Autonomic failure: Clinicopathologic, physiologic, and genetic aspects

Over the past century, generations of neuroscientists, pathologists, and clinicians have elucidated the underlying causes of autonomic failure found in neurodegenerative, inherited, and antibody-mediated autoimmune disorders, each with pathognomonic clinicopathologic features. Autonomic failure affects central autonomic nervous system components in the α-synucleinopathy, multiple system atrophy, characterized clinically by levodopa-unresponsive parkinsonism or cerebellar ataxia, and pathologically by argyrophilic glial cytoplasmic inclusions (GCIs). Two other central neurodegenerative disorders, pure autonomic failure characterized clinically by deficits in norepinephrine synthesis and release from peripheral sympathetic nerve terminals; and Parkinson's disease, with early and widespread autonomic deficits independent of the loss of striatal dopamine terminals, both express Lewy pathology. The rare congenital disorder, hereditary sensory, and autonomic neuropathy type III (or Riley-Day, familial dysautonomia) causes life-threatening autonomic failure due to a genetic mutation that results in loss of functioning baroreceptors, effectively separating afferent mechanosensing neurons from the brain. Autoimmune autonomic ganglionopathy caused by autoantibodies targeting ganglionic α3-acetylcholine receptors instead presents with subacute isolated autonomic failure affecting sympathetic, parasympathetic, and enteric nervous system function in various combinations. This chapter is an overview of these major autonomic disorders with an emphasis on their historical background, neuropathological features, etiopathogenesis, diagnosis, and treatment.