Clinical Reasoning: A 65-year-old man with asymmetric weakness and paresthesias

Section 1

A 65-year-old man with well-controlled diabetes presented with 3 months of progressive left-side predominant weakness accompanied by painless paresthesias of his bilateral upper and lower extremities. The onset was with tingling and numbness in his toes, which later involved his fingers. Over a few weeks, he developed progressive weakness of his left lower extremity followed by the right lower extremity and later involvement of both upper extremities. By the time of presentation, the patient was unable to sit or walk without support and reported weight loss of 35 pounds over 3 months. The patient denied any toxic substance exposure, insect bites, recent illness or travel, family history of neuropathy, or any episodes suggestive of recurrent compressive neuropathies. His examination showed moderately severe asymmetric weakness (Medical Research Council scale: 3–4/5 on the left, 4–5/5 on the right) of the upper and lower extremities (distal more than proximal). There was asymmetric muscle atrophy; however, deep tendon reflexes were 2+ in the right biceps and triceps, 1+ in the left biceps, triceps, and bilateral ankles, and absent in the knees bilaterally. The sensory examination revealed left-sided predominant loss of pinprick in a patchy distribution in legs and loss of vibration sense in the toes. The remaining neurologic examination was unremarkable.

Section 2

The differential diagnosis for a subacute onset of progressive weakness and paresthesias of the extremities is broad. The CNS is less likely to be involved given the absence of upper motor neuron signs and intact cranial nerve examination. Some key clinical features to consider for peripheral nervous system involvement are asymmetric motor and sensory findings, patchy distribution of sensory changes, and predominantly distal weakness. One should consider mononeuritis multiplex, plexopathy, and polyradiculopathy high on the differential.¹ The causes for mononeuritis multiplex include the following:

1. Inflammatory/autoimmune (e.g., vasculitis, atypical chronic inflammatory demyelinating polyneuropathy [CIDP])

2. Hereditary (e.g., hereditary neuropathy with liability to pressure palsy [HNPP])

3. Infectious (e.g., hepatitis, HIV, parvovirus, Lyme disease, leprosy)

4. Malignancy (e.g., paraneoplastic neuropathy, lymphoma)

5. Systemic (e.g., sarcoidosis, amyloidosis)

Vasculitis typically presents with sensory or sensory-motor involvement with an asymmetric/multifocal pattern, lower limb involvement, and distal predominance along with electrodiagnostic features of axonal polyneuropathy. HNPP is an episodic, multifocal hereditary neuropathy associated with PMP22 deletion. Classic clinical presentation is characterized by transient pressure palsies without pain but with focal motor and sensory symptoms in a single nerve distribution or the brachial plexus. The electrophysiologic features are slowed distal motor latencies, most frequently in the median and peroneal nerves, conduction slowing over entrapment sites, slowed sensory conduction velocities, and conduction block in acutely symptomatic nerves. Systemic diseases, malignancy, and infectious causes would need to be explored as well given the recent weight loss, although physical examination did not reveal findings suggestive of these conditions.

Blood tests revealed unremarkable complete blood count, comprehensive metabolic panel, mildly reduced vitamin B₁₂ (163 pg/mL), normal methylmalonic acid (0.20 μmol/L), hemoglobin A1c 6.1%, creatine kinase 91 IU/L, erythrocyte sedimentation rate 18 mm/h, negative antinuclear antibodies, M protein, and nonreactive HIV I and II antibodies. CSF analysis revealed an elevated cell count of 22/μL (lymphocytic 89%) and elevated protein 127 mg/dL. MRI of the brain and entire spine with and without contrast was unremarkable except for mild degenerative disc disease in cervical and lumbar spine without any nerve root enhancement, effectively ruling out localization to the CNS and nerve roots.

Nerve conduction studies revealed conduction block in the forearm of the bilateral ulnar and left median nerves and mildly slowed conduction velocity of the left median and ulnar motor nerves (figure and tables 1 and 2). The left superficial peroneal sensory response was absent. The left sural, radial, and right ulnar sensory responses showed mildly reduced amplitudes and conduction velocities (table 1). F-wave latencies were prolonged in the left ulnar nerve (table 1). Needle EMG showed widespread active denervation in upper and lower extremities on the left side and abnormal spontaneous activity (fibrillation potentials and positive sharp waves) from cervical and lumbar paraspinal muscles (table 1).

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Figure Nerve conduction study results

(A) Left median motor conduction studies with stimulation at wrist and elbow and recordings from abductor pollicis brevis. (B) Left ulnar motor conduction studies with stimulation at wrist and elbow and recordings from first dorsal interosseous. (C) Right ulnar motor conduction studies with stimulation at wrist and elbow and recordings from the abductor digiti minimi.

Section 3

Nerve conduction studies showed conduction block in left ulnar and median nerves in the forearm, along with mildly slowed sensory velocities of bilateral ulnar and left sural and right median nerve. Sensory nerve action potential amplitudes were mildly reduced in multiple nerves (bilateral median and radial, right ulnar, and left sural). The F-wave latency of left ulnar nerve was also prolonged (∼130% of normal). Needle EMG showed neuropathic units in L4/5, L5/S1, and C7-T1-innervated muscles. These findings are consistent with the presence of multiplex mononeuritis with demyelinating pattern and polyradiculopathy.

IV immunoglobulin (IVIg) treatment (2 g/kg) over 5 days was administered, after which there was improvement in distal muscle strength.

The patient’s recent weight loss and mildly elevated CSF cell count >10/μL prompted further workup for systemic disease. Contrast-enhanced CT of the chest, abdomen, and pelvis showed lymphadenopathy in the mediastinum, upper abdomen, and hilar regions. Endobronchial ultrasound-guided bronchoscopy was performed, and the tissue biopsy demonstrated noncaseating granulomas without evidence of fungi or acid-fast bacilli, which was consistent with sarcoidosis. Based on the diagnostic criteria recently proposed by the Neurosarcoidosis Consortium Consensus Group—(1) definite when there is histologic confirmation of neurologic tissue, (2) probable when there is evidence of neurologic involvement and tissue confirmation of systemic sarcoidosis, and (3) possible when characteristic neurologic involvement is seen in the absence of any tissue diagnosis of sarcoidosis—the diagnosis of probable neurosarcoidosis was made.^2,3 Nerve biopsy was deferred since the patient was clinically improving. The patient was subsequently discharged on oral prednisone at 60 mg daily. At 1-month outpatient follow-up, he demonstrated substantial improvement as he was able to ambulate without assistance for a short distance.