Serotonin syndrome treated with cyproheptadine using NPi from a digital pupillometer as a therapeutic indicator: A case report.

RATIONALE: Serotonin syndrome is a potentially life-threatening condition resulting from the use of antidepressants, their interactions with other serotonergic medications, or poisoning. It presents with a triad of psychiatric, dysautonomic, and neurological symptoms and is sometimes fatal. While cyproheptadine is a specific treatment option, the optimal duration of its administration remains unclear. The purpose of this report is to quantitatively assess the endpoints of serotonin syndrome treatment. Based on the hypothesis that neurological pupil index (NPi) on a digital pupil recorder would correlate with the severity of the serotonin syndrome, we administered cyproheptadine using NPi as an indicator. PATIENT CONCERNS: A patient with a history of depression was brought to our hospital after he overdosed on 251 tablets of serotonin and noradrenaline reuptake inhibitors. DIAGNOSES: On day 3, the patient was diagnosed with serotonin syndrome. INTERVENTIONS: Cyproheptadine syrup was administered at 4 mg every 4 hours. The NPi of the automated pupillometer was simultaneously measured. On day 5, the NPi exceeded 3.0 cyproheptadine was discontinued. OUTCOMES: The patient was discharged on day 7. LESSONS: The lack of considerable improvement during the treatment period suggests that the patient may have improved on his own. In this case, the relationship between NPi and the severity of serotonin syndrome could not be determined.

Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19.

OBJECTIVES: To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment. METHODS: A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention. RESULTS: Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02). DISCUSSION: Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence. It is a retrospective cohort study.

Evaluation of cardiac autonomic dysfunctions in children with type 1 diabetes mellitus.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes, impacting the autonomic nerves that regulate the heart and blood vessels. Timely recognition and treatment of CAN are crucial in averting the onset of cardiovascular complications. Both clinically apparent autonomic neuropathy and subclinical autonomic neuropathy, particularly CAN pose a significant risk of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Notably, CAN can progress silently before manifesting clinically. In our study, we assessed patients with poor metabolic control, without symptoms, following the ISPAD 2022 guideline. The objective is is to determine which parameters we can use to diagnose CAN in the subclinical period. METHODS: Our study is a cross-sectional case-control study that includes 30 children diagnosed with T1DM exhibiting poor metabolic control (average HbA1c > 8.5% for at least 1 year) according to the ISPAD 2022 Consensus Guide. These patients, who are under the care of the pediatric diabetes clinic, underwent evaluation through four noninvasive autonomic tests: echocardiography, 24-h Holter ECG for heart rate variability (HRV), cardiopulmonary exercise test, and tilt table test. RESULTS: The average age of the patients was 13.73 ± 1.96 years, the average diabetes duration was 8 ± 3.66 years, and the 1-year average HbA1c value was 11.34 ± 21%. In our asymptomatic and poorly metabolically controlled patient group, we found a decrease in HRV values, the presence of postural hypotension with the tilt table test, and a decrease in ventricular diastolic functions that are consistent with the presence of CAN. Despite CAN, the systolic functions of the ventricles were preserved, and the dimensions of the cardiac chambers and cardiopulmonary exercise test were normal. CONCLUSIONS: CAN is a common complication of T1DM, often associated with the patient's age and poor glycemic control. HRV, active orthostatic tests, and the evaluation of diastolic dysfunctions play significant roles in the comprehensive assessment of CAN. These diagnostic measures are valuable tools in identifying autonomic dysfunction at an early stage, allowing for timely intervention and management to mitigate the impact of cardiovascular complications associated with T1DM.

Aerobic exercise attenuates dysautonomia, cardiac diastolic dysfunctions, and hemodynamic overload in female mice with atherosclerosis.

Cardiovascular risk increases during the aging process in women with atherosclerosis and exercise training is a strategy for management of cardiac risks in at-risk populations. Therefore, the aims of this study were to evaluate: (1) the influence of the aging process on cardiac function, hemodynamics, cardiovascular autonomic modulation, and baroreflex sensitivity in females with atherosclerosis at the onset of reproductive senescence; and (2) the impact of exercise training on age-related dysfunctions in this model. Eighteen Apolipoprotein-E knockout female mice were divided equally into young (Y), middle-aged (MA), and trained middle-aged (MAT). Echocardiographic exams were performed to verify cardiac morphology and function. Cannulation for direct recording of blood pressure and heart rate, and analysis of cardiovascular autonomic modulation, baroreflex sensitivity were performed. The MA had lower cardiac diastolic function (E'/A' ratio), and higher aortic thickness, heart rate and mean arterial pressure, lower heart rate variability and baroreflex sensitivity compared with Y. There were no differences between Y and MAT in these parameters. Positive correlation coefficients were found between aortic wall thickness with hemodynamics data. The aging process causes a series of deleterious effects such as hemodynamic overload and dysautonomia in female with atherosclerosis. Exercise training was effective in mitigating aged-related dysfunctions.

