BACKGROUND:Prompt treatment of status epilepticus (SE) is associated with better outcomes. Rectal diazepam (DZP) and nonintravenous (non-IV) midazolam (MDZ) are often used in the treatment of early SE instead of intravenous applications. The aim of this review was to determine if nonintravenous MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE seizures in children and adults. METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and MEDLINE for randomized controlled trials comparing non-IV MDZ with DZP (by any route) in patients (all ages) with early SE defined either as seizures lasting >5 min or as seizures at arrival in the emergency department. The following outcomes were assessed: clinical seizure cessation within 15 min of drug administration, serious adverse effects, time interval to drug administration, and time from arrival in the emergency department to seizure cessation. Outcomes were assessed using a random-effects Mantel-Haenszel meta-analysis to calculate risk ratio (RR), odds ratio (OR) and mean difference with 95% confidence intervals (95% CIs). RESULTS:Nineteen studies with 1933 seizures in 1602 patients (some trials included patients with more than one seizure) were included. One thousand five hundred seventy-three patients were younger than 16 years. For seizure cessation, non-IV MDZ was as effective as DZP (any route) (1933 seizures; RR: 1.03; 95% CIs: 0.98 to 1.08). No difference in adverse effects was found between non-IM MDZ and DZP by any route (1933 seizures; RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between arrival and seizure cessation was significantly shorter with non-IV MDZ by any route than with DZP by any route (338 seizures; mean difference: -3.67 min; 95% CIs: -5.98 to -1.36); a similar result was found for time from arrival to drug administration (348 seizures; mean difference: -3.56 min; 95% CIs: -5.00 to -2.11). A minimal difference was found for time interval from drug administration to clinical seizure cessation, which was shorter for DZP by any route than for non-IV MDZ by any route (812 seizures; mean difference: 0.56 min; 95% CIs: 0.15 to 0.98 min). Not all studies reported information on time intervals. Comparison by each way of administration failed to find a significant difference in terms of clinical seizure cessation and occurrence of adverse effects. The only exception was the comparison between buccal MDZ and rectal DZP, where MDZ was more effective than rectal DZP in terminating SE but only when results were expressed as OR (769 seizures; OR: 1.78; 95% CIs: 1.11 to 2.85; RR: 1.15; 95% CIs: 0.85 to 1.54). Only one study was entirely conducted in an adult population (21 patients, aged 31 to 69 years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP. CONCLUSIONS:Non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children and probably also in adults. Times from arrival in the emergency department to drug administration and to seizure cessation are shorter with non-IV MDZ than with intravenous or rectal DZP, but this does not necessarily result in higher seizure control. An exception may be the buccal MDZ, which, besides being socially more acceptable and easier to administer, might also have a higher efficacy than rectal DZP in seizure control. This article is part of a Special Issue entitled Status Epilepticus.

