Dysautonomic Symptoms Research Articles

Visit-to-visit blood pressure variability in mild cognitive impairment: A possible marker of Alzheimer's disease in the SPRINT study?

Visit-to-visit blood pressure variability in mild cognitive impairment: A possible marker of Alzheimer's disease in the SPRINT study?

Post-Acute Sequelae of COVID-19 and Cardiovascular Autonomic Dysfunction: What Do We Know?

Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID syndrome, is emerging as a major health issue in patients with previous SARS-CoV-2 infection. Symptoms commonly experienced by patients include fatigue, palpitations, chest pain, dyspnea, reduced exercise tolerance, and “brain fog”. Additionally, symptoms of orthostatic intolerance and syncope suggest the involvement of the autonomic nervous system. Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.

Cardiac tyrosine hydroxylase activation and MB-COMT in dyskinetic monkeys

The impact of age-associated disorders is increasing as the life expectancy of the population increments. Cardiovascular diseases and neurodegenerative disorders, such as Parkinson’s disease, have the highest social and economic burden and increasing evidence show interrelations between them. Particularly, dysfunction of the cardiovascular nervous system is part of the dysautonomic symptoms of Parkinson’s disease, although more studies are needed to elucidate the role of cardiac function on it. We analyzed the dopaminergic system in the nigrostriatal pathway of Parkinsonian and dyskinetic monkeys and the expression of some key proteins in the metabolism and synthesis of catecholamines in the heart: total and phosphorylated (phospho) tyrosine hydroxylase (TH), and membrane (MB) and soluble (S) isoforms of catechol-O-methyl transferase (COMT). The dopaminergic system was significantly depleted in all MPTP-intoxicated monkeys. MPTP- and MPTP + L-DOPA-treated animals also showed a decrease in total TH expression in both right (RV) and left ventricle (LV). We found a significant increase of phospho-TH in both groups (MPTP and MPTP + L-DOPA) in the LV, while this increase was only observed in MPTP-treated monkeys in the RV. MB-COMT analysis showed a very significant increase of this isoform in the LV of MPTP- and MPTP + L-DOPA-treated animals, with no significant differences in S-COMT levels. These data suggest that MB-COMT is the main isoform implicated in the cardiac noradrenergic changes observed after MPTP treatment, suggesting an increase in noradrenaline (NA) metabolism. Moreover, the increase of TH activity indicates that cardiac noradrenergic neurons still respond despite MPTP treatment.

Unusual concomitant small‐ and large‐fiber neuropathy related to hypereosinophilic syndrome

AbstractBackgroundSmall‐fiber neuropathy is a disorder clinically dominated by neuropathic pain and autonomic symptoms. In >50% of patients, no etiology can be identified. and some evidence suggests a possible role of the immune system. Among the most common manifestations of hypereosinophilic syndrome, neurological lesions have been described in the central and peripheral nervous systems. No correlation between idiopathic hypereosinophilia with systemic involvement and small‐fiber neuropathy has been described before.Case presentationWe present the case of a 21‐year‐old woman with large‐ and small‐fiber neuropathy associated with systemic idiopathic hypereosinophilic syndrome. The patient manifested a subacute itchy rash to the limbs and trunk with painless lymphadenopathy of the neck and groin, persistent lack of appetite, vomiting, and subsequent painful dysesthesia on the feet. At blood test, eosinophilic leukocytosis was detected, electrophysiological studies showed axonal sensory neuropathy on the sural nerve bilaterally, cerebrospinal fluid analysis showed a cytological–albumin dissociation, and skin biopsy was decisive in confirming a severe picture of the small fibers pathology and lymphocytic infiltrates with eosinophils in the dermis. The in‐depth diagnostic investigations excluded other significant alterations and pathologies. After steroid and immunoglobulin therapies, the patient progressively improved with resolution of the rash and vomiting episodes, resuming regular nutrition and obtaining important reduction of painful dysesthesia.ConclusionsIn the present case, we hypothesized that idiopathic hypereosinophilic syndrome was the likely cause of the atopic dermatitis and small‐fiber neuropathy, consistent with pain and dysautonomic symptoms.

