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Benign familial infantile seizures
Brain & Development 27 (2005) 172–177 www.elsevier.com/locate/braindev
Review article
Benign familial infantile seizures Federico Vigevano* Neurology Department, Bambino Gesu` Children Hospital, Piazza S. Onofrio, 4 Rome, Italy Received 8 August 2003; received in revised form 2 December 2003; accepted 25 December 2003
Abstract In recent years, numerous publications have reported localization-related epilepsy with onset during early infancy, idiopathic etiology and favourable outcome. In 1963, Fukuyama reported cases occurring in the first 2 years of life characterized by partial seizures, absence of etiologic factors and benign outcome. Watanabe studied the localization and semiology of seizures. Later Vigevano and coworkers directed attention to the presence of cases with a family history of convulsions with benign outcome during infancy, with autosomal dominant inheritance, suggesting the term ‘benign infantile familial convulsions’ (BIFC). Similar cases have been described by several authors confirming that this is a new syndrome. In the last ILAE proposal of Classification of Epilepsy Syndromes this entity is called benign familial infantile seizures. Benign infantile seizures are divided now into familial and non-familial forms, although the two forms can overlap. Genetic studies led to the identification of a marker on chromosome 19. This was not confirmed by later studies, and genetic heterogeneity was hypothesized. Recently Malacarne studying eight Italian families with BIFC mapped a novel locus on chromosome 2. In 1997, Szepetowski described the association between BIFC and a later occurrence of paroxysmal choreoathetosis. Following the identification of a specific marker on chromosome 16, this entity constitutes a variant of the familial forms, called infantile convulsions and choreoathetosis. The age at onset, the semeiology of the seizures and the genetic data distinguish the benign familial infantile seizures from the benign familial neonatal seizures. Recent data suggested that this type of epilepsy would be due to a channellopathy. q 2004 Elsevier B.V. All rights reserved. Keywords: Partial seizure; Benign evolution; Autosomal dominant inheritance; Genetic study; Channelopathy
1. Introduction In 1963, Fukuyama [1] reported cases occurring in the first 2 years of life that were characterised by partial seizures, absence of etiologic factors and benign outcome. Later, other reports evidenced the localisation and semiology of seizures [2 – 4], prognosis [5], and presence or absence of familial occurrence [6 – 8]. In particular, on several occasions, Watanabe and coworkers described cases with partial seizures of a different type: partial-epilepsy of infancy with complex partial seizures (BPE with CPS) and benign partial epilepsy with secondarily generalised seizures in infancy (BPE with SGS). Most of these cases were not familial. Vigevano and coworkers directed their attention to cases that exhibited a family history of convulsions with benign outcome during infancy and autosomal dominant inheritance, suggesting the term benign infantile familial * Tel.: þ 39-06-6859-2262; fax: þ39-06-6859-2463. E-mail address: [email protected] (F. Vigevano). 0387-7604/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2003.12.012
convulsions (BIFC). Later, both forms were reported in many different parts of the world [9 –14] confirming that these are a new epileptic syndrome. The ILAE Task Force on Classification and Terminology recently included in the list of epileptic syndromes these entities and suggested that the term ‘seizure’ is preferred to the term ‘convulsion’ [15]. Just as benign seizures with neonatal onset are distinguished in familial and non-familial forms, benign infantile seizures are also now divided into familial and non-familial forms [15]. These two forms may, however, have characteristics that overlap [16]. Genetic studies in familial forms led to the identification of a chromosome marker on chromosome 19 [17]. This was not confirmed by later studies, however, and genetic heterogeneity was hypothesised [18]. In 1997, Szepetowski [19] described the association between BIFC and variably expressed paroxysmal choreoathetosis. The identification of a specific marker on chromosome 16 constituted a variant of the familial forms, called infantile convulsions and choreoathetosis (ICCA). In 2001, Caraballo and colleagues [20] found a linkage of pure BIFC to chromosome 16
F. Vigevano / Brain & Development 27 (2005) 172–177
in the ICCA region, suggesting that this is a major genetic locus underlying both BIFC and paroxysmal choreoathetosis. But at the same time, Malacarne and colleagues found a novel locus on chromosome 2, confirming the genetic heterogeneity of this syndrome. Lastly, in 2002, Heron et al. [21] reported two families with benign familial convulsions with onset around the second month of life, coining the term ‘benign familial neonatal-infantile seizures’ with mutations in the sodiumchannel subunit gene SCN2A. Considering that convulsive manifestations are limited to a short period of time, some authors hypothesised the existence of particular etiological factors in some sporadic cases. These hypotheses appear in reports of cases of benign infantile convulsions associated with prolonged episodes of diarrhoea caused by rotavirus infections [22 – 24]. A clear cause – effect relation is still to be demonstrated.
