Novel strategy: Identifying new markers for demyelination in diabetic distal symmetrical polyneuropathy.

Objective: To develop a novel strategy for identifying acquired demyelination in diabetic distal symmetrical polyneuropathy (DSP). Background: Motor nerve conduction velocity (CV) slowing in diabetic DSP exceeds expectations for pure axonal loss thus implicating superimposed acquired demyelination. Methods: After establishing demyelination confidence intervals by regression analysis of nerve conduction data from chronic inflammatory demyelinating polyneuropathy (CIDP), we prospectively studied CV slowing in 90 diabetic DSP patients with and without at least one motor nerve exhibiting CV slowing (groups A and B) into the demyelination range by American Academy of Neurology (AAN) criteria respectively and 95 amyotrophic lateral sclerosis (ALS) patients. Simultaneously, secretory phospholipase A2 (sPLA2) activity was assessed in both diabetic groups and 46 healthy controls. Results: No ALS patient exhibited CV slowing in more than two motor nerves based on AAN criteria or the confidence intervals. Group A demonstrated a significantly higher percentage of patients as compared to group B fulfilling the above criteria, with an additional criterion of at least one motor nerve exhibiting CV slowing in the demyelinating range and a corresponding F response in the demyelinating range by AAN criteria (70.3 % vs. 1.9 %; p < 0.0001). Urine sPLA2 activity was increased significantly in diabetic groups as compared to healthy controls (942.9 ± 978.0 vs. 591.6 ± 390.2 pmol/min/ml, p < 0.05), and in group A compared to Group B (1328.3 ± 1274.2 vs. 673.8 ± 576.9 pmol/min/ml, p < 0.01). More patients with elevated sPLA2 activity and more than 2 motor nerves with CV slowing in the AAN or the confidence intervals were identified in group A as compared to group B (35.1 % vs. 5.7 %, p < 0.001). Furthermore, 13.5 % of patients in diabetic DSP Group A, and no patients in diabetic DSP Group B, fulfilled an additional criterion of more than one motor nerve with CV slowing into the demyelinating range with its corresponding F response into the demyelinating range by AAN criteria. Conclusion: A combination of regression analysis of electrodiagnostic data and a urine biological marker of systemic inflammation identifies a subgroup of diabetic DSP with superimposed acquired demyelination that may respond favorably to immunomodulatory therapy.

Pathogenesis underlying hexanucleotide repeat expansions in C9orf72 gene in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Mutations in C9orf72 and the resulting hexanucleotide repeat (GGGGCC) expansion (HRE) has been identified as a major cause of familial ALS, accounting for about 40 % of familial and 6 % of sporadic cases of ALS in Western patients. The pathological outcomes of HRE expansion in ALS have been recognized as the results of two mechanisms that include both the toxic gain-of-function and loss-of-function of C9ORF72. The gain of toxicity results from RNA and dipeptide repeats (DPRs). The HRE can be bidirectionally transcribed into RNA foci, which can bind to and disrupt RNA splicing, transport, and translation. The DPRs that include poly-glycine-alanine, poly-glycine-proline, poly-glycine- arginine, poly-proline-alanine, and poly-proline-arginine can induce toxicity by direct binding and sequestrating other proteins to interfere rRNA synthesis, ribosome biogenesis, translation, and nucleocytoplasmic transport. The C9ORF72 functions through binding to its partners-Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41). Loss of C9ORF72 function results in impairment of autophagy, deregulation of autoimmunity, increased stress, and disruption of nucleocytoplasmic transport. Further insight into the mechanism in C9ORF72 HRE pathogenesis will facilitate identifying novel and effective therapeutic targets for ALS.

Incomplete Anterior Spinal Artery Syndrome Responsive to Intrathecal Baclofen.

Anterior cord syndrome (ACS) occurs as a result of ischemia in the territory of the anterior spinal artery (ASA). Although spinal cord strokes are rare, the ASA is the most commonly affected vessel in the spinal cord. The typical presentation of an ASA stroke is paraparesis or paraplegia, bilateral loss of pain and temperature sensation, and fecal or urinary incontinence; the underlying neural structures responsible for these symptoms include the corticospinal tracts and anterior horns, anterolateral spinothalamic tracts, and lateral horns, respectively. ACS is a feared complication of aortic procedures and has been well-documented to occur during or after endovascular abdominal aortic aneurysm revascularization (EVAR). We report a case of incomplete or partial ACS presenting with delayed-onset spasticity and instability several months following EVAR, who was subsequently treated with intrathecal baclofen. We hypothesize that this patient's ischemia selectively damaged descending white matter tracts responsible for modulating the stretch receptor reflex, including damage to the corticospinal tract, which likely also impaired positional stability.

