Distal Sensory Loss Research Articles

Pregabalin for Neuropathic Pain and Itch in Recessive Dystrophic Epidermolysis Bullosa

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience neuropathic pain and itch. There is a lack of evidence on any treatment for these symptoms in patients with RDEB. To test the efficacy of pregabalin in the treatment of neuropathic pain and itch in patients with RDEB. A randomized, double-blinded, crossover trial of oral pregabalin (50-300 mg/d) vs placebo was conducted at 2 sites, Toronto (Canada) and Santiago (Chile) from January 1, 2019, to December 31, 2020. Patients eligible to participate were diagnosed with RDEB, aged 8 to 40 years, not pregnant or lactating (if female), and had evidence of probable neuropathic pain and itching defined as distal thermal sensory loss (confirmed by thermal roller), score of 4 or greater on the Douleur Neuropathique 4 questionnaire (DN4), and score greater than 4 on the 10-point visual analog scale [VAS]). Patients with a clinically important or poorly controlled medical or psychiatric condition or pregabalin intolerance or allergy were excluded. Of 41 patients screened, 3 were not eligible and 28 declined enrollment. Data analyses were performed in 2021 through 2023. Participants received both pregabalin and matched placebo (titrated to a maximum-tolerated dose of 300 mg/day) in a randomized sequence so that comparisons could be made within participants and between groups. Difference in the mean pain and itch scores between pregabalin and placebo treatment (measured using VAS) before and after intervention. In all, 10 participants were randomized to 2 groups, 6 patients (mean [SD] age, 26.7 [8.1] years; 3 females [50%]) in group 1, and 4 patients (mean [SD] age, 26.5 [7.8] years, 2 females [50%]) in group 2. Group 1 received a sequence of pregabalin-placebo while group 2 received placebo-pregabalin. Pregabalin significantly reduced mean (SD) pain scores by 1.9 (1.5) points when controlling for sequence and treatment period vs baseline, while placebo had 0.1 (2.0) points of reduction. The effect of pregabalin was a mild but significant reduction in itch compared to baseline (mean [SD] points, 0.9 [2.2]), whereas the placebo produced no reduction (0.1 [2.5]). The mean pregabalin dose was generally well tolerated. The results of this randomized crossover trial indicate that pregabalin significantly reduced pain and itch scores from baseline compared to placebo in patients with RDEB. This feasibility study provided preliminary data on the efficacy of pregabalin in managing pain and itch in RDEB and gathered essential data to inform the design of a larger cohort trial. ClinicalTrials.gov Identifier: NCT03928093.

Charcot-Marie-Tooth type 2CC misdiagnosed as Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Charcot-Marie-Tooth (CMT) is a heterogeneous group of genetic neuropathies and is typically characterized by distal muscle weakness, sensory loss, pes cavus and areflexia. Herein we describe a case of CMT2CC presenting with proximal muscle weakness and equivocal electrophysiological features, that was misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). A 30-year-old woman complained of proximal muscle weakness with difficulty climbing stairs. Neurological examination showed weakness in lower limb (LL) muscles, that was marked proximally and mild distally, and absence of deep tendon reflexes in the ankles. Nerve conduction studies (NCS) showed sensory-motor neuropathy with non-uniform NC velocity and a partial conduction block (CBs) in peroneal nerve and tibial nerves. Thus, a diagnosis of CIDP was entertained and the patient underwent ineffective treatment with intravenous immunoglobulins. At electrophysiological revaluation CB in peroneal nerve was undetectable as also distal CMAP had decreased whereas the CBs persisted in tibial nerves. Hypothesizing a hereditary neuropathy, we examined the proband's son, who presented mild weakness of distal and proximal muscles at lower limbs. Neurophysiological investigation showed findings consistent with an intermediate-axonal electrophysiological pattern. A targeted-NGS including 136 CMT genes showed the heterozygous frameshift mutation (c.3057dupG; p.K1020fs*43) in the NEFH gene, coding for the neurofilament heavy chain and causing CMT2CC. Diagnosis of a genetic neuropathy may be challenging when clinical features are atypical and/or electrophysiological features are misleading. The most common misdiagnosis is CIDP. Our report suggests that also CMT2CC patients with proximal muscle weakness and equivocal electrophysiological features might be misdiagnosed as CIDP.

