Clinical manifestations

Presentation and course

The clinical features of pure autonomic failure depend on the disease time course and the stage at which the patient is being seen.

Table 1. Clinical Features of Pure Autonomic Failure

The initial presenting symptoms may consist of vague weakness, dizziness, or male impotence. Orthostatic hypotension is defined by reduction of systolic blood pressure at least by 20 mmHg or diastolic blood pressure of 10 mmHg within 3 minutes of assuming an upright position (07). Prolonged standing or standing too quickly from a sitting or supine position are common provoking factors. Patients, especially those living in hot climates, may complain of heat intolerance and lack of sweating; excessive vasodilation may exacerbate orthostatic hypotension. One clue to the diagnosis of autonomic failure is orthostatic hypotension that often is aggravated by a big meal. Postprandial hypotension can start 10 minutes after the meal and could last up to 45 minutes. This is mediated by splanchnic vasodilation induced by the release of vasoactive intestinal polypeptide (32).

Supine hypertension was seen in up to 56% of pure autonomic failure cases in one study (41). It is usually asymptomatic but is an important cause of pressure nocturnal diuresis making orthostatic symptoms worse in the morning. Higher rates of ischemic white matter changes in neuroimaging studies suggest increased cerebrovascular burden in patients with pure autonomic failure with supine hypertension (47). Intelligence is usually preserved but cognitive function may show decline (18).

Constipation is common in the early phase along with discomfort (30). Urinary bladder symptoms are frequent in pure autonomic failure including nocturnal frequency, urgency, and urinary hesitation. Urodynamic study showed detrusor hyperreflexia in most cases. Erectile dysfunction is commonly seen in male patients with pure autonomic failure (39).

Leg restlessness (hypotensive akathisia) appears in few patients; some may move their legs to maintain their blood pressure. Patients have reported that the sensation of the movements stop when lying down (05). Hypohidrosis can be seen. A case of pure autonomic failure with cold-induced sweating has been reported (19). Another case demonstrated six years of Harlequin syndrome, consisting of unilateral anhidrosis and contralateral facial flushing and hyperhidrosis before progressing to generalized pure autonomic failure (48).

Neurologic examination is usually normal and should show no signs of pyramidal or extrapyramidal lesion, cerebellar ataxia, or other abnormal movement, which would otherwise suggest a CNS synucleinopathy. Cranial nerves exam may show Horner syndrome (04). Bradbury and Eggleston reported that two of their three patients had misshapen pupils that were reactive to light (03). Nasal congestion can be present (27), but surprisingly, saliva production is normal (21). Olfactory dysfunction in pure autonomic failure is less severe than in Parkinson disease (17). Subtle motor signs like mild generalized bradykinesia, decreased blinking frequency or reduced facial expressions (hypomimia), reduced left arm swing during walking, and mild slowing/reduction in amplitude in rapid alternating movements were found to be associated with increased risk of future phenotype conversion to a CNS synucleinopathy, specifically dementia with Lewy bodies (26). Comparison of findings in multiple system atrophy, Parkinson disease, and pure autonomic failure are listed in prior reviews (22; 09). Autonomic symptoms and findings, including neurogenic orthostatic hypotension, are common in typical Parkinson disease and diffuse Lewy body dementia, supporting the shared and overlapping pathology (36). However, the term pure autonomic failure is restricted to patients without significant motor or cognitive manifestations (09; 34).

The distinction between potential emergence of multiple system atrophy or Parkinson disease in a patient with pure autonomic manifestations remains a patient concern because of the faster progression in most multiple system atrophy cases. A British study retrospectively reviewed records of 47 autopsy confirmed multiple system atrophy cases at Queen’s Square (50). Thirty-two percent of multiple system atrophy patients developed nonmotor symptoms prior to diagnosis, including bladder dysfunction, orthostatic hypotension, or REM sleep behavior disorder. Five of these 15 patients were diagnosed initially with pure autonomic failure. Median delay to motor symptoms was 1 to 6 years.