Impact of sleep quality and physical activity on blood pressure variability.

Increased blood pressure variability (BPV) is linked to cardiovascular disease and mortality, yet few modifiable BPV risk factors are known. We aimed to assess the relationship between sleep quality and activity level on longitudinal BPV in a cohort of community-dwelling adults (age ≥18) from 17 countries. Using Withings home measurement devices, we examined sleep quality and physical activity over one year, operationalized as mean daily step count and number of sleep interruptions, both transformed into tertiles. The primary study outcome was high BPV, defined as the top tertile of systolic blood pressure standard deviation. Our cohort comprised 29,375 individuals (mean age = 58.6 years) with 127.8±90.1 mean days of measurements. After adjusting for age, gender, country, body mass index, measurement days, mean blood pressure, and total time in bed, the odds ratio of having high BPV for those in the top tertile of sleep interruptions (poor sleep) was 1.37 (95% CI, 1.28-1.47) and 1.44 (95% CI, 1.35-1.54) for those in the lowest tertile of step count (physically inactive). Combining these exposures revealed a significant excess relative risk of 0.20 (95% CI, 0.04-0.35, p = 0.012), confirming their super-additive effect. Comparing individuals with the worst exposure status (lowest step count and highest sleep interruptions, n = 2,690) to those with the most optimal status (highest step count and lowest sleep interruptions, n = 3,531) yielded an odds ratio of 2.01 (95% CI, 1.80-2.25) for high BPV. Our findings demonstrate that poor sleep quality and physical inactivity are associated with increased BPV both independently and super-additively.

Blepharoptosis As an Early Manifestation of Neuronal Intranuclear Inclusion Disease.

Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical manifestations. Our patient was a 64-year-old woman with bilateral ptosis as the chief complaint. She had bilateral miosis, and the pupil was only slightly dilated 60 min after 1% phenylephrine administration, suggesting autonomic dysfunction secondary to preganglionic sympathetic impairment. A head-up tilt test revealed asymptomatic orthostatic hypotension. She was diagnosed with NIID based on a skin biopsy and genetic testing. This study suggests that blepharoptosis is an early manifestation of NIID. Furthermore, patients with suspected NIID should be examined carefully for autonomic dysfunction.

Neuronal intranuclear inclusion disease misdiagnosed as Parkinson's disease: a case report.

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease that mainly manifests as dementia, muscle weakness, sensory disturbances, and autonomic nervous dysfunction. Herein, we report a 68-year-old Chinese woman who was hospitalized because of resting tremor and bradykinesia that had been present for 7 years. Five years prior, bradykinesia and hypermyotonia had become apparent. She had urinary incontinence and rapid eye movement sleep behavior disorder. She was diagnosed with Parkinson's disease (PD) and received levodopa and pramipexole, which relieved her motor symptoms. During hospitalization, diffusion-weighted imaging revealed a high-intensity signal along the cortical medullary junction. Moreover, a skin biopsy revealed the presence of intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells. NIID was diagnosed by testing the Notch 2 N-terminal-like C (NOTCH2NLC) gene. We report this case to remind doctors to consider NIID when diagnosing patients with symptoms indicative of Parkinson's disease. Moreover, we note that further research is needed on the mechanism by which levodopa is effective for NIID.

The effect of breathing hypoxic gas (15% FIO2 ) on physiological and behavioral outcomes during simulated driving in healthy subjects.

