Kleine-Levin syndrome elicited by encephalopathy with reversible splenial lesion.

Kleine-Levin syndrome is a rare sleep disorder of unknown etiology characterized by repetitive episodes of hypersomnia between asymptomatic periods. We report the case of a 13-year-old girl who presented with drowsiness triggered by influenza A as the first episode. Magnetic resonance imaging (MRI) on day 6 showed transient reduction of diffusion in the corpus callosum splenium. The patient was diagnosed with encephalopathy with a reversible splenial lesion. The symptoms resolved after 10 days, but additional episodes of hypersomnia lasting 5-10 days occurred 1, 5, 6, 11, 13, and 25 months after the first episode. MRI during hypersomnia indicated no lesions, and sleep duration and cognition were normal between episodes. The patient was diagnosed with Kleine-Levin syndrome. Electroencephalographic and clinical findings during the first episode were similar to those during the other episodes. Encephalopathy with a splenial lesion and Kleine-Levin syndrome may have similar pathological mechanisms causing a disturbance in consciousness.

Initial vasodilatation in a child with reversible cerebral vasoconstriction syndrome.

We describe the case of a 10-year-old boy who developed reversible cerebral vasoconstriction syndrome (RCVS) after cerebellitis. He received intravenous immunoglobulin and methylprednisolone to treat the cerebellitis. However, he then presented with a sudden severe headache, vomiting, and generalized tonic-clonic seizure. Brain magnetic resonance angiography (MRA) initially revealed diffuse cerebral vasodilatations, and diffuse multifocal segmental vasoconstrictions developed several days later. His clinical symptoms gradually resolved after several days, in the absence of any specific therapy. MRA performed 46days after symptom onset showed that the multifocal segmental vasoconstrictions had resolved, suggesting a diagnosis of RCVS. The imaging features of RCVS include multifocal segmental vasoconstriction. However, our case suggests that diffuse cerebral vasodilatation may in fact be evident during the early stage of disease.

High-dose phenobarbital with intermittent short-acting barbiturates for acute encephalitis with refractory, repetitive partial seizures.

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by repetitive seizures during the acute and chronic phases and has a poor neurological outcome. Burst-suppression coma via continuous i.v. infusion of a short-acting barbiturate is used to terminate refractory seizures, but the severe side-effects of short-acting barbiturates are problematic. We report on a 9-year-old boy with AERRPS who was effectively treated with very-high-dose phenobarbital (VHDPB) combined with intermittent short-acting barbiturates. VHDPB side-effects were mild, especially compared with those associated with continuous i.v. infusion of short-acting barbiturates (dosage, 40-75 mg/kg/day; maximum blood level, 290 µg/mL). Using VHDPB as the main treatment, short-acting barbiturates were used intermittently and in small amounts. This is the first report to show that VHDPB, combined with intermittent short-acting barbiturates, can effectively treat AERRPS. After treatment, convulsions were suppressed and daily life continued, but intellectual impairment and high-level dysfunction remained.

Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy.

We examined serum levels of various cytokines, chemokines, growth factors, and adhesion molecules in patients with uncomplicated influenza (n=20) and influenza virus-associated encephalopathy (IE) (n=18) to understand the underlying mechanism of IE. We found that IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, G-CSF, GM-CSF, TNF-α, TIMP-1, MMP-9, sE-selectin, and neutrophil elastase were elevated significantly in sera from patients with uncomplicated influenza and those with IE, compared with normal controls (n=20). Of note, neutrophil elastase, sE-selectin, IL-8, and IL-13 were elevated significantly in IE as compared with uncomplicated influenza. In the present study, for the first time, we found that serum levels of neutrophil elastase were increased in patients with IE compared with uncomplicated influenza, which suggested that cerebral endothelial damage in the development of IE was mediated by neutrophil elastase. The present study implied that anti-elastase agents are possibly an effective therapeutic protocol for IE, but this needs further elucidation.

Efficacy of long term weekly ACTH therapy for intractable epilepsy.

