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Early infantile epileptic encephalopathy with unusual favourable outcome
Brain & Development 32 (2010) 673–676 www.elsevier.com/locate/braindev
Case report
Early infantile epileptic encephalopathy with unusual favourable outcome Marı´a Rosario Cazorla a,*, Alfonso Verdu´ b, Carmen Montes c, Fernando Ayuga b a
Neuropediatric Unit, Puerta de Hierro Majadahonda Hospital, Madrid, Spain b Neuropediatric Unit, Virgen de la Salud Hospital, Toledo, Spain c Neurophysiology Department, Virgen de la Salud Hospital, Toledo, Spain
Received 15 February 2009; received in revised form 14 August 2009; accepted 24 August 2009
Abstract The authors report the case of an infant suffered from early infantile epileptic encephalopathy with suppression–burst, or Ohtahara syndrome, a severe form of epilepsy in early childhood. The patient was treated with vigabatrin causing a favourable response. This unusual outcome may be related with the normality of neuroimaging and metabolic studies, as happens with idiopathic West syndrome cases. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Ohtahara syndrome; Suppression–burst pattern; Vigabatrine
1. Introduction
2. Case report
Ohtahara syndrome (OS) or early infantile epileptic encephalopathy with suppression–burst (EIEE) is characterized by the onset within the first months of life, of tonic spasms seizures and a suppression–burst electroencephalogram (EEG) pattern in both awaking and sleeping states. Firstly described by Ohtahara et al. [1], the seizures are usually refractory to antiepileptic therapy and the prognosis is poor, with severe psychomotor retardation. We report the case of an infant with tonic spasms and a burst–suppression EEG pattern consistent with the diagnosis of EIEE, who was treated with vigabatrin and showed a good response to treatment, with normalization of the EEG and a normal psychomotor development afterwards.
A 1-month-old male infant was admitted for evaluation of seizures that started approximately at the age of 20 days. He was the first child of healthy and unrelated parents and was born at term (41 weeks of gestational age) after uncomplicated pregnancy and delivery. Ten days before admission the patient began to suffer, on the awakening state, sudden isolated episodes characterized by staring gaze, loss of contact, sialorrhea, trunk deviation and extension of the arms (Fig. 1). On admission the infant presented poor visual contact and hypotonia. The EEG recording showed interhemispheric asymmetry with continuous pseudoperiodic high voltage discharges of poly-spike waves of 5–10 s, similar to the suppression-burst pattern (Fig. 2), within higher voltage on right hemisphere. Initially he received treatment with Phenobarbital, Piridoxine and Biotin, together. Seizures subsided for a week, in spite of the abnormalities in EEG pattern. The seizures started again, in the form of clusters of tonic extensor spasms accompanied by
* Corresponding author. Address: Neuropediatric Unit, Puerta de Hierro Majadahonda Hospital, Calle Manuel de Falla, 1, 28222 Majadahonda, Madrid, Spain. Fax: +34 911917795. E-mail address: [email protected] (M.R. Cazorla).
0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.08.007
674
M.R. Cazorla et al. / Brain & Development 32 (2010) 673–676
Fig. 1. The patient’s photograph taken by his parents at 1 month of age. It shows a tonic seizure with the symmetrical extension arms.
