Serial electrodiagnostic testing: Utility and indications in adult neurological disorders.

Although existing guidelines address electrodiagnostic (EDX) testing in identifying neuromuscular conditions, guidance regarding the uses and limitations of serial (or repeat) EDX testing is limited. By assessing neurophysiological change longitudinally across time, serial electrodiagnosis can clarify a diagnosis and potentially provide valuable prognostic information. This monograph presents four broad indications for serial electrodiagnosis in adult peripheral neurological disorders. First, where clinical change has raised suspicion for a new or ongoing lesion, EDX reassessment for spatial spread of abnormality, involvement of previously normal muscle or nerve, and/or evolving pathophysiology can clarify a diagnosis. Second, where diagnosis of a progressive neuromuscular condition is uncertain, electrophysiological data from a second time point can confirm or refute suspicion. Third, to establish prognosis after a static nerve injury, a repeat study can assess the presence and extent of reinnervation. Finally, faced with a limited initial study (as when complicated by patient or environmental factors), a repeat EDX study can supplement missing or limited data to provide needed clarity. Repeat EDX studies carry certain limitations, however, such as with prognostication in the setting of remote or chronic lesions, sensory predominant fascicular injury, or mild axonal injury. Nevertheless, serial electrodiagnosis remains a valuable and underused tool in the diagnostic and prognostic evaluation of neuromuscular conditions.

Intravenous immunoglobulin and plasma exchange prescribing patterns for Guillain-Barre Syndrome in the United States-2001 to 2018.

INTRODUCTION/AIMS: Randomized controlled trials show that repeat intravenous immunoglobulin (IVIG) dosing and plasma exchange (PLEX) followed by IVIG (combination therapy) have no additional therapeutic benefit in Guillain-Barre Syndrome (GBS) non-responders. Furthermore, the delineation between GBS and Acute Onset CIDP (A-CIDP) can be particularly challenging and carries therapeutic implications. We aimed to evaluate the presence of repeat IVIG, combination therapy, and diagnostic reclassification from GBS to CIDP. METHODS: We performed a retrospective study of a large healthcare database for patients with GBS in the US from 2001 to 2018. We identified individuals initially diagnosed with GBS and later re-classified as CIDP. Multivariable logistic regression models were developed to determine associations between patient factors and repeat IVIG dosing, combination therapy, and diagnostic re-classification from GBS to CIDP. RESULTS: We identified 2325 patients with GBS. A total of 39.7% received repeat IVIG and 6.1% received combination therapy. The proportion of individuals initially diagnosed with GBS and then re-classified as CIDP was 32.0%. Repeat IVIG, combination therapy, and diagnostic reclassification remained stable over time. Female sex (OR 0.79, 95% CI 0.65-0.96) and medium-high net worth (OR 0.64, 95% CI 0.45-0.90) associated with repeat IVIG therapy, while Asian ethnicity associated with diagnostic re-classification from GBS to CIDP (OR 1.77, 95% CI 1.09-2.86). DISCUSSION: Repeat IVIG dosing was quite common in GBS before newer trials suggesting harm in non-responders, and IVIG/PLEX combination therapy continues to persist despite strong evidence against use in non-responders. Further, nearly one in three patients initially diagnosed with GBS is subsequently diagnosed with CIDP, but the reasons are unclear.

Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Top 10 Clinical Pearls in Paraproteinemic Neuropathies.

Paraproteinemic neuropathies represent an important subset of peripheral neuropathies. Once identified, further evaluation into the paraproteinemic subtype, clinical exam pattern, and electrodiagnostic phenotype helps clarify if the paraproteinemia is coincidental or causal of the neuropathy, as not all paraproteinemias cause neuropathy. Of all paraproteinemias, immunoglobulin M (IgM)-associated peripheral neuropathy, or IgM neuropathy, is of particular importance as half of IgM neuropathies also harbor anti-myelin-associated glycoprotein antibodies, which produce a characteristic demyelinating pattern on nerve conduction testing. Immunoglobulin G and immunoglobulin A paraproteinemias are less strongly associated with peripheral neuropathy, except in the setting of multiple myeloma or osteosclerotic myeloma (POEMS syndrome), which have characteristic systemic features. In multiple myeloma, chemotherapy is more likely to result in neuropathy than the myeloma itself. Finally, the presence of systemic features (e.g., cardiomyopathy, nephropathy, recurrent carpal tunnel syndrome, and autonomic insufficiency) should raise concern for hereditary or acquired light (AL) chain amyloidosis. AL amyloidosis can occur in the setting of any light or heavy chain paraproteinemia. Central to the proper evaluation of paraproteinemic neuropathy is electrodiagnostic testing, which helps delineate axonal versus demyelinating paraproteinemic neuropathy, the latter often misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy.

Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients.

BACKGROUND AND AIMS: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. METHODS: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein-protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. RESULTS: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini-Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini-Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. INTERPRETATION: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.

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.

Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic is responsible for 267 million infections and over 5 million deaths globally. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA beta-coronavirus, which causes a systemic inflammatory response, multi-organ damage, and respiratory failure requiring intubation in serious cases. SARS-CoV-2 can also trigger neurological conditions and syndromes, which can be long-lasting and potentially irreversible. Since COVID-19 infections continue to mount, the burden of SARS-CoV-2-induced neurologic sequalae will rise in parallel. Therefore, understanding the spectrum of neurological clinical presentations in SARS-CoV-2 is needed to manage COVID-19 patients, facilitate diagnosis, and expedite earlier treatment to improve outcomes. Furthermore, a deeper knowledge of the neurological SARS-CoV-2 pathomechanisms could uncover potential therapeutic targets to prevent or mitigate neurologic damage secondary to COVID-19 infection. Evidence indicates a multifaceted pathology involving viral neurotropism and direct neuroinvasion along with cytokine storm and neuroinflammation leading to nerve injury. Importantly, pathological processes in neural tissue are non-cell autonomous and occur through a concerted breakdown in neuron-glia homeostasis, spanning neuron axonal damage, astrogliosis, microgliosis, and impaired neuron-glia communication. A clearer mechanistic and molecular picture of neurological pathology in SARS-CoV-2 may lead to effective therapies that prevent or mitigate neural damage in patients contracting and developing severe COVID-19 infection.

Autonomic neuropathies.

Autonomic neuropathies represent a complex group of disorders that preferentially target autonomic fibers and can be classified as either acute/subacute or chronic in onset. Acute-onset autonomic neuropathies manifest with such conditions as paraneoplastic syndromes, Guillain-Barre syndrome, Sjögren syndrome, infection, or toxins/chemotherapy. When the presentation is acute, immune-mediated, and without a secondary cause, autoimmune autonomic ganglionopathy is likely, and should be considered for immunotherapy. Of the chronic-onset forms, diabetes is the most widespread and disabling, with autonomic impairment portending increased mortality and cardiac wall remodeling risk. Acquired light chain (AL) and transthyretin (TTR) amyloidosis represent two other key etiologies, with TTR amyloidosis now amenable to newly-approved gene-modifying therapies. The COMPASS-31 questionnaire is a validated outcome measure that can be used to monitor autonomic severity and track treatment response. Symptomatic treatments targeting orthostatic hypotension, among other symptoms, should be individualized and complement disease-modifying therapy, when possible.

Metabolic syndrome and peripheral neuropathy.

Diabetic peripheral neuropathy and metabolic syndrome (MetS) are both global health challenges with well-established diagnostic criteria and significant impacts on quality of life. Clinical observations, epidemiologic evidence, and animal models of disease have strongly suggested MetS is associated with an elevated risk for cryptogenic sensory peripheral neuropathy (CSPN). MetS neuropathy preferentially affects small unmyelinated axons early in its course, and it may also affect autonomic and large fibers. CSPN risk is linked to MetS and several of its components including obesity, dyslipidemia, and prediabetes. MetS also increases neuropathy risk in patients with established type 1 and type 2 diabetes. In this review we present animal data regarding the role of inflammation and dyslipidemia in MetS neuropathy pathogenesis. Several studies suggest exercise-based lifestyle modification is a promising treatment approach for MetS neuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy-Diagnostic pitfalls and treatment approach.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patients' ability to walk and perform activities of daily living independently. With the lack of a diagnostic biomarker, the diagnosis relies on clinical suspicion, clinical findings, and the demonstration of demyelinating changes on electrodiagnostic (EDx) testing and nerve pathology. As a result, patients can often be misdiagnosed with CIDP and unnecessarily treated with immunotherapy. Interpreting the EDx testing and cerebrospinal fluid findings in light of the clinical phenotype, recognizing atypical forms of CIDP, and screening for CIDP mimickers are the mainstays of the approach to patients suspected of having CIDP, and are detailed in this review. We also review the currently available treatment options, including intravenous immunoglobulin (IVIg), corticosteroids (CCS), and plasma exchange (PE), and discuss how to approach treatment-refractory cases. Finally, we emphasize the need to adopt objective outcome measures to monitor treatment response.

