Central Nervous Disorders Research Articles

アセタゾラミドが有効であった中枢性平衡障害の一例

We report herein on a case of disequilibrium due to central nervous disorders with a good response to acetazolamide. A 51-year-old woman presented with episodic disequilibrium and vertigo. Her symptoms began when she was a child. Her symptoms were worsened by positional change or physical exercise, lasting for several hours. She also had migraine-like headaches. Her family history was unremarkable. On examination, she showed gaze-evoked nystagmus, direction-fixed right beating positional nystagmus with down-beating nystagmus. Electronystagmography revealed saccadic pursuit, impaired optokinetic nystagmus, and disorders of visual suppression in caloric tests, suggesting central nervous disorders. MRI showed slight cerebellar atrophy without downward displacement of the cerebellar tonsil through the foramen magnum. Although she did not have family history, we clinically diagnosed her as having episodic ataxia type 2 (EA-2). She took acetazolamide (250 mg) per day. The frequency and intensity of her symptoms dramatically decreased. When we see a patient with episodic disequilibrium due to central nervous disorders, we should take EA-2 into account.

Investigation of key interactions between the second extracellular loop of dopamine D2 receptor and several hydroxy-N-{[2-(4-phenyl-piperaziny-1-yl)ethyl]phenyl}-nicotinamides

Dopaminergic receptor system has been in focus for the development of new pharmacotherapeutic agents, targeting number of central nervous system related disorders, like drug addiction, schizophrenia, depression, and Parkinson's disease, just to name a few. So far crystal structure for human D2 receptor is not known, despite it?s vital function and importance as therapeutic target. Here we present, recent progress in determination of the key receptor-ligand interactions for available arylpiperazine like ligands, using D2 receptor model, based upon crystal D3 receptor structure. To determine key interactions responsible for high dopaminergic activity, we used computer docking analysis together with experimental data. Total of 4 dopaminergic ligands showing moderate to high affinity, were tested and obtained results rationalized using ligand structures docked into proposed D2 receptor model.

Amiodarone induced hyponatremia masquerading as syndrome of inappropriate antidiuretic hormone secretion by anaplastic carcinoma of prostate.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hyponatremia. The usual causes are malignancies, central nervous system, pulmonary disorders, and drugs. Amiodarone is a broad spectrum antiarrhythmic agent widely used in the management of arrhythmias. The different side effects include thyroid dysfunction, visual disturbances, pulmonary infiltrates, ataxia, cardiac conduction abnormalities, drug interactions, corneal microdeposits, skin rashes, and gastrointestinal disturbances. SIADH is a rare but lethal side effect of amiodarone. We describe a 62-year-old male who was suffering from advanced prostatic malignancy, taking amiodarone for underlying heart disease. He developed SIADH which was initially thought to be paraneoplastic in etiology, but later histopathology refuted that. This case emphasizes the importance of detailed drug history and the role of immunohistochemistry in establishing the diagnosis and management of hyponatremia due to SIADH.

Diagnostic imaging and problems of schizencephaly.

SummaryBackgroundSchizencephaly is a rare developmental malformation of the central nervous system associated with cell migration disturbances. Schizencephaly can be uni- or bilateral and is divided into two morphological types. The cleft is defined as type I (“closed lips”) if there are fused clefts in cerebral mantle. In type II (“open lips”) the clefts are separated and filled with cerebrospinal fluid connecting lateral ventricle with the subarachnoid space.Material/MethodsWe retrospectively analysed data of patients hospitalized in the Clinical Pediatric Neurology Department of Provincial Hospital No. 2 in Rzeszow between 1998–2011. Clinical data and imaging exams were analysed in the group of children with confirmed schizencephaly.ResultsSchizencephaly was recognized in 32 children. Diagnosis was made in children at the ages between 2 weeks and 15 years – the majority of older children were born before the year 2000. Diagnostic imaging, most often magnetic resonance imaging, was performed in all of the children. In most cases coexistence of other CNS malformations was discovered. In only one patient there were no neurological symptoms, most of the children presented different developmental disorders and neurological symptoms – most often cerebral palsy and epilepsy. In the group of children with bilateral and type II schizencephaly certain symptoms occurred more often.ConclusionsSchizencephaly is a rare central nervous system developmental disorder, which is very often associated with other severe brain malformations and in most of the cases subsequent multiple neurological symptoms. The method of choice in diagnosis of schizencephaly is magnetic resonance, which shows the degree and type of cleft, coexisting abnormalities and allows differential diagnosis. With the increased availability of this method it is possible to recognize schizencephaly more often and earlier.

