Clinical Reasoning: A 67-Year-Old Woman With Progressive Tingling Sensations and Imbalance

Section 1

A 67-year-old woman presented with 4 months of progressive numbness, tingling, and weakness in her hands and feet symmetrically with gait imbalance. Symptoms started in her upper and lower extremities at approximately the same time. She denied skin changes, tremors, weight loss, autonomic symptoms, or other systemic symptoms. She did not have a family history of a neuromuscular disorder. Her initial neurologic examination was notable for proximal and distal weakness (Medical Research Council [MRC] scale shoulder abduction 4+/5; elbow flexion, elbow extension, wrist flexion, wrist extension finger extension, finger flexion 4/5; finger abduction 4+/5; hip flexion 4−/5; knee extension 4+/5; and knee flexion, dorsiflexion, plantarflexion, toe extension, toe flexion 5/5 bilaterally). Sensation to pinprick, vibration, and temperature were decreased in the distal hands and feet below the levels of the wrists and ankles, respectively. Proprioception was impaired at the toes but intact at the ankles. Her reflexes were 1 in the upper extremities and absent in the lower extremities. She did not have pes cavus.

Section 2

The combination of weakness, sensory changes, and hyporeflexia localizes to the nerve roots, plexuses, and/or peripheral nerves. The symmetric upper and lower extremity involvement suggests a systemic process, narrowing localization to a peripheral neuropathy. The simultaneous involvement of the upper and lower extremities suggests a non–length-dependent pattern. The next best diagnostic step is to characterize the patient's neuropathy with nerve conduction studies (NCS). These studies were performed, and the results are summarized in Table.

Section 3

NCS showed decreased sensory nerve action potential (SNAP) amplitudes in the upper extremities, whereas lower extremity SNAPs were normal, as can be seen in non–length-dependent or “sural-sparing” neuropathies. This pattern of SNAP abnormalities is highly specific for demyelinating neuropathies and helps differentiate them from axonal neuropathies.¹ Compound muscle action potentials (CMAPs) had mildly slowed conduction velocities with markedly prolonged distal latencies (Figure) without conduction block or marked temporal dispersion. F-wave latencies were uniformly prolonged. These findings suggest a generalized, non–length-dependent, sensorimotor, and demyelinating polyneuropathy.

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Figure Nerve Conduction Studies Demonstrating Left Median Compound Muscle Action Potential Recording at the Abductor Pollicis Brevis, With Markedly Prolonged Distal Latency Out of Proportion to Mildly Slowed Conduction Velocity

Abbreviations: APB = abductor pollicis brevis; L = left.

Section 4

The differential diagnosis for subacute or chronic sensory and motor demyelinating neuropathy includes chronic inflammatory demyelinating polyneuropathy (CIDP) and its variants; paraproteinemic neuropathy, such as anti–myelin-associated glycoprotein (MAG) neuropathy, POEMS syndrome (organomegaly, endocrinopathy, monoclonal protein, and skin changes), GALOP syndrome (gait disorder, autoantibody to a neural antigen, late-age onset, and polyneuropathy), and CANOMAD syndrome (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies); inherited polyneuropathies, such as the demyelinating subtype of Charcot-Marie-Tooth (CMT) disease; and neuropathy secondary to medication exposures, such as tumor necrosis factor inhibitors and amiodarone.^2,3 Clinical history may help differentiate between these, for example, systemic symptoms suggestive of a plasma cell dyscrasia (PCD) underlying a paraproteinemic neuropathy or medication exposures, neither of which applied to this patient. The degree of demyelinating changes on NCS may also be helpful, in our case showing less severe demyelinating changes as would be expected in CMT disease.

The best next step is to evaluate for reversible causes of demyelinating neuropathy. Serum electrophoresis and immunofixation (IFE) are essential for evaluating a monoclonal gammopathy as cause for a paraproteinemic neuropathy. Anti-MAG antibodies and vascular endothelial growth factor should also be considered, the former especially if NCS demonstrate CMAPs with markedly prolonged distal motor latencies and the latter if features of POEMS are present.⁴ Antibodies against gangliosides should also be considered. CSF studies are helpful for detecting albuminocytologic dissociation, although this finding may be seen in multiple diagnoses. In this case, SPEP/IFE and anti-MAG antibodies were sent, the former showing a restricted band in IgM and the corresponding kappa region. Anti-MAG antibodies were positive at >1:102,400 (normal <1:1,600). CSF protein was elevated at 119 mg/dL (normal 15–45 mg/dL).

The patient was given a diagnosis of anti-MAG neuropathy and initiated on treatment with rituximab, with a plan for 375 mg/m² weekly for 4 weeks and maintenance dosing every 2–3 months for 6–24 months pending her clinical course. She also underwent bone marrow and fat pad biopsies to evaluate for a hematologic malignancy, which were negative.

After receiving 2 weekly doses of rituximab, the patient experienced progressive weakness leading to difficulty with ambulation. On neurologic examination, her upper extremity strength was similar but her lower extremity strength had declined (MRC scale hip flexion 3/5; knee flexion 4+/5; knee extension 4/5; and dorsiflexion, plantarflexion, toe extension, and toe flexion 5/5 bilaterally). Sensory examination was unchanged from initial evaluation, but she was now areflexic.

Section 5

Acute worsening of symptoms of anti-MAG has been described,⁵ and paradoxical worsening with rituximab has also been reported.⁶ Our patient underwent plasmapheresis (PLEX) with reversal of her acute worsening over days. After discharge, she was continued on rituximab therapy. She experienced progressive improvement in her weakness and function over the following months.