2. Clinical and EEG data All reported cases have in common fundamental clinical elements. This clinical entity is characterised by partial seizures in clusters, with subacute onset, in children in the first or second year of life, without clear etiological factors, and with completely normal psychomotor development. Age at onset has been reported from 3 to 20 months of age, but in the familial forms it occurs mostly between 4 and 7 months. Only McCallenbach et al. [14] observed a lower age at onset ranging from 6 weeks to 10 months. However, Heron et al. [21] considered familial cases with earlier onset to be an intermediate variant between the neonatal and infantile forms. Findings for all etiological investigations, especially infectious and metabolic tests, and neuroimaging
173
examination, were normal. Histories of pregnancy and delivery were unremarkable. Familial cases include relatives of first and second degree who had benign infantile convulsions (Fig. 1) without subsequent development of other forms of epilepsy. The incidence in these families of other idiopathic epilepsies and febrile convulsions does not differ from that of the general population and there were no reports of convulsions in the neonatal period. The disorder seems to be transmitted with autosomal dominant inheritance. Greater incidence among females was reported for familial forms, but this prevalence was not confirmed among the relatives [7]. The clinical characteristics of the syndrome are summarised in Table 1. All children had absolutely normal psychomotor development before the onset of seizures. An almost constant characteristic was the occurrence of seizures in a cluster: mostly brief, successive seizures, maximum of 8– 10 daily, which did not reach a true status epilepticus. Interictal clinical condition was normal, with occasional sopor that could be attributed mostly to drug treatments. Isolated seizures in the 10– 15 days before the cluster were reported in about one-third of the cases. Seizures were usually longer in the beginning, lasting 2 –5 min, and became shorter as treatment took effect. The cluster could last 1 –3 days. As concerns the semiology of the seizures, it is difficult to say if there are real differences between the sporadic and familial forms. Elements common to both forms include motor arrest, impairment of consciousness, staring and convulsive movements. Watanabe [3] stressed the presence of limb or oral and facial automatisms in cases described as BPE with CPS, and of prompt generalisation with tonic – clonic manifestations in cases described as BPE with SGS [4]. On the other hand, in addition to the symptoms already described, Vigevano documented the presence during
Fig. 1. Family tree of a case with benign infantile familial convulsions (published with the permission of Giordano et al.).
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Table 1 Clinical characteristics of benign infantile familial seizures † Family history of seizures with a benign course and similar age at onset † Normal development before onset † Onset between the ages 3 and 10 months † No underlying disorders or neurologic abnormalities † Seizures in a cluster † Partial seizures localised in the occipito-parietal areas † Normal interictal EEG † Benign course † Normal developmental outcome
seizures of slow deviation of head and eyes to one side, diffuse hypertonia, cyanosis and unilateral limb jerks that began unilaterally and were synchronous or asynchronous [7]. The side of the head and eye deviation sometimes changed from seizure to seizure in the same patient.
Because outcome is benign, it is theoretically possible not to treat these patients. In practice, however, withholding treatment is not easy for various reasons: most patients have recurring seizures (seizures every 2– 3 h); patients not treated after the first cluster of seizures can have other seizures or clusters; diagnosis is not simple at onset, except for the familial forms. In familial cases, the decision to withhold treatment can be made more easily. However, there are reports in the literature of equally effective treatment with carbamazepine, phenobarbital, valproate or zonisamide for periods varying from 1 to 5 years. Generally, no further seizures are observed in cases treated pharmacologically. In untreated cases, there can be isolated or brief clusters within 1 year of age. In cases associated with paroxysmal choreoathetosis, the clinical picture of infantile seizures is the same as that already described. Choreoathetotic movements start during
Fig. 2. Two seizures recorded in the same patient 2 h apart. (A) The seizure onset is in the right parieto-occipital area; (B) the seizure onset is in the left parietooccipital area. See text for description of clinical manifestations.