Prognosis and complications

The disease typically has an insidious onset and slowly progressive course. This pattern is attributed to the body's compensatory mechanisms and slow neurodegeneration (30). The overall prognosis for patients with pure autonomic failure is good, even though there is ongoing disease progression. The major complications arise from symptomatic orthostatic hypotension, such as falls from syncope. Supine hypertension could eventually lead to left ventricular hypertrophy (49) and renal impairment (12). Bladder catheterization may be required in severe cases and associated complications must be kept in mind.

Clinical vignette

A 59-year-old man has five years of lightheadedness upon standing and after meals. He also reports nine years of erectile dysfunction. The course is slowly progressive. He had been able to compensate and develop strategies to cope with his symptoms to remain fully functional. He had no other medical problems, such as diabetes. His primary care physician prescribed fludrocortisone and midodrine to treat his low blood pressure. His neurologic exam was entirely normal apart from sluggish light reaction of the right pupil. His workup included unremarkable complete blood counts with differential, electrolytes and routine chemistry, thyroid function testing, serum protein electrophoresis and immunofixation, and vitamin B12 levels. His supine plasma norepinephrine level was low (14 pg/mL), with no significant change on standing. Autonomic function testing showed reduced heart rate response to deep breathing. Blood pressure response to Valsalva maneuver showed absent rebound of systolic blood pressure during phase 4 and absent late phase 2 with a pressure recovery time of 11 milliseconds (normal less than 5 milliseconds). Tilt table testing showed reduction of blood pressure from 128/89 mmHg at supine position to 85/59 mmHg within 1 minute of 70-degree upward tilt. Quantitative sudomotor axonal reflex testing showed reduction of the sweat output at all sites. Thermoregulatory sweat testing showed patchy anhidrosis.

The patient was started on droxidopa, with some improvement in his orthostatic intolerance symptoms. He continued to be seen regularly over 5-year follow-up with no remarkable change in his neurologic exam.

Biological basis

Etiology and pathogenesis

The pathophysiological basis of the clinical spectrum is best explained by the degeneration of respective parts of the autonomic nervous system. Pure autonomic failure is considered a continuum of alpha-synucleinopathies that includes Parkinson disease and diffuse Lewy body dementia (24). However, initial pure autonomic failure is also a potential onset presentation of multiple system atrophy or potentially amyloidosis.

Alpha-synuclein is a protein consisting of 140 amino acids with a molecular weight of 14 kDa, and is expressed in high levels in many nervous tissues (37). Accumulation of alpha synuclein deposits was also hypothesized to cause neuronal death through multiple mechanisms including decreased transport between the endoplasmic reticulum and Golgi apparatus, impaired mitochondrial energy production, reduced synaptic vesicle release, and lysosomal function impairment (08).

Alpha-synuclein is a defining protein for a Lewy body. The Lewy bodies found in pure autonomic failure patients are indistinguishable from the ones found in Parkinson disease patients (43).

Lewy bodies are found in different parts of the nervous system of patients with pure autonomic failure, including the myenteric plexus neurons of the esophagus, small intestine, and smooth muscle of the rectal wall. They are also found in adrenomedullary cells and the smooth muscle of the bladder. The parasympathetic and the sympathetic neurons are equally affected (01). The postganglionic components are more severely affected than preganglionic components. Cell loss is noted in the intermediolateral columns and sympathetic ganglia (28). Alpha synuclein accumulation was also shown in the small nerve fibers of the skin dermis of patients with pure autonomic failure (44; 10). A mouse model of the condition has been created (51). Inoculation of α-synuclein preformed fibrils (PFFs) into the stellate and celiac ganglia induced spreading pathology through the central and peripheral autonomic pathways. The mice developed orthostatic hypotension, constipation, hypohidrosis, and hyposmia, but not motor dysfunction; this model may produce additional pathogenic insights. A study followed 32 patients with well-characterized pure autonomic failure for about four years (46). All had CSF measures of alpha-synuclein oligomers and neurofilament light chains to assess the risk of future multiple system atrophy development (46). Five patients converted to multiple system atrophy, two to Parkinson disease, and two to Lewy body dementia. Neurofilament light chains were elevated at baseline only in the multiple system atrophy group. In all but two cases, alpha-synuclein and protein misfolding cyclic amplification supported the alpha-synucleinopathy nature of pure autonomic failure prior to the development of motor or cognitive manifestations.

