Neuromyelitis optica spectrum disorder presenting with repeated hypersomnia due to involvement of the hypothalamus and hypothalamus-amygdala linkage.

We report the case of a 46-year-old Japanese woman with neuromyelitis optica spectrum disorder presenting with repeated hypersomnia accompanied by decreased CSF orexin level. First episode associated with hypothalamic-pituitary dysfunction showed bilateral hypothalamic lesions that can cause secondary damage to the orexin neurons. The second episode associated with impaired memory showed a left temporal lesion involving the amygdala. The mechanism remains unknown, but the reduced blood flow in the hypothalamus ipsilateral to the amygdala lesion suggested trans-synaptic hypothalamic dysfunction secondary to the impaired amygdala. A temporal lesion involving the amygdala and hypothalamus could be responsible for hypersomnia due to neuromyelitis optica spectrum disorder.

Significance of Cortical Ribboning as a Biomarker in the Prodromal Phase of Sporadic Creutzfeldt-Jakob Disease.

A 63-year-old woman who presented for orofacial dystonia showed cortical ribboning, a typical MRI finding in sporadic Creutzfeldt-Jakob disease (sCJD). However, real-time quaking-induced conversion (RT-QuIC), the most sensitive method for an early diagnosis of sCJD, was negative. She developed sCJD six months later, at which time RT-QuIC became positive. The cerebral blood flow showed a decrease in the cerebral cortex (especially in the supramarginal gyrus) consistent with cortical ribboning, but an increase in the basal ganglia, probably involved in orofacial dystonia. Cortical ribboning on MRI might be a better biomarker than RT-QuIC in the prodromal phase of sCJD.

A cerebrospinal fluid microRNA analysis: Progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy described as a syndrome of postural instability, supranuclear vertical gaze palsy, dysarthria, dystonic rigidity of the neck and trunk, dementia, and pseudobulbar palsy. The clinical diagnosis of PSP is often difficult because there are no established biomarkers, and diagnosis is currently based on clinical and imaging findings. Furthermore, the etiology and pathogenesis of PSP remain unknown. Dysregulation of microRNAs (miRNAs/miRs) has been reported to serve an important role in neurodegenerative diseases. However, the miRNA profiles of patients with PSP are rarely reported. The present study aimed to examine cerebrospinal fluid miRNAs, which are considered to be more sensitive indicators of changes in the brain, to elucidate the pathophysiology of PSP and to establish specific biomarkers for diagnosis. The present study used a microarray chip containing 2,632 miRNAs to examine cerebrospinal fluid miRNA expression levels in 11 patients with PSP aged 68­82 years. A total of 8 age­ and sex­matched controls were also included. A total of 38 miRNAs were significantly upregulated and one miRNA was significantly downregulated in the cerebrospinal fluid of patients with PSP. The patients were divided into two groups based on disease stage (early onset and advanced), and changes in miRNA expression were examined. The miRNAs that were most significantly upregulated or downregulated in the early onset group were miR­204­3p, miR­873­3p and miR­6840­5p. The target genes of these miRNAs were associated with molecules related to the ubiquitin­proteasome system and autophagy pathway. Furthermore, these miRNAs were found to target genes that have been reported to have epigenetic changes following an epigenome­wide association study of brain tissues of patients with PSP. This suggested that these miRNAs and genes may have some involvement in the pathogenesis of PSP. However, the sample size of the present study was small; therefore, a greater number of patients with PSP should be examined in future studies.

Rapid Eye Movement Sleep Behavior Disorder-like Symptoms Due to Arousal Responses Associated with Severe Obstructive Sleep Apnea-hypopnea.

A 78-year-old man suspected of having α-synucleinopathies received a high score on a validated questionnaire for rapid eye movement (REM) sleep behavior disorder (RBD). Although he did in fact have unpleasant dreams and vigorous behaviors, polysomnography (PSG) found only obstructive sleep apnea-hypopnea (OSAH). The RBD-like symptoms corresponded with arousal responses, namely augmented inspiratory effort and leg movements, to his frequent apnea-hypopnea events during REM sleep. Thus, severe OSAH might cause RBD-like symptoms. PSG can discriminate real RBD from RBD-like symptoms associated with severe OSAH and therefore may be essential for determining an appropriate course of treatment in certain patients.

Ascending spinal tract formation in chick embryo originating from different spinal regions.

