Autonomic dysfunction following COVID-19 infection: an early experience.

PURPOSE: Post-COVID-19 syndrome is a poorly understood aspect of the current pandemic, with clinical features that overlap with symptoms of autonomic/small fiber dysfunction. An early systematic analysis of autonomic dysfunction following COVID-19 is lacking and may provide initial insights into the spectrum of this condition. METHODS: We conducted a retrospective review of all patients with confirmed history of COVID-19 infection referred for autonomic testing for symptoms concerning for para-/postinfectious autonomic dysfunction at Mayo Clinic Rochester or Jacksonville between March 2020 and January 2021. RESULTS: We identified 27 patients fulfilling the search criteria. Symptoms developed between 0 and 122 days following the acute infection and included lightheadedness (93%), orthostatic headache (22%), syncope (11%), hyperhidrosis (11%), and burning pain (11%). Sudomotor function was abnormal in 36%, cardiovagal function in 27%, and cardiovascular adrenergic function in 7%. The most common clinical scenario was orthostatic symptoms without tachycardia or hypotension (41%); 22% of patients fulfilled the criteria for postural tachycardia syndrome (POTS), and 11% had borderline findings to support orthostatic intolerance. One patient each was diagnosed with autoimmune autonomic ganglionopathy, inappropriate sinus tachycardia, vasodepressor syncope, cough/vasovagal syncope, exacerbation of preexisting orthostatic hypotension, exacerbation of sensory and autonomic neuropathy, and exacerbation of small fiber neuropathy. CONCLUSION: Abnormalities on autonomic testing were seen in the majority of patients but were mild in most cases. The most common finding was orthostatic intolerance, often without objective hemodynamic abnormalities on testing. Unmasking/exacerbation of preexisting conditions was seen. The temporal association between infection and autonomic symptoms implies a causal relationship, which however cannot be proven by this study.

Orthostatic hypotension is differentially associated with the cerebellar versus the parkinsonian variant of multiple system atrophy: a comparative study.

Orthostatic hypotension (OH) is a cardinal feature of autonomic failure in multiple system atrophy (MSA); however, there are few comparative data on OH in the motor subtypes of MSA. In the present retrospective study, postural blood pressure drop after 3 min of standing was determined in 16 patients with the cerebellar variant of MSA (MSA-C) and in 17 patients with the Parkinson variant (MSA-P). Twenty idiopathic Parkinson's disease (IPD) patients matched for age, sex, disease duration and dopaminergic therapy served as control group. OH frequency and severity were more pronounced in MSA-C followed by MSA-P and IPD. Differences in brainstem pathology are likely to account for the tight association of MSA-C and OH. A simple standing test should be obligatory in the work-up of patients with sporadic late-onset ataxias.

Neurogenic orthostatic hypotension as the initial feature of Parkinson disease.

Autonomic failure is a common finding in patients with Parkinson disease (PD). Here we describe a patient with PD in whom autonomic symptoms began 3 years before motor deficits.

Modelling progressive autonomic failure in MSA: where are we now?

Multiple system atrophy (MSA) is a fatal late-onset α-synucleinopathy that presents with features of ataxia, Parkinsonism, and pyramidal dysfunction in any combination. Over the last decade, efforts have been made to develop preclinical MSA testbeds for novel interventional strategies. The main focus has been on murine analogues of MSA-linked motor features and their underlying brainstem, cerebellar and basal ganglia pathology. Although progressive autonomic failure (AF) is a prominent clinical feature of patients with MSA, reflecting a disruption of both central and peripheral autonomic networks controlling cardiovascular, respiratory, urogenital, gastrointestinal and sudomotor functions, attempts of modelling this aspect of the human disease have been limited. However, emerging evidence suggests that AF-like features may occur in transgenic MSA models reflecting α-synucleinopathy lesions in distributed autonomic networks. Further research is needed to fully characterize both autonomic and motor features in optimized preclinical MSA models.

Neurogenic orthostatic hypotension of Parkinson's disease: what exploration for what treatment?

The aim of this short review is to illustrate, using orthostatic hypotension as an example, the clinical problems related to autonomic features in Parkinson's disease. Orthostatic hypotension is frequently encountered in Parkinson's disease and its diagnosis remains manometric (a fall of at least 20 and/or 10 mmHg in standing blood pressure). It is often associated with supine hypertension to be taken into account before prescribing. To distinguish between the role of disease and of drugs (not only antiparkinsonian drugs), a simple clinical test of autonomic nervous system activity (deep breathing test and standing test with measurement of 30/15 ratio) can be used. When diagnosis with multisystem atrophy is discussed, cardiac [¹²³I]-metaiodobenzylguanidine (MIBG) scintigraphy is of value showing in Parkinson's disease a decreased uptake of the radiopharmaceutical indicating postganglionic sympathetic denervation. Concerning treatment, nonpharmacological methods have to be systematically used since no drug has been specifically evaluated for the treatment of orthostatic hypotension of Parkinson's disease.

