormalities could be an EEG marker, which is clearly distinct from other typical EEG markers of an older age. However, they highlighted that it could not be only an EEG marker since it was found in a group of infants presenting with homogeneous clinical features, thus suggesting a possible new epileptic syndrome. Capovilla proposed to call this syndrome “benign partial epilepsy in infancy and early childhood with midline spikes and waves during sleep” (BIMSE) (Capovilla and Beccaria, 2000; Capovilla et al., 2006). The general features of this condition are neurological and neuroradiological normality, a normal psychomotor development, positive family history, and a benign course in all cases. Regarding clinical features, age at onset is between 4 and 30 months. The frequency of seizures is low, some children having a single episode, and others multiple episodes per year. Seizure duration ranges from 1 to 5 minutes. The episodes usually occur during wakefulness and in a quarter of cases during sleep. The semiology of seizures is characterized by loss of contact – staring as a rule – and cyanosis. Perioral 044

Fp2-F4

599

All seizures stop or are dramatically reduced within days with CBZ (Panayiotopoulos, 1999).

F4-C4 C4-P2 P2-O2 Fp2-F8 F8-T4 T4-T6 T6-O2 Fp1-F3 F3-C3 C3-P1 P1-O1 Fp1-F7 F7-T3 T3-T5 T5-O1 Fz Cz ECG

Fig. 61.3. Interictal EEG of an 8-year-old patient with idiopathic childhood occipital epilepsy Gastaut type: multiple and repetitive spikes are evident over right occipital area induced by eyes closure (fixation-off sensitivity).

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cyanosis and motion arrest are among the main clinical symptoms. In contrast, lateralizing signs and automatisms are rarely observed. EEG is normal when awake, with typical sleep EEG abnormalities, well differentiated from the typical high-voltage diphasic spikes followed by a slow wave, found in benign epilepsy with centrotemporal spikes (Dalla Bernardina et al., 2005). All children reported had a normal development during the follow-up period.

THE AUTOSOMAL DOMINANT ENTITIES Table 61.2 summarizes the main features of all these entities.

Benign familial and nonfamilial infantile seizures Idiopathic focal epilepsies during the first year of life are mainly classified as benign familial and nonfamilial forms of infantile seizures: they are a wide chapter in the context of epilepsy in pediatric age. In the past, seizures with onset during the first months of life were considered as having bad prognosis and symptomatic etiology. After the first description by

Fukuyama (1963), the existence of infantile seizures with a benign evolution has been defined and accepted. Presently, the international classification of epilepsies and epileptic syndromes (Engel, 2001) includes benign infantile seizures, which are divided into familial and nonfamilial forms. In the last years, some variants of these two forms or other similar entities have been described. Idiopathic focal epilepsies in infancy are a group of diseases characterized by onset during the first 2 years in normal children. They could be familial, with a characteristic autosomal dominant trait of inheritance and a typical onset around the sixth month, or nonfamilial, which usually occur later. Seizures are partial with or without secondary generalization and are typically grouped in clusters of many per day. In most cases interictal EEGs are normal. Outcome is always excellent with a normal psychomotor development after seizures. Although cases from all over the world with such a syndrome have been reported, prevalence and incidence remain unknown. In a series described by Caraballo et al. (2003), benign infantile seizures have been listed as the third most common type of epilepsy in the first 2 years of life.

Table 61.2 Main features of autosomal dominant idiopathic focal epilepsy during infancy BNS

BFNS

BFNIS

BFIS

BNFIS

Genetic Onset – typical –range

Sporadic

AD

AD

AD

Sporadic

1st week 1st month

1st week 1st month

5th–6th month 3rd–9th month

3rd–20th month

Type of seizures

Focal with SG

Focal with SG

Within 3rd month 2 days–7th month Focal with SG

Focal with SG

Occurrence

Repetitive

Cluster

Cluster

Other type of epilepsies Other clinical features

–

Repetitive (15% SE) BECTS in 10%

Focal sometimes with SG Cluster

–

–

–

–

Myokymia

–

–

NS – –

NS 20, 8 KCNQ2, KCNQ3

NS 2 SCN2A

Paroxysmal choreoathetosis Migraine NS 16, 19, 2 SCN2A

Interictal EEG Chromosomal loci Genes

NS – –

BNS, benign neonatal seizures; BFNS, benign familial neonatal seizures; BFNIS, benign familial neonatal infantile seizures; BFIS, benign familial infantile seizures; BNFIS, benign nonfamilial infantile seizures; NS, not significant; SG, secondary generalization; SE, status epilepticus; BECTS, benign epilepsy with centro-temporal spikes.

IDIOPATHIC FOCAL EPILEPSIES

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CLINICAL PRESENTATION

BFIS associated with other neurological symptoms

Benign familial infantile seizures

In 1997 Szepetowski et al. (1997) described in four French families an association of BFIS with paroxysmal choreoathetosis appearing later in life, and they proposed a new syndrome called “familial infantile convulsion and choreoathetosis (ICCA).” Linkage to chromosome 16 and dominant transmission were also clearly defined (Szepetowski et al., 1997). Familial hemiplegic migraine (FHM) is a rare, severe autosomal dominant subtype of migraine with aura associated with hemiparesis. Most of the families that have been reported were linked to chromosome 19p13, and had missense mutations in the CACNA1A gene (Ducros et al., 2001). In two families with FHM linked to 1q23, two missense mutations in the ATP1A2 gene were identified (Vanmolkot et al., 2003). Two novel mutations in the ATP1A2 gene were also found. In particular, one mutation was detected in a Dutch-Canadian family, in which FHM was associated with BFIS (Terwindt et al., 1997). In the reported Dutch-Canadian family BFISs were followed at an older age by FHM and concurred to co-segregate to chromosome 1q23. This finding suggests that BFIS may have a wider association with other neurological diseases.