The present study aimed to assess spinal tract formation in neurons originating from cervical (C7), brachial (C14), and thoracic (T4) regions, with the lumbar (LS2) region as a reference, in a chick embryo. For the assessment of the spinal tracts, we introduced a vector expressing human placental alkaline phosphatase into progenitor cells generated after neural tube closure and belonging to the above segments, using in ovo electroporation. The ascending axons took primarily similar paths: dorsal commissural, ventral commissural, and dorsal non-commissural paths, with some variance depending on their originating segments. Some populations of non-commissural neurons later extended their axons following a ventral path. The elongation rates of these axons are primarily constant and tended to increase over time; however, some variations depending on the originating segments were also observed. Some of the dorsally ascending axons entered into the developing cerebellum, and spinocerebellar neurons originating from T4 projected their axons into the cortex of the cerebellum differently from those from LS2. These results unveil an overall picture of early ascending spinal tract formation.

Premedication of hemin for eradication therapy of Helicobacter pylori in patients with porphyria.

Eradication therapy of Helicobacter pylori may be safe if hemin has been intravenously administered in advance, even in patients with a history of recurrent acute porphyria attack.

An autopsy case of Creutzfeldt-Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology.

We report an autopsy case of Creutzfeldt-Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77-year-old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 point mutation. Post-mortem examination revealed marked spongiosis, neuronal loss, and astrocytic gliosis in the cerebral cortex. Mild to moderate spongiosis and neuronal loss were observed in the limbic cortex and basal ganglia. There was no spongiform change in the hippocampus, brain stem or cerebellum. Many senile plaques and neurofibrillary tangles were found, and the Braak stages were stage C and stage IV, respectively. Immunostaining for prion protein (PrP) revealed granular (synaptic-type) and patchy PrP deposition in the cerebral cortex and especially in the hippocampus. Most patchy PrP deposits were colocalized with amyloid beta plaques, but some of them were isolated. The relatively strong PrP deposition and coexistence of Alzheimer-type pathology of this case are remarkable. We suppose that amyloid beta plaques might act as a facilitating factor for PrP deposition.

Light exercise without lactate elevation induces ischemic tolerance through the modulation of microRNA in the gerbil hippocampus.

Previously we studied the possible neuroprotective effects of ischemia-resistant exercise in a gerbil model of transient whole-brain ischemia and evaluated the histology, expression of specific proteins, and brain function under different conditions. The present study investigated the neuroprotective effects of light exercise, without lactate elevation, in a gerbil model of ischemia/reperfusion injury. Transient whole-brain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. A group of animals was subjected to treadmill exercise before ischemia induction. Hippocampal neuronal damage and miRNA expression, as well as behavioral deficits and plasma lactate levels, were evaluated. Light exercise suppressed hippocampal neuron loss and preserved short-term memory. Moreover, 14 miRNAs (mmu-miR-211-3p, -327, -451b, -711, -3070-3p, -3070-2-3p, -3097-5p, -3620-5p, -6240, -6916-5p, -6944-5p, 7083-5p, -7085-5p, and -7674-5p) were upregulated and 6 miRNAs (mmu-miR-148b-3p, -152-3p, -181c-5p, -299b-5p, -455-3p, and -664-3p) were downregulated due to ischemia. However, the expression of these miRNAs remained unchanged when animals performed light exercise before the ischemic event. Differentially expressed miRNAs regulate multiple biological processes such as inflammation, metabolism, and cell death. These findings suggest that light exercise reduces neuronal death and behavioral deficits after transient ischemia by regulating hippocampal miRNAs.

Repeated anti-N-methyl-D-aspartate receptor encephalitis coexisting with anti-myelin oligodendrocyte glycoprotein antibody-associated diseases: A case report.

The coexistence of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated diseases has been reported. We report the case of a 36-year-old woman who presented with repeated typical anti-NMDAR encephalitis coexisting with unusual symptoms not consistent with anti-NMDAR encephalitis. Apart from the anti-NMDAR encephalitis, her first episode was characterized by balance disability with bilateral medial frontal cortical lesions, suggesting the involvement of the cortico-reticular projections and the basal ganglia-brainstem projections. The second episode presented with Broca's aphasia caused by involvement of the Broca's area and lower part of the precentral gyrus. The detection of MOG-Ab in both episodes suggested the coexistence of MOG-Ab-associated diseases. Thus, an evaluation of MOG-Ab should be considered when anti-NMDAR encephalitis presenting with atypical symptoms is encountered.

Orexin secretion abnormality involved in excessive somnolence in CNS lymphoma without hypothalamic lesions.

A 72-year-old woman developed excessive somnolence as one of the symptoms of diffuse large B-cell lymphoma in the central nervous system (CNS). Although somnolence might be caused by reduced orexin secretion associated with hypothalamic lesions, neither brain MRI nor 18F-fluorodeoxyglucose positron emission tomography identified hypothalamic lesions. However, the decreased cerebrospinal fluid (CSF) orexin levels recovered to near normal values with improvement of somnolence after chemotherapy. The alteration of CSF orexin levels suggested the involvement of potential hypothalamic lesions. Therefore, measurements of CSF orexin levels may be useful for understanding the pathological background of somnolence in CNS lymphoma without hypothalamic lesions.

