Effect of levodopa on postural blood pressure changes in Parkinson disease: a randomized crossover study.

PURPOSE: We investigated the effect of levodopa on postural blood pressure changes in individuals with Parkinson disease (PD) with (PD+OH) and without neurogenic OH (PD-OH). METHODS: We performed a prospective randomized crossover study with autonomic testing performed ON and OFF levodopa. The primary outcome was the change in systolic blood pressure (SBP) from supine to 70° tilt at 3 min (ΔSBP-3'). Secondary outcomes included indices of baroreflex function and blood pressure and heart rate during tilt. RESULTS: We enrolled 40 individuals with PD (21 PD+OH, 19 PD-OH), mean age (SD) 73.2 years (7.9), 13 women (32.5%)). There was no difference in age, sex, disease duration, and severity between PD+OH and PD-OH. Mean difference in ΔSBP-3' ON versus OFF levodopa in the whole study population was - 3.20 mmHg [- 7.36 to 0.96] (p = 0.14). Mean difference in ΔSBP-3' was - 2.14 mmHg [- 7.55 to 3.28] (p = 0.45) in PD+OH and - 5.14 mmHg [- 11.63 to 1.35] (p = 0.14) in PD-OH. Mean difference in ΔSBP ON versus OFF levodopa was greater at 7 and 10 min (- 7.52 mmHg [- 11.89 to - 3.15], p = 0.002, and - 7.82 mmHg [- 14.02 to - 1.67], p = 0.02 respectively). Levodopa was associated with lower absolute values of blood pressure in both PD+OH and PD-OH and cardiovascular noradrenergic baroreflex impairment. CONCLUSION: Levodopa decreases blood pressure in both PD with and without autonomic failure, but it does not cause a greater fall in blood pressure from supine to standing at 3 min. Levodopa-induced baroreflex sympathetic noradrenergic impairment may contribute to lower blood pressure. Lower standing blood pressure with levodopa may increase the risks of fall and syncope.

Orthostatic Hypotension in Adults With Hypertension: A Scientific Statement From the American Heart Association.

Although orthostatic hypotension (OH) has long been recognized as a manifestation of autonomic dysfunction, a growing body of literature has identified OH as a common comorbidity of hypertension. This connection is complex, related to pathophysiology in blood pressure regulation and the manner by which OH is derived as the difference between 2 blood pressure measurements. While traditional therapeutic approaches to OH among patients with neurodegenerative disorders focus on increasing upright blood pressure to prevent cerebral hypoperfusion, the management of OH among patients with hypertension is more nuanced; resting hypertension is itself associated with adverse outcomes among these patients. Although there is substantial evidence that intensive blood pressure treatment does not cause OH in the majority of patients with essential hypertension, some classes of antihypertensive agents may unmask OH in patients with an underlying autonomic impairment. Practical steps to manage OH among adults with hypertension start with (1) a thorough characterization of its patterns, triggers, and cause; (2) review and removal of aggravating factors (often pharmacological agents not related to hypertension treatment); (3) optimization of an antihypertensive regimen; and (4) adoption of a tailored treatment strategy that avoids exacerbating hypertension. These strategies include countermaneuvers and short-acting vasoactive agents (midodrine, droxidopa). Ultimately, further research is needed on the epidemiology of OH, the impact of hypertension treatment on OH, approaches to the screening and diagnosis of OH, and OH treatment among adults with hypertension to improve the care of these patients and their complex blood pressure pathophysiology.

Headache among combat-exposed veterans and service members and its relation to mild traumatic brain injury history and other factors: a LIMBIC-CENC study.

