Atypical Electrophysiological Findings in a Patient with Acute Motor and Sensory Axonal Neuropathy.

Guillain-Barré syndrome (GBS) is an immune-mediated polyradiculoneuropathy with acute onset and rapid clinical worsening; early diagnosis and immunomodulating therapy can ameliorate the course of disease. During the first days, however, nerve conduction studies (NCSs) are not always conclusive. Here, we describe a 73-year-old man presenting with progressive muscular weakness of the lower limbs, ascending to the upper limbs, accompanied by distal sensory disturbances. Neuroimaging of brain and spine and NCSs were unremarkable; cerebrospinal fluid analysis revealed no albuminocytologic dissociation. Based on typical clinical features, and on positivity for serum GD1b-IgM antibodies, GBS with proximal conduction failure at multiple radicular levels was postulated, and a standard regime of intravenous immunoglobulin was administered. Four weeks later, the patient presented with flaccid tetraparesis, areflexia, and reduction of position sense, tingling paresthesias, and initial respiratory distress. Repeat NCS still revealed almost normal findings, except for the disappearance of right ulnar nerve F-waves. A few days thereafter, the patient developed severe respiratory insufficiency requiring mechanical ventilation for 2 weeks. On day 50, NCS revealed for the first time markedly reduced compound muscle action potentials and sensory nerve action potentials in all tested nerves, without signs of demyelination; needle electromyography documented widespread denervation. The diagnosis of acute motor and sensory axonal neuropathy was made. After 3 months of intensive rehabilitation, the patient regained the ability to walk with little assistance and was discharged home. In conclusion, normal NCS findings up to several weeks do not exclude the diagnosis of GBS. Very proximal axonal conduction failure with late distal axonal degeneration should be taken into consideration, and electrodiagnostic follow-up examinations, even employing unusual techniques, are recommended over several weeks after disease onset.

Cortical afferent inhibition abnormalities reveal cholinergic dysfunction in Parkinson's disease: a reappraisal.

Parkinson's disease (PD) is a multisystem neurodegenerative disorder affecting, besides the dopaminergic function, multiple neurotransmission systems, including the cholinergic system. Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation (TMS) of motor cortex; this test is named short latency afferent inhibition (SAI). SAI abnormalities have been reported in PD patients with gait disturbances and many non-motor symptoms, such as visual hallucinations (VHs), REM sleep behavior disorder (RBD), dysphagia, and olfactory impairment. The findings of these TMS studies strongly suggest that cholinergic degeneration is an important contributor to a number of clinical features of PD. TMS and neuropsychological raise the possibility that the presence of RBD, VHs and olfactory dysfunction indicate increased risk of cognitive impairment in patients with PD. Longitudinal studies of the patients are required to verify whether SAI abnormalities can predict a future severe cognitive decline. TMS can provide simple measures that may represent suitable biomarkers of cholinergic neurotransmission in PD. SAI studies enable an early recognition of PD patients with cholinergic system degeneration, and this might allow future targeted cholinergic treatment approaches, in addition to dopaminergic therapy, to ameliorate non-motor and motor clinical symptoms in PD patients.

Herpes Simplex Virus Type 2 Myelitis: Case Report and Review of the Literature.

Non-traumatic myelopathies can result from a wide spectrum of conditions including inflammatory, ischemic, and metabolic disorders. Here, we describe the case of a 60-year old immunocompetent woman who developed acute back pain followed by rapidly ascending flaccid tetraparesis, a C6 sensory level, and sphincter dysfunction within 8 h. Acyclovir and steroids were started on day 2 and herpes simplex virus type 2 (HSV-2) was confirmed by polymerase chain reaction in cerebrospinal fluid. Magnetic resonance imaging revealed a bilateral anterior horn tractopathy expanding from C2 to T2 and cervicothoracic cord swelling. Screening for paraneoplastic antibodies and cancer was negative. Neurophysiology aided in the work-up by corroborating root involvement. Recovery was poor despite early initiation of antiviral treatment, adjuvant anti-inflammatory therapy, and neurorehabilitation efforts. The clinical course, bilateral affection of the anterior horns, and early focal atrophy on follow-up magnetic resonance imaging take a necrotizing myelitis potentially caused by intraneuronal spread of the virus into consideration. Further, we summarize the literature on classical and rare presentations of HSV-2 myeloradiculitis in non-immunocompromised patients and raise awareness for the limited treatment options for a condition with frequent devastating outcome.

Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis.

Canine degenerative myelopathy (CDM) represents a unique naturally occurring animal model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs, neuropathologic findings, and involvement of the superoxide dismutase 1 (SOD1) mutation. A definitive diagnosis can only be made postmortem through microscopic detection of axonal degeneration, demyelination and astroglial proliferation, which is more severe in the dorsal columns of the thoracic spinal cord and in the dorsal portion of the lateral funiculus. Interestingly, the muscle acetylcholine receptor complexes are intact in CDM prior to functional impairment, thus suggesting that muscle atrophy in CDM does not result from physical denervation. Moreover, since sensory involvement seems to play an important role in CDM progression, a more careful investigation of the sensory pathology in ALS is also warranted. The importance of SOD1 expression remains unclear, while oxidative stress and denatured ubiquinated proteins appear to play a crucial role in the pathogenesis of CDM. In this updated narrative review we performed a systematic search of the published studies on CDM that may shed light on the pathophysiological mechanisms of human ALS. A better understanding of the factors that determine the disease progression in CDM may be beneficial for the development of effective treatments for ALS.

Information-seeking behaviour for epilepsy: an infodemiological study of searches for Wikipedia articles.

Millions of people worldwide use the internet daily as a source of health information. Wikipedia is a popular free online encyclopaedia used by patients and physicians to search for health-related information. Our aim was to evaluate information-seeking behaviour of English-speaking internet users searching Wikipedia for articles related to epilepsy and epileptic seizures. Using Wiki Trends, which provides quantitative information on daily viewing of articles, data on global search queries for Wikipedia articles related to epilepsy and seizures were analysed. The daily Wikipedia article views on syncope, psychogenic non-epileptic seizures, migraine, and multiple sclerosis served as comparative data. The period of analysis covered was from January 2008 to December 2014. Overall, the Wikipedia article "epilepsy and driving" was found to be more frequently visited than the articles "epilepsy and employment" or "epilepsy in children". Since January 2008, the Wikipedia article "multiple sclerosis" was more often visited compared to the articles "epilepsy", "syncope", "psychogenic non-epileptic seizures" or "migraine"; the article "epilepsy" ranked 3,779 and was less frequently visited than "multiple sclerosis", ranked at 571, in traffic on Wikipedia. The highest peak in search volume for the article "epilepsy" coincided with the news of a celebrity having seizures. Fears and worries about epileptic seizures, their impact on driving and employment, and news about celebrities with epilepsy might be major determinants in searching Wikipedia for information.

A Common Reference-Based Indirect Comparison Meta-Analysis of Buccal versus Intranasal Midazolam for Early Status Epilepticus.

