Antiphospholipid Antibodies in Children with Age-Dependent Epileptic Encephalopathy.Purpose:Antiphospholipid antibodies (aPLs) have been found in the serum of patients with several neurologic disorders. Serum aPLs were detected in 19–26% of adult patients both with chronic epilepsy and with newly diagnosed seizure disorders. In children with partial epilepsy, Angelini et al. (1998) found aPLs in 13% of these cases. We studied the serum aPLs in 31 children with age-dependent epileptic encephalopathy: early infantile epileptic encephalopathy with suppression burst (EIEE), West syndrome (WS), and Lennox–Gastaut syndrome (LGS).Methods:Two children with EIEE, 20 with WS, and nine with LGS in the Pediatric Unit of Nihon University Itabashi Hospital were enrolled in the study. Inclusion criteria were (a) reliable diagnosis of age-dependent epileptic encephalopathy, (b) no signs or symptoms consistent with clinical immune system disorders and collagen diseases, and (c) negative for anticardiolipinβ2-glycoprotein I antibodies. Anticardiolipin antibodies (aCLs) of serum immunoglobulin G (IgG class) were measured with the enzyme-linked immunosorbent assay (ELISA) method. A value of aCL<10 U/ml is within normal limits. All of the subjects were classified in two groups. The patients in group A were diagnosed within 3 years, and those in group B were diagnosed beyond 3 years.Results:In the two patient with EIEE, the peak values of aCL were 57.9 and 35.6 U/ml. In patients with WS, the positive rate for the peak aCL levels was 91.7%, and the mean (±SD) level was 40.4± 39.2U/ml in group A, whereas the corresponding figures were 25% and12.7± 17.0 U/ml in group B. In patients with LGS, the positive rate for the peak aCL levels was 100%, and the mean level was 20.3± 6.6U/ml in group A, whereas the corresponding figures were 50% and 11.0± 12.2 U/ml in group B. We divided all the patients into a seizure-free group and a seizure-uncontrolled group. The mean peak value was 15.2± 17.8 in the seizure-free group and 38.8± 35.1 in the seizure-uncontrolled group.Discussion:A high positive rate of aPLs was found among patients with WS, characterized by early onset and long duration of epilepsy. These patients were poor responders to antiepileptic drugs (AEDs). Immunomodulatory therapies (intravenous Igs) have been shown to be effective in some children with this type of intractable epilepsy. Conversely, aPLs were more frequent among patients with localization–related epilepsies than in those with idiopathic generalized epilepsies. Several AEDs such as carbamazepine and phenytoin have been implicated as activators of antinuclear antibody production and drug-induced systemic lupus erythematosus. These antibodies are usually associated with autoimmune disorders such as primary antiphospholipid syndrome in rheumatic and connective tissue disorders. Two main pathogenic mechanisms have been proposed to explain the relationship between positive aPLs and neurologic symptoms (i.e., thrombotic and ischemic events within the CNS, and immune-mediated cellular damage from neuronal synaptic membrane attack). It has been shown that aPLs can disrupt neuronal function by directly acting on nerve terminals and reducingγ-aminobutyric acid-receptor–mediated chloride currents, suggesting a direct and reversible mechanism through which aPLs might lower the seizure threshold. It has also been postulated that antibodies to endothelium frequently coexist with aPLs and may induce apoptosis within the CNS. The high prevalence of positive aPLs in children with epilepsy indicates that immunologic dysfunction is associated with epilepsy, in at least some children. Conversely, aCL may appear after viral infections, and we speculate that some viral infections may be related to the age-dependent epileptic encephalopathyConclusions:The level of aPLs is related to disease severity and seizure frequency in patients with age-dependent epileptic encephalopathy, and aPLs may be useful to indicate prognosis and treatment effect. Regional Hyperperfusion in Temporal Lobe Seizures with Dystonic Posturing, Evaluated by Ictal–Interictal Subtraction SPECT.Purpose:Ictal hyperperfusion areas evaluated by multimodality registration methods may demonstrate anatomic localization of ictal symptoms. Dystonic posturing (DP) is one of the most reliable lateralizing indicators for temporal lobe epilepsy (TLE). Areas of regional hyperperfusion associated with DP in TLE were evaluated by using ictal–interictal subtraction single-photon emission computed tomography (SPECT).Methods:Twenty-three patients were randomly selected from 97 TLE patients who underwent operations between 1988 and 2000 in Shizuoka Medical Institute of Neurological Disorders (National Epilepsy Center). All ictal events were noted by reviewing long-term video-EEG monitoring records (by Y.I. and M.M.). The patients were divided into three groups according to the ictal symptoms: group D with unilateral DP, group H with elevated muscle tonus but without DP, and group N without DP or alternation of muscle tonus. For SPECT (Headtome set-070, Shimazu, Tokyo) sampling, each patient was injected with the same tracer during the ictal and interictal periods. Ictal and interictal SPECT and thin-slice magnetic resonance imaging (MRI; Sierra 1.5-T; General Electric, Milwaukee, WI, U.S.A.) were input into the automatic multimodality registration program (Dr. View/Linux, Asahikasei, Tokyo) to generate ictal–interictal subtraction images of SPECT on MRI for individual patients. Ictal hyperperfusion areas were evaluated by K.M. and M.T.Results:Six patients belonged to group D, nine patients to group H, and eight patients to group N. Statistically significant hyperperfusion was observed in the putamen (five patients in group D, two in group H and group N; p<0.01). Other ictal symptoms (such as autonomic symptoms, oral automatism, ocular or head deviation or both) showed no statistically significant differences except unilateral upper-limb automatism (four patients in group