Patients who meet electrodiagnostic criteria for CIDP rarely present with a sensory predominant DSP phenotype.

INTRODUCTION: It is unknown how often patients with electrodiagnostic evidence of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a potentially treatable condition, present with a distal symmetric polyneuropathy (DSP) phenotype. METHODS: We reviewed the records of patients who presented to our electrodiagnostic laboratory between January 1, 2011, to December 31, 2019, and fulfilled electrodiagnostic criteria for CIDP to identify those who presented with a sensory predominant DSP phenotype. RESULTS: One hundred sixty-two patients had a chronic acquired demyelinating neuropathy, of whom 138 met criteria for typical or atypical CIDP. Nine of these patients presented with a sensory predominant DSP phenotype, among whom six were eventually diagnosed with distal acquired demyelinating symmetric (DADS) neuropathy; one with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes (POEMS) syndrome; and two with idiopathic DSP. The prevalence of acquired chronic demyelinating neuropathies among all patients presenting with a DSP phenotype was estimated to be 0.34%. DISCUSSION: Patients who meet electrodiagnostic criteria for CIDP rarely present with a sensory predominant DSP phenotype, and electrodiagnostic testing rarely identifies treatable demyelinating neuropathies in patients who present with a DSP phenotype.

Evolving concepts on the role of dyslipidemia, bioenergetics, and inflammation in the pathogenesis and treatment of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most widespread and disabling neurological conditions, accounting for half of all neuropathy cases worldwide. Despite its high prevalence, no approved disease modifying therapies exist. There is now a growing body of evidence that DPN secondary to type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) represents different disease processes, with T2DM DPN best understood within the context of metabolic syndrome rather than hyperglycemia. In this review, we highlight currently understood mechanisms of DPN, along with their corresponding potential therapeutic targets. We frame this discussion within a practical overview of how the field evolved from initial human observations to murine pathomechanistic and therapeutic models into ongoing and human clinical trials, with particular emphasis on T2DM DPN and metabolic syndrome.

Foot measures in patients with pes cavus with and without charcot-marie-tooth disease: A pilot study.

INTRODUCTION: Pes cavus often signals the presence of Charcot-Marie-Tooth (CMT) in adult patients, although its prevalence in the general population makes it a finding of unclear significance. METHODS: We undertook a pilot double cohort study to investigate the feasibility of comparing preselected bedside and radiographic foot measures in pes cavus patients with and without CMT. RESULTS: A total of 16 CMT and 11 non-CMT patients were recruited. Although no findings consistently met statistical significance, recruitment was highly limiting. CONCLUSIONS: Formalized foot measurement comparisons of CMT and non-CMT pes cavus are feasible. Larger studies will be necessary to determine if there are differences in foot structure based on the presence of a hereditary neuropathy. Muscle Nerve 59:122-125, 2019.

Fibromyalgia syndrome and small fiber, early or mild sensory polyneuropathy.

INTRODUCTION: Pain mechanisms in fibromyalgia syndrome (FMS) are not clearly understood. Growing evidence appears to suggest a role for small fiber polyneuropathy (SFPN) in some FMS patients, as measured by epidermal nerve fiber density (ENFD). We aimed to better characterize and distinguish the subset of patients with both fibromyalgia and small fiber, early or mild sensory polyneuropathy (FM-SFSPN). METHODS: 155 FMS patients with neuropathic symptoms completed a Short Form McGill Questionnaire and visual analog scale in addition to having skin biopsies, nerve conduction studies (NCS), and serologic testing. RESULTS: Sural and medial plantar (MP) response amplitudes correlated with ENFD, with markers of metabolic syndrome being more prevalent in this subset of patients. Pain intensity and quality did not distinguish patients. DISCUSSION: The FM-SFSPN subset of patients may be identified through sural and MP sensory NCS and/or skin biopsy but cannot be identified by pain features and intensity. Muscle Nerve 58: 625-630, 2018.

Infections and the relationship to treatment in neuromuscular autoimmunity.