<b>4. レギュレーションの立場から</b>

In confirmatory clinical trials, missing data may lead to a loss of power and accuracy, and represent a potential source of bias for the estimates of treatment effect (ICH-E9). Recently, the EMA guidelines (2010) and the NAS report in the U.S. (2010) have been published, and missing data has become one of the topics of high interest in biostatistics. In particular, clinical trials in the central neurological disease area (pain and psychiatric disease) have the following characteristics: missing data due to treatment withdrawal or dropout are more frequent than in other disease areas, and the reasons for discontinuation tend to differ between treatment groups. In this paper, we describe the considerations for the handling of missing data, and present actual cases in the central neurological disease area, in which the handling of missing data was discussed in new drug application (NDA) review and consultation at the Pharmaceuticals and Medical Devices Agency (PMDA).

Un cas familial d’encéphalopathie nécrosante aiguë post-infectieuse associé à une mutation du gène RANBP2

Acute necrotizing encephalopathy is a rare neurologic disease most often triggered by a febrile viral event affecting an otherwise healthy infant. The clinical course is characterized by rapid deterioration of the neurological condition that often leads to coma and requires intensive care. The diagnosis is usually suggested by MRI, which shows symmetrical and focal necrotic lesions of thalami. Acute necrotizing encephalopathy has been linked in recent studies to an autosomal-dominant mutation of the gene for the protein RAN-binding protein 2. We report three cases in siblings of Tunisian origin. Two of them presented with acute necrotizing encephalopathy at the age of 9 months in the immediate aftermath of a viral infection. The molecular study conducted in the family showed that both patients and their mother were carriers of the missense mutation gene RAN-binding protein 2. Although the role of Ran BP2 protein is incompletely known, mutation of the RANBP2 gene causes rare, reversible central neurologic disorders. Suspected diagnosis is facilitated by MRI, which shows specific lesions of multifocal, symmetric involvement of the thalami, brainstem tegmentum, supratentorial white matter, and cerebellum. Due to the low frequency of the disease and its non-specific clinical presentation, the diagnosis of acute necrotizing encephalopathy is a major challenge, while preventative measures can be proposed in familial mutation.

Application of the 2012 revised diagnostic definitions for paediatric multiple sclerosis and immune-mediated central nervous system demyelination disorders

BackgroundRecently, the International Paediatric Multiple Sclerosis Study Group (IPMSSG) definitions for the diagnosis of immune-mediated acquired demyelinating syndromes (ADS) of the central nervous system, including paediatric multiple sclerosis (MS), have...

Evoked pressure curves from the external anal sphincter following transcranial magnetic stimulation in healthy volunteers and patients with faecal incontinence

The hypothesis was tested that evoked pressure curves (EPCs) after transcranial magnetic stimulation (TMS) would provide additional neuropathophysiological information on the descending pathways to the external anal sphincter (EAS) in patients with faecal incontinence (FI). Twenty-five healthy subjects and 69 patients with FI were investigated. TMS was applied to the vertex, and EPCs were recorded with a probe placed through the EAS. TMS was performed with the EAS at rest and during contraction (facilitated responses). At least three responses were recorded for each modality. Clinical data and anorectal manometric, electrophysiological perineal and transanal ultrasound recordings were compared with respect to the EPC results. There was no statistically significant difference between the EPCs of healthy subjects and FI patients. Twenty-three per cent of the FI patients had abnormal EPC latencies, with significantly lower voluntary contraction amplitudes (P=0.03) and significantly higher rectal sensation (P=0.04) than the other group. We found no significant difference between FI patients with and without abnormal EPC latencies in terms of clinical characteristics and electrophysiological and endoanal ultrasound parameters. There was no difference in the identified causes of the FI between the two groups. As abnormal EPC latencies were found in 23% of FI patients with no known central neurological disease, abnormal EPC latencies might reveal undetected lesions of descending pathways in patients with FI.

