Dysautonomia associated with immune checkpoint inhibitors.

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. CONCLUSION: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society.

INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. CONCLUSION: Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Seronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors have improved clinical outcomes including survival in several malignancies but have also been associated with a range of immune-related adverse events (irAEs). Neurological irAEs are rare compared to the more typical skin, gastrointestinal, and endocrine toxicities, and are often underrecognized and challenging to diagnose. Here, we report a case of seronegative autoimmune autonomic ganglionopathy (AAG) induced by dual immune checkpoint inhibitor therapy (ICI) in a patient with metastatic melanoma. CASE PRESENTATION: A patient with metastatic melanoma was treated with ipilimumab and nivolumab. He developed a constellation of new symptoms including nausea, fatigue, and severe orthostatic hypotension refractory to fluid resuscitation. An infectious, cardiac, neurologic, and endocrine workup were unrevealing. Cardiovascular autonomic testing revealed poor sympathetic nervous system responses. He was diagnosed with seronegative AAG and significantly improved with immunomodulatory therapies including IVIG and steroids as well as varying doses of midodrine and fludrocortisone. He was able to restart nivolumab without recurrence of his symptoms. However, the AAG reoccurred when he was re-challenged with ipilimumab and nivolumab due to disease progression. While the AAG was manageable with steroids at that time, unfortunately his melanoma became resistant to ICI. CONCLUSIONS: Immune checkpoint inhibitors can have a wide range of unusual, rare irAEs, including neurotoxicity such as AAG. Clinicians should maintain suspicion for this toxicity so that treatment can be rapidly provided to avoid disability.

Pyridoxine Toxicity Small Fiber Neuropathy With Dysautonomia: A Case Report.

Pyridoxine (vitamin B6) toxicity is a well-known cause of primary sensory, length-dependent, axonal polyneuropathy. Although sensory symptoms predominate, autonomic symptoms have also been reported in some cases. To date, there is no objective evidence of autonomic dysfunction reported in the literature. We present the case of a 41-year-old woman with 2 years of progressive burning pain, numbness, tingling, and weakness in a stocking-glove distribution who was found to have severe pyridoxine toxicity. Concurrent presence of large and small fiber nerve dysfunction was noted in the form of abnormal electromyography/nerve conduction study demonstrating a chronic sensory polyneuropathy and autonomic testing demonstrating abnormal responses to quantitative sweat testing and cardiovagal function testing. This case highlights the need for consideration of small fiber nerve damage by obtaining autonomic testing in cases of pyridoxine toxicity.

Western diet in the perinatal period promotes dysautonomia in the offspring of adult rats.

The present study investigated the impact of a western diet during gestation and lactation on the anthropometry, serum biochemical, blood pressure and cardiovascular autonomic control on the offspring. Male Wistar rats were divided into two groups according to their mother's diet received: control group (C: 18% calories of lipids) and westernized group (W: 32% calories of lipids). After weaning both groups received standard diet. On the 60th day of life, blood samples were collected for the analysis of fasting glucose and lipidogram. Cardiovascular parameters were measured on the same period. Autonomic nervous system modulation was evaluated by spectrum analysis of heart rate (HR) and systolic arterial pressure (SAP). The W increased glycemia (123±2 v. 155±2 mg/dl), low-density lipoprotein (15±1 v. 31±2 mg/dl), triglycerides (49±1 v. 85±2 mg/dl), total cholesterol (75±2 v. 86±2 mg/dl), and decreased high-density lipoprotein (50±4 v. 38±3 mg/dl), as well as increased body mass (209±4 v. 229±6 g) than C. Furthermore, the W showed higher SAP (130±4 v. 157±2 mmHg), HR (357±10 v. 428±14 bpm), sympathetic modulation to vessels (2.3±0.56 v. 6±0.84 mmHg2) and LF/HF ratio (0.15±0.01 v. 0.7±0.2) than C. These findings suggest that a western diet during pregnancy and lactation leads to overweight associated with autonomic misbalance and hypertension in adulthood.

Drugs with potential cardiac adverse effects: Retrospective study in a large cohort of parkinsonian patients.

