Mast Cell Activation Syndrome: current understanding and research needs.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities which have gained increased attention from patients and medical providers. While several descriptive publications about MCAS exist, there are many gaps in knowledge resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell (MC) activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to MC activation in MCAS patients remain to be elucidated. The purpose of this manuscript is to summarize the known literature, identify gaps in knowledge, and highlight research needs. Several topics are covered: 1) Contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; 2) Mechanistic research; 3) Management of typical and refractory symptoms, and 4) MCAS-specific education for patients and healthcare providers.

Head-down tilt reduces the heart rate in postural tachycardia syndrome in acute setting: a pilot study.

BACKGROUND: Reduced preload and thoracic blood volume accompany postural tachycardia syndrome (POTS). Head-down tilt (HDT) increases both preload and intrathoracic blood volume. The objective of this study was to assess the safety and efficacy of HDT in POTS in acute settings. METHODS: This retrospective study evaluated POTS patients. Analyzed data included heart rate, blood pressure, cerebral blood flow velocity (CBFv) in the middle cerebral artery, and capnography. The baseline supine hemodynamic data were compared with the data obtained at the second minute of the -10° HDT. A linear mixed-effects model was used to assess the effect of HDT on hemodynamic variables. RESULTS: The HDT was explored in seven POTS patients and an additional seven POTS patients without HDT served as controls. In the HDT arm, four POTS patients had overlapping diagnoses of myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) and one patient had comorbidity of post-acute sequelae of SARS-CoV-2 infection (PASC). HDT lowered heart rate by 10% and increased end-tidal CO2 by 8%. There was no change in other cardiovascular variables. CONCLUSIONS: In the acute setting, HDT is safe. HDT reduces the heart rate presumably by modulating baroreflex by enhancing preload and stroke volume, which in turn increases thoracic blood volume with a net effect of parasympathetic cardiovagal activation and/or sympathetic withdrawal. This pilot study provides a foundation to proceed with longitudinal studies exploring the long-term effect of repetitive HDT in conditions associated with preload failure such as POTS, ME/CSF, and PASC.

Cerebral blood flow and end-tidal CO2 predict lightheadedness during head-up tilt in patients with orthostatic intolerance.

Orthostatic intolerance (OI) is a common problem. Reliable markers of OI are missing, as orthostatic blood pressure and heart rate poorly correlate with orthostatic symptoms. The objective of this study was to assess the relationship between orthostatic lightheadedness and cerebral blood flow. In this retrospective study patients with OI were evaluated at the Autonomic Laboratory of the Department of Neurology, Brigham and Women's Faulkner Hospital, Boston. The 10-minute head-up tilt test was performed as a part of autonomic testing. Orthostatic lightheadedness was evaluated at every minute of the head-up tilt. Heart rate, blood pressure, capnography, and cerebral blood flow velocity (CBFv) in the middle cerebral artery using transcranial Doppler were measured. Repeated-measures design with a linear mixed-effects model was used to evaluate the relationship between orthostatic lightheadedness and hemodynamic variables. Correlation analyses were done by calculating Pearson's coefficient. Twenty-two patients with OI were compared to nineteen controls. Orthostatic CBFv and end-tidal CO2 decreased in OI patients compared to controls (p < 0.001) and predicted orthostatic lightheadedness. Orthostatic heart rate and blood pressure failed to predict orthostatic lightheadedness. The lightheadedness threshold, which marked the onset of lightheadedness, was equal to an average systolic CBFv decrease of 18.92% and end-tidal CO2 of 12.82%. The intensity of lightheadedness was proportional to the CBFv and end-tidal CO2 decline. Orthostatic lightheadedness correlated with systolic CBFv (r=-0.6, p < 0.001) and end-tidal CO2 (r=-0.33, p < 0.001) decline. In conclusion, orthostatic CBFv and end-tidal CO2 changes predict orthostatic lightheadedness and can be used as objective markers of OI.

Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19.