BACKGROUND: Intranasal and buccal midazolam have recently emerged as possible alternatives to intravenous or rectal diazepam or intravenous lorazepam in the treatment of early status epilepticus (SE). However, to date no randomized controlled trial (RCT) has directly compared intranasal midazolam with buccal midazolam. OBJECTIVE: The aim of this study was to indirectly compare intranasal midazolam with buccal midazolam in the treatment of early SE using common reference-based indirect comparison meta-analyses. METHODS: RCTs comparing intranasal or buccal midazolam versus either intravenous or rectal diazepam for early SE were systematically searched. Random-effects Mantel-Haenszel meta-analyses were performed to obtain odds ratios (ORs) for the efficacy and safety of intranasal or buccal midazolam versus either intravenous or rectal diazepam. Adjusted indirect comparisons were then made between intranasal and buccal midazolam using the obtained results. RESULTS: Fifteen studies, with a total of 1662 seizures in 1331 patients (some studies included patients with more than one episode of SE) were included; 1303 patients were younger than 16 years. Indirect comparisons showed no difference between intranasal and buccal midazolam for seizure cessation (OR 0.98, 95% CI 0.32-3.01, comparator: intravenous diazepam; OR 0.87, 95% CI 0.46-1.64, comparator: rectal diazepam). For serious adverse effects, we found a large width and asymmetrical distribution of confidence intervals around the obtained OR of 2.81 (95% CI 0.39-20.12; comparator: rectal diazepam). No data were available for OR using intravenous diazepam as the comparator. CONCLUSIONS: Indirect comparisons suggest that intranasal and buccal midazolam share similar efficacy in the treatment of early SE in children. Intranasal midazolam should be used with caution and under clinical monitoring of vital functions. RCTs directly comparing intranasal midazolam with buccal midazolam are required to confirm these findings.

A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia.

BACKGROUND: Protein aggregate myopathies are increasingly recognised conditions characterised by a surplus of endogenous proteins. The molecular and mutational background for many protein aggregate myopathies has been clarified with the discovery of several underlying mutations. Familial idiopathic hyperCKaemia is a benign genetically heterogeneous condition with autosomal dominant features in a high proportion of cases. METHODS: In 10 patients from three Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia, we performed linkage analysis and exome sequencing as well as morphological and biochemical investigations. RESULTS AND CONCLUSIONS: We show, by Sanger and exome sequencing, that the protein aggregate myopathy with benign evolution and muscle inclusions composed of excess CASQ1, affecting three Italian families, is due to the D244G heterozygous missense mutation in the CASQ1 gene. Investigation of microsatellite markers revealed a common haplotype in the three families indicating consanguinity and a founder effect. Results from immunocytochemistry, electron microscopy, biochemistry and transfected cell line investigations contribute to our understanding of pathogenetic mechanisms underlining this defect. The mutation is common to other Italian patients and is likely to share a founder effect with them. HyperCKaemia in the CASQ1-related myopathy is common and sometimes the sole overt manifestation. It is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed, and the condition could be more common than supposed.

Wikipedia and neurological disorders.

Our aim was to evaluate Wikipedia page visits in relation to the most common neurological disorders by determining which factors are related to peaks in Wikipedia searches for these conditions. Millions of people worldwide use the internet daily as a source of health information. Wikipedia is a popular free online encyclopedia used by patients and physicians to search for health-related information. The following Wikipedia articles were considered: Alzheimer's disease; Amyotrophic lateral sclerosis; Dementia; Epilepsy; Epileptic seizure; Migraine; Multiple sclerosis; Parkinson's disease; Stroke; Traumatic brain injury. We analyzed information regarding the total article views for 90 days and the rank of these articles among all those available in Wikipedia. We determined the highest search volume peaks to identify possible relation with online news headlines. No relation between incidence or prevalence of neurological disorders and the search volume for the related articles was found. Seven out of 10 neurological conditions showed relations in search volume peaks and news headlines. Six out of these seven peaks were related to news about famous people suffering from neurological disorders, especially those from showbusiness. Identification of discrepancies between disease burden and health seeking behavior on Wikipedia is useful in the planning of public health campaigns. Celebrities who publicly announce their neurological diagnosis might effectively promote awareness programs, increase public knowledge and reduce stigma related to diagnoses of neurological disorders.

Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis.

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.

Neurostimulation in Alzheimer's disease: from basic research to clinical applications.