Background: Headache (HA) is a common persistent complaint following mild traumatic brain injury (mTBI), but the association with remote mTBI is not well established, and risk factors are understudied. Objective: Determine the relationship of mTBI history and other factors with HA prevalence and impact among combat-exposed current and former service members (SMs). Design: Secondary cross-sectional data analysis from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium prospective longitudinal study. Methods: We examined the association of lifetime mTBI history, demographic, military, medical and psychosocial factors with (1) HA prevalence ("lately, have you experienced headaches?") using logistic regression and (2) HA burden via the Headache Impact Test-6 (HIT-6) using linear regression. Each lifetime mTBI was categorized by mechanism (blast-related or not) and setting (combat deployed or not). Participants with non-credible symptom reporting were excluded, leaving N = 1,685 of whom 81% had positive mTBI histories. Results: At a median 10 years since last mTBI, mTBI positive participants had higher HA prevalence (69% overall, 78% if 3 or more mTBIs) and greater HA burden (67% substantial/severe impact) than non-TBI controls (46% prevalence, 54% substantial/severe impact). In covariate-adjusted analysis, HA prevalence was higher with greater number of blast-related mTBIs (OR 1.81; 95% CI 1.48, 2.23), non-blast mTBIs while deployed (OR 1.42; 95% CI 1.14, 1.79), or non-blast mTBIs when not deployed (OR 1.23; 95% CI 1.02, 1.49). HA impact was only higher with blast-related mTBIs. Female identity, younger age, PTSD symptoms, and subjective sleep quality showed effects in both prevalence and impact models, with the largest mean HIT-6 elevation for PTSD symptoms. Additionally, combat deployment duration and depression symptoms were factors for HA prevalence, and Black race and Hispanic/Latino ethnicity were factors for HA impact. In sensitivity analyses, time since last mTBI and early HA onset were both non-significant. Conclusion: The prevalence of HA symptoms among formerly combat-deployed veterans and SMs is higher with more lifetime mTBIs regardless of how remote. Blast-related mTBI raises the risk the most and is uniquely associated with elevated HA burden. Other demographic and potentially modifiable risk factors were identified that may inform clinical care.

Sensory hypersensitivities are associated with post-traumatic headache-related disability.

OBJECTIVE: To examine whether sensory hypersensitivity contributes to headache-related disability in a secondary analysis of patients with post-traumatic headache. BACKGROUND: Up to one-third of individuals with traumatic brain injuries report persistent headache 3 months post-injury. High rates of allodynia and photophobia have been observed in clinical studies and animal models of post-traumatic headache, but we do not fully understand how sensory amplifications impact post-traumatic headache-related disability. METHODS: We identified a cross-sectional sample of patients from the American Registry for Migraine Research database with new or worsening headaches post-head injury from 2016 to 2020 and performed a secondary analysis of those data. We modeled the relationship between sensory sensitivity and Migraine Disability Assessment scores using questionnaires. Candidate variables included data collection features (study site and year), headache-related and general clinical features (headache frequency, migraine diagnosis, abuse history, sex, age, cognitive and affective symptom scores), and sensory symptoms (related to light, sound, and touch sensitivity). RESULTS: The final sample included 193 patients (median age 46, IQR 22; 161/193, 83.4% female). Migraine Disability Assessment scores ranged from 0 to 260 (median 47, IQR 87). The final model included allodynia, hyperacusis, photosensitivity, headache days per month, abuse history, anxiety and depression, cognitive dysfunction, and age (R2 = 0.43). An increase of one point in allodynia score corresponded to a 3% increase in headache disability (95% CI: 0%-7%; p = 0.027), an increase of one-tenth of a point in the photosensitivity score corresponded to a 12% increase (95% CI: 3%-25%; p = 0.002), and an increase of one point in the hyperacusis score corresponded to a 2% increase (95% CI: 0%-4%; p = 0.016). CONCLUSIONS: Increased photosensitivity, allodynia, and hyperacusis were associated with increased headache-related disability in this sample of patients with post-traumatic headache. Symptoms of sensory amplification likely contribute to post-traumatic headache-related disability and merit an ongoing investigation into their potential as disease markers and treatment targets.

Validation of the Utah Photophobia Symptom Impact Scale (version 2) as a headache-specific photophobia assessment tool.