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infancy or childhood, are of dystonic type, occur at rest or can be induced by exertion or anxiety [19]. When described, interictal EEG before and after the cluster is normal. We reported lateralised slow waves and spikes in the occipito-parietal areas in the interictal EEG performed during a cluster of seizures. In the presence of secondary generalisation, ictal EEG disclosed a focal discharge characterised by recruiting rhythm of increasing amplitude spreading over the hemisphere and involving the entire brain. The alternating clinical pattern, was confirmed by recordings in the same patient of seizures with onset occurring sometimes on the right hemisphere, sometimes on the left (Fig. 2). The site of origin of the seizures seems to be a distinguishing characteristic. According to Watanabe, the site of origin in the cases described as BPE with CPS [3] is the temporal area, while the site varies in cases described as BPE with SGS [4]. In familial cases, the seizures originate in the parieto-occipital area, with the side varying from one seizure to another [7]. Actually, in 2001, while comparing cases with familial and non-familial benign infantile convulsions, Lispi et al. [16] found that the site of origin is not a statistically significant distinction between the two groups.
3. Differential diagnosis The brutal onset of seizures in clusters led to the search for particular etiological factors, especially in the sporadic cases, but alterations of metabolic or infectious nature were never identified and neuroimaging findings were always normal. There have been reports of very similar clinical pictures closely associated with episodes of diarrhoea caused by rotavirus infection, but in these cases there is no clear evidence that diarrhoea is the etiological factor of the seizure [22 –24]. A simple casual coincidence cannot be excluded. Autosomal dominant transmission is evident in the familial cases. Because of the strong similarity to benign neonatal familial convulsions (BNFC), researchers at first tried to find the chromosome markers described in this syndrome [25,26]. In 1994, Malafosse demonstrated that BIFC is not an allelic form of BNFC, excluding the marker on chromosome 20 [27]. In 1997, linkage analysis was carried out in five Italian BIFC families and a locus was mapped on chromosome 19q12-13.1 between markers D19S49 and D19245 [17]. Later, in a linkage analysis of seven families of Italian origin, Gennaro and co-workers [18] demonstrated the presence of linkage to chromosome 19q in a single family, suggesting genetic heterogeneity within the families examined. The studies on familial cases with ICCA are especially interesting. In 1997, Szepetowski [19] demonstrated linkage to the pericentromeric region of
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chromosome 16 in four French families with this syndrome. This finding was later confirmed by Lee and co-workers [28] in a family of Chinese origin. In 2001, Caraballo et al. found linkage on chromosome 16p12-q12, the same region as ICCA, in seven families with only benign familial infantile convulsions. Considering that a previous report described a large family affected by paroxysmal kinesigenic dyskinesia without infantile convulsions, with linkage to the ICCA region [29], Caraballo hypothesised that chromosome 16p12-q12 is a major genetic locus underlying both benign familial infantile convulsions and paroxysmal dyskinesias. At approximately the same time, while studying eight Italian families with benign familial infantile convulsions, Malacarne et al. [30] mapped a novel locus to chromosome 2q24, thus demonstrating a genetic heterogeneity, as in other autosomal dominant idiopathic epilepsies. Sporadic and familial benign idiopathic seizures may appear in the neonatal period [31,32]; similarly, sporadic and familial idiopathic seizures may appear in the first year of life, especially around the sixth month. There are many clinical similarities between the two forms, since they are both seizures in clusters limited to a short period of life, with benign outcome and autosomal dominant inheritance. A possible association with late onset motor manifestation [33] has been reported also for benign neonatal familial convulsions. In 1988, two genetic mutations KCNQ2 and KCNQ3, respectively, were identified in this form [34,35], both associated with potassium channels. For this reason, benign neonatal familial seizures are currently considered a potassium channellopathy. By analogy, we can hypothesise that BFIC are also a channellopathy. As support for this hypothesis, it must be remembered that in 2002 Heron et al. [21] reported the presence of a mutation in the sodium-channel subunit gene SCN2A in two families with seizure onset between 1 and 3 months of life, therefore intermediate between neonatal and infantile forms. The authors coined the term ‘benign familial neontal-infantile seizures’ for their cases; however, at the present time it is difficult to sustain the existence of a third clinical form. In the first year of life, familial convulsions may be caused by pyridoxine dependency or deficiency [36]. However, in this disorder, convulsions resistant to treatment appear in the first days of life and the clinical condition is always severe. Lastly, Capovilla and Beccaria recently described 12 nonfamilial cases with benign partial epilepsy with onset in infancy and early childhood with vertex spikes and waves during sleep on EEG [37]. This form differs from benign infantile convulsions because of later onset (13 – 30 months), less frequent seizures rarely in clusters, lack of ictal automatisms and presence of peculiar interictal EEG anomalies.
