Hypermobile Ehlers-Danlos Syndrome: Cerebrovascular, Autonomic and Neuropathic Features.

Corneal nerve loss measured by corneal confocal microscopy predicts pain severity in Parkinson's disease.

Alcohol use disorder-associated pain: clinical and preclinical evidence.

Treating sarcoidosis: when less is more.

The Diagnosis of Small Fiber Neuropathy Should Be Expanded and Standardized.

To assess ocular surface symptoms, corneal sensitivity (CS), and corneal confocal microscopy (CCM) findings in fibromyalgia (FMS) patients compared to healthy controls and to investigate the effect of oral serotonin-noradrenaline reuptake inhibitor (SNRI) treatment on these parameters. Newly diagnosed FMS patients (42 eyes) and healthy controls (50 eyes) were included in this prospective controlled study. 5-Item Dry Eye Questionnaire (DEQ-5), esthesiometry, and CCM were performed. Subbasal nerve plexus was analysed with ACCMetrics, and corneal nerve fibre density (CNFD), branch density (CNBD), fibre length (CNFL), and fractal dimension (CNFrD) were obtained. Dendritic cell (DC) density was measured with ImageJ. Microneuromas were manually counted. Tortuosity was graded using Oliveira-Soto scale. FMS patients received SNRI treatment for 6th months. All measurements were repeated at 3rd and 6th months of treatment. DEQ-5 score was higher in FMS at all follow-ups (p < 0.0001), and decreased with treatment (p < 0.0001). CS in FMS was lower (p = 0.002), with no change following treatment (p = 0.202). CNFL, CNFD, CNBD, and CNFrD values were lower in FMS (p<0.05), and reached the control level at the 3rd month (p>0.05). Tortuosity, microneuromas, and mature DC (mDC) in FMS were higher than control at baseline (p < 0.05). Following treatment, tortuosity in FMS remained higher than in the control (p < 0.05), while mDC and microneuromas showed no significant difference between the groups (p > 0.05). Ocular symptoms and corneal nerve pathologies were more common in FMS patients compared to healthy controls. Treatment of FMS with SNRIs provided promising outcomes by ameliorating symptoms and improving corneal nerve morphology.

Laser therapy has emerged as a promising modality for managing neuropathic pain and neuroinflammatory skin disorders. Its efficacy is attributed to its ability to modulate neuroimmune mechanisms, enhance microcirculation, and promote tissue repair. This review aims to provide a comprehensive analysis of laser therapy applications in conditions such as postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome, small fiber neuropathy, and inflammatory dermatoses with a neurogenic component, including atopic dermatitis and psoriasis. The paper includes an overview of mechanisms, laser types, clinical evidence, and treatment protocols, with a critical appraisal of existing literature.

Myofibrillar myopathy (MFM) is a pathologically defined but genetically heterogeneous myopathy; however, myofibrillar pathology may be absent in some patients with pathogenic variants in MFM-related genes. The natural history of MFM and myopathies associated with MFM-related genes remains poorly characterized. We retrospectively reviewed patients evaluated at Mayo Clinic (January 1993-March 2024) with either pathologically confirmed MFM or myopathies associated with MFM-related genes. Patients without genetic testing or skeletal muscular manifestations were excluded. Eighty patients were identified; 56 were genetically characterized (23 with DES, 10 with MYOT, 9 with LDB3, 2 with FLNC, 2 with BAG3, 2 with CRYAB, 1 with FHL1, and 7 others). Myofibrillar pathology was observed in 60 of 65 biopsied patients. The median age at symptom onset was 42.3 years (interquartile range [IQR] 20.2-57.0); 66 presented with muscular onset and 14 with cardiac onset. With a median disease duration of 13.1 years (IQR 8.1-24.0) from symptom onset to last visit, all patients had weakness, commonly distal-predominant (n = 34), followed by proximal-predominant (n = 24) and diffuse (n = 11) weakness. Dysphagia occurred in 16 patients, with 4 requiring feeding tubes. Peripheral neuropathy was found in 21 patients (13 with axonal large fiber neuropathy and 8 with small fiber neuropathy), mostly mild in severity. Gait aids were required in 46 patients (median 10.0 years after onset), and 17 became wheelchair-bound (median 19.0 years after onset). By age 60, 67% and 31% of patients with desminopathy required gait aids and were wheelchair-bound, respectively, compared with 12% and 0% of those with myotilinopathy and 25% and 0% of those with LDB3-related myopathy. Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset. Seven patients (2 with DES, 1 with ACTA1, 4 genetically uncharacterized) died, mainly due to cardiopulmonary complications. Patients with desminopathy exhibited earlier and higher rates of cardiac involvement (p < 0.001), more frequent respiratory involvement (p = 0.029), earlier gait aid dependence (p = 0.018) despite a similar age at ambulation loss (p = 0.418), lower prevalence of peripheral neuropathy (p = 0.022), and a similar mortality rate (p = 1.000). MFM and myopathies associated with MFM-related genes are clinically heterogeneous, with desminopathy showing earlier cardiac manifestations and gait aid requirement and more frequent cardiopulmonary involvement. Given the phenotypic variability, genetic diagnosis is crucial for patient management and prognosis.

