Search

Postural tachycardia syndrome (POTS) is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. PoTS is distinct from the syndromes of autonomic failure usually associated with orthostatic hypotension, such as pure autonomic failure and multiple system atrophy. Individuals affected by PoTS are mainly young (aged between 15 years and 40 years) and predominantly female. The symptoms--palpitations, dizziness and occasionally syncope--mainly occur when the patient is standing upright, and are often relieved by sitting or lying flat. Common stimuli in daily life, such as modest exertion, food ingestion and heat, are now recognized to be capable of exacerbating the symptoms. Onset of the syndrome can be linked to infection, trauma, surgery or stress. PoTS can be associated with various other disorders; in particular, joint hypermobility syndrome (also known as Ehlers- Danios syndrome hypermobility type, formerly termed Ehlers-Danlos syndrome type III). This Review describes the characteristics and neuroepidemiology of POTS, and outlines possible pathophysiological mechanisms of this syndrome, as well as current and investigational treatments. [ABSTRACT FROM AUTHOR]

Neurogenic orthostatic hypotension is a cardinal feature of generalised autonomic failure and commonly is the presenting sign in patients with primary autonomic failure. Orthostatic hypotension can result in considerable morbidity and even mortality and is a major management problem in disorders such as pure autonomic failure, multiple system atrophy and also in Parkinson’s disease. Treatment is ideally two pronged, using non-pharmacological and pharmacological measures. Drug treatment ideally is aimed at restoring adequate amounts of the neurotransmitter noradrenaline. This often is not achievable because of damage to sympathetic nerve terminals, to autonomic ganglia or to central autonomic networks. An alternative is the use of sympathomimetics (that mimic the effects of noradrenaline, but are not identical to noradrenaline), in addition to other agents that target physiological mechanisms that contribute to blood pressure control. L-threo-dihydroxyphenyslerine (Droxidopa) is a pro-drug which has a structure similar to noradrenaline, but with a carboxyl group. It has no pressor effects in this form. It can be administered orally, unlike noradrenaline, and after absorption is converted by the enzyme dopa decarboxylase into noradrenaline thus increasing levels of the neurotransmitter which is identical to endogenous noradrenaline. Experience in Caucasians and in Europe is limited mainly to patients with dopamine beta hydroxylase deficiency. This review focuses on two studies performed in Europe, and provides information on its efficacy, tolerability and safety in patients with pure autonomic failure, multiple system atrophy and Parkinson’s disease. It also addresses the issue of whether addition of dopa decarboxylase inhibitors, when combined with l-dopa in the treatment of the motor deficit in Parkinson’s disease, impairs the pressor efficacy of Droxidopa. [ABSTRACT FROM AUTHOR]

Children with Congenital Central Hypoventilation Syndrome (CCHS) typically present as newborns with alveolar hypoventilation. With the advent of genetic testing, parents of affected children and other unrelated adults, all heterozygous for the disease-defining PHOX2B polyalanine expansion mutation with the 20/25 genotype, are being identified in adulthood. Though children with PHOX2B mutation-confirmed CCHS demonstrate ANS dysregulation, including altered heart rate and blood pressure control, it is unknown if adults with CCHS have similarly affected autonomic function in blood pressure control. An autonomic profile of blood pressure control has been studied with recording of muscle sympathetic activity and spectral analysis of heart rate and blood pressure variability of one adult patient with alveolar hypoventilation and the 20/25 PHOX2B genotype. All parameters of heart rate variability were reduced. Cardiac baroreflex sensitivity was decreased. Sympathetic responses to Valsalva maneuver, hypoxemia, isometric exercise and cold pressor were blunted. In summary, we found a reduced cardiac baroreflex and a blunted sympathetic mediated response in the individual with adult-onset CCHS, possibly due to dysfunction in the afferent pathway. Our results confirm that PHOX2B affects the development of the autonomic nervous system, possibly causing absence of normal maturation of carotid body and visceral sensory ganglia and leading to autonomic dysfunction in adult-onset CCHS. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) and pure autonomic failure (PAF) represent distinct pathological models of autonomic failure in humans. We have investigated the neuroendocrine, behavioural and autonomic cardiovascular responses to the 35% CO2 challenge. Nine patients with MSA, nine with PAF and five control subjects received a single breath of 35% CO2. Peripheral autonomic failure (i.e., PAF) was associated with significantly lower resting noradrenaline levels. All groups demonstrated a significant pressor response to CO2. In controls, the mean pressor response was +60.2 mm Hg, which was significantly smaller in both the PAF (+26.8 mm Hg, P < 0.01) and MSA (+18.3 mm Hg, P < 0.001) patients. In addition, the onset of the response was significantly delayed in both MSA (140.2 s) and PAF (154.2 s) patients compared with controls (32.4 s, P = 0.04 and P = 0.03, respectively). Noradrenaline levels increased only in controls. Central autonomic impairment (i.e., MSA) was associated with lower cortisol release (+8.8% in MSA compared with +35.2% in control and +23.7% in PAF) and fewer somatic symptoms of emotional arousal. Both MSA and PAF exhibit marked sympathetic autonomic impairment, however, residual (albeit differing) sympathetic pathways can still maintain a partial cardiovascular response. A central autonomic lesion, however, also appears to be associated with blunting of both cortisol and emotional responses to this stress paradigm. [ABSTRACT FROM AUTHOR]

