Innate but not adaptive immune responses contribute to behavioral seizures following viral infection

Purpose: To examine the role of innate immunity in a novel viral infection–induced seizure model. Methods: C57BL/6 mice, mouse strains deficient in interleukin (IL)‐1RI, IL‐6, tumor necrosis factor (TNF)‐RI, or myeloid differentiation primary response gene 88 (MyD88), or transgenic mice (OT‐I) were infected with Theiler’s murine encephalomyelitis virus (TMEV) or were mock infected. Mice were followed for acute seizures. Tissues were examined for neuron loss, the presence of virus (viral RNA and antigen), perivascular cuffs, macrophages/microglia, and gliosis, and mRNA expression of IL‐1, TNF‐α, and IL‐6. Results: IL‐1 does not play a major role in seizures, as IL‐1RI‐ and MyD88‐deficient mice displayed a comparable seizure frequency relative to controls. In contrast, TNF‐α and IL‐6 appear to be important in the development of seizures, as only 10% and 15% of TNF‐RI‐ and IL‐6‐deficient mice, respectively, showed signs of seizure activity. TNF‐α and IL‐6 mRNA levels also increased in mice with seizures. Inflammation (perivascular cuffs, macrophages/microglia, and gliosis) was greater in mice with seizures. OT‐I mice (virus persists) had a seizure rate that was comparable to controls (no viral persistence), thereby discounting a role for TMEV‐specific T cells in seizures. Discussion: We have implicated the innate immune response to viral infection, specifically TNF‐α and IL‐6, and concomitant inflammatory changes in the brain as contributing to the development of acute seizures. This model is a potential infection‐driven model of mesial temporal lobe epilepsy with hippocampal sclerosis.     

"Periodic" Seizures

Summary: Purpose: To describe regularly recurring ictal phenomena as recorded in a single patient whose seizure disorder related to a left temporal cavernous angioma. Methods: Seizures were recorded by left temporal subdural strip electrodes which were bilaterally placed because of ambiguous seizure origin and right temporal memory dysfunction at Wada testing. Seizure length, interseizure intervals, and interseizure onset intervals were visually assessed. The coefficient of variation was used as an estimate of variability in seizure periodicity. Results: Mean seizure durations varied from 68 to 95 s; coefficients of variation varied from 0.08 to 0.18, values similar to other periodic biological phenomena. Mean daily seizure intervals varied from 96 to 152 s with coefficients of variation ranging from 0.12 to 0.35. Interseizure onset intervals had smaller coefficients of variation (0.03–0.20). Manifestations of these simple partial seizures included a rising epigastric sensation and nausea. Conclusions: Previously described periodic EEG phenomena are interictal events or appear with peripheral events of similar cadence. Therefore, we remain unaware of any documentation of periodic ictal electrographic events. The restricted propagation and duration of these recorded seizures may have simplified their pathophysiology allowing a stereotyped involvement of excitatory and inhibitory mechanisms producing the periodicity.     

Chronic Theiler's virus infection in mice: appearance of myelin basic protein in the cerebrospinal fluid and serum antibody directed against MBP

Myelin basic protein (MBP) appears frequently in the cerebrospinal fluid (CSF) of mice with chronic demyelination following intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV); antibody to MBP can frequently be found in the sera. The peaks of the immune responses to both MBP and TMEV coincide with the time course of the clinical signs of disease. Adsorption of mouse sera with TMEV or MBP indicate the non-identity of the antigens and the specificity of the antisera as measured by ELISA. Immunoblot analysis of sera confirmed the ELISA findings. The mechanism of induction of antibody directed against MBP and its role in TMEV-associated demyelination remain to be determined.     