Neonatal Fc Receptor Inhibitor Therapeutics in Neuromuscular Disease.

ABSTRACT: The Neonatal Fc Receptor (FcRn) is integral to a wide variety of processes including IgG recycling, serum albumin turnover, and bacterial opsonization. Thus, targeting FcRn will increase antibody degradation including pathogenic IgGs. FcRn inhibition provides a novel therapeutic mechanism by which autoantibody titers are reduced resulting in clinical improvement and disease abatement. The FcRn targeting mechanism is similar to that of intravenous immunoglobulin (IVIg) in which saturated FcRn facilitates accelerated pathogenic IgG degradation. Recently, the FcRn inhibitor efgartigimod was approved for the treatment of myasthenia gravis. Subsequently, clinical trials of this agent have been conducted for numerous inflammatory conditions involving pathogenic autoantibodies. These disorders include the Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and inflammatory myositis. Other disorders traditionally treated with IVIg may also benefit from FcRn inhibition in certain contexts. This manuscript discusses the mechanism of FcRn inhibition, preclinical data, and the results of clinical trials of this agent for a wide range of neuromuscular diseases.

The clinical neurophysiology of COVID-19-direct infection, long-term sequelae and para-immunization responses: A literature review.

The COVID-19 pandemic resulting from the SARS-CoV-2 virus is in its third year. There is continuously evolving information regarding its pathophysiology and its effects on the nervous system. Clinical neurophysiology techniques are commonly employed to assess for neuroanatomical localization and/or defining the spectrum of neurological illness. There is an evolving body of literature delineating the effects of the SARS-CoV-2 virus on the nervous system as well as para-immunization responses to vaccination against this virus. This review focuses on the use of neurophysiological diagnostic modalities in the evaluation of potential acute and long-term neurological complications in patients that experience direct infection with SARS-CoV-2 and analyzes those reports of para-immunization responses to vaccination against the SARS-CoV-2 virus. The neurophysiological modalities to be discussed include electroencephalography (EEG), evoked potentials (EPs), nerve conduction studies and electromyography (EMG/NCV), autonomic function tests, transcranial magnetic stimulation (TMS) and Transcranial Doppler ultrasound (TCD).

Needle EMG muscle identification: A systematic approach to needle EMG examination.

The proper performance of needle electromyography (EMG) requires that the examiner obtain a brief but comprehensive history, perform a directed examination and generate a short differential diagnosis as part of the initial patient encounter. Equally as important is to set reasonable expectations for this study's performance as electronic media do not necessarily portray all of the nuances of an electrodiagnostic study. In addition to these preliminary steps, this minimonograph discusses equipment used in EMG evaluations, EMG examination techniques, muscles commonly sampled, pain reduction techniques, and special considerations that may require study modification such as anticoagulation, lymphedema, obesity and supervening infection. Clinicians performing these studies will maximize useful data collection while minimizing patient discomfort if all of these recommendations are followed.

Neurologic and neuroscience education: Mitigating neurophobia to mentor health care providers.

Neurologic disorders are among the most frequent causes of morbidity and mortality in the United States. Moreover, the current shortfall of neurologists is expected to worsen over the coming decade. As a consequence, many patients with neurologic disorders will be treated by physicians and primary care providers without formal neurologic training. Furthermore, a pervasive and well-described fear of neurology, termed neurophobia, has been identified in medical student cohorts, residents, and among general practitioners. In this article, members of the American Academy of Neurology A.B. Baker Section on Neurological Education review current guidelines regarding neurologic and neuroscience education, contextualize the genesis and the negative consequences of neurophobia, and provide strategies to mitigate it for purposes of mentoring future generations of health care providers.

Nerve conduction studies and EMG in carpal tunnel syndrome: Do they add value?