Central nervous system. Neurogenic orthostatic hypotension occurs due to extensive loss of sympathetic innervation (25). This process leads to postural dizziness, dimming vision, neck or head discomfort (coat hanger headache), and syncope due to cerebral hypoperfusion (27).

Cardiovascular system. With time, the body partially adapts to the frequent hypotension so there is compensatory hypertension when the patient is supine, which is caused by an increase in systemic vascular resistance (42). The fixed pulse rate can be explained by parasympathetic failure (31).

Genitourinary. Patients have low bladder compliance attributed to the preganglionic neuropathology in the pelvic nerves. The postganglionic lesion leads to denervation hypersensitivity. EMG evidence of denervation in the external sphincter is more characteristic of multiple system atrophy. Lewy bodies are also found in the bladder (39).

Gastrointestinal. The exact mechanisms that produce gastrointestinal disturbances in pure autonomic failure are poorly understood but disruption of local neuronal circuits and the enteric nervous system are suspected. Constipation is a much more common problem for patients (30). Dysphagia symptoms could be due to the accumulation of alpha-synuclein in the myenteric plexus in the esophagus (01).

Hematological. The sympathetic system acting through beta-2 adrenergic receptors physiologically modulates erythropoiesis through increased erythropoietin production. Reduced sympathetic stimulation leads to mild anemia which further aggravates the symptoms of orthostatic hypotension. Direct measurements of the erythrocyte mass and total blood volume showed decreases in hemoglobin due to decreased erythropoietin production (38).

Muscular. Leg restlessness has been reported as a problem, but the pathophysiology remains a mystery (05).

Epidemiology

In a study, the age of onset varied from 51 to 80 years with a mean of 67 years. The disorder is slightly more common in men (06).

Prevention

There are no means of prevention reported in literature.

Differential diagnosis

The differential diagnosis for pure autonomic failure includes: multiple system atrophy, Parkinson disease with autonomic failure, autoimmune autonomic neuropathy, paraneoplastic autonomic neuropathy, diabetic autonomic neuropathy, and amyloidotic autonomic neuropathy.

According to the diagnostic criteria of multiple system atrophy proposed in 2008, definite multiple system atrophy is an autopsy diagnosis. The diagnosis of probable multiple system atrophy can be established if there is:

A sporadic, progressive, adult-onset (> 30 years) disease characterized by:

Patients with multiple system atrophy who present with only autonomic and urinary dysfunction can be incorrectly diagnosed with pure autonomic failure, so it is important to wait five years before diagnosing pure autonomic failure (02). In multiple system atrophy, the dysfunction of parasympathetic and sympathetic systems is central in location, but in pure autonomic failure the impairment is peripheral. The progression of multiple system atrophy is faster than that of pure autonomic failure, and the prognosis is poorer. Early in the disease process, the distinction may be difficult, but distinguishing findings are usually evident during follow-up. It is imperative to take a proper history and physical examination.

Singer and colleagues reported that a preganglionic pattern of sweat loss (intact QSART response in the presence of global anhidrosis in thermoregulatory sweat test), severe bladder dysfunction from onset, supine norepinephrine level of more than 100 pg/mL, and a vagal composite autonomic severity score of less than 2 (mild vagal impairment) were the strongest predictors of future conversion to multiple system atrophy (45). Imaging can also help differentiate the two disorders. Multiple system atrophy has brainstem or cerebellar atrophy, with T2 hyperintensity of the pons (the hot-crossed bun sign), which is not present in pure autonomic failure (52).