D, one in group H, and none in group N; p<0.01). Other factors such as age, sex, duration of illness, presence of MRI lesion or SPECT tracer (nine patients with[123I]-IMP and 14 with[99mTc]-ECD) were not statistically significant.Conclusions:A strong correlation between DP and putaminal hyperperfusion was demonstrated. Some patients showed a wide hyperperfusion area extending from the mesial temporal lobe to the putamen that may correspond to the propagation of epileptic discharges. Hyperactivity of the putamen is suggested to be associated with contralateral dystonic posturing. Epilepsy with Psychosis: Endocrine Psychic Syndrome.Case 1:A 9-year-old girl has had paroxysmal episodes of microspia and complex partial seizures without aura since age 8 years. She experienced visual hallucinations such as the strange face of an old lady and six moving ballerinas at age 9 years. In addition, she experienced auditory hallucination of a voice, something invisible coming close to her, and the feeling of fear. She broke her sister's comic book in a quick temper. Electroencephalogram (EEG) showed repetitive spikes on the left occipital and posterotemporal regions during both the psychotic state and remission. Brain magnetic resonance imaging (MRI) showed no definite abnormality. Brain single-photon emission computed tomography (SPECT) showed a subtle change in hypoperfusion in the left hemisphere. No definite differences were found during both states in EEG or SPECT. Her psychotic symptoms appeared after a lucid period of 30 min to 2 days and are followed by habitual complex partial seizures. It seemed that the psychotic symptoms of case 1 developed after seizures. We therefore considered that her symptoms correlated with the postictal stage, so-called postictal psychosis. However, her biochemical studies showed hyperthyroidism. Her psychotic symptoms disappeared soon after taking thiamazole.Case 2:A 21-year-old woman experienced complex partial seizures and secondarily generalized tonic–clonic seizures since age 2 years. She was admitted to the pediatrics department for recurrent vomiting. After admission, she complained that a ghost disturbed her eating. She experienced hearing voices of neighbors, delusions of reference and persecution, and delusions of speech with bizarre and grotesque features. In addition, she showed irritation, agitation, and violent behavior to her family. The EEG showed theta waves on bilateral frontocentroparietotemporal regions during psychosis. The same findings of EEG were observed during remission. Brain MRI showed a high-intensity area in the right cingulate gyrus. Brain SPECT showed hypoperfusion in the right mesial and lateral temporal regions during both states. However, hyperperfusion in bilateral frontal cortex were observed during psychosis. No correlation was noted between her psychotic symptoms and seizure activity or medication. We therefore considered that her psychotic symptoms resembled interictal chronic psychosis. However, her biochemistry data and the Ellsworth-Howard test showed pseudohypoparathyroidism type II. Her psychotic symptoms disappeared after treatment with a vitamin D analogue. We were able to discontinue all antipsychotic drugs.Conclusions:More than 150 years ago, von Basedow first described psychotic illness in a patient with exophthalmic goiter. Brownlie et al. reported psychosis associated with thyrotoxicosis. Eight among their 18 patients experienced hallucination, and 10 cases, including two schizophreniform cases, had good prognosis after an adequate treatment. Conversely, Hey et al. reported a case of Capgras syndrome in association with pseudohypoparathyroidism. This patient had mental retardation, epilepsy, and schizophrenia-like symptoms. Because of psychosis, he had a history of electroconvulsive therapy. Pollard et al. reported a 13-year-old Asian girl who showed hysterical paralysis and a rapid-cycling mood disorder. The mood disorder responded to treatment of pseudohypoparathyroidism with a vitamin D analogue.Although endocrine psychic syndrome is not unusual, epileptic psychosis combined with endocrine disease, as in our cases, is confusing as to whether the symptoms mimicked postictal or chronic psychosis. We propose to reconsider the association of psychiatric problems with endocrine disease when we encounter epilepsy patients with psychosis. Single Small Enhancing CT Lesions (SSECTL) in Epilepsy in India.Purpose:Single small enhancing CT lesions (SSECTLs) are extremely common in Indian epilepsy patients seen for the first time with seizures. Various hypotheses exist regarding their etiology, ranging from tuberculomas to neurocysticercosis, on the basis of histology and excisions done in a small percentage of cases. It also has been observed that these lesions disappear spontaneously over a short period after treatment with antiepileptic drugs (AEDs), causing doubts about their etiology and raising questions regarding management. The present study was carried out to observe such patients with SSECTLs with respect to persistence or disappearance of these lesions with AED treatment alone.Methods:All the new patients who attended our neurology clinics, with seizures, generalized or focal, were studied for the purpose of the present study. Apart from historical details and the seizure characteristics, complete neurologic examinations were done and recorded in specified form. Routine blood counts, erythrocyte sedimentation rate, urine examination, blood biochemistry, chest radiograph, and EEG were carried out. Computed tomography (CT) scan was done at the first instance and repeated after≥10–12 weeks of AED wherever possible. All the patients were given AEDs alone.Results:All the patients with first-ever seizures during the study period formed the subjects of this study; 43.5% of the patients had normal scans, whereas in 56.5%, the scans were abnormal. Of the patients, 12.9% had specific abnormalities, which included meningioma (5), gliosis (21), atrophy (21), multiple neurocysticercosis (43), and multiple infarcts (18), among others. 