Pure Autonomic Failure Versus Prodromal Dysautonomia in Parkinson's Disease: Insights from the Bedside

Abstract

Autonomic failure may include orthostatic hypotension, supine hypertension, bowel and bladder disturbances, impaired thermal regulation, and sexual dysfunction, all of which can be features of Parkinson's disease (PD) and other a‐synucleinopathies. All patients with pure autonomic failure, most patients with multiple system atrophy, and 18% of patients with PD will develop symptomatic orthostatic hypotension. However, the extent of central and peripheral norepinephrine deficiency, parasympathetic nuclei degeneration, and arterial baroreflex failure may be differentially impaired in these disorders. Consequently, clinical features and prognostic implications of autonomic dysfunction in a‐synucleinopathies may be more complex than previously envisioned. The case described in this report highlights the clinical similarities between PD and pure autonomic failure, raising the question of whether pure autonomic failure represents a restricted Lewy body synucleinopathy or an early manifestation of PD.

Autonomic failure may include orthostatic hypotension (OH), supine hypertension, bowel and bladder disturbances, impaired thermal regulation, and sexual dysfunction, all of which can be features of Parkinson's disease (PD) and other α‐synucleinopathies. All patients with pure autonomic failure (PAF), most with multiple system atrophy (MSA), and 18% with PD will develop symptomatic OH.1 However, the extent of central and peripheral norepinephrine deficiency, parasympathetic nuclei degeneration, and arterial baroreflex failure may be differentially impaired in these disorders.2, 3 As a result, clinical features and prognosis of autonomic dysfunction in α‐synucleinopathies may be more complex than previously envisioned. Here we report the long‐term follow‐up (10 years) of a patient with severe autonomic dysfunction as presenting symptom of PD, analyzing the possible differential diagnosis with PAF and MSA. The patient described below provided written informed consent to be described anonymously, and the authors acted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Case Report

A 68‐year‐old man was admitted to the emergency unit for syncope and chest pain associated with orthostatism. Over the previous 12 months, he had reported three syncopal events, constipation, erectile dysfunction, and profuse sweating. His blood pressure (BP) was 148/98 mmHg supine, and 80/50 mmHg upright. Electrocardiography (ECG), 24‐hour ECG monitoring, and coronary angiography were normal, whereas echocardiography revealed left ventricular hypertrophy. Autonomic evaluation revealed nocturnal hypertension with a “reverse dipping” pattern on ambulatory BP monitoring; a significant BP drop in the lying‐to‐standing test (53/28 mmHg at 3 minutes; normal, < 20/10 mmHg [systolic/diastolic]); decreased heart rate variability, as measured by deep‐breathing test (expiratory:inspiratory ratio = 1.01; normal, ≥ 1.1), lying‐to‐standing test (30:15 ratio = 1.0; normal, ≥ 1.04), and Valsalva maneuver (Valsalva ratio = 1.04; normal, ≥ 1.14); and markedly low catecholamine plasma levels in both supine and orthostatic positions (Fig. 1). Brain magnetic resonance imaging, peripheral nerve‐conduction studies (bilateral evaluation of the peroneal, tibial, ulnar, median, and sural nerves for distal latencies, amplitudes, and motor and/or sensory nerve‐conduction velocities), vestibular tests, carotid/vertebral Doppler ultrasonography, and neurological examination were normal. A ¹²³metaiodobezilguanidyne (MIBG) cardiac positron emission tomography scan demonstrated widespread sympathetic denervation (Fig. 1). He was managed with midodrine 15 mg daily and fludrocortisone 0.1 mg daily. 3 years later, he developed resting tremor in the right hand and foot associated with mild bradykinesia. A brain DAT‐SCAN study (¹²³I‐N‐fluoropropyl‐2β‐carbomethoxy‐3β‐[4‐iodophenyl] nortropane single‐photon emission computed tomography) revealed abnormal radioligand binding that affected the left putamen. A diagnosis of PD was made, and treatment with rasagiline (1 mg daily) was started, which lowered his score on part III of the Unified Parkinson's Disease Rating Scale (UPDRS‐III [motor part]) from 11 to 6. Scores on the Scale for Outcome in Parkinson's Disease‐Autonomic and the Nonmotor Symptom Scale were 30 and 50, respectively. Significant alterations were observed on the cardiovascular, sexual function, gastrointestinal tract, and fatigue subitems. Moreover, the patient reported excessive sweating, mild alterations of smell, and mild problems sustaining concentration. No alterations were reported in mood/cognition, perceptual problems/hallucinations, or urinary functions. 4 years later, upon worsening of tremor and bradykinesia (UPDRS‐III score, 14), low‐dose levodopa (l‐dopa)/carbidopa (50/12.5 mg three times daily) was administered for 2 weeks, and produced significant motor improvement (UPDRS‐III score, 7). However, OH worsened, with an increase in the frequency of item 1 on the Nonmotor Symptom Scale (lightheadedness when standing) from 3 (frequent) to 4 (very frequent). In addition, presyncopal episodes associated with standing were reported 1 to 3 hours after each l‐dopa dose, with documented BP falls > 30/15 mmHg (systolic/diastolic).