oculogyric movements. The mean number of clusters per day were five and consisted of 20–25 spasms per cluster. Karyotype was normal (46, XY) and TORCH screening was negative. Brain MRI didnot reveal abnormalities, the same for a comprehensive metabolic study in samples of blood, urine and cerebrospinal fluid. The EEG recording continued showing a nearly suppression–burst pattern through sleeping and awaking states, with persistent epileptiform discharges in right hemisphere. In order to decrease the number of episodes, vigabatrin was added (100 mg/kg per day), at the age of 5 weeks. Consequently, a week later, seizures decreased and, at 16 days after admission, at the age of 1 month and a
half, they ceased completely without further recurrences. The EEG pattern showed a correlative improvement (Fig. 3). The period between the bursts became longer, and a complete disappearance of the discharges with normalization of basal activity was recorded at the age of 2 months (Fig. 4). Following the cessation of seizures, the infant presented in the physical examination, alert state decreased and mild hypertonia. Progressively the muscle tone and his visual contact improved. One month later vigabatrin was withdrew. At 3 months the neurological examination as well as the psychomotor development were normal. On follow-up, the patient has not suffered any type of seizures and several EEG recordings have been normal. At 2 years his motor and language developments remain within normal limits. He walks down stairs with the help of a hand rail, jumps, understands simple commands, and can form short sentences. 3. Discussion The case presented can be considered as a remarkably atypical Ohtahara syndrome. The type of seizures, the pseudo-rhythmic periodicity with bursts, periods of near suppression observed in EEG recordings, and the early age of presentation, fit the criteria for this epileptic syndrome [2,3]. Other epileptic syndromes of early infancy may be ruled out. The lack of myoclonus and the fact that EEG abnormalities persisted throughout wakeful-
Fig. 2. EEG recording 1 month of age. It shows burst–suppression pattern. Bursts of spikes are intermixed with high-amplitude slow waves. The periodicity is pseudo-rhythmic with an interval ranged in 5–10 s, and there is a near flat period between the burst. The pattern was similar during the awake and sleep states.
M.R. Cazorla et al. / Brain & Development 32 (2010) 673–676
675
Fig. 3. EEG recording 6 weeks of age. Interictal electroencephalogram in wakefulness. A week after treatment with vigabatrin. Background activity normalization and erratic spikes on hemispheres.
Fig. 4. Interictal electroencephalogram 2 months of age. Typical sleep spindles. Normal registry.
ness and sleep are not consistent with the syndrome of early myoclonic encephalopathy related to early infantile epileptic encephalopathy, in which the EEG shows a suppression–burst pattern enhanced by sleep and not
manifested usually in awakening states [4]. Tonic spasms in clusters without hypsarrythmia have also been described in infants [5]. This benign entity affects infants in the first year of life, without evidence of regression,
676
M.R. Cazorla et al. / Brain & Development 32 (2010) 673–676
normal EEG (awake and sleep), normal neuroimaging and neurometabolic investigations, and without neurological or cognitive sequelae. Another type of epileptic syndrome with spasms, described by Gobbi et al. [6], is the periodic spasms without hypsarrhythmia associated to focal seizures and cortical malformations. The normal neuroimage in our case excludes this diagnosis. The two syndromes have a later start age of the spasms, frequently after the first year of life. Early infantile epileptic encephalopathy with suppression–burst is one of the most severe epileptic syndromes of infancy. It evolves into West syndrome in 75% of patients, and a significant number of cases of West syndrome evolve into Lennox–Gastaut syndrome. This time-dependent evolution led to the speculation by Yamatogui and Ohtahara [3] of ‘‘age-dependent” epileptic encephalopathies that included early infantile epileptic encephalopathy (Otahara syndrome), West syndrome and Lennox–Gastaut syndrome. These syndromes share common features like a characteristic age preference, a continuous severe massive epileptic EEG abnormality, and a poor prognosis as regards to the frequently drug resistance seizures and the psychomotor development which is always severely affected. These authors have reported recently an entity called ‘‘severe