Distal Neuropathy Research Articles

Acupuncture for HIV-associated distal symmetric peripheral neuropathy: A protocol for systematic review and meta-analysis.

Background:Human immunodeficiency virus (HIV)-associated distal symmetric peripheral neuropathy (DSPN) is one of the most frequent neurological complications of HIV infection, and causes pain and dysaesthesias in millions globally. Many individuals with this infection report using acupuncture to manage their symptoms, but evidence supporting the use of acupuncture is limited. This systematic review will assess the effectiveness and safety of acupuncture for patients with HIV-associated DSPN.Methods:Databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Scopus, Web of science, AMED (Allied and Complementary Medicine), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, Wanfang Database, VIP Database and clinical trials registers (the WHO International Clinical Trials Registry Platform portal and www.ClinicalTrials.gov) will be electronically searched from inception to December 1, 2020. All randomized controlled trials in English or Chinese without restriction on publication status will be included. Selection of studies, extraction of data, and assessment of studies quality will be independently performed by 2 reviewers. The primary outcome measure will be the change in pain intensity assessed by validated scales. Secondary outcomes include change in neurologic summary scores, quality of life, physical function evaluated by admitted tools, and adverse events related to acupuncture reported in the included trials. If possible, a meta-analysis will be conducted to provide an estimate of the pooled treatment effect using Review Manager 5.3 statistical software. Otherwise, qualitative descriptive analysis will be given. The results will be presented as the risk ratio for binary data and the mean difference (MD) or standardized MD for continuous data.Results:The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference.Conclusion:This review will be the first review entirely focused on assessing the effectiveness and safety of acupuncture for HIV-associated DSPN.PROSPERO registration number:CRD42020210994.

Reduced Thalamic Volume and Metabolites in Type 1 Diabetes with Polyneuropathy.

Thalamus is essential in processing of sensory information. This study explored the associations between thalamic volume and intra-thalamic metabolites and associations to clinical and experimental characteristics of sensory function in adults with diabetic polyneuropathy. 48 adults with type 1 diabetes and confirmed distal symmetric peripheral neuropathy (DPSN) and 28 healthy controls participated in a cross-sectional study and underwent a brain magnetic resonance imaging scan. Estimates for thalamic volume were extracted using voxel-based morphometry and intra-thalamic N-acetylaspartate/creatine (NAA/cre) levels were assessed by magnetic resonance spectroscopy. Associations between thalamic volume and clinical measures, quantitative sensory testing and neuropathic phenotype were explored. In diabetes, reduced gray matter volume was identified including bilateral thalamus (all p≤0.001) in comparison to healthy participants. Thalamic volume estimates were positively associated to intra-thalamic NAA/cre (r=0.4; p=0.006), however not to diabetes duration (p=0.5), severity of DSPN (p=0.7), or presence of pain (p=0.3). Individuals with the lowest thalamic volume had greatest loss of protective sensation (light touch using von Frey-like filaments, p=0.037) and highest pain tolerance to electric stimulation (tetanic stimulation, p=0.008) compared to individuals with the highest thalamic volume. In this cohort with type 1 diabetes and severe DSPN, thalamic atrophy was present and associated with reduced NAA/cre, indicating thalamic structural loss and dysfunction. Thalamic atrophy was associated to reduced sensory function involving large fiber neuropathy and sensation to tetanic stimulation that may reflect synaptic transmission. This may ultimately contribute to the current understanding of the pathophysiology behind the perception changes evident in DSPN.

Diagnostic utility of Sudoscan for detecting bortezomib-induced painful neuropathy: a study on 18 patients with multiple myeloma.

