Immunological studies in focal epilepsy

Serum immunoglobulins, T-lymphocyte subsets and HLA investigations were carried out in 24 patients with focal, mainly temporal lobe, epilepsy and in 30 of their first degree relatives. The mean serum level of IgA was significantly decreased in the epileptic probands compared with controls. In the relatives, there was a significant decrease in mean IgM levels. The epileptic group had significantly fewer circulating T4 "helper" lymphocytes (absolute and percent) and an increased percentage of T8 "cytotoxic"/"suppressor" lymphocytes than the controls. The effect of antiepileptic drug treatment on these results is discussed. The frequencies of 63 HLA specificities determined were not significantly different in probands compared with controls. Among 5 of the most commonly occurring haplotypes there was a lower frequency of the haplotype A1,B8 in epileptic probands, which is in accordance with an earlier study on benign focal epilepsy in children. The immunological findings support the possibility that focal epilepsy may be linked to a genetically dependent immune dysregulation. The latter may contribute to the variability underlying the multifactorial inheritance of the epilepsies.     

The effect of carbamazepine on serum immunoglobulin concentrations

Serum IgA, IgG and IgM concentrations were determined in 30 patients with partial epilepsy before and during carbamazepine therapy. None of them had received anti-epileptic drugs prior to the study. The IgA and IgM concentrations decreased significantly during the 1st month of treatment ( P < 0.0001). No further decrease was observed during the subsequent 3 months. 15 patients were followed for 8-30 months. The IgA concentrations remained low, while the IgM concentrations tended to increase. However, the IgM concentrations did not reach the levels which were found before carbamazepine was started. Carbamazepine had no influence on the mean IgG serum concentration. There was no relationship between the IgA and IgM concentrations in serum and the serum concentrations of carbamazepine.     

Serum concentrations of immunoglobulins in patients with epilepsy treated with carbamazepine

The concentrations of IgA, IgG and IgM were determined in sera of 16 patients, all of whom had partial epilepsy and had received CBZ as the only drug since the beginning of therapy. Fifty-three healthy subjects served as controls. Serum concentrations of IgA and IgG were significantly higher in patients than in controls (IgA: P = 0.05; IgG: P = 0.01). The concentration of IgM was not significantly different from that of the controls (P = 0.1). The IgG serum levels in the controls were lower with increasing age. Furthermore, IgG serum levels were higher with increasing CBZ concentrations.     

Seizures among families of Indian probands with different epileptic syndromes

OBJECTIVES: To investigate the contribution of hereditary factors in the causation of different epilepsy syndromes. MATERIAL AND METHODS: Occurrence of seizures among first- and second-degree relatives of 5628 Indian probands with epilepsy, and 3357 probands with non-epilepsy neurological disorders (who acted as control population) was documented. Syndromic concordance between epilepsy probands and affected relatives was investigated. RESULTS: Twenty percent epilepsy probands (1129) had affected relatives. Relatives of epilepsy probands were more often affected compared with relatives of non-epilepsy probands (OR: 3.4). Probands with some epilepsy syndromes more often had a positive family history. Relatives of younger probands were at greater risk of having epilepsy. Sibs were more often affected compared with other first- and second-degree relatives (OR: 1.3 and 4.6). Sibs having generalized epilepsies and syndromes and febrile convulsions (FC) were at greater odds of syndromic concordance with probands compared with second-degree relatives. Sibs and second-degree relatives having idiopathic/cryptogenic epilepsy had greater odds for concordance compared with those with symptomatic epilepsies. CONCLUSIONS: One-fifth of probands with all types of epileptic syndromes have family history of seizures. Familial risk of epilepsy correlated with the epilepsy syndrome among probands and their age at presentation. Risk of relatives being affected varied as a function of the relation with probands. Concordance of epilepsy syndromes varied both as a function of the epilepsy syndrome and relation with the probands.     

