Journal of the Neurological Sciences 176 (2000) 162–165 www.elsevier.com / locate / jns
Autosomal dominant temporal lobe epilepsy in a Japanese family a, a,b b a a Akio Ikeda *, Takeharu Kunieda , Susumu Miyamoto , Hidenao Fukuyama , Hiroshi Shibasaki a
Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606, Japan b Department of Neurosurgery, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto 606, Japan Received 22 December 1999; received in revised form 10 May 2000; accepted 10 May 2000
Abstract We described autosomal dominant familial temporal lobe epilepsy in a Japanese family in which three individuals (one man and his two children) were affected. Their seizures commonly consisted of auditory symptoms and infrequent nocturnal generalized seizures. Repeated EEGs did not provide confirmative epileptiform discharges, but cranial MRI in one patient showed mild left hippocampal atrophy, and decreased glucose metabolism in the left temporal area was demonstrated by 18F-deoxyglucose positron emission tomography (FDG-PET). A confirmative diagnosis in one of the patients by FDG-PET was helpful for diagnosis in other patients in the same family. Seizure onset was adolescent commonly among the three patients, but better seizure control was achieved in the father as compared with the two children. 2000 Published by Elsevier Science B.V. Keywords: Familial temporal lobe epilepsy; Autosomal dominant inheritance; FDG-PET
Hereditary epileptic syndromes manifesting predominantly partial seizures were little recognized except for ‘benign childhood epilepsy with centrotemporal spike’ according to the epilepsy classification proposed by International League Against Epilepsy (ILAE) in 1989 [1]. Recently, several hereditary partial epilepsies like familial temporal lobe epilepsy (TLE) [2] and autosomal dominant nocturnal frontal lobe epilepsy [3] have been described. Familial TLE has different characteristics from the more typical form of TLE, namely mesial TLE which is characterized by significant hippocampal atrophy without clear inheritance except for febrile convulsion [4]. More recently it was suggested from the clinical point of view that familial TLE, unlike the initial description, is a rather heterogeneous syndrome [5]. Those reports of familial TLE came from Australia [2] and Canada [5] based on white families, and it is uncertain whether similar syndrome is also present in other races or not. Furthermore, autosomal dominant lateral temporal epilepsy *Corresponding author. Tel.: 181-75-751-4346; fax:181-75-751-3202. E-mail address:
[email protected] (A. Ikeda).
(ADLTE) has been recently also described in which auditory and visual ictal symptoms were predominant, and autosomal dominant transmission was linked to chromosome 10q [6,7]. We herein describe a Japanese family in which three members suffered from TLE, being consistent with autosomal dominant inheritance (Fig. 1). There was no consanguinity in this family tree. Patient 1, a 19-year-old woman, was a product of normal pregnancy and delivery, and her developmental milestones were normal. No febrile convulsions occurred. She had the first seizure at the age of 15 years which was a generalized tonic clonic seizure during sleep. Afterwards, she started having attacks of suddenly hearing of highpitched buzzing sound for 10–30 s followed by a lightheadedness. Those attacks were often associated with inability to read Japanese sentences including Kanji (Chinese characters). They occurred 3–5 times per month. She ´ ` vu or jamais did not have epigastric rising sensation, deja vu. Interictally the patient had no neurological deficits. Repeated routine EEGs showed only infrequent sharp transients in the left anterior temporal area while asleep. A cranial MRI showed a mild volume reduction of the left
0022-510X / 00 / $ – see front matter 2000 Published by Elsevier Science B.V. PII: S0022-510X( 00 )00333-6
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Fig. 1. Pedigree of the present family including three patients with familial temporal lobe epilepsy. An arrow indicates a proband. The number indicates the age of each family member at the time of examination.
hippocampus (Fig. 2A), but no clear T2-high intensity abnormality was detected. FDG-PET revealed mildly decreased glucose metabolism in the left temporal lobe (Fig. 2B). The patient was initially treated by valproic acid (VPA) 600 mg / day, but the partial seizures still occurred every 1–3 months with the trough blood level of 62–70 mg / l. Thus, VPA was changed to carbamazepine (CBZ)
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500 mg / day, and with its trough blood level of 7.2–8.6 mg / l, the patient was free from seizures for more than 2 years afterwards. Patient 2, a brother of Patient 1, was a 24-year-old man, who had the first generalized tonic clonic seizure occurred while asleep at the age of 16 years. He had no febrile convulsion. The patient had partial seizures also consisting of a high-pitched buzzing sound with hearing disturbance which was often associated with epigastric rising sensation and was followed by a lightheadedness. They occurred once per month. He had generalized seizures once every several years, but since the age of 23 years, he had generalized seizures every month, and the partial seizures also occurred once per week to month. Interictally there were no neurological deficits, and repeated EEGs showed only sharp transients in the left anterior temporal area. A cranial MRI was normal. The patient was initially treated by VPA 800 mg / day. After it was changed to CBZ 500 mg / day at the age of 23 years, he had no generalized or partial seizures for more than a year and half with the trough blood level of CBZ of 7.9 mg / l. Patient 3, the father of patients 1 and 2, was a 51-yearold, full-time employee with the past history of febrile convulsion. At the age of 16 years, the first nocturnal generalized seizure occurred. His habitual seizures started also with a high-pitched buzzing sound, followed by loss of awareness. At times the patient noticed that his seizures
Fig. 2. Coronal scan of brain MRI (A) and axial scan of [18]-F-deoxyglucose positron emission tomography (B) in patient 1. (A) shows mild left hippocampal atrophy (indicated by an arrow), and (B) reveals mildly decreased glucose metabolism in the left temporal lobe (indicated by arrows).