BACKGROUND: Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for infantile spasms, and is effective for many other intractable epilepsies. While spasms may respond to ACTH for weeks, a substantial proportion of patients develop recurrent seizures over a yearly period. To maintain efficacy, we treated two children with intractable epilepsy with weekly ACTH therapy for 1 year and described the changes in clinical seizures, electroencephalograms, developmental assessments and side effects. SUBJECTS AND METHODS: A girl with infantile spasms due to lissencephaly and a boy with atypical absence seizures were studied. In both cases, seizures were frequent and resistant to antiepileptic drugs; electroencephalograms showed continuous epileptiform activities, and the patients' development was delayed and stagnant prior to ACTH treatment. The initial ACTH therapy (daily 0.015 mg/kg for 2 weeks, 0.015 mg/kg every 2 days for 1 week, 0.0075 mg/kg every 2 days for 1 week), was transiently effective in both cases. The second-round ACTH therapy consisted of the initial ACTH therapy protocol followed by weekly ACTH injections (0.015 mg/kg or 0.0075 mg/kg) for 1 year. Both cases were followed for at least 1 year after therapy. RESULTS: In both patients, clinical seizures were completely controlled during and 1 year after the second-round AHCH therapy. Continuous epileptiform discharges disappeared, while intermittent interictal epileptiform discharges remained. Both patients showed some developmental gains after achieving seizure control. No serious side effects were recorded. CONCLUSION: Further studies are warranted to determine if a long-term weekly ACTH is a safe and effective treatment for intractable epilepsy.

Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination.

We retrospectively collected three patients with clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination, and reviewed five patients, including two patients previously reported. The five patients (all males, aged 1 to 9) presented with fever, vomiting, or headache as the initial symptoms (day 0), suggesting meningitis, at 13 to 21 days after mumps vaccination. Consciousness disturbance, delirious behavior, seizures, or dysarthria was observed on days 1 to 3, which had completely resolved before day 11. Hyponatremia was observed in all patients. A cerebrospinal fluid study showed pleocytosis, and confirmed the vaccine strain genome. MRI revealed reduced diffusion in the splenium of the corpus callosum on days 2 to 4, which had completely disappeared on the follow-up studies performed on days 7-15. EEG showed high voltage slow wave in three patients, which later normalized. These findings led to a diagnosis of MERS after mumps vaccination. MERS after mumps vaccination may be more common than previously considered. MERS is suspected when a male patient after mumps vaccination presents with neurological symptoms with hyponatremia, following symptoms of aseptic meningitis, and MRI would be performed to examine the splenium of the corpus callosum.

A case of atypical benign partial epilepsy with action myoclonus.

We describe a boy, 3 years and 6 months old, who experienced a rolandic seizure accompanied by a cluster of atypical absence seizures, the EEGs for which corresponded to those of atypical benign partial epilepsy (ABPE). Of note, this patient suffered from developmental delay beginning in infancy and exhibited giant middle-latency somatosensory evoked potentials with action myoclonus. With the exceptions of ethosuximide, acetazolamide, and adrenocorticotropic hormone, which have been reported to be effective in ABPE, the atypical absence seizures were intractable despite extensive treatment with various anticonvulsants. The drugs that were effective led to a remarkable reduction in seizure frequency and EEG improvement, but the efficacy was temporary. The patient demonstrated moderate mental retardation without regression and could not walk with support or speak any meaningful words at the age of 3 years and 6 months. Based on thorough differential diagnosis, although further studies will be necessary, we propose that this boy may present a new phenotype of ABPE: ABPE with action myoclonus.

Acute encephalopathy with a truncation mutation in the SCN1A gene: a case report.

A girl aged 1 year 9 months had recurrent episodes of febrile status epilepticus. She recovered completely after the first three episodes. However, at 9 months she developed acute encephalopathy resulting in severe neurologic sequelae. Diffusion-weighted magnetic resonance imaging revealed diffuse high-intensity signals over the cortex and subcortical white matter in the acute phase and severe diffuse cerebral atrophy in the chronic phase. Mutations were detected in the neuronal voltage-gated sodium channel alpha subunit type 1 (SCN1A) gene. SCN1A sequence analysis revealed a truncation mutation:e x1-c.126Adel (D43fs). Our patient was likely afflicted by severe myoclonic epilepsy in infancy, and the fourth episode of status epilepticus was similar to acute encephalopathy. This report provides further insight into the molecular pathophysiology underlying acute encephalopathy.

