The degeneration may be in the form of lesions in the central nervous system, as in multiple system atrophy (MSA) or the loss of autonomic nerves, as in Parkinson disease. Most geriatric cases involve damage to the nerves that results in loss of autonomic reflexes, also known as autonomic failure or pure autonomic failure (PAF).
Many of these conditions are characterized by misfolding and abnormal deposition of proteins, such as alpha-synuclein, amyloid, and tau. Substantial current research on geriatric dysautonomias focuses on the basis for relationships among baroreflex-sympathoneural failure (manifested by neurogenic orthostatic hypotension, nOH), movement disorders, and alpha synuclein deposits (Principles of Autonomic Medicine, 507).
Neurogenic Orthostatic Hypotension (nOH):
A neurodegenerative form of dysautonomia in which the autonomic system loses the ability to properly regulate blood pressure as one moves from sitting or lying down to standing. nOH is a common symptom of multiple systems atrophy (MSA), Parkinson’s disease (PD), and pure autonomic failure (PAF).
Multiple System Atrophy (MSA):
MSA typically develops after age 40 and is most common between the ages of 50 and 59. Multiple system atrophy (MSA) is a disease that involves progressive degeneration of multiple portions of the central nervous system that regulate the autonomic nervous system. Several unconscious “vegetative” functions fail, such as digestion, urination, speech and swallowing mechanisms, and cardiovascular reflexes. It can lead to heart rate issues, low blood pressure (orthostatic hypotension), sexual dysfunction, decreased sweating (anhidrosis), sleep apnea, dry mouth, constipation, loss of bladder control, cognitive symptoms, and movement related symptoms.
No one knows what causes MSA. There is no convincing evidence that in the United States the disease is inherited. No environmental toxin is known to cause it. A currently prevalent but controversial view is that misfolded alpha-synuclein acts like a prion (an abbreviation for “proteinaceous infectious particle”). A prion is a misfolded protein that can cause misfolding of the same protein (templating), in a kind of chain reaction. The prion theory of MSA posits that misfolded alpha-synuclein is transmitted from cell to cell, induces misfolding of alpha-synuclein in target glial cells, and as a result of the glial cell pathophysiology produces central neurodegeneration as is found in MSA. So far, the theory has not been tested completely. In particular, there is no evidence for infectious spread of MSA from human to human.
According to another view, MSA reflects a form of autoimmune process where the patient’s immune system attacks and destroys particular brain cells. These concepts are not mutually exclusive since misfolded alpha-synuclein could arouse an autoimmune response. Brain tissue from MSA patients shows abnormal accumulations of alpha-synuclein in glial cells (glial cytoplasmic inclusions, or GCIs), which are not neurons. Perhaps the accumulations interfere with the ability of glial cells to produce the nerve growth factor, glial cell line-derived neurotrophic factor (GDNF). Whether GCIs cause or are a result of the disease and the mechanisms by which alpha-synuclein accumulates in glial cells are unknown. (Principles of Autonomic Medicine, 549 -551)
Pure Autonomic Failure (PAF):
Pure autonomic failure (PAF, previously called Bradbury-Eggleston syndrome) is a slowly progressive neurodegenerative disorder of the autonomic nervous system. PAF is a rare disease that typically presents in midlife to late in life and features persistent falls in blood pressure in addition to symptoms from many organ systems such as genitourinary, gastrointestinal, and neurological. PAF is predominantly peripheral in origin with deposits of alpha-synuclein. In some cases, PAF may progress to a disorder with more central nervous system involvement.
While chronic and causing disability, PAF is not thought to be lethal. PAF patients report progressively worsening dizziness when standing up, after a large meal, upon exposure to environmental heat, or after exercise. The patients often learn to sit or stand with their legs twisted pretzel-like, since this decreases pooling of blood in the legs. In men, erectile failure is an early symptom. Often the patients have decreased sweating. Blood pressure responses to the Valsalva maneuver in PAF always show the abnormal pattern that indicates baroreflex-sympathoneural failure.
There is growing evidence that at least some of the noradrenergic deficiency that characterizes PAF reflects functional abnormalities in sympathetic nerves, such as decreased efficiency of vesicular storage of catecholamines, rather than simply a loss of the nerves. This is a matter of active research now. Because of “denervation supersensitivity” and baroreflex-sympathoneural failure, patients with PAF can have surprisingly large increases in blood pressure in response to adrenoceptor-stimulating drugs.
At least in some patients, PAF evolves into dementia with Lewy bodies and orthostatic hypotension (DLB+OH), to Parkinson’s disease with orthostatic hypotension (PD+OH), or a combination (Principles of Autonomic Medicine, 517-520).
Diabetic Autonomic Neuropathy:
Dysautonomia is common in diabetes. Diabetes is probably the most common cause of autonomic neuropathy. Among patients with diabetes, the occurrence of autonomic neuropathy is an adverse prognostic factor.
Diabetes often involves chronic pain in the feet (painful diabetic neuropathy). Loss of sympathetic noradrenergic innervation in the feet accompanies the neuropathy. Diabetics can also have neurogenic orthostatic hypotension with evidence of failure of baroreflex regulation of sympathetic noradrenergic system outflows. Poor control of the urinary bladder is another sign of diabetic autonomic neuropathy. Patients have difficulty starting the urinary stream or have urinary retention that can require self-catheterization.