epilepsy with multiple independent spike foci” (or Markand–Blume–Ohtahara syndrome) which seems to be a variant of the aforementioned age-dependent epileptic encephalopathies [7]. This is supported by the fact of some suppression–burst EEG patterns evolve into hypsarrhythmia and latter into a pattern of multiple independent spike foci [8], instead the slow spike-wave pattern of the Lennox–Gastaut syndrome. Taken together all these evolutions, our patient does not fit for any of them. In contrast to early myoclonic encephalopathy, in which inborn errors of metabolism are by far the most common cause, in early infantile epileptic encephalopathy predominate ‘‘anatomical” etiologies such as hemimegalencephaly, porencephaly, lissencephaly, Aicardi syndrome, dentate-olivary dysplasia, mamillary bodies agenesis and cortical dysplasias. Some mitochondrial diseases have also been reported. There are also cryptogenic or idiopathic Ohtahara syndrome cases, and it has been postulated that they are possibly due to indetectable microdysgenesis or migration disorders. In any case, our patient did not show identifiable CNS malformations and an inborn error of metabolism was reasonably excluded. Thus our patient can be considered as an idiopathic case. Treatment response in early infantile epileptic encephalopathy is usually poor. Several treatments have been tried, as valproate, benzodiazepines, ACTH, corticosteroids, pyridoxal phosphate, vigabatrin, zonisamide, intravenous gammaglobulines and ketogenic diet [9,10]. Ohno et al. [11] described a case similar to ours with an
atypical EEG burst–suppression pattern and a fairly good response to zonisamide. Otherwise successful resection has been reported in some cerebral dysgenesis such as focal cortical dysplasias or hemimegalencephaly with less severe outcome of the patient’s development [12]. Although vigabatrine may have deleterious effects in visual field, we considered that it was convenient to give a chance to this drug by trying a short course based on the beneficial effect that it has in some cases of West syndrome [13]. The result was unexpectedly good. We consider that the somewhat atypical EEG pattern, and the idiopathic nature of the early infantile epileptic encephalopathy may be important factors for the outcome in our patient. In summary our case shows that some cases of idiopathic Ohtahara syndrome have shown to be heterogeneous and can be admitted variant forms with better prognosis. References [1] Ohtahara S, Ishida K, Yamatogi Y, Inoue H. On the specific age dependent epileptic sindrome: The early-infantile epileptic encephalopathy with suppression–burst (in Japanese). No To Hattatsu (Tokyo) 1976;8:270–80. [2] Campistol J, Garcı´a-Garcı´a JJ, Lobera E, Sanmartin FX, Conill J, Ferna´ndez-Alvarez E. Sindrome de Ohtahara: una forma de epilepsia edad-dependiente. Rev Neurol 1997;25:212–4. [3] Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression–bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev 2002;24:13–23. [4] Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression–burst. J Clin Neurophysiol 2003;20:398–407. [5] Caraballo RH, Fejerman N, Bernardina BD, Ruggieri V, Cerso´simo R, Medina C, et al. Epileptic spasms in clusters without hypsarrhythmia in infancy. Epileptic Disord 2003;5:109–13. [6] Gobbi G, Bruno L, Pini A, Giovanardi Rossi P, Tassinari CA. Periodic spasms: an unclassified type of epileptic seizure in childhood. Dev Med Child Neurol 1987;29:766–75. [7] Yamatogi Y, Ohtahara S. Multiple independent spike foci and epilepsy, with special reference to a new epileptic syndrome of ‘‘severe epilepsy with multiple independent spike foci”. Epilepsy Res 2006;70(Suppl. 1):S96–S104. [8] Saneto RP, Sotero de Menezes M. Persistence of suppression– bursts in a patient with Ohtahara syndrome. J Child Neurol 2007;22:631–4. [9] Yelin K, Alfonso I, Papazian O. Sı´ndrome de Ohtahara. Rev Neurol 1999;29:340–2. [10] Baxter PS, Gardner-Medwin D, Barwick DD, Ince P, Livingston J, Murdoch-Eaton D. Vigabatrin monotherapy in resistant neonatal seizures. Seizure 1995;4:57–9. [11] Ohno M, Shimotsuji Y, Abe J, Shimada M, Tamiya H. Zonisamide treatment of early infantile epileptic encephalopathy. Pediatr Neurol 2000;23:341–4. [12] Komaki H, Sugai K, Sasaki M, Hashimoto T, Arai N, Takada E, et al. Surgical treatment of a case of early infantile epileptic encephalopathy with suppression–bursts associated with focal cortical dysplasia. Epilepsia 1999;40:365–9. [13] Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord 2007;9:353–412.
