Severe Neuropathy Research Articles

Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies

Mutations in genes encoding molecular chaperones, for instance the genes encoding the subunits of the chaperonin CCT (chaperonin containing TCP-1, also known as TRiC), are associated with rare neurodegenerative disorders. Using a classical molecular dynamics approach, we investigated the occurrence of conformational changes and differences in physicochemical properties of the CCT5 mutations His147Arg and Leu224Val associated with a sensory and a motor distal neuropathy, respectively. The apical domain of both variants was substantially but differently affected by the mutations, although these were in other domains. The distribution of hydrogen bonds and electrostatic potentials on the surface of the mutant subunits differed from the wild-type molecule. Structural and dynamic analyses, together with our previous experimental data, suggest that genetic mutations may cause different changes in the protein-binding capacity of CCT5 variants, presumably within both hetero- and/or homo-oligomeric complexes. Further investigations are necessary to elucidate the molecular pathogenic pathways of the two variants that produce the two distinct phenotypes. The data and clinical observations by us and others indicate that CCT chaperonopathies are more frequent than currently believed and should be investigated in patients with neuropathies.

Distal anterior interosseous nerve to ulnar nerve motor branch reverse end-to-side transfer in a case of severe ulnar neuropathy.

Reverse end-to-side (RETS) distal transfer is gaining popularity in cases of proximal nerve damage with the nerve in continuity, allowing the nerve to potentially retain its ability to regenerate and recover. While preserving the original axon pool, RETS could provide an additional pool of motor axons and/or possibly "babysit" the muscle endplates and distal denervated nerve Schwann cells until reinnervation from the original pool occurs. The authors present a video demonstrating anterior subcutaneous transposition of the ulnar nerve at the elbow coupled with a distal anterior interosseous nerve to ulnar nerve RETS in a case of severe posttraumatic ulnar neuropathy at the elbow. The video can be found here: https://stream.cadmore.media/r10.3171/2022.9.FOCVID2282.

Diabetes mellitus and road traffic-aposition paper of the Austrian Diabetes Association (update 2023)

Public safety (prevention of accidents) is the primary objective in assessing fitness to drive amotor vehicle. However, general access to mobility should not be restricted if there is no particular risk to public safety. For people with diabetes mellitus, the Führerscheingesetz (Driving Licence Legislation) and the Führerscheingesetz-Gesundheitsverordnung (Driving Licence Legislation Health enactment) regulate important aspects of driving safety in connection with acute and chronic complications of the disease. Critical complications that may be relevant to road safety include severe hypoglycemia, pronounced hyperglycemia and hypoglycemia perception disorder as well as severe retinopathy and neuropathy, endstage renal disease and certain cardiovascular manifestations. If there is asuspicion of the presence of one of these complications, adetailed evaluation is required.In addition, the individual antihyperglycemic medication should be checked for existing potential for hypoglycemia. Sulfonylureas, glinides and insulin belong to this group and are therefore associated with the requirement of a5-year limitation of the driver's license. Other antihyperglycemic drugs without potential for hypoglycemia such as Metformin, SGLT‑2 inhibitors (Sodium-dependent-glucose-transporter‑2 inhibitors, gliflozins), DPP-4-inhibitors (Dipeptidyl-Peptidase inhibitors, gliptins), and GLP‑1 analogues (GLP‑1 rezeptor agonists) are not associated with such atime limitation.The relevant laws which regulate driving safety give room for interpretation, so that specific topics on driving safety for people with diabetes mellitus are elaborated from amedical and traffic-relevant point of view. This position paper is intended to support people involved in this challenging matter.

Porphyric neuropathy in black South Africans: a case series

Abstract Porphyria is a rare disorder that results from mutations in the genes important in haem biosynthesis. Several types are described. Acute attacks lead to central, autonomic and peripheral nervous system manifestations. These acute attacks typically occur in acute intermittent porphyria, and less so in variegate porphyria. The neuropathy in this condition can mimic Guillain-Barré syndrome (GBS), and is often misdiagnosed and incorrectly treated. It is rare in general, but considered to be extremely uncommon in the black African population. We describe five black South African patients, three of whom were diagnosed with variegate porphyria, with the presenting manifestation of a severe neuropathy. The neuropathy was atypical in nature and variable in presentation and highlight the importance of considering porphyria in such patients.

