A Woman With a Demyelinating and Axonal Neuropathy

A 50-year-old female was referred for a progressive neuropathy, possible CIDP which did not respond to IVIG treatment. She started having symptoms 2 years prior to presentation with burning pain in the feet and leg weakness with numbness. The pain was present day and night. She had no real tingling. She received gabapentin with some improvement of the pain, but the numbness persisted. The patient was adopted.

Past medical history is only remarkable for hypothyroidism treated with radiation, and she is on thyroid supplementation.

On exam, vital signs and mentation were normal. Cranial nerve examination was unremarkable, except for poorly reactive pupils to light and accommodation. There was distal weakness in the upper and lower extremities at 4–4.5/5 in the legs. She had weakness in the upper extremities. There was minimal interossei weakness. Reflexes were normal in the arms and absent in the legs. She had diminished vibration and pinprick sensations in both legs. There was diminished pain and temperature up to the mid-calf bilaterally. There was decreased position sense in the toes. She had minimal high arches, but there was no atrophy of the feet muscles. No prominent atrophy was seen in the legs.

What is the Differential Diagnosis?

This patient has a progressive neuropathy, and she was initially diagnosed with CIDP, but the prominent small-fiber sensory deficit is unusual for this disorder.

Other possibilities to consider include a hereditary neuropathy such as Charcot–Marie–Tooth disease, but because she was adopted, there was no family medical history.

The pupillary abnormalities indicate an autonomic nervous system dysfunction; although such dysfunction occurs in CIDP, it is rare. Other possibilities include TTR amyloidosis which is a neuropathy with demyelinating and axonal features and has prominent dysautonomic symptoms.

What Tests will be Done?

Thyroid antibodies, T4, T3, methylmalonic acid, glucose tolerance test, homocysteine, and immunoelectrophoresis were all unremarkable.

EMG

This EMG showed a mixed neuropathy showing axonal and demyelinating features with distal denervation. There was also absent sympathetic skin response.

Other Tests

A lumbar puncture was not done.

A nerve and muscle biopsy were done, and it showed evidence of amyloid deposits with some demyelination and axonal degeneration. The muscle biopsy showed neurogenic atrophy and amyloid deposits ( Fig. 70B-1 ).

DNA testing for TTR gene revealed a pathogenic variant of PGLU-T-4GLY (E74G) heterogenous.

What is the Diagnosis?

This patient was diagnosed as having familial TTR amyloidosis. The patient was worked up for cardiomyopathy, and there were minor changes in the left ventricle on cardiac MRI. She is currently receiving diflunisal, inotersen, and tafamidis as well as doxycycline and is stable.

Summary

A 50-year-old female presented with a demyelinating and axonal neuropathy with dysautonomia. She failed IVIG therapy and was diagnosed having TTR amyloidosis and is currently on medication and is stable.

Discussion for Cases 70A and 70B

These two patients have amyloid TTR polyneuropathy. The difference between the two cases is that when the first case was seen the only treatment available was a liver transplant which the patient declined. Since then, the second case who had a prominent neuropathy with demyelinating and axonal features with dysautonomia is currently being treated with medications for amyloidosis and is doing well.

Familial TTR amyloidosis affects the small myelinated and unmyelinated fibers presenting with pain, paresthesias, and autonomic symptoms. Patients may have disassociated sensory abnormalities initially with the progression of neuropathy; large sensory and motor fibers are involved. Careful observation of autonomic disturbance is important in the evaluation of patients with a neuropathy. Patients may also develop gait abnormalities and falls. The examination may show weakness, but the sensory findings are predominant and usually in a length-dependent pattern. Patients may also present with an entrapment neuropathy. A common misdiagnosis is CIDP, although the presentation in CIDP affects primarily large fibers. Pain occurs more frequently in amyloid neuropathy, and autonomic dysfunction is seen in about one-third of CIDP cases, but up to 75% of amyloid neuropathies. The most common focal neuropathy is bilateral median neuropathy at the wrist and it may also affect peripheral nerves in the lumbosacral plexus forming tumor-like deposits.

Screening for nonneurological systemic features of amyloidosis is important, but those symptoms are nonspecific and would include findings related to complication of cardiac disorders and hypertension.

Early diagnosis is crucial in familial TTR amyloidosis. This is caused by 30 different mutations of the TTR gene. The incidence of this varies across the globe, with 8.7 per million per year in Portugal and only 0.3 cases in the United States. The symptoms can be neurological, cardiac, and/or mixed.

There are several newer treatments that are useful particularly in TTR amyloidosis including patisiran and vutrisiran, antiinflammatory drugs, a small RNA interfering molecule, and antisense oligonucleotides. Liver transplant can be used in severe cases that do not respond to therapy.

Important Points

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Amyloidoses are conditions associated with amyloid deposits in tissue, demonstrated with Congo red–positive material by birefringence; these are formed by aggregates of β-pleated fibrillar proteins of 7.5–10 nm in diameter.
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The histological diagnosis of amyloidosis is made using rectal, fat pad, or sural nerve biopsy.
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TTR familial amyloidosis is caused by deposits of TTR in tissues, due to a defect in chromosome 18q. The disease has variable presentations with sensorimotor neuropathy, carpal tunnel syndrome, autonomic dysfunction, vitreous opacities, cardiomyopathy, and renal failure.
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Nerve biopsy and particularly DNA testing for amyloidosis should be done in atypical CIDP patients particularly with prominent small-fiber and autonomic dysfunction.
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Therapy for TTR amyloidosis now includes several new drugs that are beneficial. These also include antiinflammatory drugs, small interferon RNA molecules, and antisense oligonucleotides to prevent the formation of amyloid.