IntroductionIn the past few years, treatment of multiple myeloma has undergone a deep change for the employment of novel treatment comprising proteasome inhibitors. Bortezomib is a first-line drug in therapy of multiple myeloma. The onset of peripheral neuropathy is a dose-limiting collateral effect of the drug. This neuropathy is a distal symmetric neuropathy that affects both large and small fibers. Nerve conduction study (NCS) can be used for the diagnosis of bortezomib neuropathy, but this technique demonstrates alterations of the large nerve fibers. Sudoscan is a novel technique utilized to offer an evaluation of sudomotor function. The main objective of this study was to compare the sensitivity and diagnostic specificity of Sudoscan with respect to the nerve conduction study after bortezomib treatment.Material and methodsA total of 18 multiple myeloma patients were studied, 10 (55.5%) men and 8 (44.5%) women. Patients were analyzed at baseline and after 6 months of treatment with bortezomib. Subjects were submitted to nerve conduction study and electrochemical skin conductance evaluation with the Sudoscan device. Patients were also submitted to a clinical measure of pain and neuropathy.ResultsAt baseline NCS showed that only the mean sural SAP amplitude was below the 2SD lower limit of normal in 3 (16.7%) patients, while at same time we found an alteration of Sudoscan profiles in 2 (11.1%) patients. After 6 months of treatment, the NCS profiles were altered in 13 (72.2%) patients, and the Sudoscan profiles were modified in 11 (61.1%) subjects.ConclusionsOur results suggest that Sudoscan can be considered for the diagnosis of bortezomib-induced neuropathy. It is objective, reproducible, and surely easier than the traditional nerve conduction study. Sudoscan may be a useful help to manage the therapeutic interventions in multiple myeloma.

Клинические аспекты применения витаминов группы В

Polyneuropathy is a common disorder of the peripheral nervous system. Diabetic neuropathy is the most common and most studied variant of polyneuropathies. The duration of carbohydrate metabolism disorders and inadequate glycemic control are risk factors for nervous system damage in diabetes. Distal neuropathy is a common type of neuropathy associated with diabetes. Interconnecting pathological mechanisms initiated by high blood glucose result in the damage of peripheral nerve fibers. Clinical presentations of distal neuropathy depend on the damage of proximal or distal and sensory or motor nerve fibers and the involvement of the vegetative nervous system. Medications improving metabolic processes in nerve fibers and reducing the severity of peripheral nerve damage are beneficial in addressing the harmful effects of hyperglycemia. Neurometabolic therapy includes thiamine, pyridoxine, and cyanocobalamin (B vitamins) which provide neurotropic effects. B vitamins acting as co-factors in many enzymatic reactions significantly affect the normal functioning of nerve fibers. B vitamins are effective and safe agents used to treat peripheral nervous system diseases for many years. This paper discusses the potential use of B vitamins for diabetic neuropathy and the COVID-19 treatment and rehabilitation. KEYWORDS: polyneuropathy, hyperglycemia, diabetes, distal neuropathy, B vitamins, thiamine, pyridoxine, cyanocobalamin, COVID-19. FOR CITATION: Biryukova E.V., Shinkin M.V. Clinical aspects of B vitamin use. Russian Medical Inquiry. 2021;5(9):579–585 (in Russ.). DOI: 10.32364/2587-6821-2021-5-9-579-585.

Update on prevention of diabetic foot ulcer

The diabetic foot ulcer is the most important reason for non-traumatic limb amputation. Based on recent data, it has been estimated that up to 34% of type 2 diabetes patients may develop diabetic foot ulcers once in their lifetime. Risk factors for developing foot ulcers are distal sensorimotor peripheral neuropathy, peripheral arterial disease, previous ulcers, and/or amputations. Understanding the factors that place patients with diabetes mellitus at high ulceration risk and the early treatment of risk factors, and continuous education of the patient (and/or caregivers) are essential for the prevention and management of diabetic foot complications. Implementing strategies to prevent these complications is a key aspect of diabetes care, but the most effective strategy in prevention has to be investigated. More evidence from well-designed studies is needed on this topic.

The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease

Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7AM1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V. Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology.

Prevalence of retinopathy in diabetic patients with and without distal sensory peripheral neuropathy