Identification and Characterization of Novel Founder Mutations in NDRG1: Refining the Genetic Landscape of Charcot-Marie-Tooth Disease Type 4D in Bulgaria.

Charcot-Marie-Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims.

Insights into phenotypic variability caused by GARS1 pathogenic variants.

Pathogenic variants of the glycyl-tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot-Marie-Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy. This cross-sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed. The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients. GARS1 variants may produce a dHMN phenotype with "split hand" and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.

Recent Advances in Biomolecular Patho-Mechanistic Pathways behind the Development and Progression of Diabetic Neuropathy.

Diabetic neuropathy (DN) is a neurodegenerative disorder that is primarily characterized by distal sensory loss, reduced mobility, and foot ulcers that may potentially lead to amputation. The multifaceted etiology of DN is linked to a range of inflammatory, vascular, metabolic, and other neurodegenerative factors. Chronic inflammation, endothelial dysfunction, and oxidative stress are the three basic biological changes that contribute to the development of DN. Although our understanding of the intricacies of DN has advanced significantly over the past decade, the distinctive mechanisms underlying the condition are still poorly understood, which may be the reason behind the lack of an effective treatment and cure for DN. The present study delivers a comprehensive understanding and highlights the potential role of the several pathways and molecular mechanisms underlying the etiopathogenesis of DN. Moreover, Schwann cells and satellite glial cells, as integral factors in the pathogenesis of DN, have been enlightened. This work will motivate allied research disciplines to gain a better understanding and analysis of the current state of the biomolecular mechanisms behind the pathogenesis of DN, which will be essential to effectively address every facet of DN, from prevention to treatment.

Late Onset of Severe Demyelinating Peripheral Neuropathy in a 62-Year-Old African American Woman.

Hereditary neuropathies are typically associated with an early onset of symptoms, but same types of neuropathies may also manifest late, after the age 50 years. A 62-year-old African American woman presented with a 6-year history of gait unsteadiness and has been using a walker since the age 57 years after an unwitnessed fall. Gradual worsening of walking difficulties was later followed by decreased dexterity. The family history was negative for neuromuscular disorders, including neuropathy. On examination, the patient had both distal and proximal weakness with distal sensory loss to all modalities and hyporeflexia. Charcot Marie Tooth Examination Score was 12. Previous electrodiagnostic testing at the age 60 years showed severe sensorimotor demyelinating polyneuropathy with bilateral severe carpal tunnel syndrome. Genetic testing showed a homozygous pathogenic mutation in SH3TC2 gene (c.2860C>T; p.Arg954*), associated with CMT4C. CMT4C is the most common recessive demyelinating sensorimotor polyneuropathy and overall comprises 0.4%-1.7% of all patients with Charcot-Marie-Tooth disease. It is more common in French Canadians and Spanish Roma and in recent natural history study; only 1 of 56 patients was African American. This report demonstrates sporadic occurrence of CMT4C in other ethnic groups as well.

A novel IGHMBP2 variant and clinical diversity in Vietnamese SMARD1 and CMT2S patients.

Pathogenic variants in the IGHMBP2 gene are associated with two distinct autosomal recessive neuromuscular disorders: spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320) and Charcot-Marie-Tooth type 2S (CMT2S; OMIM #616155). SMARD1 is a severe and fatal condition characterized by infantile-onset respiratory distress, diaphragmatic palsy, and distal muscular weakness, while CMT2S follows a milder clinical course, with slowly progressive distal muscle weakness and sensory loss, without manifestations of respiratory disorder. Whole-exome sequencing of the IGHMBP2 gene was performed for eight Vietnamese patients with IGHMBP2-related neuromuscular disorders including five patients with SMARD1 and the others with CMT2S. We identified one novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) in a SMARD1 patient. Besides that, two patients shared the same pathogenic variants (c.1235 + 3A > G/c.1334A > C) but presented completely different clinical courses: one with SMARD1 who deceased at 8 months of age, the other with CMT2S was alive at 3 years old without any respiratory distress. This study is the first to report IGHMBP-2-related neuromuscular disorders in Vietnam. A novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) expressing SMARD1 phenotype was detected. The presence of three patients with the same genotype but distinct clinical outcomes suggested the interaction of variants and other factors including relating modified genes in the mechanism of various phenotypes.

