Mismatch between subjective and objective dysautonomia.

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Initial validation of the Mass. General Neuropathy Exam Tool (MAGNET) for evaluation of distal small-fiber neuropathy.

INTRODUCTION/AIMS: Diagnosis of small-fiber neuropathy (SFN) is hampered by its subjective symptoms and signs. Confirmatory testing is insufficiently available and expensive, so predictive examinations have value. However, few support the 2020 SFN consensus-case-definition requirements or were validated for non-diabetes neuropathies. Thus we developed the Massachusetts General Hospital Neuropathy Exam Tool (MAGNET) and measured diagnostic performance in 160 symptomatic patients evaluated for length-dependent SFN from any cause and 37 healthy volunteers. METHODS: We compared prevalences of abnormalities (vital signs, pupil responses, lower-limb appearance, pin, light touch, vibration and position sensitivity, great-toe strength, muscle stretch reflexes), and validated diagnostic performance against objective SFN tests: lower-leg skin-biopsy epidermal neurite densities and autonomic function testing (AFT). Sensitivity/specificity, feasibility, test-retest and inter-rater reliability, and convergence with the Utah Early Neuropathy Scale were calculated. RESULTS: Patients' ages averaged 48.5 ± 14.7 years and 70.6% were female. Causes of neuropathy varied, remaining unknown in 59.5%. Among the 46 with abnormal skin biopsies, the most prevalent abnormality was reduced pin sharpness at the toes (71.7%). Inter-rater reliability, test-retest reliability, and convergent validity excelled (range = 91.3-95.6%). Receiver operating characteristics comparing all symptomatic patients versus healthy controls indicated that a MAGNET threshold score of 14 maximized predictive accuracy for skin biopsies (0.74) and a 30 cut-off maximized accuracy for predicting AFT (0.60). Analyzing patients with any abnormal neuropathy-test results identified areas-under-the-curves of 0.87-0.89 for predicting a diagnostic result, accuracy = 0.80-0.89, and Youden's index = 0.62. Overall, MAGNET was 80%-85% accurate for stratifying patients with abnormal versus normal neuropathy test results. DISCUSSION: MAGNET quickly generates research-quality metrics during clinical examinations.

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.

Autoantibodies Against Trisulfated Heparin Disaccharide and Fibroblast Growth Factor Receptor-3 May Play a Role in the Pathogenesis of Neuropathic Corneal Pain.

PURPOSE: The aim of this study was to describe cases of patients with presumable dysimmune small-fiber neuropathy (SFN)-related neuropathic corneal pain (NCP), presenting with autoantibodies against trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor-3 (FGFR-3). METHODS: This study was a case series of 3 patients with NCP with positive anti-TS-HDS and/or anti-FGFR-3 autoantibodies and systemic SFN as confirmed by positive skin biopsy results. RESULTS: All 3 patients were women with a mean age of 34.3± 6.1 years. They suffered from moderate to severe persistent chronic ocular discomfort (10/10, 10/10, and 9/10 on a visual analogue scale, respectively). Although 1 patient suffered from ocular pain and photophobia alone, the other 2 patients experienced additional non-ocular pain. One of the patients had pain on her face and head, and 1 patient reported neck and lower back pain. Two patients had high anti-TS-HDS IgM titers, whereas 1 patient had both high anti-TS-HDS IgM and anti-FGFR-3 IgG titers. Skin biopsy confirmed the presence of SFN in all patients by demonstrating decreased intraepidermal nerve fiber density. CONCLUSIONS: The presence of anti-TS-HDS and anti-FGFR-3 autoantibodies in patients with NCP with positive skin biopsy findings for SFN highlights the potential role of dysimmune SFN in the pathogenesis of this disease.

Urodynamic autonomic bladder dysfunction in women with complex chronic pelvic pain is associated with small fiber polyneuropathy.

AIMS: Small fiber neuropathy/polyneuropathy (SFN) has been found to be present in 64% of complex (refractory or multisystem) chronic pelvic pain (CPP) patients. The small fiber dysfunction seen in SFN can negatively impact autonomic control of micturition in addition to pain. This study investigated the clinical association of autonomic dysfunction (detrusor underactivity and primary bladder neck obstruction [BNO]) on video urodynamics (VUDS) with SFN in patients with CPP. METHODS: This was a retrospective observational study, querying data from patients with complex CPP. Inclusion criteria were: the presence of complex (refractory or multisystem) CPP, and completion of both (1) subspecialty autonomic neurology evaluation for SFN and (2) high-quality VUDS performed according to ICS standards. Autonomic bladder dysfunction (BNO or detrusor underactivity) on VUDS was compared to the presence of SFN. RESULTS: Thirty-two female patients with complex CPP met criteria. Of the 32, 23 (72%) were found to have SFN. Patient with autonomic bladder dysfunction (BNO or detrusor underactivity) were more likely to have SFN (OR = 9.5 [95% CI: 1.641, 55.00], p = 0.007). Post-void residual volume was higher in the SFN group (p = 0.011 [95% CI: 13.12, 94.0]) and symptoms of urge urinary incontinence were more likely to be present (p = 0.000 [95% CI: -3.4, -1.25]). CONCLUSIONS: Patients with complex CPP with autonomic bladder dysfunction are more likely to have SFN. This suggests patients with complex CPP should be considered for diagnosis and treatment of SFN, particularly if BNO or detrusor underactivity is noted on VUDS evaluation.