Salivary immunoglobulin concentrations in patients with epilepsy treated with carbamazepine

Various anti-epileptic drugs may affect the immune system. An IgA-depressing effect of carbamazepine has been proposed, but only serum concentrations have been studied. IgA constitutes a small fraction of the serum immunoglobulins, while it is the predominating one in external secretions. In the present study the concentrations of IgA, IgG and IgM in unstimulated saliva were determined by single radial immunodiffusion in 34 patients with partial epilepsy, and being treated with carbamazepine alone. Median salivary IgA concentration in the patients was 208 × 10^-3 g/l, compared to 150 × 10^-3 g/l in 41 healthy controls. Salivary IgG and IgM concentrations were also somewhat higher in the patients than in the controls, while the albumin concentrations were similar in the two groups. However, the differences in the immunoglobulin concentrations between patients and controls were not significant at a 5 % level. There was no significant correlation between the concentrations of IgA in saliva and serum.     

Immunoglobulin abnormalities in relatives of IgA deficient epileptics

Summary Serum levels of IgA were found to be reduced in some patients with epilepsy. Further studies revealed that only epileptics with constitutional factors for seizures showed, if ever, IgA deficiency, particularly those treated with hydantoins (up to 25%). In order further to substantiate the association of immunoglobulin alterations with epilepsy nine families in whom the disease was clustered were investigated. An IgA deficiency was detected in 16 of the 19 epileptics (three without hydantoin medication), but in none of their 45 non-epileptic relatives. However, four of the relatives had a low IgM. Seven other families were tested in each of which only one IgA deficient epileptic was known. No other family members were found with a low IgA, but 24 of 58 such relatives had increased IgM serum concentrations. The association of IgA deficiency and epilepsy with IgM imbalances in relatives of IgA deficient epileptics gives additional support for the hypothesis that immune imbalances and certain forms of epilepsy might be linked.Supported by the Swiss National Science Foundation (Grant number 3.077-0.76)     

Familial occurrence of febrile seizures and epilepsy in severe myoclonic epilepsy of infancy (SMEI) patients with SCN1A mutations

PURPOSE: The role of the familial background in severe myoclonic epilepsy of infancy (SMEI) has been traditionally emphasized in literature, with 25-70% of the patients having a family history of febrile seizures (FS) or epilepsy. We explored the genetic background of SMEI patients carrying SCN1A mutations to further shed light on the genetics of this disorder. METHODS: We analyzed the occurrence of FS and epilepsy among first- and second-degree relatives (N = 867) of 74 SMEI probands with SCN1A mutations (70 de novo, four inherited) and compared data with age-matched and ethnically matched control families. Familial clustering and syndromic concordance within the affected relatives in both groups were investigated. RESULTS: The frequency of FS or epilepsy in relatives of SMEI patients did not significantly differ from that in controls (FS: 13 of 867 vs. 12 of 674, p = 0.66; epilepsy: 15 of 867 vs. six of 674, p = 0.16). Different forms of epilepsy were identified in both relatives of SMEI probands and controls. Twenty-eight relatives with FS and epilepsy were distributed in 20 (27%) of 74 SMEI families; among the controls, 18 affected relatives were clustered in 13 (18.5%) of 70 families. No pedigree showed several affected members, including the four with inherited mutations. CONCLUSIONS: A substantial epileptic family background is not present in our SMEI patients with SCN1A mutations. These data do not confirm previous observations and would not support polygenic inheritance in SMEI. The investigation of the family background in additional series of SMEI patients will further shed light on the genetics of this syndrome.     

癫痫患者抗脑抗体及脑组织中HLA—Ⅱ类抗原的表达

目的:为获得癫痫患者免疫学异常的证据,本实验检测了患者血清中抗脑抗体(Anti-encephalic antibodies,AEAb)及脑组织人类白细胞抗原Ⅱ类抗原(Human leukocyte antigen class Ⅱantigen,HLA class Ⅱ antigen,HLA-Ⅱ类抗原),并与正常对照组比较。对象及方法:1.用ELISA方法测定37例癫痫患者血清抗脑自身抗体;2.借助免疫组织化学方法观察了HLA—Ⅱ类抗原在脑组织中表达与分布。结果:1.癫痫患者血清抗脑抗体高于正常对照;2.癫痫患者脑组织中星形胶质细胞和小胶质细胞异常表达HLA—Ⅱ类抗原。讨论:本实验证实癫痫患者存在一定程度的自身免疫应答异常。脑组织胶质细胞表面HLA—Ⅱ类抗原表达异常可能通过多种机制参与癫痫发病。     