Neuromuscular manifestations of wild type transthyretin amyloidosis: a review and single center's experience.

Transthyretin amyloidosis (ATTR) is a condition defined by accumulation of insoluble transthyretin amyloid deposits in multiple organs, especially in the peripheral nerve and heart muscle. ATTR may result from transthyretin mutations (variant ATTR or ATTRv) or may occur with normal transthyretin genotype (wild type ATTR or ATTRwt). ATTRwt was previously known as "senile amyloidosis" and causes cardiomyopathy which may lead to heart failure with a preserved ejection fraction, affecting predominantly elderly men. The exact prevalence of ATTRwt in the general population remains unclear, but its occurrence may be underestimated in women. It was observed that a proportion of ATTRwt cardiomyopathy patients may develop slowly progressing neuropathy that is milder and indolent in comparison with typical progressive neuropathy associated with ATTRv. Furthermore, the causality of neuropathy is often uncertain in patients with ATTRwt. Neuropathy symptoms, including distal sensory loss, unsteadiness and (neuropathic) pain are common in elderly patients with multiple potential causes, and as ATTRwt patients are typically older, relatively high prevalence of peripheral neuropathy is expected with frequent comorbidities. Relatively high prevalence of ATTRwt in elderly population contrasts few documented cases of neuropathy caused by ATTRwt, and there is uncertainty whether ATTRwt neuropathy is an infrequent occurrence or a significant manifestation of multisystemic ATTRwt. We review neurologic and musculoskeletal manifestations of ATTRwt and present clinical features of a single center cohort of ATTRwt patients with suspected peripheral neuropathy.

Expression pattern analysis and characterization of the hereditary sensory and autonomic neuropathy 2 A (HSAN2A) gene with no lysine kinase (WNK1) in human dorsal root ganglion

Inherited painless neuropathies arise due to genetic insults that either block the normal signaling of or destroy the sensory afferent neurons in the dorsal root ganglion (DRG) responsible for transducing noxious stimuli. Complete loss of these neurons leads to profound insensitivity to all sensory modalities including pain. Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare genetic neuropathy characterized by a progressive distal early onset sensory loss. This syndrome is caused by autosomal recessive mutations in the with-no-lysine protein kinase 1 (WNK1) serine-threonine kinase gene. Of interest, disease-associated mutations are found in the large exon, termed “HSN2,” which encodes a 498 amino acid domain C-terminal to the kinase domain. These mutations lead to truncation of the HSN2-containing proteins through the addition of an early stop codon (nonsense mutation) leading to loss of the C-terminal domains of this large protein. The present study evaluates the transcripts, gene structure, and protein structure of HSN2-containing WNK1 splice variants in DRG and spinal cord in order to establish the basal expression patterns of WNK1 and HSN2-containing WNK1 splice variants using multiplex fluorescent situ hybridization. We hypothesized that these transcripts would be enriched in pain-sensing DRG neurons, and, potentially, that enrichment in nociceptive neurons was responsible for the painless phenotypes observed. However, our in-depth analyses revealed that the HSN2-WNK1 splice variants were ubiquitously expressed but were not enriched in tachykinin 1-expressing C-fiber neurons, a class of neurons with a highly nociceptive character. We subsequently identified other subpopulations of DRG neurons with higher levels of HSN2-WNK1 expression, including mechanosensory large fibers. These data are inconsistent with the hypothesis that this transcript is enriched in nociceptive fibers, and instead suggest it may be related to general axon maintenance, or that nociceptive fibers are more sensitive to the genetic insult. These findings clarify the molecular and cellular expression pattern of this painless neuropathy gene in human tissue.