Selenium is an antioxidant component of several selenoproteins which might have the potential to prevent chronic diseases including cardiovascular disease (CVD). Selenium only supplementation does not seem to be beneficial for the primary prevention of CVD, as showed by a recent Cochrane systematic review with meta-analysis including two large trials conducted in the USA (SELECT and NPC) [[1]Rees K. Hartley L. Day C. Flowers N. Clarke A. Stranges S. Selenium supplementation for the primary prevention of cardiovascular disease.Cochrane Database Syst Rev. 2013 Jan 31; 1 (CD009671)PubMed Google Scholar]: compared with placebo, selenium supplementation did not show any statistically significant differences on all cause mortality (RR 0.97, 95% CI 0.88–1.08), CVD mortality (RR 0.97, 95% CI 0.79–1.2), non-fatal CVD events (RR 0.96, 95% CI 0.89–1.04) or all CVD events (fatal and non-fatal) (RR 1.03, 95% CI 0.95–1.11). The statistical question addressed by the above mentioned meta-analysis was whether or not selenium supplements showed superiority versus placebo based on the end-point of reduction of CVD, and the conclusion was that the limited trial evidence available to date does not support its use in the primary prevention of CVD. Trial-sequential analysis (TSA) is a new statistical technique which aims to improve the interpretation of meta-analyses, and particularly of those yielding negative results [[2]Wetterslev J. Thorlund K. Brok J. Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.J Clin Epidemiol. 2008; 61: 64-75Abstract Full Text Full Text PDF PubMed Scopus (1174) Google Scholar]. Such a method provides informative conclusions in terms of "proof of no effectiveness" ("futility") or "no proof of effectiveness" (inconclusive results), which are two mutually exclusive categories [[3]Messori A. Fadda V. Maratea D. Trippoli S. ω-3 Fatty Acid supplements for Secondary prevention of cardiovascular disease: from "No proof of effectiveness" to "Proof of No effectiveness".JAMA Intern Med. 2013; 17: 1-2Crossref Scopus (25) Google Scholar]. We applied TSA to re-examine the 2 randomized studies included in the Cochrane meta-analysis. Our analysis considered the end-point of all CVD events (fatal and non fatal). Our main assumptions included two-sided testing, risk of type 1 error = 5%, and power = 80%. For cardiovascular events, the intervention effect was set at an event frequency of 12.5% for the control group (equal to the event frequency of the 2 control groups of the Cochrane meta-analysis) and a relative risk reduction of 10%. The main result of TSA was expressed presenting the graph of cumulative z-curve, where the boundaries for concluding superiority or inferiority or futility were calculated according to the O'Brien-Fleming alpha-spending function. Our analysis was undertaken using a specific statistical software (User Manual for TSA, Copenhagen Trial Unit 2011, software downloadable at http://www.ctu.dk/tsa). Figure 1 shows our results. Applying TSA to these 2 randomized trials yielded a conclusion of futility, i.e. proof of no effectiveness; this result is more informative than the mere conclusion of no proof of effectiveness. Furthermore, our TSA estimated that the optimal information size would be 21,028 patients, but at the cumulative number of 18,452 patients the results were already sufficient to reach the conclusion of futility. Noteworthy, the final part of the z-curve was far beyond the boundary of futility. Futility was confirmed by an additional TSA carried out to test non fatal CVD events (optimal information size: 23,797 patients; conclusion of futility already at 18,452 patients). Since our TSA provided the proof of no effectiveness of selenium supplements for preventing CVD, further trials in this area should be discouraged. TSA is a useful technique to integrate the results of conventional meta-analyses, differentiating between futility and inconclusive results. None. The authors have no conflict of interest, or any financial or personal interest.

Several Transcranial Magnetic Stimulation (TMS) techniques can be applied to noninvasively measure cortical excitability and brain plasticity in humans. TMS has been used to assess neuroplastic changes in Alzheimer's disease (AD), corroborating findings that cortical physiology is altered in AD due to the underlying neurodegenerative process. In fact, many TMS studies have provided physiological evidence of abnormalities in cortical excitability, connectivity, and plasticity in patients with AD. Moreover, the combination of TMS with other neurophysiological techniques, such as high-density electroencephalography (EEG), makes it possible to study local and network cortical plasticity directly. Interestingly, several TMS studies revealed abnormalities in patients with early AD and even with mild cognitive impairment (MCI), thus enabling early identification of subjects in whom the cholinergic degeneration has occurred. Furthermore, TMS can influence brain function if delivered repetitively; repetitive TMS (rTMS) is capable of modulating cortical excitability and inducing long-lasting neuroplastic changes. Preliminary findings have suggested that rTMS can enhance performances on several cognitive functions impaired in AD and MCI. However, further well-controlled studies with appropriate methodology in larger patient cohorts are needed to replicate and extend the initial findings. The purpose of this paper was to provide an updated and comprehensive systematic review of the studies that have employed TMS/rTMS in patients with MCI and AD.

BACKGROUND AND PURPOSE: Acute unilateral optic neuritis is associated with a thickening of the retrobulbar portion of the optic nerve as revealed by transorbital sonography, but no comparison has been made between nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis versus healthy controls. We evaluated optic nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis and healthy controls and compared optic nerve sheath diameter and optic nerve diameter with visual-evoked potentials in patients.MATERIALS AND METHODS: A case-control study was performed in 2 centers. Twenty-one consecutive patients with onset of visual loss during the prior 10 days and established acute noncompressive unilateral optic neuritis were compared with 21 healthy controls, matched for sex and age (+/- 5 years). Two experienced vascular sonographers performed the study by using B-mode transorbital sonography. Visual-evoked potentials were performed on the same day as the transorbital sonography and were evaluated by an expert neurophysiologist. Sonographers and the neurophysiologist were blinded to the status of the patient or control and to clinical information, including the side of the affected eye.RESULTS: The median optic nerve sheath diameter was thicker on the affected side (6.3 mm; interquartile range, 5.9-7.2 mm) compared with the nonaffected side (5.5 mm; interquartile range, 5.1-6.2 mm; P<.0001) and controls (5.2 mm; interquartile range, 4.8-5.5 mm; P<.0001). The median optic nerve diameter was 3.0 mm (range, 2.8-3.1 mm) on the affected side and 2.9 mm (range, 2.8-3.1 mm) on the nonaffected side (P = not significant.). Both sides were thicker than those in controls (2.7 mm; interquartile range, 2.5-2.8 mm; P=.001 and .009). No correlation was found between optic nerve sheath diameter and optic nerve diameter and amplitude and latency of visual-evoked potentials in patients with optic neuritis.CONCLUSIONS: Transorbital sonography is a promising toot to support the clinical diagnosis of acute optic neuritis. Further studies are needed to define its specific role in the diagnosis and follow-up of optic neuritis.

