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Clinical Efficacy and Adverse Effects of Clobazam in Patients with Refractory Epilepsy.Purpose:A new antiepileptic drug (AED), clobazam (CLB), was introduced in Japan in 2000. In previous studies, CLB was effective in 30–80% of epilepsy patients. A retrospective study of the clinical efficacy and adverse effects of CLB was performed in patients with refractory epilepsy. The development of tolerance to CLB and related factors also was studied.Methods:Patients with refractory epilepsy who had one or more seizures per month despite treatment with three or more AEDs were included in the study. CLB was prescribed as an add-on therapy, once or twice per day. In patients who were taking other benzodiazepines (BZDs), the other BZDs were gradually tapered as the dosage of CLB was increased. The patients were followed up for>6 months.Results:Seventy-two patients were studied. Their ages ranged from 1 to 37 years (16.4± 10.2 years, mean± SD). Twenty-one patients had symptomatic generalized epilepsy (early myoclonic encephalopathy, one; West syndrome, four; Lennox–Gastaut syndrome, 12), 48 had localization-related epilepsy (cryptogenic, one), and three had severe myoclonic epilepsy in infancy. The mean minimum dosage of CLB was 0.13 mg/kg/day in patients with body weight<20 kg, or 5.3 mg/day in those with body weight of≥20 kg. The mean maximum dosage was 0.4 mg/kg/day in patients with body weight<20 kg, or 16.7 mg/day in those with body weight of≥20 kg. CLB reduced the frequency of seizures by≥50% in 48% of the subjects (18% with no seizure, 6% with 75% reduction, and 24% with 50–75% reduction). CLB was effective for both generalized epilepsy (42.5%) and focal epilepsy (50%), and especially for temporal lobe epilepsy (TLE) (60%). CLB was effective for partial seizures (55.5%), primary (57%) and secondarily generalized (40%) tonic–clonic seizures, and tonic seizures (46%). It was not effective for spasms (0), atonic seizures (0), and the majority of absence seizures (25%). CLB was effective in 10 nonresponders to clonazepam (CZP). Among the adverse effects of CLB, the incidences of somnolence, salivation, and aggressiveness were 29%, 1.3%, and 13.8%, respectively, which was lower than the incidence previously reported for patients taking CZP; and the incidence of depression was 13.8%, which was higher than that reported for patients taking CZP. Similar to several other BZDs, in some patients, tolerance to CLB developed. In 65% of patients, tolerance to CLB developed within 1 year (55% within 6 months). Tolerance was not observed in other patients who had taken CLB for>1 year. In 55% of the cases in whom tolerance to CLB developed, the frequency of seizures returned to the original frequency before starting CLB treatment, whereas in the remaining 45% of cases, the frequency of seizures increased slightly and was lower than the frequency before starting CLB treatment. The mean CLB dosage in patients in whom tolerance did not develop (16.7 mg/day) was lower than the dosage in those in whom tolerance developed (19.0 mg/day). The mean serumN-desmethyl CLB concentration in long-term users who did not develop tolerance was very high (3,071 ng/ml).Conclusions:CLB was effective for both refractory generalized and localization-related epilepsies and was especially effective for TLE. CLB was effective at a lower dosage than previously reported. The incidence of some adverse effects such as somnolence, salivation, and aggressiveness was lower for CLB than for CZP. CLB was also effective in some patients who had tolerance to other BZDs. In those who developed tolerance to CLB, tolerance appeared within 6 months in most cases. Patients who did not develop tolerance to CLB had a higher serumN-desmethyl CLB concentration, which may be an important factor. Antihistaminergic/Allergic Drug-Induced Seizures in Children at Our Outpatient Clinic.Purpose:It is well known that antihistaminergic (AH) or antiallergic (AA) drugs and theophyline (Theo) have proconvulsant effects. The North Kyushu Study Group on Pediatric Allergy reported that in children with bronchial asthma treated with and without Theo had similar prevalence of seizures of 0.42%. However, reports on this issue by pediatric neurologists are rare. Therefore we retrospectively investigated the relation between administration of AH drugs or Theo and seizure occurrence in our patients with febrile convulsions (FCs) or epilepsy.Methods:The 1,037 patients visited our outpatient neurologic clinic between January 1999 and July 2001. Among them, 158 had FCs, and 350 had epilepsy. By reviewing the clinical charts of these 508 patients, we selected those who had seizures while they were administered AH drugs or Theo for upper respiratory infection or asthma. Then we investigated the causal relation of these drugs with seizures.Results:Among 158 patients with FCs who visited our clinic many times, 17 (10.7%) had seizures while receiving AH drugs or Theo: four received Theo (2.5%; one of them received ketotifen, and another, azelastine), and 13 (8.2%) received AH or AA drugs. Among 350 patients with epilepsy, 11 (3.1%) had