Dysautonomia, Hypermobility Spectrum Disorders and Mast Cell Activation Syndrome as Migraine Comorbidities.

PURPOSE OF REVIEW: Dysautonomia refers to the dysfunction of the autonomic nervous system and encompasses a wide variety of autonomic symptoms and disorders. The most common autonomic disorders are postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope (NCS), and orthostatic hypotension (OH), which may be encountered in clinical practice as part of a triad of dysautonomia, hypermobility spectrum disorders (HSD), and mast cell activation syndrome (MCAS). Migraine is one of the most common comorbidities of POTS, HSD, and MCAS; conversely, these conditions are also prevalent in patients with migraine, especially in those with multiple systemic symptoms, such as chronic dizziness, lightheadedness, orthostatic intolerance, joint pain, and allergic symptoms. Diagnostic criteria, pathophysiologic mechanisms, and therapeutic considerations in patients with migraine and comorbid dysautonomia, HSD, and MCAS are reviewed. RECENT FINDINGS: Numerous studies indicate a significant overlap and shared pathophysiology in migraine, dysautonomia, HSD, and MCAS. In clinical setting, dysautonomia, HSD, and MCAS may present a diagnostic and therapeutic challenge in patients with migraine and require a high index of suspicion on the part of the neurologist. Diagnosis and treatment of these complex disorders in patients with migraine is essential to comprehensive patient-centric care, reduced symptom burden, and improved functional impairment secondary to both migraine and comorbidities.

Prevalence of gastrointestinal, cardiovascular, autonomic and allergic manifestations in hospitalized patients with Ehlers-Danlos syndrome: a case-control study.

OBJECTIVE: Previous observations suggest an association between Ehlers-Danlos syndrome (EDS) and gastrointestinal (GI), cardiovascular, immune, and autonomic nervous system dysfunction. We sought to determine whether a hospital diagnosis of EDS is associated with a higher prevalence of these manifestations vs hospitalized patients without EDS. We also evaluated hospital outcomes. METHODS: A total of 6,021 cases and matched controls were acquired from the 2016 National Inpatient Sample. In total, 2,007 EDS patients were identified via ICD-10 code. After bivariate analyses, multivariate logistic regression models were used to adjust for potential confounders. RESULTS: GI conditions were found in 44% of EDS patients vs 18% of controls [odds ratio (OR) = 3.57, 95% CI: 3.17, 4.02, P < 0.0001], with irritable bowel syndrome, gastroparesis and coeliac disease strongly associated with EDS. Autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope and orthostatic hypotension was found in 20% of EDS patients vs 6% of controls (OR = 4.45, 95% CI: 3.71, 5.32, P < 0.0001). EDS patients were more likely to have food allergy (OR = 3.88, 95% CI: 2.65, 5.66, P < 0.0001) and cardiovascular complications such as mitral valve disorders, aortic aneurysm and dysrhythmias (OR = 6.16, 95% CI: 4.60, 8.23, P < 0.0001). These conditions remained highly associated with EDS after considering confounders. EDS patients were 76% more likely to have longer than average hospitalizations (OR = 1.76, 95% CI: 1.54, 2.02, P < 0.0001). CONCLUSION: GI, cardiovascular, autonomic and allergic manifestations are significantly more prevalent in EDS patients compared with hospitalized patients without EDS. Physicians should consider EDS in patients with unexplained GI, cardiovascular, autonomic and allergic conditions and exercise precautions when treating EDS patients in a hospital setting.

When POTS is the tip of the iceberg: Rare cases of dysautonomia as a possible manifestation of another disorder.

BACKGROUND: Postural tachycardia syndrome (POTS) is a heterogenous disorder of the autonomic nervous system that is commonly associated with small fiber neuropathy, Ehlers-Danlos Syndrome and autoimmune disorders, but association with rare conditions may also occur. METHODS: Reported here are clinical features, diagnostic tests and treatment outcomes of 6 unique patients who presented with POTS and were subsequently diagnosed with Fabry disease, McArdle disease, Complex V mitochondrial disease, carcinoid tumor, Hodgkin's lymphoma and chemotherapy-induced neuropathy. RESULTS: All patients (age range 15-57 years, 3 females, 3 males) presented with orthostatic intolerance of at least 6 months duration, and all patients had co-morbid small fiber neuropathy. Five patients presented with symptoms of POTS months to years before the underlying or associated medical condition was discovered, and three out of six patients experienced either complete resolution or significant improvement of POTS after treatment of the underlying or associated medical condition. CONCLUSION: In rare cases, POTS can present as a possible manifestation of genetic, neoplastic or neurotoxic disorders. Unusual clinical features that fall outside of the typical spectrum of dysautonomia can point toward the presence of another disorder and help guide further diagnostic investigation.

Chronic Fatigue Syndrome: From Chronic Fatigue to More Specific Syndromes.

