Valeria Iodice

Postural tachycardia syndrome—current experience and concepts

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–Danlos 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.

Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure.

OBJECTIVE To report preliminary results of a prospective ongoing study of multiple system atrophy (MSA) and Parkinson disease (PD), with a large subset of patients with PD with autonomic failure (25%), to evaluate autonomic indices that distinguish MSA from PD. METHODS We used consensus criteria, detailed autonomic studies (Composite Autonomic Symptom Scale, Composite Autonomic Scoring Scale, thermoregulatory sweat test, and plasma catecholamines), and functional scales (Unified MSA Rating Scale [UMSARS] I-IV and Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis. RESULTS We report the results of a study on 52 patients with MSA (mean [SD], age, 61.1 [7.8] years; body mass index (calculated as weight in kilograms divided by height in meters squared), 27.2 [4.6]; Hoehn-Yahr grade, 3.2 [0.9]; UMSARS I score, 21.5 [7.4]; and UMSARS II score, 22.7 [9.0]) and 29 patients with PD, including PD with autonomic failure (mean [SD], age, 66.0 [8.1] years; body mass index, 26.6 [5.5]; Hoehn-Yahr grade, 2.2 [0.8]; UMSARS I score, 10.4 [6.1]; and UMSARS II score, 13.0 [5.9]). Autonomic indices were highly significantly more abnormal in MSA than PD (P < .001) for the Composite Autonomic Scoring Scale (5.9 [1.9] vs 3.3 [2.3], respectively), Composite Autonomic Symptom Scale (54.4 [21.8] vs 24.7 [20.5], respectively), and thermoregulatory sweat test (percentage anhidrosis, 57.4% [35.2%] vs 9.9% [17.7%], respectively). These differences were sustained and greater at 1-year follow-up, indicating a greater rate of progression of dysautonomia in MSA than PD. CONCLUSIONS The severity, distribution, and pattern of autonomic deficits at study entry will distinguish MSA from PD, and MSA from PD with autonomic failure. These differences continue and are increased at follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic and postganglionic, while MSA is preganglionic.

Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests

Background Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by autonomic failure, manifested as orthostatic hypotension or urogenital dysfunction, with combinations of parkinsonism that is poorly responsive to levodopa, cerebellar ataxia and corticospinal dysfunction. Published autopsy confirmed cases have provided reasonable neurological characterisation but have lacked adequate autonomic function testing. Objectives To retrospectively evaluate if the autonomic characterisation of MSA is accurate in autopsy confirmed MSA and if consensus criteria are validated by autopsy confirmation. Methods 29 autopsy confirmed cases of MSA evaluated at the Mayo Clinic who had undergone formalised autonomic testing, including adrenergic, sudomotor and cardiovagal functions and Thermoregulatory Sweat Test (TST), from which the Composite Autonomic Severity Score (CASS) was derived, were included in the study. Results Patient characteristics: 17 men, 12 women; age of onset 57±8.1 years; disease duration to death 6.5±3.3 years; first symptom autonomic in 18, parkinsonism in seven and cerebellar in two. Clinical phenotype at first visit was MSA-P (predominant parkinsonism) in 18, MSA-C (predominant cerebellar involvement) in eight, pure autonomic failure in two and Parkinsons disease in one. Clinical diagnosis at last visit was MSA for 28 cases. Autonomic failure was severe: CASS was 7.2±2.3 (maximum 10). TST% was 65.6±33.9% and exceeded 30% in 82% of patients. The most common pattern was global anhidrosis. Norepinephrine was normal supine (203.6±112.7) but orthostatic increment of 33.5±23.2% was reduced. Four clinical features (rapid progression, early postural instability, poor levodopa responsiveness and symmetric involvement) were common. Conclusion The pattern of severe and progressive generalised autonomic failure with severe adrenergic and sudomotor failure combined with the clinical phenotype is highly predictive of MSA.

Autonomic dysfunction in parkinsonian disorders: assessment and pathophysiology

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterised by motor dysfunction (parkinsonism) and several non-motor features. Dysautonomia is a significant non-motor feature as well as a neuropsychiatric symptom. Autonomic dysfunction can occur even in the early stages of PD, often preceding the onset of the classic motor symptoms of PD. The patterns of autonomic features in PD are different from other parkinsonian disorders. Detection of autonomic dysfunction may therefore be helpful in diagnosing PD in the early or pre-motor stages, and/or in differentiating it from other parkinsonian disorders, such as multiple system atrophy and progressive supuranuclear palsy. The aim of this review is to describe aspects of autonomic dysfunction, including symptoms, assessment and pathophysiology, resulting from autonomic impairment in PD and other parkinsonian syndromes.