Case report
Early infantile epileptic encephalopathy with unusual favourable outcome Marı´a Rosario Cazorla a,*, Alfonso Verdu´ b, Carmen Montes c, Fernando Ayuga b a
Neuropediatric Unit, Puerta de Hierro Majadahonda Hospital, Madrid, Spain b Neuropediatric Unit, Virgen de la Salud Hospital, Toledo, Spain c Neurophysiology Department, Virgen de la Salud Hospital, Toledo, Spain
Received 15 February 2009; received in revised form 14 August 2009; accepted 24 August 2009
Abstract The authors report the case of an infant suffered from early infantile epileptic encephalopathy with suppression–burst, or Ohtahara syndrome, a severe form of epilepsy in early childhood. The patient was treated with vigabatrin causing a favourable response. This unusual outcome may be related with the normality of neuroimaging and metabolic studies, as happens with idiopathic West syndrome cases. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Ohtahara syndrome; Suppression–burst pattern; Vigabatrine
1. Introduction
2. Case report
Ohtahara syndrome (OS) or early infantile epileptic encephalopathy with suppression–burst (EIEE) is characterized by the onset within the first months of life, of tonic spasms seizures and a suppression–burst electroencephalogram (EEG) pattern in both awaking and sleeping states. Firstly described by Ohtahara et al. [1], the seizures are usually refractory to antiepileptic therapy and the prognosis is poor, with severe psychomotor retardation. We report the case of an infant with tonic spasms and a burst–suppression EEG pattern consistent with the diagnosis of EIEE, who was treated with vigabatrin and showed a good response to treatment, with normalization of the EEG and a normal psychomotor development afterwards.
A 1-month-old male infant was admitted for evaluation of seizures that started approximately at the age of 20 days. He was the first child of healthy and unrelated parents and was born at term (41 weeks of gestational age) after uncomplicated pregnancy and delivery. Ten days before admission the patient began to suffer, on the awakening state, sudden isolated episodes characterized by staring gaze, loss of contact, sialorrhea, trunk deviation and extension of the arms (Fig. 1). On admission the infant presented poor visual contact and hypotonia. The EEG recording showed interhemispheric asymmetry with continuous pseudoperiodic high voltage discharges of poly-spike waves of 5–10 s, similar to the suppression-burst pattern (Fig. 2), within higher voltage on right hemisphere. Initially he received treatment with Phenobarbital, Piridoxine and Biotin, together. Seizures subsided for a week, in spite of the abnormalities in EEG pattern. The seizures started again, in the form of clusters of tonic extensor spasms accompanied by
* Corresponding author. Address: Neuropediatric Unit, Puerta de Hierro Majadahonda Hospital, Calle Manuel de Falla, 1, 28222 Majadahonda, Madrid, Spain. Fax: +34 911917795. E-mail address: [email protected] (M.R. Cazorla).
0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.08.007
674
M.R. Cazorla et al. / Brain & Development 32 (2010) 673–676
Fig. 1. The patient’s photograph taken by his parents at 1 month of age. It shows a tonic seizure with the symmetrical extension arms.
