Sex and age impact prevalence and symptoms of vasovagal syncope: Implications for accurate diagnosis

Syncope is characterized by the transient loss of consciousness followed by spontaneous recovery. The mechanism which underlies this condition is reduced blood flow to the brain [1]. Vasovagal syncope, often termed reflex syncope, is the most common type of syncope [1]. Vasovagal Syncope is caused by the abnormal autonomic reflex to certain stimuli such as pain, micturition/defecation, fear, seeing blood, etc., which results in vasodilation and often times, bradycardia [1].

Orthostatism, Constipation, and Early Satiety

A 65-year-old woman with a history of Graves disease, status post radioactive iodine therapy, and a biopsy-proven benign calcified breast nodule sought care for evaluation of multiple symptoms. She had constipation for 8 years, with prior fecal urgency, and intermittent diarrhea for the previous year. She was diagnosed with irritable bowel syndrome. Her weight remained stable until 1 1/2 years earlier, and she had lost 6.8 kg. For the previous 3 years, the patient had experienced multiple urinary symptoms including hesitancy, urgency, incontinence, and retention. She was diagnosed with a cystocele, the correction of which did not help. She had noted difficulty focusing her eyes when moving from a dark to a well-lit environment, or vice versa. She also reported orthostatic light-headedness for 1½years, which worsened on exposure to a hot environment. Neurologic examination showed abnormally dilated pupils with prominently sluggish constriction in response to light. Autonomic reflex screening indicated patchy postganglionic sympathetic sudomotor, marked cardiovagal, and cardiovascular adrenergic failure, with neurogenic orthostatic hypotension. Thermoregulatory sweat testing showed 82% anhidrosis. A nuclear medicine gastric-emptying study indicated delayed gastric emptying and colonic hypomotility. Serum testing was markedly positive for ganglionic (alpha 3) acetylcholine receptor autoantibodies. The patient was diagnosed with autoimmune autonomic ganglionopathy. The patient received intravenous immunoglobulin. She returned and reported 80% improvement in all symptoms, and neurologic examination showed normal pupillary response to light. Autonomic reflex screening indicated improvement of her adrenergic function, and thermoregulatory sweat testing showed an impressive improvement of her sudomotor function. Her postganglionic sympathetic sudomotor and cardiovagal function remained impaired. Gastric emptying remained mildly delayed. She was maintained on intravenous immunoglobulin, which was later tapered after azathioprine was started. Autoimmune autonomic ganglionopathy usually presents subacutely, much like other autoimmune neurologic diseases. Typical features of this disorder are the impaired pupillary reaction to light and prominent sicca symptoms, indicating prominent cranial parasympathetic (cholinergic) impairment. Also consistent with this diagnosis are the prominent gastrointestinal tract symptoms. Prominent cholinergic failure helps distinguish autoimmune autonomic ganglionopathy from peripheral autonomic neuropathy or neurodegenerative disorders such as pure autonomic failure.

Constipation and Syncope

A 43-year-old woman sought care for severe constipation associated with syncopal episodes. Her constipation alternated with explosive diarrhea. Chronic left-sided abdominal pain and severe bloating developed after eating. She was diagnosed with irritable bowel syndrome. After the initial onset of symptoms, nausea, bloating, and intractable vomiting developed. Symptoms were exacerbated by food and were partially relieved with vomiting. She had multiple episodes of bilious, undigested emesis per day. Trials of antiemetics and motility agents provided no substantial relief. She adopted a liquid diet, avoided solid foods, and eventually had a gastrostomy tube placed. She lost at least 15.9 kg over 2 years. Review of systems was significant for generalized fatigue and a burning sensation in her hands and feet. Her medical history was pertinent for Graves disease previously treated with remote thyroid radioablation, and she was now taking thyroid hormone replacement therapy. Neurologic examination findings were normal except for unreactive pupillary light reflexes. A gastrointestinal tract transit study showed persistently delayed colonic transit with mildly delayed gastric emptying. Autonomic reflex screening showed diffuse postganglionic sympathetic sudomotor, severe cardiovagal, and severe cardiovascular adrenergic impairment. Thermoregulatory sweat testing showed diffuse anhidrosis. Creatinine value was mildly increased. The serum was strongly positive for ganglionic (alpha 3) acetylcholine receptor-immunoglobulin G. The findings strongly suggested an autonomic autoimmune polyganglionopathy, with autoimmune gastrointestinal dysmotility as the predominant phenotype. She received intravenous immunoglobulin. She had complete resolution of her previous constipation, nausea, and vomiting. She regained 22.7 kg. Her gastrostomy tube was removed. Repeated gastrointestinal tract transit studies approached normal findings. Repeated autonomic testing and thermoregulatory sweat testing showed improvement. Over several months, the intravenous immunoglobulin dose was tapered. The patient remained asymptomatic for 8 years on long-term immunosuppression with azathioprine, she had a recurrence of her previous symptoms. Repeated gastrointestinal tract transit studies again showed delayed gastrointestinal tract emptying. Another intravenous immunoglobulin course controlled her symptoms, with normalization of gastrointestinal tract transit studies. Autoimmune gastrointestinal dysmotility can manifest as either hypomotility or hypermotility but most often presents as gastroparesis or pseudo-obstruction. Symptoms include nausea, vomiting, bloating, early satiety, diarrhea, constipation, and involuntary weight loss. It can be idiopathic or paraneoplastic. Risk factors for idiopathic cases include personal or family histories of autoimmunity.