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4. Conclusion The diagnosis of benign infantile epilepsy with partial seizures is still difficult [38]. Early diagnosis is possible only in the familial forms. In the sporadic forms with either complex partial or secondarily generalised seizures, diagnosis can be suspected in consideration of the criteria presented above, with exclusion of any possible etiologic factor. It is obvious that in sporadic cases, hypothetical diagnosis can be confirmed only with the demonstration of benign outcome. The familial forms are dominant. Definitive identification of the genetic marker will probably be possible in the near future. It can be hypothesised that epileptic seizures are particularly likely to appear during this period of life. It should not be forgotten that other forms of cryptogenic or symptomatic epilepsy, especially infantile spasms, also appear during this period. This could explain why subjects with a specific genetic predisposition have seizures in this period of life. With the exclusion of any etiological or favouring factor in the sporadic cases, and consequently the symptomatic nature of these seizures, we must, in any case, hypothesise the existence of a genetic predisposition to convulsions, even if non-specific. We cannot even exclude the possibility that the sporadic cases are actually identical to the familial ones, only with less expressivity.
References [1] Fukuyama Y. Borderland of epilepsy with special reference to febrile convulsions and so-called infantile convulsions. Seishin-Igaku (Clin Psychiatry) 1963;5:211–23. [2] Watanabe K, Yamamoto N, Negoro T, Takaesu E, Aso K, Furune S, et al. Benign complex partial epilepsies in infancy. Pediatr Neurol 1987;3:208 –11. [3] Watanabe K, Yamamoto N, Negoro T, Takahashi I, Aso K, Maehara M. Benign infantile epilepsy with complex partial seizures. J Clin Neurophysiol 1990;7:409– 16. [4] Watanabe K, Negoro T, Aso K. Benign partial epilepsy with secondarily generalized seizures in infancy. Epilepsia 1993;34: 635 –8. [5] Sugiura M, Matsumoto A, Watanabe K, Negoro T, Takaesu E, Iwase K. Long-term prognosis of generalized convulsions in the first year of life, with special reference to benign infantile convulsions. Jpn J Epil Soc 1983;1:116–21. [6] Vigevano F, Di Capua M, Fusco L, Ricci S, Sebastianelli R, Lucchini P. Sixth-month benign familial convulsions. Epilepsy Res Suppl 1992;6:127 –9. [7] Vigevano F, Fusco L, Di Capua M, Ricci S, Sebastianelli R, Lucchini P. Benign infantile familial convulsions. Eur J Pediatr 1992;151: 608–12. [8] Vigevano F, Sebastianelli R, Fusco L, Di Capua M, Ricci S, Lucchini P, et al. Benign infantile familial convulsions. In: Malafosse A, Genton P, Hirsch E, Marescaux C, Broglin D, Bernasconi R, editors. Idiopathic generalized epilepsies: clinical, experimental and genetic aspects. London: John Libbey; 1994. p. 45–9. [9] Lee WL, Low PS, Rajan U. Benign familial infantile epilepsy. J Pediatr 1993;123:588 –90.
[10] Luovigsson P, Olafsson E, Rich SS, Johannesson G, Anderson VE. Benign infantile familial epilepsy: three families with multiple affected members in three generations. Epilepsia 1993; 34(Suppl 2):18. [11] Echenne B, Humbertclaude V, Rivier F, Malafosse A, Cheminal R. Benign infantile epilepsy with autosomal dominant inheritance. Brain Dev 1994;16:108 –11. [12] Capovilla G, Giordano L, Tiberti S, Valseriati D, Menegati E. Benign partial epilepsy in infancy with complex partial seizures (Watanabe’s syndrome): 12 non-Japanese new cases. Brain Dev 1998;20:105–11. [13] Giordano L, Accorsi P, Valseriati D, Tiberti A, Menegati E, Zara F, et al. Benign infantile familial convulsions: natural history of a case and clinical characteristics of a large Italian family. Neuropediatrics 1999;30:99–101. [14] Mc Callenbach P, De Coo RFM, Vein AA, Arts WFM, Oosterwijk JC, Hageman G, et al. Benign familial infantile convulsions: a clinical study of seven Dutch families. Eur J Paediatr Neurol 2002; 6:269–83. [15] Engel Jr. J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on classification and terminology. Epilepsia 2001;42:796–803. [16] Lispi ML, Cusmai R, Vigevano F. Benign partial epilepsy in infancy: sporadic versus familial forms. Ann Neurol 2001;(Suppl 1):102. [17] Guipponi M, Rivier F, Vigevano F, Beck C, Crespel A, Echenne B, et al. Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19. Hum Mol Genet 1997;6:473–7. [18] Gennaro E, Malacarne M, Carbone I, Riggio MC, Bianchi A, Bonanni P, et al. No evidence of a major locus for benign familial infantile convulsions on chromosome 19q12-q13.1. Epilepsia 1999;40: 1799–803. [19] Szepetowski P, Rochette J, Berquin P, Piussan C, Lathrop GM, Monaco AP. Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16. Am J Hum Genet 1997;61: 889 –98. [20] Caraballo R, Pavek S, Lemainque A, Gastaldi M, Echenne B, Motte J, et al. Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am J Hum Genet 2001;68: 788 –94. [21] Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, Bleasel A, et al. Sodium-channel defects in benign familial neonatalinfantile seizures. Lancet 2002;360:851– 2. [22] Itou J, Takahashi Y, Kusunoki Y, Oki J, Chou K. Convulsions associated with mild acute diarrhea. Shounika-Rinsho (Jpn J Pediatr) 1988;41:2011–5. [23] Contino MF, Lebby T, Arcinue EL. Rotaviral gastrointestinal infection causing afebrile seizures in infancy and childhood. Am J Emerg Med 1994;12:94– 5. [24] Imai K, Otani K, Yanagihara K, Li Z, Futagi Y, Ono J, et al. Ictal video-EEG recording of three partial seizures in a patient with the benign infantile convulsions associated with mild gastroenteritis. Epilepsia 1999;40:1455– 8. [25] Leppert M, Anderson VE, Quattlebaum T, Stauffer D, O’Connell P, Nakamura Y, et al. Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 1989;337:647–8. [26] Ryan SG, Wiznitzer M, Hollman C, Torres MC, Szekeresova M, Schneider S. Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity. Ann Neurol 1991;29:469–73. [27] Malafosse A, Beck C, Bellet H, Di Capua M, Dulac O, Echenne B, et al. Benign infantile familial convulsions are not an allelic form of the benign familial neonatal convulsions gene. Ann Neurol 1994;35: 479 –82. [28] Lee WL, Tay A, Ong HT, Goh LM, Monaco AP, Szepetowski P. Association of infantile convulsions with paroxysmal dyskinesias
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[29]
[30]
[31] [32]
[33]
(ICCA syndrome): confirmation of linkage to human chromosome 16p12-q12 in a Chinese family. Hum Genet 1998;103:608– 12. Bennett LB, Roach ES, Bowcock AM. A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16. Neurology 2000;54:125– 30. Malacarne M, Gennaro E, Madia F, Pozzi S, Vacca D, Barone B, et al. Benign familial infantile convulsions: mapping of a novel locus on chromosome 2q24 and evidence for genetic heterogeneity. Am J Hum Genet 2001;68:1521 –6. Miles DK, Holmes GL. Benign neonatal seizures. J Clin Neurophysiol 1990;7:369–79. Plouin P. Benign neonatal convulsions (familial and nonfamilial). In: Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey; 1985. p. 2–11. Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ, Steinlein OK. Myokymia and neonatal epilepsy caused by a mutation in the voltage
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sensor of the KCNQ2 Kþ channel. Proc Natl Acad Sci USA 2001;98: 12272– 7. Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18:25 –9. Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, Leppert M. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998;18: 53–5. Bankier A, Turner M, Hopkins IJ. Pyridoxine-dependent seizures: a wider clinical spectrum. Arch Dis Child 1983;58:415–8. Capovilla G, Beccaria F. Benign partial epilepsy in infancy and early childhood with vertex spikes and waves during sleep: a new epileptic form. Brain Dev 2000;22:93– 8. Okumura A, Hayakawa F, Kato T, Kuno K, Negoro T, Watanabe K. Early recognition of benign partial epilepsy in infancy. Epilepsia 2000;41:714 –7.