Cerebral babesiosis and acute respiratory distress syndrome in a dog

To describe a case of cerebral babesiosis and acute respiratory distress syndrome (ARDS) in a dog. A 5-year-old male neutered Scottish Terrier was referred to the emergency department of the Ecole Nationale Vétérinaire de Toulouse for evaluation of progressive dyspnea and clinical signs suggestive of central neurological disease. Thoracic radiographs showed a diffuse and heavy interstitial/alveolar lung pattern. Babesiosis was diagnosed based on blood smear evaluation. The dog died of cardiopulmonary arrest 6 hours after presentation. Cerebral babesiosis and ARDS were confirmed at necropsy. Major pathological findings included erythrocyte aggregation in the lungs, liver, and brain. This case report describes an unusual clinical presentation of Babesia canis canis infection, the most common species associated with babesiosis in Europe. In addition, this is to our knowledge the first case of Babesia-associated ARDS confirmed by histopathology in a dog.

IPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF

The possibility of generating neural stem/precursor cells (NPCs) from induced pluripotent stem cells (iPSCs) has opened a new avenue of research that might nurture bench-to-bedside translation of cell transplantation protocols in central nervous system myelin disorders. Here we show that mouse iPSC-derived NPCs (miPSC-NPCs)-when intrathecally transplanted after disease onset-ameliorate clinical and pathological features of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Transplanted miPSC-NPCs exert the neuroprotective effect not through cell replacement, but through the secretion of leukaemia inhibitory factor that promotes survival, differentiation and the remyelination capacity of both endogenous oligodendrocyte precursors and mature oligodendrocytes. The early preservation of tissue integrity limits blood-brain barrier damage and central nervous system infiltration of blood-borne encephalitogenic leukocytes, ultimately responsible for demyelination and axonal damage. While proposing a novel mechanism of action, our results further expand the therapeutic potential of NPCs derived from iPSCs in myelin disorders.

Dynamic expression of miR-132, miR-212, and miR-146 in the brain of different hosts infected with Angiostrongylus cantonensis

Increasing evidence shows that microRNAs (miRNAs) are a family of regulatory molecules involved in many physiological processes, including the inflammation in central nervous system (CNS) and neurological disorders. Angiostrongylus cantonensis (A. cantonensis) is the major cause of human infectious eosinophilic meningitis and can induce CNS injury. In the present study, we investigated the expression of miRNAs involved in neuronal functions such as miR-132-3p/212-3p, and miR-146a-5p, inflammation-related miRNA, in the modulation of inflammation of CNS of mice and rats induced by A. cantonensis. The functions of differentially expressed miRNAs were analyzed through bioinformatics methods, and the expression of chosen target genes were investigated by quantitative reverse transcription polymerase chain reaction. The results showed that miR-146a-5p upregulated in the brain of rats after 21 days; A. cantonensis infection and the expression of miR-132-3p and miR-146a-5p upregulated in the brain of mice model infected by A. cantonensis. The expression of the target genes of mmu-miR-146a-5p such as Irak1 and Traf6 downregulated in 14 days and 21 days after A. cantonensis infection. Our results supply more information about the involvement of the miRNAs in the regulation of inflammation of CNS induced by A. cantonensis.

The Role of Secretory Phospholipase A2 in the Central Nervous System and Neurological Diseases

Secretory phospholipase A2 (sPLA2s) are small secreted proteins (14-18 kDa) and require submillimolar levels of Ca(2+) for liberating arachidonic acid from cell membrane lipids. In addition to the enzymatic function, sPLA2 can exert various biological responses by binding to specific receptors. Physiologically, sPLA2s play important roles on the neurotransmission in the central nervous system and the neuritogenesis in the peripheral nervous system. Pathologically, sPLA2s are involved in the neurodegenerative diseases (e.g., Alzheimer's disease) and cerebrovascular diseases (e.g., stoke). The common pathology (e.g., neuronal apoptosis) of Alzheimer's disease and stroke coexists in the mixed dementia, suggesting common pathogenic mechanisms of the two neurological diseases. Among mammalian sPLA2s, sPLA2-IB and sPLA2-IIA induce neuronal apoptosis in rat cortical neurons. The excess influx of calcium into neurons via L-type voltage-dependent Ca(2+) channels mediates the two sPLA2-induced apoptosis. The elevated concentration of intracellular calcium activates PKC, MAPK and cytosolic PLA2. Moreover, it is linked with the production of reactive oxygen species and apoptosis through activation of the superoxide producing enzyme NADPH oxidase. NADPH oxidase is involved in the neurotoxicity of amyloid β peptide, which impairs synaptic plasticity long before its deposition in the form of amyloid plaques of Alzheimer's disease. In turn, reactive oxygen species from NADPH oxidase can stimulate ERK1/2 phosphorylation and activation of cPLA2 and result in a release of arachidonic acid. sPLA2 is up-regulated in both Alzheimer's disease and cerebrovascular disease, suggesting the involvement of sPLA2 in the common pathogenic mechanisms of the two diseases. Thus, our review presents evidences for pathophysiological roles of sPLA2 in the central nervous system and neurological diseases.