Chiari drop attacks: surgical decompression and the role of tilt table testing.

BACKGROUND: Chiari I malformation (CM1) is characterized by impaired CSF flow through the foramen magnum. Dysfunctional autonomic cardiovascular regulation may result in syncope. Syncope may be the primary presenting symptom of CM1: a syndrome termed Chiari drop attack. It has been postulated that Chiari drop attack is secondary to dysautonomia caused by hindbrain compression. There has been recent debate regarding the association between CM1, dysautonomia and Chiari drop attack. METHODS: We selected patients with Chiari drop attacks who had negative workups for cardiac syncope, followed by tilt table testing and subsequent surgical decompression. We report test results and clinical outcomes following CM1 decompression. RESULTS: Ten patients met the inclusion criteria: 5 patients had positive and 5 negative tilt table tests. Following decompression, 7 had symptomatic improvement or resolution and 3 failed to improve. The sensitivity and specificity of the tilt table test for detecting clinical improvement with surgical decompression was 43 and 33%, respectively. Tilt table testing had 40% accuracy in predicting clinical response to decompression. CONCLUSIONS: In this short series, surgical decompression of CM1 has a high success rate (70%) for patients with Chiari drop attacks. Tilt table testing has poor predictive value in judging the clinical response to surgical decompression and is not a useful test to guide surgical decision- making.

Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy.

OBJECTIVE: It has been demonstrated that the increased blood pressure (BP) caused by a single dose of water alleviates orthostatic hypotension (OH) and postprandial hypotension (PPH) in patients with autonomic failure (AF). The aim of this study was to evaluate the practical effect of daily water drinking on OH and PPH in the morning when patients with AF are usually most affected. METHODS: In five patients with multiple system atrophy (MSA) characterized by intractable OH and PPH, we measured seated, standing and postprandial BP in the morning without and with ingestion of 350 ml tap water at 07.30 hours for seven successive days. The changes from the basal BP level at 07.30 hours (DeltaBP) were assessed as an index of the effect of water drinking. RESULTS: Water drinking elicited a rapid pressor response in all patients. The DeltaBP during sitting, standing and after a meal following water drinking (day 1 and day 7) was significantly higher than without water drinking (day 0). The effects of reducing OH and PPH on day 7 were equivalent to those on day 1. No adverse effects associated with daily water drinking were observed, except later diuresis, which occurred in one patient. CONCLUSIONS: Daily water drinking demonstrated constant pressor effects in the morning with no severe adverse effects in MSA patients. This finding suggests that water drinking should be tried as a practical measure to prevent or reduce OH and PPH.

iNOS expression in rat aorta is increased after spinal cord transection: a possible cause of orthostatic hypotension in man.

Orthostatic hypotension commonly occurs in persons with spinal cord injury (SCI), limiting rehabilitation and independence. Findings of increased production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) after exposure to simulated microgravity suggest that increased iNOS expression contributes to OH in persons with SCI. To test this possibility, male Wistar rats underwent surgical transection of the spinal cord (T10) or sham-SCI surgery followed by euthanasia 3, 7 or 14 days later. Expression in thoracic aortic of inducible (iNOS), endothelial (eNOS) and neuronal (nNOS) NOS was then determined. In SCI rats, expression of iNOS mRNA was decreased at 3 days, had returned to normal levels of expression at 7 days and was increased at 14 days post-SCI (1.8-fold). In contrast, levels of eNOS mRNA were increased at 3 days (1.4-fold), then declined over time reaching levels by day 14 that were reduced compared to sham-SCI (0.23-fold). There were no significant effects of SCI on nNOS expression. These findings suggest a possible role for increased iNOS expression in the pathogenesis of OH in persons with SCI.

Is cerebral autoregulation impaired in Parkinson's disease? A transcranial Doppler study.