A novel HSPB1S139F mouse model of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait abnormalities. Genetic mutations in heat shock proteins have been linked to CMT2. Specifically, mutations in the heat shock protein B1 (HSPB1) gene encoding for heat shock protein 27 (Hsp27) have been linked to CMT2F and distal hereditary motor and sensory neuropathy type 2B (dHMSN2B) subtype. The goal of the study was to examine the role of an endogenous mutation in HSPB1 in vivo and to define the effects of this mutation on motor function and pathology in a novel animal model. As sphingolipids have been implicated in hereditary and sensory neuropathies, we examined sphingolipid metabolism in central and peripheral nervous tissues in 3-month-old HspS139F mice. Though sphingolipid levels were not altered in sciatic nerves from HspS139F mice, ceramides and deoxyceramides, as well as sphingomyelins (SMs) were elevated in brain tissues from HspS139F mice. Histology was utilized to further characterize HspS139F mice. HspS139F mice exhibited no alterations to the expression and phosphorylation of neurofilaments, or in the expression of acetylated α-tubulin in the brain or sciatic nerve. Interestingly, HspS139F mice demonstrated cerebellar demyelination. Locomotor function, grip strength and gait were examined to define the role of HspS139F in the clinical phenotypes associated with CMT2F. Gait analysis revealed no differences between HspWT and HspS139F mice. However, both coordination and grip strength were decreased in 3-month-old HspS139F mice. Together these data suggest that the endogenous S139F mutation in HSPB1 may serve as a mouse model for hereditary and sensory neuropathies such as CMT2F.

Anti-myelin-associated glycoprotein neuropathy: Where do we stand?

Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti-MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off-label immunotherapy is common, there are currently no proven effective disease-modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti-MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti-MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti-MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B-cell-depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti-MAG neuropathy patients.

Effects of intensive rehabilitation on functioning in patients with mild and moderate Charcot-Marie-Tooth disease: a real-practice retrospective study.

Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies and can lead to progressive muscular weakness, pes cavus, loss of deep tendon reflexes, distal sensory loss, and gait impairment. There are still no effective drugs or surgical therapies for CMT, and supportive treatment is limited to rehabilitative therapy and surgical treatment of skeletal deformities. Many rehabilitative therapeutic approaches have been proposed, but timing and cadence of rehabilitative intervention are not clearly defined, and long-term follow-up is lacking in literature. The aim of this real-practice retrospective study was to assess the effectiveness of an intensive neurorehabilitation protocol on muscle strength and functioning in CMT patients. We analyzed data of patients with diagnosis of mild to moderate CMT. The rehabilitation program lasted 2-4 h a day, 5 days a week, for 3 weeks and consisted of manual treatments, strengthening exercises, stretching, core stability, balance and resistance training, aerobic exercises, and tailored self-care training. Data were collected at baseline (T0), after treatment (T1), and at the 12-month mark (T2) in terms of the following outcome measures: muscle strength, pain, fatigue, cramps, balance, walking speed, and ability. We included 37 CMT patients with a median age of 50.72 ± 13.31 years, with different forms: demyelinating (n = 28), axonal (n = 8), and mixed (n = 1). After intensive rehabilitation treatment, all outcomes significantly improved. This improvement was lost at the 1-year mark. Taken together, these findings suggest that an intensive rehabilitation program improves short-term symptoms and functional outcomes in a cohort of inpatients affected by mild to moderate CMT.

