autonomic dysfunction

**Definition:** Dysfunction of the autonomic nervous system (ANS), which includes sympathetic (thoracolumbar T1-L2; preganglionic ACh/nicotinic, postganglionic norepinephrine/adrenergic, except sweat glands which use ACh/muscarinic) and parasympathetic (craniosacral CN III, VII, IX, X, S2-S4; ACh at both synapses) divisions. It may be primary (idiopathic/degenerative) or secondary (systemic disease, drugs, toxins).

**Pathophysiology:** Damage can occur at central (brainstem, hypothalamus, intermediolateral cell column), preganglionic, ganglionic, or postganglionic levels. The baroreceptor reflex (carotid sinus via CN IX, aortic arch via CN X, to the nucleus tractus solitarius, then sympathetic outflow) is impaired. On standing, pooling of blood doesn't trigger a sufficient rise in HR and vascular tone, which causes orthostatic hypotension.

**Clinical features by system:** - Cardiovascular: orthostatic hypotension (drop of ≥20 mmHg systolic or ≥10 mmHg diastolic within 3 min of standing), a fixed resting HR, supine hypertension, syncope, and postprandial hypotension. - GI: gastroparesis (early satiety, nausea, bloating), constipation or diarrhea. - GU: urinary retention or overflow incontinence, neurogenic bladder, erectile dysfunction, and retrograde ejaculation. - Sudomotor: anhidrosis or hypohidrosis and heat intolerance. - Pupillary: Horner syndrome (ptosis, miosis, anhidrosis) from sympathetic interruption. - Hypoglycemia unawareness in diabetics.

**Key causes and associations:** - Diabetic autonomic neuropathy: the most common cause in the developed world. - Alpha-synucleinopathies: Parkinson disease, Lewy body dementia, multiple system atrophy (Shy-Drager; parkinsonism or cerebellar signs plus early severe autonomic failure), and pure autonomic failure. - Guillain-Barré syndrome: labile BP, arrhythmias. - Amyloidosis, alcohol, and vitamin B12 deficiency. - Paraneoplastic syndromes and autoimmune autonomic ganglionopathy (anti-ganglionic nicotinic ACh receptor antibodies). - Lambert-Eaton syndrome and botulism. - Chagas disease (megacolon, megaesophagus), HIV, and leprosy. - Familial dysautonomia (Riley-Day), an AR disorder in Ashkenazi Jews: decreased tears, absent fungiform papillae, labile BP, and insensitivity to pain. - Drugs: anticholinergics, alpha-blockers, antihypertensives, TCAs, and antipsychotics. Chemotherapy such as vincristine. - Spinal cord injury: autonomic dysreflexia in lesions at or above T6 (a noxious stimulus below the lesion, like bladder distension, causes severe hypertension, headache, and reflex bradycardia). - POTS (postural orthostatic tachycardia syndrome): HR rise ≥30 bpm on standing (≥40 in adolescents) without orthostatic hypotension, typically in young women.

**Diagnosis:** Orthostatic vitals, tilt-table testing, and the Valsalva maneuver (loss of the normal phase IV overshoot and HR response). Also heart rate variability with deep breathing, the quantitative sudomotor axon reflex test (QSART), and thermoregulatory sweat test. Plasma norepinephrine (supine vs standing) helps localize the lesion. In pure autonomic failure (postganglionic), supine norepinephrine is low and doesn't rise on standing. In MSA (preganglionic/central), supine norepinephrine is normal.

**Management:** - Non-pharmacologic: increased fluid and salt intake, compression stockings, an abdominal binder, slow position changes, head-of-bed elevation, and small frequent meals. - Pharmacologic: fludrocortisone (volume expansion), midodrine (alpha-1 agonist), and droxidopa (norepinephrine prodrug). Pyridostigmine is an alternative. Midodrine and droxidopa can cause supine hypertension. - Treat the underlying cause (glycemic control, stop offending drugs). - Organ-specific therapy: metoclopramide for gastroparesis, and bethanechol or intermittent catheterization for urinary retention.

**Board pearls:** - Orthostatic hypotension without a compensatory HR rise suggests neurogenic autonomic failure. If the HR rises appropriately, think hypovolemia or drugs. - Autonomic neuropathy in diabetes is usually accompanied by peripheral neuropathy. - Autonomic dysfunction plus parkinsonism suggests MSA. - Autonomic dysreflexia is a medical emergency, so sit the patient upright, remove the trigger (check the bladder and bowel), and give antihypertensives if needed.