Introduction: Diabetic Retinopathy is the most common cause of preventable blindness among working-aged group. Diabetic neuropathy is also a common complication of diabetes. As the prevalence of diabetes increases the complications are also increasing. Early detection of DR will significantly reduce the chances of vision loss. Aim of the Study: This study was done to assess the prevalence of diabetic retinopathy in patients with diabetic neuropathy and in patients without neuropathy. Materials and Methods: This is an analytical cross sectional study conducted at the patients attending OPD from January 2016 to November 2016. Total 200 patients who include 100 patients with neuropathy and 100 patients without neuropathy were screened for the presence of DR. presence of distal sensory peripheral neuropathy was diagnosed by using biothesiometry. Ocular examination included best corrected visual acuity, anterior segment examination using slit lamp examination, intra ocular pressure measurement using non contact tonometer. A dilated fundus examination was done with indirect ophthalmoscopy and slit lamp biomicroscopy. Results & Discussion: In this study, among the patients without neuropathy 30 percent of the patients had diabetic retinopathy of various stages and among the patients without neuropathy 44 percent of the patients had retinopathy. More advanced forms of the disease were seen in the DSPN group. Conclusion: This study clearly shows the increased prevalence of DR in patients with DSPN. Patients with DSPN have more severe disease compared with the non neuropathy group. It is also found that CSME is more common in the DSPN group. Keywords: CSME, Diabetic Retinopathy, Distal Sensory Peripheral Neuropathy, Diabetic retinopathy, Microvascular Complications.

Caspr 2 antibody associated disease–An unusual presentation

Introduction: Antibodies to Voltage Gated Potassium Channels (VGKC) are directed against Leucine-rich Glioma- Inactivated1 (LGI1) and Contactin Associated Protein like 2 (Caspr2). Common presentations of Caspr2 antibody associated diseases include limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. New clinical phenotypes are being considered to the spectrum of Caspr2 antibody associated disease. Here we report a case of Caspr2 antibody associated disease with an unusual clinical presentation. Case Report: 40 year old male presented with distal symmetrical sensorimotor neuropathy of 4 months duration. Subsequently he had developed neurobehavioral symptoms in the form of irritability, episodic memory impairment and seizures. After medical evaluation he was diagnosed to have anti Caspr2 antibody associated disease. Patient showed improvement with an immunosuppressive therapy, but had recurrence of autoimmune encephalitis 1 month later. Along with that, he had also developed right vocal cord palsy, for which no other cause was identified. Patient improved with second line immunosuppressive therapy. He had no further recurrence and is under follow up. Keywords: Voltage gated potassium channels, Leucine-rich Glioma-inactivated 1, Contactin associated protein, Limbic encephalitis, Neuromyotonia.

Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known.Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients.Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G>A mutation. One patient concomitant with homozygote c.665C>T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration.Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G>A mutation is a hot spot mutation in late-onset cblC disease.

ATP7A mutation with occipital horns and distal motor neuropathy: A continuum

ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489) (Kennerson et al., 2010). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein (Møller, 2015). Thus far OHS and SMAX3 only partially overlap. In fact patients with OHS usually have no distal motor neuropathy signs but, on the other hand, occipital horns, which are the main sign of OHS, have not been described in SMAX3 patient. We describe here a patient bearing a missense ATP7A mutation with associated signs of distal motor neuropathy as well as occipital horns, confirming that OHS and SMAX3 are a continuum.

Incidence of peripheral nerve injury in revision total shoulder arthroplasty: an intraoperative nerve monitoring study