Orthostatic hypotension (OH) is one of the many autonomic disturbances observed in Parkinson's disease (PD). It has been debated whether an additional impairment of cerebral autoregulation (CA) in PD patients may exacerbate the consequences of OH upon brain perfusion. We assessed CA in PD patients and the potential influence of dopaminergic agents. CA was determined by means of transcranial Doppler (TCD) monitoring of the middle cerebral artery (MCA) at rest and during a thigh cuff release test inducing a systemic blood pressure (BP) drop. Fourteen patients were investigated when taking their usual dopaminergic medication and after drug discontinuation for 12 h. A control group was composed of 11 age-matched subjects (CS). In comparison with PD patients, CS presented a significantly higher increase of the mean cerebral blood flow velocities in the MCA after the BP drop. Mean velocities were increased above the initial values in all CS, whereas a flattened curve was observed in PD patients. No significant differences could be further observed between the PD patients regarding the BP, the cerebrovascular resistance, the heart rate and the pulsatility index. These results provide evidence of an impaired cerebral autoregulation in PD patients which appears independent of dopaminergic treatment.

Assessment of autonomic dysfunction of multiple system atrophy with laryngeal abductor paralysis as an early manifestation.

Laryngeal abductor palsy (LAP) is common in the advanced stages of multiple system atrophy (MSA). However, occurrence of LAP in the early stages might make a diagnosis of MSA difficult. To search for a clue to diagnosis of MSA with LAP as an early manifestation, we assessed the clinical features of autonomic dysfunction and the central cardiovascular control circuits in two MSA patients who had LAP as a cardinal symptom in the early stages. Development of autonomic dysfunction was preceded or followed by LAP. The autonomic symptom occurring predominantly in the earliest stages was urinary disturbance rather than orthostatic hypotension. Although screening cardiovascular autonomic function tests did not conclusively indicate a diagnosis of MSA, vasopressin release in response to head-up tilt and growth hormone response to clonidine administration demonstrated inappropriate responses, suggesting that the noradrenergic neurons of the caudal ventrolateral medulla were impaired. Diagnosis of atypical MSA with LAP in the early stages might be accelerated by a detailed investigation focused on urinary symptoms and neuroendocrine approaches.

Cerebral vasomotor reactivity in Parkinson's disease, multiple system atrophy and pure autonomic failure.

Parkinson's disease (PD), multiple system atrophy (MSA) and pure autonomic failure (PAF) are neurodegenerative disorders frequently associated with orthostatic hypotension and syncope, though with different underlying mechanisms. Cerebral hemodynamic responses in these three neurodegenerative diseases are still incompletely studied and it is possible that they would be differentially affected. We measured blood flow velocity (BFV) in the middle cerebral artery (MCA) and vertebral artery (VA) in patients with these disorders and investigated whether cerebral vasomotor reactivity (VMR) differs in these three disorders. Twenty-four patients (9 with PD, 10 with MSA and 5 with PAF) were studied. VMR was assessed in the MCA and VA, using transcranial Doppler (TCD) and Diamox test (injection of 1 g acetazolamide i.v.) with the patients in a recumbent position. The percent difference between BFV before and after acetazolamide injection was defined as VMR% and the results were compared by ANOVA. The mean MCA and VA blood flow velocities were similar in the three disorders and within normal limits for our laboratory. The mean MCA VMR values were 37.5+/-24.0%, 27.9+/-28.0% and 38.0+/-33.9% in PD, MSA and PAF, respectively. The VA VMR values were 22.9+/-23.6%, 32.4+/-38.0% and 18.9+/-18.3%, respectively, with no significant differences between the groups. We conclude that BFV is normal in PD, MSA and PAF and that the VMR, as investigated by TCD and the Diamox test, did not disclose differences in cerebral vasomotor responses between these conditions.

Cardiac response rate variability in physically abused women of childbearing age.

Physical abuse directly affects maternal and fetal/infant health, with documented reports of higher rates of pregnancy termination, neonatal death, and lower birth weights. Although the Centers for Disease Control and Prevention recommend repeated interviews of women of childbearing age to screen for abuse, the paper-and-pencil instruments available for such screening are adversely affected by the hesitancy of women to disclose physical abuse. Biophysical measures of physiological stress adaptations may hold potential for identifying physically abused childbearing women. This pilot investigation used a Latin square design to assess the effects of physically abusive trauma on the cardiac rate response of three clinical groups and one control group of childbearing-age women. Participants were screened using the Childbearing Health Questionnaire. Cardiac response rates were measured during a standardized orthostatic challenge using a Tanito cardiac rate response monitor. Forty participants participated with an average age of 27. Multiple analyses of variance revealed that there were significant differences between cardiac rate responses at the 5-min interval. Post hoc testing using Dunnett's t indicated that only the abused pregnant women had significantly higher cardiac responses to orthostatic challenges; differences were apparent at the 5-min testing period. The findings suggest that physical abuse may alter the vasovagal response beyond the attenuation associated with pregnancy. These findings support further testing with larger samples to identify vasovagal changes in abused pregnant women.

