Differential Findings on Anorectal Manometry in Patients with Parkinson's Disease and Defecatory Dysfunction.

Introduction: Gastrointestinal dysfunction, particularly constipation, is among the most common non-motor manifestations in Parkinson's Disease (PD). We aimed to identify high-resolution anorectal manometry (HR-ARM) abnormalities in patients with PD using the London Classification. Methods: We conducted a retrospective review of all PD patients at our institution who underwent HR-ARM and balloon expulsion test (BET) for evaluation of constipation between 2015 and 2021. Using age and sex-specific normal values, HR-ARM recordings were re-analyzed and abnormalities were reported using the London Classification. A combination of Wilcoxon rank sum and Fisher's exact test were used. Results: 36 patients (19 women) with median age 71 (interquartile range [IQR]: 69-74) years, were included. Using the London Classification, 7 (19%) patients had anal hypotension, 17 (47%) had anal hypocontractility, and 3 women had combined hypotension and hypocontractility. Anal hypocontractility was significantly more common in women compared to men. Abnormal BET and dyssynergia were noted in 22 (61%) patients, while abnormal BET and poor propulsion were only seen in 2 (5%). Men had significantly more paradoxical anal contraction and higher residual anal pressures during simulated defecation, resulting in more negative recto-anal pressure gradients. Rectal hyposensitivity was seen in nearly one third of PD patients and comparable among men and women. Conclusion: Our data affirms the high prevalence of anorectal disorders in PD. Using the London Classification, abnormal expulsion and dyssynergia and anal hypocontractility were the most common findings in PD. Whether the high prevalence of anal hypocontractility in females is directly related to PD or other confounding factors will require further research.

Stellate ganglion block catheter for paroxysmal sympathetic hyperactivity: calming the 'neuro-storm'.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) is an autonomic disorder affecting patients with severe acquired brain injury characterized by intermittent sympathetic discharges with limited therapeutic options. We hypothesized that the PSH pathophysiology could be interrupted via stellate ganglion blockade (SGB). CASE PRESENTATION: A patient with PSH after midbrain hemorrhage followed by hydrocephalus obtained near-complete resolution of sympathetic events for 140 days after SGB. CONCLUSION: SGB is a promising therapy for PSH, overcoming the limitations of systemic medications and may serve to recalibrate aberrant autonomic states.

Epileptic Seizure Induced by Head-Up Tilt: A Case Series Study.

PURPOSE: Epilepsy and syncope can be difficult to distinguish, with misdiagnosis resulting in unnecessary or incorrect treatment and disability. Combined tilt-table and video EEG (vEEG) testing (tilt-vEEG) is infrequently used to parse these entities even at large centers. Because of the discovery of a rare case of epileptic seizure induced by head-up tilt (HUT) (no prior cases have been published), the authors sought to verify the rarity of this phenomenon. METHODS: An observational, retrospective case series study of all combined tilt-vEEG studies performed at Stanford Health Care over a 2-year period was performed. Studies were grouped into categories: (1) abnormal tilt and normal vEEG; (2) abnormal vEEG and normal tilt; (3) abnormal vEEG and abnormal tilt; (4) normal tilt and normal vEEG, with neurologic symptoms; and (5) normal tilt and normal vEEG without neurologic symptoms. RESULTS: Sixty-eight percent of patients had an abnormal study (categories A-C), with only 3% having both an abnormal tilt and an abnormal EEG (category C). Of these, one patient had a focal epileptic seizure induced by HUT. With HUT positioning, the patient stopped answering questions and vEEG showed a left temporal seizure; systolic blood pressure abruptly dropped to 89 mm Hg (64 mm Hg below baseline); heart rate did not change, but pacemaker showed increased firing (threshold: <60 bpm). CONCLUSIONS: Combined tilt-table and vEEG evaluation was able to identify a previously unreported scenario-head-up tilt provocation of an epileptic seizure-and improve treatment. Combined tilt and vEEG testing should be considered for episodes that persist despite treatment to confirm proper diagnosis.

