Altered vaccine-induced immunity in children with Dravet syndrome.

Dravet syndrome (DS) is a refractory epileptic syndrome. Vaccination is the trigger of the first seizure in about 50% of cases. Fever remains a trigger of seizures during the course of the disease. We compared ex vivo cytokine responses to a combined aluminium-adjuvanted vaccine of children with DS to sex- and age-matched heathy children. Using ex vivo cytokine responses of peripheral-blood mononuclear cells and monocytes, we found that vaccine responsiveness is biased toward a proinflammatory profile in DS with a M1 phenotype of monocytes. We provide new insight into immune mechanisms associated with DS that might guide research for the development of new immunotherapeutic agents in this epilepsy syndrome.

Epilepsy with myoclonic atonic seizures and chronic cerebellar symptoms associated with antibodies against glutamate receptors N2B and D2 in serum and cerebrospinal fluid.

A 3-year-old boy with normal development presented with acute cerebellitis at one year and 10 months of age. His truncal ataxia resolved without treatment. He experienced a relapse of truncal ataxia and atonic seizures at 2 years and one month of age. Five months later, he experienced myoclonic atonic seizures. By 3 years of age, the truncal ataxia had become severe, and the frequency of myoclonic atonic seizures increased. Compared to controls, we found higher levels of anti-C-terminal GluN2B and anti-N terminal GluD2 antibodies in the serum, and anti-N terminal GluN2B and anti-C terminal GluD2 antibodies in the cerebrospinal fluid (CSF). A cell-based assay revealed the presence of anti-NMDA-type glutamate receptor antibody in the serum, but absence in the CSF. Ictal EEG of myoclonic atonic seizures showed generalized spike and wave complexes. The patient was diagnosed with myoclonic atonic epilepsy. Adrenocorticotrophic hormone therapy resolved the truncal ataxia and myoclonic atonic seizures, along with the decreased serum anti-C-terminal GluN2B and anti-N-terminal GluD2 antibodies, and CSF anti-N-terminal GluN2B and anti-C-terminal anti-GluD2 antibodies. Our results suggest that the anti-GluN2B and anti-GluD2 antibodies may be associated with myoclonic atonic epileptic seizures and chronic cerebellitis.

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.

Prevalence and Characteristics of Vaccination Triggered Seizures in Dravet Syndrome in Hong Kong: A Retrospective Study.

BACKGROUND: Dravet syndrome is a rare epileptic encephalopathy characterized by treatment-resistant polymorphic seizures. Seizure onset usually occurs during the first year of life, and seizures are often associated with heat-related triggering factors (e.g., fever, photosensitivity, or hot bath). It has been reported that children with Dravet syndrome often present with recurrent febrile seizures and vaccination-related seizures. METHODS: We analyzed the occurrence of vaccination-related seizures (defined as the development of a seizure within 48 hours post vaccination) in 54 patients with Dravet syndrome. Patients were divided into two groups according to whether seizures occurred within 48 hours of vaccination (i.e., vaccination-proximate group) or not (vaccination-distant group). RESULTS: There was no significant difference in the vaccination-proximate group and vaccination-distant group for the presence of SCN1A mutation. In our Dravet syndrome cohort, the vaccination-proximate group consisted of 17 (31.5%) patients with Dravet syndrome. Thus vaccination-related seizures are a common triggering factor in Dravet syndrome, reported in up to one third of our patients. CONCLUSION: Vaccination-related seizures may act as the triggering factor for the onset of seizures in children with Dravet syndrome, especially before the definitive diagnosis of Dravet syndrome can be made within the first year of life. We suggest further study of guidelines and protocols for the prevention and management of vaccination-related seizures in children with recurrent febrile seizures pending a definitive diagnosis of Dravet syndrome in the first 12 months of life.

Myoclonic status epilepticus as a presentation of caspr2 antibody-associated autoimmune encephalitis.