Clinical significance of assaying anti-MOG antibody in cerebrospinal fluid in MOG-antibody-associated diseases: A case report.

The serum diagnosis of anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) associated diseases can be confirmed by the presence of the MOG-Ab, yet its levels in cerebrospinal fluid (CSF) are of unknown significance. We report the case of a 59-year-old woman with a history of 12 recurrent central nervous system lesions in the optic nerve, cerebrum, and spinal cord. The woman's condition improved by each steroid therapy. She tested seronegative for MOG-Ab, yet CSF-positive, leading to a diagnosis of MOG-Ab-associated encephalomyelitis. Our experience suggests measuring MOG-Ab in CSF and serum to prevent the underdiagnosis of MOG-Ab-associated diseases.

The interaction between somatosensory and auditory cognitive processing assessed with event-related potentials.

Event-related potentials induced by somatosensory and after auditory stimulation or bilateral somatosensory stimulation in young adults were studied, aiming to evaluate interactions of cognitive processing of somatosensory and auditory information. In experiment 1, event-related potentials were elicited by four stimulus conditions which were randomly presented with an interstimulus interval of 20 +/- 3 milliseconds: electric stimuli delivered to the right median nerve (Con 1), auditory stimuli delivered to both ears (Con 2), electric and subsequent auditory stimuli (Con 3), and electric stimuli delivered to the bilateral median nerve (Con 4). In experiment 2, Con 2 was changed to electric stimulation of the left median nerve. The subtraction of grand averaged event-related potentials of Con 1 and Con 2 from those of Con 3 demonstrated a positive-negative peak complex with a positive peak at approximately 165 to 170 milliseconds after stimuli and a negative peak with a mean latency of 372 milliseconds in experiment 1. In experiment 2, the subtraction of event-related potentials in Con 1 and 2 from those in Con 4 revealed positive and negative peaks resembling those in experiment 1, but the distribution or latencies of the peaks differed from those in experiment 1. We speculate that the subtracted positive and negative peaks reflect different cognitive processing of bimodal and bifocal sensory information.

Serum microRNA expression profiling in patients with multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by α­synuclein positive glial cytoplasmic inclusions in oligodendrocytes. The clinical diagnosis of MSA is often challenging as there are no established biomarkers and diagnoses are now based on clinical findings alone. At present, the etiology and pathogenesis of MSA are unclear. It has been reported that dysregulation of microRNA (miRNA/miR) serves an important role in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The miRNA profile of patients with MSA remains to be established. The present study investigated the serum miRNA expression level of 10 patients with MSA, using microarray chips including 668 miRNAs. It was identified that 50 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated in the serum of the patients with MSA. The most upregulated miRNA was miR­16, which may induce the accumulation of α­synuclein. The target genes of some miRNAs upregulated in MSA (including miR­17, 20a, 24, 25, 30d and 451) were associated with autophagy­associated molecules. The present study concluded that the expression pattern of miRNAs may be a clinical biomarker for MSA and targeting these miRNAs may provide a novel treatment for MSA.

Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy.

OBJECTIVE: It has been demonstrated that the increased blood pressure (BP) caused by a single dose of water alleviates orthostatic hypotension (OH) and postprandial hypotension (PPH) in patients with autonomic failure (AF). The aim of this study was to evaluate the practical effect of daily water drinking on OH and PPH in the morning when patients with AF are usually most affected. METHODS: In five patients with multiple system atrophy (MSA) characterized by intractable OH and PPH, we measured seated, standing and postprandial BP in the morning without and with ingestion of 350 ml tap water at 07.30 hours for seven successive days. The changes from the basal BP level at 07.30 hours (DeltaBP) were assessed as an index of the effect of water drinking. RESULTS: Water drinking elicited a rapid pressor response in all patients. The DeltaBP during sitting, standing and after a meal following water drinking (day 1 and day 7) was significantly higher than without water drinking (day 0). The effects of reducing OH and PPH on day 7 were equivalent to those on day 1. No adverse effects associated with daily water drinking were observed, except later diuresis, which occurred in one patient. CONCLUSIONS: Daily water drinking demonstrated constant pressor effects in the morning with no severe adverse effects in MSA patients. This finding suggests that water drinking should be tried as a practical measure to prevent or reduce OH and PPH.