This paper summarises the views of four experts on the place of neurophysiological testing (EDX) in patients presenting with possible carpal tunnel syndrome, in guiding their treatment, and in reevaluations. This is not meant to be a position paper or a literature review, and heterogeneous viewpoints are presented. Nerve conduction studies should be performed in patients presenting with possible carpal tunnel syndrome to assist diagnosis, and may need to be repeated at intervals in those managed conservatively. There is evidence that local corticosteroid injection is safe and effective for many patients, thereby avoiding or deferring surgical decompression. All patients should undergo EDX studies before any invasive procedure for CTS (injection or surgery). Needle EMG studies are not obligatory, but may be needed in those with severe disease and those in whom an alternate or concomitant diagnosis is suspected.

Guillain-Barré syndrome after influenza vaccination in the United States, a report from the CDC/FDA vaccine adverse event reporting system (1990-2009).

OBJECTIVES: To determine the rate of Guillain-Barré syndrome (GBS) after administration of influenza vaccine in the United States and to provide further information about the characteristics and temporal profile of these incidents. METHODS: Data were acquired from the Vaccine Adverse Event Reporting System, supplemented by data from the Center for Biologics and Research under the Freedom of Information Act between 1990 and 2009. RESULTS: There were 802 cases (mean age, 54.72 ± 18.4 years) of GBS reported after influenza vaccination in the United States between 1990 and 2009. Among the 802 vaccinated patients with available data, 624 (77.8%) developed GBS within 6 weeks and 78 (9.7%) after 6 weeks, whereas these data were unavailable for the remaining 100 patients (13%). The reporting rate of post-influenza vaccine GBS was within the range expected in the general population or approximately 0.46 cases per million vaccinations. A non-Gaussian distribution of GBS within the first 6 weeks post-vaccination was noted, given that the peak incidence occurred in the second week. CONCLUSIONS: The incidence of post-influenza vaccine GBS is similar to the incidence of idiopathic GBS in the general population. Although the nonnormal distribution of post-vaccination GBS suggests that some cases may be triggered by vaccination, the greater risk of complications from influenza virus infections makes vaccination the first-line strategy for infection prevention and support the current guidelines on vaccination.

Analysis of data from the CDC/FDA vaccine adverse event reporting system (1990-2009) on Guillain-Barre syndrome after hepatitis vaccination in the USA.

We used data from the Vaccine Adverse Event Reporting System, supplemented by additional data provided by the Center for Biologics Evaluation and Research, to identify 189 patients with Guillain-Barré syndrome (GBS) reported after hepatitis vaccination with a mean age of 30.65 years, affecting men and women equally. Among vaccinated patients, 133 (70%) developed GBS within six weeks, 30 (15.9%) after six weeks, and for the remaining 26 (13.7%), the time between GBS occurrence and vaccination was not specified. The reporting rate of post-hepatitis vaccine GBS is approximately 3.4 cases per one million vaccinations, which is in the range expected in the general population. The unbalanced distribution of reports in the first six weeks after vaccination suggests that some cases of GBS may be triggered by vaccination. Nonetheless, the low incidence of hepatitis vaccine-associated GBS, and the dramatic incidence reduction of hepatitis and its complications after vaccination, support the current guidelines for vaccination.

Guillain-Barré syndrome after H1N1 vaccination in the United States: a report using the CDC/FDA Vaccine Adverse Event Reporting System (2009).

BACKGROUND: Although the Guillain-Barré syndrome (GBS) can be associated with the seasonal influenza vaccine, there is no definite evidence that GBS is associated with H1N1 influenza vaccination. The objective of this report is to study the occurrence and characteristics of GBS after H1N1 vaccine administration in the United States in 2009. METHODS: Data were acquired from the Vaccine Adverse Event Reporting System and supplemented by additional information obtained from the Center for Biologics Evaluation and Research, under the Federal Freedom of Information Act. RESULTS: A total of 62 individuals (mean age 46.51 ± 22.41 years), 33 of whom were men, developed GBS associated with the H1N1 influenza vaccination in 2009. Sixty GBS cases were reported within 6 weeks after vaccination, with 31 cases (50.0%) reported in the first 2 weeks. The estimated rate of occurrence of GBS was 6.2 cases per 10 million vaccinations, which is comparable to the rate of GBS in the general population. CONCLUSION: The higher rate of GBS reports in the first 6 weeks after H1N1 vaccination suggests that some GBS cases may be triggered by H1N1 vaccination. This warrants early recognition, treatment, and active surveillance in the postvaccination setting.

