Syncope, Urinary Retention, and Neuropathy in a 40-Year-Old

Amanda Kennedy, MD, MPH; Jeffrey Kaplan, MD; Dianna Quan, MD


February 27, 2023

When presenting with a neuropathy, the distal small myelinated and unmyelinated nerve fibers are initially affected, leading to prominent and early autonomic dysfunction; loss of pain and temperature sensation in distal lower extremities; and numbness, pain, or paresthesias.[6,9] Over time, sensory loss ascends and begins to affect vibration, proprioception, and touch sensations, with muscle weakness beginning soon after.[6] In most patients, progressive sensation loss and weakness affect the upper legs, trunk, and upper extremities within 5 years after symptom onset.[6,9]

Symptoms also include erectile dysfunction and orthostatic hypotension, dry eyes, and gastrointestinal symptoms, including constipation or diarrhea, or both.[6,9] Owing to focal deposition of ATTRv, patients may present with bilateral carpal tunnel syndrome that does not improve after surgical intervention.[6,9] ATTRv amyloidosis is often fatal owing to severe autonomic neuropathy, which leads to cachexia and inanition from poor gastrointestinal function and nutritional status.[11]Cardiac failure is another common cause of death.[5] Progression can be monitored with various scoring systems, including the Neuropathy Impairment Score, Neuropathy Impairment Score in the Lower Limbs, the polyneuropathy disability score, and the familial amyloid polyneuropathy staging system.[10,11]

Other conditions to consider in patients who present with similar symptoms include chronic inflammatory demyelinating polyneuropathy (CIDP); peripheral neuropathy due to toxic or metabolic causes, such as diabetes, chronic alcohol abuse, and vitamin B12 deficiency; lumbar spinal stenosis; light chain amyloidosis; and other inherited neuropathies, including hereditary gelsolin amyloidosis and apolipoprotein AI amyloidosis.[2,3]

Misdiagnosis is common; 15%-37% of patients with ATTRv amyloidosis with neuropathy are initially misdiagnosed with CIDP because of elevated cerebrospinal fluid protein levels.[10] If a patient with CIDP is not responding to immunotherapy, consider testing for neuropathy due to ATTRv amyloidosis.[9] If bilateral carpal tunnel syndrome is found, consider ATTRv amyloidosis, especially if carpal tunnel release surgery does not improve symptoms.[6]

Laboratory studies should include serum protein electrophoresis and immunofixation, to rule out immunoglobulin light chain amyloidosis; urinalysis to look for proteinuria; and studies to rule out metabolic causes of neuropathy, including measurement of A1c and vitamin B12.[2] Electromyography and nerve conduction studies should be performed. Such studies as heart rate measurement during deep breathing, sudomotor function, and tilt-table testing can help identify autonomic dysfunction.[6,10] The diagnosis should include both DNA analysis to identify a TTR gene mutation and a tissue biopsy to demonstrate the presence of ATTRv. Tissues that can be used include sural nerve; abdominal fat pad; salivary glands; and cardiac, gastric, rectal or renal tissue.[6]

Cardiac evaluation may include brain natriuretic peptide testing, troponin testing, transthoracic echocardiography, ECG, nuclear scintigraphy, and cardiac MRI. Cardiac MRI reveals a classic late enhancement due to the infiltrating amyloid deposits and can reveal atrial or ventricular amyloid infiltration.[2,6,11]


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