Interleukin-6 levels are increased in temporal lobe epilepsy but not in extra-temporal lobe epilepsy

Previous studies have reported activation of inflammatory cytokines in seizures, but clinical characteristics of epilepsy associated with cytokine activation have not been well established. In this study, serum levels of interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1RA) were measured, and clinical characteristics of epilepsy were assessed in 86 well-evaluated patients with refractory focal epilepsy and in 5 patients with controlled focal epilepsy. Epilepsy was evaluated based on patient histories, electroclinical findings, and high-resolution brain MRI scans. Sixty-three healthy blood donors served as controls. IL-6 concentrations were chronically increased in epilepsy patients (11%) compared with healthy controls (0%) (P = 0.007). Increased levels of IL-6 were more prevalent in patients with temporal lobe epilepsy (TLE) compared to patients with extra-TLE (P = 0.028). Also the mean and the median serum levels of IL-6 were higher in patients with TLE than in patients with extra-TLE (P = 0.042). Concentrations of IL-1RA were not significantly different in patients compared with controls. Indicated by increased levels of IL-6 in TLE, epilepsy type is important in determining chronic overproduction of cytokines in refractory focal epilepsy. The results may reflect a chronic immunological process in the brain in patients with refractory epilepsy.     

Children with Focal Sharp Waves: Clinical and Genetic Aspects

Summary: Purpose: To investigate the spectrum of clinical manifestations in children with benign focal sharp waves in the EEG to gain further insight into the genetic background of clinical and EEG symptomatology in a family study. Methods: All 147 children (134 with seizures, 13 without) met the following inclusion criteria: (a) at least one EEG with focal sharp waves characteristic of benign partial epilepsies, and (b) at least 1 sibling investigated by EEG. The families were questioned orally or in writing regarding the occurrence of seizures. Patients’ records were evaluated by a standardized scheme. Results: The following types of seizures occurred: febrile convulsions (FC), afebrile generalized tonic-clonic seizures (GTCS), simple and (rarely) complex partial seizures; and rolandic seizures in the strict sense. Neonatal seizures were overrepresented (6%); there were no indications of lesional causes. FC occurred in 38 children (26%). As compared with unselected cases of FC, complex symptoms were overrepresented. Family data suggested a maternal preponderance in the transmission of FC liability. Affected relatives of FC probands manifested FC more often than did relatives of probands without FC. Families of 32 patients with typical rolandic seizures (24% of the 134 probands with seizures) showed no aggregation of rolandic epilepsy, but did show variable seizure types. In the entire sample, EEG investigations showed focal sharp waves in 11% of siblings aged 2–10 years. No relation existed between clinical symptomatology and sharp wave findings in siblings. In 66% of probands, the EEG disclosed generalized genetic patterns. Siblings with generalized spike-waves (sw) and/or theta rhythm had focal sharp waves more often than those without sw andor theta rhythm. Conclusions: The phenotypic expression of the genetic anomaly underlying focal sharp waves shows considerable variability. The clinical and EEG findings are in agreement with a multifactorial pathogenesis of epilepsies with “benign” focal epileptiform sharp waves.     

Clinical Indicators of Genetic Susceptibility to Epilepsy

Summary: We evaluated clinical indicators of genetic susceptibility to epilepsy in the families of 1,957 adults with epilepsy (probands) ascertained from voluntary organizations. Very few of the probands in this series had idiopathic epilepsy syndromes. Among relatives of probands with postnatal CNS insults, risks of epilepsy were no higher than in the general population. Risk was increased in relatives of probands without identified CNS insults (i.e., those with idiopathic/cryptogenic epilepsy) or with neurological deficit presumed present at birth, compared with relatives of probands with postnatal CNS insults. Among relatives of probands with idiopathic/cryptogenic epilepsy, risks were higher in parents and siblings, but not in offspring, of probands with generalized onset as compared with partial onset seizures. Risks in offspring were higher if the probands had onset of idiopathic/cryptogenic epilepsy before age 10 as compared with age 10 years, but risks in parents and siblings were not associated with the proband's age at onset. These results suggest that genetic susceptibility increases risk of some forms of cryptogenic epilepsy and of epilepsy associated with neurological deficit presumed present at birth, but not of postnatal symptomatic epilepsy. The influences on risk in offspring may differ from those in parents and siblings.     

