Ichiro Kuki

Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus

Status epilepticus is one of the most common neurological emergencies in children and adults. Febrile status epilepticus cases are often associated with inflammatory neurological diseases caused by specific pathogens or antineuronal autoimmunity. In addition, there is a subgroup of super-refractory status epilepticus triggered by fever and having no known cause.1 This condition is designated as either acute encephalitis with refractory, repetitive partial seizures (AERRPS)2 or febrile infection-related epilepsy syndrome (FIRES).3 The pathogenesis of AERRPS/FIRES is currently unknown. A close relationship between febrile illness and status epilepticus suggests deleterious effects of inflammation and autoimmunity on the onset and progression of seizure. However, immune mechanisms in human status epilepticus associated with isolated fever have not been fully elucidated. We report a comprehensive study of the inflammatory mediators in paediatric cases of AERRPS. We show a marked upregulation of proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) of patients with this condition. We defined AERRPS using the criteria shown in online supplementary table S1. Between April 2010 and July 2013, 14 patients with AERRPS and 14 patients with other inflammatory neurological diseases (OIND) were enrolled in the study. Serum and CSF specimens from patients with AERRPS and OIND were collected between 0 and 39 days from the onset of neurological symptoms. Eighteen patients with non-inflammatory neurological diseases (NIND) served as a control group. Additionally, the Shizuoka Institute of Epilepsy and Neurological Disorders provided us with 13 conserved CSF specimens from patients with AERRPS who fulfilled the same criteria, which we also included in our analysis. …

Quinidine therapy for West syndrome with KCNTI mutation: A case report

The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2years and 6months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.

Hemorrhagic shock and encephalopathy syndrome – the markers for an early HSES diagnosis

BackgroundThe hemorrhagic shock and encephalopathy syndrome (HSES) is a devastating disease that affects young children. The outcomes of HSES patients are often fatal or manifesting severe neurological sequelae. We reviewed the markers for an early diagnosis of HSES.MethodsWe examined the clinical, biological and radiological findings of 8 patients (4 months to 9 years old) who met the HSES criteria.ResultsAlthough cerebral edema, disseminated intravascular coagulopathy (DIC), and multiple organ failure were seen in all 8 cases during their clinical courses, brain computed tomography (CT) scans showed normal or only slight edema in 5 patients upon admission. All 8 patients had normal platelet counts, and none were in shock. However, they all had severe metabolic acidosis, which persisted even after 3 hours (median base excess (BE), -7.6 mmol/L). And at 6 hours after admission (BE, -5.7 mmol/L) they required mechanical ventilation. Within 12 hours after admission, fluid resuscitation and vasopressor infusion for hypotension was required. Seven of the patients had elevated liver enzymes and creatine kinase (CK) upon admission. Twenty-four hours after admission, all 8 patients needed vasopressor infusion to maintain blood pressure.ConclusionCT scan, platelet count, hemoglobin level and renal function upon admission are not useful for an early diagnosis of HSES. However, the elevated liver enzymes and CK upon admission, hypotension in the early stage after admission with refractory acid-base disturbance to fluid resuscitation and vasopressor infusion are useful markers for an early HSES diagnosis and helpful to indicate starting intensive neurological treatment.

Characteristic Neuroradiologic Features in Hemorrhagic Shock and Encephalopathy Syndrome

Hemorrhagic shock and encephalopathy syndrome is a devastating disease, but the pathogenesis remains unclear. The aim of this study was to examine the usefulness of neuroimaging in establishing a diagnosis and elucidating the pathogenesis. We analyzed the neuroradiologic features of 22 patients who fulfilled the Levin criteria. All patients underwent brain computed tomography (CT), and 14 patients underwent brain magnetic resonance imaging (MRI) including diffusion-weighted imaging in 10 patients. Initial CT showed normal findings in 14 of 18 (78%) patients, but subsequently hypodensities appeared in bilateral watershed zones and progressed to whole brain edema. MRI revealed cytotoxic edema, showing hyperintensities in bilateral watershed zones on diffusion-weighted imaging with a low apparent diffusion coefficient. Serial neuroimaging showed characteristic features of a widespread brain ischemic event mainly in watershed zones in hemorrhagic shock and encephalopathy syndrome.

A case of succinic semialdehyde dehydrogenase deficiency with status epilepticus and rapid regression

BACKGROUND Clinical phenotypic expression of SSADH deficiency is highly heterogeneous, and some infants may develop refractory secondary generalized seizures. PATIENT A 9-month-old boy manifested partial seizures, developing severe status epilepticus, and conventional antiepileptic drugs were ineffective. Use of ketamine contributed to the control of status epilepticus, achieving a reduction in frequency of partial seizures, and improving EEG findings without apparent complications. Diffusion-weighted images showed hyperintensities in the bilateral basal ganglia and fornix, and multiple T2 hyperintensity lesions were detected. (123)I-iomazenil (IMZ) SPECT revealed a decrease in binding of (123)I-iomazenil predominantly in the left temporal region by the 18th day of hospitalization. However, repeated IMZ-SPECT on the 46th day of hospitalization demonstrated almost no accumulation across a broad region, sparing the left temporal region. The patient showed rapid regression, refractory myoclonus, and severe progressive brain atrophy. CONCLUSION IMZ-SPECT findings demonstrated reduced benzodiazepine receptor binding and its dynamic changes in an SSADH-deficient patient. Considering the down regulation of the GABAA receptor, ketamine should be included in pharmacotherapeutic strategies for treatment of refractory status epilepticus in SSADH-deficient patients.

