Clinical Reasoning: A 23-Year-Old Man With Progressive Asymmetric Weakness and Numbness

Section 1

A 23-year-old man presented with numbness, tingling, and weakness in his extremities progressing over 4 months. He initially noticed left thumb numbness and tingling that spread throughout his hand, followed a month later by sensory changes in both legs and left leg weakness. Previously a lacrosse player, he lost the ability to run. He denied neck or lower back pain. He denied any preceding illness but had received the coronavirus 2019 (COVID-19) Moderna vaccine booster 3 days before symptom onset.

His initial neurologic examination was notable for distal weakness of both upper and lower extremities, more pronounced on the left. Shoulder abduction, elbow extension and flexion, and wrist extension and flexion strength were graded 5/5 bilaterally using the Medical Research Council scale; finger abduction (interosseous) and thumb abduction (abductor pollicis brevis) were 4/5 bilaterally; hip flexion and knee extension and flexion were 5/5 bilaterally; ankle dorsiflexion was 4/5 bilaterally; ankle plantar flexion was 5/5 bilaterally; toe extension was 1/5 on the left and 4/5 on the right; and toe flexion was 5/5 bilaterally. Sensation to pinprick was decreased distally in both upper and lower extremities with 8 seconds timed vibration sensation at bilateral great toes while proprioception was intact. The Romberg sign was absent. Reflexes were absent throughout. He could march on his toes but not on his heels.

Section 2

The combination of motor weakness, sensory abnormalities, and areflexia suggests a disorder of the lower motor neurons, which may localize to the nerve roots, plexuses, or peripheral nerves. Simultaneous upper and lower extremity involvement suggests a diffuse process and narrows the localization to the peripheral nerves with a non–length-dependent pattern suggestive of an inflammatory polyneuropathy. The next best diagnostic step is to obtain nerve conduction studies (NCSs), which may help differentiate between a demyelinating and axonal neuropathy and elucidate further patterns such as uniformity or symmetry. These were performed and are summarized in the Table.

Section 3

NCSs showed normal sensory nerve action potentials in absolute terms, but amplitudes were asymmetric in 2 nerves (sural: right 11.6uV and left 21.5uV; median: right 18.4uV and left 41.0uV). Compound muscle action potentials (CMAPs) had slowed conduction velocities in multiple nerves, several with associated conduction block. The peroneal-extensor digitorum brevis CMAP had particularly slowed conduction velocities with conduction block (Figure). The left median and tibial F-wave latencies were prolonged. The needle electromyography portion of the electrodiagnostic study was normal.

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Figure Left Peroneal Compound Muscle Action Potential Recording at the Extensor Digitorum Brevis With Conduction Block Between the Ankle and the Fibular Head

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Although the NCS abnormalities were much more striking in motor nerves, the asymmetric SNAPs along with the patient's sensory symptoms and deficits on examination suggest sensorimotor involvement. Taken together, NCSs demonstrated a generalized, non–length-dependent, sensorimotor, demyelinating polyneuropathy.

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, inherited polyneuropathies, and neuropathy secondary to medication exposures. This is a short list compared with that for axonal neuropathies, which includes numerous metabolic, toxic, infectious, and other etiologies.¹ Regarding the possibility of CIDP, the patient's NCS met diagnostic criteria for multifocal CIDP in the 2021 revised European Academy of Neurology/Peripheral Nerve Society guidelines.² Specifically, motor conduction criteria for demyelination was seen in at least 2 nerves and in more than one limb (in this case, right ulnar and peroneal CMAP motor conduction blocks among other criteria), and sensory conduction abnormalities were seen in at least 2 nerves (in this case, left median and right sural SNAPs). The initial approach to a demyelinating neuropathy is to complete a detailed clinical history encompassing toxic exposures, family history, and a thorough review of systems. This is followed by laboratory studies corresponding to the differential diagnosis.¹

In this case, the patient did not have toxic exposures, a contributory family history, or systemic symptoms suggestive of a plasma cell dyscrasia. He had unremarkable serum electrophoresis, immunofixation, free light chains, anti-MAG antibodies, and vascular endothelial growth factor. Given the noncontributory history and normal serum studies, CIDP or a CIDP variant was strongly considered. To further evaluate for this possibility, cerebrospinal fluid (CSF) studies were obtained and revealed a borderline protein of 45 mg/dL (normal 15–45 mg/dL) with no pleocytosis.

Section 5

CIDP subtypes include typical CIDP as characterized classically by symmetric and proximal and distal weakness, acute CIDP, sensory CIDP, chronic immune sensory polyradiculopathy, motor CIDP, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), and distal acquired demyelinating and symmetric neuropathy.³ Our patient's neuropathy was best characterized as sensorimotor, asymmetric, and subacute. These elements were most consistent with a diagnosis of MADSAM. It should be noted that if NCSs were interpreted without the context of the patient's history and examination, the predominant motor involvement may suggest multifocal motor neuropathy, a disorder distinct from CIDP characterized by asymmetric, purely motor nerve dysfunction.³

The patient was started on 2 g/kg of intravenous immunoglobulins (IVIg) administered over 2 days. Three days after the initial dose, he noticed dark-colored urine and fatigue. Laboratory studies 5 days after IVIg were notable for hemoglobin 12.3 g/dL, below his baseline of 15 g/dL. Three days later, repeat hemoglobin was 10.6 g/dL. Aspartate transaminase and alanine transaminase were found to be elevated at 54 and 107 U/L, respectively.

Section 6

Dark-colored urine along with downtrending hemoglobin after IVIg administration suggests hemolytic anemia, a rare complication. In this case, additional studies supported this diagnosis, including an elevated reticulocyte index (2.2%), elevated indirect bilirubin (0.8 mg/dL), and low haptoglobin (<8 mg/dL). Lactate dehydrogenase was normal, and urinalysis was unremarkable, but these negative studies did not exclude the diagnosis. The direct antiglobulin test (DAT) was negative. The blood type was AB-negative, Rh-negative. With the trough in hemoglobin, the patient received high-dose steroids, and the long-term treatment was switched to subcutaneous immunoglobulin. He did not experience further adverse effects and had gradual improvement in motor strength and sensory symptoms.

Author Contributions

Emma H. Kaplan: drafted and revised the manuscript for content, analyzed and interpreted the data. Kaveh Torabian: drafted and revised the manuscript for content, analyzed and interpreted the data. Camille V. Edwards: revised the manuscript for content. Michelle C. Kaku: revised the manuscript for content. Pria Anand: revised the manuscript for content. K. H. Vincent Lau: revised the manuscript for content, had a major role in acquisition of the data, analyzed and interpreted the data.