Arx expansion mutation perturbs cortical development by augmenting apoptosis without activating innate immunity in a mouse model of X-linked infantile spasms syndrome.

X-linked infantile spasms syndrome (ISSX) is a clinically devastating developmental epileptic encephalopathy with life-long impact. Arx(GCG)10+7 , a mouse model of the most common triplet-repeat expansion mutation of ARX, exhibits neonatal spasms, electrographic phenotypes and abnormal migration of GABAergic interneuron subtypes. Neonatal presymptomatic treatment with 17ß-estradiol (E2) in Arx(GCG)10+7 reduces spasms and modifies progression of epilepsy. Cortical pathology during this period, a crucial point for clinical intervention in ISSX, has largely been unexplored, and the pathogenic cellular defects that are targeted by early interventions are unknown. In the first postnatal week, we identified a transient wave of elevated apoptosis in Arx(GCG)10+7 mouse cortex that is non-Arx cell autonomous, since mutant Arx-immunoreactive (Arx+) cells are not preferentially impacted by cell death. NeuN+ (also known as Rbfox3) survival was also not impacted, suggesting a vulnerable subpopulation in the immature Arx(GCG)10+7 cortex. Inflammatory processes during this period might explain this transient elevation in apoptosis; however, transcriptomic and immunohistochemical profiling of several markers of inflammation revealed no innate immune activation in Arx(GCG)10+7 cortex. Neither neonatal E2 hormone therapy, nor ACTH(1-24), the frontline clinical therapy for ISSX, diminished the augmented apoptosis in Arx(GCG)10+7 , but both rescued neocortical Arx+ cell density. Since early E2 treatment effectively prevents seizures in this model, enhanced apoptosis does not solely account for the seizure phenotype, but may contribute to other aberrant brain function in ISSX. However, since both hormone therapies, E2 and ACTH(1-24), elevate the density of cortical Arx+-interneurons, their early therapeutic role in other neurological disorders hallmarked by interneuronopathy should be explored.This article has an associated First Person interview with the first author of the paper.

Spontaneous remission of West syndrome following a human herpesvirus 7 infection in a Chinese infant: A case report.

RATIONALE: West syndrome (WS) is an age-dependent epileptic encephalopathy that is characterized by intractable epileptic seizures, hypsarrhythmia, and observed through electroencephalogram (EEG) and significant neurodevelopmental regression. The spontaneous remission of epileptic seizure is clinically rare and has not previously been reported in a Chinese infant. Herein, we reported a Chinese infant with WS whose seizures disappeared following a human herpesvirus 7 (HHV-7) infection. PATIENT CONCERNS: The male Chinese infant was born at the gestational age of 36 weeks with a birth weight of 1.65 kg and an Apgar score of 7 at the first minute. At the age of 6 months, the infant developed seizures that manifested as flexor spasms with trunk involvement and mental regression. DIAGNOSIS: Brain magnetic resonance imaging revealed leukomalacia of the posterior horn and a reduction in the size of the periventricular of the bilateral ventricle and the corpus callosum. An EEG revealed hypsarrhythmia and typical spasm seizures. Therefore, the infant was diagnosed with symptomatic WS. INTERVENTIONS: The infant was treated with adequate vitamin B6 intravenous drip and oral treatment with topiramate and levetiracetam. OUTCOMES: The observed seizures disappeared spontaneously 40 days after onset, without any changes in the anti-epileptic drug treatment, following a febrile rash due to a HHV-7 infection. LESSONS: Spontaneous remission of epileptic seizures can occur following viral infection of HHV-7 in children with WS. The mechanism behind this spontaneous remission warrants further research.

Investigation of neuronal auto-antibodies in children diagnosed with epileptic encephalopathy of unknown cause.