Electrophysiological study of the bulbocavernosus reflex: normative data.

In the clinical setting the bulbocavernosus reflex (BCR) is elicited by squeezing the glans penis and digitally palpating the contraction of the bulbocavernosus (BC) muscle. In neurophysiology the BCR is obtained by stimulating the dorsal nerve of the penis or clitoris and by recording the response from BC muscle and it should be performed in selected patients with suspected urinary, bowel, or sexual neurogenic dysfunction. The BCR is considered one of the sacral neurophysiological tests of the greatest clinical utility. Previous normative data were obtained on small samples. The aim of this study was to determine normative values for the BCR in a large sample of men. We studied a large population (105 men; mean age 53 years, range 19-73 years) without central or peripheral neurological diseases. In each subject the sacral reflex was elicited by electrical stimulation of the base of the dorsum penis and recorded using a surface electrode from the BC muscle. We recorded the latency, calculated at onset, and the maximal amplitude of response, calculated peak to peak. We were able to detect the BCR in all the men. No correlation between BCR latency and age was found (r=0.136; p=0.160). The mean onset latency value was 33.0±4.85 ms (mean±2SD, range 26.8-39.4). The mean amplitude value was 16.53±12.21 μV (mean±2SD, range 4.2-43.6). Our normative data on the BCR were similar to previously published data.

Intracranial pseudolymphoma presenting with grand mal seizures

Primary central nervous system lymphoproliferative disorders comprise a heterogenous group of intracranial disease, predominantly of the high-grade non-Hodgkin’s lymphoma type. We report a 56-year-old woman who developed new-onset grand mal seizures and was found to have two small uniformly enhancing dural-based lesions, which were radiologically concerning for meningiomas. Biopsy demonstrated findings consistent with benign, reactive lymphoid tissue. The patient’s seizures resolved post-operatively. To our knowledge, this is the first reported patient with intracranial pseudolymphoma presenting as grand mal seizures. This case highlights this rare differential consideration in a patient with symptomatic dural-based lesion.

Children With Central and Peripheral Neurologic Disorders Have Distinguishable Patterns of Dysphagia on Videofluoroscopic Swallow Study

To determine whether findings on videofluoroscopic swallow studies reveal different patterns of dysphagia between children with central and peripheral neurologic disorders, a retrospective study of 118 videofluoroscopic swallow studies was completed. There were 3 groups: cerebral palsy with only spastic features (n = 53), cerebral palsy with dyskinetic features (n = 34), and neuromuscular disorders (myotonic dystrophy I, n = 5; spinal muscular atrophy I-II, n = 8; Duchenne muscular dystrophy, n = 8; other neuromuscular disorder, n = 10). Interpretation of the videofluoroscopic swallow studies was not blinded. The video fluoroscopic swallow study findings were compared dichotomously between the groups. Children with cerebral palsy demonstrated dysphagia in 1 or all phases of swallowing. In neuromuscular disorder, muscle weakness results in pharyngeal residue after swallow. The underlying swallowing problem in neuromuscular disorder is muscle weakness whereas that in cerebral palsy is more complex, having to do with abnormal control of swallowing. This study serves as a first exploration on specific characteristics of swallowing in different neurologic conditions and will help clinicians anticipate what they might expect.

Effects of Telfairia occidentalis (Fluted Pumpkin; Cucurbitaceae) in Mouse Models of Convulsion, Muscle Relaxation, and Depression