oculogyric movements. The mean number of clusters per day were five and consisted of 20–25 spasms per cluster. Karyotype was normal (46, XY) and TORCH screening was negative. Brain MRI didnot reveal abnormalities, the same for a comprehensive metabolic study in samples of blood, urine and cerebrospinal fluid. The EEG recording continued showing a nearly suppression–burst pattern through sleeping and awaking states, with persistent epileptiform discharges in right hemisphere. In order to decrease the number of episodes, vigabatrin was added (100 mg/kg per day), at the age of 5 weeks. Consequently, a week later, seizures decreased and, at 16 days after admission, at the age of 1 month and a
half, they ceased completely without further recurrences. The EEG pattern showed a correlative improvement (Fig. 3). The period between the bursts became longer, and a complete disappearance of the discharges with normalization of basal activity was recorded at the age of 2 months (Fig. 4). Following the cessation of seizures, the infant presented in the physical examination, alert state decreased and mild hypertonia. Progressively the muscle tone and his visual contact improved. One month later vigabatrin was withdrew. At 3 months the neurological examination as well as the psychomotor development were normal. On follow-up, the patient has not suffered any type of seizures and several EEG recordings have been normal. At 2 years his motor and language developments remain within normal limits. He walks down stairs with the help of a hand rail, jumps, understands simple commands, and can form short sentences. 3. Discussion The case presented can be considered as a remarkably atypical Ohtahara syndrome. The type of seizures, the pseudo-rhythmic periodicity with bursts, periods of near suppression observed in EEG recordings, and the early age of presentation, fit the criteria for this epileptic syndrome [2,3]. Other epileptic syndromes of early infancy may be ruled out. The lack of myoclonus and the fact that EEG abnormalities persisted throughout wakeful-
Fig. 2. EEG recording 1 month of age. It shows burst–suppression pattern. Bursts of spikes are intermixed with high-amplitude slow waves. The periodicity is pseudo-rhythmic with an interval ranged in 5–10 s, and there is a near flat period between the burst. The pattern was similar during the awake and sleep states.
M.R. Cazorla et al. / Brain & Development 32 (2010) 673–676
675
Fig. 3. EEG recording 6 weeks of age. Interictal electroencephalogram in wakefulness. A week after treatment with vigabatrin. Background activity normalization and erratic spikes on hemispheres.
Fig. 4. Interictal electroencephalogram 2 months of age. Typical sleep spindles. Normal registry.
ness and sleep are not consistent with the syndrome of early myoclonic encephalopathy related to early infantile epileptic encephalopathy, in which the EEG shows a suppression–burst pattern enhanced by sleep and not
manifested usually in awakening states [4]. Tonic spasms in clusters without hypsarrythmia have also been described in infants [5]. This benign entity affects infants in the first year of life, without evidence of regression,
676
M.R. Cazorla et al. / Brain & Development 32 (2010) 673–676
normal EEG (awake and sleep), normal neuroimaging and neurometabolic investigations, and without neurological or cognitive sequelae. Another type of epileptic syndrome with spasms, described by Gobbi et al. [6], is the periodic spasms without hypsarrhythmia associated to focal seizures and cortical malformations. The normal neuroimage in our case excludes this diagnosis. The two syndromes have a later start age of the spasms, frequently after the first year of life. Early infantile epileptic encephalopathy with suppression–burst is one of the most severe epileptic syndromes of infancy. It evolves into West syndrome in 75% of patients, and a significant number of cases of West syndrome evolve into Lennox–Gastaut syndrome. This time-dependent evolution led to the speculation by Yamatogui and Ohtahara [3] of ‘‘age-dependent” epileptic encephalopathies that included early infantile epileptic encephalopathy (Otahara syndrome), West syndrome and Lennox–Gastaut syndrome. These syndromes share common features like a characteristic age preference, a continuous severe massive epileptic EEG abnormality, and a poor prognosis as regards to the frequently drug resistance seizures and the psychomotor development which is always severely affected. These authors have reported recently an entity called ‘‘severe