Clinical Information

Autoimmune dysautonomia encompasses disorders of peripheral autonomic synapses, ganglionic neurons, autonomic nerve fibers, and central autonomic pathways mediated by neural-specific IgG or effector T cells. These disorders may be idiopathic or paraneoplastic, subacute or insidious in onset, and may present as a limited disorder or generalized pandysautonomia. Pandysautonomia is usually subacute in onset and severe, and includes impaired pupillary light reflex, anhidrosis, orthostatic hypotension, cardiac arrhythmias, gastrointestinal dysmotility, sicca manifestations, and bladder dysfunction. Limited dysautonomia is confined to 1 or just a few domains, is often mild and may include sicca manifestations, postural orthostatism and cardiac arrhythmias, bladder dysfunction or gastrointestinal dysmotilities. Diagnosis of limited dysautonomia requires documentation of objective abnormalities by autonomic reflex testing, thermoregulatory sweat test, or gastrointestinal motility studies.

The most commonly encountered autoantibody marker of autoimmune dysautonomia is the neuronal ganglionic alpha-3- (acetylcholine receptor: AChR) autoantibody. This autoantibody to date is the only proven effector of autoimmune dysautonomia. A direct relationship has been demonstrated between antibody titer and severity of dysautonomia in both alpha-3-AChR-immunized animals and patients with autoimmune dysautonomia. Patients with high alpha-3-AChR autoantibody values (>1.0 nmol/L) generally have profound pandysautonomia. Dysautonomic patients with lower alpha-3-AChR autoantibody values (0.03-0.99 nmol/L) have limited dysautonomia.

Importantly, cancer is detected in 30% of patients with alpha-3-AChR autoantibody. Cancers recognized most commonly include small-cell lung carcinomas, thymoma, adenocarcinomas of breast, lung, prostate, and gastrointestinal tract, and lymphoma. Cancer risk factors include a past or family history of cancer, history of smoking, or social/environmental exposure to carcinogens. Early diagnosis and treatment of the neoplasm favors neurologic improvement and lessens morbidity.

Autoantibodies to other onconeural proteins shared by neurons, glia or muscle (eg, antineuronal nuclear antibody-type 1: ANNA-1, CRMP-5-IgG, N-type voltage-gated calcium channel, muscle AChR and sarcomeric [striational antigens]) serve as additional markers of paraneoplastic or idiopathic dysautonomia. A specific neoplasm is often predictable by the individual patient’s autoantibody profile.