Small fiber neuropathy associated with ANCA positivity: a case series and brief literature review.

INTRODUCTION: Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of immune-mediated small fiber neuropathy are driven by vasculitis, though antinuclear cytoplasmic antibodies [ANCA] antibodies have not commonly been reported in association with SFN, thus far. We present this case series to discuss the observation of a possible novel association between ANCA and SFN. METHODS: This is a retrospective case series of 6 patients with SFN and ANCA positivity, with and without systemic manifestations. Patients included were diagnosed with SFN by skin biopsy or autonomic function testing and were seropositive for ANCA by ELISA. RESULTS: Six patients are outlined, including 4 females and 2 males. Antigen specific antibodies were MPO alone in 4 cases, PR3 alone in 1 case and both MPO and PR3 in 1 case. Systemic vasculitis was noted in 2 patients. Five patients received immunosuppression. Three patients experienced partial improvement, while symptoms stabilized in 3 patients. DISCUSSION: This is the first series of patients with suspected immune-mediated SFN and ANCA antibody positivity, raising the possibility of ANCA mediated isolated SFN. This is in contradistinction to the more typical ANCA-mediated peripheral neuropathy manifestations of mononeuropathy multiplex or axonal sensorimotor neuropathy. We cannot unequivocally prove ANCA-associated vasculitis [AAV] causality in these cases; however, the stabilization in SFN symptomatology and associated improvement in ANCA antibody titer, after AAV treatment, may be indicative of an association.

Peripheral Neuropathies in Infectious Diseases.

Peripheral nerve disorders may be the presenting manifestation of a systemic infection, and early recognition of these syndromes is essential for prompt diagnosis and treatment. Mechanisms associated with infectious disorders of the peripheral nerve are often complex and multiple, with secondary inflammation, direct infectious invasion of nerves, and toxicities of antimicrobial medications playing a role. Here, we provide a complete review of the most common infectious pathogens that can affect the peripheral nerves.

Clinical, electrophysiologic, and imaging features of zoster-associated limb paresis.

INTRODUCTION: Paresis is a long-recognized complication of herpes zoster, but there has been comparatively little study of zoster-associated limb paresis (ZALP). METHODS: In this study we reviewed 49 Mayo Clinic patients with ZALP. RESULTS: The mean age of onset was 71 years, 67% were men, and the lower limb was affected in 55%. The mean weakness score was 2.0 (0 = normal strength, 4 = plegia). Most patients developed postherpetic neuralgia (PHN, 92% at 1 month and 65% at 3 months), and the average minimum duration of weakness was 193 days. ZALP was caused by radiculopathy (37%), plexopathy (41%), mononeuropathy (14%), and radiculoplexus neuropathy (8%). MRI demonstrated nerve enlargement, T2 signal prolongation, or enhancement in a majority (64%) of affected plexi and peripheral nerves. CONCLUSIONS: ZALP is associated with considerable weakness. It typically lasts at least several months, localizes to plexus or peripheral nerve in 63%, and is associated with high rates of PHN.

Peripheral neuropathies of rheumatologic disease and gluten-related disorders.

Peripheral nervous system disease is a common and often debilitating feature of many systemic rheumatologic disorders. Such involvement takes many forms, reflecting the variety of underlying pathophysiology, though most patients present with painful multifocal neuropathy (usually vasculitic) or a distal sensory more than motor peripheral neuropathy (sometimes vasculitic and nearly always axonal). The presence of peripheral nervous system involvement is often an early signal of the generalization of inflammatory disease in blood vessels or extravascular tissues, though peripheral neuropathy is not itself an independent predictor of mortality. Nonetheless, progressive multifocal neuropathy, motor neuropathy, small fiber neuropathy, and sensory neuronopathy should be treated early and aggressively with immunosuppression (or the gluten-free diet in appropriate situations) to limit morbidity. Given the rapidly evolving therapeutic landscape, partnership with a rheumatologist is essential. Treatment is usually sustained for 1 to 2 years, and remission is possible in many cases within 6 to 12 months, with variable rates of relapse and treatment resistance. Patients should be meticulously monitored for relapse with serial laboratory testing, electrodiagnostic studies, and clinical examination. Functional rating scores, such as the neuropathy impairment scale and the total neuropathy score are useful for longitudinal assessment.

Symmetric leukoencephalopathy associated with systemic lupus erythematosus: A systematic review of a distinctive neurorheumatologic syndrome.