BALB/c substrain differences in susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease

We report differences among BALB/c substrains in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, an immune-mediated inflammatory demyelinating disease and experimental model for human multiple sclerosis. BALB/cJ and BALB/cAnNCr mice are susceptible, while BALB/cByJ and BALB/cCum are resistant. Hybrids between BALB/cBy and BALB/cAnNCr were intermediate, although closer to the resistant parent. Backcrosses gave results compatible with differential susceptibility being related to a single segregating locus. Exposure of resistant BALB/cByJ mice to low dose irradiation, 2 days prior to infection, rendered them susceptible to TMEV-induced demyelination. The susceptibility pattern of TMEV-induced demyelinating disease among BALB/c substrains is distinct from those of several autoimmune disorders.     

Risk Factors for Developing Seizures After a Stroke

Summary: We evaluated development of seizures in 219 consecutive patients who had ischemic or hemorrhagic stroke. Subjects with transitory ischemic attacks, sub-arachnoid, subdural, and epidural hemorrhages or those with previous history of epilepsy were excluded. Mean follow-up time was 11.5 months (range 1–72 months). Twenty-two of 219 stroke patients (10.04%) had seizures. Twelve (54.55%) were of early onset (<1 month after the stroke), and 10 (45.45%) were of late onset. No statistically significant differences were evident between the early- and late-onset seizure group in comparisons of type of stroke, localization, and size of the lesion. Six of 22 patients (27%) had seizure recurrence. Seizures developed in (a) 13 of 183 patients with ischemic stroke (7.1%) and 9 of 36 patients with hemorrhagic stroke (25%) (p = 0.01); (b) 16 of 93 patients with cortical lesions (17%) and 6 of 126 patients with subcortical lesions (4.7%) (p = 0.01); and (c) 14 of 66 patients with a lesion comprising more than one lobe (21.2%) and 8 of 153 patients with a lesion comprising less than one lobe (5.2%) (p < 0.01). We conclude that patients with hemorrhagic stroke, cortical lesions, and lesions involving more than one lobe are at higher risk of developing seizures.     

The Depiction of Seizures in Film

PURPOSE: The purpose was to describe the depiction of epilepsy in English language film. METHODS: The list of films, developed by consulting several databases, film scholars, and neurologists, includes every film suggested by any source. By using the saturation techniques of grounded theory, names of films were sought until no new names were received. All films were reviewed by an experienced board-certified neurologist. RESULTS: Seizures were depicted in 20 films. Generally, seizures are used in film to develop narrative or enrich character. They serve four functions: (a) a principal character has epilepsy; thus the condition is critical to character and narrative; (b) a seizure is used to drive the narrative; (c) a seizure is used to enrich a minor role; and (d) a seizure is feigned to distract attention from another activity. CONCLUSIONS: Conclusions can be drawn in four areas: character, accuracy of depiction, roles and responses of onlookers, and the place of epilepsy in the films: (a) Epilepsy is one dimension linked with other aspects of an individual to enrich character; (b) Seizures are depicted fairly accurately, but their frequent representation as uncontrollable and violent is exaggerated and out of date; (c) In the films, the onlookers' responses range from fear to taking correct measures; and (d) The presence of epilepsy is never arbitrary, but the function varies. Overall, the view of epilepsy conveyed in film continues to be distorted, sensationalized, and presented in the most frightening ways.     

Epileptic Seizures in Elderly Patients with Dementia

All inpatients aged greater than 55 years with dementia in the Dundee Psychiatric Service were surveyed for seizure occurrence by interviewing staff and reviewing records. Of 208 patients, 19 (9.1%) were recorded as having seizures. The seizures were major in 92% and occurred at a rate of approximately 2.3 seizures per patient per year. Patients with epilepsy were significantly younger than a control group of dementia inpatients and were significantly more cognitively impaired on the survey Clifton Assessment Procedure for the Elderly (CAPE), but not on the Mini Mental State Examination. Of 111 reported accidents, only 5 appeared to be associated with epilepsy. Although epileptic seizures are relatively common in patients with severe dementia, they rarely caused severe problems.     