OBJECTIVE: To present an updated version of the Utah Photophobia Symptom Impact Scale version 2 (UPSIS2), providing robust clinical and psychometric validation, to improve headache-specific evaluation of light sensitivity and headache-related photophobia. BACKGROUND: The original UPSIS filled a gap in available tools for assessment of headache-associated light sensitivity by providing patient-reported evaluation of the impact of light sensitivity on activities of daily living (ADLs). We have since revised the original questionnaire to provide a more robust item construct and refined validation approach. METHODS: We conducted a psychometric validation of the UPSIS2 through a primary analysis of an online survey of volunteers with recurrent headaches recruited from the University of Utah clinics and surrounding community. Volunteers completed the original UPSIS and UPSIS2 questionnaire versions in addition to measures of headache impact, disability, and frequency. The UPSIS2 now includes a pre-defined recall period and a 1-4 Likert scale with standardized response anchors to improve clarity. Internal construct validity, external construct validity, and test-retest reliability, were evaluated. RESULTS: Responses were obtained from 163 volunteers, with UPSIS2 scores ranging from 15 to 57 (out of a possible 15-60) with a mean (standard deviation) of 32.4 (8.80). Construct validity was satisfactory, as evidenced by sufficient unidimensionality, monotonicity, and local independence. Reliability was excellent, with Rasch test reliability = 0.90 and Cronbach's alpha = 0.92, and an intraclass correlation of 0.79 (95% confidence interval 0.65-0.88) for participants who took the test twice. UPSIS2 correlates well with other headache measures (Spearman's correlations >0.50), as well as the original UPSIS (Spearman's correlation = 0.87), indicating good convergent validity. UPSIS2 scores differ significantly across International Classification of Headache Disorders (third edition) groups, indicating good known group validity. CONCLUSION: The UPSIS2 provides a well-validated headache-specific outcome measure for the assessment of photophobia impact on ADLs.

Autonomic dysfunction and exercise intolerance in concussion: a scoping review.

PURPOSE: Concussion commonly results in exercise intolerance, often limiting return to activities. Improved understanding of the underlying mechanisms of post-concussive exercise intolerance could help guide mechanism-directed rehabilitation approaches. Signs of altered cardiovascular autonomic regulation-a potential contributor to exercise intolerance-have been reported following concussion, although it is not clear how these findings inform underlying mechanisms of post-concussive symptoms. Systematic summarization and synthesis of prior work is needed to best understand current evidence, allowing identification of common themes and gaps requiring further study. The purpose of this review was to (1) summarize published data linking exercise intolerance to autonomic dysfunction, and (2) summarize key findings, highlighting opportunities for future investigation. METHODS: The protocol was developed a priori, and conducted in five stages; results were collated, summarized, and reported according to PRISMA guidelines. Studies including injuries classified as mild traumatic brain injury (mTBI)/concussion, regardless of mechanism of injury, were included. Studies were required to include both autonomic and exercise intolerance testing. Exclusion criteria included confounding central or peripheral nervous system dysfunction beyond those stemming from the concussion, animal model studies, and case reports. RESULTS: A total of 3116 publications were screened; 17 were included in the final review. CONCLUSION: There was wide variability in approach to autonomic/exercise tolerance testing, as well as inclusion criteria/testing timelines, which limited comparisons across studies. The reviewed studies support current clinical suspicion of autonomic dysfunction as an important component of exercise intolerance. However, the specific mechanisms of impairment and relationship to symptoms and recovery require additional investigation.

Neurologic Manifestations of Common Variable Immunodeficiency: Impact on Quality of Life.