Autonomic dysfunction in post-COVID patients with and witfhout neurological symptoms: a prospective multidomain observational study

The autonomic nervous system (ANS) can be affected by COVID-19, and dysautonomia may be a possible complication in post-COVID individuals. Orthostatic hypotension (OH) and postural tachycardia syndrome (POTS) have been suggested to be common after SARS-CoV-2 infection, but other components of ANS function may be also impaired. The Composite Autonomic Symptom Scale 31 (COMPASS-31) questionnaire is a simple and validated tool to assess dysautonomic symptoms. The aim of the present study was to administer the COMPASS-31 questionnaire to a sample of post-COVID patients with and without neurological complaints. Participants were recruited among the post-COVID ambulatory services for follow-up evaluation between 4 weeks and 9 months from COVID-19 symptoms onset. Participants were asked to complete the COMPASS-31 questionnaire referring to the period after COVID-19 disease. Heart rate and blood pressure were manually taken during an active stand test for OH and POTS diagnosis. One-hundred and eighty participants were included in the analysis (70.6% females, 51 ± 13 years), and OH was found in 13.8% of the subjects. Median COMPASS-31 score was 17.6 (6.9–31.4), with the most affected domains being orthostatic intolerance, sudomotor, gastrointestinal and pupillomotor dysfunction. A higher COMPASS-31 score was found in those with neurological symptoms (p < 0.01), due to more severe orthostatic intolerance symptoms (p < 0.01), although gastrointestinal (p < 0.01), urinary (p < 0.01), and pupillomotor (p < 0.01) domains were more represented in the non-neurological symptoms group. This study confirms the importance of monitoring ANS symptoms as a possible complication of COVID-19 disease that may persist in the post-acute period.

The importance of thinking about Guillain-Barr\xe9 syndrome during the COVID-19 pandemic: a case with pure dysautonomic presentation

Guillain-Barré syndrome (GBS) is a peripheral nervous system disease caused by an immune-mediated inflammatory mechanism, usually triggered by a previous infectious process or vaccine; its typical presentation is a rapid and progressive bilateral limb hyposthenia, associated with sensory deficits and reduction or absence of osteotendinous reflexes. However, also autonomic nervous system can be involved with heart rate fluctuations, blood pressure instability, pupillary dysfunction, and urinary retention. Since the beginning of COVID-19 pandemic, GBS has been reported among neurological complications of SARS-CoV-2 infection, although etiopathological mechanisms still have to be clearly defined. We report the case of a 79-year-old man with multiple comorbidities, including diabetes, who was affected by SARS-CoV-2 interstitial pneumonia and developed dysautonomic symptoms after 10 days of hospitalization. A neurological evaluation was performed, and GBS was considered as a possible cause of the clinical manifestations. This hypothesis was confirmed by electrophysiological study and further supported, ex-juvantibus, by the satisfactory response to immunoglobulin treatment. In our opinion, this case of pure dysautonomic presentation of GBS in a SARS-CoV-2 positive patient is relevant because it suggests to consider GBS upon SARS-CoV-2 infection even if the symptoms have uncommon characteristics (e.g., pure vegetative manifestations) and if there are confounding factors which could lead to a misdiagnosis (e.g., old age, SARS-CoV-2 infection consequences and diabetes).

Dysautonomia in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders is associated with exercise intolerance and cardiac atrophy.

Dysautonomia is a recognized manifestation in patients with joint hypermobility (JH) disorders. Symptoms can be highly debilitating and commonly include physical deconditioning and poor aerobic fitness. In this study, the prevalence of dysautonomia, range of associated symptoms, patient-reported physical activity levels, and echocardiographic features were assessed retrospectively in a cohort of 144 patients (94% female) with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD). Echocardiographic parameters of left ventricular size and function were compared between patients with and without dysautonomia as well as to reported values from healthy controls. Dysautonomia was identified in 65% of female and 44% of male subjects and was associated with a high burden of symptomatology, most commonly exercise intolerance (78%). Exercise capacity was limited by dysautonomia, often postural symptoms, in half of all patients. We observed a reduction in physical activity following the onset or significant flare of hEDS/HSD, most strikingly noting the proportion of dysautonomic patients with sedentary lifestyle, which increased from 44% to 85%. JH-related dysautonomia was associated with smaller cardiac chamber sizes, consistent with the previous reports in positional orthostatic tachycardia syndrome. Dysautonomia is prevalent in patients with hEDS/HSD, and exercise intolerance is a key feature and leads to drastic decline in physical activity. Unfavorable cardiac geometry may underlie dysautonomia symptoms and may be due to cardiac atrophy in the setting of aerobic deconditioning.

Symptoms of mast cell activation: The patient perspective

Symptoms of mast cell activation: The patient perspective

Dysautonomia and functional impairment in rare developmental and epileptic encephalopathies: the other nervous system.