Functional cortical deafferentation from the subcortical structures in a patient with early myoclonic encephalopathy: a functional neuroimaging study.

We, for the first time, used functional neuroimaging analyses for a girl with early myoclonic encephalopathy (EME). The interictal single photon emission computed tomography (SPECT) and [18F]-fluoro-D-deoxyglucose positron emission tomography (FDG-PET) at 1 month of age showed hypoperfusion and hypometabolism of bilateral basal ganglia, thalami, and the right parietooccipital cerebral cortices, showing that there is profound dysfunction of the basal ganglia and thalamus as well as cerebral cortex. On the other hand, subtraction ictal SPECT of tonic spasms clearly showed hyperperfusion of the bilateral basal ganglia, thalami, brainstem, and deep cortical layer of bilateral frontoparietal cortices. The present study suggests that functional deafferentation of the cortex from subcortical structures exists in EME, and that these imaging abnormalities may provide insight into the pathophysiology of suppression-burst pattern in EME.

Reduced levels of interleukin-1 receptor antagonist in the cerebrospinal fluid in patients with West syndrome.

We measured the levels of pro- and anti-inflammatory cytokines in the cerebrospinal fluid (CSF) of 24 patients with West syndrome to clarify whether inflammatory cytokines were involved in the pathophysiology of West syndrome. There was no significant elevation of any of the three pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, in patients with West syndrome as compared with those in controls. However, level of anti-inflammatory cytokine, IL-1 receptor antagonist was significantly decreased in the CSF of patients with West syndrome. Further study is needed to elucidate whether an immune system disturbance is involved in the pathophysiology of West syndrome.

Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis.

Pyridoxine dependent seizure (PDS) is a disorder of neonates or infants with autosomal recessive inheritance characterized by seizures, which responds to pharmacological dose of pyridoxine. Recently, mutations have been identified in the ALDH7A1 gene in Caucasian families with PDS. To elucidate further the genetic background of PDS, we screened for ALDH7A1 mutations in five PDS families (patients 1-5) that included four Orientals. Diagnosis as having PDS was confirmed by pyridoxine-withdrawal test. Exon sequencing analysis of patients 1-4 revealed eight ALDH7A1 mutations in compound heterozygous forms: five missense mutations, one nonsense mutation, one point mutation at the splicing donor site in intron 1, and a 1937-bp genomic deletion. The deletion included the entire exon 17, which was flanked by two Alu elements in introns 16 and 17. None of the mutations was found in 100 control chromosomes. In patient 5, no mutation was found by the exon sequencing analysis. Furthermore, expression level or nucleotide sequences of ALDH7A1 mRNA in lymphoblasts were normal. Plasma pipecolic acid concentration was not elevated in patient 5. These observations suggest that ALDH7A1 mutation is unlikely to be responsible for patient 5. Abnormal metabolism of GABA/glutamate in brain has long been suggested as the underlying pathophysiology of PDS. CSF glutamate concentration was elevated during the off-pyridoxine period in patient 3, but not in patient 2 or 5. These results suggest allelic and non-allelic heterogeneities of PDS, and that the CSF glutamate elevation does not directly correlate with the presence of ALDH7A1 mutations.

A case of Fukuyama-type congenital muscular dystrophy with a very mild mental deficit.

A boy had the clinical features of congenital muscular dystrophy with a very mild mental deficit. A muscle biopsy at one year of age showed the typical findings of Fukuyama-type congenital muscular dystrophy, including selective loss of immunoreactions for alpha dystroglycan. Magnetic resonance imaging showed no findings suggestive of migration disorders. The diagnosis of Fukuyama-type congenital muscular dystrophy was confirmed by a molecular assay at 8 years of age, and his haplotype analysis was heterozygous. At 9 years of age, his FIQ on the Wechsler Scale for Children revealed 69, while his IQ on the Tanaka Binnet scale of intelligence was 97. In this report the relationship between mild clinical condition of the studied case and its genotype is discussed.