Axonal Transport Defects in Retinal Ganglion Cell Diseases.

For the survival and maintenance of retinal ganglion cells (RGCs), axonal transportation is fundamental. Axonal transportation defects can cause severe neuropathies leading to neuronal loss. Axonal transport defects usually precede axonal degeneration and RGC loss in disease models. To date, the main causes of axonal transport defects have not been fully understood. Therefore, elucidation of the mechanisms that lead to transport defects will help us to develop novel therapeutic targets and early diagnostic tools. In this review, we provide an overview of optic neuropathies and axonal degeneration with a focus on axonal transport.

Stings on wings: Proteotranscriptomic and biochemical profiling of the lesser banded hornet (Vespa affinis) venom.

Distinct animal lineages have convergently recruited venoms as weaponry for prey capture, anti-predator defence, conspecific competition, or a combination thereof. Most studies, however, have been primarily confined to a narrow taxonomic breadth. The venoms of cone snails, snakes, spiders and scorpions remain particularly well-investigated. Much less explored are the venoms of wasps (Order: Hymenoptera) that are infamous for causing excruciating and throbbing pain, justifying their apex position on Schmidt's pain index, including some that are rated four on four. For example, the lesser banded wasp (V. affinis) is clinically important yet has only been the subject of a few studies, despite being commonly found across tropical and subtropical Asia. Stings from these wasps, especially from multiple individuals of a nest, often lead to clinically severe manifestations, including mastocytosis, myasthenia gravis, optic neuropathy, and life-threatening pathologies such as myocardial infarction and organ failure. However, their venom composition and activity remain unexplored in the Indian subcontinent. Here, we report the proteomic composition, transcriptomic profile, and biochemical and pharmacological activities of V. affinis venom from southern India. Our findings suggest that wasp venoms are rich in diverse toxins that facilitate antipredator defence. Biochemical and pharmacological assessments reveal that these toxins can exhibit significantly higher activities than their homologues in medically important snakes. Their ability to exert potent effects on diverse molecular targets makes them a treasure trove for discovering life-saving therapeutics. Fascinatingly, wasp venoms, being evolutionarily ancient, exhibit a greater degree of compositional and sequence conservation across very distant populations/species, which contrasts with the patterns of venom evolution observed in evolutionarily younger lineages, such as advanced snakes and cone snails.

446. Hyperlactatemia and Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI): Still present even with modern antiretroviral therapy (ART)

Abstract Background Hyperlactatemia and lactic acidosis represent a rare but dangerous manifestation of mitochondrial toxicity associated with NRTIs. Although mitochondrial toxicity has been linked to the NRTI class, it is more prevalent with older agents such as zidovudine (AZT), didanosine (ddI) and stavudine (d4t). Methods Prompted by the diagnosis of symptomatic hyperlactatemia in 4 people with HIV on newer NRTIs between September 2019 and December 2021, we present a single-center case series to illustrate its subtle presentation and management. Hyperlactatemia was defined as a serum lactate of 1.6-4 mmol/L and lactic acidosis was defined as a serum lactate of > 4mmol/L. Results 75% of the patients were male, the mean age was 57.8 years, and 100% were Caucasian. 75% (3/4) were either overweight or obese (body mass index > 25 kg/m2). 75% had a CD4 lymphocyte count < 200 cells/mm3 at the time of human immunodeficiency virus (HIV) diagnosis and 50% had the diagnosis for >10 years. The most common symptom reported was non-specific fatigue (100%), followed by widespread myalgias (75%). 1 patient reported severe peripheral neuropathy affecting activities of daily living and 1 patient reported palpitations and night sweats. The mean duration of symptoms prior to reporting was 27.5 months. At the time of diagnosis of symptomatic hyperlactatemia, 75% had a CD4 lymphocyte count > 200 cells/mm3, the mean serum lactate was 2.7 mmol/L (1.9 mmol/L - 3.9 mmol/L), 50% were on abacavir (ABC) and lamivudine (3TC), and 50% were on tenofovir alafenamide (TAF) and emtricitabine (FTC). After stopping ART for 2 weeks, mean serum lactate decreased to 0.6 mmol/L (0.4 mmol/L – 1.1 mmol/L). 100% reported an improvement in quality of life after NRTI cessation and were managed with an NRTI-sparing regimen. Clinical characteristics are noted in Table 1. Conclusion This case series highlights the insidious nature of symptoms related to NRTI-associated mitochondrial toxicity including hyperlactatemia. Management strategies are not well defined for hyperlactatemia; however, NRTI-sparing regimens may offer improvement in quality of life. Despite improved tolerability of modern ART, clinicians should be aware of and monitor for symptoms of this potentially life-threatening side effect. Disclosures Carlos Malvestutto, MD MPH, Gilead Sciences: Advisor/Consultant|Viiv Healthcare: Advisor/Consultant.