Cardiovascular autonomic dysfunction in MSA and Parkinson's disease: Similarities and differences

In Parkinsons disease and multiple system atrophy (MSA), cardiovascular dysfunction may occur for a variety of reasons and may manifest itself through inappropriate changes and/or levels in blood pressure, heart rate and/or regional vascular perfusion in a range of situations. The early occurrence of orthostatic hypotension often leads to consideration of MSA, especially in the presence of other features of autonomic failure. Orthostatic hypotension, however, is increasingly recognised in PD, and especially with increasing age, severity of disease and as a result of drug therapy, sometimes for associated disorders. Investigation of cardiovascular autonomic dysfunction in Parkinsonism is therefore important for a variety of reasons, that include determining the precise diagnosis and in predicting prognosis. In Parkinsonian disorders, understanding the pathophysiological basis of the cardiovascular autonomic dysfunction aids targeting of therapy, improves management strategies and provides benefit for such patients.

Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy

Objective: To evaluate the efficacy of immunotherapy in the treatment of patients with seropositive and seronegative putative autoimmune autonomic ganglionopathy (AAG) using validated autonomic function tests and instruments. Background: AAG is an immune-mediated disorder characterized by prominent and selective involvement of autonomic nerve fibers or ganglia. Treatment with IV immunoglobulin (IVIg) or plasma exchange (PE) has been reported to be effective in single case reports. Methods: We studied six patients, four with seropositive and two with seronegative putative AAG, who underwent autonomic function tests and completed two validated questionnaires, to assess autonomic symptoms before and after immunomodulatory treatment. Patients were treated with standard doses of IVIg, PE, or immunosuppressants in a specific sequential therapy protocol depending on clinical response. Results: Of the six patients (all women, mean ages 49.3 ± 10.6 years), four patients were ganglionic (α3) AChR autoantibody positive and two were autoantibody negative. All patients showed clinical improvement after treatment. Sudomotor function assessed by quantitative sudomotor axon reflex test and thermoregulatory sweat test improved in four patients after treatment. Conclusions: Immunomodulatory treatment can be effective in both seropositive and seronegative putative autoimmune autonomic ganglionopathy. Plasma exchange or combined therapy with immunosuppressive agents should be considered in patients who do not benefit from IV immunoglobulin alone.

A prospective, 1-year follow-up study of postural tachycardia syndrome.

OBJECTIVE To prospectively evaluate patients who met standard criteria for postural tachycardia syndrome (POTS), at baseline and 1-year follow-up, using standard clinical and laboratory methods to assess autonomic function. METHODS Fifty-eight patients met the study criteria (orthostatic symptoms and a heart rate increment of ≥ 30 beats/min on head-up tilt) and completed 12 months of follow-up. All patients were enrolled and completed the study from January 16, 2006, through April 15, 2009. Patients underwent standardized autonomic testing, including head-up tilt, clinical assessment, and validated questionnaires designed to determine the severity of autonomic symptoms. RESULTS Patients were predominantly young females (n=49, 84%), with 20 patients (34%) reporting an antecedent viral infection before onset of symptoms. More than one-third (37%) no longer fulfilled tilt criteria for POTS on follow-up, although heart rate increment on head-up tilt did not differ significantly at 1 year (33.8 ± 15.1 beats/min) compared with baseline (37.8 ± 14.6 beats/min) for the entire cohort. Orthostatic symptoms improved in most patients. Autonomic dysfunction was mild as defined by a Composite Autonomic Severity Score of 3 or less in 55 patients (95%) at baseline and 48 patients (92%) at 1 year. CONCLUSION To our knowledge, this is the first prospective study of the clinical outcomes of patients with POTS. Orthostatic symptoms improved in our patients, with more than one-third of patients no longer fulfilling tilt criteria for POTS, although the overall group change in heart rate increment was modest. Our data are in keeping with a relatively favorable prognosis in most patients with POTS.