40.4% of patients showed nonspecific abnormalities on their scans such as low attenuation (51), high-attenuation disks (67), high-attenuation rings (241), generalized edema (56), and calcified spots (75). A follow-up scan was possible in 219 cases. Of these, 131 (59.8%) showed complete resolution, whereas 53 (24.2%) had significant resolution, but 35 (16%) remained unresolved.Discussion:The appearing and disappearing CT scan lesions in epilepsy in India have been an enigma. Initially these were thought to be tuberculous granulomas, as tuberculosis is one of the commonest diseases prevalent in this region. Disappearance of these lesions or healing by calcification by antituberculosis therapy (ATT) was taken as evidence for the hypothesis of tuberculosis. When some of these patients had to discontinue ATT because of adverse drug reactions, it was noted that these lesions disappear also without ATT. Subsequently, some histopathologic studies were conducted, with an evidence of neurocysticercosis in some of these patients, which resolved with cysticidal drugs. However, a majority of these patients who neither had ATT nor cysticidal therapy had their lesions resolve spontaneously on follow-up CT scans. Our study also supports the hypothesis. However, a small number of cases were seen in which these lesions either do not resolve or increase on follow-up CT scans. It is probable that these lesions do not represent one single etiology, and they must be managed appropriately.Conclusions:The SSECTL are one of the most common findings on CT in patients of epilepsy in India. These lesions resolve spontaneously without any specific treatment such as ATT or cysticidal therapy in the majority of patients. Therefore, there is an ample justification in treating them initially with AEDs only. A Neuropathological Study on the Limbic System in Dentatorubral-Pallidoluysian Atrophy.Purpose:Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by progressive myoclonic epilepsy (PME), dementia, and cerebellar ataxia. According to the age at onset, DRPLA is classified into juvenile, early-adult, and late-adult types. In the juvenile type, PME is most frequently observed, whereas seizures or PME sometimes and rarely occurs in early- and late-adult types. In general, glutamate transporters and calcium-binding proteins (parvalbumin and calbindin-D28K) are believed to reflect glutamate neurotoxicity and functions of theγ-aminobutyric acid (GABA)ergic inhibitory interneurons in the limbic system, respectively. To investigate epileptogenesis in DRPLA, we examined the expressions of glutamate transporters and calcium-binding proteins in the limbic system in autopsy cases of DRPLA.Methods:Fourteen autopsy cases of clinicopathologically confirmed DRPLA, comprising nine cases of juvenile type with PME and five cases of late-adult type without PME, as well as 10 age-matched controls, were studied. Immunohistochemistry was performed on serial sections of the temporal lobe including the hippocampus, amygdaloid complex, and entorhinal cortex, by using mouse monoclonal antibodies to parvalbumin and calbindin-D28K (Sigma-Aldrich, St. Louis, MO, U.S.A.) and rabbit polyclonal antibodies to excitatory amino acid transporters 1 (EAAT1), EAAT2, and EAAT3 (Wako Pure Chemicals Industries, Japan). The degree of immunoreactivity was evaluated by semiquantitative visual inspection.Results:The number of interneurons immunoreactive for parvalbumin or calbindin-D28K seemed to be lower in cases of the juvenile type of DRPLA with PME compared with that in cases of late-adult type of DRPLA not manifesting PME. Reduction of calbindin-D28K–immunoreactive neurons appeared to be more prominent than that of parvalbumin-immunoreactive neurons. It is noteworthy that four of five cases of the juvenile type, in which seizure occurred before puberty and the amygdaloid complex could be examined, and one case of the adult type completely lacked the amygdaloid immunoreactivity for parvalbumin or calbindin-D28K. The amygdaloid lesion is likely to be related to PME in DRPLA as either a cause or a result. Conversely, the expression of glutamate transporters seemed to be mildly affected. Three cases of juvenile type and one case of adult type showed a reduced expression of EAAT1 or EAAT2 or both in the entorhinal cortex, hippocampus, or amygdaloid complex. The expression of neuronal glutamate transporter EAAT3 was comparatively preserved in most of the remaining neurons in all subjects.Conclusions:An active debate has continued on the subject of whether the cerebral or subcortical lesions are more involved in the epileptogenesis in DRPLA. Neuropathologically, various brainstem changes, such as atrophy of the brainstem tegmentum, have been delineated. Previously we performed neuropathologic analysis of the brainstem in the same subjects and failed to find any PME-specific lesions. The current study showed that the GABAergic interneurons were altered more definitively in cases of juvenile type manifesting PME, whereas glutamate transport might not be severely disturbed in the limbic system in DRPLA. Recently, neuroradiologic studies have shown the presence of cerebral cortical atrophy in DRPLA. Furthermore, the extensive involvement of cerebral cortical neurons was demonstrated by immunohistochemistry against mutant atrophin-1, a responsible protein for DRPLA, particularly in the juvenile type. Taking these findings together, we speculate that the occurrence of PME in DRPLA may be related to the lesions of the cerebral cortex, including the limbic system. We also believe that further functional analysis of the cerebral cortex is useful to examine treatment for the usually intractable PME in DRPLA. Prevalence and Localizing Value of Emotional Facial Paresis in Medically Refractory Temporal Lobe Epilepsy.Purpose:The selection of patients with medically refractory temporal lobe epilepsy (TLE) for surgery depends on the concordance of data from clinical, electroencephalographic (EEG), radiologic, and neuropsychological evaluation. Although the clinical examination is often normal, contralateral emotional facial paresis (EFP) has been observed in patients with medically refractory mesial TLE (MTLE). Emotional facial paresis refers to unilateral lower facial weakness during emotional expression such as smiling, along with normal voluntary facial movements. We intended to determine the frequency of occurrence of EFP and its lateralizing significance in identifying appropriate candidates for anterior temporal lobectomy (ATL) with amygdalohippocampectomy.Methods:We investigated the prevalence, predictive value, and associations of EFP among 50 consecutive patients who underwent ATL during the period from November 1999 to July 2001 and satisfied the following criteria: (a) magnetic resonance imaging (MRI) findings consistent with mesial temporal sclerosis (MTS) and concordant interictal and ictal EEG data; and (b) seizure free or≥90% seizure reduction for≥6 months after ATL. Fifty age- and sex-matched normal subjects acted as controls. Facial asymmetry was assessed at rest and during volitional movements. EFP was looked for during conversation, by provoking a smile. The whole examination undertaken during the video-EEG monitoring was available for review. To ascertain observer bias, two investigators (A.J. and J.C.) independently examined the first 20 patients for the presence or absence of emotional facial paresis. The interobserver agreement was 80% with a kappa value of 0.63. Subsequently, one investigator (A.J.) assessed all subjects, and controversies were resolved by reexamination along with J.C. or K.R. We used standard deviation to define the dispersion, andttest (two-tailed) and Fisher's exact test to evaluate the significance of the association of different clinical characteristics between patient and control groups, and between patients with and without emotional facial paresis.Results:The patients comprised 27 male and 23 female subjects. The age at ATL ranged from 14 to 55 years, and the mean duration of epilepsy before ATL was 17.8 years. When compared with eight (16%) of 50 control subjects, 36 (72%) of 50 MTLE patients exhibited unilateral EFP; the difference was highly significant (p<0.0001). The presence of contralateral EFP correctly predicted the side of ATL in 86.1% of patients. Patients with EFP had a longer duration of epilepsy compared with those without this sign (19.2± 8.0 vs. 14.4± 6.1 years; p= 0.048). We did not find any significant association between EFP and the following clinical characteristics: age at epilepsy onset, age at ATL, gender, and antecedent history of febrile seizures. Both the patients and the control subjects had EFP more frequently involving the right side of the face. Of the eight control subjects who had EFP, seven had it on the right. Whereas 13 (54.2%) of 24 patients with right MTLE had EFP (on the left side in 11), 23 (88.5%) of 26 with left MTLE had emotional facial paresis (right side in 20; p= 0.011).Conclusions:Our observations confirm that EFP contralateral to the side of MTS is a valuable localizing sign in correctly predicting the epileptogenic temporal lobe. To our knowledge, the significant association we observed between left MTLE and more frequent occurrence of emotional facial paresis has not been previously documented. The value of EFP in localizing the ictal-onset zone in patients with bilateral MTS is uncertain. We hypothesize that the presence of an intact right hemisphere and pathologic changes more extensive than MTS may be required for EFP to be readily manifest. Convulsive Episodes in Patients with Group A Xeroderma Pigmentosum.Purpose:Xeroderma pigmentosum is an autosomal recessive disease characterized by sunlight hypersensitivity, freckles, and skin cancers. In addition to these skin lesions, patients with group A xeroderma pigmentosum (A-XP) show progressive and severe neurologic complications of unknown causes. However, few A-XP patients with seizure disorders have been reported in the literature (Mimaki et al., 1988), and no systematic search for seizure disorders in A-XP patients has been performed. We aimed to clarify the incidence of convulsive episodes in patients with A-XP.Methods:We investigated the history of convulsive episodes of 33 A-XP patients in our institute by reviewing the medical charts or conducting interviews with caregivers.Results:Five patients had episodes of convulsions at age 12 years (YoT, male), 13 (MA, female), 14 (HM, female), 16 (YY, female), and 19 and 21 (YaT, male) years. YoT and YY were siblings, and they had another healthy brother who had no history of convulsive episodes. Their parents also had no history of convulsions. Among family members of MA, HM, and YaT, no seizure disorder was identified. YoT, MA, HM, and YY exhibited brief episodes of loss of consciousness with cessation of movement. Valproate acid (VPA) was effective for these episodes. YaT had a brief cessation of respiration at age 19 years, which disappeared after phenobarbital (PB) administration. PB was discontinued by the family after 6 months of treatment, and he (YaT) had a generalized tonic seizure with left upper extremity focality at age 21 years. He has been taking PB again, and no further episode appeared for the past 4 years. A few low-voltage theta rhythms were the dominant background activities of drug-induced sleep EEG recordings of these five patients. Except HM, no apparent epileptic discharge was found on interictal EEG recordings. HM showed periodic high-voltage sharp waves at bilateral frontal regions on drug-induced sleep EEG recording when she was 15 years old. Except MA, no A-XP patient had an episode of febrile seizure. MA had a single febrile seizure when she was 4 years old.Conclusions:Because these five patients exhibited recurrent afebrile seizures, we diagnosed them as having epilepsy. However, we could not identify the precise type of epilepsy, in part because of few EEG findings. A-XP patients exhibit