Background and Purpose : Amongst the impulse control disorders (ICDs) associated with dopamine replacement therapy in patients with Parkinson’s disease (PD) is a repetitive complex stereotyped behaviour called punding. Disruption of the reciprocal loops between the striatum and structures in the prefrontal cortex (PFC) following dopamine depletion may predispose to these behavioural disorders in PD. We aimed at assessing the effects of transcranial magnetic stimulation (rTMS) over the dorsolateral PFC (DLPFC) on punding in PD. Metods : We used low-frequency (LF) rTMS in four PD patients presenting punding. Results : Punding was transiently reversed by LF rTMS of DLPFC without enhancing motor impairment. The effect was more sustained after right DLPFC rTMS. Conclusions : LF rTMS produces a transient beneficial effect in PD patients with punding, similar to that reported in PD patients with levodopa-induced dyskinesias. RTMS might have therapeutic potential for the treatment of punding and perhaps other ICDs in PD . effects were observed after sham stimulation. Similar results were obtained for the Hoarding distress rating score.

Fixation-off sensitivity (FOS) is a phenomenon induced by elimination of central vision/fixation, and may either manifest clinically with seizures or only represent an EEG abnormality. FOS is characterized by posterior or generalized epileptiform discharges that consistently occur after closing of the eyes and last as long as the eyes are closed. It is most commonly encountered in patients with idiopathic childhood occipital epilepsies, but may also be observed in cases of symptomatic or cryptogenic focal and generalized epilepsies, as well as in asymptomatic non-epileptic individuals. FOS should be differentiated from pure forms of scotosensitivity, in which EEG discharges or epileptic seizures are elicited by darkness, and from epileptiform discharges triggered by eye closure, which refer to eye closure sensitivity. Although FOS is probably associated with occipital hyperexcitability its intrinsic epileptogenic potential is presumed to be low.

Resting motor threshold (rMT) assessed by means of Transcranial Magnetic Stimulation (TMS) is thought to reflect trans-synaptic excitability of cortico-spinal neurons. TMS studies reporting rMT in idiopathic generalized epilepsies (IGEs) yielded discrepant results, so that it is difficult to draw a definitive conclusion on cortico-spinal excitability in IGEs by simple summation of previous results regarding this measure. Our purpose was to carry out a systematic review and a meta-analysis of studies evaluating rMT values obtained during single-pulse TMS in patients with IGEs. Controlled studies measuring rMT by single-pulse TMS in drug-naive patients older than 12 years affected by IGEs were systematically reviewed. rMT values were assessed calculating mean difference and odds ratio with 95% confidence intervals (CI). Fourteen trials (265 epileptic patients and 424 controls) were included. Patients with juvenile myoclonic epilepsy (JME) have a statistically significant lower rMT compared with controls (mean difference: −6.78; 95% CI −10.55 to −3.00); when considering all subtypes of IGEs and IGEs other than JME no statistically significant differences were found. Overall considered, the results are indicative of a cortico-spinal hyper-excitability in JME, providing not enough evidence for motor hyper-excitability in other subtypes of IGE. The considerable variability across studies probably reflects the presence of relevant clinical and methodological heterogeneity, and higher temporal variability among rMT measurements over time, related to unstable cortical excitability in these patients.