BACKGROUND AND OBJECTIVES: Common variable immunodeficiency is a systemic disease and not solely a disease of humoral immunity. Neurologic symptoms associated with common variable immunodeficiency are underrecognized and warrant further study. This work aimed to characterize the neurologic symptoms reported by people living with common variable immunodeficiency. METHODS: We conducted a single academic medical center study of neurologic symptoms reported by adults previously diagnosed with common variable immunodeficiency. We used a survey of common neurologic symptoms to determine the prevalence of these symptoms in a population with common variable immunodeficiency and further assessed these patient-reported symptoms with validated questionnaires and compared symptom burden with other neurologic conditions. RESULTS: A volunteer sample of adults (aged 18 years or older) previously diagnosed with common variable immunodeficiency at the University of Utah Clinical Immunology/Immune Deficiency Clinic who were able to read and comprehend English and willing and able to answer survey-based questions were recruited. Of 148 eligible participants identified, 80 responded and 78 completed the surveys. The mean age of respondents was 51.3 years (range 20-78 years); 73.1% female and 94.8% White. Patients with common variable immunodeficiency reported many common neurologic symptoms (mean 14.6, SD 5.9, range 1-25), with sleep issues, fatigue, and headache reported by more than 85%. Validated questionnaires addressing specific neurologic symptoms supported these results. T-scores on Neuro QoL questionnaires for sleep (mean 56.4, SD 10.4) and fatigue (mean 54.1, SD 11) were higher, indicating more dysfunction, than in the reference clinical population (p < 0.005). The Neuro QoL questionnaire for cognitive function showed a lower T-score (mean 44.8, SD 11.1) than that in the reference general population (p < 0.005), indicating worse function in this domain. DISCUSSION: Among survey respondents, there is a marked burden of neurologic symptoms. Given the impact of neurologic symptoms on health-related quality-of-life measures, clinicians should screen patients with common variable immunodeficiency for the presence of these symptoms and offer referral to neurologists and/or symptomatic treatment when indicated. Frequently prescribed neurologic medications may also affect the immune system, and neurologists should consider screening patients for immune deficiency before prescribing them.

Cutaneous heat and light-induced pain thresholds in post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: The purpose of this study was to characterize cutaneous heat and light-induced pain thresholds in people with post-traumatic headache (PTH) compared with healthy controls (HCs). BACKGROUND: Photophobia and allodynia are common in PTH, and there is emerging evidence to support multimodal sensory dysfunction. METHODS: In this age- and sex-matched cohort study, individuals with PTH (n = 20) and HCs (n = 20), aged 18-65 years, were recruited from an institutional database of research volunteers, from the concussion clinic, and via the use of approved flyers posted on the Mayo Clinic Campus in Scottsdale, Arizona. Participants were assessed using the Allodynia Symptom Checklist (ASC-12), Photosensitivity Assessment Questionnaire (PAQ), State Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI). Quantitative sensory testing quantified heat pain thresholds. A light stimulation device quantified light-induced pain thresholds. Subsequently, heat pain thresholds were obtained immediately, 10, and 40 min after a bright light stressor. RESULTS: The mean photophobia symptom severity score, based on the PAQ, was higher in participants with PTH compared with HCs, mean 0.62 (SD = 0.25) versus mean 0.24 (SD = 0.24), p < 0.001. Light-induced pain thresholds were lower in participants with PTH (median = 90.5 lux and quartiles = 17.8 to 378.5) compared with HCs (median = 863.5 lux and quartiles = 519.9 to 4906.5) and were independent from BDI and STAI (p < 0.001). Allodynia scores did not differ between participants with PTH and HCs after adjusting for BDI and STAI scores. Baseline forehead heat pain thresholds were not different, participants with PTH mean 41.9°C (SD = 0.89) versus HCs mean 44.3°C (SD = 0.89), p = 0.061; however, forearm heat pain thresholds were lower in participants with PTH compared with HCs, mean 40.8°C (SD = 0.80) versus mean 44.4°C (SD = 0.80), p = 0.002. The forehead heat pain threshold change from baseline post bright light stressor in participants with PTH versus HCs was different immediately (mean -1.2 (SD = 0.53), p = 0.025), 10 min (mean -1.8 (SD = 0.74), p = 0.015), and 40 min (mean -1.8 (SD = 0.88), p = 0.047). The forearm heat pain threshold change immediately post bright light stressor in participants with PTH versus HCs was different, mean -1.9°C (SD = 0.58), p = 0.001, however, not different at 10 and 40 min. CONCLUSIONS: Photophobia is higher and light-induced pain thresholds are lower in participants with PTH. Exposure to a light stressor reduced heat pain thresholds in participants with PTH immediately post bright light stressor, but not in HCs. This study provides evidence for multimodal sensory dysfunction in people with PTH.