Cardiac positron emission tomography scans differentiate the two diseases based on uptake of 6-fluorodopamine (6FD-PET), which demonstrates cardiac innervation by the postganglionic sympathetic neurons. The findings indicate that in pure autonomic failure the uptake is decreased or lost and in multiple system atrophy it is normal (16). Similar findings are seen in Parkinson disease patients with autonomic failure and to a lesser degree in Parkinson disease patients without clearly evidenced orthostatic hypotension.

With single-photon emission computerized tomography there is decreased uptake of I-metaiodobenzylguanidine (MIBG-SPECT) on the myocardial scintigrams in pure autonomic failure (55). A study of 18 patients with nonmotor signs but suspected synucleinopathy such as autonomic postural hypotension, REM sleep disorder, or cognitive signs found 94% had an abnormal MIBG myocardial scintigraphy (40). This test might identify patients prior to DaTscan abnormalities.

Sphincter EMG results are frequently abnormal in multiple system atrophy and normal in pure autonomic failure, but this test is no longer typically utilized.

Early in the disease process, testing with QSART is normal in multiple system atrophy, but becomes abnormal as the disease advances because of transsynaptic defect. QSART is usually abnormal in pure autonomic failure (28).

Neuropathological involvement in multiple system atrophy is in the preganglionic and the central nervous systems. In pure autonomic failure there is predominately postganglionic pathology with a loss of ganglionic neurons. Patients with multiple system atrophy have characteristic glial cytoplasmic inclusions; in pure autonomic failure there are Lewy bodies (01).

The 1996 American Academy of Neurology Consensus Statement states that, “A minority of patients with PD defined by the United Kingdom Parkinson’s disease Brain Bank criteria may also develop autonomic failure, including orthostatic hypotension” (07). Clinical features of Parkinson disease with autonomic failure include asymmetric parkinsonism, including rigidity, bradykinesia, tremor, and postural instability. Orthostatic hypotension happens late in most of Parkinson disease cases especially if patients are on levodopa. In 20% of cases it can happen early. Other autonomic manifestations include early constipation and sometimes urinary urgency. The preganglionic pattern of anhidrosis is often seen distally. Singer and colleagues found that a composite autonomic severity score of less than 7, orthostatic rise in norepinephrine more than 65 pg/mL, and the presence of subtle motor signs were the strongest predictors for future conversion to dementia with Lewy bodies/Parkinson disease (45).

In their 4-year prospective cohort study, Kaufmann and associates followed 74 subjects who had initial diagnosis of pure autonomic failure after five years of symptoms (26). They reported that 34% of patients with pure autonomic failure converted to a manifest CNS synucleinopathy, either to dementia with Lewy bodies (18%), to Parkinson disease (8%), or to multiple system atrophy (8%). This risk of conversion was around 14% per year. The presence of probable REM sleep behavioral disorder was strongly associated with conversion to a CNS synucleinopathy. The combination of probable REM sleep behavior disorder and deficits in olfaction predicted conversion to Parkinson disease/dementia with Lewy bodies. The combination of probable REM sleep behavior disorder and preserved olfaction strongly predicted future conversion to multiple system atrophy. They proposed that REM sleep behavior disorder, olfactory loss, or subtle motor deficits should be considered as nonsupportive features of pure autonomic failure (26).

Clinical features that may help in the differential diagnosis of pure autonomic failure versus autoimmune autonomic neuropathy are abnormal deep tendon reflexes and complaints of a dry mouth (28). Patients should be asked about sensory loss or neuropathic pain. The history should also include a recent viral infection or surgical procedure.