An Atypical Presentation of Immune-mediated, Demyelinating Polyneuropathy with Multiple Antibodies to Nerve and Myelin Proteins Following SARS-CoV2 mRNA Vaccination (P10-5.009)

<h3>Objective:</h3> This case describes an atypical demyelinating polyneuropathy temporally associated with SARS-CoV2 mRNA vaccination and characterized by the presence of multiple co-existing autoantibodies. <h3>Background:</h3> A 62-year-old woman developed distal, symmetric upper and lower extremity sensorimotor impairments and areflexia three weeks after SARS-CoV2 booster vaccination (Pfizer-BioNTech). Initial cerebrospinal fluid analysis demonstrated cytoalbuminologic dissociation (protein 76mg/dL). Intravenous immunoglobulin (IVIg) (2 gm/kg total) was prescribed. The patient’s symptoms and signs resolved. Asymmetric, proximal appendicular weakness, distal appendicular sensory loss, gait impairment, and areflexia reoccurred approximately one week later. Plasma exchange (PLEX) was completed, resulting in marked clinical improvement. Clinical worsening again reoccurred in the weeks following PLEX completion. Electrodiagnostic and serologic studies were obtained. Immunomodulatory therapies were escalated with IVIg (repeat 2 gm/kg), corticosteroid, and rituximab therapies prescribed. Sustained symptom improvement was evidenced. <h3>Design/Methods:</h3> Case report with literature review. <h3>Results:</h3> Nerve conduction and electromyography studies demonstrated absent F-waves, prolonged distal motor latencies, and reduced recruitment of normal motor units consistent with a demyelinating polyneuropathy. Ga1NAc-GD1a IgG, beta-tubulin IgG, and neurofascin-155 IgG antibodies were detected in serum samples obtained prior to IVIg therapy (Washington University Neuromuscular Laboratory Demyelinating Neuropathy Panel). <h3>Conclusions:</h3> The patient’s clinical syndrome was ultimately consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The asymmetric pattern of weakness, robust initial treatment response(s), and severe fluctuations were atypical for classical CIDP, but consistent with demyelinating disease marked by specific autoantibodies. Uniquely, Ga1NAc-GD1a IgG, beta-tubulin IgG, and neurofascin-155 IgG antibodies were identified. Antibodies against axons and myelin proteins have been recently reported in patients with acute and chronic demyelinating polyneuropathies. Antibodies to neurofascin isoforms, anti-tubulin and Ga1NAc-GD1a can result in severe phenotypes with variable treatment responses, including robust treatment response to B-cell targeted therapies. To our knowledge, this is a novel case due to multiple co-existing, potentially pathogenic, autoantibodies. A possible immune-mediated mechanism precipitated by SARS-CoV2 vaccination requires further investigation. <b>Disclosure:</b> Dr. Saban has nothing to disclose. Dr. Leech has nothing to disclose. Dr. Carlson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medscape. Dr. Carlson has received research support from Horizon Therapeutics. Dr. Carlson has a non-compensated relationship as a Health Service Subcommittee Member with American Academy of Neurology that is relevant to AAN interests or activities. Dr. Sauer has nothing to disclose. The institution of Dr. Ragole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. The institution of Dr. Ragole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Ragole has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion Pharmaceuticals. The institution of Dr. Ragole has received research support from Alexion Pharmaceuticals.

Evidence of Lumbosacral Plexus Involvement on MR Neurography in Early Guillain-Barré Syndrome (P14-8.015)