Current Diagnosis and Treatment of Painful Small Fiber Neuropathy.

PURPOSE OF REVIEW: Small fiber neuropathy (SFN) could cause significant morbidity due to neuropathic pain and autonomic dysfunction. SFN is underdiagnosed and the knowledge on the condition is limited among general public and health care professionals. This review is intended to enhance the understanding of SFN symptoms, causes, diagnostic tools, and therapeutic options. RECENT FINDINGS: There is evidence of SFN in up to 40% patients with fibromyalgia. The causes of SFN are glucose metabolism defect, dysimmune, gluten sensitivity and celiac disease, monoclonal gammopathy, vitamin deficiencies, toxic agents, cancer, and unknown etiology. Auto-antibodies targeting neuronal antigens trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor 3 (FGFR3) are found in up to 20% of patients with SFN. Treatment of SFN includes treating the etiology and managing symptoms. SFN should be considered in patients with wide-spread body pain. The search for known causes of SFN is a crucial step in disease management.

Causes of neuropathy in patients referred as "idiopathic neuropathy".

INTRODUCTION: The etiology of neuropathy was idiopathic in 20%-30% of patients despite thorough investigation, based on results from the 1980s and 1990s. Since then, new etiologies have been recognized, and skin biopsy has been used to confirm small-fiber neuropathy. METHODS: The authors reviewed the charts of 373 patients with idiopathic neuropathy who were referred to a neuropathy center between 2002 and 2012. RESULTS: Among the 284 eligible patients, 93 (32.7%) remained idiopathic. The most common cause was impaired glucose metabolism (72 patients, 25.3%), including diabetes in 26 and prediabetes in 46. Other etiologies were chronic inflammatory demyelinating polyneuropathy (CIDP) in 57 (20%) and monoclonal gammopathy in 20 (7%), as well as toxic, Sjögren disease, celiac disease, other immune-mediated diseases, vitamin B12 deficiency, amyloidosis, vitamin B1 and B6 deficiency, vasculitis, hypothyroidism, hereditary, Lyme disease, and anti-sulfatide antibody. CONCLUSIONS: The major causes of undiagnosed neuropathies were impaired glucose metabolism, CIDP, and monoclonal gammopathies. Despite thorough evaluation 32.7% remained idiopathic. Muscle Nerve 53: 856-861, 2016.

Trends in Outcome and Hospitalization Cost among Adult Patients with Acute Ischemic Stroke in the United States.

INTRODUCTION: New treatments for acute ischemic stroke (AIS) have been introduced and are expected to improve patients' overall outcomes. We assessed the impact of new therapeutic strategies on outcome and cost of hospitalization among adult patients with AIS in the United States. METHODS: Patients with AIS admitted in the United States in 1993-1994 and 2006-2007 were listed using the Nationwide Inpatient Survey database. We determined the rates of occurrence, hospitalization outcomes, and mean hospital charges for all patients. We further analyzed these variables in the ventilated and nonventilated patients. RESULTS: We identified 386,043 patients with AIS admitted in the United States in 1993-1994 and 749,766 patients in 2006-2007. The length of hospitalization was significantly higher in 1993-1994 compared with 2006-2007: 6.9 ± 4.2 days versus 4.66 ± 3 days, respectively. In-hospital mortality rate was 8.9% in 1993-1994 and 5.6% in 2006-2007 (P < 0.0001). There was a significant increase in mean hospital charges in 2006-2007 compared with 1993-1994 ($21,916 ± $14,117 versus $9,646 ± $5,727). The length of hospitalization was significantly shorter in 2006-2007 in nonventilated patients. There was a significant increase in mean hospital charges in 2006-2007 compared with 1993-1994 in both ventilated ($81,528 ± $64,526 versus $25,143 ± $17,172, P<0.0001) and nonventilated patients ($21,085 ± $13,042 versus $10,000 ± $6,300, P<0.0001). The mortality rate was significantly lower in 2006-2007 in both subgroups: 46.5% versus 59.8% in ventilated patients and 4.2% versus 8.2% in nonventilated patients (P < 0.0001). CONCLUSION: Our study suggests that new therapeutic strategies have improved outcomes and increased cost of hospitalization among adult patients with AIS in the United States over a period of 13 years. The hospitalization cost was significantly higher in the ventilated and nonventilated patients in 2006-2007, which may reflect the impact of new therapeutic strategies, the availability of more intensive care units and stroke centers, and the lower mortality rate in this time period.