Figure 1.

(A) A¹²³metaiodobezilguanidyne (¹²³ MIBG) scan demonstrates widespread cardiac sympathetic denervation. (B) A [¹²³I] n‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl) nortropane single‐photon emission computed tomography (DAT‐SCAN) reveals abnormal radioligand binding affecting the left putamen. (C) Catecholamine plasma concentrations indicate low norepinephrine levels in both supine and standing positions.

More than 10 years after the onset of autonomic features and 7 years after the onset of motor features, dysautonomia with prominent OH remained a major l‐dopa–limiting source of disability, with motor symptoms modestly improved on rasagiline 1 mg daily (UPDRS‐III score, 15).

In this report, we describe the long‐term follow‐up of a patient with severe autonomic dysfunction as a presenting symptom of PD. The clinical features initially suggested MSA or PAF, but the abnormal MIBG scan and the low orthostatic catecholamine plasma levels argued against a diagnosis of MSA, and the profuse sweating was atypical for PAF (Table 1). The early differential diagnosis of α‐synucleinopathies is challenging given the different prognosis (10‐year survival rate: MSA, 33%; PAF, 87%: PD with OH, 74%; PD without OH, 93%)3 and the heterogeneous pathogenic mechanisms involved (Table 1).4, 5, 6, 7, 8 MSA is characterized by glial cytoplasmic inclusions of α‐synuclein with central catecholaminergic deficiency, degeneration of parasympathetic nuclei, and preserved peripheral sympathetic innervation.9 Conversely, PAF and PD are characterized by neuronal inclusions of α‐synuclein deposited as cytoplasmic Lewy bodies, differing only in their distribution. PAF affects predominantly peripheral structures,9 whereas PD also involves central structures (Table 1), as suggested by the frequent association between OH, cognitive impairment, and rapid eye movement sleep behavioral disorder.10

Table 1.

Pathological alterations associated with autonomic dysfunction in α‐synucleinopathies