BACKGROUND: A symmetric leukoencephalopathy can occur in the context of systemic lupus erythematosus (SLE), often as a first manifestation of underlying rheumatologic disease. Recognition of this distinctive syndrome can prompt investigation for SLE when undiagnosed, or prompt treatment initiation when the diagnosis is already known. Earlier recognition of this syndrome could lead to more effective treatment of the disease. METHODS: Clinical, laboratory, and radiographic features of three patients were described from an academic medical center in the United States with treatment dates between 2015 and 2022. A systematic review of literature from 1991 to 2023 yielded data for an additional 23 patients. RESULTS: Twenty-six total patients with symmetric leukoencephalopathy were included in this study. The median age of the patients was 37 years (range 10-69), 22 patients (85 %) were female, and 4 (15 %) were male. Fourteen of 26 patients (54 %) had this as the first clinical manifestation of SLE. Contrast enhancement was present on MRI brain in 3/26 (88 %) patients. Twenty patients (77 %) were treated with pulse-dose steroids, and all but one patient received some immunomodulatory therapy. Seven patients (27 %) progressed to death. No meaningful predictive differences were found between patients who survived and those who did not. CONCLUSIONS: In this case series and literature review patients developed symmetric leukoencephalopathy in systemic lupus erythematosus most often as the first clinical manifestation of SLE. Clinicians should consider this syndrome in any patient with acute onset of symmetric leukoencephalopathy on brain magnetic resonance imaging.

Neurologic Complications of Endocrine Disorders.

OBJECTIVE: This article provides an overview of the neurologic complications of the most prevalent endocrine disorders in adults with an emphasis on relevant neurologic symptoms, signs, and laboratory and neuroimaging findings. LATEST DEVELOPMENTS: Although the mechanisms of many of the neurologic complications discussed here remain unclear, our understanding of the impacts of diabetes and hypothyroidism on the nervous system and muscle, including complications of rapid correction of chronic hyperglycemia, has advanced in recent years. Recent large studies have not demonstrated a convincing association between subclinical or overt hypothyroidism and cognitive decline. ESSENTIAL POINTS: Neurologists must become familiar with the neurologic complications of endocrine disorders not only because they are common and treatable (and often reversible) but also because they may be iatrogenic, as is the case with adrenal insufficiency in the setting of long-term corticosteroid therapy.

Zoster-associated mononeuropathies (ZAMs): a retrospective series.

INTRODUCTION: Zoster-associated limb paresis is an uncommon complication of herpes zoster (HZ) and one whose precise pathophysiologic mechanism is poorly understood. Occasionally, the paresis results from a zoster-associated mononeuropathy (ZAM). METHODS: Mayo Clinic records between 1996 and 2010 were reviewed for patients with ZAM whose clinical, electrophysiologic, and radiographic features were then abstracted. RESULTS: Ulnar (2), median (3), femoral (1), and sciatic (2) mononeuropathies were identified. Most patients had moderate to severe weakness in affected muscles, and most had post-herpetic neuralgia (88% at 1 month and 71% at 4 months). The minimum duration of weakness was prolonged (mean, 281.9 days; range, 45-1242 days). Nerve magnetic resonance imaging (MRI) was abnormal, demonstrating nerve enlargement (4/4 cases), T2 signal hypertintensity (2/4 cases), or enhancement (1/4 cases). CONCLUSIONS: While ZAM is an uncommon occurrence following cutaneous HZ, it is associated with significant weakness, high rates of post-herpetic neuralgia, and prolonged morbidity.

Adalimumab for CNS sarcoidosis: single-center experience and literature review.

BACKGROUND: Tumor necrosis factor (TNF) alpha is critical in the development of granulomas and multiple recent reports have highlighted the role of infliximab, an infused TNF alpha inhibitor, in the treatment of neurosarcoidosis. As a self-injected TNF alpha inhibitor, adalimumab has certain advantages over infused medications, including greater patient freedom and autonomy. Experience with adalimumab is not well reported in the literature. OBJECTIVE: To report clinical experience with adalimumab in the treatment of central nervous system (CNS) sarcoidosis by combining observations in our center with those that have been reported in the literature. METHODS: Patients were identified from the Mass General Brigham Research Patient Data Registry and in the literature by searching PubMed. Patients with CNS manifestations of sarcoidosis treated with adalimumab were included for retrospective review and analyzed for baseline characteristics, treatment indications, outcomes, and adverse effects. RESULTS: Adalimumab was commonly started after failure of or intolerance to infliximab and methotrexate. Of those with adequate follow-up, 5/10 ultimately improved, remission was maintained in 3/10, and 2/10 with active disease remained stable without further worsening. One patient suffered a relapse, likely multifactorial in etiology, but has remained relapse free on adalimumab for 10 months subsequently. Three patients ultimately discontinued adalimumab. CONCLUSIONS: Preliminary evidence suggests that adalimumab may be a reasonable therapeutic option for patients with neurosarcoidosis affecting the CNS, including those with medically refractory disease.