AIM: Cryptogenic forms of epileptic encephalopathies (EE) with their well-known features of drug-resistance, mental deterioration and partial response to immunotherapies are ideal candidates for screening for neuronal autoantibodies (NAA). METHOD: Fifty consecutive pediatric patients with a diagnosis of EE of unknown cause were included. Nine NAAs were tested by ELISA, RIA or cell-based assays. Clinical features of seronegative and seropositive patients were compared. RESULTS: NAAs were found in 7/50 (14%) patients. They were N-methyl-d-aspartate receptor in two (4%), glycine receptor in two (4%), contactin-associated protein-like 2 in one (2%), glutamic acid decarboxylase in one (2%) and type A gamma aminobutyric acid receptor in one patient (2%). Furthermore, serum IgGs of two patients negative for well-characterized NAAs, showed strong reactivity with the uncharacterized membrane antigens of live hippocampal neurons. There were no significant differences between seropositive and seronegative patients by means of epilepsy duration, anti-epileptic drug resistance, EE type, types of seizures, seizure frequencies, EEG features or coexisting autoimmune diseases. Some seropositive patients gave good-moderate response to immunotherapy. DISCUSSION: Potential clues for the possible role of autoimmunity in seropositive patients with EE were atypical prognosis of the classical EE type, atypical progression and unusual neurological findings like dyskinesia.

Serial Analysis of Multiple Serum Cytokine Responses to Adrenocorticotropic Hormone Therapy in Patients With West Syndrome.

Adrenocorticotropic hormone (ACTH) therapy is effective for West syndrome; however, the underlying mechanism of action remains unknown. This study explored this mechanism in 5 Japanese patients with West syndrome, injected with ACTH for 28 days. Serum samples were obtained before and 30, 120, and 720 minutes after ACTH injection divided into an "early" (1-4 days) and a "late" (10-28 days) group. Responses to ACTH over time were analyzed by measuring the levels of 27 cytokines. In the early group, serum levels of interleukins-5, -9, and -17, basic fibroblast growth factor, interferon (IFN-γ), IFN-γ-inducible protein 10, chemokine ligand (CCL) 3 and 4, and platelet-derived growth factor were higher in all patients before ACTH administration than in the 720-minute time point. In the late group, no definite trend was observed except for decreased CCL2 levels after ACTH administration. These changes may correlate with mechanisms underlying the anticonvulsant effects of ACTH.

[Immunological mechanism of prednisone in the treatment of infantile spasm].

OBJECTIVE: To investigate the immunological mechanism of prednisone in the treatment of infantile spasm (IS) by evaluating the immune function of IS children before and after treatment. METHODS: Thirty children with IS were enrolled as IS group. Thirty healthy infants who underwent physical examination were enrolled as healthy control group. Fasting venous blood was collected for both groups before and after prednisone treatment. Chemiluminescence was used to measure serum levels of interleukin-1B (IL-1B), interleukin-2R (IL-2R), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Immunoturbidimetric assay was used to measure serum levels of immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG). Flow cytometry was used to measure the percentages of T lymphocyte subsets (CD3+, CD4+, and CD8+). The clinical outcome and electroencephalographic findings were evaluated for all IS children after prednisone treatment. RESULTS: The IS group had significantly higher serum levels of IL-2R, IL-8, and TNF-α than the healthy control group before treatment (P<0.05). The mean number of daily ictal clusters was positively correlated with the levels of IL-2R, IL-8, and TNF-α in IS children, the mean number of total daily seizures was positively correlated with IL-8 level, and any two indices out of IL-2R, IL-8, and TNF-α were positively correlated with each other (P<0.05). Among the 30 IS children treated with prednisone, 19 achieved seizure control; electroencephalography showed that 18 children achieved complete remission of hyperarrhythmia. After treatment, the IS group had significant reductions in the numbers of daily ictal clusters and total daily seizures, significant improvement in developmental quotient (P<0.05), and significant reductions in serum levels of IL-2R, L-8, and TNF-α, the percentage of CD4+ T lymphocytes, and CD4+/CD8+ ratio (P<0.05), as well as a significant increase in the percentage of CD8+ T lymphocytes (P<0.05). CONCLUSIONS: IS children have immune dysfunction. Prednisone can control seizures in IS children, possibly by regulating and improving immune dysfunction.

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy.

Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis, and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Herein we discuss the progress on animal models of epilepsy and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler's murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of proinflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology-specific therapies for the epilepsies and attendant comorbidities, including the drug-resistant forms.

Inflammation in Epileptic Encephalopathies.

West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12%-15%), or of unknown origin. The current treatment options include hormonal treatment (adrenocorticotropic hormone and high-dose steroids) and the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate proinflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review, we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of WS? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation.