To elucidate the features of plexin D1-immunoglobulin (Ig)G-associated neuropathic pain and its relationship to atopic myelitis (AM) in a nationwide Japanese survey. A preliminary survey questionnaire was sent to 1574 selected departments (neurology and pediatrics/pediatric neurology) to explore the numbers of AM and plexin D1-IgG-positive patients between 2018 and 2022. A secondary survey collected detailed patient data via a questionnaire. In the preliminary survey, 987 (62.7%) institutions responded, reporting 87 AM patients (49 women) and 11 plexin D1-IgG-positive non-AM patients (8 women). The secondary survey collected 71 AM (plexin D1-IgG-positive: 6/31) and 11 plexin D1-IgG-positive non-AM patients (83.7% recovery rate). In AM, paresthesia/dysesthesia was most frequently experienced (> 90%), followed by pain (> 70%). The underlying diseases in 17 plexin D1-IgG-positive patients, all of whom had neuropathic pain, were AM and small fiber neuropathy in 6 each, neuromyelitis optica spectrum disorder with aquaporin-4-IgG in 2, and painful trigeminal neuropathy, erythromelalgia, and multiple sclerosis in 1 each. When 14 plexin D1-IgG-positive patients (excluding 3 patients with established demyelinating diseases) were compared with 25 plexin D1-IgG-negative AM patients, onset ≥ 50 years old, pain at onset, and allodynia/erythromelalgia/facial pain during the entire disease course were significantly more common in the plexin D1-IgG-positive group. Conversely, atopic disorders and hyperIgEemia were associated with plexin D1-IgG-negative AM but not plexin D1-IgG-positive patients. Both AM and plexin D1-IgG-positive patients present long-standing neuropathic pain, whereas plexin D1-IgG is particularly associated with aged-onset neuropathic pain, allodynia, erythromelalgia, and facial pain, but not atopy.

A nociceptor excitability test for identifying alterations of the Nav1.7 channels in humans.

The clinical utility of serum neurofilament light chain (sNfL) in the evaluation and management of peripheral neuropathy (PN) remains poorly defined. This study aimed to evaluate the utility of sNfL for diagnosing PN, assessing disease activity, and monitoring treatment response using a commercially available assay. This was a retrospective cohort study at the University of Pennsylvania between June 2024 and March 2025. Patients with, or at risk for, PN who underwent sNfL testing were included. Demographics, PN etiology, clinical findings, and sNfL levels were analyzed. One hundred and twenty-eight patients were included: 41 with chronic inflammatory demyelinating polyneuropathy (CIDP), 36 with transthyretin amyloidosis (ATTR), 13 with vasculitic PN, 13 with Charcot-Marie-Tooth disease (CMT), 6 with multifocal motor neuropathy (MMN), 4 with anti-MAG neuropathy, 4 with Guillain-Barré syndrome (GBS), and 11 with other PN types. Of these, 113 had definite large fiber PN; 14 were asymptomatic TTRv carriers, and one had small fiber neuropathy. Elevated sNfL levels were observed in 31 patients (24%). The odds ratio of having elevated sNfL in treatable vs. non-treatable PN was 28.33 (95% CI: 5.04-159.18). Among CIDP and ATTRv-PN patients, sNfL was most often elevated in treatment-naïve or refractory cases and decreased with treatment. Routine sNfL testing is warranted in selected patients with PN, such as treatment-naïve or refractory CIDP, active vasculitic PN, and ATTRv-PN. Elevated sNfL in patients with PN should prompt evaluation for a potentially treatable cause and may offer useful adjunctive information to support clinical decision-making.