<h3>Objective:</h3> To describe a case of early Guillain-Barré Syndrome (GBS) with novel findings of lumbosacral plexus involvement on MR neurography. <h3>Background:</h3> GBS is an acute inflammatory polyradiculoneuropathy characterized by progressive sensory loss, weakness, areflexia, CSF albumino-cytologic dissociation and cauda equina enhancement on MRI. Diagnosis of early GBS can be challenging, as CSF and electrodiagnostic studies can be normal/non-diagnostic in the first 1–2 weeks. We describe a case of early GBS with cauda equina enhancement and lumbosacral plexus abnormalities on MR neurography, seen only three days after symptoms onset and before any diagnostic abnormalities in CSF or electrodiagnostic testing were detected. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 67-year-old man presented with a 3-day history of rapidly progressive gait instability and leg weakness, 14 days after an uncomplicated L5-S1 fusion. Diffuse arm and leg weakness, distal leg sensory loss, hypoactive arm reflexes and absent leg reflexes were detected on exam. CSF analysis showed normal cells and protein (55mg/dL, reference&lt;60mg/dl). Electrodiagnostic testing showed mildly prolonged F-response latencies of the median and ulnar nerves, absent peroneal F-response, normal tibial F-response latency and absent tibial H-responses, without other findings suggestive of demyelination, and normal needle EMG. Lumbar spine MRI showed enhancement of ventrally positioned nerve roots of the cauda equina and no central or foraminal stenosis. Lumbosacral plexus MR neurography showed prominent enlargement, hyperintensity and enhancement of bilateral lower lumbosacral nerve roots and the proximal sciatic nerves. Plasma exchange was initiated with subsequent improvement in his symptoms and exam findings. <h3>Conclusions:</h3> Diagnosis of early GBS can be challenging, as CSF and electrodiagnostic testing can be normal/non-diagnostic. MRI and MR neurography are useful surrogate tests which may have greater sensitivity in detecting early GBS compared to CSF and electrodiagnostic testing. Involvement of the lumbosacral plexus by imaging is a novel finding, which can further assist in diagnosing early GBS cases. <b>Disclosure:</b> Dr. Weng has nothing to disclose. The institution of Darryl Sneag, 12603 has received research support from GE Healthcare. Dr. Pavlakis has nothing to disclose.

Teaching Neuro Images : Hypertrophic olivary degeneration in a young man with POLG gene mutation

A 30-year-old man with sensorineural hearing loss presented with subacute somnolence, slurred speech, and unsteady gait following treatment with peginterferon α-2b and ribavirin for chronic hepatitis C virus. Examination revealed scanning speech, horizontal nystagmus, gait ataxia, and symmetric hyporeflexia with distal sensory loss. There was no palatal myoclonus. Metabolic and serologic workup and blood lactate were unrevealing. Brain MRI demonstrated bilateral hypertrophic olivary degeneration (HOD, figure). Whole exome sequencing identified a homozygous pathogenic p.W748S POLG mutation.1 Differential diagnosis of bilateral HOD includes mutations in the nuclear genes crucial to mitochondrial function, POLG and SURF1 .2

Management of Intractable Painful Diabetic Peripheral Neuropathy: The Perspective of a Pain Specialist

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. The most common diabetic neuropathy (DN) is distal symmetric polyneuropathy, with characteristic glove- and stocking-like presentation of distal sensory or motor function loss. Because painful DN is associated with increased mortality and morbidity, early recognition and preventive measures are essential. Nevertheless, diagnosing DN or painful DN is challenging, particularly in patients with early and mild neuropathy, and there is no established gold standard. Furthermore, there is no established DN treatment other than improved glycemic control, and only symptomatic management is available for painful DN. However, thanks to health-conscious living, almost one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. These include antidepressants (tricyclic acid, serotonin-norepinephrine reuptake inhibitor), anticonvulsants (calcium-channel blocker, sodium channel blocker), and others (sarpogrelate). A more precise and distinct symptom profile from patients with painful DN may help identify patients more responsive to one treatment versus another. In addition to pharmacological, physical, cognitive, or educational management for painful DN, large randomized clinical trials are needed to identify the most effective minimally invasive interventions. Transcutaneous electrical nerve stimulation, pain scrambler therapy, sympathetic ganglion block, and botulinum toxin injections have been investigated as alternative therapeutic outcomes.

Living without pain. Case series of patients with hereditary sensory and autonomic neuropathies in a Canadian tertiary care centre.