The incidence of nerve injuries in revision total shoulder arthroplasty (TSA) is not well defined in the literature and may be higher than that in primary procedures, with 1 study reporting a complication rate of 50% for shoulder revisions. Given that continuous intraoperative nerve monitoring (IONM) can be an effective tool in diagnosing evolving neurologic dysfunction and preventing postoperative injuries, the purpose of this study was to report on IONM data and nerve injury rates in a series of revision TSAs. A retrospective cohort review of consecutive patients who underwent revision TSA was performed from January 2016 to March 2020. Indications for revision included infection (n = 7); failed total arthroplasty and hemiarthroplasty secondary to pain, dysfunction, and/or loose components (n = 36); and periprosthetic fracture (n = 1). Of the shoulders, 32 underwent revision to a reverse TSA, 6 underwent revision to an anatomic TSA, and 6 underwent spacer placement. IONM data included transcranial electrical motor evoked potentials (MEPs), somatosensory evoked potentials, and free-run electromyography. The motor alert threshold was set at ≥80% signal attenuation in any peripheral nerve. Patients were screened for neurologic deficits immediately following surgery, prior to administration of an interscalene nerve block, and during the first 2 postoperative visits. Additional data collection included surgical indication, sex, laterality, age at surgery, procedure performed, body mass index, history of tobacco use, Charlson Comorbidity Index, medical history, and preoperative range of motion. A total of 44 shoulders in 38 patients were included, with a mean age of 63.2 years (standard deviation, 13.0 years). Of the procedures, 22.4% (n = 10) had an MEP alert, with 8 isolated to a single nerve (7 axillary and 1 radial) and 1 isolated to the axillary and musculocutaneous nerves. Only 1 patient experienced a major brachial plexus alert involving axillary, musculocutaneous, radial, ulnar, and median nerve MEP alerts, as well as ulnar and median nerve somatosensory evoked potential alerts. Age, sex, body mass index, Charlson Comorbidity Index, and preoperative range of motion were not found to be significantly different between cases in which an MEP alert occurred and cases with no MEP alerts. In the postoperative period, no minor or major nerve injuries were found whereas distal peripheral neuropathy developed in 4 patients (9.1%). Among 44 surgical procedures, no patients (0%) had a major or minor nerve injury postoperatively and 4 patients (9.1%) complained of distal peripheral neuropathy postoperatively. In this study, we have shown that through the use of IONM, the rate of minor and major nerve injuries can be minimized in revision shoulder arthroplasty.

Anatomic versus reverse shoulder arthroplasty, are nerve injury rates different?

BackgroundThe true incidence of iatrogenic neurological injury following total shoulder arthroplasty (TSA) surgery remains controversial at a cited rate of 1%-18.7%. Additionally, there is a reported incidence of new onset distal peripheral neuropathy (DPN) of 7.1% and 12.3%, for anatomic (aTSA) and reverse (rTSA) shoulder replacements, respectively. The purpose of this present study is to report on nerve injury rates of a large, consecutive series of primary TSA (ie, rTSA and aTSA) performed by one surgeon, utilizing intraoperative neuromonitoring and consistent implant design. MethodsA retrospective cohort review of consecutive patients who underwent primary TSA was performed from January 2016 to March 2020. Intraoperative neuromonitoring data included transcranial electrical motor evoked potentials (MEPs), somatosensory evoked potentials, and free-run electromyography. Motor alert threshold was set at ≥ 80% signal attenuation in any one or more peripheral nerves. Patients were screened for neurological deficits immediately following surgery and in the first 2 postoperative visits. Additional data collection included surgical indication, gender, laterality, age at surgery, procedure performed, body mass index, history of tobacco use, Charlson comorbidity index, past medical history and preoperative range of motion. ResultsA total of 290 consecutive shoulders in 270 patients were included. Ninety-one (31.4%) shoulders underwent aTSA, while 199 (68.6%) underwent rTSA. Patients in the rTSA cohort were significantly older (70.1 vs. 61.3 years; P < .001), had higher Charlson comorbidity index scores (4.3 vs. 3.0; P < .001), and shorter operative time (81.8 vs. 99.7; P < .001). A total of 96 MEP alerts occurred in 65 (22.4%) operations, with a significantly higher proportion of these occurring in patients undergoing aTSA. MEP alerts occurred in 28 (39.8%) aTSA versus 37 (18.5%) rTSA (P = .024). Logistical regression found operative time (P = .003, odds ratio = 1.020 [95%: 1.007-1.033]) was predictive of a MEP alert. The axillary nerve was the most commonly alerted nerve accounting for 61.5% of all alerts. Zero patients had a major or minor nerve injury in this large cohort. Nine patients (3.1%) had DPN in the postoperative period. ConclusionIn 290 surgeries, no (0%) patients had a postoperative major or minor nerve injury, and 9 (3.1%) patients complained of postoperative distal peripheral neuropathy. Patients that had MEP alerts had significantly longer operative times and were more likely to be in the aTSA group compared to the rTSA group. This may be attributed to longer exposure and implantation times on the glenoid side for an anatomic as opposed to a reverse arthroplasty. Level of evidenceLevel III; Retrospective Cohort study.