Erectile and urinary dysfunction may be the presenting features in patients with multiple system atrophy: a retrospective study.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism and cerebellar, autonomic, urinary, and/or pyramidal dysfunction. Urinary and erectile dysfunction (ED) symptoms are prominent early features in men with MSA. Autonomic failure, considered until recently to be the cause of ED in these men, is commonly expressed through symptoms of orthostatic hypotension (OH). The aim of this retrospective study is to examine the chronological relationship between the development of urogenital symptoms and those of OH in patients diagnosed with MSA and discuss its significance in the aetiology of ED in these patients. A total of 71 male patients, referred to a Uro-Neurology department with a diagnosis of 'probable MSA', were reviewed in terms of 'autonomic' symptoms only--OH and lower urinary tract symptoms, accompanied by ED--present at the time of their referral. Laboratory investigations including anal sphincter EMG and/or autonomic function tests (AFTs) were performed in 75 and 90% of the patients, respectively. At presentation, urinary complaints were recorded in 96% of patients and ED in all patients that this was inquired about. The onset of ED had preceded the onset of bladder symptoms in 58% and the onset of OH symptoms in 91% of these men. Bladder symptoms also preceded symptoms of OH in 76% of patients. Sphincter EMG was abnormal in 91% and AFTs in 77% of the patients tested. Almost all patients with abnormal EMG had troublesome urinary symptoms. AFTs showed similar sensitivity relating to symptoms. At presentation, urogenital symptoms are common in patients with probable MSA and are often not accompanied by symptoms of OH. The earlier occurrence of ED in men with MSA suggests a lack of a causal relationship to hypotension. The notion that MSA possibly affects the dopaminergic mechanism of erectile function is discussed.

Pure autonomic failure in association with human alpha-synucleinopathy.

We studied an autopsy case with pure autonomic failure, using anti-alpha-synuclein antibody. Until now there has been no report about the immunohistochemical properties of alpha-synuclein in pure autonomic failure. In conventional stainings, both pre- and post-ganglionic lesions of the sympathetic and parasympathetic nervous systems were found. Lewy bodies and Lewy neurites were abundant especially in the sympathetic nervous system. These inclusions were immunoreactive to anti-alpha-synuclein antibody. The intensity of alpha-synuclein immunoreactivity was stronger in the halos than in the cores of the Lewy bodies. The edges of the swollen neurites had strong immunoreactivity. The substantia nigra was well preserved, and no cortical Lewy bodies were seen. These findings indicate that pure autonomic failure is one of the Lewy body type alpha-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, targeting the peripheral autonomic nervous system.

Drug treatment of orthostatic hypotension because of autonomic failure or neurocardiogenic syncope.

Orthostatic hypotension either because of autonomic failure or neurocardiogenic syncope can be very incapacitating and should be treated accordingly. Drug therapy is frequently needed to alleviate orthostatic symptoms. The physiopathological basis of neurocardiogenic syncope and of autonomic failure is completely different and their treatment should be distinct. In the past 5 years, many randomized, placebo-controlled trials have shed light on the efficacy of specific pressor drugs. In patients with orthostatic hypotension because of autonomic failure, alpha-adrenoceptor agonists, and midodrine in particular, have been shown to increase standing blood pressure and decrease orthostatic symptoms. Other drugs such as octreotide, indomethacin or ergotamine have also been shown to elevate standing blood pressure and/or orthostatic tolerance. Fludrocortisone is a well known and frequently used pressor drug but randomized controlled studies are needed to measure its efficacy. In patients with orthostatic hypotension associated with neurocardiogenic syncope, clinical trials have demonstrated that beta-blockers, especially beta(1)-selective agents without intrinsic sympathomimetic activity such as atenolol, midodrine and paroxetine can decrease recurrence of syncope. Treatment algorithms, such as those presented in this review, should always be interpreted in the light of individual patient characteristics. Many of the drugs used for orthostatic hypotension have multiple indications and contraindications that should influence therapeutic decisions. Little is known about the effectiveness and tolerability of specific combinations of pressor drugs. Consequently, sound clinical judgment and close follow-up of patients should always guide combination therapy.

Recognizing and treating diabetic autonomic neuropathy.