INTRODUCTION: This study aimed to identify infections in patients with myasthenia gravis, dermatomyositis, and chronic inflammatory demyelinating polyradiculoneuropathy, and to investigate the relationship between infection and immunomodulation. METHODS: A retrospective chart review examined 631 patients with myasthenia gravis (n = 358), chronic inflammatory demyelinating polyradiculoneuropathy (n = 124), and dermatomyositis (n = 149) patients over a 10-year time period. RESULTS: Infection rates were similar at approximately 19% in all 3 diseases. Of the infections in which a causative organism was identified, pneumonia, sepsis, and opportunistic infections were the leading diagnoses. A multivariate model demonstrated a significant association between infection and an increased dose of plasma exchange, mycophenolate mofetil, and corticosteroid therapy. DISCUSSION: There are few large studies investigating rates of infections in patients with autoimmune neuromuscular disorders and the relationship to immunomodulation. This study not only demonstrates the remarkably similar infection rates across the 3 diseases studied, but also shows their relationship to commonly used immunotherapies. Muscle Nerve 57: 927-931, 2018.

Hypoglossal nerve palsy: 245 cases.

INTRODUCTION: Apart from a case series of 100 subjects in 1996 and several small cohorts, there have been no large retrospective series of cranial nerve XII (CN XII) palsy. METHODS: From 1984 to 2014, 245 cases of CN XII palsy were identified via retrospective chart review using historical and exam findings that confirmed the diagnosis. In addition to clinical characteristics, univariate and multivariate models were investigated to predict neoplastic CN XII palsy. RESULTS: Major etiologic categories included: postoperative (29.3%), idiopathic (15.1%), primary neoplastic (14.2%), metastatic malignancy (13.0%), inflammatory (7.3%), radiation (6.1%), and traumatic (4.1%). A multivariate model revealed male gender and a personal history of cancer as predictive of neoplastic CN XII palsy. CONCLUSIONS: The most frequent etiologies and disease categories of CN XII palsy were identified, and male gender and personal history of cancer were found to be predictive of a neoplastic cause of CN XII palsy. Muscle Nerve 54: 1050-1054, 2016.

Comparison of intraepidermal nerve fiber density and confocal corneal microscopy for neuropathy.

OBJECTIVE: Compare the diagnostic characteristics of intraepidermal nerve fiber density (IENFD) and confocal corneal microscopy (CCM) for distal symmetric polyneuropathy (DSP) and small fiber neuropathy (SFN). METHODS: Participants with obesity were recruited from bariatric surgery clinics and testing was performed prior to surgery. DSP and SFN were determined using the Toronto consensus definitions of probable neuropathy. IENFD was assessed from 3 mm punch biopsies of the distal leg and proximal thigh. CCM was performed on both eyes with manual and automated counting. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was also completed. Diagnostic capability was determined using areas under the receiver operating characteristics curve (AUC) from logistic regression. RESULTS: We enrolled 140 participants (mean [standard deviation [SD]] age: 50.3 years [7.1], 77.1% female, BMI: 44.4 kg/m2 [6.7]). In this population, 22.9% had DSP and 14.3% had SFN. Distal leg IENFD had the largest AUC (95% confidence interval) for DSP (0.78, 0.68-0.89) and SFN (0.85, 0.75-0.96). Proximal thigh IENFD (DSP: AUC: 0.59, 0.48-0.69, SFN: AUC: 0.59, 0.46-0.73) and CCM metrics (DSP: AUC range: 0.55-0.60, SFN: AUC range: 0.45-0.62) had poorer diagnostic capability than distal leg IENFD for DSP/SFN (P < 0.05). MNSIq had similar diagnostic capability to distal leg IENFD for both DSP/SFN (DSP: AUC: 0.76, 0.68-0.85, SFN: AUC: 0.81, 0.73-0.88). More participants (52%) preferred skin biopsies to CCM. INTERPRETATION: Distal leg IENFD was the best quantitative measure of DSP/SFN. CCM had poor diagnostic characteristics and fewer patients preferred this test to IENFD. The MNSIq had similar diagnostic characteristics to distal leg IENFD, indicating its value as a diagnostic tool in the clinical setting. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT03617185.

Defining postoperative C5 palsy and recovery: a systematic review.