Slimmer’s palsy following an intermittent fasting diet

BackgroundIsolated common peroneal neuropathy (CPN) is the most common lower extremity mononeuropathy and the third most common mononeuropathy overall in adults. It often associated with multiple aetiologies, such as trauma, hereditary neuropathies and iatrogenic causes. We report a rare case of acute bilateral foot drop in a late adolescent female following a rapid weight loss attributable to intermittent fasting diet.Case presentationA 19-year-old female presented with worsening bilateral foot drop following a rapid intentional weight loss by intermittent fasting diet. She lost 20% of her baseline bodyweight within a period of 4 months. Systemic disease and metabolic screenings for neuropathy differentials were unremarkable. Electrophysiological studies revealed severe entrapment neuropathy involving bilateral common peroneal nerves (CPN). Her confounding risk factors for CPN injury include contact sport activities and habitual leg crossing during sitting. Following a dietary modification and physical therapy she achieved complete recovery of weakness and function on follow-up.ConclusionsIn a patient with bilateral PN rapid weight loss, prognosis is good and complete neurologic recovery can be attained through combination of cessation of extreme diet and physical therapy.

Abductor Digiti Minimi and Anterior Interosseous to Ulnar Motor Nerve Transfer: The Super Turbocharge End-to-Side Transfer.

Anterior interosseous nerve to ulnar motor nerve supercharged end-to-side (SETS) nerve transfer to restore intrinsic function is a recently adopted nerve transfer in severe ulnar neuropathy. Its success is predicated on the critical threshold number of axons innervating the intrinsic muscles. Given the relative expendability of the abductor digiti minimi (ADM) muscle and the critical function of the other intrinsic muscles, the authors modified their SETS transfer to redirect axons from the ADM to turbocharge the ulnar motor nerve to innervate the more critical intrinsic muscles. They refer to this procedure as a super turbocharged end-to-side (STETS) procedure. The ADM has been used previously as a muscle/tendon transfer for thumb opposition and more recently as a nerve transfer to reinnervate the thenar branch of the median nerve. Although current methods of assessment of reinnervation are likely unable to differentiate between contributions from the anterior interosseous nerve SETS versus ADM STETS transfer, this technique follows the fundamentals of modern nerve surgery, where directing the maximum number of nerve fibers in a timely fashion to the most critical target is paramount for the best functional recovery. The authors suggest that the STETS technique may optimize outcomes in ulnar neuropathy without additional patient morbidity.

Bortezomib Induced Peripheral and Severe Autonomic Neuropathy Characterized By Dizziness, Orthostatic Hypotension, and Weight Loss