Sarcoidosis is a systemic granulomatous disorder of an unknown origin. Small fiber neuropathy is the most common neurological complication, and is considered to be the result of chronic inflammation It remains significantly understudied. We report a case of sarcoidosis revealed by chronic leg pain attributed to small fiber neuropathy.

Insulin resistance is increasingly recognized in type 1 diabetes as a risk factor for chronic complications and cardiovascular disease. Sudomotor dysfunction, reflecting small fiber neuropathy, can be assessed non-invasively by electrochemical skin conductance (ESC). This study evaluated the association between sudomotor function and insulin resistance in adults with type 1 diabetes. The study included 476 adults with type 1 diabetes (247 men), aged 42 (IQR: 33-53) years, with a disease duration of 24 (IQR: 19-32) years, and HbA1c level of 7.9 (IQR: 7.2-8.9)%. Sudomotor function was evaluated using the SUDOSCAN device. Insulin resistance was assessed using the estimated glucose disposal rate formula (eGDR), which is based on HbA1c, waist-to-hip ratio, and the presence of hypertension. The study group was subdivided into three groups based on tertiles of eGDR (<5.5, 5.5-9.5, >9.5 mg/kg/min). Participants with lower eGDR (lower insulin sensitivity) had lower feet ESC 71 (IQR: 50-81) vs 79 (IQR: 63-85) vs 83 (IQR: 74-86) μS; P < 0.0001. We found a positive correlation between feet ESC and eGDR (Rs = 0.28, P < 0.001). In a multiple linear regression model, feet ESC was independently associated with eGDR (β = 0.16, P = 0.001). Insulin resistance is associated with impaired sudomotor function in adults with type 1 diabetes.

Sarcoidosis is a systemic inflammatory disorder of unknown cause, mainly affecting the lungs and lymph nodes. Symptoms are diverse and range from dyspnea and cough to fatigue, cognitive impairment, and pain. An important cause of pain in patients with sarcoidosis is small fiber neuropathy (SFN), with an estimated prevalence of 33 to 86%. The underlying pathogenesis of SFN in sarcoidosis is not known. In sarcoidosis, symptoms related to SFN can be grouped into general symptoms (e.g., fatigue), sensory symptoms (e.g., pain and numbness), and autonomic symptoms (e.g., gastrointestinal dysmotility, palpitations, or sexual dysfunction). Presentation of SFN in patients with sarcoidosis is heterogeneous and can either be length-dependent or nonlength-dependent. The small fiber neuropathy screening list assesses the frequency and severity of symptoms suggestive of SFN. As a diagnostic gold standard is lacking for SFN, the diagnosis is made on different levels of certainty based on the presence of clinical signs, normal nerve conduction studies, and either abnormal quantitative sensory testing or decreased intraepidermal nerve fiber density on skin biopsy. Autonomic dysfunction in sarcoidosis is even more difficult to diagnose, often under-recognized, and may also have a negative impact on quality of life. At present, only symptomatic relief can sometimes be achieved. While treatment of sarcoidosis usually includes corticosteroids and other immunosuppressants, these drugs are not proven effective in alleviating SFN symptoms related to sarcoidosis. This review provides an overview of symptoms, available diagnostic tools, and treatment options specific to sarcoidosis-associated SFN and autonomic dysfunction.