Effect of Pregnancy on Development of Seizures

Some women develop seizures or experience increased seizure frequency during pregnancy. Although the reason for this increased susceptibility during pregnancy has not been established, hormonal changes have been hypothesized to be a factor. This study compared the rates of kindling in rats kindled during the first, second, or third trimester and female controls during diestrus. No significant differences in kindling rate were found between the controls and the pregnant rats. Although some differences in kindling rate were seen when the animals were separated into groups depending on stage of pregnancy kindled, these did not reach statistical significance. Using this model, seizure susceptibility was not significantly altered during pregnancy.     

Alcohol, Seizures, and Epilepsy

Summary: Seizures, epilepsy, and alcohol are complexly interrelated. Although it is commonly perceived that patients with epilepsy experience problems with seizure control if they use alcohol, this is not confirmed by the few experimental studies that have tested the hypothesis. The last 30 years have emphasized the role of withdrawal from alcohol as a mechanism of seizure production. However, this is but one of many potential mechanisms by which seizures and epilepsy may be related to alcohol use and abuse. The rare but clear situations in which alcohol can act as a convulsant drug need further study, and mechanisms by which the long-term neurotoxic effects of alcohol lead to chronic epilepsy also need further elucidation.     

Seizures of Idiopathic Generalized Epilepsies

Summary:  Idiopathic generalized epilepsies (IGEs) comprise at least 40% of epilepsies in the United States, 20% in Mexico, and 8% in Central America. Here, we review seizure phenotypes across IGE syndromes, their response to treatment and advances in molecular genetics that influence nosology. Our review included the Medline database from 1945 to 2005 and our prospectively collected Genetic Epilepsy Studies (GENESS) Consortium database. Generalized seizures occur with different and similar semiologies, frequencies, and patterns, ages at onset, and outcomes in different IGEs, suggesting common neuroanatomical pathways for seizure phenotypes. However, the same seizure phenotypes respond differently to the same treatments in different IGEs, suggesting different molecular defects across syndromes. De novo mutations in SCN1A in sporadic Dravet syndrome and germline mutations in SCN1A, SCN1B, and SCN2A in generalized epilepsies with febrile seizures plus have unraveled the heterogenous myoclonic epilepsies of infancy and early childhood. Mutations in GABRA1, GABRG2, and GABRB3 are associated with absence seizures, while mutations in CLCN2 and myoclonin/EFHC1 substantiate juvenile myoclonic epilepsy as a clinical entity. Refined understanding of seizure phenotypes, their semiology, frequencies, and patterns together with the identification of molecular lesions in IGEs continue to accelerate the development of molecular epileptology.     

Endogenous gamma interferon produced in central nervous system by systemic infection infection with Theiler's virus in mice

Theiler's virus GD VII strain causes acute encephalomyelitis by intracerebral inoculation. We established acute encephalomyelitis in mice by the intravenous (i.v.) inoculation of Theiler's virus GD VII strain. Replication of Theiler's virus injected i.v. could be observed in both the brain and spinal cord of mice, and interferon (IFN)-γ could be detected in the extracts of brain and spinal cord in parallel with viral replication. Furthermore, by the injection of anti-IFN-γ monoclonal antibody (mAb) on Day 1 post-infection (p.i.), mortality and virus titres in the spinal cord increased compared with the control mice treated with normal rat globulin. The histological exacerbation of inflammation was observed in spinal cord of anti-IFN-γ mAb-treated mice. These results indicate that endogenous IFN-γ, produced locally in the brain and spinal cord of mice through both antiviral action and anti-inflammatory action of IFN-γ in central nervous system, plays an important role in Theiler's virus infection.     