The development of different methods of brain stimulation provides a promising therapeutic tool with potentially beneficial effects on subjects with impaired cognitive functions. We performed a systematic review of the studies published in the field of neurostimulation in Alzheimer's disease (AD), from basic research to clinical applications. The main methods of non-invasive brain stimulation are repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Preliminary findings have suggested that both techniques can enhance performances on several cognitive functions impaired in AD. Another non-invasive emerging neuromodulatory approach, the transcranial electromagnetic treatment, was found to reverse cognitive impairment in AD transgenic mice and even improves cognitive performance in normal mice. Experimental studies suggest that high-frequency electromagnetic fields may be critically important in AD prevention and treatment through their action at mitochondrial level. Finally, the application of a widely known invasive technique, the deep brain stimulation (DBS), has increasingly been considered as a therapeutic option also for patients with AD; it has been demonstrated that DBS of fornix/hypothalamus and nucleus basalis of Meynert might improve or at least stabilize cognitive functioning in AD. Initial encouraging results provide support for continuing to investigate non-invasive and invasive brain stimulation approaches as an adjuvant treatment for AD patients.

Clearly written, easily comprehended? The readability of websites providing information on epilepsy.

There is a general need for high-quality, easily accessible, and comprehensive health-care information on epilepsy to better inform the general population about this highly stigmatized neurological disorder. The aim of this study was to evaluate the health literacy level of eight popular English-written websites that provide information on epilepsy in quantitative terms of readability. Educational epilepsy material on these websites, including 41 Wikipedia articles, were analyzed for their overall level of readability and the corresponding academic grade level needed to comprehend the published texts on the first reading. The Flesch Reading Ease (FRE) was used to assess ease of comprehension while the Gunning Fog Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Automated Readability Index, and Simple Measure of Gobbledygook scales estimated the corresponding academic grade level needed for comprehension. The average readability of websites yielded results indicative of a difficult-to-fairly-difficult readability level (FRE results: 44.0±8.2), with text readability corresponding to an 11th academic grade level (11.3±1.9). The average FRE score of the Wikipedia articles was indicative of a difficult readability level (25.6±9.5), with the other readability scales yielding results corresponding to a 14th grade level (14.3±1.7). Popular websites providing information on epilepsy, including Wikipedia, often demonstrate a low level of readability. This can be ameliorated by increasing access to clear and concise online information on epilepsy and health in general. Short "basic" summaries targeted to patients and nonmedical users should be added to articles published in specialist websites and Wikipedia to ease readability.

Terminology of psychogenic nonepileptic seizures.

Several different terms have been used to describe "psychogenic nonepileptic seizures" (PNES) in the literature. In this study, we evaluated the most common English terms used to describe PNES on Google and in PubMed using multiple search terms (https://www.google.com and http://www.ncbi.nlm.nih.gov/pubmed). The information prevalence of the five terms most frequently used to refer to PNES in PubMed were: psychogenic non(-)epileptic seizure(s), followed by pseudo(-)seizure(s), non(-)epileptic seizure(s), psychogenic seizure(s), and non(-)epileptic event(s). The five most frequently adopted terms to describe PNES in Google were: psychogenic non(-)epileptic seizure(s), followed by non(-)epileptic event(s), psychogenic attack(s), non(-)epileptic attack(s), and psychogenic non(-)epileptic attack(s). The broad spectrum of synonyms used to refer to PNES in the medical literature reflects a lack of internationally accepted, uniform terminology for PNES. In addition to "seizure(s)," lay people use the word "attack(s)" to describe PNES. Although considered obsolete, some terms, e.g., pseudoseizure(s), are still used in the recent medical literature. Adopting a uniform terminology to describe PNES could facilitate communication between epileptologists, physicians without specific expertise in epilepsy, and patients.

Trigemino-cervical-spinal reflexes after traumatic spinal cord injury.

