Rare case of anti-CV2 paraneoplastic polyneuropathy associated with lung adenocarcinoma.

We describe the first case of anti-CV2 paraneoplastic polyneuropathy associated with lung adenocarcinoma. Our patient presented with progressive unsteadiness and numbness involving bilateral upper and lower limbs. He had symmetrical length-dependent lower motor neuron pattern of weakness and numbness involving both small and large fibres with prominent sensory ataxia. An extended workup for the polyneuropathy involving a serum paraneoplastic antineuronal antibody panel showed a positive reaction for anti-CV2 antibody. CT scan of the thorax, abdomen and pelvis revealed a right upper lung nodule and histopathological examination of the nodule revealed lung adenocarcinoma. He was scheduled for chemotherapy following his discharge and there was improvement of his sensorimotor polyneuropathy following his chemotherapy.

Not myopathic, but autonomic changes in patients with long-COVID syndrome: a case series.

INTRODUCTION: Neurological sequelae following SARS-CoV-2 infection still represent a serious concern both for neurologists and neuroscientists. In our paper, we investigated pain, myalgia, and fatigue as symptoms in long-COVID patients with an electrophysiological approach, comprising the evaluation of sympathetic skin responses (SSRs) and quantitative electromyography (qEMG). MATERIALS AND METHODS: Twelve patients were enrolled (mean age, 47.7 ± 11.6 years), referred to our attention because of myalgia, pain, or muscle cramps, which persisted about 6 months after the diagnosis of SARS-CoV-2 infection. They underwent conventional electroneurography (ENG), needle electromyography (EMG), and SSRs; moreover, qEMG was performed by sampling at least 20 motor unit potentials (20-30 MUPs) during weak voluntary contraction in deltoid and tibialis anterior muscles. The mean duration, amplitude, and percentage of polyphasic potentials were assessed and compared with healthy and age-matched volunteers. RESULTS: ENG did not disclose significant changes compared to healthy subjects; needle EMG did not reveal denervation activity. In addition, qEMG showed MUPs similar to those recorded in healthy volunteers in terms of polyphasia (deltoid: p = 0.24; TA: p = 0.35), MUP area (deltoid: p = 0.45; TA: p = 0.44), mean duration (deltoid: p = 0.06; TA: p = 0.45), and amplitude (deltoid: p = 0.27; TA: p = 0.63). SSRs were not recordable from lower limbs in seven patients (58%) and from the upper ones in three of them (25%). CONCLUSION: Our data suggest an involvement of the autonomic system, with a focus on cholinergic efferent sympathetic activity, without any evidence of myopathic changes.

Brain motor and fear circuits regulate leukocytes during acute stress.

The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.

Management of Spinal Muscular Atrophy in the Adult Population.

Spinal muscular atrophy (SMA) is a group of neurodegenerative disorders resulting from the loss of spinal motor neurons. 95% of patients share a pathogenic mechanism of loss of survival motor neuron (SMN) 1 protein expression due to homozygous deletions or other mutations of the SMN1 gene, with the different phenotypes influenced by variable copy numbers of the SMN2 gene. Advances in supportive care, disease modifying treatment and novel gene therapies have led to an increase in the prevalence of SMA, with a third of SMA patients now represented by adults. Despite the growing number of adult patients, consensus on the management of SMA has focused primarily on the pediatric population. As the disease burden is vastly different in adult SMA, an approach to treatment must be tailored to their unique needs. This review will focus on the management of the adult SMA patient as they age and will discuss proper transition of care from a pediatric to adult center, including the need for continued monitoring for osteoporosis, scoliosis, malnutrition, and declining mobility and functioning. As in the pediatric population, multidisciplinary care remains the best approach to the management of adult SMA. Novel and emerging therapies such as nusinersen and risdiplam provide hope for these patients, though these medications are of uncertain efficacy in this population and require additional study.

Emerging technologies for management of patients with amyotrophic lateral sclerosis: from telehealth to assistive robotics and neural interfaces.

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and subsequently paralysis. It begins subtly with focal weakness but spreads relentlessly to involve most muscles, thus proving to be effectively incurable. Typically, death due to respiratory paralysis occurs in 3-5 years. To date, it has been shown that the management of ALS patients is best achieved with a multidisciplinary approach, and with the help of emerging technologies ranging from multidisciplinary teleconsults (for monitoring the dysphagia, respiratory function, and nutritional status) to brain-computer interfaces and eye tracking for alternative augmentative communication, until robotics, it may increase effectiveness. The COVID-19 pandemic created a spasmodic need to accelerate the development and implementation of such technologies in clinical practice, to improve the daily lives of both ALS patients and caregivers. However, despite the remarkable strides that have been made in the field, there are still issues to be addressed. This review will be discussed on the eureka moment of emerging technologies for ALS, used as a blueprint not only for neurodegenerative diseases, examining the current technologies already in place or being evaluated, highlighting the pros and cons for future clinical applications.

Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial.

Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFß-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.

Treatment related fluctuation and response to intravenous immunoglobulin therapy in post COVID-19 Guillain-Barre syndrome.