Psychophysiological science proposes close interactions between cognitive processes and autonomic responses, yet the consequences of autonomic failure on cognitive functioning have not been documented. This pilot study investigates, for the first time, the cognitive profile of 14 patients with Pure Autonomic Failure (PAF). Each patient was administered a comprehensive battery of neuropsychological tests and neuroimaging investigation. A number of patients (n = 6) presented with cognitive impairment. The two most frequent types of impairment were: deficits of speed and attention, and executive functioning. Impairments of free recall memory, intellectual functioning, nominal and calculation functions were also documented, albeit in a much lower frequency. These cognitive changes were not always associated with white matter abnormalities. We speculate that the cognitive impairments associated with PAF represent consequences of systemic hypotension with cerebral underperfusion. However, a failure in integrated bodily arousal responses during cognitive behaviours may also contribute to some of the observed deficits. [ABSTRACT FROM AUTHOR]

On head down tilt to the supine horizontal position (tilt reversal) after head up tilt (HUT), patients with orthostatic hypotension may show an increase in blood pressure (BP) relative to baseline readings. We assessed this BP overshoot in 8 patients with pure autonomic failure (PAF, 64±13 years) and 8 patients with multiple system atrophy (MSA, 66±10 years). BP was intermittently measured during pre-tilt supine, HUT (60°, 10 min), and post-tilt supine periods. In addition, beat-to-beat BP was measured continuously using the Portapres model 2 device to calculate stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR). There was systolic BP overshoot of = 15mmHg after tilt reversal in 5 out of 8 PAF, but in only one of 8 MSA. A mean increase of systolic BP in PAF was significantly higher than that in MSA (p<0.01). TPR increased over baseline level after tilt reversal, although there was no significant difference. SV and CO levels during the post-tilt supine period were similar to baseline levels. In conclusion, BP overshoot was prominent in the PAF group but not in the MSA group. The phenomenon of BP overshoot while supine, especially in PAF, may have implications for long term cardiac and vascular damage in such patients. [ABSTRACT FROM AUTHOR]

Patients with syndromes of generalised autonomic failure often have extreme posture-related lability of blood pressure, with both orthostatic hypotension and recumbent hypertension. Whether these changes influence intraocular pressure (IOP) is not known. Mean arterial pressure (MAP) and IOP were measured in response to variations in posture between +45° and -20° in 8 normal subjects and 9 subjects with primary generalised chronic autonomic failure (AF). With postural change normal subjects showed minimal change in MAP (p=0.6) and small but significant changes in IOP (p < 0.001). Subjects with AF showed large and significant changes in both MAP (p < 0.001) and IOP (p < 0.001). Two AF subjects had raised IOP when recumbent, despite normal IOP at +45°. There was significant covariance of MAP and IOP (p < 0.001 overall, p=0.004 in normal subjects, p=0.006 in AF subjects). However, individually, those patients with large changes in IOP could not be predicted from changes in MAP. These data show that patients with autonomic failure are subject to large posture-related changes in IOP. These appear to be related to the large posture-induced changes in systemic blood pressure which occur in these patients. [ABSTRACT FROM AUTHOR]