The impact of pre-morbid headaches on headache features and long-term health outcomes following traumatic brain injury: Insights from the American Registry for Migraine Research.

OBJECTIVE: To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long-term patient health outcomes. BACKGROUND AND METHODS: This was an exploratory analysis of patients with TBI who were enrolled in the American Registry for Migraine Research (ARMR), a multicenter, prospective, longitudinal patient registry composed of patients with International Classification of Headache Disorders, 3rd edition (ICHD-3)-defined headache diagnoses. The ARMR study enrolled 2,707 patients between February 1, 2016 and May 6, 2020, 565 of whom qualified for this analysis. Those with headaches prior to their TBI were compared to those without headaches prior to their TBI for ICHD-3 diagnoses, headache frequency and intensity, headache-related disability (Migraine Disability Assessment score), symptoms of anxiety (General Anxiety Disorder [GAD-7]), depression (two items from Patient Health Questionnaire-9), post-traumatic stress disorder (PTSD), cutaneous allodynia (12-item Allodynia Symptom Checklist [ASC-12]), cognitive dysfunction (Migraine Attacks Subjective Cognitive Impairments Scale [Mig-SCog]), pain interference (Patient-Reported Outcomes Measurement Information System-Pain Interference), and work productivity (Work Productivity and Activity Impairment). RESULTS: Among 565 participants with TBI, 350 had headaches prior to their TBI. Those with pre-TBI headaches were less likely to receive a diagnosis of post-traumatic headache (PTH; 14/350 [4.0%] vs. 21/215 [9.8%], p = 0.006), even though 25.7% reported new or worsening headaches within 7 days of their TBI. Those with pre-TBI headaches had higher ASC-12 scores (2.4 ± 3.5 vs. 1.8 ± 3.4, p = 0.030), Mig-SCog scores (9.3 ± 4.7 vs. 8 ± 4.9, p = 0.004), and GAD-7 scores (6.9 ± 5.1 vs. 6.2 ± 5.4, p = 0.039), and were more likely to have a migraine diagnosis (335/350 [95.7%] vs. 192/215 [89.3%], p = 0.003). CONCLUSIONS: Those with headaches prior to TBI are less likely to receive a diagnosis of PTH. They have more severe symptoms of cutaneous allodynia, cognitive impairment, and generalized anxiety. This analysis suggests that pre-TBI headaches might impact post-TBI headache diagnoses and associated features.

Sensory Phenotypes for Balance Dysfunction After Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Recent team-based models of care use symptom subtypes to guide treatments for individuals with chronic effects of mild traumatic brain injury (mTBI). However, these subtypes, or phenotypes, may be too broad, particularly for balance (e.g., 'vestibular subtype'). To gain insight into mTBI-related imbalance we 1) explored whether a dominant sensory phenotype (e.g., vestibular impaired) exists in the chronic mTBI population, 2) determined the clinical characteristics, symptomatic clusters, functional measures, and injury mechanisms that associate with sensory phenotypes for balance control in this population, and 3) compared the presentations of sensory phenotypes between individuals with and without previous mTBI. METHODS: A secondary analysis was conducted on the Long-Term Impact of Military-Relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium. Sensory ratios were calculated from the Sensory Organization Test, and individuals were categorized into one of eight possible sensory phenotypes. Demographic, clinical, and injury characteristics were compared across phenotypes. Symptoms, cognition, and physical function were compared across phenotypes, groups, and their interaction. RESULTS: Data from 758 Service Members and Veterans with mTBI and 172 with no lifetime history of mTBI were included. Abnormal visual, vestibular, and proprioception ratios were observed in 29%, 36%, and 38% of people with mTBI, respectively, with 32% exhibiting more than one abnormal sensory ratio. Within the mTBI group, global outcomes (p<0.001), self-reported symptom severity (p<0.027), and nearly all physical and cognitive functioning tests (p<0.027) differed across sensory phenotypes. Individuals with mTBI generally reported worse symptoms than their non-mTBI counterparts within the same phenotype (p=0.026), but participants with mTBI in the Vestibular-Deficient phenotype reported lower symptom burdens than their non-mTBI counterparts [e.g., mean(SD) Dizziness Handicap Inventory = 4.9(8.1) for mTBI vs. 12.8(12.4) for non-mTBI, group*phenotype interaction p<0.001]. Physical and cognitive functioning did not differ between groups after accounting for phenotype. DISCUSSION: Individuals with mTBI exhibit a variety of chronic balance deficits involving heterogeneous sensory integration problems. While imbalance when relying on vestibular information is common, it is inaccurate to label all mTBI-related balance dysfunction under the 'vestibular' umbrella. Future work should consider specific classification of balance deficits, including specific sensory phenotypes for balance control.