OBJECTIVE: The purpose of this study was to describe cerebrovascular, neuropathic, and autonomic features of post-acute sequelae of coronavirus disease 2019 ((COVID-19) PASC). METHODS: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog, and orthostatic intolerance consistent with PASC. Controls included patients with postural tachycardia syndrome (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor, and tilt tests), cerebrovascular (cerebral blood flow velocity [CBFv] monitoring in middle cerebral artery), respiratory (capnography monitoring), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers. RESULTS: Nine patients with PASC were evaluated 0.8 ± 0.3 years after a mild COVID-19 infection, and were treated as home observations. Autonomic, pain, brain fog, fatigue, and dyspnea surveys were abnormal in PASC and POTS (n = 10), compared with controls (n = 15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0 ± 13.4%) and POTS (-20.3 ± 15.1%), compared with controls (-3.0 ± 7.5%, p = 0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n = 6) and with (n = 3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p = 0.002). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs 60%) but not in inflammatory markers (67% vs 70%). Supine and orthostatic hypocapnia was observed in PASC. INTERPRETATION: PASC following mild COVID-19 infection is associated with multisystem involvement including: (1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; (2) small fiber neuropathy and related dysautonomia; (3) respiratory dysregulation; and (4) chronic inflammation. ANN NEUROL 2022;91:367-379.

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Mast cell disorders are associated with decreased cerebral blood flow and small fiber neuropathy.

BACKGROUND: Mast cell disorders including hereditary alpha tryptasemia (HαT) and idiopathic mast cell activation syndrome (MCAS) can be associated with neurologic symptoms such as orthostatic intolerance, pain, and cognitive impairment. The origin of these symptoms is not well understood. OBJECTIVE: To characterize neurologic findings in patients with HαT and MCAS through objective measurements. METHODS: Patients with a confirmed diagnosis of HαT or MCAS with neurologic symptoms were referred for standardized autonomic testing encompassing Valsalva maneuver, deep breathing, sudomotor and tilt tests with cerebral blood flow velocity (CBFv) determination, and skin biopsies for small fiber neuropathy (SFN). RESULTS: There were 15 patients with HαT (age 44.4 ± 15.9 years), 16 with MCAS (34.4 ± 15.5), and 14 matched controls who were evaluated. Baseline serum tryptase level was increased in patients with HαT when compared with patients with MCAS (14.3 ± 2.5 ng/mL vs 3.8 ± 1.8; P <.001) and neurologic symptoms were similar between the 2 groups. When compared with controls, orthostatic CBFv was reduced in HαT (-24.2 ± 14.3%; P <.001) and MCAS (-20.8 ± 5.5%; P <.001). Reduced nerve fibers consistent with SFN were found in 80% of patients with HαT and 81% of those with MCAS. Mild-to-moderate dysautonomia was detected in all patients with HαT and MCAS when results of sympathetic, parasympathetic, and sudomotor tests were combined. CONCLUSION: We provide evidence of reduced orthostatic CBFv and SFN associated with mild-to-moderate autonomic dysfunction in patients with HαT and MCAS. Our findings suggest that comprehensive autonomic testing may be helpful to explain neurologic symptoms and guide treatment in patients with HαT and MCAS.

Qpack-a Python package for QASAT-quantitative scale for grading cerebral blood flow, autonomic testing, and skin biopsies.

Quantitative grading of testing has research and clinical relevance. QASAT (quantitative scale for grading of cardiovascular reflex tests, transcranial Doppler, sudomotor testing, and small fiber densities from skin biopsies) is an objective instrument for grading dysautonomia, related small fiber neuropathy and cerebral blood flow. QASAT uses established autonomic tests (deep breathing, Valsalva maneuver, tilt test, sudomotor test) and skin biopsies for assessment of small fibers. Calculations of scores are complex. This paper presents a qpack-an open source software package that implements QASAT in a Python programming language. The qpack automatically generates reproducible scores of each test and reduces calculation errors. Datasets for verifying the correct qpack implementation are provided. The goal of qpack is to facilitate availability, reproducibility, and quality of autonomic studies and skin biopsies for assessment of small fibers. Qpack is easy to use with standard Python distributions, can be incorporated into routine clinical or research autonomic testing and it is freely available.

Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome.