We present a case of autoimmune encephalitis associated with antibodies targeting contact in-associated protein-like 2. This case is notable because of the presentation with myoclonic status epilepticus and the prolonged clinical course of refractory seizures, which are demonstrated in the accompanying videos, and not previously associated with this condition. Treatment with prednisone, intravenous immunoglobulin, plasma exchange, rituximab, cyclophosphamide, and mycophenolate mofetil resulted in significant functional improvement. Historically, myoclonic status epilepticus is associated with a grave prognosis and minimal chance of meaningful recovery. This case demonstrates that autoimmune encephalitis remains an important differential diagnosis in patients with such a presentation, and that early recognition and the appropriate institution of immunotherapy can result in seizure control and functional recovery. [Published with video sequences].

[A case of myoclonic astatic epilepsy with autoantibody for glutamate receptor epsilon 2].

A 3-year-old boy was admitted to our hospital with repetitive drop attacks and generalized tonic-clonic seizures. Brain MRI, SPECT and blood laboratory tests did not show any abnormalities, while antibody to glutamate receptor epsilon 2 (GluR epsilon 2) in spinal fluid was positive. Interictal EEG showed generalized 6 to approximately 7 Hz slow, wave and ictal EEG showed 1 to approximately 2 Hz high amplitude generalized spike and slow wave burst. We made a diagnosis as myoclonic astatic epilepsy (MAE). However, his seizures were refractory to almost all antiepileptic drugs, steroid pulse therapy and gamma-globulin therapy. Eight months after the first attack, administration of ACTH therapy was effective. Seizures disappeared and EEG findings improved. To our knowledge, there have been no previous reports of MAE in which autoantibody to GluR epsilon 2 was positive. It is suggested that autoimmunity in this case was associated with the pathogenesis of MAE.

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.

[Immunological study in patients with severe myoclonic epilepsy in childhood]. / Estudio inmunológico en pacientes con epilepsia mioclónica severa en la infancia.

OBJECTIVE: Clinical and experimental data support the role of immune mechanisms in the pathogeny of childhood epilepsy. The purpose of this report is to study the immunological aspects in severe myoclonic epilepsy in infancy (SMEI). PATIENTS AND METHODS: 12 patients selected according to the following criteria: no previous personal history of disease, frequent familial history of epilepsy, beginning in the first year of life with seizures usually febriles, onset of afebrile seizures between 18 months and 4 years, normal EEG and psychomotor development are at the onset, seizures resistant to antiepileptic drugs. The following immunological evaluation, has been carried out: granulocytes phagocytic activity, lymphocytics subpopulations, serum immunoglobulins and IgG subclasses, hemolytic capacity of complement, lymphocytic transformation test. RESULTS: In five cases the immunological study was normal; five cases had IgA deficiency, associated in two to high serum IgG1 levels and in two to high IgG1 and low IgG2 levels; one case shows an IgM increase associated to hemolytic capacity of complement deficiency (CH50); four cases have a reduced response to different mitogens. CONCLUSIONS: The value of this results is doubtful. It is possible that genetical and environmental factors are involved in SMEI and that the immunological abnormalities found favor the hyperergic reactions in given circumstances.

Estudio inmunológico en pacientes con epilepsia mioclónica severa en la infancia / Inmunological study in patients with severe myoclonic epilepsy in infancy