Quantitative gastrointestinal function and corresponding symptom profiles in autonomic neuropathy.

Purpose: Peripheral neuropathies with autonomic nervous system involvement are a recognized cause of gastrointestinal dysmotility for a wide spectrum of diseases. Recent advances in wireless motility capsule testing allow improved sampling of regional and whole gut motility to aid in the diagnosis of gastrointestinal motility disorders and may provide additional insight into segment-specific enteric involvement of peripheral neuropathies affecting autonomic nervous system function. Methods: We utilized standardized autonomic nervous system (ANS) reflex assessment and wireless motility capsule testing to evaluate 20 individuals with idiopathic autonomic neuropathy and unexplained gastrointestinal symptoms. Additionally, we examined the relationship between quantifiable autonomic neuropathy and gastrointestinal dysmotility at specific neuroanatomical levels. Symptom profiles were evaluated using the 31-item Composite Autonomic Symptom Score questionnaire (COMPASS-31) and compared to wireless motility capsule data. Results: We found that transit times were predominately abnormal (delayed) in the foregut (10 of 20; 50%), while contractility abnormalities were far more prominent in the hindgut (17 of 20; 85%), and that motility and symptom patterns, as assessed by the COMPASS-31 GI domain items, generally corresponded. Finally, we also found that there was neuroanatomical overlap in the presence of autonomic reflex abnormalities and WMC-based transit and/or contractility abnormalities. Conclusions: We found that transit times were predominately abnormal in the foregut and midgut, while contractility abnormalities were far more prominent in the hindgut in individuals with idiopathic autonomic neuropathy. There was a high rate of agreement in segmental wireless motility capsule data with neuroanatomically corresponding standardized ANS function measures (e.g., cardiovagal, sudomotor, adrenergic). Expanded sudomotor testing, including additional neuroanatomical segments, could provide additional indirect assessment of visceral involvement in ANS dysfunction.

Postural orthostatic tachycardia syndrome (POTS): Priorities for POTS care and research from a 2019 National Institutes of Health Expert Consensus Meeting - Part 2.

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.

Mild traumatic brain injury affects the features of migraine.