seizures while receiving such drugs: five received Theo (1.4%; three of them received ketotifen), and six (1.7%) received AH or AA drugs. A representative case is presented.Case IY:A 3-year-old boy (birth history: 40 weeks; 3,725 g; Apgar, 8 of 10; HIE grade 1) had a history of spastic diplegia, asthma, and atopic dermatitis. On July 15, 1995, he became febrile and asthmatic. He received some drugs and had seizures. On August 16, he visited our clinic and 200 mg of theophyline, 3 mg of pemirolast, and 3 mg of cyproheptadine were administered. He had seizures in that evening. Thereafter, 100 mg of Theo was continued, and seizures occurred every other day. On October 12, he had status epileptics. Seizures ceased after the second IV diazepam. Serum concentrations of carbamazepine (CBZ), valproic acid (VPA), and Theo were 3.5, 33.6, and 2.7μg/ml, respectively. Since October 12, Theo was stopped. Meanwhile, no seizure occurred. Pemirolast (3 mg) and cyproheptadine (3 mg) were continued, and he had seizures once a month. Since May 1996, the dose of cyproheptadine was increased to 4 mg. In August 1996, he had seizures. Pemirolast and cyproheptadine were stopped, and since then, no seizures have occurred. On June 1, 1997, Theo was again administered for severe asthmatic attacks. Serum concentrations of CBZ, VPA, and Theo were 4.8, 84.9, and 9.3μg/ml, respectively. He had seizures on June 18, 19, 20, and 21, and Theo was discontinued. Thereafter, he remained seizure free.Conclusions:Our results suggested that AH drug or Theo-related seizures occurred more frequently in FC patients than in epilepsy patients. One factor contributing to this result may be the fact that recently we (pediatric neurologists) have become aware of a risk of seizure induction by AH drugs and Theo in epilepsy patients. Some patients have no seizures while receiving these drugs. Our results suggest that Theo and some AH drugs may induce seizures, although not all patients with FC or epilepsy are sensitive to these drugs. Our study was designed with a small number of subjects. Although statistical analysis is not possible, our results may suggest that physicians must pay more attention to AH drugs than to Theo as seizure-inducing agents. A Case of Migraine-Like Headache and Metamorphopsia Caused by Epileptogenicity of an Occipital Lesion: Successful Treatment with Sumatriputan.Case Report:A 20-year-old man with a history of complex partial seizures since age 9 years had experienced some episodes of pulsatile right hemicrania followed by a visual sensation of distortion of the left part of objects (metamorphopsia). During an attack, only hemicrania improved after treatment with an analgesic, whereas metamorphopsia continued with little change. The patient was admitted to our hospital when a neuroophthalmologic examination triggered worsening of the symptoms. After hemicrania was successfully treated with sumatriptan, metamorphopsia also remitted gradually. A twilight state existed for a while after the treatment. The waking and sleeping EEGs showed occipital slow activity predominating on the right but no epileptogenic discharge. On computed tomographic (CT) scanning, right occipital cortical and subcortical calcifications were observed, and magnetic resonance imaging (MRI) showed parenchymal atrophy in the surrounding areas. Single-photon emission CT (SPECT) with[123I]IMP was performed on day 12 after admission, and right occipitotemporal hypoperfusion and ipsilateral temporal hyperperfusion were detected.Discussion:This is a case of paroxysmal metamorphopsia triggered by pulsatile hemicrania, with evidence of morphologic and functional abnormality in the occipital lobe. Sumatriptan was effective in relieving not only hemicrania but also lingering metamorphopsia. In general, patients with lesions of the occipital lobe often have elemental visual hallucinations such as light, color, lines, and circles. Conversely, distortions of objects, such as metamorphopsia in a narrow sense, usually occur in those with temporal lobe lesions. Furthermore, visual phenomena such as typical migranous aura based on the concept of spreading depression cannot continue for>60 min. The SPECT findings imply that the epileptic discharge originated from the occipital lobe and propagated toward the temporal lobe, and cells with a lower epileptogenic threshold were easily excited for a long period. We concluded that the patient was irritated by local changes of the vascular system because of the lesion, and then migraine triggered epileptogenic visual seizure. Initial Effect and Long-Term Outcome of the Combination Therapy with ACTH and Clonazepam for Patients with West Syndrome: A Further Study.Purpose:To treat West syndrome, we usually use high-dose vitamin B6 therapy at first; and if this not effective, we administer adrenocorticotropic hormone (ACTH) and clonazepam (CZP) together; and after the end of the treatment with ACTH, we continue to use CZP as maintenance therapy. In this study, we reviewed the initial effect and long-term outcome of this combination therapy with ACTH and CZP for the treatment of West syndrome.Methods:During 20 years from April 