Objetivo. Hechos clínicos y experimentales han mostrado el papel de mecanismos inmunitarios en la patogenia de la epilepsia en el niño. El propósito de este trabajo es estudiar los aspectos inmunológicos de la epilepsia mioclónica severa de la infancia (EMSI). Pacientes y métodos. Se seleccionaron 12 casos de acuerdo con los siguientes criterios: sin antecedentes personales de enfermedad, historia familiar de epilepsia frecuente, comienzo en el primero año con crisis habitualmente febriles, aparición entre los 18 meses y 4 años de crisis afebriles, EEG y desarrollo psicomotor normales al comienzo y crisis resistentes a los fármacos antiepilépticos. Se ha realizado la siguiente evaluación inmunológica: actividad fagocítica de los granulocitos, subpoblaciones linfocitarias, inmunoglobulinas séricas y subclases de IgG, capacidad hemolítica del complemento y test de transformación linfocitaria. Resultados. En cinco niños el estudio inmunológico ha sido normal; en cinco casos había disminución de IgA, asociada en dos a incremento de IgG1 y en dos a incremento de IgG1 y disminución de IgG2; un caso muestra incremento de IgM asociado a ausencia de capacidad hemolítica del complemento (CH50); cuatro casos mostraban respuesta disminuida a diferentes mitógenos, asociada en tres a anomalías en las inmunoglobulinas. Conclusiones. El valor de estos hallazgos es dudoso. Es posible que en la EMSI intervengan factores genéticos y factores ambientales y que las alteraciones inmunológicas encontradas faciliten reacciones de tipo hiperérgico en determinadas circunstancias (AU)

Objective. Clinical and experimental data support the role of immune mechanisms in the pathogeny of childhood epilepsy. The purpose of this report is to study the immunological aspects in severe myoclonic epilepsy in infancy (SMEI). Patients and methods. 12 patients selected according to the following criteria: no previous personal history of disease, frequent familial history of epilepsy, beginning in the first year of life with seizures usually febriles, onset of afebrile seizures between 18 months and 4 years, normal EEG and psychomotor development are at the onset, seizures resistant to antiepileptic drugs. The following immunological evaluation, has been carried out: granulocytes phagocytic activity, lymphocytics subpopulations, serum immunoglobulins and IgG subclasses, hemolytic capacity of complement, lymphocytic transformation test. Results. In five cases the immunological study was normal; five cases had IgA deficiency, associated in two to high serum IgG1 levels and in two to high IgG1 and low IgG2 levels; one case shows an IgM increase associated to hemolytic capacity of complement deficiency (CH50); four cases have a reduced response to different mitogens. Conclusions. The value of this results is doubtful. It is possible that genetical and environmental factors are involved in SMEI and that the immunological abnormalities found favor the yperergic reactions in given circumstances (AU)

Lack of association between juvenile myoclonic epilepsy and HLA-DR13.

PURPOSE: We sought to replicate and extend a previously reported positive association between juvenile myoclonic epilepsy and HLA-DR13. METHODS: Ninety-three subjects with juvenile myoclonic epilepsy and 93 normal blood donors, entirely of white origin with their families mostly of French extraction, underwent DNA-based HLA-DR13 and DQB6 typing. RESULTS: None of the investigated alleles or combination of alleles (DRB1*1301-DQB1*0603 or DRB1*1302-DQB1*0604) showed a significant difference between patients and controls. CONCLUSIONS: Unlike previously reported positive association, in this population, there is no evidence that susceptibility to juvenile myoclonic epilepsy is associated with HLA-DR13.

Is HLA-DRW13 (W6) associated with juvenile myoclonic epilepsy in Arab patients?

In a study of 32 unrelated Arab patients with juvenile myoclonic epilepsy (JME), we compared the frequencies of human leukocyte antigen (HLA) class I and II alleles with those of unrelated healthy controls. A significant difference between the phenotypic frequencies in JME patients and controls was observed for DRW13, the split of DRW6 (37.5 vs 11% of controls). The strength of association as measured by the relative risk was 4.85 for this antigen (p = 0.002). The possible association of JME with HLA-DRW6 recently reported in Caucasians was confirmed in this study. This finding speaks for the homogeneity of the disease among Arabic and Caucasian JME patients. The existence of this association is evidence of a locus in the HLA region that influences expression of JME.

[High-dose immunoglobulin treatment of epilepsy in children]. / Hochdosierte Immunglobulinbehandlung der Epilepsie bei Kindern.