Children With PANS May Manifest POTS.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by an abrupt-onset of severe psychiatric symptoms including OCD, anxiety, cognitive difficulties, and sleep issues which is thought to be a post-infection brain inflammatory disorder. We observed postural orthostatic tachycardia syndrome (POTS) which resolved with immunomodulation in a patient with Pediatric acute-onset neuropsychiatric syndrome (PANS). Here, we aim to present a case of POTS and to examine the prevalence of (POTS) in our PANS cohort, and compare the clinical characteristics of patients with and without POTS. Study Design: We conducted this cohort study of patients meeting PANS criteria who had at least three clinic visits during the study period. We included data from prospectively collected questionnaires and medical record review. We present a case followed by statistical comparisons within our cohort and a Kaplan-Meier analysis to determine the time-dependent risk of a POTS diagnosis. Results: Our study included 204 patients: mean age of PANS onset was 8.6 years, male sex (60%), non-Hispanic White (78%). Evidence of POTS was observed in 19/204 patients (9%) with 5/19 having persistent POTS defined as persistent abnormal orthostatic vitals, persistent POTS symptoms, and/or continued need for pharmacotherapy for POTS symptoms for at least 6 months). In this PANS cohort, patients with POTS were more likely to have comorbid joint hypermobility (63 vs 37%, p = 0.04), chronic fatigue (42 vs 18%, p = 0.03), and a family history of chronic fatigue, POTS, palpitations and syncope. An unadjusted logistic regression model showed that a PANS flare (abrupt neuropsychiatric deterioration) was significantly associated with an exacerbation of POTS symptoms (OR 3.3, 95% CI 1.4-7.6, p < 0.01). Conclusions: Our study describes a high prevalence of POTS in patients with PANS (compared to the general population) and supports an association between POTS presentation and PANS flare within our cohort.

Cutaneous α-synuclein is correlated with autonomic impairment in isolated rapid eye movement sleep behavior disorder.

STUDY OBJECTIVES: To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson's disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. RESULTS: P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p < 0.05) and total autonomic impairment (CASS total r = 0.6, p < 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. CONCLUSIONS: In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

Myasthenia Symptom Burden, Fatigue, and Sleep: Are They Related?

OBJECTIVE: Our aim is to explore the relationship between myasthenia gravis (MG)-related symptom burden, sleep quality, and fatigue in a diverse group of self-identified MG patients. METHODS: Patients provided relevant myasthenia disease data and completed the MG QOL-15, Epworth sleepiness scale, Pittsburgh Sleep Quality Index, and fatigue severity score (FSS) online. MG activities of daily living scale (MG-ADL) was completed on a follow-up telephone interview. RESULTS: One hundred ninety-six patients completed the online survey and 99 provided MG-ADL data. The mean age was 52 ± 15.34 years, 88 were acetylcholine receptor antibody positive, and 21 were muscle specific kinase positive. The mean MG-ADL was 6.81, indicating a moderate MG disease burden. Forty-seven (24%) reported high Epworth sleepiness scale scores, 152 (77%) reported high Pittsburgh Sleep Quality Index scores, and 162 (82%) reported high FSS scores. Correlation analysis correcting for body mass index and sleep apnea revealed a moderate positive correlation between MGQOL-15, MG-ADL, and FSS. CONCLUSIONS: There is a moderate positive correlation between various MG-specific outcome measures and fatigue severity.

Cyclic vomiting syndrome: Pathophysiology, comorbidities, and future research directions.

Cyclic vomiting syndrome (CVS) is characterized by severe episodic emesis in adults and children. Cannabinoid hyperemesis syndrome is an increasingly recognized CVS-like illness that has been associated with chronic cannabis use. There are significant gaps in our understanding of the pathophysiology, clinical features, comorbidities, and effective management options of CVS. Recommendations for treating CVS are based on limited clinical data, as no placebo-controlled, randomized trials have yet been conducted. Diseases associated with CVS, including migraine, mitochondrial disorders, autonomic dysfunction, and psychiatric comorbidities, provide clues about pathophysiologic mechanisms and suggest potential therapies. We review our current understanding of CVS and propose future research directions with the aim of developing effective therapy. Establishing a multicenter, standardized registry of CVS patients could drive research on multiple fronts including developing CVS-specific outcome measures to broaden our understanding of clinical profiles, to serve as treatment end points in clinical trials, and to provide a platform for patient recruitment for randomized clinical trials. Such a robust database would also facilitate conduct of research that aims to determine the underlying pathophysiological mechanisms and genetic basis for CVS, as well as identifying potential biomarkers for the disorder. Soliciting government and industry support is crucial to establishing the necessary infrastructure and achieving these goals. Patient advocacy groups such as the Cyclic Vomiting Syndrome Association (CVSA), which partner with clinicians and researchers to disseminate new information, to promote ongoing interactions between patients, their families, clinicians, investigators, to support ongoing CVS research and education, must be an integral part of this endeavor.