1979 to March 1999, we used combination therapy of ACTH and clonazepam to treat 41 patients. Nineteen patients were classified as having cryptogenic West syndrome, and the other 22, as symptomatic. The onset ages of West syndrome in these patients were from 3 months to 21 months (mean, 7 months). The period from disease onset to the start of treatment ranged from 12 days to 6 months (mean, 1.5 months). ACTH (0.025 mg/kg; later, 0.0125 mg/kg) was injected intramuscularly every day for the first 2 weeks, every other day for the next 2 weeks, twice a week for another 2 weeks, and once a week for the last 2 weeks. We added a daily dose of 0.025 mg/kg of CZP at the start of ACTH and doubled its dose every week in general up to the maintenance dose between 0.1 and 0.2 mg/kg/day. We continued to administer CZP after completion of the ACTH therapy.Results:For the initial effect, both the seizures and the hypsarrhythmia on EEG disappeared in 33 (80.5%) patients. In six patients, the seizures or the EEG abnormalities were improved. In two patients, both the seizures and hypsarrhythmia persisted. We analyzed the long-term outcome for 10 years by the Kaplan–Meier method. The seizure-suppression rate for cryptogenic West syndrome patients without mental retardation was 70.1% in 3 years, and no patients showed seizure recurrence thereafter. The rate for cryptogenic West syndrome patients with mental retardation was 58.3% in 5 years, and the final rate decreased to 29.2%. Half of the patients with symptomatic West syndrome showed seizure recurrence within a year, and the final suppression rate was 24.5%. To sum up the outcome for all patients, 17 (41.5%) patients showed seizures within a year. The seizure-suppression rate was 50.7% in 3 years, 43.4% in 5 years, and 29.7% in 10 years. As for the EEG findings at the final observations, the paroxysmal discharges disappeared in 11 (68.8%) of 16 patients who showed very effective short-term results and with seizures controlled in the long term. The evolving epilepsies in 17 seizure-recurrence cases included three cases of recurrence of West syndrome and eight cases of Lennox–Gastaut syndrome. As for the prognosis of mental development, among the five cryptogenic patients who had no mental retardation at onset and showed good short-term response and long-term seizure control, two patients showed normal development at older than 3 years.Conclusions:Various methods have been tried for the treatment of West syndrome in various institutions. ACTH is usually used for its treatment. Only a few studies have focused on the efficacy of CZP for West syndrome. Our combination therapy of ACTH and CZP showed effective short-term results and a good long-term outcome, except in patients with mental retardation. These results indicate that the ACTH-CZP regimen is an effective treatment for West syndrome. Intravenous Sodium Valproate in Refractory Seizures.Purpose:Valproic acid (VPA) has evolved as a major antiepileptic drug (AED) for treatment of seizures. The role of intravenous VPA (IVVPA) is still not established. Clinical and electrophysiologic evidence suggests it to be effective for status epilepticus (SE) after failure of first-line AEDs.Methods:We report our experience on use of IVVPA in 18 patients with SE with seizures of different types and etiologies. They had not responded to therapeutic regimens of oral or parenteral conventional AEDs. There were four patients each with viral encephalitis (VE) and hypoxic ischemic encephalopathy (HIE), two each with tubercular meningitis, multiple cerebral infarcts, multiple neurocysticercosis, and idiopathic generalized tonic–clonic seizures (GTCSs). There was a single patient with subacute sclerosing panencephalitis (SSPE) and right frontal hematoma seen in SE. Seizures were of different types[epilepsia partialis continua (EPC), seven; nonconvulsive SE (NCSE), two; GTCSs, three; and myoclonic SE (MSE), six].Results:IVVPA was infused at a dose of 20 mg/kg at a rate of 20 mg/min to all patients. Seizures were controlled in all except one patient within 6–14 h, without any complication or adverse effects, even in patients with cardiovascular instability. The patient who did not respond (although frequency of attacks was reduced) to IVVPA even with a dose of 35 mg/kg was an 18-year-old boy with SSPE.Conclusions:We conclude that IVVPA appears to be effective and safe when rapid control of seizures is the goal, even in elderly persons with cardiovascular instability. No intensive care monitoring is required, unlike that with conventional IV AEDs. It can be recommended as the drug of choice for EPC and HIE, which is usually refractory to oral AEDs. The possible mechanism for its efficacy when other AEDs fail may be due to its rapid penetration into brain tissue. Application of Diffusion Tensor Imaging in the Evaluation of Cerebellar Atrophy Associated with Phenytoin.Purpose:To assess the clinical usefulness of diffusion tensor imaging in the evaluation of cerebellar atrophy associated with phenytoin (PHT).Methods and Materials:Sixteen patients and sex/age-matched normal controls participated in this study. The patient groups consisted