BACKGROUND: Headache is one of the most common symptoms after concussion, and mild traumatic brain injury (mTBI) is a risk factor for chronic migraine (CM). However, there remains a paucity of data regarding the impact of mTBI on migraine-related symptoms and clinical course. METHODS: Of 2161 migraine patients who participated in the American Registry for Migraine Research between February 2016 and March 2020, 1098 completed questions assessing history of TBI (50.8%). Forty-four patients reported a history of moderate to severe TBI, 413 patients reported a history of mTBI. Patients' demographics, headache symptoms and triggers, history of physical abuse, allodynia symptoms (ASC-12), migraine disability (MIDAS), depression (PHQ-2), and anxiety (GAD-7) were compared between migraine groups with (n = 413) and without (n = 641) a history of mTBI. Either the chi-square-test or Fisher's exact test, as appropriate, was used for the analyses of categorical variables. The Mann-Whitney test was used for the analyses of continuous variables. Logistic regression models were used to compare variables of interest while adjusting for age, gender, and CM. RESULTS: A significantly higher proportion of patients with mTBI had CM (74.3% [307/413] vs. 65.8% [422/641], P = 0.004), had never been married or were divorced (36.6% [147/402] vs. 29.4% [187/636], P = 0.007), self-reported a history of physical abuse (24.3% [84/345] vs. 14.3% [70/491], P <  0.001), had mild to severe anxiety (50.5% [205/406] vs. 41.0% [258/630], P = 0.003), had headache-related vertigo (23.0% [95/413] vs. 15.9% [102/640], P = 0.009), and difficulty finding words (43.0% [174/405] vs. 32.9% [208/633], P <  0.001) in more than half their attacks, and headaches triggered by lack of sleep (39.4% [155/393] vs. 32.6% [198/607], P = 0.018) and reading (6.6% [26/393] vs. 3.0% [18/607], P = 0.016), compared to patients without mTBI. Patients with mTBI had significantly greater ASC-12 scores (median [interquartile range]; 5 [1-9] vs. 4 [1-7], P < 0.001), MIDAS scores (42 [18-85] vs. 34.5 [15-72], P = 0.034), and PHQ-2 scores (1 [0-2] vs. 1 [0-2], P = 0.012). CONCLUSION: Patients with a history of mTBI are more likely to have a self-reported a history of physical abuse, vertigo, and allodynia during headache attacks, headaches triggered by lack of sleep and reading, greater headache burden and headache disability, and symptoms of anxiety and depression. This study suggests that a history of mTBI is associated with the phenotype, burden, clinical course, and associated comorbid diseases in patients with migraine, and highlights the importance of inquiring about a lifetime history of mTBI in patients being evaluated for migraine.

Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.

Determinants of pain interference and headache impact in patients who have chronic migraine with medication overuse: Results from the MOTS trial.

OBJECTIVE: "Pain interference" and "headache impact" refer to negative consequences that pain and headache have on one's life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse. METHODS: Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model. RESULTS: PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact. CONCLUSIONS: Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms.

Photophobia and allodynia in persistent post-traumatic headache are associated with higher disease burden.

OBJECTIVE: To assess photophobia and allodynia in subjects with post-traumatic headache and examine how these sensory hypersensitivities associate with clinical measures of disease burden. BACKGROUND: Post-traumatic headache is the most frequent and disabling long-term consequence of mild traumatic brain injury. There is evidence of sensory dysfunction in acute post-traumatic headache, and it is known from other headache conditions that sensory amplifications correlate with more severe disease. However, systematic studies in post-traumatic headache are surprisingly scarce. METHODS: We tested light and tactile sensitivity, along with measures of disease burden, in 30 persistent post-traumatic headache subjects and 35 controls. RESULTS: In all, 79% of post-traumatic headache subjects exhibited sensory hypersensitivity based on psychophysical assessment. Of those exhibiting hypersensitivity, 54% exhibited both light and tactile sensitivity. Finally, sensory thresholds were correlated across modalities, as well as with headache attack frequency. CONCLUSIONS: In this study, post-traumatic headache subjects with both light and tactile sensitivity had significantly higher headache frequencies and lower sensitivity thresholds to both modalities, compared to those with single or no sensory hypersensitivity. This pattern suggests that hypersensitivity across multiple modalities may be functionally synergistic, reflect a higher disease burden, and may serve as candidate markers of disease.

Arachnoiditis, a complication of epidural blood patch for the treatment of low-pressure headache: A case report and systematic review.