Management of cyclic vomiting syndrome in adults: Evidence review.

BACKGROUND: This evidence review was conducted to inform the accompanying clinical practice guideline on the management of cyclic vomiting syndrome (CVS) in adults. METHODS: We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and focused on interventions aimed at prophylactic management and abortive treatment of adults with CVS. Specifically, this evidence review addresses the following clinical questions: (a) Should the following pharmacologic agents be used for prophylaxis of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, or mitochondrial supplements? (b) Should the following pharmacologic agents be used for abortive treatment: triptans or aprepitant? RESULTS: We found very low-quality evidence to support the use of the following agents for prophylactic and abortive treatment of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, and mitochondrial supplements. We have moderate certainty of evidence for the use of triptans as abortive therapy. We found limited evidence to support the use of ondansetron and the treatment of co-morbid conditions and complementary therapies. CONCLUSIONS: This evidence review helps inform the accompanying guideline for the management of adults with CVS which is aimed at helping clinicians, patients, and policymakers, and should improve patient outcomes.

Role of chronic cannabis use: Cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome.

Cannabis is commonly used in cyclic vomiting syndrome (CVS) due to its antiemetic and anxiolytic properties. Paradoxically, chronic cannabis use in the context of cyclic vomiting has led to the recognition of a putative new disorder called cannabinoid hyperemesis syndrome (CHS). Since its first description in 2004, numerous case series and case reports have emerged describing this phenomenon. Although not pathognomonic, a patient behavior called "compulsive hot water bathing" has been associated with CHS. There is considerable controversy about how CHS is defined. Most of the data remain heterogenous with limited follow-up, making it difficult to ascertain whether chronic cannabis use is causal, merely a clinical association with CVS, or unmasks or triggers symptoms in patients inherently predisposed to develop CVS. This article will discuss the role of cannabis in the regulation of nausea and vomiting, specifically focusing on both CVS and CHS, in order to address controversies in this context. To this objective, we have collated and analyzed published case series and case reports on CHS in order to determine the number of reported cases that meet current Rome IV criteria for CHS. We have also identified limitations in the existing diagnostic framework and propose revised criteria to diagnose CHS. Future research in this area should improve our understanding of the role of cannabis use in cyclic vomiting and help us better understand and manage this disorder.

Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association.

The increasing recognition of cyclic vomiting syndrome (CVS) in adults prompted the development of these evidence-based guidelines on the management of CVS in adults, which was sponsored by the American Neurogastroenterology and Motility Society (ANMS) and the Cyclic Vomiting Syndrome Association (CVSA). GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework was used and a professional librarian performed the literature search. The expert committee included the President of the CVSA who brought a patient perspective into the deliberations. The committee makes recommendations for the prophylaxis of CVS, treatment of acute attacks, diagnosis, and overall management of CVS. The committee strongly  recommends that adults with moderate-to-severe CVS receive a tricyclic antidepressant (TCA), such as amitriptyline, as a first-line prophylactic medication and receive topiramate or aprepitant as alternate prophylactic medications. Zonisamide or levetiracetam and mitochondrial supplements (Coenzyme Q10, L-carnitine, and riboflavin) are conditionally recommended as alternate prophylactic medications, either alone or concurrently with other prophylactic medications. For acute attacks, the committee conditionally recommends using serotonin antagonists, such as ondansetron, and/or triptans, such as sumatriptan or aprepitant to abort symptoms. Emergency department treatment is best achieved with the use of an individualized treatment protocol and shared with the care team (example provided). The committee recommended screening and treatment for comorbid conditions such as anxiety, depression, migraine headache, autonomic dysfunction, sleep disorders, and substance use with referral to appropriate allied health services as indicated. Techniques like meditation, relaxation, and biofeedback may be offered as complementary therapy to improve overall well-being and patient care outcomes.

Wired for Threat: Clinical Features of Nervous System Dysregulation in 80 Children.