of long-standing PHT users (n= 6), olivopontocerebellar atrophy (OPCA; n= 4), autoimmune disease (n= 3), and multiple sclerosis (n= 3). All studies were performed by using a 1.5-T Philips Gyroscan Intera system. Diffusion-weighted imaging was performed by using single-shot echoplanar imaging, with navigator echo-phase correction and SENSE, along six independent axes with diffusion weighting of b= 600 s/mm2. Data were processed on a Windows-2000 PC equipped with IDL, by which vector map and functional anisotropy (FA) map were generated. FA of cerebellar peduncles and cerebellar white matter were measured and compared between PHT users and other cerebellar atrophy groups.Results:In PHT users, FA values of middle cerebellar peduncle and transverse pontine fiber were not statistically different from those of normal controls. Non-PHT cerebellar atrophy showed significantly decreased FA of middle cerebellar peduncles and transverse pontine fibers. On vector maps, these changes also were prominently represented as loss of fiber direction on color-coded images.Conclusions:The results suggest that PHT-induced cerebellar atrophy may be a direct injury to cerebellar Purkinje cells, whereas other types of cerebellar atrophy may be induced by deterioration of efferent fibers to the cerebellum from the brainstem. Diffusion tensor imaging is useful in the differential diagnosis of cerebellar atrophy associated with PHT. Fanconi Syndrome Caused by Valproic Acid: Report of Four Severely Disabled Children.Background:Fanconi syndrome (FS) includes rickets associated with multiple defects of the proximal renal tubules and is characterized by generalized aminoaciduria, glycosuria, and proteinuria, resulting in metabolic acidosis, hypophosphatemia, and hypokalemia. Although the exact mechanism remains unknown, valproic acid (VPA) has been reported as a rare cause of FS. We have recently encountered four severely disabled children in whom FS developed after prolonged administration of VPA.Case Report:Case 1: This 4-year-old boy with microcephalus experienced seizures at age 2 months, and VPA was therefore started. He was bedridden. At age 2 years 7 months, hypokalemia of unknown origin developed. At age 4 years 2 months, routine laboratory examinations disclosed metabolic acidosis, hypophosphatemia, hypouricemia, and proteinuria. VPA was replaced by zonisamide (ZNS), and sodium citrate, phosphate supplementation, and vitamin D3 were added. Two months after the discontinuation of VPA, the urinary abnormalities disappeared. Case 2: This 8-year-old girl had West syndrome at age 3 months, and oral administration of VPA was started. She had spastic quadriplegia and was fed with a nasogastric tube. At age 8 years, the laboratory findings were compatible with FS. Immediate correction of the metabolic acidosis was started. VPA was stopped, and sodium citrate, vitamin D3, and phosphate supplement were administered. She regained normal renal functions within 2 months after the VPA therapy was stopped. Case 3: This severely disabled 14-year-old girl was treated with VPA from age 7 years. At age 13 years, she sometimes had a fever of unknown origin. Routine laboratory examinations revealed metabolic acidosis, hypophosphatemia, hypouricemia, proteinuria, glycosuria, generalized hyperaminoaciduria, and renal tubular dysfunction. A renal biopsy revealed interstitial nephritis without immune deposits. VPA was replaced by ZNS, and alkalization therapy was started. After discontinuation of VPA, she had no further febrile episodes. One year later, her laboratory data became almost normal except for the hypouricemia. Case 4: This 2-year-old girl had West syndrome at age 8 months, and VPA was started. She had spastic quadriplegia. At age 2 years, she was admitted to our hospital because of pneumonia. The laboratory findings on admission were compatible with FS. She was hypouricemic and hypokalemic, associated with metabolic acidosis. She exhibited proteinuria and increased FEUA. VPA was stopped, and vitamin D3 was administered. Her laboratory data became normal within 1 month after the discontinuation of VPA.Discussion:These four patients showed both clinical and biochemical evidence of FS. The reversion to normal of all clinical evidence of proximal tubular dysfunction after the cessation of VPA therapy is supportive evidence of a close relation between VPA and renal involvement. Although VPA has known adverse effects, renal effects are relatively uncommon. A direct effect of VPA on the mitochondria of the proximal tubules or interstitial nephritis caused by drug hypersensitivity was suspected to be the major mechanism causing VPA-induced FS. It is interesting that almost all reported patients with VPA-associated FS have been severely disabled and in a bedridden state, like our four patients. Although the relation between FS and a bedridden state remains unclear, a bedridden state may be a risk factor for FS in children with epilepsy taking VPA. We must pay attention to FS in children with epilepsy treated with VPA, especially in the severely disabled. [ABSTRACT FROM AUTHOR] |
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