A pediatric patient of hemorrhagic acute transverse myelitis.

An 11-year-old boy presented with progressive leg hypesthesia but no history of trauma. Dysuria and constipation appeared subsequent to gait difficulty. He was admitted 8days after onset. Spinal magnetic resonance imaging (MRI) revealed longitudinal hyperintensity with cord swelling and hypointensity on T2-weighted images, suggesting severe inflammation and microbleeding change, respectively. Gadolinium contrast-enhanced MRI demonstrated mild enhancement in the lesions. Platelet count and coagulation findings were normal, and cerebrospinal fluid analysis showed no pleocytosis. He was diagnosed with idiopathic acute transverse myelitis (ATM), and intravenous methylprednisolone pulse therapy and plasmapheresis were initiated. On day 14, motor dysfunction aggravated suddenly, accompanied by expanding hemorrhagic lesions. Thereafter, administration of intravenous immunoglobulin, repeated intravenous methylprednisolone pulse therapy and prednisolone for one month resulted in complete recovery four months later. Both anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies were negative. We presented the first pediatric case showing hemorrhagic spinal lesions in the clinical course of ATM. This severe complication should be recognized in the management of ATM.

Efficacy and safety of everolimus in patients younger than 12 months with congenital subependymal giant cell astrocytoma

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that activates mammalian target of rapamycin and produces tumor growth in several organs. We present five patients younger than 12 months who were diagnosed with TSC and treated with everolimus (EVL), after which congenital subependymal giant astrocytoma (cSEGA) promptly regressed in all patients. All patients achieved at least 50% reduction in the volume of cSEGA within 6 months. The most rapid reduction of cSEGA volume (79.1%) was found during the initial 3 months of EVL treatment. Patients underwent EVL treatment for an average of 27 months (range: 4-55 months). Mean EVL maintenance dose was 1.35 mg per day. EVL blood trough concentrations ranged from 2.0 to 11.7 ng/ml. The cSEGA became larger after discontinuing EVL in two patients. In all four patients who had multiple cardiac rhabdomyomas (CRMs), the CRMs showed accelerated regression after receiving EVL. Adverse events were noted in four patients: infection, stomatitis, and increased triglycerides. Four patients had febrile status epilepticus, which occurred during acute encephalopathy in a patient, and after discontinuing EVL in another. Three patients were still receiving EVL at their latest evaluations. Maintenance therapy with EVL is an effective therapeutic option for patients with cSEGA, and moreover may have additional favorable effects on other complications, even in early infancy; however, adverse effects should be carefully monitored.

Three Cases of KCNT1 Mutations: Malignant Migrating Partial Seizures in Infancy with Massive Systemic to Pulmonary Collateral Arteries

KCNT1 mutations are gain-of-function mutations in potassium channels resulting in severe infantile epilepsy. Herein we describe 3 infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure.

Seizure freedom from temporal lobe epilepsy with mesial temporal lobe tumor by tumor removal alone without hippocampectomy despite remaining abnormal discharges on intraoperative electrocorticography: Report of two pediatric cases and reconsideration of the surgical strategy

Background: In the surgical treatment of temporal lobe epilepsy with mesial temporal lobe tumor, whether to remove the hippocampus aiming for a better seizure outcome in addition to removing the tumor is a dilemma. Two pediatric cases treated successfully with tumor removal alone are presented. Case Description: The first case was an 11-year-old girl with a ganglioglioma in the left uncus, and the second case was a 9-year-old girl with a pleomorphic xanthoastrocytoma in the left parahippocampal gyrus. In both cases, the hippocampus was not invaded, merely compressed by the tumor. Tumor removal was performed under intraoperative electrocorticography (ECoG) monitoring. After tumor removal, abnormal discharges remained at the hippocampus and adjacent temporal cortices, but further surgical interventions were not performed. The seizures disappeared completely in both cases. Conclusions: When we must decide whether to remove the hippocampus, the side of the lesion, the severity and chronicity of the seizures, and the presence of invasion to the hippocampus are the factors that should be considered. Abnormal discharges on ECoG at the hippocampus or adjacent cortices are one of the factors related to epileptogenicity, but it is simply a result of interictal irritation, and it is not an absolute indication for additional surgical intervention.

An unusual manifestation of Sjögren syndrome encephalitis

Sjögren syndrome (SS) is a systemic inflammatory and autoimmune disease characterized by systemic disorders of the exocrine glands, predominantly the salivary and lacrimal glands. Here, we report a 4-year-old boy who presented with the repetition of generalized tonic-clonic seizures for 1-2 min. Initially, he was diagnosed with idiopathic autoimmune encephalitis and was treated with steroids. He was eventually diagnosed with SS based on the examination results, such as inflammatory cell infiltration into the minor salivary glands and positive serum anti-SSA/Ro antibody. Although central nervous system complications are rare in pediatric SS, this condition should be considered in the differential diagnosis when a patient presents with idiopathic autoimmune encephalitis of unknown cause. Furthermore, SS can occur in relatively young children and can present without imaging abnormalities.