Variable	MSA	PD	PAF
Type of ɑ‐synuclein deposits	Major glial cytoplasmic and minor neuronal cytoplasmic and intranuclear inclusions	Lewy bodies (neuronal cytoplasmic inclusions)	Lewy bodies (neuronal cytoplasmic inclusions)4
Site of ɑ‐synuclein deposits	CNS (one recent report of p‐ɑ‐Syn deposition also in dermal nerve fibers)5	CNS and PNS	PNS (sporadic autopsy reports of CNS depositions)6
Nigrostriatal dopaminergic neurons	Neuronal loss in MSA‐P; moderate neuronal loss in MSA‐C	Neuronal loss	Report of cases with neuronal loss6
Onuf nucleus (segments S2–S4 of the spinal cord)	Degeneration	Normal	Normal
Cardiac postganglionic sympathetic fibers	Not affected	Affected (selective involvement)	Affected
Extracardiac postganglionic sympathetic fibers	Postganglionic autonomic fibers involvement in sweat glands7	Minimal loss	Affected
Sudomotor fibers	Involvement of preganglionic and postganglionic7 fibers; generalized and progressive anhidrosis	Length‐dependent involvement of postganglionic fibers; mild, distal, nonprogressive anhidrosis–hyperhidrosis	Involvement of postganglionic fibers; early generalized anhidrosis
Autonomic skin nerve fibers	Only one report of p‐ɑ‐Syn deposition in dermal nerve fibers5	P‐ɑ‐Syn inclusions8	P‐ɑ‐Syn inclusions8
Diagnostic implications
Central dopamine transporter imaging	Reduced uptake	Reduced uptake	Sporadic reports of reduced uptake6
123MIBG (metaiodobenzyl‐ guanidine) scintigraphy	Normal uptake	Reduced uptake	Reduced uptake
Supine basal plasma NE levels	Normal	Decreased in PD with OH	Decreased
Head‐up tilt response plasma NE levels	Moderately decreased	Decreased in PD with OH	Decreased

MSA, multisystem atrophy; PD, Parkinson's disease; PAF, pure autonomic failure; p‐α‐Syn, phosphorylated α‐synuclein; CNS, central nervous system; PNS, peripheral nervous system; MSA‐P, multisystem atrophy with parkinsonian features; MSA‐C, multisystem atrophy with cerebellar features; NE, norepinephrine; OH, orthostatic hypotension.

The case reported here highlights the clinical similarities between PD and PAF, raising the question of whether PAF represents a restricted Lewy body synucleinopathy or an early manifestation of PD, as proposed by Kaufmann and colleagues.4 The possibility exists that certain biological processes, as yet unrecognized, may succeed in restricting Lewy body pathology to the peripheral autonomic nervous system (as lifelong PAF) or may fail by allowing its slow spread into the central nervous system (as prodromal dysautonomia in PD). Understanding these biological processes may inform the development of future neuroprotective strategies in PD.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

A.M.: 1A, 1B, 1C, 3A

A.J.E.: 1B, 3A, 3B

M.Z.: 1B, 1C, 3B

A.R.: 1B, 1C, 3B

M.R.: 1B, 3B

S.M.: 1C, 3B

L.L.: 1B, 3B

Disclosures

Funding Sources and Conflict of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: Dr. Merola has received grant support from UCB Pharma and speaker honoraria from CSL Behring, UCB Pharma, and Teva Pharmaceuticals; he also has received personal compensation from Edge Consulting S.r.l., MediK S.r.l., and Sthetos S.r.l. Dr. Espay is supported by the National Institutes of Health (grant 1K23MH092735); he has received grant support from CleveMed/Great Lakes Neurotechnologies and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Chelsea Therapeutics, TEVA, Impax, Merz, Pfizer, Acadia, Cynapsus, Solstice Neurosciences, Lundbeck, and USWorldMeds; royalties from Lippincott Williams & Wilkins and Cambridge University Press; and honoraria from Abbvie, UCB, USWorldMeds, Lundbeck, Acadia, the American Academy of Neurology, and the Movement Disorders Society; in addition, he serves as Associate Editor of the Journal of Clinical Movement Disorders and on the editorial board of Parkinsonism and Related Disorders. Dr. Zibetti has received speaker and/or consulting honoraria from Medtronic, Lundbeck, UCB Pharma, and Abbvie. Dr. Romagnolo has received grant support from Abbvie and travel grants from Novartis and Merck Serono; he also has received personal compensation from Edge Consulting S.r.l. and Sthetos S.r.l. Prof. Lopiano has received honoraria for lecturing and travel grants from Medtronic, UCB Pharma, and AbbVie. Dr. Rosso and Dr. Maule report no sources of funding and no conflicts of interest.