Wednesday, June 13, 2012

Dysautonomia: 1869 to 1999

The term 'neurasthenia' was popularized by Dr. George Miller Beard in 1869 as a condition to describe primarily women who had the sudden onset of weakness, fatigue, pain, and passing out. Thought to arise as a consequence of "civilization", the diagnosis could frequently be made after a recovery from a brief illness (1). Urbanization stresses in the competitive business environment were thought to contribute to this disease of a "weak nervous system".  

To look at the term 'dysautonomia' proper, one turns to the Veterinary literature, where the term is well entrenched (2). In 1907, dysautonomia was first described as affecting horses in Scotland. The major symptoms of the clinical syndrome were dysphagia and gastric dysmotility, with horses becoming severely cachetic and malnourished. Horses grazing in particular fields seemed prone to dysautonomia, and the term, "grass sickness" was coined. The prognosis for horses was poor, with most horses suffering death or euthanasia. Survivors were rare and there was no effective treatment. Mortality was estimated at 95% and famous thoroughbred racehorses affected by "grass sickness" were Mister Baileys and Dubai Millennium. 

In 1949, Familial Dysautomomia (FD) was discovered by Drs. Conrad Milton Riley and Richard Lawrene Day, hence 'Riley-Day' Syndrome (3). From 1949-1959, a series of clinical markers were determined: two clinical tests, to include the Histamine Test and Tongue Markers; and two physiologic studies, to include urine and plasma catecholamine levels and a lack of compensation for conditions of low oxygen and high carbon-dioxide levels (4).

From 1969-1979, Drs. Aguayo and Pearson used electron microscopy to show that the FD defect was a decreased number of small, unmyelinated neurons (4).

In 1982, feline dysautonomia was reported in the veterinary literature by Key and Gaskell, from the University of Bristol. The diagnosis was prevalent, with hundreds of cases reported around 1985. Cats displayed dry mucous membranes, pupillary dilation, and protrusion of the third eyelid. Only about one-quarter of the cases survived. In 1983, canine dysautonomia was first described in Britain, then subsequently in Europe and America. In 1991, the United Kingdom reported dysautonomia in wild hares (2).

In 1993, the FD defect was located on Chromosome 9. In 1995, patients with FD participated in clinical trials that formed the basis of pharmacologic agent midodrine being FDA approved (4).  

Symptomatic orthostatic intolerance is a presenting complaint of mostly young women who are subsequently diagnosed with Postural Orthostatic Tachycardia Syndrome (POTS). In 1997, Grubb et al. defined the criteria which impose an increase in heart rate to 30 beats/min or an increased heart rate of 120 beats/min or greater when changing from a supine to the standing position (5,6). From 1997-1999, additional neurophysiologic invesigations were described to further assess FD: Cold Face Stimulation, laser doppler Flowmeter, and temperature assessment as correlated with cardiac risk (4). 

In 1999, precise mapping of the FD gene was performed to show that the site was 9q31, and dysautonomia was reported in the llama of the Netherlands (4). At the same time, Schondorf et al. estimated the prevalence of orthostatic intolerance in patients with chronic fatigue syndrome was 40% (Schondorf)(7).

While the initial term 'neurasthenia' as coined by Beard was not based on autonomic dysfunction per se, Dr. George Miller Beard holds esteem for recognizing a clinical syndrome. Dr. Beard went against the grain of science at the time, being a proponent of medical electrical stimulation therapy, as well as being against the use of the death penalty. 'Dysautonomia' proper is an original term with a longer history in the veterinarian literature than that applied to humans. It is the intense and valuable work by Drs. Riley and Day that not only rooted Familial Dysautonomia as an entity, but entrenched the concept of the autonomic nervous system as having assigned pathophysiology. That pathophysiology seems well applied to patients with the genomic expression and clinical diagnosis of FD, in the sense that there are a variety of ANS clinical tests that are available to quantify the syndrome. There is a need for these tests to be applied to the general dysautonomia and POTS patient populations, so that further quantification may be made on a broader scale.

For Images of Animals with Dysautonomia, Click Here.
Images of Animals with Dysautonomia


(1) A Handbook of Practical Treatment, John H. Musser, MD and O.A. Kelly, MD, 1912.  
(2)  Dennis O'Brien DVM, PhD, DACVIM-Neurology Department of Veterinary Medicine; Surgery College of Veterinary Medicine University of Missouri, Columbia, MO 65211.
(3) Riley CM, Day RL, Greely D, Langford WS. Central autonomic dysfunction with defective lacrimation. Pediatrics 3(4):468-477, 1949.  PMID 18118947.
(5) Grubb B.P., Kosinske D., et al. The postural tachycardia syndrome: a neurocardiogenic variant    identified during head-up tilt table testing. Pacing Clin Electrophysiol,  1997; 20:2205-2212.
(6) Grubb B.P., Kanjwal Y., and Kosinski D. The postural tachycardia syndrome: a concise guide to diagnosis and management. J Cardiovasc Electrophysiol, 2006; 17:108-112.
(7) Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst 1999;75:192-201.

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