ULTRASOUND GUIDED TIBIAL NERVE BLOCK IN MANAGEMENT OF PAINFUL DIABETIC NEUROPATHY

Background: Diabetic neuropathy (DN) refers to signs and symptoms of neuropathy in patients with diabetes in whom other causes of neuropathy have been excluded. Distal symmetrical neuropathy is the most common form accounting for 75 % of DN. Objective: To determine the pain relief efficacy of three successive ultrasound guided tibial nerve block at the ankle with bupivacaine and betamethasone, as a primary outcome in the management of chronic painful diabetic neuropathy of the foot resistant to medical management, compared to ultrasound guided placebo tibial nerve block. Serum glucose levels for assessment of diabetes control and patients satisfaction were measured as a secondary outcome. Patients and Methods: After obtaining the Ethics Committee’s approval of Anesthesia Department of Al-Zahra’a University Hospital, and the patients’ written informed consent, 40 Patients (aged 18-60y) with chronic painful distal diabetic polyneuropathy were prospectively enrolled in this double blind and random study. The patients were classified randomly into two equal groups: Group (I): Control group: patients who received ultrasound guided tibial nerve injection by sterile cold normal saline (28 C), and Group (II): Steroid group: Patients received ultrasound guided tibial nerve injection by betamethasone (7mg amp) which was diluted in 7ml saline, then 1mg was diluted in 0.25% bupivacaine. Each limb was injected in both groups by three successive injections each other week in alteration with other limb, then followed up monthly for 3 months. Results: Three successive ultrasound guided tibial nerve block at ankle level with 1mg betamethasone in 0.25% bupivacaine decreased LANSS score and analgesic requirements with more patient satisfaction in distal painful diabetic neuropathy resistant to medical treatment. Conclusion: The therapeutic benefits provided by ultrasound guided tibial nerve block with bupivacaine and betamethasone more effective than placepo block. Pain and other symptoms decrease abruptly after the first tibial nerve block and disappear after the third tibial nerve block.

HEREDITARY NEUROPATHIES & ALS: P.109 Expanding the phenotype of ATP7A-related copper transport diseases: Understanding the pathophysiology of neuropathy and copper metabolism

Genetic disorders related to ATP7A copper transporter includes classical Menkes disease (MD) and its milder form occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN). The DMN phenotype was recently described and is thought to be a distinct and clinical isolate phenotype of ATP7A related disorders, with different pathophysiology of MD and OHS. We describe clinical, biochemical, radiological characteristics and functional studies in fibroblast of two patients with a novel ATP7Agene mutation. Two related patients, nephew (patient 1) and uncle (patient 2) with the diagnosis of OHS. Patient 2 presents clinical manifestations of OHS and DMN and worsening of the neuropathy after copper treatment and functional motor recovery after a few weeks of treatment withdrawal. Genetic studies: The patients are hemizygous for c.4236delA (p.K1412NFsX15) in the exon 23 of the ATP7Agene (NM_000052.4). Pathogenic mutations of neuropathies-related genes were ruled out in a genetic panel. Mutations in the ATP7Agene presenting with the association of motor distal neuropathy and clinical features of MD or OHS have not been reported previously. It has been hypothesized that the ATP7A mutations leading to DNM may have a different impact on the function of the protein than those mutations causing MD or OHS phenotype. Further studies in the evaluation of the biological mechanisms of this novel mutation could contribute to a better understanding of the complex pathophysiology of ATP7A related disorders. Supplementation with copper-histidinate seems plausible when plasma copper is low, however, exogenous copper could be also dangerous and lead to cellular intoxication. Treatment with copper-histidinate in patients with OHS and DMN should be cautiously considered and monitored, since different repercussion of mutations in ATPA7 function may determine the copper treatment effect.

AUTOPHAGIC MYOPATHIES / MYOFIBRILLAR MYOPATHIES / DISTAL MYOPATHIES / POMPE DISEASE: P.10 Distal myopathy associated with two novel variants in SPTAN1