Objective: It is known from neuropathological and imaging studies that the neuronal degeneration in Huntington's disease (HD) is already quite severe when the first symptoms of the disease become clinically evident. This study was aimed at detecting neurophysiological changes, as assessed by means of transcranial magnetic stimulation (TMS), involved in the early pathogenesis of the neurodegeneration in HD.Methods: Motor cortex excitability was examined in 12 patients with HD in the early clinical stage of the disease and in 15 age-matched control subjects, using a range of TMS protocols. Central motor conduction time, resting and active motor threshold, duration of the cortical silent period, the short-interval paired-pulse intracortical inhibition (SICI) and the paired-pulse intracortical facilitation (ICF) were examined.Results: The early-stage HD patients showed a statistically significant reduction in ICF. The other measures did not differ significantly from the control subjects.Conclusions: Our findings provide neurophysiological evidence that changes in motor function are present in the early HD. Since ICF is thought to depend upon the activity of intracortical glutamatergic excitatory circuits, the results of our study support the theory that altered NMDA receptor function plays an important role in the pathogenesis of HD.Significance: These findings may provide clues to the underlying pathophysiology of the disease. A more complete understanding of the changes in motor cortex excitability that occur early in the course of HD will lead to a better definition of the disease process and may allow earlier diagnosis and intervention. (c) 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

A case of Marchiafava-Bignami (MB) syndrome with selective callosal involvement was evaluated by clinical examination and magnetic resonance imaging (MRI) in the acute phase and 6 months after the onset of symptoms; at the same time, the corticospinally and transcallosally mediated effects elicited by transcranial magnetic stimulation (TMS) were investigated. The first MRI study showed the presence of extensive abnormal signal intensity throughout the entire corpus callosum. After high-dose corticosteroid administration her symptoms rapidly resolved, in parallel with the reversion of MRI changes, except for severe cognitive impairment. Follow-up TMS examination revealed persistent transcallosal inhibition (TI) abnormalities. This report indicates that the measurement of TI during the course of MB syndrome is useful for evaluating functional changes to the corpus callosum, including their evaluation with time and after treatment and for elucidating the pathophysiology of MB syndrome.

We present a previously unreported case of isolated oculomotor nerve palsy as the inaugural clinical sign of meningeal carcinomatosis (MC). Gadolinium-enhanced magnetic resonance images (MRI) were unremarkable. Cerebrospinal fluid (CSF) analysis showed malignant cells consistent with a pulmonary adenocarcinoma; the chest CT revealed a small pulmonary mass in the upper right lobe. This case highlights the importance of considering MC in all patients who develop sudden oculomotor palsy; lumbar punctures should always be performed on patients with normal MRI when other possible causes of oculomotor palsy have been ruled out.

Hepatic myelopathy (HM) is a rare complication of chronic liver diseases usually associated with a portosystemic shunt, causing a progressive spastic paraparesis, and is likely to be overlooked. Thirteen patients with liver cirrhosis associated with surgical or spontaneous portosystemic shunts were studied to determine the frequency and gravity of HM. Six patients exhibited clear-cut signs of spinal cord involvement and four of them exhibited varying degrees of disability.Neurological examination did not reveal any abnormalities in the other patients.Motor evoked potentials (MEPs) were measured in all patients; in five of them the examinations were done before and after orthotopic liver transplantation (OLT).The patients with clinical signs of spinal cord involvement exhibited severe neurophysiological abnormalities, whereas milder but unequivocal MEP abnormalities were found in four of the seven patients with normal clinical examination.The clinical and neurophysiological features of patients with slight MEP abnormalities improved after OLT, whereas the patients with a more advanced stage of disease (severe MEPs abnormalities) did not.Our findings indicate that MEP studies may disclose an impairment of the corticospinal pathways even before HM is clinically manifest and provide evidence that early diagnosis of HM and subsequent immediate liver transplantation have to be recommended.

To determine whether a peculiar neurophysiological profile may contribute to characterize dementia with Lewy bodies (DLB) vs. Alzheimer disease (AD), we used transcranial magnetic stimulation to examine the excitability of two different inhibitory systems of the motor cortex, short latency intracortical inhibition (SICI) and short latency afferent inhibition (SAI) in 10 patients with DLB, in 13 patients with AD and in 15 healthy subjects. SICI and SAI were significantly reduced in AD patients, while both were not significantly different from the controls in DLB patients. The differential pattern of SICI and SAI exhibited by AD vs. DLB may have diagnostic significance in discriminating DLB from AD. Furthermore, this technique may help to clarify the pathophysiological entity of DLB; since SAI is a cortical phenomenon that depends on central cholinergic activity, our findings suggest that the mechanisms of cholinergic depletion in DLB may be different from that in AD, while normal SICI may reflect a less pronounced dysregulation of the intracortical GABAergic inhibitory circuitries in DLB.