Rational design, synthesis, and structure-activity relationships of novel factor Xa inhibitors: (2-substituted-4-amidinophenyl)pyruvic and -propionic acids.

An inhibitor of factor Xa (fXa), the m-substituted benzamidine AXC1578 (1a), was structurally modified with the aim of increasing its potency. In particular, pyruvic acid and propionic acid substituents were incorporated into the P1 benzamidine moiety to introduce a favorable interaction with the oxy-anion hole in the catalytic triad region of fXa. This strategy was based on computational docking studies using the extracted active site of fXa. The validity of the computational model was supported by the acquisition of X-ray crystal structures of the 1a-trypsin and 3b-trypsin complexes (the homology around the active sites of fXa and trypsin is high). The above modifications significantly increased the inhibitory activity toward fXa, whereas the high selectivity for fXa versus thrombin was maintained or enhanced. Compounds 3b, 3c, 3e, and 4b are considered to be potential lead compounds for the development of orally active anticoagulant drugs because they demonstrated potent activity when administered orally to cynomolgus monkeys.

Two successful cases of bromide therapy for refractory symptomatic localization-related epilepsy.

Potassium bromide was tried for two children with daily convulsive focal motor seizures with unconsciousness and focal motor seizure status. The treatment resulted in complete cessation of the attacks. It has been reported that bromide is effective for generalized tonic-clonic seizures and not for complex partial seizures, such as convulsive focal motor seizures with unconsciousness. However, our experiences provide evidence that bromide is one of the useful therapeutic agents for intractable symptomatic localization-related epilepsy.

[Therapeutic effect of cyclosporin A combined with methylprednisolone pulse therapy on hemophagocytic syndrome with the central nervous system involvement].

Two pediatric cases of hemophagocytic syndrome (HPS) with the central nervous system (CNS) involvement are reported. Case 1, a two-month-old girl with primary hemophagocytic lymphohistiocytosis, showed high fever, skin rash and hemorrhagic diathesis followed by convulsion, impairment of consciousness and involuntary movements. Case 2, an eight-year-old boy, complained of visual hallucination in the course of measles complicated with interstitial pneumonitis. MRI of the two cases disclosed multiple T2-hyperintense areas in the CNS. Both clinical symptoms and MRI findings of these cases significantly improved in response to cyclosporin A (CsA) combined with methylprednisolone (mPSL) pulse therapy. Although the pathogenesis of CNS lesions in HPS remains to be elucidated, the etiologic role of hypercytokininemia is obviously important. Because CsA and mPSL have a potent inhibitory effect on the action of cytokines, it is rational and worthwhile to use these agents in the treatment of HPS with CNS involvement.

Total Synthesis of Vancomycin Aglycon-Part 1: Synthesis of Amino Acids 4-7 and Construction of the AB-COD Ring Skeleton.

A triazene-based synthetic strategy for the construction of the complex biaryl ethers and a Suzuki coupling reaction were the key steps in the synthesis of precursor 1 of the aglycon of vancomycin, which already contains the complete skeleton of the target compound. The cleavage of the triazene unit from the D ring and the removal of the other protecting groups led to the aglycon of vancomycin. These strategies should be particularly valuable for the synthesis of other naturally occurring glycopeptide antibiotics and offer opportunities for the synthesis of combinatorial libraries of compounds of the vancomycin family for chemical biology studies.

Total Synthesis of Vancomycin Aglycon-Part 2: Synthesis of Amino Acids 1-3 and Construction of the AB-COD-DOE Ring Skeleton.

A triazene-based synthetic strategy for the construction of the complex biaryl ethers and a Suzuki coupling reaction were the key steps in the synthesis of precursor 1 of the aglycon of vancomycin, which already contains the complete skeleton of the target compound. The cleavage of the triazene unit from the D ring and the removal of the other protecting groups led to the aglycon of vancomycin. These strategies should be particularly valuable for the synthesis of other naturally occurring glycopeptide antibiotics and offer opportunities for the synthesis of combinatorial libraries of compounds of the vancomycin family for chemical biology studies.