Seizures after spontaneous supratentorial intracerebral hemorrhage

PURPOSE: To characterize seizures after intracerebral hemorrhage (ICH), evaluating the risk of occurrence and relapse, predisposing factors, and prognostic significance, and to assess the utility of antiepileptic drug (AED) therapy as used in clinical practice. METHODS: The study sample consisted of 761 patients with spontaneous, nonaneurysmal, supratentorial ICH. Seizures were classified as immediate (within 24 h of ICH) and early (within 30 days of ICH). Baseline variables and clinical events were compared in the seizure and nonseizure group by using a multivariate regression model of failure time data. RESULTS: Fifty-seven patients had one or more seizures. The 30-day actuarial risk of a post-ICH seizure was 8.1%. Lobar location and small volume of ICH were independent predictors of immediate seizures. Early seizures were associated with lobar location and neurologic complications, mainly rebleeding. In patients with lobar ICH, the risk of early seizures was reduced by prophylactic AED therapy. Among seizure patients, history of alcohol abuse increased the risk of status epilepticus. Immediate and early seizures were not independent predictors of in-hospital mortality. CONCLUSIONS: Patients with ICH are exposed to a substantial risk of seizures; however, short-term mortality was not affected, and the risk of epilepsy was lower than previously thought. The likelihood of immediate seizures is influenced by factors that are inherent characteristics of ICH, whereas the chance of developing early seizures is influenced not only by certain characteristics of ICH, but also by unpredictable events. A brief period of therapy soon after ICH onset may reduce the risk of early seizures in patients with lobar hemorrhage.     

Valproate Monotherapy in 30 Patients with Partial Seizures

This retrospective pilot study describes 30 patients diagnosed and treated for complex partial seizures (CPS) and simple partial seizures (SPS) with and without generalization who received valproate (VPA) monotherapy after lack of response or allergic reaction for carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB). Seizures were tabulated daily on seizure calendars by the patients. Three time periods were examined for seizure frequency, 90 days before VPA treatment and 90 and 180 days after VPA treatment. Twenty-two were "controlled" or "improved" (reduction of seizure activity by greater than or equal to 51%) 6 months following the initiation of VPA. VPA was particularly effective in 17 patients who had secondarily generalized tonic-clonic seizures (GTCS) as a subtype of partial seizures. Failure of response to VPA in eight patients appears to be related to their type of partial seizure (SPS or CPS alone, without GTCS) and duration of uncontrolled recurrent seizures. Etiology and compliance were not related to treatment failure. This study supports the need for a double-blind controlled trial with VPA in patients with partial seizures.     

Effects of Seizures and Their Treatment on Fetal Brain

Summary:  Purpose: To describe the effects of pregnancy on seizures, the effects of seizures during pregnancy on the fetus, and the effects of antiepileptic drugs (AEDs) on fetal brain and development.
Methods: The available literature was reviewed and summarized.
Results: There is a paucity of prospective studies. Retrospective studies indicate that, during pregnancy, alterations in seizure frequency can occur in an unpredictable fashion. Generalized tonic-clonic seizures may have adverse effects on the fetus. It is unclear whether complex partial seizures or absence seizures have negative consequences. AEDs may have potentially detrimental effects on the fetus and its subsequent development, but the full spectrum and clinical significance are under investigation. Monotherapy is strongly encouraged.
Conclusions: Dealing with the pregnant epileptic patient is a difficult and challenging task. Although there are several risks for the mother and the fetus, most epileptic women bear normal, healthy children.     

Effects of Menopause on Seizures in Women with Epilepsy

Summary: Purpose: Although important associations between epilepsy and women's hormonal phases are described, the relation of menopause to epilepsy has received little attention. Methods: By using a structured interview, we studied menopausal women with epilepsy seen at the University of Maryland Epilepsy Center over a 1-year period from 1994 to 1995. We analyzed the characteristics and temporal relation of the seizures to menopause and compared the frequency and severity of the seizures with those in a similar group of premenopausal women. Results: We identified 61 menopausal women (46 who were postmenopausal and 15 perimenopausal) and compared them with 46 premenopausal women. No statistically significant differences were noted in either the frequency or the severity of seizures comparing all menopausal or only postmenopausal with premenopausal women. However, 12 (20%) of the 61 menopausal women noted that their seizures first began during or after menopause, with eight having no proven cause for their seizures. Many individual women described changes in their seizures with menopause. Among the 61 menopausal women, 49 had established epilepsy before the onset of menopause, and 20 (41%) reported worsening of their seizures with menopause, 13 (27%) noted improvement, and 16 (33%) described no changes. These observations were similar for peri- and post-menopausal women. Of the 15 menopausal women taking hormone replacement therapy, the six taking progestin were significantly less likely to report worsening of their seizures. Conclusions: These findings support the view that hormonal influences are important in women with seizures. Although, in aggregate, menopausal (combined perimenopausal and post-menopausal) and postmenopausal women's seizures were similar in frequency and severity to those of other women, menopause was associated with changes in seizures for some women. Moreover, menopause may be a previously unrecognized factor for some new-onset seizures. The relations between menopause and epilepsy deserve to be more fully investigated.     