Treatment related fluctuation (TRF) poses a special challenge in the treatment of Guillain-Barre syndrome (GBS). Many cases of GBS following COVID-19 infection have been reported in literature till date, but treatment related fluctuation (TRF) in post COVID-19 GBS has not been reported till date. We report a 35-year-old male patient who developed GBS following COVID-19 infection and had TRF after intravenous immunoglobulin (IV-IG) therapy. He required ventilator support but repeat IV-IG therapy led to complete recovery. Significant proximal muscle involvement, cranial nerve palsy, no antecedent diarrhea and absence of anti-GM1 antibodies are important predictors of TRF in GBS and need to be recognized early in the course of this illness. Early recognition of TRF and differentiating it from other forms of immune mediated neuropathy such as acute onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP) are important for prognostication and management.

Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS. METHOD: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured. RESULTS: Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure. DISCUSSION: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.

Electrophysiological features of acute inflammatory demyelinating polyneuropathy associated with SARS-CoV-2 infection.

OBJECTIVE: To assess whether patients with acute inflammatory demyelinating polyneuropathy (AIDP) associated with SARS-CoV-2 show characteristic electrophysiological features. METHODS: Clinical and electrophysiological findings of 24 patients with SARS-CoV-2 infection and AIDP (S-AIDP) and of 48 control AIDP (C-AIDP) without SARS-CoV-2 infection were compared. RESULTS: S-AIDP patients more frequently developed respiratory failure (83.3% vs. 25%, P=0.000) and required intensive care unit (ICU) hospitalization (58.3% vs. 31.3%, P=0.000). In C-AIDP, distal motor latencies (DMLs) were more frequently prolonged (70.9% vs. 26.2%, P=0.000) whereas in S-AIDP distal compound muscle action potential (dCMAP) durations were more frequently increased (49.5% vs. 32.4%, P=0.002) and F waves were more often absent (45.6% vs. 31.8%, P=0.011). Presence of nerves with increased dCMAP duration and normal or slightly prolonged DML was elevenfold higher in S-AIDP (31.1% vs. 2.8%, P=0.000);11 S-AIDP patients showed this pattern in 2 nerves. CONCLUSION: Increased dCMAP duration, thought to be a marker of acquired demyelination, can also be oserved in critical illness myopathy. In S-AIDP patients, an increased dCMAP duration dissociated from prolonged DML, suggests additional muscle fiber conduction slowing, possibly due to a COVID-19-related hyperinflammatory state. Absent F waves, at least in some S-AIDP patients, may reflect α-motor neuron hypoexcitability because of immobilization during the ICU stay. These features should be considered in the electrodiagnosis of SARS-CoV-2 patients with weakness, to avoid misdiagnosis.

De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation.

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.

SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum.

BACKGROUND AND PURPOSE: The aim of our study was to describe patients with the p.D12Y variant (previously reported as D11Y) in SOD1 showing heterogeneous clinicopathological features. METHODS: We performed clinical, electrophysiological, magnetic resonance imaging (MRI) and muscle pathology studies in four SOD1 p.D12Y variant-positive patients. RESULTS: The SOD1 p.D12Y clinical manifestations ranged from a benign phenotype characterized by distal distribution of muscular weakness and long survival to classic forms of amyotrophic lateral sclerosis with poor prognosis. Two patients with the distal clinical phenotype showed MRI and muscle pathology alterations indicating a concurrent muscle involvement. In one of these patients significant myopathic changes were associated with rimmed vacuolar pathology. CONCLUSIONS: We expand the clinical spectrum of SOD1 p.D12Y variant, including predominant lower motor neuron forms with long survival and classic forms with aggressive course. Some patients may have concomitant distal myopathy without other explanations. Given clinical, MRI and muscle pathology alterations, SOD1 should be considered in the differential diagnosis of molecularly undefined distal myopathies with rimmed vacuoles.

Guillain-Barré syndrome during SARS-CoV-2 pandemic: A case report and review of recent literature.

Acute demyelinating inflammatory polyneuropathy (AIDP) is the most common type of Guillain-Barré syndrome (GBS) in Europe, following several viral and bacterial infections. Data on AIDP-patients associated with SARS-CoV-2 (coronavirus-2) infection are scarce. We describe the case of a 54-years-old Caucasian female patient with typical clinical and electrophysiological manifestations of AIDP, who was reported positive with PCR for SARS-CoV-2, 3 weeks prior to onset of the neurological symptoms. She did not experience a preceding fever or respiratory symptoms, but a transient loss of smell and taste. At the admission to our neurological department, a progressive proximally pronounced paraparesis, areflexia, and sensory loss with tingling of all extremities were found, which began 10 days before. The modified Erasmus Giullain-Barré Syndrome outcome score (mEGOS) was 3/9 at admission and 1/12 at day 7 of hospitalization. The electrophysiological assessment proved a segmental demyelinating polyneuropathy and cerebrospinal fluid examination showed an albuminocytologic dissociation. The neurological symptoms improved significantly during treatment with immunoglobulins. Our case draws attention to the occurrence of GBS also in patients with COVID-19 (coronavirus disease 2019), who did not experience respiratory or general symptoms. It emphasizes that SARS-CoV-2 induces immunological processes, regardless from the lack of prodromic symptoms. However, it is likely that there is a connection between the severity of the respiratory syndrome and further neurological consequences.