Case Reports Patient 1. An 80 year-old woman was admitted to our department for a sudden onset of a sensorimotor defi cit in her right upper and lower limbs; she also complained of neck pain radiating into her right shoulder. The patient presented a sarcoidosis of the lung with hylar and mediastinal lymphadenopathy, and anterior uveitis, diagnosed in 1994. Sarcoid pathology of noncaseating granuloma with giant cells was detected in the lung biopsy specimen. She was treated with oral steroids for 1 year; for the last 10 years there had been no signs of disease. Neurological examination revealed right-sided hemiplegia and severe hypesthesia over the left side. The plantar response was extensor on the right side. Computed tomography of the brain and cervical spine was normal; magnetic resonance imaging (MRI) of the cervical spinal cord revealed a mass that was extramedullary in the right lateral aspect of the spinal canal at the level C 2 –C 3 and compressing the spinal cord ( fi g. 1 a–c). Surprisingly the plasma level of angiotensin-converting enzyme (ACE) Dear Sir, Sarcoidosis is a chronic systemic disorder of unknown etiology characterized in affected organs by an accumulation of epithelioid granulomas without caseation or staining for infectious agents and derangement of the normal tissue architecture [1] . These granulomas often incorporate multinucleated giant cells and lymphocytes. In the past decade, there has been signifi cant progress in our understanding of the immunopathogenesis of the disease, but the etiology of this enigmatic condition still eludes us. Clinical neurological involvement occurs in approximately 5% of patients. However, autopsy results suggest that subclinical involvement may be present in up to 25% of patients. Neurosarcoidosis is a great mimicker and an uncommon presentation of sarcoidosis; it is therefore a diagnostic challenge, especially when there is no prior history of systemic sarcoidosis [2–8] . A typical imaging feature is thickening and enhancement of the basilar leptomeninges of the brain. Other imaging fi ndings, such as enhancing or nonenhancing parenchymal lesions, dural and bone lesions may occur in the head and spine. Spinal sarcoidosis is a rare condition, whose natural history and therapeutic outcome are still not fully known, and extramedullary extradural mass formation is even rarer. We describe 2 additional cases Received: June 23, 2005 Accepted: October 12, 2005 Published online: January 6, 2006

Objective: Adults with Down syndrome (DS) develop progressive cognitive impairment resembling the cognitive profile of Alzheimer's disease (AD). Although the specific neurobiological correlates of cognitive deficits in DS are still not completely understood, it has been proposed that cholinergic dysfunction may contribute to some of these deficits in DS who develop AD. A recently devised test of motor cortex excitability, the short latency afferent inhibition (SAI), has been proven to be helpful in exploring some cholinergic circuits of the human brain. The authors used this test to assess the involvement of the cholinergic transmission in the DS.Methods: We evaluated the SAI in 12 patients with DS and in 15 healthy subjects.Results: SAI was significantly reduced in DS patients when compared with the controls; the values correlated with the patient's age and the score on Dementia Scale for Down Syndrome. SAI was increased after administration of a single dose of donezepil in a subgroup of 5 patients.Conclusions: Our findings suggest that, with respect to this putative marker of central cholinergic activity, dementia in aging DS shares pathophysiological similarities to AD in the general population.Significance: This technique may help to clarify the pathophysiological basis of cognitive dysfunction in DS and may represent an additional tool for the diagnosis of Alzheimer-type dementia in subjects with DS. (c) 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE:To reverse the profile of abnormal intracortical excitability in patients with restless legs syndrome (RLS) by administering the dopaminergic agonist cabergoline.METHODS:The effects of this drug on motor cortex excitability were examined with a range of transcranial magnetic stimulation (TMS) protocols before and after administration of cabergoline over a period of 4 weeks in 14 patients with RLS and in 15 healthy volunteers. Measures of cortical excitability included central motor conduction time; resting and active motor threshold to TMS; duration of the cortical silent period; short latency intracortical inhibition (SICI) and intracortical facilitation using a paired-pulse TMS technique.RESULTS:Short latency intracortical inhibition was significantly reduced in RLS patients compared with the controls and this abnormal profile was reversed by treatment with cabergoline; the other TMS parameters did not differ significantly from the controls and remained unaffected after treatment with cabergoline. Cabergoline had no effect on cortical excitability of the normal subjects.CONCLUSIONS:As dopaminergic drugs are known to increase SICI, our findings suggest that RLS may be caused by a central nervous system dopaminergic dysfunction. This study demonstrates that the cortical hyperexcitability of RLS is reversed by cabergoline, and provides physiological evidence that this dopamine agonist may be a potentially efficacious option for the treatment of RLS.