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were triggered by the telephone bell. Repeated EEGs revealed no clear epileptiform discharges. Interictally no neurological abnormalities were present. The patient was on phenytoin and phenobarbital, and currently on VPA, and his seizures occurred only once every several years especially when the patient took anticonvulsants irregularly. Among the three affected members of the family reported here, there were several common features as follows. (1) The onset age of seizures was 15 or 16 years, and the first attack was a nocturnal generalized seizure; (2) haitual, partial seizures started with a high-pitched buzzing sound; (3) repeated EEGs revealed no clear focal epileptiform discharges except for rare sharp transients in the anterior temporal area. These common features strongly suggest that all the three patients suffered from the same type of epileptic disorder. Berkovic et al. [2] described familial TLE in 38 individuals from 13 unrelated white families, and characterized it as follows in contrast with TLE associated with hippocampal sclerosis [4]. Seizure onset was in adolescence or early adult life, and seizure type was simple partial, complex partial, and / or secondarily generalized seizures. Febrile convulsion was rarely observed. MRI was usually normal, and seizures were well controlled in most cases, thus regarded as benign clinically. With regard to its ictal semiology, simple partial seizures with psychic or autonomic symptoms were predominant, and only three out of those 38 patients had auditory symptoms [2]. Those descriptions of familial TLE are in good agreement with the characteristics of the three patients described in this report, except that patient 1 had mild left hippocampal atrophy on MRI. Recently, the Montreal group also characterized familial TLE based on their 36 affected patients from 11 kindreds [5], and they concluded that the syndrome of familial TLE has heterogeneous clinical manifestations and is not always benign. More than a half of the affected patients whose MRIs were available showed unilateral hippocampal atrophy. Therefore, it seems that the presence of hippocampal atrophy in patient 1 does not contradict the diagnosis of familial TLE. ADLTE was recently reported in two large families with an autosomal dominant transmission [6,7], and 13 affected members in a family were described [6]. The number of seizure that occur are only 3–6 per year even without treatment, and can be well controlled by medication with a long remission. Seizures mainly occur at night, and simple partial seizures were one of the predominant types, consisting of visual (flashes, lights, colors, and single figures) or auditory (buzzing or humming like a machine) symptoms. EEG was examined in seven patients, and only two patients showed sharp waves in the left temporo-occipital area, and the other five patients had normal EEGs. Brain MRI and CT examinations were done in five and three patients, respectively, which did not show consistent abnormality. They concluded that an epileptogenic area was suspected in the lateral temporal area, close to the junction with the occipital area. Seventeen patients in the
other family [7] also had simple partial seizures invariably of auditory symptoms, and their seizures were well controlled by medication. The patients in the family in the present report have many common features to those in ADLTE, especially for ictal semiology and clinical course. When classifying epileptic syndrome in this family members, EEG did not provide confirmatory findings in any of the three patients; nothing more than sharp transients in the anterior temporal region. Focal epileptiform discharges were rather uncommon (about 20%) in patients with familial TLE [2], and thus, it was thought that the presence of a positive family history of TLE is the most important diagnostic clue [2]. In patient 1, the FDG-PET study and MRI demonstrated decreased glucose metabolism and mild hippocampal atrophy, respectively, in the left temporal area, both of which support the diagnosis of TLE. Furthermore, high-pitched buzzing sound with or without the following disturbance of word comprehension also supports the presence of epileptogenic zone in the left lateral temporal area. Since all these findings strongly suggest the diagnosis of TLE in patient 1, it is plausible to assume that patients 2 and 3 also had TLE. Initial auditory symptoms of seizures like in the present patients are often misleading because those symptoms could be recognized as nonspecific initial symptoms in generalized seizures in idiopathic generalized epilepsy. Since idiopathic generalized epilepsy is often clinically hereditary, the positive finding of the FDG-PET study in patient 1 was clinically useful for a diagnosis of familial TLE in this family. With regard to the mode of inheritance in familial TLE, the recently reported two large studies revealed autosomal dominant inheritance with the overall penetrance rate of 60–80% [2,6,7] or with incomplete penetrance [5]. In our family, autosomal dominant inheritance was strongly suggested since the father and his two children were affected. All the three patients were initially treated by VPA presumably because idiopathic generalized epilepsy was suspected. The seizures in the two children (patients 1 and 2) were not controlled by VPA, but they were well controlled by CBZ. The seizures in the father (patient 3) were relatively better controlled by VPA than in his two children. In view of the fact that CBZ is more effective for partial seizures than VPA, the above finding may suggest that an epileptogenicity in patient 3 was weaker than that in patients 1 and 2, although the onset age was almost the same among the three patients.
Acknowledgements This study was supported by Grants-in-Aid for Scientific Research (A) 09308031, (A) 08558083, on Priority Areas 08279106, and (C) 10670583 from the Japanese Ministry of Education, Science, Sports and Culture, and Research for the Future Program from the Japan Society for the Promotion of Science JSPS-RFTF97L00201. The authors
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thank Dr. Kazuo Hashikawa in Osaka University School of Medicine for conducting the FDG-PET examination in patient 1.
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