BACKGROUND: Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT. METHODS: Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated. RESULTS: CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status. CONCLUSION: For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.

Antibodies against peptides of NMDA-type GluR in cerebrospinal fluid of patients with epileptic spasms.

OBJECTIVE: We investigated the contribution of antibodies against N-methyl-d-aspartate (NMDA)-type glutamate receptor (GluR) in cerebrospinal fluid (CSF) to the clinical features of patients with epileptic spasms (ES). METHODS: CSF samples were collected from 33 patients with ES with median (range) age 1.8 (0.2-8.5) years. Thirty patients without ES with 3.5 (0.5-7.0) years were also studied as disease controls. The CSF levels of antibodies against peptides of NMDA-type GluR subunits (GluN2B & GluN1) were measured by enzyme-linked immunosorbent assay. RESULTS: The levels of antibodies against the n-terminal of GluN2B (GluN2B-NT2), c-terminal of GluN2B (GluN2B-CT) and n-terminal of GluN1 (GluN1-NT), were significantly higher in patients with ES than in disease controls (p < 0.01, p < 0.01 & p = 0.03). Levels of antibodies to GluN2B-NT2 & CT were not related with ACTH therapy nor conventional CSF factors (cell counts, protein level, etc). Levels of antibodies to GluN2B-NT2 & CT showed evidence of correlation within a linear regression model with intervals from the onset to the examination of CSF until 25 months (p = 0.01 & p = 0.01). The correlation was significant in patients with unknown cause (p = 0.01). Five of 33 patients (four unknown cause & one chromosomal anomaly) had higher level of antibodies to GluN2B-NT2 exceeding mean + 1 SD of all ES patients, and they had poor motor (score 0) and cognitive outcomes (score 0 or 1). CONCLUSION: The CSF level of antibodies against GluN2B in ES patients with unknown cause was estimated to increase after onset. We hypothesize that some ES patients may have immune process after the onset of ES.

Current and Emerging Therapies of Severe Epileptic Encephalopathies.

In this article, we review the treatment options for the pediatric epileptic encephalopathies and provide an update on the new and emerging therapies targeted at the underlying pathophysiology of many of these syndromes. We illustrate how the identification of the specific genetic and autoimmune causes has made possible the evaluation and development of novel, better targeted therapies, as and at times, avoidance of potentially offending agents.

Successful treatment for West syndrome with severe combined immunodeficiency.

Several immune mechanisms are suspected in the unknown etiology of West syndrome (WS). We report a male infant who suffered from WS and X-linked T-B+NK- severe combined immunodeficiency (X-SCID) with a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). He promptly began vitamin B6 and valproic acid treatment, but infantile spasms (IS) and hypsarrhythmia persisted. Administration of intravenous immunoglobulin and the change to topiramate (TPM) at 7 months of age resulted in the rapid resolution of IS. The CD4/8 ratio in his peripheral blood increased from 0.04-0.09 to 0.20-1.95 following unrelated cord blood transplantation (UCBT). In vitro lymphocyte proliferation in response to phytohemagglutinin or concanavalin A and the ability of B lymphocytes to produce antibodies improved as well. Electroencephalogram findings became normal 1 month after UCBT. Thus, we consider that T-cell dysfunction and/or impairments in T-B cell interactions due to X-SCID may have played important roles in the onset of WS. Immune-modulating therapies along with the administration of TPM effectively treated this severe epileptic syndrome in our patient.

Mechanisms of epileptogenesis in pediatric epileptic syndromes: Rasmussen encephalitis, infantile spasms, and febrile infection-related epilepsy syndrome (FIRES).