A case of sensory ataxia as the presenting manifestation of neurosarcoidosis.

Sarcoidosis rarely selectively affects the cauda equina with characteristic motor and sensory impairments.Using imaging, we report a case of cauda equina polyradiculopathy presenting with progressive sensory ataxia without clinical or electrophysiological evidence of motor involvement. Neurosarcoidosis was diagnosed pathologically by proximal dorsal root biopsy after systemic investigations for inflammatory, infectious, and neoplastic etiologies were found to be negative. There was clinical and radiographic improvement with corticosteroids. In addition, we review previously reported cases of cauda equina sarcoidosis.

Spinal Decompression Sickness in an Experienced Scuba Diver: A Case Report and Review of Literature.

Decompression sickness from diving is a rare but potentially reversible cause of spinal injury. Early treatment with hyperbaric oxygen is associated with a better neurologic outcome, making prompt recognition and management clinically important. We describe a case of a 65-year-old diver who presented with thoracic back pain and bilateral leg weakness after a 70 feet of sea water (fsw) (21 meters of sea water [msw]) dive, with no acute abnormality on spinal magnetic resonance imaging (MRI). He made a partial recovery after extended hyperbaric oxygen therapy. We discuss the epidemiology and pathophysiology of central nervous system injury in decompression sickness, as well as acute management and prognostic factors for recovery, including the role of adjunctive therapies and the implications of negative MRI. Ultimately, clinicians should make the diagnosis of spinal cord decompression sickness based primarily on clinical evaluation, not on MRI findings.

Safety, tolerability, pharmacokinetics, and effects on human experimental pain of the selective ionotropic glutamate receptor 5 (iGluR5) antagonist LY545694 in healthy volunteers.

The objective of this study was to establish in healthy volunteers the maximally tolerated multiple dose (MTMD) of the ionotropic glutamate receptor 5 antagonist LY545694 (part A), and to investigate whether that dose had analgesic or antihyperalgesic effects in the brief thermal stimulation (BTS) pain model (Part B). Part A was a double-blind, placebo-controlled study in 3 groups of 10 healthy men. To simulate an extended-release formulation, study drug was administered orally over 6hours (12 equally divided aliquots at 30-minute intervals). Part B was a double-blind, placebo-controlled, double-dummy, 3-way crossover study in 27 healthy men. At each of the 3 study periods, subjects received either LY545694 (MTMD; as determined during part A) as a simulated, twice daily extended-release formulation for 4 doses over 3days, gabapentin (600mg 8hours apart; 6 doses over 3days; positive control), or matching placebo. The BTS model was induced twice with a 1-hour interval on each of the 2 study days, before drug administration and at the time of expected peak analgesia of LY545694. Plasma exposure for LY545694 was approximately linear over the 25- to 75-mg dose range. The MTMD of LY545694 was 25mg twice daily. Areas of secondary hyperalgesia were significantly smaller after administration of LY545694 and gabapentin compared with placebo (P<.0001 and P=.0004, respectively), but there was no difference between areas after administration of gabapentin and LY545694 (P=.400). Neither gabapentin nor LY545694 reduced the painfulness of skin heating during BTS model induction. The most common treatment-emergent adverse event was dizziness. The results of this study suggest that LY545694 should be explored further as a potential treatment for chronic pain involving neuronal sensitization.

Natural history of herpes zoster: late follow-up of 3.9 years (n=43) and 7.7 years (n=10).

