Chapter 27 - Pure autonomic failure

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Abstract

In this chapter, we describe the history, presentation, diagnosis and treatment of pure autonomic failure (PAF). The pathology underlying this condition is thought to involve the deposition of alpha synuclein in the autonomic ganglia leading to diminished norepinephrine release and progressive autonomic dysfunction. We focus on various neurophysiological tests that may be used to evaluate the function of the peripheral autonomic nervous system including quantitative sudomotor axon reflex testing, thermoregulatory sweat testing, and others. These may help evaluate and diagnose various disorders of autonomic failure and neurogenic orthostatic hypotension including multiple system atrophy and Parkinson's disease dysautonomia. Management of PAF, including the therapeutic role of recent advances in pharmacologic treatment, is discussed.

Introduction

Pure autonomic failure (PAF) is a rare sporadic neurodegenerative disorder characterized by progressive failure of autonomic regulation. Described initially in 1925 by Bradbury and Eggleston, the disease is characterized by an indolent course associated with worsening orthostatic hypotension (OH) and other markers of sympathetic and parasympathetic dysregulation. PAF is often distinguished as a separate entity from autonomic failure associated with diseases of the CNS such as Parkinson's disease (PD) with autonomic features. Symptoms of cerebral hypoperfusion and supine hypertension can make autonomic failure difficult to manage. α-Synucleinopathy and formation of Lewy bodies in the peripheral autonomic nervous system often underlie the pathology of PAF, although occasional cases have lacked Lewy bodies. This chapter describes the characteristics of PAF as a disease including history, presentation, diagnosis, pathology and treatment, and focuses on neurophysiologic findings, evaluation and treatment.

Section snippets

History

The 1996 PAF consensus statement mentions three characteristic features of the disease: OH, absence of other neurologic features, and reduced supine plasma norepinephrine levels. The original Bradbury and Eggleston series published in 1925 discussed 3 patients who described symptoms of OH. On examination, the authors noted other symptoms of autonomic failure in these patients including a slow, unchanging pulse rate, anhidrosis, erectile dysfunction, and constipation. Symptoms improved somewhat

Presentation

The most common presenting feature of autonomic failure is OH. Patients are typically middle-aged males (70% male with a mean age of 63 presenting with symptoms for about 5 years as noted in Kaufmann et al., 2017). Symptoms progress slowly initially with presyncope and lightheadedness. A coat-hanger distribution headache due to hypoperfusion of the neck muscles upon standing is common, as noted by Bleasdale-Barr and Mathias (1998). Exacerbation of symptoms by heat or a large meal is common.

Pathophysiology

The protein α-synuclein occurs in neuronal or glial cytoplasm of patients with PD, DLB, MSA, and PAF. It remains unclear whether the protein itself causes disruption of cellular function. In PAF, the largest concentrations of Lewy bodies are found in the sympathetic and parasympathetic ganglia and pre- and postganglionic autonomic neurons. Lewy bodies can also be found in a number of other peripheral tissues, including adipose and the urinary bladder. Lewy bodies can also be found in the

Treatment/Management (Brief Overview)

Treatment strategies for PAF focus on symptom control with a tri-pronged approach. Typically, the patient is symptomatic mainly due to neurogenic orthostatic hypotension. Treatment involves avoiding exacerbating factors, use of conservative measures and lifestyle changes, and, finally, pharmacologic treatment.

Avoidance of exacerbating factors such as use of diuretics, vasodilators (sildenafil, nitrates), and norepinephrine release blockers (alpha blockers or tricyclic antidepressants) is

Future Directions

Prognosis in PAF remains good overall, with a greater than 20-year survival expected in most patients. However, a number of PAF patients progress to more severe forms of synucleinopathy. The pathogenic role of α-synuclein still appears somewhat unclear. Patients with PAF who do not demonstrate evidence of α-synuclein deposition may have a different disorder. Further identification and evaluation of these patients will help elucidate the pathophysiology, nature, prognosis, and management of this

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