The mechanisms of epileptogenesis in pediatric epileptic syndromes are diverse, and may involve disturbances of neurodevelopmental trajectories, synaptic homeostasis, and cortical connectivity, which may occur during brain development, early infancy, or childhood. Although genetic or structural/metabolic factors are frequently associated with age-specific epileptic syndromes, such as infantile spasms and West syndrome, other syndromes may be determined by the effect of immunopathogenic mechanisms or energy-dependent processes in response to environmental challenges, such as infections or fever in normally-developed children during early or late childhood. Immune-mediated mechanisms have been suggested in selected pediatric epileptic syndromes in which acute and rapidly progressive encephalopathies preceded by fever and/or infections, such as febrile infection-related epilepsy syndrome, or in chronic progressive encephalopathies, such as Rasmussen encephalitis. A definite involvement of adaptive and innate immune mechanisms driven by cytotoxic CD8(+) T lymphocytes and neuroglial responses has been demonstrated in Rasmussen encephalitis, although the triggering factor of these responses remains unknown. Although the beneficial response to steroids and adrenocorticotropic hormone of infantile spasms, or preceding fever or infection in FIRES, may support a potential role of neuroinflammation as pathogenic factor, no definite demonstration of such involvement has been achieved, and genetic or metabolic factors are suspected. A major challenge for the future is discovering pathogenic mechanisms and etiological factors that facilitate the introduction of novel targets for drug intervention aimed at interfering with the disease mechanisms, therefore providing putative disease-modifying treatments in these pediatric epileptic syndromes.

Immune-mediated steroid-responsive epileptic spasms and epileptic encephalopathy associated with VGKC-complex antibodies.

Autoantibodies that bind to voltage-gated potassium-channel complex proteins (VGKC-complex antibodies) occur frequently in adults with limbic encephalitis presenting with cognitive impairment and seizures. Recently, VGKC-complex antibodies have been described in a few children with limbic encephalitis, and children with unexplained encephalitis presenting with status epilepticus. We report a case of infantile-onset epileptic spasms and developmental delay compatible with epileptic encephalopathy. Our patient was a female infant, aged 4 months at presentation. She had evidence of immune activation in the central nervous system with elevated cerebrospinal fluid neopterin and mirrored oligoclonal bands, which prompted testing for autoantibodies. VGKC-complex antibodies were elevated (201 pmol/L, normal<100), but extended antibody testing, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2), was negative. The patient showed a partial response to steroid treatment, which was started late in the disease course. On review at 13 months of age, her development was consistent with an age of 5 to 6 months. These results suggest that VGKC-complex antibodies might represent a marker of immune therapy responsiveness in a subgroup of patients with infantile epileptic encephalopathy.

Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES).

Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4-year-old boy that was associated with elevated voltage-gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody-associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word-finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low-dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications.

Peripheral lymphocyte subset and serum cytokine profiles of patients with West syndrome.

OBJECTIVE: To clarify the immune pathophysiology of West syndrome (WS). STUDY DESIGN: We measured peripheral blood lymphocyte subset and serum cytokine profiles in 76 WS patients and 26 age-matched controls. Adrenocorticotropic hormone (ACTH) is one of the most effective therapy for WS and presumably immune-modulating; therefore, we compared the measured parameters between before ACTH (pre-ACTH) WS patients and controls, between cryptogenic and symptomatic WS patients before ACTH (pre-ACTH), and between before (pre-ACTH) and after (post-ACTH) ACTH WS patients. The post-ACTH group included those who received the last ACTH dose within 1 month of sampling. RESULTS: CD3+ CD25+, CD19+, and CD19+ CD95+ cells were found to be significantly lower in the pre-ACTH group than in the controls. Interleukin (IL)-1 receptor antagonist (RA), 5, 6, and 15; eotaxin; basic fibroblast growth factor (bFGF); and interferon gamma-inducible protein (IP)-10 levels were higher in pre-ACTH group than in the controls. No significant differences were found between the pre-ACTH cryptogenic and symptomatic groups. CD4+ cells, CD3+ cells, CD4+/8+ ratio, IL-1 beta, IL-12, and macrophage inflammatory protein (MIP)-1 beta were significantly higher in pre-ACTH group than in the post-ACTH group. CONCLUSIONS: Our study revealed immunological alterations in WS patients, and these responses were modified by ACTH therapy. Further study is needed to elucidate whether or how the immune system alteration is involved in the pathophysiology of WS.

A pilot study on the changes in immunity after ACTH therapy in patients with West syndrome.