marked diffuse brain atrophy after age 5 years (Ohinata et al., 2002), which makes it difficult to obtain apparent epileptic discharges on routine EEG recordings. From the clinical standpoint, YaT is considered to have symptomatic localization-related epilepsy, showing complex partial seizures at age 19 years with secondary generalization at 21 years. The other four patients might exhibit complex partial seizures (due to localization-related epilepsy) or atypical absence seizures (due to generalized epilepsy), but few typical EEG findings, making it difficult to differentiate the types of epilepsy. Nevertheless, we diagnosed five (15%) of 33 A-XP patients as having symptomatic epilepsy. In contrast, we found only one (3%) patient with a history of febrile seizures. In the general population,∼3% of all people living to age 80 years in the United States will be diagnosed with epilepsy (Westbrook, 2000). The cumulative incidence of febrile seizures in Europe and the United States is 2–5%, and that in Japan is 8–10% (Maeda, 2001). Taking these figures together, in comparison with the general Japanese population, Japanese A-XP patients show a lower incidence of febrile seizures, whereas they exhibit a higher prevalence of epilepsy. Neurohumoral Behavior of Epilepsy with Neurocysticercosis in Nepal.Purpose:Epilepsy due to neurocysticercosis (NC) is common in Nepal. The 120 epilepsy cases with NC confirmed by magnetic resonance imaging (MRI),Diagnostic and Statistical Manual of Mental DisordersIV, and International League Against Epilepsy criteria were subjected to enzyme-linked immunosorbent assay (ELISA) testing for comparative study of serum anti-cysticercus antibody levels between epilepsy with various types of NC before and after treatment with antihelminthic, correlation with therapeutic efficacy of cysticide, and identification of a prognostic indicator. Comparative MRI studies of the brain were done with various types of NC before and after treatment to evaluate drug efficacy, resolution rate of the cerebral lesion, and correlation with antibody titer.Methods:Ninety persons with epilepsy with single benign parenchymal NC and 30 with multiple benign parenchymal NC were subjected to ELISA before and 1 month after the unified treatment regimen with albendazole, 15 mg/kg/body wt daily, for 8 days, and oral cortisone. Comparative studies of serum antibody titers and correlation between mean optical density (OD) and therapeutic efficacy of cysticide before and after treatment were done to evaluate the therapeutic efficacy. Assessment of antibody titer was done to understand the efficacy of treatment and to find an indicator of prognosis. MRI scan of the brain was done before and 8 days after the treatment to assess the resolution of the cerebral lesion and correlation with antibody titer.Results:The sensitivity of ELISA for serum anti-cysticercus antibodies in epilepsy with multiple benign parenchymal NC was 93.3%, showing strong positivity in contrast to epilepsy with single benign parenchymal NC, with a sensitivity of 77.8%. Comparative studies of the sensitivity of ELISA between epilepsy with single and multiple benign parenchymal NC before treatment were significant (F= 15.47; p≤ 0.0001). The mean ODs of epilepsy cases with single benign parenchymal NC before and after treatment were mean, 1.387; SD, 0.433; and m, 0.314 SD, 0.102, respectively (F= 430.31; p= 0.0001). In contrast, the ODs of epilepsy with multiple benign parenchymal NC were m, 1.757; SD, 0.321; and m, 0.482; SD, 0.164, respectively (p= 0.0001). The differences between the OD of epilepsy with single (m, 0.314; SD, 0.102) and multiple benign parenchymal NC (m, 0.482; SD, 0.164) before and after treatment were highly statistically significance (F= 43.93; p= 0.0001). MRI study after treatment for epilepsy with various types of NC revealed that of 90 epilepsy cases with single benign parenchymal NC, 94.4% resolved completely, 2.2% resolved partially, and 3.3% showed no change, whereas, of 30 epilepsy cases with multiple benign parenchymal NC, 40% resolved completely, 30% resolved partially, and 30% showed no change. The comparative therapeutic responses to albendazole in epilepsy cases with single benign parenchymal NC and multiple benign parenchymal NC revealed that the former responded better than the latter (i.e., the cure and resolution rate was 94.4% vs. 40% for epilepsy with single benign parenchymal NC vs. multiple benign parenchymal NC). Epilepsy with single benign parenchymal NC having low serum OD showed better response to treatment, in contrast to epilepsy with multiple benign parenchymal NC having higher serum OD.Conclusions:Epilepsy with NC is the biologic marker of poverty and poor sanitation in the community of an undeveloped country. The low serum OD in epilepsy with single benign parenchymal NC showed a better response to the treatment in contrast to epilepsy with multiple benign parenchymal NC having higher serum OD. These results indicate that low serum antibody titer of epilepsy with NC predicts good prognosis and better therapeutic efficacy of antihelminthic treatment. The evaluation of the serum antibody titer of epilepsy with NC may be used for the diagnosis, assessment of therapeutic efficacy of antihelminthic treatment, and prediction of prognosis. Probable Molecular Dysfunction by Autoantibodies Against NMDA-Receptor GluRℇ2 in Epilepsies After Acute Encephalitis.Purpose:Glutamate receptors (GluRs) in the central nervous system play an important role in the excitatory synapse and have been implicated in neurodegenerative diseases and symptomatic epilepsy. After Rogers et al. reported that autoantibodies against GluR3 were involved in some cases of Rasmussen encephalitis, studies focused on other neurologic diseases with a possible causal relation to autoantibodies against GluRs. In 1999, we found autoantibodies against theN-methyl-d-aspartate (NMDA) GluRℇ2 subunit in sera and CSF from patients with chronic progressive epilepsia partialis continua, Rasmussen