Hereditary sensory and autonomic neuropathies (HSANs) are a group of heterogeneous genetic disorders presenting predominantly with sensory and autonomic dysfunction. They are a diverse group of diseases of the peripheral nervous system characterized by profound distal sensory loss and various autonomic and motor disturbances. The primary objective of this study was to describe the clinical presentation of children with HSAN to paediatricians. We present clinical features and genetic etiology of patients with HSAN followed in a Canadian tertiary paediatric centre, including suggestions for their monitoring, management, and long-term follow-up. A retrospective chart review of all patients with HSAN followed from the years 2000 through 2021 was performed. Collected data consisted of patients' demographics, clinical characteristics, imaging, and management. Eight patients were included. The average age at diagnosis was 3.19 ± 2.83 years. Insensitivity to pain (100%), dysautonomia (100%), global development delay (87.5%), emesis (62.5%), and self-injury (62.5%) were the most prevalent manifestations of HSAN. The most common co-morbidities were gastroesophageal reflux disease (50%), obstructive sleep apnea (37.5%), attention-deficit hyperactivity disorder (37.5%), and iron deficiency (37.5%). Management was multi-disciplinary, involving neurologists, orthopeds, developmental paediatricians, sleep specialists, and psychiatrists. HSANs are a diverse group of diseases, characterized by profound distal sensory loss, acral mutilations, and variable autonomic disturbances. It is important to recognize the diagnosis in the paediatrician's office in order to set up surveillance and prevent complications.

Charcot-Marie-Tooth Disease and Implications on Corneal Refractive Surgery.

Charcot–Marie–Tooth (CMT) disease is the most common inherited polyneuropathy, with a characteristic phenotype of distal muscle weakness, atrophy, and sensory loss. Variable ocular involvement has been documented in patients with CMT, with optic atrophy as the most frequently reported symptom. Although the Charcot–Marie–Tooth Association has generally deemed laser-assisted in situ keratomileuses (LASIK) a safe option for patients with CMT, reports of corneal refractive surgery are lacking in this patient population. This commentary discusses the current understanding of CMT, including its ocular manifestations, and additional specific testing to consider when evaluating these patients for corneal refractive surgery.

082 A rare mimic of inflammatory myopathy

A 37 year-old female presented with 5-weeks of neck pain, proximal weakness and dysphonia. Exami- nation showed facial rash, proximal weakness, areflexia and distal sensory loss. She had a 6-year history of sensory neuropathy, treated functional B12 deficiency and fibromyalgia. Serum showed elevated CK (360U/L) and borderline positive Anti-Ro52. Electrophysiology showed worsening sensory neuropathy and new myopathic features. She deteriorated soon after receiving intravenous corticosteroids and immu- noglobulins. CK increased to 1796 U/L and she developed bulbar failure requiring respiratory support.Muscle biopsy electron microscopy showed lipid accumulation suggesting a metabolic disorder. Serum acylcarnitines and urinary organic acids were abnormal, consistent with Riboflavin Transporter Deficiency (RTD). Riboflavin 500mg three times daily was initiated, urinary organic acids normalised and the patient regained full-power with neurorehabilitation.RTD is a rare cause of peripheral and cranial neuropathy, with autosomal recessive inheritance due to variants in riboflavin transporter genes and onset up to young adulthood. Mutation carrier frequencies should generate 70 new cases per year worldwide, though only ~80 case-reports exist in the literature suggesting under-recognition. Riboflavin is a precursor for coenzymes important for carbohydrate, amino acid and lipid metabolism. Untreated, the disorder is fatal, though the majority of patients improve with Riboflavin supplementation.elena.purcaru@gmail.com

Effectiveness of Ayurveda in Organophosphorus poisoning w.s.r. to Organophosphate-induced delayed polyneuropathy – A case Report.

Organophosphate (OP) compound poisoning is a major problem in a developing country like India mostly in rural areas. Organophosphorus pesticide inhibits acetylcholinesterase at nerve synapses. In the current case, 36-years patient was diagnosed with Organophosphate-induced delayed polyneuropathy (OPIDP) had a history of suicide attempts complaining of severe weakness, pain, and tingling sensation in Bilateral upper and lower limb after 15 days. Organophosphate-induced delayed polyneuropathy (OPIDP) develops after several weeks from exposure it is characterized by distal weakness and sensory loss which can be progressive. In Ayurveda the case was diagnosed and treated on the bases of Vishajanaya Vatavyadhi (Diseased induced by Poisoning) under the Umbrella of Urustambha. It was categorized in different stages of the disease and was treated accordingly with the help of different ayurvedic medications and Procedures for 9 follow-ups for 2 years.