Pure autonomic failure

Pure autonomic failure

Usually results in the middle to late life with postural hypotension or syncope.

A rare, sporadic disorder that is more common in men.

Orthostatic hypotension is the hallmark of PAF, but genitourinary or bowel dysfunction may proceed or accompany it.

It has no known genetic or environmental cause.

Maybe associated with other aspects of autonomic dysfunction including genitourinary, bowel, thermoregulatory, and systemic manifestations of disease, such as anemia requiring a multi discipline treatment approach.

An alpha-synucleinopathy characterized by predominately peripheral deposition of alpha-synnuclein ganglia and nerves.

Patients do not experience other CNS dysfunctions other than rapid eye movement sleep behavior disorder.

The disorder may, however, progress to other synucleinopathies characterized by CNS involvement such as multiple system atrophy, Parkinson’s disease, or dementia with Lewy bodies.

In PAF Lewy body involvement is predominately in peripheral inclusions, however essential structures may also manifest pathology.

Noradrenergic nerve fiber loss has been demonstrated.

Sympathetic ganglia and peripheral autonomic nerves show alpha-synuclein deposition, leading to primarily postganglionic pattern of autonomic denervation.

Dysfunction or loss of peripheral sympathetic nerves leads to the impaired production of catecholamines, including norepinephrine.

Plasma concentrations of norepinephrine are low in patients when they lie down, and do not increase, or only marginally increase upon standing.

There is impaired catecholamine biosynthesis in PAF.

Postganglionic denervation is also present with loss of noradrenergic and cholinergic autonomic nerves in skin biopsies of patients with PAF: The loss of these nerves underlies impaired vasoconstriction which allows venous pooling and orthostatic hypotension as well as sweat glands denervation leading to anhidrosis.

Receptor hypersensitivity is a characteristic of PAF as pressers with direct peripheral action on sympathetic receptors produce exaggerated blood pressure responses.

Heart sympathetic innervation is affected with PAF with low concentrations of markers related to sympathetic innervation evident on CT tomography or PET.

Its hallmark is sympathetic denerbation, however parasympathetic function is also impaired.

The diagnosis should be considered  in patients  presenting with subacute chronic orthostatic hypotension in the absence of significant Parkinson’s disease, dementia, neuropathy, or medical condition such as valvular heart disease, congestive heart failure, or chronic kidney disease.

Genitourinary dysfunction may be the initial symptom in the number of patients: 50% have bladder disturbances and 65% of men have erectile dysfunction.

Constipation is reported more than half of the patients with PAF and is frequently an early symptom.

Abnormal sweating occurs in approximately half of all patients with PAF and may be noted in patients as a reduction in sweating or excessive sweating, the latter due to compensatory hyperhidrosis.

More than 80% of patients with PAF have lack of smell on objective olfactory testing.

Patients may experience subtle signs of neurologic dysfunction searches mild bradykinesia, hypomimia, or reduced blink rate, and slowing in reduced arm swing.

Cognitive function may be subtedly affected with deficits in speed, attention, and executive functioning.

Mild anemia is noted in approximately half of all patients.

Supine hypertension and white blood pressure fluctuations can lead to hypertension, impaired renal function with proteinuria, left ventricular hypertrophy and increased arterial stiffness.

Diagnosis criteria is characterized by orthostatic hypotension.

Autonomic function testing is crucial to delineate whether orthostatic hypotension is due to a neurologic cause.

The autonomic reflex screen characterizes autonomic defects wild defining the severity and distribution of postganglionic sudomotor, cardiovagal, and adrenergic functions.

Patients  with PAF often have a reduction in quantitative sudomotor axon reflex test (QSART) volumes with impaired cardiovagal function on heart rate to deep breathing and Valsalva maneuver.

Brain imaging in PAF is normal.

Laboratory test supporting the diagnosis of PAF include low supine norepinephrine levels with minimal or no increase on standing.

The combination of autonomic function testing, functional imaging, and orthostatic catecholamines can help differentiate PAF from other synucleinopathies.

Patients have a slowly progressive course over decades.

Median survival is 12.5 years.

A subset of patients evolve into synucleinopathy with a significant CNS involvement – Parkinson’s disease, Lewy body disease or multiple systemic atrophy.

No cure exists for PAF, but patients may be improved with measures to control blood pressure fluctuation.

Educating the patient regarding triggers of orthostatic hypotension, lifestyle modifications to avoid hot environments, increasing plasma volume through intake of fluid and salt, elevating the head of the bed, reducing nocturia and problematic early morning orthostatic hypotension are measures that can be beneficial.

Pharmacologic measures including midodrine, and droxidopa can be used.

Midodrine is an alpha one adrenal receptor agonist that leads to peripheral vasoconstriction, and droxidopa is a pro drug that converts to norepinephrine in central and peripheral tissues.

Fludrocortisone increases sodium and water reabsorption and expands intravascular volume.

Pyridostigmine acetylcholinesterase inhibitor that potentiates neurotransmission through peripheral cholinergic ganglia and can improve orthostatic hypotension.






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