INTRODUCTION: It is well known that Bortezomib (B), a proteasome inhibitor used in the treatment of Multiple Myeloma (MM) causes peripheral neuropathy in an estimated 75% of patients and compromises their quality of life. There are reports of dizziness, muscle weakness and other unusual neurologic complications caused by B. Among patients that received B based induction, we observed peripheral neuropathy as expected. In addition, in a small subset we observed profound weight loss, dizziness, orthostatic hypotension (OH) and diarrhea. Some patients with weight loss required appetite stimulants and patients with OH/dizziness required medication for symptom control. The conglomeration of symptoms frequently impairs patients' performance status requiring interruption of therapy. B was given in combination with lenalidomide and dexamethasone (VRD) but we feel the neuropathic symptoms are more due to B since the combination of just lenalidomide and dexamethasone is not known to cause such complications. There are few publications on autonomic neuropathy (AN) caused by B but we believe it is under recognized and under diagnosed. Herein we report a series of patients managed at our center that presented with significant weight loss and dizziness suggestive of AN, prompting us to explore further and bring awareness to this problem. METHODS: From January 2018 to July 2022, patients with MM treated in our own practice and patients induced by our referring practices and sent to our center for transplant were evaluated. We identified patients who complained of significant weight loss and dizziness and reviewed medical records, looked at the characteristics they exhibited, and identified a pattern of symptoms and clinical course. Statistics are descriptive and this retrospective study was approved by our Institutional Review Board. RESULTS: Twelve patients were noted to have symptoms suggestive of AN. 11 of 12 received VRD and one received Daratumumab, B and dexamethasone based induction. B was administered subcutaneously and given twice weekly. The median age was 62.5 years (range 51-76). Eight were African American and 4 White; 8 female, 3 had diabetes but no neuropathy, 8 had bone disease, 2 renal failure at presentation. The interval between initiation of therapy and AN symptoms was a median of 107 days (range 50-219) and the median B dose was 20.8 mg/m2 (range 9-31 mg/m2). All 12 patients had weight loss and was the most recognizable symptom. The median weight loss and percentage weight loss (compared to baseline weight) were 19.5 Kgs (range 7-37 Kgs) and 21% (range 7-41) respectively. 7 of 12 patients had loss of appetite and 8 had diarrhea. Further treatment was held due to decline in performance status in all 12 patients. Six patients received appetite stimulants; 2 megestrol and 4 dronabinol. OH and an increase in heart rate in the standing position was seen in all 12 patients. 10 of the 12 patients had dizziness; 3 patients received fludrocortisone and one received midodrine. 11 of 12 patients also had peripheral neuropathy of whom 10 required medications for neuropathic pain and 10 required narcotic analgesics. 10 of 12 patients received a transplant and 2 declined. Transplant was delayed by 6 months (range 2-11) to enable recovery and the end-point was weight gain, resolution of OH and clinical improvement. Post-transplant 4 patients had persistent diarrhea and 1 had persistent dizziness. One patient developed severe mucositis, dysphagia, poor appetite and required hyperalimentation, nasogastric feeding and a feeding gastrostomy tube. 10 of 12 patients had persistent peripheral neuropathy and are using medications. Two of the 12 patients progressed and are receiving salvage treatment but there are no deaths. With a median follow up of 23 months (range 8-42), the median survival since diagnosis is 27 months. CONCLUSIONS: Severe AN characterized by weight loss, dizziness, OH in association with loss of appetite, diarrhea and painful neuropathy is an under recognized complication of Bortezomib. This generally results in interruption of disease directed therapy and delays autologous transplantation. Transplantation without resolution of symptoms could possibly worsen the morbidity and delay post-transplant recovery. To the best of our knowledge, we are the first group to report a series of patients with this symptom complex and strongly feel it requires to be studied further in a larger cohort of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Electrodiagnostic Predictors of Outcomes After In Situ Decompression of the Ulnar Nerve

Patients with severe ulnar neuropathy at the elbow frequently experience suboptimal surgical outcomes. Clinical symptoms alone may not accurately represent the severity of underlying nerve injury, calling for objective assessment tools, such as electrodiagnostic studies. The goal of our study was to determine whether specific electrodiagnostic parameters can be used to predict the outcomes after in situ decompression of the ulnar nerve. This prospective study enrolled consecutive patients aged ≥18 years diagnosed with ulnar neuropathy at the elbow. Patients completed a baseline battery of motor, sensory, functional, and electrodiagnostic tests before undergoing in situ decompression of the ulnar nerve. They were reassessed at 6 weeks, 3 months, 6 months, and 12 months after surgery. Forty-two patients completed at least 2 follow-up assessments and were included in the study. When controlling for other electrodiagnostic measurements and demographic factors, none of the electrodiagnostic parameters were predictive of outcomes at 12 months after surgery. Patients with decreased compound muscle action potential amplitudes demonstrated slower trends of recovery in grip strength, pinch strength, and overall scores on the Michigan Hand Outcomes Questionnaire as well as its function, work, and activities of daily living subscales, Disabilities of the Arm, Shoulder, and Hand questionnaire, and the Carpal Tunnel Questionnaire. Decreased motor nerve conduction velocity was predictive of slower recovery of 2-point discrimination and pinch strength. Compound muscle action potential amplitude, but not other conventional electrodiagnostic parameters, was predictive of functional outcomes after in situ decompression of the ulnar nerve. This parameter should play a role in determining the timing and prognosis of treatment for ulnar neuropathy at the elbow. Prognostic II.