Telfairia occidentalis (Cucurbitaceae) is a leafy vegetable used in soup and folk medicine in southern Nigeria. Ethnobotanical survey revealed that preparations of the plant are used in the treatment of central nervous system-related disorders including convulsion. This study was conducted to investigate the effect of the hydroethanolic leaf extract of T. occidentalis in mouse models of convulsion, muscle relaxation, and depression. The strychnine and isoniazid convulsion, traction and climbing muscle relaxation, and forced swim and tail suspension depression tests were used in this study. The extract was administered orally (p.o.) at dose range of 25-800 mg/kg while distilled water (10 mL/kg p.o.) served as negative control. Diazepam (5 mg/kg p.o.) was used as positive control in the convulsion and muscle relaxation models while imipramine (64 mg/kg p.o.) served the same purpose in the depression tests. T. occidentalis significantly increased the onset (P<.001) and reduced the duration of convulsion (P<.05, .01) in the strychnine test and increased the time to death (P<.05, .01, .001) in the isoniazid model. The extract insignificantly increased the reaction time in the traction test while it significantly increased the time in the climbing test (P<.001). In the forced swim and tail suspension models, T. occidentalis significantly (P<.001) and dose-dependently increased the duration of immobility. The results obtained in this study suggest that the hydroethanolic leaf extract of T. occidentalis possesses anticonvulsant and muscle relaxant properties, thus justifying its folkloric use.

Neurologic complications of anesthesia

Neurologic complications related to anesthesia are infrequent but can be serious. Neurologists are often consulted to evaluate patients with postoperative symptoms and must be ready to discriminate those truly caused by the anesthetic drug or procedure from the more common postoperative complications that are unrelated to the anesthesia itself. This practical review relies on cases to illustrate common reasons for neurologic consultation in the postsurgical setting. It also briefly summarizes what to expect when patients with central or peripheral neurologic disease undergo surgery under general or regional anesthesia.

Upbeat nystagmus at caudal brainstem lesions in four cases with multiple sclerosis and its related disorders

Upbeat nystagmus (UBN) is relatively rare. Little is known about UBN in acute central nervous system inflammatory disorders, including multiple sclerosis (MS), neuromyelitis optica (NMO) and related disorders. We investigated two patients with MS, one with clinically isolated syndrome and one with brainstem inflammation possibly related to NMO who developed UBN because of brainstem lesions. Three of the four patients presented caudal medulla lesions and one presented a caudal pontomesencephalic lesion on magnetic resonance imaging. Caudal brainstem lesions may cause UBN in these disorders, probably by impairing the ventral tegmental tract.

Selective and rapid expansion of human neural progenitor cells on substrates with terminally anchored growth factors

Human neural progenitor cells (hNPCs) are a potential source for cell transplantation therapy in central nervous disorders. Neurosphere culture, the standard method for obtaining hNPCs, suffers from several limitations including the heterogeneity of cells in a neurosphere and the limitation of growth rate due to the presence of differentiated cells in the neurospheres. To overcome these limitations, we developed culture substrates that enable the selective expansion of hNPCs in adherent culture. Epidermal growth factor and basic fibroblast growth factor were fused with hexahistidine (EGF-His and bFGF-His, respectively) and were immobilized alone or in combination onto Ni ion-bound glass through coordination. When hNPCs derived from human fetal brain were cultured on these substrates, adhesion and proliferation of hNPCs took place most efficiently on the substrate with both EGF-His and bFGF-His compared to substrates with either factor alone and to a control substrate without growth factors. The rate of cell proliferation was two-fold higher in the adherent culture on the substrate immobilized with both EGF-His and bFGF-His than in the standard neurosphere culture. A cell population obtained after 5 days of culture on the substrate contained nestin-expressing progenitors (>90%). We conclude that the culture substrate with co-immobilized EGF and bFGF is effective for the selective expansion of hNPCs.

Central and peripheral nervous systems: master controllers in cancer metastasis

Central and sympathetic nervous systems govern functional activities of many organs. Solid tumors like organs are also innervated by sympathetic nerve fibers. Neurotransmitters released from sympathetic nerve fibers can modulate biological behaviors of tumor cells. Multiple physiologic processes of tumor development may be dominated by central and sympathetic nervous systems as well. Recent studies suggest that dysfunction of central and sympathetic nervous systems and disorder of the hormone network induced by psychological stress may influence malignant progression of cancer by inhibiting the functions of immune system, regulating metabolic reprogramming of tumor cells, and inducing interactions between tumor and stromal cells. Over-release of inflammatory cytokines by tumors may aggravate emotional disorder, triggering the vicious cycles in tumor microenvironment and host macroenvironment. It is reasonable to hypothesize that cancer progression may be controlled by central and sympathetic nervous systems. In this review, we will focus on the recent information about the impacts of central and sympathetic nervous systems on tumor invasion and metastasis.