Ikuko Sato

Dynamic cortical activity during spasms in three patients with West syndrome: A multichannel near-infrared spectroscopic topography study

Summary:  Purpose: To investigate spatial and temporal cortical activity during clusters of naturally occurring epileptic spasms in patients with West syndrome (WS) by using multichannel near‐infrared spectroscopy (mNIRS).

Utility of subtraction ictal SPECT images in detecting focal leading activity and understanding the pathophysiology of spasms in patients with West syndrome

PURPOSES The aims of the study were to evaluate the detectability of focal leading activity in three cases of West syndrome having focal abnormal activity on EEG by comparing subtraction ictal images and raw ictal images, and to interpret the results in 16 cases. METHODS Subtraction images were constructed using iNeurostat (revision 2). RESULTS In three cases with focal abnormal activity on EEG, subtraction ictal images reflected the EEG findings; in contrast, raw ictal images did not. Diverse degrees of cortical hyperperfusion, ranging from zero to 10 sites, seen in the other 13 cases seemed to reflect spasm pathophysiology and rapid spasm propagation. Subtraction ictal images also allowed the ready detection of hyperperfusion of subcortical structures and of a tight cortico-subcortical relationship in a subset of cases. CONCLUSIONS We showed the superiority of subtraction ictal images in detecting the focal epileptic region and in showing propagation pathways from the cortex to subcortical structures. A subset of spasms in WS may be focal cortical-onset secondarily generalized seizures. We believe that subtraction analysis is valuable in patients with complex WS who have partial seizures and spasms simultaneously along with focal epileptic EEG activity, as they will likely be candidates for epilepsy surgery.

Histamine H1 antagonists block M-currents in dissociated rat cortical neurons

We investigated the effects of histamine H1 antagonists on acutely dissociated neurons from the rat cortex using the patch-clamp technique. First-generation antihistamines, such as pyrilamine, d-chlorpheniramine, diphenhydramine, and ketotifen, suppressed M-currents in a concentration-dependent manner with respective half-inhibition concentrations (C50) of 35.9, 48.5, 34.8, and 47.8 microM at a holding potential of -26.5 mV. Astemizole, a second-generation antihistamine, inhibited M-currents with a C50 of 18.1 microM, but cetirizine did not do so, up to a concentration of 300 microM. Neither ranitidine nor cimetidine, both H2 antagonists, suppressed M-currents. The C50 of pyrilamine significantly decreased with membrane hyperpolarization, suggesting that it acts directly on M channel pores. The inhibition of M channels may be involved in the neurotoxic effects of histamine H1 antagonist overdose.

Schinzel–Giedion syndrome: A further cause of early myoclonic encephalopathy and vacuolating myelinopathy

Here, we report a male child with Schinzel-Giedion syndrome associated with intramyelinic edema detected on brain magnetic resonance imaging (MRI) and persistent suppression-burst pattern on electroencephalography (EEG) with erratic myoclonus of the extremities and face. Similar to nonketotic hyperglycinemia, Schinzel-Giedion syndrome may be recognized as another causative genetic disease of early myoclonic encephalopathy and vacuolating myelinopathy.

Successful treatment of a 2-year-old girl with intractable myasthenia gravis using tacrolimus

We used tacrolimus to successfully treat a patient with childhood-onset oropharyngeal myasthenia gravis (MG). A girl (2 years, 5 months old) with oropharyngeal MG responded partially to treatment including pyridostigmine bromide, intravenous immunoglobulin, and prednisolone (2 mg/kg/day) for 7 weeks, but this resulted in worsening of her eye symptoms. By contrast, tacrolimus at 2 mg/day resulted in complete remission of the MG, which made it possible to reduce the dose of prednisolone. This is a rare report of the use of tacrolimus as an effective treatment for patients with intractable childhood-onset MG.

Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression.

Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing’s disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXRα. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing’s disease.

A case with central and peripheral hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) plus cataract

Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease, characterized by both central and peripheral hypomyelination. We describe a 21-year-old male with mildly progressive ataxia, mental retardation, pituitary hypogonadotropic hypogonadism, delayed dentition, and cataract. Brain magnetic resonance imaging showed hypomyelinated white matter, cerebellar atrophy, and a thin corpus callosum. The literature suggests that abnormal findings upon sural nerve biopsy may indicate peripheral hypomyelination, even in the absence of clinically and physiologically evident peripheral neuropathy. A sural nerve biopsy of this patient was normal, and this finding is further discussed. Taken together with previous reports, this case suggests that 4H syndrome can be regarded as a spectrum disorder, the cardinal signs of which may be central hypomyelination, ataxia, hypogonadotropic hypogonadism, and hypodontia.

Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells

We generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter/luciferase chimeric reporter construct that is highly sensitive to angiotensin II (AII) and potassium, and defined AII receptor blocker (ARB) effects. In the presence of AII, all ARBs suppressed AII-induced CYP11B2 transcription. However, telmisartan alone increased CYP11B2 transcription in the absence of AII. Telmisartan dose-dependently increased CYP11B2 transcription/mRNA expression and aldosterone secretion. Experiments using CYP11B2 promoter mutants indicated that the Ad5 element was responsible. Among transcription factors involved in the element, telmisartan significantly induced NGFIB/NURR1 expression. KN-93, a CaMK inhibitor, abrogated the telmisartan-mediated increase of CYP11B2 transcription/mRNA expression and NURR1 mRNA expression, but not NGFIB mRNA expression. NURR1 over-expression significantly augmented the telmisartan-mediated CYP11B2 transcription, while high-dose olmesartan did not affect it. Taken together, telmisartan may stimulate CYP11B2 transcription via NGFIB and the CaMK-mediated induction of NURR1 that activates the Ad5 element, independent of AII type 1 receptor.

Successful Treatment With Sumatriptan in a Case With Cyclic Vomiting Syndrome Combined With 18q— Syndrome

The authors present a 14-year-old girl with 18q— syndrome combined with cyclic vomiting syndrome. Since the age of 5 years, she has been admitted to hospital 30 times. Despite trying many prophylactic treatments, no medication has inhibited the vomiting attacks successfully. Intranasal sumatriptan was effective at halting the vomiting attacks. This is the first case of 18q— syndrome combined with cyclic vomiting syndrome successfully treated with sumatriptan. This report may allow us to consider sumatriptan use in patients suffering from misery attack of cyclic vomiting syndrome combined with chromosomal abnormality of 18q— syndrome.

Efficacy of Continuous Acyclovir Infusion in Neonatal Herpes Virus Encephalitis

We have successfully eliminated herpes simplex virus-2 from the central nervous system in a case of neonatal herpes simplex virus encephalitis with a continuous acyclovir infusion. A male infant delivered from a healthy 22-year-old woman without genital or systemic herpes symptoms around delivery began to develop fever and intractable seizures. He was started on intermittent intravenous acyclovir (20 mg/kg every 8 h) based on the diagnosis of herpes encephalitis. The virus was not eliminated with intermittent acyclovir and vidarabine, while continuous acyclovir was ultimately effective in eliminating herpes simplex virus from his central nervous system. This report demonstrates the efficacy of continuous acyclovir infusion in neonatal herpes simplex virus encephalitis.