Paraneoplastic autonomic dysfunction can demonstrate similar features to pure autonomic failure, so a careful history is warranted. A complete blood work-up should be done, along with a paraneoplastic panel. The neoplasm in such patients is most likely to be a small cell lung carcinoma (53). A variety of antibodies are associated with this syndrome. These are mostly ganglionic acetylcholine receptor and ANNA-1 (HU).

Skin biopsy detection of phosphorylated α-synuclein in small fiber nerve fibers is an emerging method that may distinguish Lewy body versus multiple system atrophy pathology (14). One study compared 31 multiple system atrophy and 54 Parkinson disease patients validated by current clinical consensus criteria; 24 matched controls were also analyzed. Nearly all Parkinson disease and all multiple system atrophy but no control subjects had positive phosphorylated α-synuclein staining. Parkinson disease patients also had reduced epidermal nerve fiber density counts unlike multiple system atrophy or control subjects. The combination of findings discriminated between multiple system atrophy and Parkinson disease with over 90% sensitivity and specificity (14). Application of this method in pure autonomic failure patients is still uncertain. A large multicenter trial including pure autonomic failure patients is ongoing (14).

Diagnostic workup

Pure autonomic failure is a diagnosis of exclusion. A complete history and thorough physical examination are essential. The majority of experts advocate waiting at least five years after symptom onset before giving the final diagnosis to ensure that no nonautonomic systems become involved. Important diagnostic exclusions include autonomic neuropathy, diabetes, familial amyloidosis, adrenal insufficiency, medication effects, and rheumatological causes. Rarely, paraneoplastic condition can mimic the condition, but it most often manifests in a subacute onset; ANNA-1 (anti-HU) and AChR ganglionic antibodies are most prominent. These syndromes are rarely chronic without an identified underlying malignancy.

One of the most important factors to determine orthostatic hypotension is the simple measurement of blood pressure. Blood pressure should be noted in the supine and the standing positions, throughout the day, at least three times. Orthostatic hypotension is defined by a systolic blood pressure drop of at least 20 mmHg and a diastolic drop of at least 10 mmHg following position changes (these must happen within 3 minutes of standing) (07). Some require a 30 mmHg drop in systolic blood pressure to increase specificity. Symptoms produced should also be noted. Mild asymptomatic orthostatic hypotension is relatively common in the elderly population and may require no evaluation or treatment. Autonomic expert consensus advocates screening for this condition (13).

A patient who is suspected to have pure autonomic failure should have standardized autonomic reflex screening tests consisting of sudomotor, cardiovagal, and cardioadrenergic testing in a standardized lab.

The following are reported findings in pure autonomic failure but are not necessarily specific for this entity: (a) there is no overshoot of the blood pressure during phase 4 Valsalva maneuver testing during continuous blood pressure monitoring; (b) respiratory sinus arrhythmia is decreased; (c) abnormal quantitative sudomotor axon reflex testing (QSART); (d) abnormal beat-to-beat blood pressure response to Valsalva maneuver; and (e) orthostatic hypotension on head-up tilt with inadequate heart rate response (21).

Neuropharmacological test findings include: a reduced plasma supine norepinephrine level (45).

Cardiac PET shows decreased 6-fluorodopamine uptake indicating cardiac denervation (16). SPECT scintigraphy reveals decreased uptake of I-MIBG (MIBG-SPECT) on the myocardial scintigrams in pure autonomic failure (55).

Management

Pure autonomic failure requires a careful communicative relationship with the patient, patient’s family, and other care providers. A special session or sessions may be needed to educate the patient and all parties involved in the patients care. Patients living in hot climates, especially older patients, need to be warned against dehydration and the effects of vasodilation. Sexual dysfunction may produce marital or relationship challenges and counseling should be offered if needed. Patients should be cautioned against alcohol use that may cause skin vasodilation and reduce orthostatic tolerance. Always offer emotional and supportive care and consultation to social workers if necessary. A more comprehensive approach to the management of autonomic failure can be found in the MedLink article, Treatment of autonomic neuropathy.