Adrenocorticotropic hormone (ACTH) has been the first-line drug for the treatment of West syndrome, although the therapy has various adverse effects. ACTH depresses resistance to a variety of bacterial, viral, protozoal, and fungal agents. The timing of the various vaccinations is delayed after ACTH therapy in Japan, because the immune system is believed to be affected for approximately 6 months. However, the duration of the effect of ACTH on the immune system is not known. Therefore, we examined changes in the immunity levels before and after ACTH therapy. We measured white blood cell counts, lymphocyte counts, T/B cell counts, CD4(+) and CD8(+) T cell counts, CD 4/8 ratio, lymphocyte blastoid transformation by PHA or Con-A, and the levels of IgA, IgM, and IgG before, immediately after, and 1, 3, 6, and 12 months after ACTH therapy. The lymphocyte counts and CD4(+) T cell counts were significantly decreased immediately after and at 1 and 3 months after the therapy, and did not return to the previous levels even at 6 months and 12 months after ACTH treatment; however, these levels returned to within normal limits (within the 95% confidence interval). Immunoglobulin levels did not change after the ACTH therapy. Helper T cells were more depressed than cytotoxic T cells after ACTH therapy.

Maternal IgG suppresses NMDA-induced spasms in infant rats and inhibits NMDA-mediated neurotoxicity in hippocampal neurons.

Maternal immunoglobulin G (IgG) was derived from Wistar rats that just delivered the new offsprings. We examined the effect of this maternal IgG on infantile spasms induced by N-methyl-d-aspartate (NMDA) in immature rats. Pup animals were treated subcutaneously with 10 mg/kg/day maternal IgG from day 11 to day 15 after birth followed by a single intraperitoneal dose of NMDA (15 mg/kg). Administration of maternal IgG decreased the severity and increased the number of ACTH immunoreactive cells in the cortex of rats with NMDA-induced spasms. Furthermore, maternal IgG inhibited NMDA-induced intracellular LDH activity in cultured hippocampal neurons in a dose-dependent manner. The results indicate that maternal IgG can attenuate NMDA-induced seizures. In infantile spasms, some factors may during pregnancy negatively affect the transfer of maternal IgG from mother to fetus thereby causing a decrease in the amount of protective maternal IgG.

Remission associated with human herpesvirus infection in west syndrome.

Generally, West syndrome is an intractable epileptic syndrome in infancy, although spontaneous remission has been reported in some cases. An immunologic response to infection might be one of the factors involved in the remission of West syndrome, but the mechanisms remain unknown. On the other hand, exanthema subitum is a common disease occurring in infancy with the characteristics of fever and rash. Two kinds of human herpesvirus, 6 and 7, have been isolated as causal agents of exanthema subitum. We experienced one symptomatic case and three cryptogenic cases of West syndrome that showed spontaneous remission. In the symptomatic case, the subject showed a temporary remission; however, in the other cases, the remissions were long term. In the present study, we report the patients' improvement and electroencephalographic (EEG) findings. In all of our cases, hypsarrythmia disappeared on the EEG findings, the human herpesvirus 6 IgG antibodies increased in all four cases, and the herpesvirus 7 IgG antibodies increased in two cases. We postulate that the remission of the four cases proceeded from infection by exanthema subitum. The changes in serum antibody values suggest that the spontaneous remission of West syndrome was related to human herpesvirus 6 and 7 infections.

Spontaneous improvement of intractable epileptic seizures following acute viral infections.

In general, epileptic seizures become more serious following infections. However, transient and permanent improvement of epileptic seizures has been observed following acute viral infections, without a recent change in anti-epileptic therapy. Questionnaires were sent to 73 institutions, throughout Japan, where pediatric neurologists care for children with epilepsy to characterize this phenomenon through clinician survey. Completed surveys were received from 11 institutions, and 21 cases were selected for the study. The age of the patients were 6 months to 17 years. The West syndrome or epilepsy subsequent to West syndrome cases were 16 out of 21. Two cases of symptomatic generalized epilepsy and one case each of symptomatic partial epilepsy, continuous spike-waves of slow sleep and severe myoclonic epilepsy in infancy were also reported. These seizures disappeared within 2 weeks subsequent to viral infections such as, exanthema subitum, rotavirus colitis, measles and mumps. The disappearance of intractable epileptic seizures following acute viral infections might be related to the inflammatory processes or the increased levels of antibodies after viral infections.