To determine whether functional impairments and autonomic symptoms are correlated in young people with developmental and epileptic encephalopathies (DEEs). Cross-sectional, online surveys (2018-2020) of parents recruited from family groups obtained information on several aspects of children's conditions including functional abilities (mobility, hand use, eating, and communication), 18 autonomic symptoms in six groups (cardiac, respiratory, sweating, temperature, gastrointestinal, and other), and parental stress. Bivariate and multivariable logistic regression analyses examined associations of dysautonomias with functional impairment, adjusted for type of DEE and age. Of 313 participants with full information on function and dysautonomias, 156 (50%) were females. The median age was 8 years (interquartile range 4-12y); 255 (81%) participants had symptoms in at least one autonomic symptom group; 283 (90%) had impairment in at least one functional domain. The number of functional impairment domains and of autonomic symptom groups varied significantly across DEE groups (both p<0.001). The number of functional impairment domains and of autonomic symptom groups were correlated (Spearman's r=0.35, p<0.001) on bivariate and multivariable analysis adjusted for DEE group and age. Parental stress was also independently correlated with dysautonomias (p<0.001). Parent-reported dysautonomias are common in children with DEEs. They correlate with extent of functional impairment and may contribute to caregiver stress. What this paper adds Dysautonomic symptoms are common in young people with developmental and epileptic encephalopathies (DEEs). Burden of dysautonomias is strongly correlated with burden of functional impairments. Aspects of dysautonomic function may provide biomarkers of DEE disease severity.

Neurosonological Findings Related to Non-Motor Features of Parkinson's Disease: A Systematic Review.

Non-motor symptoms (NMS) in Parkinson’s disease (PD), including neuropsychiatric or dysautonomic complaints, fatigue, or pain, are frequent and have a high impact on the patient’s quality of life. They are often poorly recognized and inadequately treated. In the recent years, the growing awareness of NMS has favored the development of techniques that complement the clinician’s diagnosis. This review provides an overview of the most important ultrasonographic findings related to the presence of various NMS. Literature research was conducted in PubMed, Scopus, and Web of Science from inception until January 2021, retrieving 23 prospective observational studies evaluating transcranial and cervical ultrasound in depression, dementia, dysautonomic symptoms, psychosis, and restless leg syndrome. Overall, the eligible articles showed good or fair quality according to the QUADAS-2 assessment. Brainstem raphe hypoechogenicity was related to the presence of depression in PD and also in depressed patients without PD, as well as to overactive bladder. Substantia nigra hyperechogenicity was frequent in patients with visual hallucinations, and larger intracranial ventricles correlated with dementia. Evaluation of the vagus nerve showed contradictory findings. The results of this systematic review demonstrated that transcranial ultrasound can be a useful complementary tool in the evaluation of NMS in PD.

Clinical Reasoning: A 65-Year-Old Woman With Tremor.

A 65-year-old woman was referred to our hospital for the evaluation of tremor, which had initially appeared in her right upper limb 3 years previously and progressed to her left upper limb and head 2 years previously. The tremor was most prominent during movement, but also occurred during rest. The patient felt unsteady when walking, although she denied falling and slowness of movement and symptoms of dysautonomia (e.g., positional lightheadedness, urinary dysfunction). She reported that her short-term memory had worsened and that the tremor intruded on her activities of daily living. The patient reported no medical history or previous trauma, hypoxic insult, or neurotoxic exposure, and no drug or alcohol use. There was no family history of tremor.

123I-Metaiodobenzylguanidine Myocardial Scintigraphy in Discriminating Degenerative Parkinsonisms.

ABSTRACTBackground 123I‐Metaiodobenzylguanidine (123I‐MIBG) myocardial scintigraphy is a useful technique to differentiate Parkinson's disease (PD) from atypical parkinsonisms, since it is generally abnormal in PD and normal in the latter. Reduction of myocardial MIBG uptake is a supportive feature in the latest PD diagnostic criteria.ObjectivesTo explore the clinical contribution of myocardial scintigraphy in discriminating different forms of parkinsonisms, especially when atypical features are present.MethodsForty‐one patients with parkinsonism underwent a 123I‐MIBG myocardial scintigraphy in our Movement Disorders Center. Disease evolution was reviewed by applying the latest disease criteria for PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), as appropriate. Three diagnostic times were defined: T1 (before scintigraphy execution), T2 (immediately after the exam) and T3 (two years later). Early and delayed heart/mediastinum (H/M) ratios and washout rate (WR) were analyzed.ResultsMyocardial scintigraphy showed impaired MIBG uptake in 12 out of 15 patients with a definite PD diagnosis, while normal uptake was found in 20 of 26 patients with no‐PD. Early and delayed H/M ratios were significantly lower in PD compared to overall no‐PD patients and MSA patients. 123I‐MIBG myocardial scintigraphy was abnormal in all PD patients with dysautonomia. After 123I‐MIBG myocardial scintigraphy (T2), in 9 patients (22%) an improvement of diagnostic accuracy was reached.ConclusionsDiagnostic accuracy of myocardial scintigraphy in distinguishing PD from atypical parkinsonism was suboptimal. Nevertheless, this study confirmed the relevance of 123I‐MIBG myocardial scintigraphy for the discrimination of PD from atypical parkinsonism, especially when dysautonomic symptoms are present.