Cytomegalovirus antibodies in epileptics receiving diphenylhydantoin

Cytomegalovirus (CMV) antibodies were determined by indirect haemagglutination in 53 epileptics receiving long-term diphenylhydantoin (DPH) therapy and in 53 matched controls. Absorption of serum IgG, IgA and IgM performed in 12 sera showed that the antibodies were of the IgG class. A decreased incidence of high CMV antibody titres (greater than or equal to 320) was found in epileptics (11.3%) compared with controls (34.0%) (0.02 greater than P greater than 0.01), whereas antibody titres greater than or equal to 40 were found in 37.7% of epileptics and in 45.3% of controls (n.s.). The CMV antibody incidence and titre range were similar in patients with symptomatic (37.9%) and idiopathic (37.5%) epilepsy, suggesting that the DPH treatment was responsible for the decreased antibody occurrence in patients. No correlation between CMV antibody titres and the serum immunoglobulin levels or the DPH concentration or clearance could be established in the epileptics.     

精神分裂症患者及其亲属免疫学研究

目的 :了解散发性首发精神分裂症患者及其一级亲属免疫球蛋白及补体成份与正常人是否存在差异。　方法 :用免疫透射比浊法测精神分裂症患者及其一级亲属及健康者血清中免疫球蛋白及补体成份的含量 ,并相互比较。　结果 :精神分裂症患者及其一级亲属IgA、IgG及C4显著高于正常人(P <0 .0 5～ 0 0 1)。　结论 :精神分裂症患者及其一级亲属存在同样免疫学异常 ,遗传因素可能是构成精神分裂症免疫学异常的基础     

Serum and CSF immunological findings in ALS

Serum and CSF immunological findings were analysed in 37 patients with amyotrophic lateral sclerosis (ALS). ALS patients had significantly higher mean values of serum IgG and complement component C4 and significantly lower mean value of total haemolytic titre of complement (THC) compared with normal controls. Incidence of immune complexes (ICs) was significantly higher in sera of ALS patients than in normal controls. There was no significant difference regarding mean serum levels of IgM, IgA, and complement components C3 and Factor B between patients and controls. The blood-brain barrier (BBB) damage was found in 46% of patients. Intrathecal IgG synthesis was detected in six patients (16%). These results support the hypothesis of immune system involvement in ALS.     

GABA Levels in Cerebrospinal Fluid of Patients with Epilepsy

Abstract: The lumbar cerebrospinal fluid (CSF) γ-aminobutyric acid (GABA) levels were measured in 27 patients with epilepsy, another three epileptic patients with status epilepticus and three epileptic patients with chronic cerebellar ataxia. The mean lumbar CSF GABA levels of the 27 patients with epilepsy were not significantly different from those of normal controls. Six of these 27 patients who had daily partial complex and partial motor seizures showed significantly low CSF GABA levels as did the six other patients, three each with status epilepticus and chronic cerebellar ataxia. These findings suggest that some epileptic patients have impaired brain GABAergic neurons.     

Serum IgA, IgG, and IgM concentrations in patients with epilepsy and matched controls: a cohort-based cross-sectional study

Conflicting reports have been published on serum immunoglobulin (Ig) concentrations in patients with epilepsy. Serum IgA, IgG, and IgM concentrations were determined in a cohort of 958 patients and in a reference population of 581 subjects. Overall, 8.2% of patients with epilepsy and 1.9% of control subjects had low serum IgA concentrations. Low serum IgA levels were measured in 19.1% of patients currently on phenytoin therapy and in 11.9% of patients who had previously been treated with phenytoin, whereas only 3.8% of patients who had never been on phenytoin therapy had low serum IgA. In multivariate analysis low serum IgA concentrations were associated with phenytoin medication and female gender. No differences in serum IgG and IgM concentrations were observed between patients and control subjects. However, in patients with epilepsy, low serum IgG concentrations were associated with concomitant autoimmune diseases, and low IgM levels with older age at the onset of epilepsy, long duration of epilepsy, and autoimmune diseases. In conclusion, the prevalence of low serum IgA concentrations was increased in patients with epilepsy, but serum IgG and IgM concentrations were similar in patients with epilepsy and reference subjects. The low serum IgA concentrations were associated with phenytoin medication. In addition to current phenytoin medication, previous phenytoin therapy also was associated with low serum IgA concentrations. This implies that phenytoin medication may have permanent immunological effects in some patients.     