Other manifestations of diabetic autonomic neuropathy include erectile dysfunction, resting tachycardia, diarrhea or constipation, esophageal dysfunction, and decreased stomach contractions (gastroparesis). Cardiac sympathetic neuroimaging often cannot accurately assess the status of myocardial noradrenergic innervation in patients with diabetes because the disease also involves patchy narrowing of coronary arterioles. Since injected cardiac sympathetic imaging agents are delivered to the heart by way of the coronary arterial tree, it is difficult or impossible to distinguish patchy loss of sympathetic innervation from locally decreased delivery of the tracer.
The high prevalence, multiple manifestations, and prognostic significance of diabetic autonomic neuropathy contrast with remarkably poor understanding of the mechanisms (Principles of Autonomic Medicine, 421-422).
Insulin Neuritis: Another form of neuropathy in diabetes is caused by insulin treatment and has been called insulin neuritis. Insulin neuritis is brought on by a rapid improvement in glucose levels in the setting of long-term high glucose levels (hyperglycemia). In diabetics who have a greater than 4% decrease in their hemoglobin A1c level over 3 months, the risk of developing insulin neuritis exceeds 80%.
The pattern of pain in insulin neuritis follows a “stocking and glove” distribution, with more proximal involvement as the condition worsens. Unlike the usually painful diabetic neuropathy in chronic diabetes, pain in insulin neuritis comes on abruptly. Pathologically, insulin neuritis is a small fiber neuropathy that affects autonomic and sensory non-myelinated fibers. There is also evidence of microvascular disease, as reflected by retinopathy and excretion of albumin in the urine. In addition to pain, patients with insulin neuritis have a high frequency of orthostatic hypotension, lightheadedness, or syncope. In men, erectile failure is also usually present.
Autonomic function testing in insulin neuritis reveals decreased heart rate responses to deep breathing or the Valsalva maneuver and abnormal beat-to-beat blood pressure responses during Phase II and Phase IV of the Valsalva maneuver. These findings fit with baroreflex-cardiovagal and baroreflex-sympathoneural failure (Principles of Autonomic Medicine, 523).
Hypoglycemia: In healthy people hypoglycemia rapidly activates the sympathetic adrenergic system (SAS). The high circulating epinephrine concentrations help restore glucose levels. Epinephrine exerts many noticeable effects, such as pallor, sweating, trembling, and a fast pulse rate and augments the experience of distress.
Epinephrine and glucagon are the body’s two main glucose counter-regulatory hormones. Patients with type 1 diabetes or severe, insulin-dependent type 2 diabetes have a lack of glucagon release in response to hypoglycemia. In hypoglycemia unawareness there is a failure of hypoglycemia to trigger epinephrine secretion. Because of this, the patient does not experience the characteristic warning symptoms of low blood glucose levels. There can be prolonged, severe hypoglycemia that results in seizures, syncope, or brain damage.
Hypoglycemia unawareness goes away after 2 to 3 weeks of careful avoidance of hypoglycemia. The mechanism by which hypoglycemia shifts the threshold for SAS activation to lower plasma glucose concentrations is unknown (Principles of Autonomic Medicine, 424).
Parkinson’s disease (or Parkinson disease, PD) is the second most common neurodegenerative disease of the elderly (the first is Alzheimer’s disease). PD is well known to be characterized by a movement disorder that includes slowness (bradykinesia), limb rigidity, tremor at rest, and imbalance. The key gross anatomic change in the brain in PD is a loss of black pigmentation in the substantia nigra (from the Latin for “black substance”) in the midbrain of the brainstem. The loss of black pigment probably reflects a decreased number of neurons that contain the catecholamine dopamine.
Most patients with PD have evidence for loss of sympathetic nerves in the heart. The discovery of loss of cardiac sympathetic nerves in PD provided clear evidence that PD is more than a brain disease and more than a movement disorder. It is also a disease that involves loss of sympathetic noradrenergic nerves and a form of dysautonomia. Sympathetic noradrenergic denervation was the first identified mechanism for a non-motor aspect of PD.
Orthostatic Hypotension in Parkinson’s Disease: Orthostatic hypotension (OH) in Parkinson’s patients is a common non-motor symptom. It may cause falls, syncope (sudden loss of consciousness), lightheadedness, cognitive impairment, dyspnea, fatigue, blurred vision, should, neck, or low-back pain upon standing. Neurogenic orthostatic hypotension (nOH) in Parkinson’s disease is caused by the failure of the autonomic nervous system to regulate blood pressure in response to postural changes. The occurs because there of an insufficient release of norepinephrine (Principles of Autonomic Medicine, 395-397).
Autonomic dysfunction is also seen with Alzheimer’s disease (the most common neurodegenerative disease of the elderly) and dementia with Lewy bodies (DLB). DLB is a progressive form of dementia caused by a build-up of abnormal protein particles in the brain known as Lewy bodies. Symptoms autonomic dysfunction in dementia patients may include orthostatic dizziness, syncope, falls, urinary tract symptoms and constipation (Principles of Autonomic Medicine, 543-544).