Review article
Benign familial infantile seizures Federico Vigevano* Neurology Department, Bambino Gesu` Children Hospital, Piazza S. Onofrio, 4 Rome, Italy Received 8 August 2003; received in revised form 2 December 2003; accepted 25 December 2003
Abstract In recent years, numerous publications have reported localization-related epilepsy with onset during early infancy, idiopathic etiology and favourable outcome. In 1963, Fukuyama reported cases occurring in the first 2 years of life characterized by partial seizures, absence of etiologic factors and benign outcome. Watanabe studied the localization and semiology of seizures. Later Vigevano and coworkers directed attention to the presence of cases with a family history of convulsions with benign outcome during infancy, with autosomal dominant inheritance, suggesting the term ‘benign infantile familial convulsions’ (BIFC). Similar cases have been described by several authors confirming that this is a new syndrome. In the last ILAE proposal of Classification of Epilepsy Syndromes this entity is called benign familial infantile seizures. Benign infantile seizures are divided now into familial and non-familial forms, although the two forms can overlap. Genetic studies led to the identification of a marker on chromosome 19. This was not confirmed by later studies, and genetic heterogeneity was hypothesized. Recently Malacarne studying eight Italian families with BIFC mapped a novel locus on chromosome 2. In 1997, Szepetowski described the association between BIFC and a later occurrence of paroxysmal choreoathetosis. Following the identification of a specific marker on chromosome 16, this entity constitutes a variant of the familial forms, called infantile convulsions and choreoathetosis. The age at onset, the semeiology of the seizures and the genetic data distinguish the benign familial infantile seizures from the benign familial neonatal seizures. Recent data suggested that this type of epilepsy would be due to a channellopathy. q 2004 Elsevier B.V. All rights reserved. Keywords: Partial seizure; Benign evolution; Autosomal dominant inheritance; Genetic study; Channelopathy
1. Introduction In 1963, Fukuyama [1] reported cases occurring in the first 2 years of life that were characterised by partial seizures, absence of etiologic factors and benign outcome. Later, other reports evidenced the localisation and semiology of seizures [2 – 4], prognosis [5], and presence or absence of familial occurrence [6 – 8]. In particular, on several occasions, Watanabe and coworkers described cases with partial seizures of a different type: partial-epilepsy of infancy with complex partial seizures (BPE with CPS) and benign partial epilepsy with secondarily generalised seizures in infancy (BPE with SGS). Most of these cases were not familial. Vigevano and coworkers directed their attention to cases that exhibited a family history of convulsions with benign outcome during infancy and autosomal dominant inheritance, suggesting the term benign infantile familial * Tel.: þ 39-06-6859-2262; fax: þ39-06-6859-2463. E-mail address: [email protected] (F. Vigevano). 0387-7604/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2003.12.012
convulsions (BIFC). Later, both forms were reported in many different parts of the world [9 –14] confirming that these are a new epileptic syndrome. The ILAE Task Force on Classification and Terminology recently included in the list of epileptic syndromes these entities and suggested that the term ‘seizure’ is preferred to the term ‘convulsion’ [15]. Just as benign seizures with neonatal onset are distinguished in familial and non-familial forms, benign infantile seizures are also now divided into familial and non-familial forms [15]. These two forms may, however, have characteristics that overlap [16]. Genetic studies in familial forms led to the identification of a chromosome marker on chromosome 19 [17]. This was not confirmed by later studies, however, and genetic heterogeneity was hypothesised [18]. In 1997, Szepetowski [19] described the association between BIFC and variably expressed paroxysmal choreoathetosis. The identification of a specific marker on chromosome 16 constituted a variant of the familial forms, called infantile convulsions and choreoathetosis (ICCA). In 2001, Caraballo and colleagues [20] found a linkage of pure BIFC to chromosome 16
F. Vigevano / Brain & Development 27 (2005) 172–177
in the ICCA region, suggesting that this is a major genetic locus underlying both BIFC and paroxysmal choreoathetosis. But at the same time, Malacarne and colleagues found a novel locus on chromosome 2, confirming the genetic heterogeneity of this syndrome. Lastly, in 2002, Heron et al. [21] reported two families with benign familial convulsions with onset around the second month of life, coining the term ‘benign familial neonatal-infantile seizures’ with mutations in the sodiumchannel subunit gene SCN2A. Considering that convulsive manifestations are limited to a short period of time, some authors hypothesised the existence of particular etiological factors in some sporadic cases. These hypotheses appear in reports of cases of benign infantile convulsions associated with prolonged episodes of diarrhoea caused by rotavirus infections [22 – 24]. A clear cause – effect relation is still to be demonstrated.