BACKGROUND: The autonomic nervous system (ANS) is a complex network where sympathetic and parasympathetic domains interact inside and outside of the network. Correlation-based network analysis (NA) is a novel approach enabling the quantification of these interactions. The aim of this study is to assess the applicability of NA to assess relationships between autonomic, sensory, respiratory, cerebrovascular, and inflammatory markers on post-acute sequela of COVID-19 (PASC) and postural tachycardia syndrome (POTS). METHODS: In this retrospective study, datasets from PASC (n = 15), POTS (n = 15), and matched controls (n = 11) were analyzed. Networks were constructed from surveys (autonomic and sensory), autonomic tests (deep breathing, Valsalva maneuver, tilt, and sudomotor test) results using heart rate, blood pressure, cerebral blood flow velocity (CBFv), capnography, skin biopsies for assessment of small fiber neuropathy (SFN), and various inflammatory markers. Networks were characterized by clusters and centrality metrics. RESULTS: Standard analysis showed widespread abnormalities including reduced orthostatic CBFv in 100%/88% (PASC/POTS), SFN 77%/88%, mild-to-moderate dysautonomia 100%/100%, hypocapnia 87%/100%, and elevated inflammatory markers. NA showed different signatures for both disorders with centrality metrics of vascular and inflammatory variables playing prominent roles in differentiating PASC from POTS. CONCLUSIONS: NA is suitable for a relationship analysis between autonomic and nonautonomic components. Our preliminary analyses indicate that NA can expand the value of autonomic testing and provide new insight into the functioning of the ANS and related systems in complex disease processes such as PASC and POTS.

Network meta-analysis of prophylactic pancreatic stents and non-steroidal anti-inflammatory drugs in the prevention of moderate-to-severe post-ERCP pancreatitis.

BACKGROUND: There is an ongoing debate that non-steroidal anti-inflammatory drugs (NSAID) or prophylactic pancreatic stents (PPS) are more beneficial in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). In our present network meta-analysis, we aimed to compare PPSs to rectal NSAIDs in the prevention of moderate and severe PEP in average- and high-risk patients. METHODS: We performed a systematic search for randomized controlled trials (RCT) from MEDLINE (via PubMed), Embase and Cochrane Central databases. RCTs using prophylactic rectal NSAIDs or PPSs in patients subjected to ERCP at average- and high-risk population were included. The main outcome was moderate and severe PEP defined by the Cotton criteria. Pairwise Bayesian network meta-analysis was performed, and interventions were ranked based on surface under cumulative ranking (SUCRA) values. RESULTS: Seven NSAID RCTs (2593 patients), and 2 PPS RCTs (265 patients) in the average-risk, while 5 NSAID RCTs (1703 patients), and 8 PPS RCTs (974 patients) in the high-risk group were included in the final analysis. Compared to placebo, only PPS placement reduced the risk of moderate and severe PEP in both patient groups (average-risk: RR = 0.07, 95% CI [0.002-0.58], high-risk: RR = 0.20, 95% CI [0.051-0.56]) significantly. Rectal NSAID also reduced the risk, but this effect was not significant (average-risk: RR = 0.58, 95% CI [0.22-1.3], high-risk: RR = 0.58, 95% CI [0.18-2.3]). Based on SUCRA, PPS placement was ranked as the best preventive method. CONCLUSION: Prophylactic pancreatic stent placement but not rectal NSAID seems to prevent moderate-to-severe PEP better both, in average- and high-risk patients.

TS-HDS and FGFR3 antibodies in small fiber neuropathy and Dysautonomia.

INTRODUCTION: The specificity of trisulfated heparin disaccharide/fibroblast growth factor receptor 3 (TS-HDS/FGFR3) antibodies in the diagnosis of autoimmune small fiber neuropathy (SFN) is unclear. METHODS: This was a retrospective study of patients evaluated for SFN and dysautonomia in the Brigham and Women's Faulkner Hospital Autonomic Laboratory in 2019-2020. Associations were assessed between TS-HDS/FGFR3 antibodies and SFN markers, including epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD), and autonomic dysfunction assessed by Valsalva maneuver, deep breathing, sudomotor, and tilt testing. RESULTS: Of 322 patients; 28% had elevated anti-TS-HDS, 17% had elevated anti-FGFR3, 96% had autonomic dysfunction, 71% had abnormal ENFD, and 49% had abnormal SGNFD. TS-HDS/FGFR3 antibodies were present in patients with autonomic dysfunction irrespective of whether they had normal or abnormal skin biopsies unless ENFD/SGNFD were combined for anti-FGFR3 seropositivity. DISCUSSION: TS-HDS/FGFR3 antibodies are present in patients with evidence of autonomic dysfunction. Further studies are needed to document the clinical value of these antibodies in assessment of immune mediated dysautonomia.

Hereditary alpha-tryptasemia in 101 patients with mast cell activation-related symptomatology including anaphylaxis.