Diabetic autonomic neuropathy can cause heart disease, gastrointestinal symptoms, genitourinary disorders, and metabolic disease. Strict glycemic control can slow the onset of diabetic autonomic neuropathy and sometimes reverse it. Pharmacologic and nonpharmacologic therapies are available to treat symptoms.

[Blood pressure and heart rate regulation in diabetics]. / Régulation de la pression artérielle et de la fréquence cardiaque chez les diabétiques.

Cardiac autonomic neuropathy (CAN) is frequent in subclinical stages. Its prognostic value has been demonstrated. Cardiac autonomic neuropathy induces different functional cardiac changes, especially a reduction in left ventricular contractility and changes in ventricular repolarisation. It is also associated with changes in the daily variations in blood pressure. The association of CAN and silent myocardial ischaemia significantly worsens the prognosis. The investigation of CAN in the greatest number of diabetic patients is therefore justified. The study of heart rate variations during deep respiration, active orthostatism or Valsalva manoeuvre, is still the reference. This method is simple, reproducible and may be carried out in the clinical setting in 10 to 15 minutes. The results must be strictly interpreted with rigour with respect to age. Orthostatic hypotension is a late sign of sympathetic nervous system disease. Spectral analysis of blood pressure variations on orthostatism or the study of cutaneous blood flow during activating the sympathetic system tests of greater sensitivity, should be developed. The demonstration of subclinical CAN should lead to the careful use of drugs which may induce orthostatic hypotension and certain antiarrhythmics, to search for disorders of ventricular repolarisation and for silent myocardial ischaemia in diabetics with several risk factors.

[Autonomic dysfunction syndromes associated with orthostatic intolerance]. / Síndromes de disfunción autonómica asociados con intolerancia ortostática.

In recent years increased interest has focused on the nature and pathophysiology of orthostatic intolerance and syndromes associated with autonomic disorders. Understanding the pathophysiology underlying these syndromes has led to the recognition of several distinct clinical entities with overlapping features and the associated need to reclassify many of the previously unrecognized syndromes. Among the clinical manifestations, syncope and near syncope are frequently associated with orthostatic intolerance. In addition, however, a wide spectrum of symptoms have been described ranging from chronic fatigue to recurrent neurally mediated vasodepressor reactions. The present review focuses on the pathophysiology and classification of syndromes of autonomic dysfunction associated with orthostatic intolerance. Primary and secondary causes of dysautonomia as well as therapeutic approach to these frequently unrecognized syndromes is presented.

[An autopsied case of Parkinson's disease manifesting Shy-Drager syndrome].

We report an autopsied case of Parkinson's disease manifesting Shy-Drager syndrome. At the age of 63 years, the patient noticed an onset of progressive orthostatic dizziness, which was followed by constipation, dysuria, and sexual impotence. When he was 66 years old, syncopal attack for a few minutes, tremor in the bilateral hands, and memory disturbance developed. On admission, his blood pressure was 142/72 mmHg in supine position, which fell to 58/42 mmHg on standing with appropriate increase of heart rate. Neurological examination revealed hallucination, memory disturbance, masked face, muscular rigidity, bradykinesia, mild postural tremor, and autonomic dysfunction including severe orthostatic hypotension, hypohydrosis, constipation, dysuria, and sexual impotence. Electroencephalogram showed diffuse slowing. Brain CT demonstrated absence of severe atrophy of the cerebellum, and brain stem. Pharmacological study revealed denervation hypersensitivity to the intravenously administrated noradrenaline. A diagnosis of Shy-Drager syndrome was made, and he was treated with anti parkinsonian drugs. However, no improvement was observed in his clinical symptoms. Seven months later, he died of pneumonia. Neuropathological examination revealed marked neuronal cell loss and gliosis in the substantia nigra and locus ceruleus. Lewy bodies were seen in those pigmented nuclei, dorsal vagal nucleus, hypothalamus and nucleus basalis of Meynert. No abnormality was found in the intermediolateral nucleus of the spinal cord. This is the first report on a Japanese patient who presented clinically Shy-Drager syndrome and pathologically typical Parkinson's disease. In this patient, from the pharmacological and pathological findings, sympathetic ganglia were supposed to be the responsible lesion for orthostatic hypotension.

Prevention of supine hypotensive syndrome in pregnant women treated with transcranial magnetic stimulation.

In our studies of transcranial magnetic stimulation in pregnant women with major depressive disorder, two subjects had an episode of supine hypotensive syndrome and one subject had an episode of dizziness without hypotension. Prevention of the supine hypotensive syndrome in pregnant women receiving transcranial magnetic stimulation is described.