OBJECTIVE: After spinal cord injury (SCI) reorganization of spinal cord circuits occur both above and below the spinal lesion. These functional changes can be determined by assessing electrophysiological recording. We aimed at investigating the trigemino-cervical reflex (TCR) and trigemino-spinal reflex (TSR) responses after traumatic SCI. METHODS: TCR and TSR were registered after stimulation of the infraorbital nerve from the sternocleidomastoid, splenius, deltoid, biceps and first dorsal interosseous muscles in 10 healthy subjects and 10 subjects with incomplete cervical SCI. RESULTS: In the control subjects reflex responses were registered from the sternocleidomastoid, and splenium muscles, while no responses were obtained from upper limb muscles. In contrast, smaller but clear short latency EMG potentials were recorded from deltoid and biceps muscles in about half of the SCI patients. Moreover, the amplitudes of the EMG responses in the neck muscles were significantly higher in patients than in control subjects. CONCLUSION: The reflex responses are likely to propagate up the brainstem and down the spinal cord along the reticulospinal tracts and the propriospinal system. Despite the loss of corticospinal axons, synaptic plasticity in pre-existing pathways and/or formation of new circuits through sprouting processes above the injury site may contribute to the findings of this preliminary study and may be involved in the functional recovery. SIGNIFICANCE: Trigemino-cervical-spinal reflexes can be used to demonstrate and quantify plastic changes at brainstem and cervical level following SCI.

Descending motor pathways and cortical physiology after spinal cord injury assessed by transcranial magnetic stimulation: a systematic review.

We performed here a systematic review of the studies using transcranial magnetic stimulation (TMS) as a research and clinical tool in patients with spinal cord injury (SCI). Motor evoked potentials (MEPs) elicited by TMS represent a highly accurate diagnostic test that can supplement clinical examination and neuroimaging findings in the assessment of SCI functional level. MEPs allows to monitor the changes in motor function and evaluate the effects of the different therapeutic approaches. Moreover, TMS represents a useful non-invasive approach for studying cortical physiology, and may be helpful in elucidating the pathophysiological mechanisms of brain reorganization after SCI. Measures of motor cortex reactivity, e.g., the short interval intracortical inhibition and the cortical silent period, seem to point to an increased cortical excitability. However, the results of TMS studies are sometimes contradictory or divergent, and should be replicated in a larger sample of subjects. Understanding the functional changes at brain level and defining their effects on clinical outcome is of crucial importance for development of evidence-based rehabilitation therapy. TMS techniques may help in identifying neurophysiological biomarkers that can reliably assess the extent of neural damage, elucidate the mechanisms of neural repair, predict clinical outcome, and identify therapeutic targets. Some researchers have begun to therapeutically use repetitive TMS (rTMS) in patients with SCI. Initial studies revealed that rTMS can induce acute and short duration beneficial effects especially on spasticity and neuropathic pain, but the evidence is to date still very preliminary and well-designed clinical trials are warranted. This article is part of a Special Issue entitled SI: Spinal cord injury.

Subjective memory impairment and cholinergic transmission: a TMS study.

Subjective memory impairment (SMI) is being increasingly recognized as a preclinical phase of Alzheimer disease (AD). Short latency afferent inhibition (SAI) is helpful in demonstrating dysfunction of central cholinergic circuits, and was reported to be abnormal in patients with AD and amnestic multiple domain mild cognitive impairment. In this study, we found normal SAI in 20 subjects with SMI. SAI could be a useful biomarker for identifying, among individuals with memory complaints, those in whom cholinergic degeneration has occurred.

Epilepsy-related stigma in European people with epilepsy: correlations with health system performance and overall quality of life.

We aimed to relate the percentages of encountered epilepsy-related stigma in people with epilepsy with quantitative indicators of the quality of health systems and quality of life by country in Europe. The epilepsy-related stigma percentages were obtained from the largest population-based study in people with epilepsy available. We correlated percentages of people with perceived stigma per European country with data on the country's overall health system performance, health expenditure per capita in international dollars, and the Economist Intelligence Unit's quality-of-life index. We found a nonsignificant trend towards negative correlation between the epilepsy-related stigma percentage and the overall health system performance (r=-0.16; p=0.57), the health expenditure per capita in international dollars (r=-0.24; p=0.4), and the Economist Intelligence Unit's quality-of-life index (r=-0.33; p=0.91). Living in a European country with a better health system performance and higher health expenditure per capita does not necessarily lead to a reduction in perceived epilepsy-related discrimination, unless the public health system invests on awareness programs to increase public knowledge and reduce stigma.