INTRODUCTION/OBJECTIVE: Drugs with potential cardiac adverse effects are commonly prescribed in Parkinson's disease (PD). To describe demographic and clinical characteristics in a group of PD patients with cardiac events and to evaluate risk factors. PATIENTS AND METHODS: We sampled 506 consecutive PD patients (211 women/295 men), median age 68.3±10.6 years (range 36-95) and median disease duration 11.2±6.5 years (range 1-49). Medications with potential cardiac effects, i.e. QT prolongation (citalopram, escitalopram, venlafaxine, sertraline, domperidone, amantadine, solifenacin), ventricular arrhythmia (rivastigmine, clozapine, midodrine, sildenafil, tadalafil) and ischemic heart disease (rasagiline, entacapone, tadalafil) were recorded. Demographic and clinical data were collected prospectively; cardiac events were obtained retrospectively. RESULTS: Twenty-four patients (4.7%) (9 women/15 men) presented a cardiac event. Fifteen (62.5%) patients had dysautonomia, 4 (16.6%) a history of heart disease and 8 (33.3%) were taking one or more drugs with a definite potential cardiac adverse effect. Age (75.9±6.6 yr vs. 67.8±11 yr), disease duration (14.7±3.6 yr vs. 11±6.5 yr), dysautonomia (62.5% vs. 24.5%) and dementia associated with PD (37.5% vs. 14.6%) were significantly higher in the group with cardiac events (P<0.05). Cofactors increasing the risk for cardiovascular events were age and dysautonomia. DISCUSSION/CONCLUSION: Our results indicate that the neurodegenerative process in Parkinson's disease is associated with a higher risk of cardiovascular complications.

Long lasting dysautonomia due to botulinum toxin B poisoning: clinical-laboratory follow up and difficulties in initial diagnosis.

BACKGROUND: Botulism is an acute form of poisoning caused by one of four types (A, B, E, F) toxins produced by Clostridium botulinum, ananaerobic, spore forming bacillus. Usually diagnosis of botulism is considered in patients with predominant motor symptoms: muscle weakness with intact sensation and preserved mental function. CASE PRESENTATION: We report a case of 56-year-old Caucasian female with a history of arterial hypertension, who presented with acute respiratory failure and bilateral ptosis misdiagnosed as brainstem ischemia. She had severe external and internal ophtalmoplegia, and autonomic dysfunction with neither motor nor sensory symptoms from upper and lower limbs. Diagnosis of botulinum toxin poisoning was made and confirmed by serum antibody testing in the mouse inoculation test. CONCLUSIONS: Ophtalmoplegia, autonomic dysfunction and respiratory failure can be caused by botulism. Early treatment and intensive care is essential for survival and recovery. The electrophysiological tests are crucial to correct and rapid diagnosis. Botulism (especially type B) should be considered in any case of acute or predominant isolated autonomic dysfunction.

Assessment of changes in cardiac autonomic tone resulting from inflammatory response to the influenza vaccination.

A total of 71 healthy volunteers opting to have a routine influenza vaccination were investigated for potential changes in cardiovascular autonomic tone resulting from the temporary inflammatory effects of an influenza vaccination. A number of temporal and frequency domain parameters of heart rate and breathing were assessed 2-5 days prior to vaccination and 1-4 days postvaccination. Three lead electrocardiograph (ECG), beat-to-beat finger blood pressure and chest plethysmography signals were measured. After an extended resting period, patients performed metronome-guided breathing at six breaths per min for a period of 2 min. Standard Ewing tests of autonomic function were also performed. All volunteers completed a vaccine symptom questionnaire. A subgroup of 15 volunteers who reported significant symptomatic reaction to the vaccination for at least 24 h following vaccination were identified based on the results of the questionnaire. A significant reduction in measures of heart rate variability (HRV) obtained during metronome-guided breathing was noted following vaccination in the subgroup of 15 symptomatic volunteers. No significant changes were observed in standard Ewing assessment, fractal dimension analysis, baroreflex sensitivity assessment or resting HRV. There was no evidence of significant reduction in autonomic tone following vaccination in the full sample of 71 volunteers. Results suggest a significant change in HRV response to a small inflammatory provocation and suggest further investigation of the inflammatory causes of dysautonomia is of value.