BACKGROUND: The negative effect of perceived stress on health has become a cultural epidemic. Despite many health implications, the clinical impact of stress on the nervous system is not well understood. This case series describes the symptom profiles of 80 children with nervous system dysregulation attributed to maladaptive neuroendocrine responses to stress. METHODS: We reviewed of 80 children with nervous system dysregulation identified from a single, tertiary care pediatric neurology clinic. Included patients were between five and 17 years of age, with unexplained medical symptoms lasting three months or longer affecting at least four of six neurological domains: (1) somatization, (2) executive function, (3) autonomic function, (4) digestion, (5) sleep, and (6) emotional regulation. Medical symptoms, diagnoses, and detailed social histories were collected. RESULTS: Of 80 children, 57 were female (71%), 57 were Caucasian (71%), with median age of 14 years. Symptoms had a mean duration of 32 months, and included: 100% somatic symptoms, 100% emotional dysregulation, 92.5% disrupted sleep, 82.5% autonomic dysregulation, 75% executive dysfunction, and 66% digestive problems. Overall, 94% reported chronic or traumatic stressors; adverse childhood experiences were present in 65%. CONCLUSIONS: Perceived stress impacts many functions of the neuroendocrine system through experience-dependent plasticity, resulting in a constellation of symptoms and functional impairments we describe as nervous system dysregulation. The pathophysiology of these symptoms involves dysregulation of subcortical, hormonal, and autonomic circuits, which remain largely untested. Recognition and understanding of maladaptive neurophysiology in stress-related symptoms has important implications for diagnosis, treatment, and advances in health research.

The clinical utility of qualitative electroencephalography during tilt table testing - A retrospective study.

OBJECTIVE: To assess electroencephalography (EEG) changes during tilt table testing in syncope and other orthostatic syndromes. METHODS: We retrospectively reviewed consecutive tilt table studies with simultaneous EEG from April 2014 to May 2016 at our center. All patients had video EEG during tilt table. All patients had at least 10 min of head up tilt unless they had syncope or did not tolerate the study. Video EEG was interpreted by epileptologists. RESULTS: Eighty-seven patients met the inclusion criteria. Mean age was 45 years, and 55 were women. Seven patients (∼8%) had syncope during tilt table, 11 patients (∼12%) had significant neurogenic orthostatic hypotension and a separate group of 11 patients (∼12%) had significant orthostatic tachycardia. Valsalva responses were abnormal in 7 of the 11 patients with orthostatic hypotension, suggesting an underlying neurogenic orthostatic hypotension. Visually discernable EEG changes were seen in only 3 patients (∼43%) who had syncope and in 1 patient (∼9%) with orthostatic tachycardia. CONCLUSIONS: Qualitative EEG analysis based on visual inspection during tilt table study revealed abnormalities in less than half the patients with syncope and a very small fraction with orthostatic tachycardia. SIGNIFICANCE: Routine qualitative EEG recording might not be clinically useful during tilt table studies.

A case series of REM sleep behavior disorder in pure autonomic failure.

PURPOSE: Data on the prevalence of RBD in patients with PAF are limited, with discrepancies in the literature regarding prevalence. We aimed to provide further data on this association with a series of eight patients with PAF. METHODS: We reviewed the electronic medical records of all patients seen at the Stanford neurology clinics from 2012 to 2016 who were given a provisional diagnosis of PAF (343 patients), and further screened by procedure codes to identify those patients who underwent both attended video-polysomonography and autonomic testing (18 patients), and met strict exclusionary criteria (8 patients). RESULTS: The mean age of our patients was 69 years, and 63 % were women. The mean duration of autonomic symptoms was 11.2 years, and the mean duration of dream enactment was 3.75 years. All patients demonstrated evidence of adrenergic failure on autonomic testing. Five out of 8 (63 %) met diagnostic criteria for RBD, confirmed on vPSG. CONCLUSIONS: Our series supports the concept that RBD in PAF may be more common than previously reported, and that the presence of RBD suggests brainstem involvement in some cases of PAF. In addition, the timing of RBD symptoms relative to the emergence of autonomic symptoms may be useful to help distinguish these conditions.

Pediatric Anti-ganglionic Antibody Positive Autonomic Neuropathy: Clinical Presentation and Response to Treatment.

BACKGROUND: Autoimmune autonomic neuropathy is rare in children. There are few pediatric reports documenting anti-ganglionic antibodies. METHODS: We present two children with anti-ganglionic antibody positive autonomic neuropathy, including their presentation, results of testing, and treatment course. RESULTS: Both children had delayed diagnoses because of the presence of vague autonomic symptoms. Treatment with multiple immunotherapies appears to bring at least a partial response and can be monitored with anti-ganglionic antibody titers. CONCLUSION: Our findings contribute to the sparse literature in pediatric autoimmune autonomic neuropathy and highlight the need for additional studies to create diagnostic criteria and define optimal treatment regimens.