encephalitis, and other diseases. To elucidate the pathophysiologic mechanisms of intractable epilepsy after acute encephalitis or encephalopathies, we studied the autoantibodies in sera and CSF from such patients.Methods:With the tetracycline-induction system, we established stable NIH3T3 transformant cell lines expressing the NMDA-type GluRℇ2 subunit. Cell extracts of the transformants were transferred to nitrocellulose membranes to detect the presence of antibodies against GluRℇ2. The membrane was exposed to sera from patients and was stained by second antibodies coupled to alkaline phosphatase. Four peptides (an N-terminal, and three C-terminal fragments) were synthesized from GluRℇ2 cDNA by using bacterial fusion protein vectors. Homogenates of the transformants and bacteria were transferred to nitrocellulose membranes, and the membranes were incubated with the patients' sera or CSF, and stained by second antibodies coupled to alkaline phosphatase. Fifteen patients with epilepsies after acute encephalitis (influenza virus; two patients, herpes simplex virus; two, varicella zoster virus; one, others) and three after acute encephalopathies (influenza vaccination, others) were studied. Ages at onset were from 2 to 36 years (0–5 years, eight patients; 6–10 years, four; 11–15 years, three; older than 16 years, three). Cerebral palsy was found in eight patients, and mental retardation (IQ<70) in 11 of 18 patients. Seizure outcome ranged from seizure free (five patients), monthly (four), weekly (five), to daily (three).Results:Immunoglobulin G (IgG) and IgM autoantibodies against the NMDA GluRℇ2 subunit were positive in 13 and 12, respectively, of 18 patients. IgM autoantibodies disappeared in two patients, and IgG autoantibodies changed from absence to presence in three patients evolutionally. Two patients continued to have the autoantibodies even several years after acute encephalitis. Production of autoantibodies against GluRℇ2 was related significantly to episodes of convulsive status epilepticus in the acute stage of encephalitis (p= 0.19; Spearman's correlation coefficient by rank test) and insignificantly to cell counts and protein levels in CSF, duration of unconsciousness, and the latency of first convulsion from onset. Comparing neuropsychological outcomes between patients with and without the autoantibodies, the autoantibodies were causally related to mental retardation (p<0.03, Mann–WhitneyUtest), motor impairment (p<0.03,χ2 for independent test), and seizure frequencies (p<0.03, Spearman's correlation coefficient by rank test). The epitopes of the autoantibodies existed mainly in the c-terminal of GluRℇ2 molecules. In five patients (broader type), both n- and c-terminals were epitopes of the autoantibodies; in eight (narrow type), only c-terminals were epitopes. Comparing the relations between broadness of epitopes and clinical factors, no significant correlation was found for age at onset (p= 0.11, Spearman's correlation coefficient by rank test), concentration of proteins in CSF (p= 0.07, Spearman's test), and latency of convulsion from the onset of illness (p= 0.09, Spearman's test). The broadness of epitopes was not related to neuropsychological outcomes but was related to lower cell counts in CSF. The spectra of epitopes were broader in CSF than in sera.Conclusions:Production of the autoantibodies might be related to destruction of brain tissue by a convulsive status and might contribute to severe neuropsychological outcomes. Relationship Between Clinical Characteristics and Magnetoencephalographic Findings in Typical and Atypical Benign Childhood Epilepsy with Centrotemporal Spikes.Purpose:Benign childhood epilepsy with centrotemporal spikes (BECT) is an electroclinical syndrome characterized by partial sensorimotor seizures (sylvian seizures: SSs) with centrotemporal spikes (rolandic discharges: RDs). Typically the prognosis is excellent with remission before age 16 years. However, some patients with BECT initially seem to evolve into atypical or complicated types, one of which has been called atypical benign partial epilepsy of childhood (ABPC) by Aicardi. Recently, the search for the predictor of evolution into atypical or complicated types was attempted. In this article, we use the termcomplicated BECT(CECT) to include atypical or complicated types. We report the detailed analysis of the generator of RDs in BECT and CECT by using magnetoencephalography (MEG).Methods:Sixteen children with BECT undertook MEG examination; seven were excluded because of insufficient numbers of RDs for analysis, leaving nine patients. All three patients with CECT were characterized as having frequent atonic seizures (negative myoclonus) or hemifacial or hand twitching, with continuous spike–waves during slow wave sleep in EEG, and also mental deterioration. MEG activity was recorded during sleep by using a whole-head 204-channel neuro-magnetometer (Neuromag-204) with simultaneous EEG recordings. Locations and directions of estimated dipoles of high-amplitude MEG sharp waves were displayed on magnetic resonance images. The data were sampled at 300 Hz with a 160-Hz low-pass filter and analyzed under 45-Hz low-pass filter and 1- to 3-Hz high-pass filter. Analysis of three types of MEG spikes was performed: current dipoles of the first of the highest or lowest peak. Therefore, a uniform pattern of MEG spikes was analyzed individually.Results:In nine (56.3%) of 16 patients with BECT and all three (100%) patients with CECT, sufficient numbers of MEG spikes (>30 spikes in several sampling sequences for about several minutes each) were detected for analysis. Five typical BECT patients had only SSs during sleep, typical unilateral RDs, and over a 2-year seizure-free period, except one patient. These patients had typical MEG spikes characterized by current dipoles showing relatively limited localization and regular directions. The remaining four patients with BECT had clinical characteristics other than SSs, such as refractory SSs, perioral twitching