2. Clinical and EEG data All reported cases have in common fundamental clinical elements. This clinical entity is characterised by partial seizures in clusters, with subacute onset, in children in the first or second year of life, without clear etiological factors, and with completely normal psychomotor development. Age at onset has been reported from 3 to 20 months of age, but in the familial forms it occurs mostly between 4 and 7 months. Only McCallenbach et al. [14] observed a lower age at onset ranging from 6 weeks to 10 months. However, Heron et al. [21] considered familial cases with earlier onset to be an intermediate variant between the neonatal and infantile forms. Findings for all etiological investigations, especially infectious and metabolic tests, and neuroimaging
173
examination, were normal. Histories of pregnancy and delivery were unremarkable. Familial cases include relatives of first and second degree who had benign infantile convulsions (Fig. 1) without subsequent development of other forms of epilepsy. The incidence in these families of other idiopathic epilepsies and febrile convulsions does not differ from that of the general population and there were no reports of convulsions in the neonatal period. The disorder seems to be transmitted with autosomal dominant inheritance. Greater incidence among females was reported for familial forms, but this prevalence was not confirmed among the relatives [7]. The clinical characteristics of the syndrome are summarised in Table 1. All children had absolutely normal psychomotor development before the onset of seizures. An almost constant characteristic was the occurrence of seizures in a cluster: mostly brief, successive seizures, maximum of 8– 10 daily, which did not reach a true status epilepticus. Interictal clinical condition was normal, with occasional sopor that could be attributed mostly to drug treatments. Isolated seizures in the 10– 15 days before the cluster were reported in about one-third of the cases. Seizures were usually longer in the beginning, lasting 2 –5 min, and became shorter as treatment took effect. The cluster could last 1 –3 days. As concerns the semiology of the seizures, it is difficult to say if there are real differences between the sporadic and familial forms. Elements common to both forms include motor arrest, impairment of consciousness, staring and convulsive movements. Watanabe [3] stressed the presence of limb or oral and facial automatisms in cases described as BPE with CPS, and of prompt generalisation with tonic – clonic manifestations in cases described as BPE with SGS [4]. On the other hand, in addition to the symptoms already described, Vigevano documented the presence during
Fig. 1. Family tree of a case with benign infantile familial convulsions (published with the permission of Giordano et al.).
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Table 1 Clinical characteristics of benign infantile familial seizures † Family history of seizures with a benign course and similar age at onset † Normal development before onset † Onset between the ages 3 and 10 months † No underlying disorders or neurologic abnormalities † Seizures in a cluster † Partial seizures localised in the occipito-parietal areas † Normal interictal EEG † Benign course † Normal developmental outcome
seizures of slow deviation of head and eyes to one side, diffuse hypertonia, cyanosis and unilateral limb jerks that began unilaterally and were synchronous or asynchronous [7]. The side of the head and eye deviation sometimes changed from seizure to seizure in the same patient.
Because outcome is benign, it is theoretically possible not to treat these patients. In practice, however, withholding treatment is not easy for various reasons: most patients have recurring seizures (seizures every 2– 3 h); patients not treated after the first cluster of seizures can have other seizures or clusters; diagnosis is not simple at onset, except for the familial forms. In familial cases, the decision to withhold treatment can be made more easily. However, there are reports in the literature of equally effective treatment with carbamazepine, phenobarbital, valproate or zonisamide for periods varying from 1 to 5 years. Generally, no further seizures are observed in cases treated pharmacologically. In untreated cases, there can be isolated or brief clusters within 1 year of age. In cases associated with paroxysmal choreoathetosis, the clinical picture of infantile seizures is the same as that already described. Choreoathetotic movements start during
Fig. 2. Two seizures recorded in the same patient 2 h apart. (A) The seizure onset is in the right parieto-occipital area; (B) the seizure onset is in the left parietooccipital area. See text for description of clinical manifestations.
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infancy or childhood, are of dystonic type, occur at rest or can be induced by exertion or anxiety [19]. When described, interictal EEG before and after the cluster is normal. We reported lateralised slow waves and spikes in the occipito-parietal areas in the interictal EEG performed during a cluster of seizures. In the presence of secondary generalisation, ictal EEG disclosed a focal discharge characterised by recruiting rhythm of increasing amplitude spreading over the hemisphere and involving the entire brain. The alternating clinical pattern, was confirmed by recordings in the same patient of seizures with onset occurring sometimes on the right hemisphere, sometimes on the left (Fig. 2). The site of origin of the seizures seems to be a distinguishing characteristic. According to Watanabe, the site of origin in the cases described as BPE with CPS [3] is the temporal area, while the site varies in cases described as BPE with SGS [4]. In familial cases, the seizures originate in the parieto-occipital area, with the side varying from one seizure to another [7]. Actually, in 2001, while comparing cases with familial and non-familial benign infantile convulsions, Lispi et al. [16] found that the site of origin is not a statistically significant distinction between the two groups.