High-dose, intravenously administered immunoglobulins have been successfully applied to a few cases of childhood epilepsy and led to a reduction of the seizure frequency in a number of studies. In the present study 4 patients with myoclonic-astatic petit mal or myoclonic absence were treated with intravenously administered immunoglobulins (400 mg/kg for 5 days). Deterioration occurred in 1 patient, 1 patient showed no effect, and 2 patients showed a partial and transient response. Theoretically, the rationale for immunoglobulin therapy in epilepsy is based on the assumption of autoimmune mechanisms as being the underlying pathogenesis. However, a review of the literature showed that the few studies available differ in the forms of epilepsy treated and the effects obtained. No study correlated the effects of immunoglobulin administration with a presumptive autoimmune disorder. As a result, high-dose intravenous immunoglobulin treatment of childhood epilepsy remains empirical and the group of patients who might benefit from such a treatment continues to be poorly defined.

Use of intravenous immunoglobulins in drug-resistant epilepsy.

Among the 257 pediatric patients examined, 104 were classified as having drug-resistant epilepsy (DRE). In all of them genetic, metabolic, chromosomal and infectious causes were investigated, and brain imaging with computed tomography scans and nuclear magnetic resonance were obtained. Since treatment with gammaglobulins (GGs) has been reported to be useful in pediatric cases of epilepsy, informed consent for GGs treatment was obtained in 43 patients with DRE. The etiology or evidence of brain lesions was identified in 16 of them. In 31 of these patients, neither conventional drug treatment, nor a trial with adrenocorticotropic hormone was successful. Intact monomeric GGs, 400 mg/kg, were given intravenously. A second dose was given after 15 days and, thereafter, every 21 days for a maximum of ten injections (protocol A), or every 2nd day for a maximum of five doses (protocol B). In every patient, the type of epilepsy was identified according to the classification of the International League Against Epilepsy. The frequency of seizures was recorded for a period beginning at least 6 months before the administration of GGs. Immunological evaluation was also performed before and after the treatment with GGs. A transient decrease of the seizure frequency was noted in 12 subjects. In another patient with infantile idiopathic myoclonic epilepsy, seizures disappeared for 30 months. In 1 case a persistent 80% reduction in the number of seizures was observed. A persistent disappearance of seizures was noted in a subject with complex partial seizures (CPS) that followed an idiopathic infantile spasm syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

CSF anomalies in children affected by Epilepsia Partialis Continua (EPC).

In two children affected with "Epilepsia Partialis Continua" (EPC) of progressive type, probably secondary to a slow encephalitis, the percentage of T-lymphocytes in CSF was lower than normal (30% compared to 90%). The CSF-T-lymphocytes are characterized by their ability to form E-rosettes. In one patient signs of intrathecal synthesis of IgG, especially oligoclonal bands at isoelectrofocusing, were observed. These results confirm, that in this type of EPC some immunological parameters in the CSF are impaired; so the aetiological hypothesis of an infectious disease, caused by a non-conventional viral agent, is supported.

Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6.

Although certain forms of epilepsy have long been suspected to be inherited, heterogeneity has made it difficult to find the genes responsible for any subtypes. We found that families ascertained through patients with juvenile myoclonic epilepsy show linkage with the BF and HLA loci on human chromosome 6. There is some evidence that the locus may be outside the HLA complex and no evidence as yet of an association with any allele of the HLA complex.

Immunological homogeneity of Lafora body, corpora amylacea, basophilic degeneration in heart, and intracytoplasmic inclusions of liver and heart in type IV glycogenosis.

Antisera against Lafora bodies were made in rabbits by subcutaneous injection of the myocardium from a patient died of Lafora disease. Using this antisera, immunohistochemistry revealed that corpora amylacea, the basophilic degeneration of myocardium and deposits of type IV glycogenosis contained the materials which were antigenically common to Lafora bodies.

Mapping genes in juvenile myoclonic epilepsy.

The genetics of the various forms of epilepsy can be best understood by knowing where the affected gene is located. Genetic methodologies used to explore the genetics of epilepsy now include segregation analysis, linkage analysis and recombinant DNA technology. Juvenile myoclonic epilepsy (JME), a form of idiopathic epilepsy with a strong genetic component, provides informative pedigrees for linkage studies. Preliminary results demonstrate the heterogenous nature of the JME syndrome.