Cluster Headache Pathophysiology—A Disorder of Network Excitability?

Patients’ accounts of cluster headache attacks, ictal restlessness, and electrophysiological studies suggest that the pathophysiology involves Aδ-fibre nociceptors and the network processing their input. Continuous activity of the trigeminal autonomic reflex throughout the in-bout period results in central sensitization of these networks in many patients. It is likely that several factors force circadian rhythmicity upon the disease. In addition to sensitization, circadian changes in pain perception and autonomic innervation might influence the excitability of the trigeminal cervical complex. Summation of several factors influencing pain perception might render neurons vulnerable to spontaneous depolarization, particularly at the beginning of rapid drops of the pain threshold (“summation headache”). In light of studies suggesting an impairment of short-term synaptic plasticity in CH patients, we suggest that the physiologic basis of CH attacks might be network overactivity—similarly to epileptic seizures. Case reports documenting cluster-like attacks support the idea of distinct factors being transiently able to induce attacks and being relevant in the pathophysiology of the disorder. A sustained and recurring proneness to attacks likely requires changes in the activity of other structures among which the hypothalamus is the most probable candidate.

Cardiovascular Autonomic Reflex Tests and 7 Heart Rate Variability Indices for Early Diagnosis of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes Individuals

Background: Cardiovascular autonomic neuropathy (CAN) is a common complication of type 2 Diabetes mellitus (T2D), and prevalence varies according to the methodology used. CAN should be diagnosed in the subclinical stage when an intensive treatment of T2D could avoid the progression to irreversible phases. Objective: Determine the prevalence of early involvement (EI) of CAN in T2D individuals comparing two methodologies. Methods: This was a cross-sectional study that included 183 T2D individuals who were monitored in a Tertiary centre. The diagnosis of CAN was based on the results of four cardiovascular autonomic reflex tests (CARTs: expiration-inspiration index, Valsalva maneuver, orthostatic test, and changes in blood pressure after standing) and of seven heart rate variability (7HRV) indices (CARTs plus the spectral analysis). The findings were validated in an independent cohort comprised of 562 T2D individuals followed in a Primary care setting. Results: With the use of 7HRV, 30.6% and 77.8% of individuals in the Tertiary and in the Primary centers, respectively, were classified as without CAN; 25.1% and 15.3% as EI and 44.3% and 6.9% as definitive CAN, respectively. The use of CARTs decreased the proportion of individuals without CAN in both centers (7.1% and 47%) and increased the frequency of EI (30.6% and 36.6%) and definitive CAN (62.3% and 16.4%), respectively. The concordance between both evaluated methodologies was weak. Conclusion: Higher proportions of T2D individuals were diagnosed with EI and with definitive CAN with the use of CARTs.