Continuous haemodynamic responses to head-up tilt (HUT) and its reversal were studied in 21 subjects with sympathetic denervation due to primary chronic autonomic failure; 10 had pure autonomic failure (PAF; peripheral failure) and 11 had multiple system atrophy (MSA; central failure); 8 healthy subjects (controls) also were studied. Supine systolic, diastolic and mean arterial pressure (MAP) and total peripheral resistance (TPR) were highest in PAF. The MAP response to HUT and tilt reversal were different between groups. After HUT, MAP increased in controls (12±4 mmHg), but decreased in PAF and MSA (41±4 & 19±4 mmHg respectively); the fall in PAF was greater than in MSA. With tilt reversal, MAP returned promptly, but not entirely to pretilt levels in controls, with small (insignificant) overshoots in MSA and PAF. The TPR response to HUT and tilt reversal was different between groups. After HUT, TPR increased in controls (0.31±0.04 PRU), decreased in PAF (0.23±0.1 PRU) and was unchanged in MSA. With tilt reversal, TPR remained elevated (15 %) above baseline in the controls and rose in PAF (13 %) with no change in MSA. There were no differences in supine heart rate (HR), stroke volume (SV) or cardiac output (CO) between the three groups; HR, SV or CO responses to HUT or tilt reversal also did not differ between the groups. Thus, after HUT, MAP decreased, with greater hypotension induced in PAF than MSA. Since CO did not differ between groups, the decrease in TPR appears to account for the greater fall in BP in PAF than in MSA. The elevated TPR at rest pre-tilt and after tilt reversal probably contributed to supine hypertension in PAF. These haemodynamic observations may aid therapeutic strategies to reduce orthostatic hypotension and prevent supine hypertension. [ABSTRACT FROM AUTHOR]

n effective baroreflex and autonomic pathways normally ensure that blood pressure (BP) is satisfactorily maintained, despite various stimuli in daily life that include postural changes. We describe a 20-year-old man with a cerebellar hematoma and acute hydrocephalus, who had a vermian and partial right cerebellar hemisphere resection followed by orthostatic hypertension (OHT) and mutism. On standing his systolic BP rose over 60 mmHg with a fivefold increase in plasma noradrenaline. After a period of 8 weeks, postural BP regulation improved along with his ability to communicate. We conclude that transient impairment of cerebellar autonomic modulation or dysfunction of the baroreflex medullary circuit, may have resulted in OHT. [ABSTRACT FROM AUTHOR]

Nocturnal polyuria is a common symptom in autonomic failure. In patients with urinary bladder involvement nocturia can be troublesome and considerably add to their disabilities. Nocturnal diuresis and natriuresis account for overnight weight loss that appears to worsen the extent of, and symptoms resulting from, orthostatic hypotension in the morning. Some patients are considerably incapacitated and find it difficult to function until late morning; even a light breakfast and minimal exertion can substantially worsen symptoms. This partly may be helped by the use of head-up tilt at night. Nocturnal polyuria probably results in redistribution of body fluids, reducing central filling pressure, stroke volume, cardiac output and thus blood pressure. This is consistent with recent studies confirming that orthostatic hypotension is worse in the morning and indicating that there are greater changes in stroke volume and cardiac output on standing in the morning compared to the evening. The reduction in overnight fluid loss presumably reverses this cycle of events, thus reducing morning orthostatic hypotension.

A response by Dr. Robert D. Hoeldtke to a letter to the editor about his article "Nitrosative stress in early type I diabetes," in the previous issue is presented.

Background: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed.Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score.A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)].Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.Methods: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed.Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score.A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)].Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.Results: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed.Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score.A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)].Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.Conclusions: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed.Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score.A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)].Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression. [ABSTRACT FROM AUTHOR]