Continuous glucose monitoring (CGM) has emerged as a complementary and more dynamic method for evaluating glycemic control in people with diabetes. Relevant studies examining the association between CGM parameters, including time in range (TIR), glycemic variability (GV), and time in tight range (TITR), and diabetic nephropathy, retinopathy, and neuropathy, were reviewed. Evidence consistently demonstrates that lower TIR and TITR, as well as higher GV, are associated with increased risk and severity of microvascular complications in both type 1 and type 2 diabetes. Studies employing corneal confocal microscopy and sudomotor function testing further support these associations for small-fibre neuropathy. Although CGM-guided therapy improves TIR and GV, data directly linking optimisation of these metrics to reduced complication rates remain limited. Most available studies are cross-sectional or retrospective, with short CGM durations and heterogeneous methodologies. CGM-derived indices provide valuable insights into glycemic quality beyond HbA1c and may serve as complementary tools for early risk stratification and individualised management of diabetic microvascular disease. However, prospective and interventional trials are required to confirm whether improving CGM metrics can translate into clinically meaningful reductions in microvascular morbidity. Broader access to CGM and standardisation of its key metrics will be essential to fully realise its potential in modern diabetes care.

Pain perception is a complex experience, the initiation of which is mediated, among others, by voltage-gated sodium channels. Pathogenic variants in the sodium channel gene SCN11A encoding for NaV1.9 have been associated with various pain loss and neuropathic pain conditions. We herein describe the novel heterozygous SCN11A variant c.197A>C; p.(Tyr66Ser) that is absent in controls and cosegregates with small fiber neuropathy in a mother-and-son duo. To a variable degree, but progressively over time, both patients developed positive and negative sensory symptoms and milder autonomic signs. Upon quantitative sensory testing, we found significant thermal hypoesthesia and pinprick hyperalgesia in both individuals. Rectangle, half-sine-, and sine-wave stimulation applied to hands and feet in both individuals revealed signs of axonal on/off-like hyperexcitability, possibly due to continuous activation of CMi-fibers that are insensitive to mechanical stimulation (also known as sleeping nociceptors). Nerve conduction studies were unremarkable, whereas pain-related evoked potentials showed pathological responses in both individuals. The intraepidermal nerve fiber density was reduced at the index patient's distal leg. Patch-clamp analyses revealed that p.(Tyr66Ser) shifted both the voltage dependence of activation and steady-state inactivation of NaV1.9 to more depolarized potentials, accompanied by accelerated deactivation and a slowdown of the channel's inactivation kinetics. In addition, overexpression of the variant in mouse sensory neurons shortened the duration of individual action potentials and enhanced action potentials after hyperpolarization. In this translational n-of-two study, we present longitudinal data on disease progression and provide functional evidence that the SCN11A variant p.(Tyr66Ser) is a strong candidate to contribute to the patients' phenotype.

Cognitive impairment in systemic autoimmune and inflammatory diseases: A narrative review focused on ANCA-associated vasculitis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and Behçet's disease.

Multidisciplinary strategies and new technologies in the management of sarcoidosis.

The role of small fiber neuropathy in female sexual dysfunction.

To investigate daytime autonomic dysregulation in patients with obstructive sleep apnea (OSA). This retrospective study was conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory and evaluated adult patients with a history of orthostatic intolerance and sleep disturbances who completed autonomic testing (deep breathing test, Valsalva maneuver, tilt test) and polysomnography between 2018 and 2024. The Quantitative Scale for Grading of Cardiovascular Autonomic Reflex Tests scoring instrument graded autonomic tests and skin biopsies for the assessment of small fibers. The apnea-hypopnea index was used to assess OSA severity. In total, 138 patients were evaluated in this study. Subjects with OSA (43 with mild and 29 with moderate/severe OSA) were compared with 66 subjects without OSA. Age, body mass index, and the prevalence of hypertension increased with the severity of sleep apnea. At least moderate autonomic failure was identified in 60% of patients without OSA and in 78% of those with OSA. Autonomic failure score was proportional to the severity of OSA (autonomic failure scores: no OSA 4.2 ± 2.54, mild OSA 5.44 ± 3.41, moderate/severe OSA 8.1 ± 4.3, P < 0.001). Small fiber neuropathy was found in 41.8% of patients without OSA and in 70.8% of patients with moderate/severe OSA. Autonomic failure associated with small fiber autonomic neuropathy is common in patients with OSA, and the degree of autonomic failure is proportional to the severity of sleep apnea. Autonomic failure can be an additional risk factor contributing to the cardiovascular complications observed in OSA.