OBJECTIVE: Postoperative C5 palsy (C5P) is a well-recognized and often-delayed complication of cervical spine surgery. Most patients recover within 6 months of onset, but the prognosis of severe cases is poor. The clinical significance and natural history of mild versus severe C5P appear to differ substantially, but palsy severity and recovery have been poorly characterized in the literature. METHODS: Owing to the varying prognoses and expanding treatment options such as nerve transfer surgery to reconstruct the C5 myotome, this systematic review attempted to describe how C5P severity is classified and how C5P and its recovery are defined, with the aim of proposing a postoperative C5P scale to support clinical decision-making. PubMed was searched for articles in English published since 2000 that offer a clear definition of postoperative C5P or its recovery. Only articles reporting exclusively on C5 palsy for patients undergoing surgery for degenerative disease were included. A single reviewer screened titles and abstracts and reviewed the full text of relevant articles, with consultation as needed from a second reviewer. Data collected included postoperative C5P definitions, classification of C5P severity, and definition and/or classification of C5P recovery. Qualitative analysis was performed. RESULTS: Full-text reviews were conducted of 98 of 272 articles identified and screened, and 43 met the inclusion criteria. Postoperative C5P was most commonly defined as a reduction in deltoid muscle strength by ≥ 1 grade using manual muscle testing (MMT), with potential biceps involvement also noted by some studies. The few studies that stratified C5P on the basis of severity unanimously characterized severe C5P as MMT grade ≤ 2. Nine studies reported on C5P recovery. Deltoid muscle strength improvement of MMT grade 5 commonly defined complete recovery, with no MMT improvement considered partial recovery. CONCLUSIONS: This review identified clear discrepancies in the definitions of C5P and its recovery, leading to heterogeneity in its evaluation and management. With the emergence of therapeutic procedures for severe C5P, standardization of the definitions of C5P and its recovery is critical. The authors propose MMT grades of 4, 3, and ≤ 2 to classify C5P as mild, moderate, and severe, respectively, and grades of 5, 4, and 3 to classify recovery as complete, sufficient, and useful, respectively.

Safety and Efficacy of Topiramate in Individuals With Cryptogenic Sensory Peripheral Neuropathy With Metabolic Syndrome: The TopCSPN Randomized Clinical Trial.

Importance: Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase neuropathy risk. Diet and exercise have shown promise but are limited by poor adherence. Objective: To determine whether topiramate can slow decline in intraepidermal nerve fiber density (IENFD) and/or neuropathy-specific quality of life measured using the Norfolk Quality of Life-Diabetic Neuropathy (NQOL-DN) scale. Design, Setting, and Participants: Topiramate as a Disease-Modifying Therapy for CSPN (TopCSPN) was a double-blind, placebo-controlled, randomized clinical trial conducted between February 2018 and October 2021. TopCSPN was performed at 20 sites in the National Institutes of Health-funded Network for Excellence in Neurosciences Clinical Trials (NeuroNEXT). Individuals with CSPN and metabolic syndrome aged 18 to 80 years were screened and randomly assigned by body mass index (<30 vs ≥30), which is calculated as weight in kilograms divided by height in meters squared. Patients were excluded if they had poorly controlled diabetes, prior topiramate treatment, recurrent nephrolithiasis, type 1 diabetes, use of insulin within 3 months before screening, history of foot ulceration, planned bariatric surgery, history of alcohol or drug overuse in the 2 years before screening, family history of a hereditary neuropathy, or an alternative neuropathy cause. Interventions: Participants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day. Main Outcomes and Measures: IENFD and NQOL-DN score were co-primary outcome measures. A positive study was defined as efficacy in both or efficacy in one and noninferiority in the other. Results: A total of 211 individuals were screened, and 132 were randomly assigned to treatment groups: 66 in the topiramate group and 66 in the placebo group. Age and sex were similar between groups (topiramate: mean [SD] age, 61 (10) years; 38 male [58%]; placebo: mean [SD] age, 62 (11) years; 44 male [67%]). The difference in change in IENFD and NQOL-DN score was noninferior but not superior in the intention-to-treat (ITT) analysis (IENFD, 0.21 fibers/mm per year; 95% CI, -0.43 to ∞ fibers/mm per year and NQOL-DN score, -1.52 points per year; 95% CI, -∞ to 1.19 points per year). A per-protocol analysis excluding noncompliant participants based on serum topiramate levels and those with major protocol deviations demonstrated superiority in NQOL-DN score (-3.69 points per year; 95% CI, -∞ to -0.73 points per year). Patients treated with topiramate had a mean (SD) annual change in IENFD of 0.56 fibers/mm per year relative to placebo (95% CI, -0.21 to ∞ fibers/mm per year). Although IENFD was stable in the topiramate group compared with a decline consistent with expected natural history, this difference did not demonstrate superiority. Conclusion and Relevance: Topiramate did not slow IENFD decline or affect NQOL-DN score in the primary ITT analysis. Some participants were intolerant of topiramate. NQOL-DN score was superior among those compliant based on serum levels and without major protocol deviations. Trial Registration: ClinicalTrials.gov Identifier: NCT02878798.