Hypoxia is mainly caused by cardiopulmonary disease or high-altitude exposure. We used a driving simulator to investigate whether breathing hypoxic gas influences driving behaviors in healthy subjects. Fifty-two healthy subjects were recruited in this study, approved by the Science and Engineering Ethical Committee. During simulated driving experiments, driving behaviors, breathing frequency, oxygen saturation (SpO2 ), and heart rate variability (HRV) were analyzed. Each subject had four driving sessions; a 10-min practice and three 20-min randomized interventions: normoxic room air (21% FIO2 ) and medical air (21% FIO2 ) and hypoxic air (equal to 15% FIO2 ), analyzed by repeated measures ANOVA. Driving behaviors and HRV frequency domains showed no significant change. Heart rate (HR; p < 0.0001), standard deviation of the RR interval (SDRR; p = 0.03), short-term HRV (SD1; p < 0.0001), breathing rate (p = 0.01), and SpO2 (p < 0.0001) were all significantly different over the three gas interventions. Pairwise comparisons showed HR increased during hypoxic gas exposure compared to both normoxic interventions, while SDRR, SD1, breathing rate, and SpO2 were lower. Breathing hypoxic gas (15% FiO2 , equivalent to 2710 m altitude) may not have a significant impact on driving behavior in healthy subjects. Furthermore, HRV was negatively affected by hypoxic gas exposure while driving suggesting further research to investigate the impact of breathing hypoxic gas on driving performance for patients with autonomic dysfunction.

Effect of psychosocial factors on autonomic nervous system activity in patients with heart failure.

Autonomic imbalance predicts worse clinical outcomes in patients with heart failure (HF). Managing the variables affecting heart rate variability (HRV) might improve the clinical outcomes of patients with HF. This study aimed to investigate variables affecting HRV. We assessed autonomic nervous system activity (low-frequency [Lf], high-frequency [Hf], and Lf/Hf ratio) in 60 patients with HF, employing standard measures to capture short-term HRV. To estimate the independent effects of variables such as well-known cardiac risk factors and psychosocial conditions on HRV, multivariate analyses were conducted. For psychosocial variables, we assessed depression and quality of life in patients and their family caregivers. We also assessed the self-care behavior of patients and their caregivers' burden. Depression in family caregivers and self-care behavior of patients were independently associated with a decreased Hf (ß-coefficient = 0.309, P = .039 and ß-coefficient = -0.029, P = .047, respectively). Depression of family caregivers and self-care behavior of patients may affect HRV in patients with HF.

Unveiling the age-related dynamics in Sjögren's syndrome: Insights from heart rate variability and autonomic function.

BACKGROUND: Sjögren's Syndrome (SS), mainly affecting women in their midlife, is characterized by persistent inflammation in glands producing tears and saliva, often leading to significant complications. This study investigates the differences in autonomic system functioning between individuals with SS and healthy controls. METHODS: From April 2019 to December 2022, 329 diagnosed primary SS (pSS) patients and 30 healthy controls were enrolled at Taipei Veterans General Hospital, Taipei, Taiwan. The study assessed autonomic nervous system functioning using various HRV metrics. Participants were divided based on age and AECG criteria, including salivary gland biopsy and autoantibody status. RESULTS: Significant differences in Heart Rate Variability (HRV) were observed between pSS patients and healthy controls. The total power index was notably lower in pSS patients (4.98 ± 1.29) than in controls (5.54 ± 1.21, p = .022). Additionally, Vagal (VAG) activity was significantly reduced in the pSS group (4.95 ± 1.33) compared to the healthy control group (5.47 ± 1.19, p = .041). Age-stratified analysis highlighted that the ≤50 years pSS group had a higher heart rate (77.74 ± 10.42) compared to the >50 years group (73.86 ± 10.35, p = .005). This group also showed a higher total power index (5.78 ± 1.30) versus the >50 years group (4.68 ± 1.19, p < .001), and significantly lower VAG activity (4.70 ± 1.26, p = .007) compared to healthy controls. Furthermore, the Standard Deviation of Normal-to-Normal Intervals (SDNN) was greater in the ≤50 years SS group (44.45 ± 37.12) than in the >50 years group (33.51 ± 26.18, p = .007). In pSS patients, those positive for both salivary gland biopsy and autoantibodies demonstrated a lower Total Power (4.25 ± 1.32) and R-wave validity (93.50 ± 4.79, p < .05) than other groups, suggesting more severe autonomic imbalance. The R-R interval variation (RRIV) was also significantly higher in this dual-positive group (696.10 ± 975.41, p < .05). Additionally, the ESSPRI for dryness was markedly higher in the dual-positive group (8.10 ± 1.45, p < .05), indicating more severe symptoms. These findings reveal significant variations in autonomic function in SS patients, especially in those with dual-positive biopsy and autoantibody status. CONCLUSION: This study demonstrates significant autonomic dysfunction in pSS patients compared to healthy controls, particularly in those positive for both salivary gland biopsy and autoantibodies. The age-stratified analysis further emphasizes the impact of aging on autonomic system functioning in pSS, suggesting a need for age-specific management approaches in pSS patient care.

Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Recovery of cardiac electrophysiological alterations by heart rate complexity based on multiscale entropy following liver transplantation.

Autonomic nervous dysfunction is a known cardiac sequalae in patients with end-stage liver disease and is associated with a poor prognosis. Heart rate analysis using nonlinear models such as multiscale entropy (MSE) or complexity may identify marked changes in these patients where conventional heart rate variability (HRV) measurements do not. To investigate the application of heart rate complexity (HRC) based on MSE in liver transplantation settings. Thirty adult recipients of elective living donor liver transplantation were enrolled. HRV parameters using conventional HRV analysis and HRC analysis were obtained at the following time points: (1) 1 day before surgery, (2) postoperative day (POD) 7, (3) POD 14, (4) POD 90, and (5) POD 180. Preoperatively, patients with MELD score ≥ 25 had significantly lower HRC compared to patients with lower MELD scores. This difference in HRC disappeared by POD 7 following liver transplantation and subsequent analyses at POD 90 and 180 continued to show no significant difference. Our results indicated a significant negative correlation between HRC based on MSE analysis and liver disease severity preoperatively, which may be more sensitive than conventional linear HRV analysis. HRC in patients with MELD score ≧ 25 improved over time and became comparable to those with MELD < 25 as early as in 7 days.

Predictors for early-onset psychotic symptoms in patients newly diagnosed with Parkinson's disease without psychosis at baseline: A 5-year cohort study.

AIMS: To investigate the risk factors for early-onset psychosis in Parkinson's disease (PD) in a cohort of patients from the Parkinson's Progression Markers Initiative. METHODS: Longitudinal data on motor and non-motor features, dopamine transporter (DAT) imaging, and cerebrospinal fluid (CSF) measurements were collected. The survival probability of psychotic symptoms, potential risk factors for psychosis development over a 5-year follow-up period, and the performance of the prediction model were evaluated. RESULTS: Among the 338 newly diagnosed patients with PD, 83 developed psychotic symptoms. Gastrointestinal autonomic dysfunction, presence of probable rapid-eye-movement sleep behavior disorder, and the ratio Aß42: total-tau could independently predict onset of psychosis in PD (hazard ratio (HR) = 1.157, 95% confidence interval (CI) 1.022-1.309, p = 0.021, HR = 2.596, 95% CI 1.287-5.237, p = 0.008, and HR = 0.842, 95% CI 0.723-0.980, p = 0.027, respectively). The combined model integrating baseline clinical predictors, DAT imaging, and CSF measurements achieved better sensitivity than the clinical predictors alone (area under the curve = 0.770 [95% CI 0.672-0.868] vs. 0.714 [95% CI 0.625-0.802], p = 0.098). CONCLUSION: We identified clinical and CSF predictors of early-onset psychosis in patients with PD. Our study provides evidence and implications for prognostic stratification and therapeutic approaches for PD psychosis.

Tilt-evoked, breathing-driven blood pressure oscillations: Independence from baroreflex-sympathoneural function.

PURPOSE: Orthostasis increases the variability of continuously recorded blood pressure (BP). Low-frequency (LF) BP oscillations (Mayer waves) in this setting are related to the vascular-sympathetic baroreflex. Mechanisms of increased high-frequency (HF) BP oscillations at the periodicity of respiration during orthostasis have received less research attention. A previously reported patient with post-neurosurgical orthostatic hypotension (OH) and vascular-sympathetic baroreflex failure had large tilt-evoked, breathing-driven BP oscillations, suggesting that such oscillations can occur independently of vascular-sympathetic baroreflex modulation. In the present study we assessed effects of orthostasis on BP variability in the frequency domain in patient cohorts with or without OH. METHODS: Power spectral analysis of systolic BP variability was conducted on recordings from 73 research participants, 42 with neurogenic OH [13 pure autonomic failure, 14 Parkinson's disease (PD) with OH, 12 parkinsonian multiple system atrophy, and 3 status post-brainstem neurosurgery] and 31 without OH (control group of 16 healthy volunteers and 15 patients with PD lacking OH), before, during, and after 5' of head-up tilt at 90 degrees from horizontal. The data were log transformed for statistical testing. RESULTS: Across all subjects, head-up tilting increased HF power of systolic BP variability (p = 0.001), without a difference between the neurogenic OH and control groups. LF power during orthostasis was higher in the control than in the OH groups (p = 0.009). CONCLUSIONS: The results of this observational cohort study confirm those based on our case report and lead us to propose that even in the setting of vascular-sympathetic baroreflex failure orthostasis increases HF power of BP variability.