COVID-19 Dysautonomia.

Objective: To report a case series of dysautonomia associated with COVID-19 infection.Methods: This is a retrospective review of patients evaluated in the autonomic clinic at our institution with suspected signs and symptoms of dysautonomia who underwent formal evaluation, including autonomic testing.Results: Six patients were identified with signs and symptoms suggestive of dysautonomia who underwent autonomic testing. All patients had symptoms typical of COVID-19 infection, though none were hospitalized for these or other symptoms. All patients reported symptoms of postural lightheadedness and near-syncope, fatigue, and activity intolerance. Five patients reported the onset of autonomic symptoms concomitant with other COVID-19 symptoms, with the other patient reporting symptom onset 6 weeks following initial COVID-19 symptoms. Autonomic testing demonstrated an excessive postural tachycardia in 4 patients, a hypertensive response with head-up tilt in 3 patients, orthostatic hypotension in 1 patient, and sudomotor impairment in 1 of the patients with excessive postural tachycardia.Conclusions: We present clinical features and results of autonomic testing in 6 patients with a history COVID-19 infection. While all patients reported typical features of orthostatic intolerance, fatigue, and activity intolerance, the results of autonomic testing were heterogenous, with orthostatic hypotension in 1 patient, excessive postural tachycardia typical of postural tachycardia syndrome in 4 patients, and postural hypertension in 3 patients.

Cardiovascular Autonomic Control, Sleep and Health Related Quality of Life in Systemic Sclerosis.

Chronic pain and dysautonomic symptoms deteriorate Systemic sclerosis (SSc) patients’ health-related quality of life with serious repercussions on social life and even on sleep. Heart Rate Variability (HRV) analysis can identify cardiovascular autonomic control impairment in subclinical condition. The aim of the present observational cross-sectional study was to assess the relationship between dysautonomic symptoms, quality of life status and cardiovascular autonomic profile. ECG and respiration were recorded at rest in 20 SSc patients. HRV analysis was performed using two different approaches: Linear spectral analysis and non-linear symbolic analysis. Pain was evaluated using the Numeric Rating Scale (NRS) and 3 questionnaires were administered for the evaluation of sleep quality (PSQI), mood tone (PHQ-9) and disability (HAQ). We found that sleep impairment was related to sympathetic predominance at rest measured as low-frequency/high-frequency ratio (LF/HF) (r = 0.48 and p = 0.033); poorer sleep quality was related to higher pain values (r = 0.48 and p = 0.034) and depressive symptoms (r = 0.82 and p < 0.01); higher pain scores were related to higher cardiovascular vagal modulation and higher disability indexes (r = 0.47 and p = 0.038 & r = 0.55 and p = 0.012, respectively). In conclusion dysautonomia and chronic pain showed a severe impact on sleep quality and disability with a consequent worsening of depressive symptom in our cohort of SSc patients.

Orthostatic Hypotension in Elderly Patients with Essential Tremor

PurposeEssential tremor (ET) is the most common movement disorder in which dysautonomia symptoms can be present. We aimed to evaluate the presence of orthostatic hypotension (OH) and its relationship with the clinical features.Patients and MethodsForty-four elderly patients with ET and 118 healthy elderly controls were included. OH was assessed via the head-up tilt table test and defined, according to the change in position, as a drop of at least 20 mmHg in systolic blood pressure and/or 10 mmHg in diastolic blood pressure. Tremor severity was evaluated using the Fahn-Tolosa-Marin Tremor Rating (FTMTR) Scale. All patients underwent geriatric comprehensive assessment.ResultsThere were no differences between the controls and patients with ET regarding age and gender. The mean age was 72.8±6.1, the mean disease duration 19.1±13.5 years and the mean FTMTR score was 30.9±17.1 in patients with ET. The frequency of OH at the 1st minute in patients with ET was higher than in controls (31.8% vs 17.8%, p=0.046). Furthermore, the frequency of jaw tremor in patients with OH was higher than in those without OH (35.7% vs 6.7%, p=0.025). About 28.6% of ET patients with OH had orthostatic symptoms.ConclusionWe demonstrated that ET patients, particularly those with jaw tremors, had OH and that most of them were asymptomatic. Therefore, in order to protect patients from complications related to OH, it would be appropriate to evaluate OH in the follow-up and treatment of elderly patients with ET.