Indomethacin has no effect on trigeminally provoked parasympathetic output

Background Unlike other non-steroidal anti-inflammatory drugs, indomethacin has been shown to be highly effective in two forms of trigeminal autonomic cephalalgias, hemicrania continua and paroxysmal hemicrania and in some forms of idiopathic stabbing headaches. This specificity is unique in the headache field. Previous findings suggest the involvement of the trigeminal autonomic reflex to play an important role in the pathophysiology of these diseases. Methods 22 healthy participants were enrolled in a double-blind, three-day within-subject design. The participants received indomethacin, ibuprofen or placebo in a randomized order. After an incubation period of 65 min the baseline lacrimation and the lacrimation during intranasal stimulation evoked by kinetic oscillation stimulation were assessed using Schirmer II lacrimation tests. The lacrimation difference in mm was calculated and compared in a repeated measures ANOVA. Results No significant differences were found between the three conditions. Conclusion In our study, neither indomethacin nor ibuprofen had an inhibitory effect on the trigeminal autonomic reflex. We suggest that blocking this reflex may not be the treatment mechanism of indomethacin.

Characteristics of cardiovascular autonomic dysfunction and association with quality of life in patients with systemic lupus erythematosus

ObjectivesCardiovascular autonomic neuropathy (CAN) may affect the clinical course of SLE leading to reduced quality of life. CAN is assessed by heart rate variability (HRV) measures and cardiovascular autonomic reflex tests (CARTs). In patients with SLE, we aimed to determine the characteristics of CAN and if CAN associates with health-related quality of life (HRQoL).MethodsPatients with SLE and healthy controls (HCs) were CAN tested with 5 min HRV and three CARTs to determine parameters reflecting parasympathetic and mixed sympathetic–parasympathetic function. Subjects were classified as having no, early or definitive CAN by having none, one or more than one abnormal CART, respectively. HRQoL as determined by the Short Form 12 (SF-12) was assessed in SLE.ResultsOf 111 patients with SLE, 92 answered the SF-12 and 54 were matched with 54 HCs for characterisation of CAN. Definitive CAN was present in 24.1% (95% CI 15% to 37%) patients with SLE and 1.9% (95% CI 0.3% to 9.8%) HCs (OR 16.8, 95% CI 2.1 to 133.8, p=0.008). The corresponding prevalences of any CAN were 53.7% (95% CI 41% to 66%) and 22.6% (95% CI 13% to 35%). SLE patients with definitive CAN showed signs of mixed sympathetic–parasympathetic dysfunction, whereas patients without CAN primarily presented with impaired parasympathetic activity. Signs of parasympathetic as well as sympathetic–parasympathetic dysfunction were associated with low physical SF-12 component score (all: β>0.211, p<0.05). The mental SF-12 component score was not associated with any CAN indices.ConclusionsCAN was a frequent finding in SLE and associated to self-report on impaired physical HRQoL. Even patients without CAN showed signs of impaired parasympathetic function compared with controls.

Assessment of Autonomic Nervous System Dysfunction in the Early Phase of Infection With SARS-CoV-2 Virus

BackgroundWe are facing the outburst of coronavirus disease 2019 (COVID-19) defined as a serious, multisystem, disorder, including various neurological manifestations in its presentation. So far, autonomic dysfunction (AD) has not been reported in patients with COVID-19 infection.AimAssessment of AD in the early phase of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus).Patients and methodsWe analyzed 116 PCR positive COVID-19 patients. After the exclusion of 41 patients with associate diseases (CADG), partitioned to patients with diabetes mellitus, hypertension, and syncope, the remaining patients were included into a severe group (45 patients with confirmed interstitial pneumonia) and mild group (30 patients). Basic cardiovascular autonomic reflex tests (CART) were performed, followed by beat-to-beat heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) analysis, along with baroreceptor sensitivity (BRS). Non-linear analysis of HRV was provided by Poincare Plot. Results were compared to 77 sex and age-matched controls.ResultsAD (sympathetic, parasympathetic, or both) in our study has been revealed in 51.5% of severe, 78.0% of mild COVID-19 patients, and the difference compared to healthy controls was significant (p = 0.018). Orthostatic hypotension has been established in 33.0% COVID-19 patients compared to 2.6% controls (p = 0.001). Most of the spectral parameters of HRV and BPV confirmed AD, most prominent in the severe COVID-19 group. BRS was significantly lower in all patients (severe, mild, CADG), indicating significant sudden cardiac death risk.ConclusionCardiovascular autonomic neuropathy should be taken into account in COVID-19 patients’ assessment. It can be an explanation for a variety of registered manifestations, enabling a comprehensive diagnostic approach and further treatment.