during wakefulness, febrile convulsions after epilepsy onset, and fewer RDs on EEG while remaining significant in number on MEG. These patients showed less concentrated MEG spikes and moderately irregular dipole directions. In all three patients with CECT, current dipoles were scattered widely around rolandic areas, showing more irregular directions.Conclusions:Although we have not developed sequential MEG data of individual patients, our MEG findings may suggest an intermediate type of BECT as a continuum between typical BECT and CECT. Scattering of epileptic foci from the restricted rolandic areas may be due to some immaturity of neuronal systems. Multifocal activated cortical areas, including excessively inhibitory or excitatory neuronal generators, may induce CECT evolution and neuropsychological dysfunction. This kind of mechanism may play a role in the formation of secondary bilateral synchrony, which is considered to cause generalized spike–waves in some cases of BECT. If sequential MEG data in the very early stages of BECT onset are obtainable individually, evolution to complicated BECT may be predictable. Our MEG findings suggest an intermediate type of BECT as a continuum between typical BECT and CECT or ABPC. If current dipoles are scattered and showing more irregular directions, even in the early stage of CECT, MEG study may be a quick predictor of complications. MEG may be able to explain the mechanism of evolution of typical BECT to complicated BECT. Safe Pregnancy in Epilepsy: Registry of Epilepsy and Pregnancy Initiative in India.Background:Care for women with epilepsy (WWE) is suboptimal in most countries. The Government of India has recently eased the legal constraints to marriage for WWE. The proportion of married among WWE is comparable to that in the community, according to a survey in Kerala State. WWE in developing countries face several difficulties. Health services are sparse and expensive. Many of them have malnutrition, anemia, or intercurrent infections. Social stigma is another major handicap.Objective:Indian Registry of Epilepsy and Pregnancy (IREP) is established to monitor reproductive functions in WWE and facilitate their optimal care under prevailing conditions.Methods:The first registry in India was started at Trivandrum (TVM) in 1998. A consensus protocol was developed in a workshop held in Trivandrum in 1998. Preconception management focuses on diagnosis, antiepileptic drug (AED) therapy, if required, and initiation of folate supplementation. We use a higher dose of folate (5 mg daily) to obviate any nutritional deficiency. The early antenatal care includes estimation of serumα-fetoprotein (16 weeks) and malformation-targeted ultrasonography (18 weeks). The couple is provided extensive counseling on the diverse aspects of epilepsy and pregnancy. It is often necessary to counsel close relatives also, as many couples live in joint families. Two intramuscular injections of vitamin K (10 mg) are recommended in the last 6 weeks of pregnancy, as oral vitamin K preparations are not widely available. Three months after delivery, babies are screened for malformations by physical examination, echocardiography and abdominal ultrasonography. We assess development and language at 1 and 3 years, respectively. Similar registries were set up on the east coast (Vishakhapattanam-VZG, 1999) and North India (Ludhiana-LDH, 2000). These registries are following a unified protocol and joined together to form IREP. Three new centers are being established in other parts of India. IREP is now pooling data with the European Registry of Epilepsy and Pregnancy.Results:As of January 2002, 547 WWE (mean age, 24 years) were enrolled (TVM, 386; VZG, 125; LDH, 36), and 320 had completed pregnancies (TVM, 224; VZG, 66; LDH, 30). AEDs included carbamazepine,141; phenytoin, 98; phenobarbitone, 83; valproate, 63; clobazam, 12; clonazepam, seven; and lamotrigine, seven. Preconception or first trimester folate supplementation was high in TVM (83%) but low in VZG (33%) and LDH (17%). There were 38 (11.9%) cases with malformations (including two terminations). Nervous system malformations included spina bifida and meningomyelocele (three). There were 20 cases of cardiac defects, including tetrology of Fallot, coarctation of the aorta, patent ductus, septal defects, and patent foramen ovale; some of latter had closed subsequently. Other malformations involved the skeleton (seven), genitourinary system (four), and anterior abdominal wall (three). Babies from one center (TVM) showed mild delay in motor and mental development at age 1 year, when compared with matched normal babies.Conclusions:The spectrum and prevalence of birth defects observed in this study are comparable to those in reports from elsewhere. Ultrasonography and echocardiography has enabled us to detect malformations like hydronephrosis, cyst in liver, and small septal defects. It is debatable whether patent foramen ovale should be recognized as an anomaly or otherwise, as several of them closed subsequently. This initiative has sensitized the medical fraternity to the special needs of WWE and has contributed to improving the standards of care for them. Wada Test and Interictal[ 18F]FDG-PET in Unilateral Temporal Lobe Epilepsy.Purpose:To investigate the association between regional glucose metabolism obtained with interictal[18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) and material-specific memory measured with the Wada test in patients with unilateral temporal lobe epilepsy.Methods:We investigated 47 consecutive patients with intractable, unilateral temporal lobe epilepsy (26 left and 21 right) who underwent presurgical evaluation including interictal18FDG-PET and the Wada test. Nine patients had non-left dominance for language (one right and eight mixed); the remainder were left dominant. To obtain regional glucose metabolism, we worked with 14 groups of regions of interest (ROIs) in either hemisphere. We calculated the PET asymmetry index (PET-AI) for each group