In the last decade, a group of chronic disorders associated with fatigue (CDAF) emerged as the leading cause of chronic fatigue, chronic pain, and functional impairment, all of which have been often labeled in clinical practice as chronic fatigue syndrome (CFS) or fibromyalgia. While these chronic disorders arise from various pathophysiologic mechanisms, a shared autoimmune or immune-mediated etiology could shift the focus from symptomatic treatment of fatigue and pain to targeted immunomodulatory and biological therapy. A clinical paradigm shift is necessary to reevaluate CFS and fibromyalgia diagnoses and its relationship to the CDAF entities, which would ultimately lead to a change in diagnostic and therapeutic algorithm for patients with chronic fatigue and chronic pain. Rather than uniformly apply the diagnoses of CFS or fibromyalgia to any patient presenting with unexplained chronic fatigue or chronic pain, it may be more beneficial and therapeutically effective to stratify these patients into more specific diagnoses in the CDAF group.

Sexual Dysfunction in Postural Orthostatic Tachycardia Syndrome (POTS): A Cross-Sectional, Case-Control Study.

Background: We aimed to determine whether patients with postural orthostatic tachycardia syndrome (POTS) have sexual dysfunction compared to age-matched healthy controls. Methods: Utilizing online COMPASS-31 to evaluate dysautonomia symptom severity, Beck's Depression Inventory Second Edition (BDII), Female Sexual Function (FSF), and International Index of Erection Function (IIEF) questionnaires, we compared sexual function scores in patients with POTS to scores obtained from sex- and age-matched healthy controls via a cross-sectional case-control study. Results: A total of 160 women with POTS, mean age 30.2 ± 7.9 (range 21-50 years), had lower FSF scores than 62 healthy age-matched female controls. IIEF scores in 29 male patients with POTS with a mean age of 30.1 ± 6.0 (range 21-47) were significantly lower than in 27 healthy age-matched male controls. Female POTS patients had significantly lower scores in the sub-domains of desire, arousal, and satisfaction, while male POTS patients had significantly lower scores in erectile and orgasmic function, desire, and satisfaction than healthy controls. Predictive factors of sexual dysfunction were depression in women and age in men. The severity of autonomic symptoms correlated with sexual dysfunction in women, but this effect disappeared after controlling for depression. Conclusions: Compared to healthy controls, women and men with POTS have significant sexual dysfunction, which needs to be considered in the diagnostic and therapeutic approaches as part of comprehensive patient care.

Immunotherapy with subcutaneous immunoglobulin or plasmapheresis in patients with postural orthostatic tachycardia syndrome (POTS).

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS), one of the most common autonomic disorders, is associated with significant morbidity and functional impairment. Although several possible etiologies have been proposed, autoimmunity has emerged as one of the leading causes with various specific and non-specific antibodies identified in patients with POTS. Treatment with intravenous immunoglobulin has been previously described. We present a case series of patients with severe POTS refractory to the standard pharmacologic and non-pharmacologic therapies treated with immunotherapy consisting of either subcutaneous immunoglobulin (SCIG) therapy or plasmapheresis (PLEX) and report their treatment outcomes. METHODS: Clinical history of 7 patients with POTS who were treated with SCIG or PLEX was reviewed. Response to treatment was assessed using COMPASS 31 and functional ability scale (FAS), completed by patients retrospectively, pre- and 3-12 months post-treatment with SCIG or PLEX. RESULTS: All patients improved following SCIG or PLEX with an average 50% reduction in COMPASS 31 score and 217% increase in FAS scores. Six out of seven patients were able to reduce or discontinue oral medications for POTS, and five patients were able to return to work or school. Four patients had skin biopsy or quantitative sudomotor axon reflex test (QSART)-proven small fiber neuropathy, and five had various positive antibodies at low titers. CONCLUSION: Patients with severe, treatment-refractory POTS experienced significant functional improvement with reduction in the autonomic symptoms following immunotherapy with SCIG or PLEX. Randomized controlled trials of SCIG and/or PLEX are needed to determine the efficacy and safety of these long-term therapies in patients with POTS.

Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series.

Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence of 17%. Mast cell chemical mediators lead to heterogeneous multisystemic inflammatory and allergic manifestations. This syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others. Although MCAS is common, it is rarely recognized, and thus, patients can suffer for decades. The syndrome is caused by aberrant mast cell reactivity due to the mutation of the controller gene. A case series is presented herein including eight patients with significant neuropsychiatric disorders that were often refractory to standard medical therapeutics. Five patients had depression, five had generalized anxiety disorder, and four had panic disorder. Other psychiatric disorders included attention-deficit hyperactivity disorder, obsessive compulsive disorder, phobias, and bipolar disorder. All eight patients were subsequently diagnosed with mast cell activation syndrome; six had comorbid autonomic disorders, the most common being postural orthostatic tachycardia syndrome; and four had hypermobile Ehlers-Danlos syndrome. All patients experienced significant improvements regarding neuropsychiatric and multisystemic symptoms after mast-cell-directed therapy. In neuropsychiatric patients who have systemic symptoms and syndromes, it is important to consider the presence of an underlying or comorbid MCAS.

Gluten-free diet in postural orthostatic tachycardia syndrome (POTS).

OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS) is a chronic disorder of the autonomic nervous system that is associated with orthostatic intolerance (OI) and gastrointestinal (GI) symptoms. We aimed to determine if a gluten-free diet (GFD) may be an effective treatment in patients with POTS. METHODS: Patients with confirmed POTS and without celiac disease who followed GFD for 4 weeks retrospectively completed pre- and post- GFD COMPASS-31 questionnaires. Paired-samples t-tests were conducted to compare COMPASS-31 scores before and after adopting GFD. RESULTS: All 20 patients (all females, age 16-62 years (mean age 33)), had POTS symptoms for 1-30 years (mean 10.8, SD = 10.23 years). Eleven patients had co-morbid mast cell activation syndrome, and 8 had hypermobile Ehlers-Danlos syndrome. Pre-GFD COMPASS-31 scores (mean 57.8) were significantly higher than post-GFD scores (mean 38.2, t(19) = -8.92, p < 0.00001), with the largest improvement noted in the OI (p < 0.00001), vasomotor, (p = 0.0034), and GI (p = 0.0004) domains and with a mean reduction in total COMPASS-31 score by 33.9% after implementing GFD. All patients reported improved symptoms on GFD with mean self-assessed improvement of 50.5% (range 10-99%). DISCUSSION: GFD may be effective in reducing the symptom burden in patients with POTS, particularly in the OI, vasomotor, and GI symptom domains. Large prospective studies are necessary to confirm whether GFD is an effective long-term treatment option for patients.

Is postural orthostatic tachycardia syndrome (POTS) a central nervous system disorder?

Postural orthostatic tachycardia syndrome (POTS), a disorder of the autonomic nervous system characterized by a rise in heart rate of at least 30 bpm from supine to standing position, has been traditionally viewed as a dysfunction of the peripheral nervous system. However, recent studies and evidence from overlapping conditions suggest that in addition to being considered a disorder of the peripheral nervous system, POTS should be viewed also as a central nervous system (CNS) disorder given (1) significant CNS symptom burden in patients with POTS; (2) structural and functional differences found on neuroimaging in patients with POTS and other forms of orthostatic intolerance; (3) evidence of cerebral hypoperfusion and possible alteration in cerebrospinal fluid volume, and (4) positive response to medications targeting the CNS and non-pharmacologic CNS therapies. This review outlines existing evidence of POTS as a CNS disorder and proposes a hypothetical model combining key mechanisms in the pathophysiology of POTS. Redefining POTS as a CNS disorder can lead to new possibilities in pharmacotherapy and non-pharmacologic therapeutic interventions in patents affected by this disabling syndrome.

POTS and Pregnancy: A Review of Literature and Recommendations for Evaluation and Treatment.

Postural Orthostatic Tachycardia Syndrome (POTS) is a disorder of the autonomic nervous system most commonly affecting women of reproductive age. Studies on POTS and pregnancy are limited, and there is a lack of clinical guidelines regarding assessment and management of pregnant women with POTS. The purpose of this review is to summarize data from the available studies on the topic of pregnancy in POTS and common comorbid conditions and to provide the clinical recommendations regarding evaluation and treatment of POTS in pregnant women, based on the available studies and clinical experience. We conclude that pregnancy appears to be safe for women with POTS and is best managed by a multi-disciplinary team with knowledge of POTS and its various comorbidities. Importantly, large, prospective studies are needed to better delineate the course and outcomes of pregnancy, as well as possible pregnancy-related complications in women with POTS. Clinicians should be aware of the clinical presentation, diagnostic criteria, and treatment options in pregnant women with POTS to optimize outcomes and improve medical care during pregnancy and post-partum period.

Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients.

OBJECTIVE: To describe clinical features, diagnostic findings, treatments, and outcomes in patients with new-onset postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders following SARS-CoV-2 infection (COVID-19). METHODS: We retrospectively reviewed medical records for patients who presented with persistent neurologic and cardiovascular complaints between April and December 2020 following COVID-19 infection. RESULTS: Twenty patients (70% female) were included in this study.Fifteen had POTS, 3 had neurocardiogenic syncope, and 2 had orthostatic hypotension. Six patients had abnormalities on cardiac or pulmonary testing, and 4 had elevated autoimmune or inflammatory markers. All patients were treated with non-pharmacologic therapies, and most required pharmacologic therapies. Six to 8 months after COVID-19, 17 (85%) patients had residual autonomic symptoms, with 12 (60%) unable to return to work. CONCLUSIONS: POTS can follow COVID-19 in previously healthy patients. Appropriate diagnostic investigations and therapies are necessary to identify and treat autonomic dysfunction after COVID-19.

Secondary headache in secondary syphilis.

We describe a patient with a history of recurrent headaches who developed severe and persistent left fronto-orbital and vertex head pain, in conjunction with a maculopapular rash, and was subsequently diagnosed with secondary syphilis. With the incidence of syphilis recently on the rise, we suggest that secondary syphilis should be considered in the differential diagnosis of any patient who presents with headache and a rash. Serologic screening tests for syphilis and a dermatology consultation should be obtained promptly for diagnostic confirmation and institution of treatment with antibiotics.