BACKGROUND: Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait characterized by multiple copies of the alpha-tryptase gene at the TPSAB1 locus. Previously described symptomatology involves multiple organ systems and anaphylaxis. The spectrum of mast cell activation symptoms is unknown, as is its association with specific genotypes. OBJECTIVE: To describe clinical, laboratory, and genetic characteristics of patients referred for the evaluation of mast cell activation-related symptoms and genotype-confirmed HαT. METHODS: We retrospectively describe clinical characteristics, baseline tryptase, and tryptase genotype in 101 patients. Patients were referred for mast cell activation-related symptoms and underwent genotyping to confirm diagnosis of HαT. RESULTS: Of 101 patients, 80% were female with average tryptase of 17.2 ng/mL. Tryptase was less than 11.4 ng/mL in 8.9% and greater than 20 ng/mL in 22.3% (range 6.2-51.3 ng/mL). KIT D816V mutation was negative in all subjects tested. 2α:3ß was the most common genotype but did not correlate with tryptase levels. Unprovoked anaphylaxis was noted in 57% of the subjects with heterogeneous genotypes. Most common symptoms include gastrointestinal, cutaneous, psychiatric, pulmonary, cardiovascular, and neurologic. A total of 85% of patients were taking H1- or H2-antihistamines with partial symptom relief. Omalizumab was effective at suppressing anaphylaxis or urticaria in 94% of the patients. CONCLUSION: HαT encompasses a broad range of baseline tryptase and should be considered in patients with symptoms of mast cell activation and tryptase levels greater than 6.2 ng/mL. Patients may present with complex symptomatology including cutaneous, gastrointestinal, neurologic, and psychiatric symptoms and anaphylaxis, some of which respond to omalizumab.

Electrochemical skin conductance: a systematic review.

PURPOSE: Currently available techniques for the evaluation of small fiber neuropathy and related sudomotor function remain suboptimal. Electrochemical skin conductance (ESC) has recently been introduced as a simple noninvasive and fast method for the detection of sudomotor dysfunction. The purpose of this review is to synthesize and appraise research using ESC measurements for sudomotor evaluation in adults. METHODS: Electronic databases including MEDLINE and Google Scholar were searched (up to March 13, 2017). The search strategy included the following terms: "electrochemical skin conductance," "Sudoscan," and "EZSCAN." Evidence was graded according to defined quality indicators including (1) level of evidence; (2) use of established tests as reference tests (e.g., quantitative sudomotor axon test [QSART], sympathetic skin responses [SSR], thermoregulatory sweat test [TST], and skin biopsies to assess sudomotor and epidermal small fibers); (3) use of consecutive/non-consecutive subjects; and (4) study design (prospective/retrospective). RESULTS: A total of 24 studies met the inclusion criteria. These were classified into preclinical, normative, comparative/diagnostic, or interventional. ESC measurement properties, diagnostic accuracy, and similarities to and differences from established tests were examined. CONCLUSIONS: ESC measurements expand the arsenal of available tests for the evaluation of sudomotor dysfunction. The advantages and disadvantages of ESC versus established tests for evaluating sudomotor/small fiber function reviewed herein should be used as evidence to inform future guidelines on the assessment of sudomotor function.

A Comparison of Unilateral Deep Brain Stimulation (DBS), Simultaneous Bilateral DBS, and Staged Bilateral DBS Lead Accuracies.

BACKGROUND: Accuracy of lead placement within the brain can affect the outcome of deep brain stimulation (DBS) surgery. Whether performing unilateral lead implantation, simultaneous bilateral lead implantation, or staged bilateral lead implantation affects accuracy has not yet been assessed. We compare lead placement errors to evaluate whether one approach affords greater lead accuracy. METHODS: We retrospectively reviewed 205 leads placed in 125 DBS surgeries. The accuracy of lead placement, defined by differences in x, y, and z coordinates and error vector magnitudes, was compared between three surgery groups: unilateral leads, bilateral leads placed simultaneously, and bilateral leads placed in staged surgeries. We also compared accuracies between first and second leads within each bilateral cohort and between second leads of the bilateral cohorts. Finally, we examined the effect of target and age on accuracy. RESULTS: The accuracy of lead placement was comparable among unilateral, simultaneous bilateral, and staged bilateral leads. Timing of placement of the second lead in bilateral cases was not found to affect accuracy. The mean number of microelectrode trajectories was greater for first leads in simultaneous bilateral DBS (p = 0.032). No significant correlation between either age or target and accuracy was found. CONCLUSION: Although there may be other important reasons for performing DBS in a staged fashion, our study finds that neither laterality nor timing of second lead placement, patient age, or target site have significant impact on DBS lead accuracy, a finding that indicates with appropriate approach selection based on patient factors, accuracy does not have to be significantly compromised.