Characterizing Heart Rate Variability Response to Maximal Exercise Testing in People with Huntington's Disease.

Background: Huntington's disease (HD) is an autosomal dominant, neurodegenerative disease that involves dysfunction in the autonomic nervous system (ANS). Heart rate variability (HRV) is a valid and noninvasive measure for ANS dysfunction, yet no study has characterized HRV response to exercise in people with HD. Objective: Characterize HRV response to exercise in individuals with HD and explore its implications for exercise prescription and cardiac dysautonomia mechanisms. Methods: 19 participants with HD were recruited as part of a cohort of individuals enrolled in the Physical Activity and Exercise Outcomes in Huntington's Disease (PACE-HD) study at Teachers College, Columbia University (TC). 13 non-HD age- and gender-matched control participants were also recruited from TC. HRV was recorded with a Polar H10 heart rate (HR) monitor before, during, and after a ramp cycle-ergometer exercise test. Results: Participants with HD showed reduced HR peak (p < 0.01) and HR reserve (p < 0.001) compared with controls. Participants with HD demonstrated reduced root mean square of successive differences between normal-to-normal intervals (RMSSD) and successive differences of normal-to-normal intervals (SDSD) at rest (p < 0.001). Participants with HD also showed differences for low frequency (LF) power (p < 0.01), high frequency (HF) normalized units (nu) (p < 0.05), LF (nu) (p < 0.001), and HF/LF ratio (p < 0.05) compared with controls. Conclusions: We found reduced aerobic exercise capacity and sympathovagal dysautonomia both at rest and during post-exercise recovery in people with HD, suggesting modified exercise prescription may be required for people with HD. Further investigations focusing on cardiac dysautonomia and underlying mechanisms of sympathovagal dysautonomia in people with HD are warranted.

Paraneoplastic autonomic neuropathies and GI dysmotility.

A number of the well-recognized autoimmune and paraneoplastic neurologic syndromes commonly involve the autonomic nervous system. In some cases, the autonomic nerves or ganglia are primary targets of neurologic autoimmunity, as in immune-mediated autonomic ganglionopathies. In other disorders such as encephalitis, autonomic centers in the brain may be affected. The presence of autonomic dysfunction (especially gastrointestinal dysmotility) is sometimes overlooked even though this may contribute significantly to the symptom burden in these paraneoplastic disorders. Additionally, recognition of autonomic features as part of the clinical syndrome can help point the diagnostic evaluation toward autoimmune and paraneoplastic etiologies. As with other paraneoplastic disorders, the clinical syndrome and the presence and type of neurologic autoantibodies help to secure the diagnosis and direct the most appropriate investigation for malignancy. Optimal management for these conditions typically includes aggressive treatment of the neoplasm, immunomodulatory therapy, and symptomatic treatments for orthostatic hypotension and gastrointestinal dysmotility.

Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease characterized by proximal muscle weakness, loss of tendon reflexes, and autonomic dysfunction. Muscle weakness usually starts in the upper legs and can progress to oculobulbar and in severe cases respiratory muscles. P/Q-type voltage-gated calcium channels (VGCCs) localized in the presynaptic motor nerve terminal and in the autonomic nervous system are targeted by antibodies in LEMS patients. These antibodies can be detected in about 90% of patients, and the presence of decrement and increment upon repetitive nerve stimulation is also a highly sensitive diagnostic test. Rapid diagnosis is important because of the association with SCLC in 50%-60% of patients, which stresses the need for vigorous tumor screening after diagnosis. Clinical parameters can predict tumor probability and guide frequency of tumor screening. Treatment of the tumor as well as symptomatic treatment and immunosuppression can effectively control symptoms in the majority of patients.