Propriospinal myoclonus associated with gluten sensitivity in a young woman.

Propriospinal myoclonus (PSM) is a rare movement disorder characterized by involuntary axial jerks originating from muscles innervated by multiple spinal segments. Most cases of PSM are idiopathic. Gluten sensitivity is a multisystemic autoimmune condition which may be associated with various neurological disorders, most commonly peripheral neuropathy and cerebellar ataxia. We report a case of a young woman who developed PSM in the setting of gluten sensitivity, indicating that gluten sensitivity should be considered in the differential diagnosis of PSM such that a gluten challenge test may prove diagnostically useful.

Atypical presentation of Creutzfeldt-Jakob disease: a rare but important cause of rapidly progressive dementia.

We report an atypical presentation of sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old woman that illustrates the difficulty in diagnosing this rare, but important, cause of rapidly progressive dementia. Despite well-established criteria, this diagnosis is often missed or substantially delayed (Table 1). In this case, a precipitous cognitive decline associated with a urinary tract infection initiallysuggested delirium. Although atypical CJD was considered as a cause when symptoms persisted, a definitive diagnosis was established postmortem when the cerebrospinal fluid (CSF) prion protein 14-3-3 tested positive. Creutzfeldt-Jakob disease must be considered in the differential diagnosis of rapidly progressive dementia as Connecticut accounts for approximately three of the more than 200 cases diagnosed nationally.

Comorbid HIV and myasthenia gravis: case report and review of the literature.

A 27-year-old woman without known risk factors contracted HIV and was given highly active antiretroviral therapy in 2006. She subsequently developed myasthenia gravis (MG) that responded to treatment with pyridostigmine bromide and azathioprine. The medical literature, consisting primarily of case reports, indicates that MG occurs in relatively immunocompetent HIV-infected persons who generally present with mild MG symptoms. As such, we recommend a high index of suspicion for MG in HIV-infected patients presenting with fatigue and weakness, especially those receiving highly active antiretroviral therapy.

Hemibody mirror movements in hemiparkinsonism-hemiatrophy syndrome.

Hemiparkinsonism-hemiatrophy syndrome (HPHA) is a relatively rare cause of secondary parkinsonism. Mirror movements (MM) are associated with a variety of congenital and acquired conditions, including some forms of parkinsonism. This report describes a patient with the HPHA phenotype who exhibited MM, a feature that has not been previously reported in this syndrome. Surface electromyography (EMG) was used to illustrate the virtually simultaneous occurrence of voluntary and involuntary movements. Needle EMG was used to diagnose a spinal accessory neuropathy. Pathological mirroring or overflow movement of the orbicularis oculi muscle is also hypothesized. The clinical features are demonstrated on video.

Structured didactic teaching sessions improve medical student neurology clerkship test scores: a pilot study.

OBJECTIVE: To determine the effectiveness of didactic case-based instruction methodology to improve medical student comprehension of common neurological illnesses and neurological emergencies. SETTING: Neurology department, academic university. PARTICIPANTS: 415 third and fourth year medical students performing a required four week neurology clerkship. MAIN OUTCOME MEASURES: Raw test scores on a 1 hour, 50-item clinical vignette based examination and open-ended questions in a post-clerkship feedback session. RESULTS: There was a statistically significant improvement in overall test scores (p<0.001). CONCLUSION: Didactic teaching sessions have a significant positive impact on neurology student clerkship test score performance and perception of their educational experience. Confirmation of these results across multiple specialties in a multi-center trial is warranted.

Coincident membranous glomerulonephritis and chronic inflammatory demyelinating polyradiculoneuropathy: questioning the autoimmunity hypothesis.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and membranous glomerulonephritis (MGN) are both autoimmune disorders that are rarely observed concurrently. We describe a patient who developed MGN nearly 20 years after the onset of CIDP, resulting in a secondary progression of his neuropathy. He responded dramatically to a novel regimen of plasma exchange and methotrexate. We propose a mechanism other than autoimmunity for the coincidence of these disorders and discuss the theoretical superiority of the treatment regimen that he received.