3. Differential diagnosis The brutal onset of seizures in clusters led to the search for particular etiological factors, especially in the sporadic cases, but alterations of metabolic or infectious nature were never identified and neuroimaging findings were always normal. There have been reports of very similar clinical pictures closely associated with episodes of diarrhoea caused by rotavirus infection, but in these cases there is no clear evidence that diarrhoea is the etiological factor of the seizure [22 –24]. A simple casual coincidence cannot be excluded. Autosomal dominant transmission is evident in the familial cases. Because of the strong similarity to benign neonatal familial convulsions (BNFC), researchers at first tried to find the chromosome markers described in this syndrome [25,26]. In 1994, Malafosse demonstrated that BIFC is not an allelic form of BNFC, excluding the marker on chromosome 20 [27]. In 1997, linkage analysis was carried out in five Italian BIFC families and a locus was mapped on chromosome 19q12-13.1 between markers D19S49 and D19245 [17]. Later, in a linkage analysis of seven families of Italian origin, Gennaro and co-workers [18] demonstrated the presence of linkage to chromosome 19q in a single family, suggesting genetic heterogeneity within the families examined. The studies on familial cases with ICCA are especially interesting. In 1997, Szepetowski [19] demonstrated linkage to the pericentromeric region of
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chromosome 16 in four French families with this syndrome. This finding was later confirmed by Lee and co-workers [28] in a family of Chinese origin. In 2001, Caraballo et al. found linkage on chromosome 16p12-q12, the same region as ICCA, in seven families with only benign familial infantile convulsions. Considering that a previous report described a large family affected by paroxysmal kinesigenic dyskinesia without infantile convulsions, with linkage to the ICCA region [29], Caraballo hypothesised that chromosome 16p12-q12 is a major genetic locus underlying both benign familial infantile convulsions and paroxysmal dyskinesias. At approximately the same time, while studying eight Italian families with benign familial infantile convulsions, Malacarne et al. [30] mapped a novel locus to chromosome 2q24, thus demonstrating a genetic heterogeneity, as in other autosomal dominant idiopathic epilepsies. Sporadic and familial benign idiopathic seizures may appear in the neonatal period [31,32]; similarly, sporadic and familial idiopathic seizures may appear in the first year of life, especially around the sixth month. There are many clinical similarities between the two forms, since they are both seizures in clusters limited to a short period of life, with benign outcome and autosomal dominant inheritance. A possible association with late onset motor manifestation [33] has been reported also for benign neonatal familial convulsions. In 1988, two genetic mutations KCNQ2 and KCNQ3, respectively, were identified in this form [34,35], both associated with potassium channels. For this reason, benign neonatal familial seizures are currently considered a potassium channellopathy. By analogy, we can hypothesise that BFIC are also a channellopathy. As support for this hypothesis, it must be remembered that in 2002 Heron et al. [21] reported the presence of a mutation in the sodium-channel subunit gene SCN2A in two families with seizure onset between 1 and 3 months of life, therefore intermediate between neonatal and infantile forms. The authors coined the term ‘benign familial neontal-infantile seizures’ for their cases; however, at the present time it is difficult to sustain the existence of a third clinical form. In the first year of life, familial convulsions may be caused by pyridoxine dependency or deficiency [36]. However, in this disorder, convulsions resistant to treatment appear in the first days of life and the clinical condition is always severe. Lastly, Capovilla and Beccaria recently described 12 nonfamilial cases with benign partial epilepsy with onset in infancy and early childhood with vertex spikes and waves during sleep on EEG [37]. This form differs from benign infantile convulsions because of later onset (13 – 30 months), less frequent seizures rarely in clusters, lack of ictal automatisms and presence of peculiar interictal EEG anomalies.
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4. Conclusion The diagnosis of benign infantile epilepsy with partial seizures is still difficult [38]. Early diagnosis is possible only in the familial forms. In the sporadic forms with either complex partial or secondarily generalised seizures, diagnosis can be suspected in consideration of the criteria presented above, with exclusion of any possible etiologic factor. It is obvious that in sporadic cases, hypothetical diagnosis can be confirmed only with the demonstration of benign outcome. The familial forms are dominant. Definitive identification of the genetic marker will probably be possible in the near future. It can be hypothesised that epileptic seizures are particularly likely to appear during this period of life. It should not be forgotten that other forms of cryptogenic or symptomatic epilepsy, especially infantile spasms, also appear during this period. This could explain why subjects with a specific genetic predisposition have seizures in this period of life. With the exclusion of any etiological or favouring factor in the sporadic cases, and consequently the symptomatic nature of these seizures, we must, in any case, hypothesise the existence of a genetic predisposition to convulsions, even if non-specific. We cannot even exclude the possibility that the sporadic cases are actually identical to the familial ones, only with less expressivity.
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