Trigger Wrist with Carpal Tunnel Syndrome Accompanied with Trifid Median Nerve: A Case Report and Literature Review.

Trigger wrist, characterized by a clicking or snapping sensation around the wrist joint during finger or wrist motion, and bifid or trifid median nerve, which occurs in carpal tunnel syndrome along with anatomical variation of median nerve, are rare conditions. We report the case of a patient with a thickened tendon caused by severe tenosynovitis and flexor tendon subluxation to the hamate hook due to bowing of the flexor retinaculum, thereby resulting in trigger wrist as well as an anatomical median nerve variation (bifid median nerve in the right wrist and trifid median nerve in the left wrist). A 59-year-old housewife visited our hospital with bilateral fingertip numbness, tingling sensation, and aggravated severe night cramping that began 2 months ago. She also complained about trigger wrist during small finger flexion. Based on magnetic resonance imaging, ultrasonography, and nerve conduction study, trifid median nerve and bilateral severe median nerve neuropathy of the wrist were diagnosed; therefore, transverse carpal tunnel release and exploration under wide-awake anesthesia were planned. Intraoperative findings showed trifid and bifid median nerves in left and right wrists, respectively. Additionally, bowing of flexor retinaculum and severe flexor tendon tenosynovitis were observed. Tenosynovitis with thickened flexor sheath resulted in subluxation of the small finger flexor tendon above the hamate hook. After transverse carpal ligament release with antebrachial fascia release and tenosynovectomy, subluxation of the flexor tendon was resolved. At 6 months postoperatively, the tingling and dullness in fingertips also resolved, and no trigger wrist or any other complications were noted.

Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.

The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD]= 6.0, range=0-28) and 14.60 (SD=7.56, range=0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p= 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p= 0.016] vs 0.06 points [p= 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p= 0.025] vs -0.03 for baseline CMTES 0-7 [p= 0.958] and 0.25 for baseline CMTES ≥ 15 [p= 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.

KIF1A novel frameshift variant p.(Ser887Profs*64) exhibits clinical heterogeneity in a Pakistani family with hereditary sensory and autonomic neuropathy type IIC

Background: Hereditary sensory and autonomic neuropathies (HSANs) are rare heterogeneous group of neurological disorders caused by peripheral nerve deterioration. The HSANs sub-clinical classes have clinical and genetic overlap which often lead to misdiagnosis. In the present study a Pakistani family with five affected members suffering from severe neuropathy were genetically analyzed to identify the disease causative element in the family. Methods: Genome wide high-density single nucleotide polymorphism (SNP) microarray analysis was carried out followed by whole exome sequencing of the affected proband and another affected sibling. Shared homozygous regions in all severely affected members were identified through homozygosity mapping approach. Results: The largest homozygous region of 14.1 Mb shared by the five severely affected members of the family was identified on chromosome 2. Subsequent exome sequencing identified a novel single nucleotide deletion c.2658del; p.(Ser887Profs*64) in KIF1A. Segregation analysis revealed that this mutation was homozygous in all five affected individuals of the family with severe clinical manifestation, while members of the family that were heterozygous carriers shared abnormal skin features (scaly skin) only with the homozygous affected members. Conclusions: A novel frameshift mutation p.(Ser887Profs*64) in KIF1A is the potential cause of severe HSANIIC in a Pakistani family along with incomplete penetrance in mutation carriers. We demonstrate that using a combination of different techniques not only strengthens the gene finding approach but also helps in proper sub-clinical characterization along with identification of mutated alleles exhibiting incomplete penetrance leading to intrafamilial clinical variability in HSAN group of inherited diseases.