Postherpetic neuralgia (PHN) is a common complication after herpes zoster (HZ). Subjects who completed a longitudinal observational 6-month study (4 visits) of the natural history of HZ were recontacted for 2 additional follow-up visits that included pain and sensory symptom assessment, quantitative sensory testing, capsaicin response test, and 3-mm punch skin biopsies in HZ-affected, mirror-image, and control skin sites. Forty-three subjects (14 with PHN at 6 months) of the original 94 subjects in the cohort were comprehensively assessed at a median 3.9 years after HZ onset (visit 5), and 10 subjects underwent a final assessment at a median 7.7 years after HZ onset (visit 6). At 3.9 years, none of the 29 subjects who had been pain free at 6 months had a recurrence of pain. Only 2 of the 14 subjects with PHN at 6 months still had pain at 3.9 years. One subject with PHN at 6 months was free of symptoms at 3.9 years but had very mild pain at 7.7 years. Sensory function continued on a path toward normalization, but was still abnormal in many subjects, especially those who met criteria for PHN at 6 months. Even at 7.7 years, reinnervation of HZ-affected skin was not apparent.

Standardized sign-out improves completeness and perceived accuracy of inpatient neurology handoffs.

OBJECTIVES: As residency programs adjust to new duty hour restrictions, the use of cross-coverage systems requiring handoffs will rise. Handoffs are vulnerable to communication failures when unstructured. Accordingly, we implemented a standardized sign-out process on our inpatient neurology services and assessed its effect on completeness and perceived accuracy of handoffs. METHODS: Residents spent the first half of their rotations utilizing unstructured sign-out. They transitioned to a structured sign-out system (using the situation-background-assessment-recommendation format) during the second half of their rotations. We analyzed survey responses before and after implementation to evaluate for an effect. RESULTS: Residents utilizing structured sign-out were significantly more likely to share test results with patients/families prior to shift changes (p = 0.037), update our electronic service list (p = 0.045), and feel all important data were being transmitted (p = 0.041). Overall satisfaction (scale 1-10) increased from 6.2 ± 1.6 to 7.4 ± 1.3 (p = 0.002). CONCLUSIONS: Our findings demonstrate that standardized sign-out improves the completeness and perceived accuracy of handoffs. Such improvement has the potential to improve patient safety and quality of care.

Effect of a single dose of pregabalin on herpes zoster pain.

BACKGROUND: The effect of pregabalin on acute herpes zoster pain has not been previously evaluated. METHODS: In a randomized, double-blind, placebo-controlled, two-session crossover study the effect of a single oral dose of pregabalin (150 mg) on pain and allodynia was evaluated in 8 subjects with herpes zoster. RESULTS: Over 6 hours of observation, pain decreased by a mean of 33% with pregabalin and 14% with placebo (p < 0.10). Effects on allodynia and SF-MPQ were not significant. CONCLUSIONS: Compared to an earlier study of gabapentin 900 mg for acute zoster pain and allodynia that followed a nearly identical protocol, pregabalin had a similar effect on pain and was well tolerated, with no difference from placebo on sleepiness. Common side effects of light-headedness, unsteady gait, and slowed thinking were almost identical to that observed in the earlier study of gabapentin. Subject recruitment proved difficult in part due to the widespread off-label use of gabapentin and pregabalin for acute zoster pain in our region of the USA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00352651.

Natural history of cutaneous innervation following herpes zoster.

As part of a comprehensive study of the natural history of herpes zoster (HZ), 57 of 94 subjects in a cohort at elevated risk for post-herpetic neuralgia (PHN) consented to collection of 3-mm skin punch biopsies from affected, mirror-image, and distant control skin at baseline and followup visits. As cutaneous innervation is reduced in longstanding severe PHN, we tested the hypothesis that development of PHN is correlated with severity of initial neural injury and/or a failure of neural recovery. Quantitative analysis using single-label PGP9.5 immunofluorescence microscopy showed epidermal profiles were reduced in zoster skin by approximately 40% at study entry compared to control and mirror skin. The density of the subepidermal plexus was approximately 15% lower in zoster skin. Mirror skin was not denervated compared to control skin. Although not significant at all visits, correlations between epidermal nerve fiber density in HZ skin and thermal sensation, allodynia, capsaicin response, and average daily pain all associated more severe abnormalities with lower epidermal innervation. There was limited evidence that the initial neural injury was more severe in the 15 eventual PHN subjects. Overall, pain and pain-related disability resolved the fastest. Sensory abnormalities and symptom aggravation by focal capsaicin application showed partial and selective recovery over 6months. In contrast, cutaneous innervation showed no recovery at all by 6months, conclusive evidence that resolution of pain and allodynia does not require cutaneous reinnervation. A much longer period of observation is needed to determine if zoster-affected skin is ever reinnervated.