Trends in outcomes and hospitalization costs for traumatic brain injury in adult patients in the United States.

Several new therapeutic strategies have been introduced for the management of adult traumatic brain injury (TBI) over the last decade, such as the development of management pathways and specialized TBI units and improved treatment of cerebral perfusion. The purpose of this study is to compare TBI-related hospitalization outcomes in the United States between two time periods, 1993-1994 and 2006-2007. We determined the rates of occurrence, in-hospital outcomes, and mean hospital charges for patients hospitalized with adult TBI in 1993-1994 using the nationally representative all-payer Nationwide Inpatient Survey (NIS) database, and compared these outcomes with homologous data from 2006-2007. The incidence of TBI admissions was reduced by 35% in 2006-2007 compared with 1993-1994; (22/100,000 versus 34/100,000 population; p<0.0001). The mean length of hospitalization (mean±SD, in days) was significantly lower in 2006-2007 than in 1993-1994 (2.5±2.4 days versus 2.7±2.6 days; p<0.0001). In-hospital mortality increased significantly in 2006-2007 compared with 1993-1994 (0.8% versus 0.4%, p<0.0001). Average hospitalization charges were significantly higher in 2006-2007 compared with 19993-1994 ($21,460±$21,212 versus $5,142±$4,625; p<0.0001), even after adjusting for inflation. In both time periods, most hospitalized adult TBI patients were graded as mild (98.2% in 1993-1994 versus 98.0% in 2006-2007; p=0.20). There was a significant increase in average hospitalization charges and death rates in all TBI severity subgroups in 2006-2007 compared with 1993-1994. The decline in rate of hospitalization between the two time periods was predominantly related to the decline in the number of admissions of patients with mild TBI. Although the number of TBI admissions was reduced, a significant increase in average hospitalization charges and in-hospital mortality rate was observed in 2006-2007 compared with 1993-1994.

Guillain-Barré syndrome after influenza vaccination in the United States, a report from the CDC/FDA vaccine adverse event reporting system (1990-2009).

OBJECTIVES: To determine the rate of Guillain-Barré syndrome (GBS) after administration of influenza vaccine in the United States and to provide further information about the characteristics and temporal profile of these incidents. METHODS: Data were acquired from the Vaccine Adverse Event Reporting System, supplemented by data from the Center for Biologics and Research under the Freedom of Information Act between 1990 and 2009. RESULTS: There were 802 cases (mean age, 54.72 ± 18.4 years) of GBS reported after influenza vaccination in the United States between 1990 and 2009. Among the 802 vaccinated patients with available data, 624 (77.8%) developed GBS within 6 weeks and 78 (9.7%) after 6 weeks, whereas these data were unavailable for the remaining 100 patients (13%). The reporting rate of post-influenza vaccine GBS was within the range expected in the general population or approximately 0.46 cases per million vaccinations. A non-Gaussian distribution of GBS within the first 6 weeks post-vaccination was noted, given that the peak incidence occurred in the second week. CONCLUSIONS: The incidence of post-influenza vaccine GBS is similar to the incidence of idiopathic GBS in the general population. Although the nonnormal distribution of post-vaccination GBS suggests that some cases may be triggered by vaccination, the greater risk of complications from influenza virus infections makes vaccination the first-line strategy for infection prevention and support the current guidelines on vaccination.

Analysis of data from the CDC/FDA vaccine adverse event reporting system (1990-2009) on Guillain-Barre syndrome after hepatitis vaccination in the USA.

We used data from the Vaccine Adverse Event Reporting System, supplemented by additional data provided by the Center for Biologics Evaluation and Research, to identify 189 patients with Guillain-Barré syndrome (GBS) reported after hepatitis vaccination with a mean age of 30.65 years, affecting men and women equally. Among vaccinated patients, 133 (70%) developed GBS within six weeks, 30 (15.9%) after six weeks, and for the remaining 26 (13.7%), the time between GBS occurrence and vaccination was not specified. The reporting rate of post-hepatitis vaccine GBS is approximately 3.4 cases per one million vaccinations, which is in the range expected in the general population. The unbalanced distribution of reports in the first six weeks after vaccination suggests that some cases of GBS may be triggered by vaccination. Nonetheless, the low incidence of hepatitis vaccine-associated GBS, and the dramatic incidence reduction of hepatitis and its complications after vaccination, support the current guidelines for vaccination.