Watanabe et al. (1987) described a series of infants having focal complex seizures with benign evolution. The majority of the above cases were not familial. Most of them presented with clusters of seizures consisting of motion arrest, decreased responsiveness, staring or blank eyes, mostly with simple automatisms, and mild convulsive movements, associated with focal paroxysmal discharges most frequently in the temporal area. All patients showed normal inter-ictal EEG and psychomotor development. In the subsequent years, other reports confirmed this syndrome (Capovilla et al., 1998), also called “benign partial epilepsy in infancy” (Watanabe and Okumura, 2000). In 1992 Vigevano et al. described cases with benign epilepsy in infancy and a family history of similar convulsions: all of them had a benign outcome, and autosomal dominant inheritance, and he suggested the term “benign familial infantile convulsions” (BFIS). In subsequent years, autosomal dominant familial cases have been reported by other authors, confirming the existence of this syndrome (Specchio and Vigevano, 2006). The first series described by Vigevano et al. (1992) consisted of five infants, three girls and two boys. All of them had one or more paternal relatives with a history of seizures occurring at the same age with benign evolution. Age at onset ranged from 4 to 7 months in the probands, whereas in their relatives it was at 4 to 8 months, and peaked around the 6th month. Onset was never in the neonatal age group, nor after the 8th month of life. This syndrome is now included in the last classification and terminology proposed by the ILAE (Engel, 2001) and is termed “benign familial infantile seizures.” Psychomotor development before the onset of seizures is normal for all children. A common characteristic for almost all cases is the occurrence of seizures in a cluster: mostly brief and successive seizures, a maximum of 8 to 10 a day, which did not reach a true status epilepticus. Interictal clinical condition is normal, with occasional somnolence, most probably caused by drugs. Seizures are usually longer at the beginning, lasting 2 to 5 minutes, and become shorter as treatment takes effect. The cluster can last 1 to 3 days. Seizures were clinically characterized by psychomotor arrest, slow deviation of the head and eyes to one side, diffuse hypertonia, cyanosis, and unilateral limb jerks, which became bilateral and synchronous or asynchronous. Although the seizures were highly stereotyped, the direction of the head and eye deviation sometimes changed from seizure to seizure in the same patient.

Benign familial neonatal–infantile seizures A seizure onset occurring between neonatal and infantile ages was reported by Kaplan and Lacey (1983). The age of onset of seizures varied from 2 days to 3.5 months. The authors used the term “benign familial neonatal–infantile seizure” (BFNIS). In 2002 Heron et al. (2002) described two families with afebrile secondary generalized partial seizures occurring between 1.9 and 3.8 months of life and having an autosomal dominant mode of inheritance, and he described a missense mutation in SCN2A, the gene coding for the a2 subunit of the voltage-gated sodium channel. Later, a novel missense mutation in the SCN2A gene was found in five additional similar families: a new sodium channelopathy was identified (Berkovic et al., 2004). The semiology of the seizures was characterized by a predominant focal motor manifestation, with head and eye deviation followed by tonic and clonic movements. Interictal EEGs were normal, or showed some epileptiform discharges in the posterior areas. All patients had a normal development before and after the seizure occurrence. The authors concluded that this peculiar mutation depicts a new sodium channelopathy, despite the possible overlapping with the previously described cases of BFIS.

ETIOLOGY AND BASIC MECHANISMS In familial cases of BFIS, autosomal dominant transmission is evident. Due to the close similarity to benign

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familial neonatal seizures (BFNS), researchers had first tried to find the chromosome markers described in this syndrome. In 1994, Malafosse et al. demonstrated that BFIS is not an allelic form of BFNS, excluding the marker on chromosome 20. In 1997, linkage analysis was carried out in five Italian BFIS families and a locus was mapped on chromosome 19q12-13.1 between markers D19S49 and D19245 (Guipponi et al., 1997). Later, Gennaro et al. (1999) demonstrated the presence of linkage to chromosome 19q, suggesting genetic heterogeneity within the examined families. Studies on familial cases with ICCA are particularly interesting. Szepetowski et al. (1997) demonstrated linkage to the pericentromeric region of chromosome 16 in the families with this syndrome. In 2001, Caraballo et al. (2001) found linkage on chromosome 16p12-q12, the same region as ICCA, in seven families with only benign familial infantile seizures. Therefore, Caraballo hypothesized that chromosome 16p12-q12 is a major genetic locus underlying both benign familial infantile seizures and paroxysmal dyskinesias. Malacarne et al. (2001) mapped a novel locus to chromosome 2q24 in eight Italian families, thus demonstrating a genetic heterogeneity, as in other autosomal dominant idiopathic epilepsies. In cases described as having benign familial neonatal– infantile seizures, an intermediate form between BFIS and benign familial neonatal seizures, a missense mutation in the SCN2A gene was found suggesting the existence of a third form (Berkovic et al., 2004), although a similar mutation of the same gene in a family with clinical features typical of BFIS was reported (Striano et al., 2006). This report would provide new evidence that BFNIS and BFIS may show some overlapping clinical and genetic characteristics. Very recently mutations of protein-rich transmembrane protein 2 (PRRT2) have been identified in families with BFIS, associated or not with paroxysmal kinesigenic dyskinesia (PKD) (Ono et al., 2012; Heron et al., 2012). Almost 90% of families carry mutations in PRRT2 gene (Schubert et al., 2012). This finding confirms the etiology of BFIS and add new insight to the pathogenesis. In the other nonfamilial forms described no clear etiological factors have been described.

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