A SUCCESSIVE CLINICAL STORY ON GUILLAIN-BARRE SYNDROME UNDER THE LIGHT OF AYURVEDA: A CASE STUDY

Guillain-Barre syndrome (GBS) is a group of autoimmune syndromes comprising the disease's demyelinating and acute axonal degenerating forms. It is also an acute-onset, monophasic, immune-mediated polyneuropathy that often follows an antecedent infection. Here is an interesting case study where a 16-year-old girl with her parents reported to the outpatient department with the chief complaint of inability to walk without support, weakness in bilateral calf muscles, weakness in bilateral upper limbs and lower limbs and tingling sensation, pulling type of pain in the right ankle joint and also the heaviness of bilateral lower limbs, more in the morning. By examination, her sensory and motor systems showed impairment; one was hypotonic, proprioception was affected, and her gait was a high steppage gait. Her assessment was done by using Hughes GBS Disability Scale- 3/6. The patient’s nerve conduction study revealed severe motor and sensory axonal neuropathy in the upper and lower limbs. By seeing the nature of the disease and the patient's symptoms, we correlated with sarvanga vata according to our classics. Treatments were koshta shodhana (gut cleansing), abhyanga (massage of the whole body with medicated oil), Shastikashali panda sweda (Rubbing of medicated rice poultice over the body), basti (transrectal administration of medicines) and oral medicaments. Panchakarma treatments were for 30 days, followed by oral medications for the next 140 days. The intervention period of 154 days showed complete recovery of all the motor and sensory deficits; however, follow-up of the patient was maintained for 269 days, looking into the sustainability of the outcomes.

Chemotherapy-induced peripheral neuropathy in children and adolescent cancer patients.

Brain cancer and leukemia are the most common cancers diagnosed in the pediatric population and are often treated with lifesaving chemotherapy. However, chemotherapy causes severe adverse effects and chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and debilitating side effect. CIPN can greatly impair quality of life and increases morbidity of pediatric patients with cancer, with the accompanying symptoms frequently remaining underdiagnosed. Little is known about the incidence of CIPN, its impact on the pediatric population, and the underlying pathophysiological mechanisms, as most existing information stems from studies in animal models or adult cancer patients. Herein, we aim to provide an understanding of CIPN in the pediatric population and focus on the 6 main substance groups that frequently cause CIPN, namely the vinca alkaloids (vincristine), platinum-based antineoplastics (cisplatin, carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), epothilones (ixabepilone), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). We discuss the clinical manifestations, assessments and diagnostic tools, as well as risk factors, pathophysiological processes and current pharmacological and non-pharmacological approaches for the prevention and treatment of CIPN.

Neuroplasticity of peripheral axonal properties after ischemic stroke.

ObjectiveThis study investigated how peripheral axonal excitability changes in ischemic stroke patients with hemiparesis or hemiplegia, reflecting the plasticity of motor axons due to corticospinal tract alterations along the poststroke stage.MethodsEach subject received a clinical evaluation, nerve conduction study, and nerve excitability test. Nerve excitability tests were performed on motor median nerves in paretic and non-paretic limbs in the acute stage of stroke. Control nerve excitability test data were obtained from age-matched control subjects. Some patients underwent excitability examinations several times in subacute or chronic stages.ResultsA total of thirty patients with acute ischemic stroke were enrolled. Eight patients were excluded due to severe entrapment neuropathy in the median nerve. The threshold current for 50% compound muscle action potential (CMAP) was higher in paretic limbs than in control subjects. Furthermore, in the cohort with severe patients (muscle power ≤ 3/5 in affected hands), increased threshold current for 50% CMAP and reduced subexcitability were noted in affected limbs than in unaffected limbs. In addition, in the subsequent study of those severe patients, threshold electrotonus increased in the hyperpolarization direction: TEh (100–109 ms), and the minimum I/V slope decreased. The above findings suggest the less excitable and less accommodation in lower motor axons in the paretic limb caused by ischemic stroke.ConclusionUpper motor neuron injury after stroke can alter nerve excitability in lower motor neurons, and the changes are more obvious in severely paretic limbs. The accommodative changes of axons progress from the subacute to the chronic stage after stroke. Further investigation is necessary to explore the downstream effects of an upper motor neuron insult in the peripheral nerve system.

Recovery From Severe Systemic Peripheral Neuropathy Secondary to Erythropoietic Protoporphyria by Liver Transplant: A Case Report

