Clinicopathological Features of Pure Autonomic Neuropathy

Abstract & Commentary

By Joshua Weaver, MD, and Norman Latov, MD, PhD. Dr. Weaver is a Clinical Neurophysiology Fellow; Dr. Latov is Professor of Neurology and Neuroscience, and Director of the Peripheral Neuropathy Clinical and Research Center, Weill Cornell Medical College.

Dr. Weaver reports no financial relationships relevant to this field of study. Dr. Latov has served as consultant to Grifols, Novartis, CSL Behring, Pfizer, Octapharma, Sanofi, Baxter Biotherapeutics, Elan Pharmaceuticals, Depomed, and Eisai Inc. He owns stock in Therapath LLC, and is beneficiary of a licensing agreement between Cornell University and Teva Pharmaceuticals for a patent related to the use of MSR1 antibodies in inflammatory diseases.

Synopsis: The clinicopathological features of nine patients with pure autonomic neuropathy, with or without antiganglionic acetylcholine antibody, were assessed. There was considerable variability in the clinical manifestations, course, unmyelinated nerve fiber loss, and response to therapy.

Source: Koike H, et al. The spectrum of clinicopathological features in pure autonomic neuropathy. J Neurol 2012 DOI 10.1007/s00415-012-6458-x.

Pure autonomic neuropathy is rare. it selectively affects only sympathetic and/or parasympathetic nerves, leaving motor and sensory functions intact. Known causes include diabetes, amyloidosis, Sjogren's syndrome, or cancer. Recent identification of antiganglionic acetylcholine receptor (AChR) antibody suggests an autoimmune etiology in some cases previously categorized as idiopathic.

Patient selection criteria included autonomic dysfunction, normal nerve conduction studies, and evidence for peripheral involvement including antiganglionic AChR antibody, denervation supersensitivity evidenced by pupillary or blood pressure responses, or sural nerve biopsy showing unmyelinated fiber damage. Patients with neurodegenerative or systemic disorders associated with autonomic neuropathy were excluded.

Of nine patients, six were men and three were women, with mean age of onset 50.4 years (+ 18.1 SD). Four had antecedent events of fever and/or infection. Four had antiganglionic AChR antibodies. Orthostatic symptoms with syncope were the most common (in eight of the nine patients), followed by gastrointestinal symptoms, abnormal perspiration, urinary symptoms, mydriasis, dry mouth and eyes, and erectile dysfunction. Of those patients with antiganglionic AChR antibodies, autonomic symptoms tended to be more widespread with the notable exception of one patient who only had orthostatic symptoms.

Autonomic testing revealed orthostatic hypotension, reduced baseline plasma norepinephrine concentration, electrocardiographic abnormalities, supersensitive pupillary and blood pressure responses to the administration of catecholamines, decreased lacrimal and salivary secretions, and decreased perspiration in the majority of the patients tested.

Sural nerve biopsies done in six patients showed normal densities of large and small myelinated nerve fibers with no evidence of axonal degeneration, demyelination, or remyelination. Electron microscopic findings revealed decreased unmyelinated fiber densities in three patients, and two showed increased amount of collagen pockets indicative of decreased sympathetic efferents. Those with longer duration showed more unmyelinated fiber loss.

Of four patients who were negative for the antiganglionic AChR antibody, one spontaneously recovered without immunomodulatory treatment, one received intravenous methylprednisolone with complete recovery, and two showed initially spontaneous recovery with later recurrence of symptoms. Three of the patients with antiganglionic AChR antibody received intravenous immunoglobulin; one showed significant improvement; one showed mild improvement; and one did not improve.

Commentary

This study documents the variable and overlapping clinical manifestations of patients with idiopathic or antiganglionic AChR antibody associated pure autonomic neuropathy. It also adds to the scarce literature on the pathological changes seen in these patients.1-3

The study raises a number of questions regarding both the diagnosis and treatment of pure autonomic neuropathy. Given that neurodegenerative central nervous system disease processes, such as multiple system atrophy, can present overlapping symptoms and signs, testing for antiganglionic AChR antibodies or sudomotor denervation could help distinguish between central and peripheral causes of dysautonomia.4

Some of the patients who were seronegative for ganglionic AChR antibodies had antecedent infections or an acute monophasic course, suggesting an autoimmune etiology as in an atypical form of Guillain–Barré syndrome. As such, immunomodulatory therapy may prevent irreversible ganglionic or small fiber damage. Further studies will be needed to identify those patients who are likely to respond to therapy.

References

1. Koike H, et al. Slowly progressive autonomic neuropathy with antiganglionic acetylcholine receptor antibody. J Neurol Neurosurg Psychiatry 2010;81:586-587.

2. Manganelli F, et al. Autoimmune autonomic ganglionopathy: A possible postganglionic neuropathy. Arch Neurol 2011;68:504-507.

3. Sandroni P, et al. Idiopathic autonomic neuropathy: Comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody. Arch Neurol 2004;61:44-48.

4. Donadio V, et al. Autonomic innervation in multiple system atrophy and pure autonomic failure. J Neurol Neurosurg Psychiatry 2010;81:1327-1335.