Assessment of autonomic dysfunction of multiple system atrophy with laryngeal abductor paralysis as an early manifestation.

Laryngeal abductor palsy (LAP) is common in the advanced stages of multiple system atrophy (MSA). However, occurrence of LAP in the early stages might make a diagnosis of MSA difficult. To search for a clue to diagnosis of MSA with LAP as an early manifestation, we assessed the clinical features of autonomic dysfunction and the central cardiovascular control circuits in two MSA patients who had LAP as a cardinal symptom in the early stages. Development of autonomic dysfunction was preceded or followed by LAP. The autonomic symptom occurring predominantly in the earliest stages was urinary disturbance rather than orthostatic hypotension. Although screening cardiovascular autonomic function tests did not conclusively indicate a diagnosis of MSA, vasopressin release in response to head-up tilt and growth hormone response to clonidine administration demonstrated inappropriate responses, suggesting that the noradrenergic neurons of the caudal ventrolateral medulla were impaired. Diagnosis of atypical MSA with LAP in the early stages might be accelerated by a detailed investigation focused on urinary symptoms and neuroendocrine approaches.

Acute Intermittent Porphyria Presenting with Posterior Reversible Encephalopathy Syndrome, Accompanied by Prolonged Vasoconstriction.

A 20-year-old Japanese woman had an attack of acute intermittent porphyria (AIP). Magnetic resonance imaging (MRI) revealed symmetrical lesions in the cerebrum and cerebellar hemisphere, corresponding to posterior reversible encephalopathy syndrome (PRES). Our administration of heme arginate gradually improved the clinical condition associated with AIP and the level of metabolite of nitric oxide (NO), which is a vascular dilator. Repeated MRI and magnetic resonance angiography revealed exacerbated PRES, part of which showed a small infarction, accompanied by progressive vasoconstriction. These findings suggest that the recovery of NO by heme replacement alone is insufficient for preventing brain damage during an AIP attack.

Changes of parvalbumin immunoreactive neurons and GFAP immunoreactive astrocytes in the rat lateral geniculate nucleus following monocular enucleation.

The expression of calcium binding proteins (CaBPs) has been linked to protection of neurons. The present study investigated the effects of monocular enucleation on the distribution of parvalbumin immunoreactive (PV-IR) neurons and glial fibrillary acidic protein immunoreactive (GFAP-IR) astrocytes in both the dorsal (dLGN) and ventral (vLGN) regions of the lateral geniculate nucleus (LGN). Our results demonstrated an increase in PV-IR neuronal density on the contralateral vLGN at 1-week post-enucleation (PE), which was maintained without significant change for 12 weeks. By contrast, PV-IR neurons in dLGN decreased significantly at all time point examined. The number of GFAP-IR astrocytes showed an initial increase from 1 to 4 weeks PE and then gradually decreased until 48 weeks in both regions of the LGN with contralateral side predominance. The present results suggest that monocular enucleation results in variable expression of PV-IR neurons and GFAP-IR astrocytes in the LGN complex, which may play an important role in neuronal degeneration and neuroplasticity of the rat visual system.

Unilateral ibotenic acid lesions of the prefrontal cortex reduce rotational behavior in 6-hydroxydopamine-lesioned rats.

Rats with 6-hydroxydopamine (6-OHDA)-induced lesions of the substantia nigra are used as a model of Parkinson.s disease (PD), and these "lesioned" rats exhibit a rotational behavior when further injected with apomorphine (APO). We examined whether lesions in the prefrontal cortex (PFC) could modify the rotational behavior in PD model rats. Rats initially received unilateral lesions of the substantia nigra by 6-OHDA injection, and then their rotational behavior was measured. Two PFC lesions were achieved by intracerebral infusions of ibotenic acid, followed by measurement of APO-induced rotation. Rotation was reduced by approximately 30% after PFC injury. The PFC may have functional influence on the basal ganglia and may be involved in the pathophysiology of the rotational behavior of PD model rats.

Dialysis-induced Subdural Hematoma in an Arachnoid Cyst Associated with Autosomal Dominant Polycystic Kidney Disease.

Arachnoid cyst (AC) is a neurological complication of autosomal dominant polycystic kidney disease (ADPKD). Although an AC can increase the risk of a subdural hematoma, the clinical presentation of bleeding into an AC associated with ADPKD is not well known. We herein report the case of a 59-year-old woman in whom the initiation of hemodialysis for renal failure led to AC bleeding. A change of anticoagulant from heparin to nafamostat mesilate allowed dialysis to continue without rebleeding. These findings suggest that hemodialysis in patients with an AC associated with ADPKD may increase the risk of bleeding. Nafamostat mesilate may be useful in such cases.