Erythropoietic protoporphyria is a rare inherited metabolic disorder involving the heme biosynthesis pathway and leads to the accumulation of protoporphyrin in the erythrocytes or liver. Although peripheral neuropathy is known to develop occasionally in other types of porphyria, it rarely occurs in patients with erythropoietic protoporphyria. A 16-year-old boy was transferred to our hospital due to end-stage liver disease secondary to erythropoietic protoporphyria. Severe systemic peripheral neuropathy, similar to that presented in Guillain-Barré syndrome, developed; it was promptly managed with mechanical ventilation. Electrophysiological assessment of the presented neuropathy showed no responsiveness, indicating severe axonopathy. Six weeks after the transfer, liver transplant was performed.Postoperatively, hepatorenal syndromes improved immediately, and his erythrocyte protoporphyrin level decreased from 6291 to 174 μg/dL red blood cells.The patient started to move his limbs gradually and was weaned from mechanical ventilation 2 months after liver transplant. Eventually, he was discharged from hospital and was able to ambulate with assistance 10 months after liver transplant. To our knowledge, this is the first report detailing the clinical course in a patient with erythropoietic protoporphyria who recovered from severe systemic peripheral neuropathy after liver transplant.

DMs-MAFM+EfficientNet: a hybrid model for predicting dysthyroid optic neuropathy.

Thyroid-associated ophthalmopathy (TAO) is a very common autoimmune orbital disease. Approximately 4%–8% of TAO patients will deteriorate and develop the most severe dysthyroid optic neuropathy (DON). According to the current data provided by clinical experts, there is still a certain proportion of suspected DON patients who cannot be diagnosed, and the clinical evaluation has low sensitivity and specificity. There is an urgent need for an efficient and accurate method to assist physicians in identifying DON. This study proposes a hybrid deep learning model to accurately identify suspected DON patients using computed tomography (CT). The hybrid model is mainly composed of the double multiscale and multi attention fusion module (DMs-MAFM) and a deep convolutional neural network. The DMs-MAFM is the feature extraction module proposed in this study, and it contains a multiscale feature fusion algorithm and improved channel attention and spatial attention, which can capture the features of tiny objects in the images. Multiscale feature fusion is combined with an attention mechanism to form a multilevel feature extraction module. The multiscale fusion algorithm can aggregate different receptive field features, and then fully obtain the channel and spatial correlation of the feature map through the multiscale channel attention aggregation module and spatial attention module, respectively. According to the experimental results, the hybrid model proposed in this study can accurately identify suspected DON patients, with Accuracy reaching 96%, Specificity reaching 99.5%, Sensitivity reaching 94%, Precision reaching 98.9% and F1-score reaching 96.4%. According to the evaluation by experts, the hybrid model proposed in this study has some enlightening significance for the diagnosis and prediction of clinically suspect DON.Graphical abstract

In Depth Viral Diversity Analysis in Atypical Neurological and Neonatal Chikungunya Infections in Rio de Janeiro, Brazil.

Chikungunya virus (CHIKV) is an arthropod-borne virus (arbovirus) transmitted by Aedes mosquitoes. The human infection usually manifests as a febrile and incapacitating arthritogenic illness, self-limiting and non-lethal. However, since 2013, CHIKV spreading through the tropics and to the Americas was accompanied by an increasing number of cases of atypical disease presentation, namely severe neuropathies and neonatal infection due to intrapartum vertical transmission. The pathophysiological mechanisms underlying these conditions have not been fully elucidated. However, arbovirus intrahost genetic diversity is thought to be linked to viral pathogenesis. To determine whether particular viral variants could be somehow associated, we analyzed the intrahost genetic diversity of CHIKV in three infected patients with neurological manifestations and three mothers infected during the intrapartum period, as well as their babies following vertical transmission. No statistically supported differences were observed for the genetic variability (nucleotide substitutions/gene length) along the genome between the groups. However, the newborn and cerebrospinal fluid samples (corresponding to virus passed through the placenta and/or the blood–brain barrier (BBB)) presented a different composition of their intrahost mutant ensembles compared to maternal or patient serum samples, even when concurrent. This finding could be consistent with the unidirectional virus transmission through these barriers, and the effect of selective bottlenecks during the transmission event. In addition, a higher proportion of defective variants (insertions/deletions and stop codons) was detected in the CSF and maternal samples and those were mainly distributed within the viral non-structural genes. Since defective viral genomes in RNA viruses are known to contribute to the outcome of acute viral infections and influence disease severity, their role in these atypical cases should be further investigated. Finally, with the in silico approach adopted, we detected no relevant non-conservative mutational pattern that could provide any hint of the pathophysiological mechanisms underlying these atypical cases. The present analysis represents a unique contribution to our understanding of the transmission events in these cases and generates hypotheses regarding underlying mechanisms, that can be explored further.