The phenotypic spectrum associated with autosomal dominant SPTAN1 variants has evolved since the initial 2008 description of infantile epileptic encephalopathy due to non-truncating mutations. Loss of function variants were reported in association with a central nervous system phenotype without epilepsy in 2018, and with a juvenile onset hereditary motor neuropathy in 2019. Here we report novel SPTAN1 variants in two patients seen in our clinic. The first presented at 9 years old with a history of mild motor and cognitive delays, dysmorphic features and abnormal gait. Examination showed distal leg muscle atrophy and weakness most significant in the ankles. Serum CK was normal; limited EMG was unremarkable but showed no evidence for neuropathy. His family history was non-contributory, and standard genetic testing was non-diagnostic. Whole exome sequencing (WES) at age 11 identified a SPTAN1 variant (c.6657delC/p.Asn2220ThrfsTer44) that was not maternally inherited (father unavailable to test). The second presented to our clinic at age 15, with reported first symptoms of abnormal standing posture and delayed motor milestones noted at 20 months. Based on symptoms of bilateral distal atrophy, pes cavus and foot drop, he was thought to have a distal motor neuropathy. An EMG at age 15 years showed evidence of distal myopathy without evidence of neuropathy; serum CK was normal. There was no family history of similar symptoms, and genetic testing including MYH7 sequencing, FSHD testing and a neuromuscular gene panel, was all negative. Examination at age 22 showed distal weakness with preserved EDB bulk, and WES identified a de novo pathogenic truncating SPTAN1 variant (c.2613delG; p.Lys871AsnfsTer5). Additional follow-up studies (including more extensive EMG and muscle biopsy) are planned, and will be reported. These patients suggest that SPTAN1 variants may be associated with a distal myopathy, expanding the clinical heterogeneity associated with mutations in this gene.

Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial

BackgroundMetformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM).MethodsThe study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed.ResultsAfter 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI − 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference − 0.33 V (95% CI − 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA1c did not confound the associations.ConclusionsEighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA1c.Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H–D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).

Corneal confocal microscopy demonstrates minimal evidence of distal neuropathy in children with celiac disease.

The aim of this study was to utilise corneal confocal microscopy to quantify corneal nerve morphology and establish the presence of sub-clinical small fibre damage and peripheral neuropathy in children with celiac disease. This is a cross-sectional cohort study of twenty children with celiac disease and 20 healthy controls who underwent clinical and laboratory assessments and corneal confocal microscopy. Corneal nerve fiber density (no.mm2), corneal nerve branch density (no.mm2), corneal nerve fiber length (mm.mm2), corneal nerve fiber tortuosity and inferior whorl length (mm.mm2) were quantified manually. Corneal nerve fiber density (34.7±8.6 vs. 32.9±8.6; P = 0.5), corneal nerve branch density (47.2±24.5 vs. 47.3±20.0; P = 0.1) and corneal nerve fiber length (20.0±5.1 vs. 19.5±4.5; P = 0.8) did not differ between children with celiac disease and healthy controls. Corneal nerve fiber tortuosity (11.4±1.9 vs 13.5±3.0; P = 0.01) was significantly lower and inferior whorl length (20.0±5.5 vs 23.0±3.8; P = 0.06) showed a non-significant reduction in children with celiac disease compared to healthy controls. Inferior whorl length correlated significantly with corneal nerve fiber density (P = 0.005), corneal nerve branch density (P = 0.04), and corneal nerve fiber length (P = 0.002). Corneal confocal microscopy demonstrates minimal evidence of neuropathy in children with celiac disease.

Diabetes mellitus is associated with elevated urinary pyrrole markers of γ-diketones known to cause axonal neuropathy

IntroductionProgressive distal symmetrical axonal neuropathy, a complication of diabetes mellitus (DM), has an unknown cause. Normal physiological metabolism and diabetic dysmetabolism are associated with the generation of γ-diketones. γ-Diketones form...

Diagnostic strategy for diabetic polyneuropathy: Focus on nerve fiber type and magnetic resonance neurography.

Recently, various neurological tests for evaluating small-fiber neuropathy have been developed. Magnetic resonance neurography has also developed as a novel method to visualize diabetic neuropathy. The current status of diabetic polyneuropathy diagnosis focusing on the types of nerve fiber and magnetic resonance neurography is summarized.

Axonal Motor Neuropathy in Rheumatoid Vasculitis: A Case Report

Necrotizing vasculitis in rheumatoid arthritis (RA) can lead to different patterns of neuropathy, including entrapment neuropathies, mononeuritis multiplex and distal symmetric sensory or sensorimotor neuropathy.