epilepsy with multiple independent spike foci” (or Markand–Blume–Ohtahara syndrome) which seems to be a variant of the aforementioned age-dependent epileptic encephalopathies [7]. This is supported by the fact of some suppression–burst EEG patterns evolve into hypsarrhythmia and latter into a pattern of multiple independent spike foci [8], instead the slow spike-wave pattern of the Lennox–Gastaut syndrome. Taken together all these evolutions, our patient does not fit for any of them. In contrast to early myoclonic encephalopathy, in which inborn errors of metabolism are by far the most common cause, in early infantile epileptic encephalopathy predominate ‘‘anatomical” etiologies such as hemimegalencephaly, porencephaly, lissencephaly, Aicardi syndrome, dentate-olivary dysplasia, mamillary bodies agenesis and cortical dysplasias. Some mitochondrial diseases have also been reported. There are also cryptogenic or idiopathic Ohtahara syndrome cases, and it has been postulated that they are possibly due to indetectable microdysgenesis or migration disorders. In any case, our patient did not show identifiable CNS malformations and an inborn error of metabolism was reasonably excluded. Thus our patient can be considered as an idiopathic case. Treatment response in early infantile epileptic encephalopathy is usually poor. Several treatments have been tried, as valproate, benzodiazepines, ACTH, corticosteroids, pyridoxal phosphate, vigabatrin, zonisamide, intravenous gammaglobulines and ketogenic diet [9,10]. Ohno et al. [11] described a case similar to ours with an
atypical EEG burst–suppression pattern and a fairly good response to zonisamide. Otherwise successful resection has been reported in some cerebral dysgenesis such as focal cortical dysplasias or hemimegalencephaly with less severe outcome of the patient’s development [12]. Although vigabatrine may have deleterious effects in visual field, we considered that it was convenient to give a chance to this drug by trying a short course based on the beneficial effect that it has in some cases of West syndrome [13]. The result was unexpectedly good. We consider that the somewhat atypical EEG pattern, and the idiopathic nature of the early infantile epileptic encephalopathy may be important factors for the outcome in our patient. In summary our case shows that some cases of idiopathic Ohtahara syndrome have shown to be heterogeneous and can be admitted variant forms with better prognosis. References [1] Ohtahara S, Ishida K, Yamatogi Y, Inoue H. On the specific age dependent epileptic sindrome: The early-infantile epileptic encephalopathy with suppression–burst (in Japanese). No To Hattatsu (Tokyo) 1976;8:270–80. [2] Campistol J, Garcı´a-Garcı´a JJ, Lobera E, Sanmartin FX, Conill J, Ferna´ndez-Alvarez E. Sindrome de Ohtahara: una forma de epilepsia edad-dependiente. Rev Neurol 1997;25:212–4. [3] Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression–bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev 2002;24:13–23. [4] Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression–burst. J Clin Neurophysiol 2003;20:398–407. [5] Caraballo RH, Fejerman N, Bernardina BD, Ruggieri V, Cerso´simo R, Medina C, et al. Epileptic spasms in clusters without hypsarrhythmia in infancy. Epileptic Disord 2003;5:109–13. [6] Gobbi G, Bruno L, Pini A, Giovanardi Rossi P, Tassinari CA. Periodic spasms: an unclassified type of epileptic seizure in childhood. Dev Med Child Neurol 1987;29:766–75. [7] Yamatogi Y, Ohtahara S. Multiple independent spike foci and epilepsy, with special reference to a new epileptic syndrome of ‘‘severe epilepsy with multiple independent spike foci”. Epilepsy Res 2006;70(Suppl. 1):S96–S104. [8] Saneto RP, Sotero de Menezes M. Persistence of suppression– bursts in a patient with Ohtahara syndrome. J Child Neurol 2007;22:631–4. [9] Yelin K, Alfonso I, Papazian O. Sı´ndrome de Ohtahara. Rev Neurol 1999;29:340–2. [10] Baxter PS, Gardner-Medwin D, Barwick DD, Ince P, Livingston J, Murdoch-Eaton D. Vigabatrin monotherapy in resistant neonatal seizures. Seizure 1995;4:57–9. [11] Ohno M, Shimotsuji Y, Abe J, Shimada M, Tamiya H. Zonisamide treatment of early infantile epileptic encephalopathy. Pediatr Neurol 2000;23:341–4. [12] Komaki H, Sugai K, Sasaki M, Hashimoto T, Arai N, Takada E, et al. Surgical treatment of a case of early infantile epileptic encephalopathy with suppression–bursts associated with focal cortical dysplasia. Epilepsia 1999;40:365–9. [13] Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord 2007;9:353–412.