[The effect of smoking on the quality of life enhancement following prosthetic rehabilitation in head and neck cancer patients who underwent surgical treatment]. / A dohányzás hatása a fej-nyak régió daganata miatt sebészi terápiában részesült betegek protetikai rehabilitációt követo életminoség-javulására.

INTRODUCTION: It is known that the quality of life (QoL) of patients surgically treated for head and neck cancer (HNC) is significantly enhanced by rehabilitation. It is also known that some of these patients will not quit smoking. AIM: To assess if smoking hampers rehabilitation-related QoL enhancement after surgery. METHOD: Applying the H&N 35 questionnaire of EORTC, we assessed the QoL of 38 smoking and non-smoking patients who underwent surgical therapy for HNC and subsequent rehabilitation. QoL was assessed after surgery (after the healing period) and 6 months after rehabilitation. RESULTS: While the QoL enhancement of nonsmokers was significant in almost all aspects, that of smoking patients did not reach the level of significance on a number of scales. The results suggest that smoking does not hamper rehabilitation directly, rather, it prevents rehabilitation from exerting its beneficial effects through its own effects. CONCLUSIONS: Smoking is a factor that measurably acts against the efforts to enhance the QoL of the surgically treated HNC patient. Therefore, it is essential that emphasis is put on smoking cessation right from the cancer diagnosis also for this reason. Orv. Hetil., 2017, 158(5), 172-177.

Natural history and biomarkers in hereditary sensory neuropathy type 1.

INTRODUCTION: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. METHODS: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. RESULTS: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14-54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = -0.8) and median motor amplitude (r2 = -0.75). CONCLUSIONS: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials.

Quality of life in head and neck cancer patients after tumor therapy and subsequent rehabilitation: an exploratory study.

PURPOSE: The aim of the study was to evaluate patient-reported quality of life effects of post-treatment intraoral and extraoral rehabilitation in head and neck cancer by repeated measures. METHODS: Fifty-nine patients were involved. Basic socio-demographic, oncological and epidemiological data were gathered, and the type of rehabilitation was recorded. For the assessment of quality of life changes, two widely used brief questionnaires, the University of Washington Quality of Life Questionnaire and the Head and Neck module of the European Organization of Research and Treatment for Cancer Quality of Life Questionnaire, were used. The questionnaires were administered to patients two times: the first time after tumor therapy, but before rehabilitation (upon arriving for rehabilitation) and the second time 6 months after the application of any particular method of rehabilitation. Quality of life data were gathered prospectively, while socio-demographic data were gathered from patient files. RESULTS: Quality of life after rehabilitation was significantly enhanced as compared to the post-treatment status, in all domains of both questionnaires (p < 0.05 and p < 0.01, Mann-Whitney U). CONCLUSIONS: The results support the hypothesis that post-treatment maxillofacial rehabilitation in head and neck cancer does not only restore lost physical capabilities, but also brings about profound changes in patients' quality of life in general.

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.

Intraparenchymal cyst development after deep brain stimulator placement.

Following deep brain stimulation (DBS) surgery, a variety of potential mechanical or functional complications ranging from perioperative events to hardware malfunction may occur. We present 2 patients who developed a unique complication of cyst formation at the tip of the DBS electrode in the absence of infection. One patient had a unilateral ventral intermediate lead placement for essential tremor, and the other had bilateral subthalamic nucleus (STN) placement for Parkinson's disease. After a period of symptom control, at 3 and 8 months after surgery, respectively, both patients developed new neurological deficits and were found to have a cyst at the left DBS lead tip. The right lead in the patient with the bilateral STN implant was without issue. Both affected leads were removed and the problematic symptoms regressed quickly over several days, though the lesion effect on the patients' initial tremor symptoms lasted for months. Bacteriological cultures of the removed electrodes and wounds were negative. We report a rare complication of DBS and show that simply removing the involved lead results in cyst resolution.