Validation of the Korean version of the Boston Autonomic Symptom Questionnaire

Background and PurposeThe Boston Autonomic Symptom Questionnaire (BASQ) is a quantitative tool using a numeric rating scale to assess the symptoms of systemic dysautonomia, including cardiovascular, gastrointestinal, urinary, sudomotor, vasomotor, and sexual functions. The aim of this study was to validate the Korean version of the BASQ (KBASQ).MethodsProspectively enrolled subjects who submitted to autonomic function tests, including tests for cardiovagal, adrenergic, and sudomotor functions, also completed the KBASQ and the Korean version of the Orthostatic Grading Scale (KOGS), a validated questionnaire or assessing orthostatic symptoms.Twenty-eight subjects completed the KBASQ twice to assess test-retest reliability. We classified the subjects to dysautonomia or normal control group according to dysautonomic symptoms and the results of autonomic function tests.ResultsThis study enrolled 225 subjects aged 54.0±18.1 years (mean±standard deviation), with a male/female ratio of 1/1.03. The internal validity of the KBASQ was excellent (Cronbach's α=0.922), and that of each of its subscales ranged from excellent to acceptable (Cronbach's α=0.709–0.952). The test-retest reliability was good, with correlation coefficients ranging from 0.354 to 0.917. The subcategory scores for the KBASQ were significantly higher in the dysautonomia group than in the normal control group. There were significant correlations among the items in the KBASQ and KOGS. There was also a significant correlation between KBASQ scores and the results of the autonomic function tests.ConclusionsThe internal validity and reliability of the KBASQ were good, indicating that it may be a useful screening tool for the systematic evaluation of autonomic symptoms in patients with dysautonomia.

Genetic and Pathological Characteristic Patterns of a Family With Neuronal Intranuclear Inclusion Disease.

Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder. This study aimed to investigate clinical, imaging, genetic, and dermatopathological characteristics of a family with adult-onset NIID. The proband was a 62-year-old woman with 3 brothers and 2 sisters. Of these, 4 had symptoms of paroxysmal visual field defect, extrapyramidal symptoms, dysautonomia, emotional changes, and cognitive dysfunction. Genetic examination revealed no abnormality related to cerebrovascular diseases. More than 200 CGG repeats of FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) whereas repeats of the proband were found 29 times, which excluded FXTAS. Quantitative reverse transcription polymerase chain reaction (PCR) and GC-rich-PCR identified an expanded GGC repeat (with ∼100 repeats) in the 5' region of NOTCH2NLC in the patient and her 2 younger brothers. Pathological examination found eosinophilic intranuclear inclusions inside adipocytes, fibrocytes, and sweat gland cells. Immunohistochemistry and immunofluorescence staining revealed positive staining for ubiquitin and p62. The detailed pathological and genetic features of this NIID family provide a valuable contribution to the existing knowledge base of this rare disorder.

Lower Urinary Tract and Gastrointestinal Dysfunction Are Common in Early Parkinson's Disease.

Purpose Autonomic dysfunction is a common nonmotor feature and early manifestation of Parkinsons disease (PD). Autonomic dysfunction in PD is associated with a worse prognosis. We sought to characterize autonomic dysfunction and identify associated factors in patients with early PD. Methods An observational, cross-sectional, descriptive, and analytical study was conducted to evaluate patients with early PD from the Parkinsons Progression Markers Initiative. We utilized the Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction questionnaire to determine the prevalence and frequencies of autonomic symptomatology. The cohort was grouped into high and low dysautonomic scores. A regression model identified variables that independently explained dysautonomic scores in our early PD cohort. Results 414 PD patients had a mean age of 61.1 (SD 9.7) years at diagnosis and mean disease duration of 6.7 (SD 6.6) months. Among all patients, 43.7% (181/414) had high dysautonomic scores. Urinary and gastrointestinal symptoms were the most prevalent and frequently reported dysautonomic symptoms. Patients with fatigue (beta = 4.28, p < 0.001), probable rapid eye movement sleep behavior disorder (beta = 2.71, p < 0.001), excessive daytime sleepiness (beta = 1.88,p=0.039), impulsivity and compulsivity (beta = 2.42, p < 0.001), and increasing age (beta = 1.05, p < 0.001) were more likely to have high dysautonomic scores. Conclusion Lower urinary tract and gastrointestinal symptoms are prevalent and frequent in early PD patients. Fatigue, sleep disorders, impulsivity and compulsivity, and age are predictors of autonomic dysfunction. Autonomic symptoms predominated in this group of early PD patients in the disease course and were associated with more severe disease.