Intelligence Test Performance of Patients with Partial and Generalized Seizures

The intellectual performance of 350 patients with seizures was examined. Seizures were classified according to the revised International Classification of Epileptic Seizures as partial (simple or complex), generalized, or partial secondarily generalized. Performance on the Wechsler Intelligence subtests served to measure intellectual ability. Patients with partial seizures performed better on Digit Span, Digit Symbol, Block Design, and Object Assembly than those with either generalized or partial secondarily generalized seizures. These subtests are functionally associated with abilities such as attention, visuospatial problem-solving, and sequencing ability.     

Epileptic Seizures Evoked by Card Games, Draughts, and Similar Games

Three Asian patients, since adolescence, had myoclonic jerks and tonic-clonic seizures during card games, draughts, and a local game "punchi." Interictal EEG showed generalized bisynchronous atypical 3-Hz spike and wave discharges. Test procedures evoked EEG dysrhythmia and clinical seizures in two patients. These patients and previously reported cases have the seizure disorder juvenile myoclonic epilepsy (impulsive petit mal), which seems particularly sensitive to provocation by cognitive functions, especially decision making. Myoclonic epilepsy is considered resistant to antiepileptic drugs other than clonazepam and valproate, but two of our patients responded well to clobazam.     

Seizures Associated with Propofol Anesthesia

Propofol is a new, fast-acting intravenous (i.v.) anesthetic. Involuntary movements or epileptic sei zures have occurred during or after propofol-induced an esthesia in ～50 reported cases; a third of the patients have had epilepsy. We report 5 patients with seizures in association with propofol anesthesia. A female epileptic patient developed severe status epilepticus; the other patients with short-lasting seizures had no previous epi lepsy. Although propofol has been used in treatment of patients of status epilepticus, the risk of precipitation of epileptic seizures warrants consideration especially when planning anesthesia for epileptic patients.     

Classification of Epileptic Seizures: A Hospital-Based Study of 1,250 Patients in a Developing Country

The 1981 International Classification of Epileptic Seizures (ICES) was used to study the distribution of seizure types in 1,250 patients attending an Epilepsy Clinic in Sri Lanka. Based on seizure symptomatology 94.6% of the cases could be classified, and by adding the routine interictal EEG findings the percentage of classifiable seizures increased to 97%. Partial seizures (73.8% cases) were three times as common as generalized seizures (23.3% cases). Of the partial seizures, simple partial seizures (SPS) accounted for only 0.4% cases, and complex partial seizures (CPS) for 8.8%, whereas partial seizures secondarily generalized (PSGS) accounted for 64.6%. PSGS had simple onset in 12.5% and complex onset in 34.8% of cases. Myoclonic seizures were the commonest of the generalized seizures, accounting for 14.6% of all cases. Tonic-clonic seizures accounted for 7.4% of cases; absence seizures accounted for only 1.3%. The study showed the 1981 ICES to be relevant and applicable in a clinical setting with limited investigatory facilities. Difficulties encountered with regard to certain subcategories could be overcome with minor modifications which made the classification operative. Routine EEG confirmed the diagnosis in a significant number of cases but changed the diagnosis in only a few, confirming that a good standardized questionnaire is the key instrument for classifying epileptic seizures.     

Seizures and epilepsy in Alzheimer's disease

Many studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD-with reported lifetime prevalence rates of 1.5-64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.