Serum immunoglobulins in brain tumours and lumbar disc diseases

Changes of serum immunoglobulin (Ig) concentrations may occur in both brain tumours and lumbar disc diseases (LDD). The purpose of this study was to investigate the changes of pre- and post-operative serum Ig levels in brain tumours and LDDs. Serum IgG, IgA and IgM levels were measured in 127 patients with brain tumour, 100 patients with LDD and 20 healthy subjects without neurological disease. Increases in one or more of the pre-operative serum Ig levels were observed in the patients with both brain tumours and LDDs compared with controls. However pre-operative serum IgG level was highly increased in all brain tumour types and LDDs (p<0.001). Serum IgA levels and IgM levels in the post-operative stage were significantly decreased in patients with acoustic neurinoma (p<0.01, p<0.001, respectively). Post-operative serum IgG, IgA and IgM levels were significantly decreased (p<0.001) in patients with meningioma. Post-operative serum IgG and IgM levels were significantly decreased (p<0.001) in patients with glioma. Patients with LDD showed a significantly decline in post-operative serum IgA and IgM levels (p<0.001). We think that decline in post-operative serum Ig levels may be of prognostic value in the patients with brain tumours and LDDs.     

Postoperative multichannel magnetoencephalography in patients with recurrent seizures after epilepsy surgery

Objectives - Juvenile myoclonic epilepsy (JME) is a common, age related, idiopathic generalized epileptic syndrome. We aimed to define the expression of JME in Indian probands and study the occurrence of seizures/ epileptic syndromes in their family members. Methods - We studied 225 JME probands with a uniform protocol, recording the type and frequency of seizures, precipitating factors, EEG data, and family history. Detailed family pedigrees were drawn to include all the 1st- and 2nd-degree relatives of probands. The seizures/epileptic syndromes in relatives examined were classified in a uniform way. Results - The clinical and EEG characteristics of 225 JME probands from India were similar to those reported in probands from different ethnic backgrounds. The incidence of febrile convulsions in probands with JME was similar to that of the general population but was much lower (0.2%) among their relatives. A positive family history of seizures among 1st- or 2nd-degree relatives was noted in 79 of 225 (35%) probands. The risk of relatives being affected as well as their risk of expressing a type of idiopathic generalized epilepsy (IGE) varied as a function of the degree of relation with the probands. Conclusions - The clinical expression of JME among probands from India is fairly similar to that reported in probands of different ethnic backgrounds. The risk of relatives being affected as well as their risk of expressing a type of IGE (including JME) varies as a function of the degree of relation with the probands. The reduced occurrence of febrile convulsions among the relatives of JME probands probably represents an ascertainment bias. A much larger database of this type should be helpful in understanding the interactions of different genes that are believed to be responsible for some of the inherited human epileptic syndromes like JME and other IGEs.     

The different patterns of the photoparoxysmal response — a genetic study

In order to investigate the significance of different patterns of the photoparoxysmal response (PPR), an electroencephalographic family study on 135 probands and 371 relatives were carried out. The PPR was subclassified in 4 phenotypically different types. Considering all types of PPR, the incidence was equal in siblings of probands with epilepsy and in siblings of probands without epilepsy. Type 4 (generalized spikes and waves) occurred more often both in probands with epilepsy and their siblings than the respective controls. Thus, the coincidence of photosensitivity will appear as higher if only a PPR with generalized spikes and waves is considered to be indicative of photosensitivity. A striking age dependency of the phenotypical expression of the PPR was found. These findings suggest that the phenotypical expression of the PPR is age-related and modified by other factors predisposing to generalized epilepsy, the varied patterns of the PPR only representing different levels of expression of the same genetically determined trait. The importance of an adaequate technique of intermittent light stimulation is discussed.     

Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families

PURPOSE: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance. METHODS: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 sodium channel subunits, and the chloride channel CLC-2 were sought. RESULTS: Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. CONCLUSIONS: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.