Correlation Between Corneal Nerve Density and Symptoms of Small Fiber Neuropathy in Patients With Fibromyalgia: The Confounding Role of Severe Anxiety or Depression.

A consistent line of investigation proposes fibromyalgia as a dysautonomia-associated neuropathic pain syndrome. Comorbid anxiety or depression amplifies fibromyalgia symptoms. The recent recognition of small fiber neuropathy in fibromyalgia patients supports the neuropathic nature of the illness. Corneal confocal microscopy accurately identifies small nerve fiber pathology. The newly developed Small-Fiber Symptom Survey captures the spectrum of small fiber neuropathy symptoms. We aimed to correlate corneal nerve density with different fibromyalgia disease severity questionnaires including the Small-Fiber Symptom Survey. We defined the possible confounding role of comorbid anxiety or depression severity in the clinical-pathological association. This is a case series of 28 women with fibromyalgia. A single ophthalmologist quantified corneal subbasal plexus nerve density. Corneal innervation was correlated (Spearman ρ) with the following clinical questionnaires scores: Small-Fiber Symptom Survey, Revised Fibromyalgia Impact Questionnaire, and COMPASS-31 (Composite Autonomic Symptom Survey 31-Item Score). Validated inquiry forms assessed the comorbid anxiety and/or depression severity. There were no clinical-pathological correlations in the group as a whole. In the subgroup of fibromyalgia women without severe anxiety or depression (n = 13), there was a strong negative correlation between corneal nerve density with the Small-Fiber Symptom Survey score (ρ = -0.771, p = 0.002) and COMPASS-31 score (ρ = -0.648, p = 0.017). Patients with profound anxiety or depression (n = 15) had more intense symptoms but had not clinical-pathological correlations. Small fiber neuropathy and dysautonomia symptoms correlate with corneal denervation in women with fibromyalgia without severe anxiety or depression. This clinical-pathological association reinforces fibromyalgia as a dysautonomia-related neuropathic pain syndrome. Severe anxiety or depression distorts fibromyalgia symptoms. Corneal confocal microscopy may become a useful procedure to study fibromyalgia patients.

Epidermal Neurite Density in Skin Biopsies From Patients With Juvenile Fibromyalgia.

Fibromyalgia (FM) is defined by idiopathic, chronic, widespread musculoskeletal pain. In adults with FM, a metaanalysis of lower-leg skin biopsy demonstrated 45% pooled prevalence of abnormally low epidermal neurite density (END). END < 5th centile of the normal distribution is the consensus diagnostic threshold for small-fiber neuropathy. However, the clinical significance of END findings in FM is unknown. Here, we examine the prevalence of small-fiber pathology in juvenile FM, which has not been studied previously. We screened 21 patients aged 13-20 years with FM diagnosed by pediatric rheumatologists. Fifteen meeting the American College of Rheumatology criteria (modified for juvenile FM) underwent lower-leg measurements of END and completed validated questionnaires assessing pain, functional disability, and dysautonomia symptoms. The primary outcome was proportion of FM patients with END < 5th centile of age/sex/race-based laboratory norms. Cases were systematically matched by ethnicity, race, sex, and age to a group of previously biopsied healthy adolescents with selection blinded to biopsy results. All 23 controls matching demographic criteria were included. Among biopsied juvenile FM patients, 53% (8/15) had END < 5th centile vs 4% (1/23) of healthy controls (P < 0.001). Mean patient END was 273/mm2 skin surface (95% CI 198-389) vs 413/mm2 (95% CI 359-467, P < 0.001). As expected, patients with FM reported more functional disability, dysautonomia, and pain than healthy controls. Abnormal END reduction is common in adolescents with FM, with similar prevalence in adults with FM. More studies are needed to fully characterize the significance of low END in FM and to elucidate the clinical implications of these findings.