of ROIs by using the formula: (L− R)/(L+ R)× 200, where L or R represents averaged glucose metabolism in each ROI on the left or right hemisphere. In addition, we created a“general asymmetry factor,” which is the mean of all the 14 PET-AIs, to diminish general effects of unilateral hemispheric hypometabolism that are commonly seen in patients with unilateral temporal lobe epilepsy. To estimate unilateral memory, we used recognition memory paradigms in the Wada test based on words, faces, and pictures and obtained three material-specific memory scores for each hemisphere. The memory asymmetry index (memory-AI) for each material was calculated by using the formula: (L− R)/6× 100, where L or R represents material-specific memory scores performed on the left or right hemisphere. In our statistical analysis, we created a linear regression model to predict the memory-AI for each material by combining the PET-AI for each ROI with the general asymmetry factor. The model was compared between subgroups according to the side of focus or the language dominance.Results:The associations between the PET-AI and the memory-AI did not significantly differ between patients with left and right foci. In four combinations of PET-AI and memory-AI, the associations were significantly different between the subgroups according to language dominance. Only patients with non-left language dominance showed positive correlation of PET-AI with memory-AI: PET-AI for the lateral frontal region with memory-AI for words (t=−3.39; p= 0.002) or for pictures (t=−2.29; p= 0.027); PET-AI for the anterior inferior temporal region and memory-AI for faces (t=−2.48; p= 0.017); and memory-AI for words and PET-AI for the anterior superior temporal regions (t=−1.99; p= 0.053).Conclusions:When we analysed the subgroups according to the side of focus, we found no significant associations between the PET-AI in any brain area and the memory-AI for any material. In contrast, when we analyzed the subgroups according to language dominance, we found four significant associations between hypometabolism in certain areas and material-specific memory deficits, and this was observed only in patients with non-left language dominance. Our results suggest that in patients with unilateral, drug-resistant temporal lobe epilepsy, functional anatomy of memory also is influenced by language dominance. Muscle Activity During Non-REM Sleep in Patients with Infantile Spasms.Purpose:Under physiologic conditions, muscle activity is abolished during rapid-eye-movement (REM) sleep but is sustained in non-REM sleep. We found a disturbance of muscle activity during REM sleep in patients with infantile spasms (ISs) (Kohyama et al., 2000). In the current study, we examined muscle activity during non-REM sleep in patients with ISs.Methods:Twelve IS patients (ages, 53–83 postconceptional weeks; mean, 64.1), who had not previously been treated, were enrolled in the study. Nine of 12 patients had a good prognosis on convulsions. One all-night polysomnography was performed for each patient, and the percentage of chin muscle atonia during non-REM sleep (%ATNR) was calculated. Seven neurologically unaffected infants (ages, 55–81 postconceptional weeks; mean, 70.4 weeks) served as age-matched controls.Results:%ATNR in IS patients ranged from 5.5 to 33.4 (mean, 19.0). The mean value was higher than that in the controls (13.8; range, 3.4–29.4), although no significant difference was obtained (p= 0.27).Conclusions:Petre-Quadens (1972) reported the normal %ATNR value in 10 children aged three months to 5 years as 14.7%. In comparison with this value, Fukuyama et al. (1979) reported elevation of %ATNR in IS patients. They also reported that the mean %ATNR value in three patients who showed unfavorable response to adrenocorticotropic hormone (ACTH; 45.3; range, 32.0–63.8) was higher than that in five IS patients with a favorable response to ACTH therapy (37.6; range, 17.7–55.1). Interestingly, Petre-Quadens (1972) also reported elevation of a similar index in children with mental retardation. Brain insults may result in the elevation of %ATNR. In the current study, however, we failed to demonstrate a significant difference in %ATNR between IS patients and age-matched controls. Petre-Quadens (1972) also observed the average %ATNR in young adults (aged 15–25 years) to be 2.4% and hypothesized that this index declines with age progression. However, based on a study with healthy young children, we found no age-related decrease of %ATNR (Furushima et al., 2002). The cited works including the current study were based on visual inspection of muscle activity, and so far, no consistent results have been obtained on %ATNR. Recently, Werth et al. (2002) analyzed chin muscle activity during non-REM sleep by using computer analysis, and found that chin muscle atonia during non-REM sleep appeared at a constant rate of 10–15% throughout the night in healthy young adults. They also examined %ATNR in patients with narcolepsy and observed that the latency to chin muscle atonia during non-REM sleep was shorter in narcoleptics (0.7± 1.1 min) than in normal controls (48.8± 28.9 min). They speculated that atonia during non-REM represents a measurement of REM propensity. The brainstem cholinergic and monoaminergic systems are involved in the state-dependent muscle activity control. Cholinergic agents microinjected into the brainstem elicit muscle-tone suppression, and the disfacilitation of serotonergic system is considered to be involved in the decrease of excitability of the hypoglossal motoneuron. %ATNR is easily measured on routine EEG recordings, with the only addition of the measurement of chin muscle tone. %ATNR is a potentially useful index reflecting the balance between the brainstem cholinergic and monoaminergic activities. Broad clinical application of %ATNR with the development of a computerized analyzing system is expected to provide new insights into the assessment of cholino-monoaminergic activities in the brainstem. [ABSTRACT FROM AUTHOR]