OBJECTIVE: To report a case of arachnoiditis as a complication of epidural blood patch procedures and to systematically review the diagnostic workup, clinical outcomes, and treatment modalities reported in the literature. BACKGROUND: Epidural blood patching is an effective treatment for low-pressure headache secondary to spontaneous cerebrospinal fluid leak or iatrogenic post-dural puncture. Spontaneous intracranial hypotension is believed to be a rare headache disorder, but recently has been diagnosed at higher frequencies, making it an important differential diagnosis for intractable headaches. Arachnoiditis has surfaced as a rare complication of epidural blood patching. Symptom presentation does not always correlate with evidence of meningeal enhancement on imaging. Optimal methods for treatment remain largely unknown. METHODS: Databases Embase and PubMed were searched for all published studies on arachnoiditis post-epidural blood patch using a combination of the following medical subject headings and keywords: arachnoiditis, arachnoid inflammation, adverse event, and epidural blood patch. All original English-language articles that described arachnoid and/or meningeal inflammation in conjunction with epidural blood patch procedures were included for analysis. Title and abstract screening, data extraction, and risk of bias assessment were conducted independently and in duplicate by two reviewers. RESULTS: Seven other cases of arachnoiditis post-blood patch placement have been documented, most of which were diagnosed via magnetic resonance imaging. Six of these were a result of a spinal-epidural anesthesia for labor and delivery. Common symptoms reported were headache, back and radicular pain, paresthesia, and motor weakness. There are currently no proven consensus-based treatment recommendations available. While intravenous methylprednisolone followed by oral prednisone taper was found to be effective in the case presented, the benefit of other multi-modal therapies was unclear. CONCLUSIONS: Headache specialists who treat postural headache should be aware of arachnoiditis as a potentially severe complication of epidural blood patch. The case presented is the first of its kind to report arachnoiditis as a complication of high-volume blood patch for the treatment of spontaneous intracranial hypotension. More studies are required to determine suitable treatment options for post-epidural blood patch arachnoiditis.

Synergistic but separable sensory changes in postural tachycardia syndrome and chronic migraine.

PURPOSE: Up to 90% of patients with postural tachycardia syndrome (PoTS) report headaches, and comorbid migraine headaches are common. Given this, pathophysiological interaction is possible, which may reveal key aspects of disease expression and treatment opportunities. We hypothesized that PoTS subjects-both with and without migraine-would show features of central sensitization, including allodynia and photophobia. METHODS: Eighty participants were evaluated, including 30 PoTS, 30 chronic migraine (CM), and 20 non-headache healthy controls (NH), using tilt table testing, psychophysical assessment of sensory sensitivity thresholds, and an online questionnaire to assess measures of headache burden and associated symptoms. Clinical characteristics and sensory thresholds were compared between disease groups and controls, as well as in a subgroup analysis within the PoTS group, based on headache phenotype. RESULTS: Sensory sensitivity thresholds were significantly lower and symptom scores were higher in both the PoTS and CM groups compared to controls. However, the patterns of expression differed between PoTS and CM, with pain threshold reductions in the forearm only of PoTS subjects (non-trigeminal sensory sensitization), compared to both periorbital and forearm sites in CM. Unexpectedly, light sensitivity thresholds were significantly lower in PoTS than in both CM and NH. CONCLUSIONS: These findings reveal an underappreciated aspect of disease burden in PoTS, and suggest network sensitization similar to, but separable from, that of migraine. The presence of both photophobia and allodynia in PoTS is reflective of exteroceptive rather than strictly interoceptive disruption, and expands our fundamental understanding of the disorder.

Neuroimmunogastroenterology: At the Interface of Neuroimmunology and Gastroenterology.

The central nervous system (CNS) is an important regulator of the gastrointestinal tract, and CNS dysfunction can result in significant and disabling gastrointestinal symptom manifestation. For patients with neuroimmunologic and neuroinflammatory conditions, the recognition of gastrointestinal symptoms is under-appreciated, yet the gastrointestinal manifestations have a dramatic impact on quality of life. The current treatment strategies, often employed independently by the neurologist and gastroenterologist, raise the question of whether such patients are being treated optimally when siloed in one specialty. Neuroimmunogastroenterology lies at the borderlands of medical specialties, and there are few resources to guide neurologists in this area. Here, we provide an overview highlighting the potential mechanisms of crosstalk between immune-mediated neurological disorders and gastrointestinal dysfunction.