Routine blood cell count, blood chemistry findings, and urine analysis results were normal. A biopsy specimen from periumbilical fat revealed no amyloid deposition. Lumbar puncture showed a slight hyperproteinorrachia (50 mg/dL; normal, <45 mg/dL). Ganglionic nAChR antibody levels were markedly increased (24.14 nmol/L; normal, <0.05 nmol/L) and diminished after 2 weeks and 1 month from the first intravenous immunoglobulin administration (19.55 and 14.17 nmol/L, respectively). The supine plasma norepinephrine concentration was reduced (41 pg/mL; normal, >70 pg/mL) and failed to increase on standing. The tonic pupil responded to pilocarpine, 0.125%, administration (right and left pupil diameter: before, 7 and 6 mm; after, 2 and 2 mm), establishing parasympathetic denervation hypersensitivity. The head-up tilt test (60°) documented a significant drop of both systolic and diastolic blood pressure (from basal values of 146/89 mm Hg to 71/52 mm Hg) without a relevant increase of heart rate, consistent with a severe sympathetic dysfunction. Twenty-four–hour Holter arterial pressure showed an inverse circadian blood pressure profile. Analysis of time-domain and frequency-domain heart rate variability on a 24-hour electrocardiography-Holter recording showed a marked reduction of heart rate variability values, indicating a striking impairment of parasympathetic cardiac autonomic function. Myocardial scintigraphy revealed a normal heart to mediastinum ratio of iodine 123–labeled metaiodobenzylguanidine (early, 2.23; late, 2.59; normal, >1.83) consistent with an intact sympathetic innervation to the heart. Neurographic findings were within the normal limits with the exception of reduced sensory action potential amplitude in the right sural nerve (4.4 μV; normal, ≥5 μV). Quantitative sensory testing4 revealed mild abnormalities of tactile thresholds and mechanical pain perception. Sympathetic skin response showed the absence of response to pain and acoustic stimuli in the lower limbs. A thermoregulatory sweat test revealed a generalized anhidrosis and results of a dynamic sweat test5 supported a postganglionic sudomotor dysfunction. The dynamic sweat test results showed a reduced sweat drop density (84/cm2; normal, >104/cm2) after stimulation with pilocarpine, 1%, at the right forearm and both sweat drop density (50/cm2; normal, >75/cm2) and sweat output (0.229 μL/cm2/min; normal, >0.260 μL/cm2/min) of the right leg. Skin samples taken from the third fingertip, thigh, and distal leg, and processed according to published procedures,4 showed a marked loss of epidermal nerve fibers (ENFs) and a poor subepidermal neural plexus. The ENF density, regardless of biopsy site, was lower than the 5% cutoff: third fingertip, 1.5 ENF/mm (5% cutoff = 6 ENF/mm); thigh, 4.7 ENF/mm (5% cutoff = 18.2 ENF/mm); and distal leg, 2.7 ENF/mm (5% cutoff = 10.2 ENF/mm). A severe loss of Meissner corpuscles (3.6/mm2; 5% cutoff = 19.7/mm2) and their myelinated endings (13.1/mm2; 5% cutoff = 32.6/mm2) was present in glabrous skin. In all skin samples, few calcitonin gene–related peptide and substance P-immunoreactive fibers were found. Innervation of dermal annexes (erector pilorum muscle, sweat glands, and vessels) appeared poor and deranged with sparse occurrence of vasoactive intestinal peptide cholinergic and dopamine β-hydroxylase noradrenergic immunoreactive fibers (Figure, A-F). Left sural nerve biopsy, performed when he was 41 years old and before the diagnosis was assessed, showed a moderate loss of large myelinated fibers on light microscopy (Figure, G and H).