Currently, there is no specific treatment to stop progression in pure autonomic failure. Management of autonomic symptoms is the mainstay of treatment. There are two categories of treatment for orthostatic hypotension (usually the main clinical feature of pure autonomic failure): nonpharmacological and pharmacological.

The following nonpharmacological maneuvers have been advised to help orthostatic hypotension: leg crossing, squatting, pressure stockings, swimming, head of bed elevation, and isotonic exercise (53). In addition, 16 oz of water may help keep the blood pressured elevated.

Pharmacological treatments include: (1) fludrocortisone, a mineralocorticoid, through its mineralocorticoid activity increases intravascular volume (0.05 to 0.20 mg/day) and increases the sensitivity of blood vessels smooth muscles to catecholamines (28); (2) midodrine, which is FDA approved for treatment of orthostatic hypotension after its efficacy was proved in three double-blind, placebo-controlled clinical trials (20; 29; 54). It is a prodrug that gets metabolized into its active metabolite, desglymidodrine, that has an alpha-adrenergic agonist activity. Hence, it constricts arterioles and decreases venous pooling via reducing venous capacitance (2.5 to 10 mg two to three times during the day). The best time to take the last dose would be no later than 5 PM, because of possible supine hypertension and insomnia. Scalp itching is a common and expected physiologic side effect and is not a sign of an allergic response (28); (3) pyridostigmine is a cholinesterase inhibitor. It works by inhibiting degradation of acetylcholine at the autonomic ganglia, thereby enhancing ganglionic cholinergic transmission in both sympathetic and parasympathetic systems. It does not worsen supine hypertension as other agents potentially do. The dose is 30 to 60 mg three times daily. However, the effect of pyridostigmine on orthostatic blood pressure is only modest. Major side effects include mainly abdominal cramps, diarrhea, and hypersalivation; and (4) droxidopa (L-threo-dihydroxyphenylserine) (Northera) is approved by the U.S. Food and Drug Administration for treatment of neurogenic orthostatic hypotension associated with primary autonomic failure (Parkinson disease and autonomic failure, pure autonomic failure, multiple system atrophy, and dopamine beta hydroxylase deficiency). It is also approved for nondiabetic autonomic neuropathy. It is a synthetic amino acid precursor that is converted to norepinephrine by the enzyme dopa decarboxylase. A randomized placebo-controlled clinical trial showed that droxidopa with a dose range from 100 to 600 mg three times daily can increase standing blood pressure and improve quality of life; the drug is generally well tolerated in patients with neurogenic orthostatic hypotension. Major adverse effects include hypertension and nausea (23). The drug is designed to have peripheral effects, but central access is recognized. Some cognitive and behavioral side effects related to treatment are suggested by a retrospective review of 101 cases that identified six probably affected patients (33). Catecholamine excess interference with critical orbitofrontal and mesolimbic circuits was suggested to be the mechanism.

Supine hypertension can be a factor that complicates treatment of adequate standing blood pressure. In a study, a heating pad placed over the abdomen for two hours lowered systolic blood pressure about 18 mmHg, on average, compared to sham pads (35). Continuous positive airway pressure also shows promise in blunting supine hypertension in autonomic failure patients (35). The proposed mechanism is that increasing intrathoracic pressure with the continuous positive airway pressure (CPAP) had a Valsalva-like blood-pressure-lowering effect while supine.

Quality of life measures are critical concerns in many conditions. Caregivers are especially impacted in autonomic failure patients. In a study of patients with Parkinson disease or multiple system atrophy, 60 with and 60 without neurogenic orthostatic hypotension (NOH) found a significantly higher care burden in the neurogenic orthostatic hypotension patients (11).

Special considerations

Pregnancy

Use caution when prescribing medications because of possible side effects.

Anesthesia

Patients with pure autonomic failure require careful monitoring due to blood pressure changes (29).