Sudomotor dysfunction in autoimmune autonomic ganglionopathy

Background: Autoimmune autonomic ganglionopathy is characterized by impairment of multiple autonomic domains of which sudomotor function is among the most common. Many patients with this disorder have difficulties with thermoregulation and anhidrosis. Our objective was to characterize the distribution and severity of sudomotor dysfunction in this disorder. Methods: Sudomotor function was analyzed in a cohort of 21 patients with ganglionic α3 nicotinic acetylcholine receptor (nAChR) antibody positive autoimmune autonomic ganglionopathy. Standard measurements of sudomotor function were used including the Thermoregulatory Sweat Test and Quantitative Sudomotor Axon Reflex Test. Results: The clinical presentation in all patients was characterized by widespread sudomotor dysfunction. Sudomotor impairment was predominantly postganglionic in 17 of the 21 patients studied. Higher ganglionic α3 nAChR antibody levels resulted in progressive postganglionic predominant dysfunction (postganglionic, r = 0.637, p = 0.002; mixed ganglionic, r = 0.709, p < 0.001). The pattern of anhidrosis on Thermoregulatory Sweat Testing was consistent with a ganglionopathy in the majority of patients (14 of 21) and a distal pattern in a minority of patients (8 of 21). These patterns of anhidrosis coupled with increasing postganglionic dysfunction in a proximal to distal pattern (foot > distal leg > proximal leg > forearm) indicate lesions at both the ganglia and distal axon of the postganglionic sudomotor sympathetic neuron. Conclusions: Our data characterize the unique sudomotor dysfunction in autoimmune autonomic ganglionopathy as widespread, predominantly postganglionic, and a result of lesions at both the ganglia and distal axon. This study provides important support to the hypothesis that this disorder represents a ganglionic neuropathy.

The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy

Differentiation of idiopathic Parkinsons disease (PD) from multiple system atrophy (MSA) can be difficult. Methods devised to help distinguish the two disorders include standardized autonomic testing and cardiac imaging with iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. MSA patients had more severe adrenergic and overall autonomic dysfunction when compared to control and PD patients. Area of anhidrosis on thermoregulatory sweat test was greater in MSA (67.4±12.42, p<0.001) versus PD patients (area of anhidrosis, 1.7±2.96). Postganglionic cardiac sympathetic innervation (iodine-123 meta-iodobenzylguanidine) expressed as heart to mediastinal ratio was significantly lower in Parkinsons disease patients (1.4±0.40, p=0.025) compared to controls (2.0±0.29), but not in multiple system atrophy (2.0±0.76). These findings indicate that autonomic dysfunction is generalized and predominantly preganglionic in multiple system atrophy, and postganglionic in Parkinsons disease. In our hands the thermoregulatory sweat test provides the best distinction between MSA and PD. However further confirmatory studies using larger patient numbers are required. Currently a combination of clinical judgment and autonomic testing is recommended to help differentiate MSA and PD.

Multiple system atrophy: Prognostic indicators of survival

Neurological and autonomic presentation in multiple system atrophy (MSA) may predict early mortality. Quantification of early autonomic failure as a mortality predictor is lacking. Early neurological and autonomic clinical features were retrospectively reviewed in 49 MSA cases (median age at onset, 56.1 years; 16 women) confirmed by autopsy at Mayo Clinic. When available, the 10‐point composite autonomic severity score derived from the autonomic reflex screen provided quantification of the degree of autonomic failure and thermoregulatory sweat test quantitated body surface anhidrosis. Symptoms at onset were autonomic in 50%, parkinsonian in 30%, and cerebellar in 20% of cases. Survival (median [95% confidence interval]) was 8.6 [6.7‐10.2] years. Survival was shorter in patients with early laboratory evidence of generalized (composite autonomic severity score ≥ 6) autonomic failure (7.0 [3.9‐9.8] vs. 9.8 [4.6‐13.8] years; P = 0.036), and early requirement of bladder catheterization (7.3 [3.1‐10.2] vs. 13.7 [8.5‐14.9] years; P = 0.003) compared with those without these clinical features. On Cox proportional analysis, prognostic indicators of shorter survival were older age at onset (hazard ratio [95% confidence interval], 1.04 [1.01‐1.08]; P = 0.03), early requirement of bladder catheterization (7.9 [1.88‐38.63]; P = 0.004), and early generalized (composite autonomic severity score ≥ 6) autonomic failure (2.8 [1.01‐9.26]; P = 0.047). Gender, phenotype, and early development of gait instability, aid‐requiring ambulation, orthostatic symptoms, neurogenic bladder, or significant anhidrosis (thermoregulatory sweat test ≥ 40%) were not indicators of shorter survival. Our data suggest that early development of severe generalized autonomic failure more than triples the risk of shorter survival in patients with MSA.