Clinical Reasoning: A 60-Year-Old Man With Asymmetric Weakness and Persistent Fever

Section 1

A 60-year-old right-handed man presented in a wheelchair with a 5-day history of progressive weakness. The weakness started in the right hand. Days later, he was unable to lift his right arm above the shoulder. He sequentially developed weakness in the left leg, the left hand, and then the right leg. Weakness progressed so rapidly that the patient was unable to walk independently on presentation. He also reported 2 days of distal numbness but denied any pain. The patient denied recent illness or travel, toxin exposure, insect bites, tobacco/alcohol addiction, or family history with similar presentations. No recent weight loss was noted. Medical history was remarkable for well-controlled diabetes mellitus. Surgical history included resection of pulmonary nodules found on routine examination 4 years ago.

On examination, the patient was febrile (38°C) with age appropriate mental status. Asymmetric weakness was noted (right/left; Medical Research Council grades): abductor pollicis brevis (0/2), first dorsal interosseous (0/2), abductor digiti minimi (0/2), finger extensors (1/2), biceps (3/4), deltoids (3/4), knee flexors (3/3), knee extensors (3/2), tibialis anterior (4/3), and gastrocnemius (5/5). The sensory examination revealed loss of pinprick in distal extremities. Deep tendon reflexes were absent in all 4 limbs. He had bilateral flexor plantar responses. Cranial nerves were intact.

Blood tests at admission were remarkable for leukocytosis of 23.7 × 10⁹/L (neutrophils: 20.22 × 10⁹/L, 85.5%; lymphocytes: 0.55 × 10⁹/L, 2.3%; eosinophils: 1.92 × 10⁹/L, 8.1%). He had increased erythrocyte sedimentation rate (40 mm/hour) and C-reactive protein (98.5 mg/L). Other serum tests including liver/kidney functions, electrolytes, hemoglobin A1c level, thyroid function, and vitamin B12 were normal.

Section 2

The progressive weakness and sensory loss in all extremities, absent reflexes, and lack of pyramidal signs are consistent with peripheral nervous system (PNS) involvement. Notably, our patient had atypical neuropathy features, including asymmetric distribution, an acute onset, and systemic symptoms such as fever and raised inflammatory markers that warranted extensive diagnostic testing. In particular, the asymmetric pattern of distribution raises concerns for the following localizations: mononeuritis multiplex, plexopathy, or polyradiculopathy.¹ The sequential involvement of multiple noncontiguous nerves, rather than in a dermatomal/myotomal or plexus pattern, suggests mononeuritis multiplex in this patient.

Mononeuritis multiplex is a unique entity mainly attributed to immune-mediated causes, including vasculitis, Lewis-Sumner syndrome, multifocal motor neuropathy, sarcoidosis, and paraneoplastic neuropathy. Other causes include infectious (hepatitis B/C, human immunodeficiency virus, leprosy etc.), neoplastic (leukemia, lymphoma etc.), or genetic diseases (hereditary neuropathy with liability to pressure palsies and amyloidosis). In this patient, the acute onset, persistent fever, and raised inflammatory markers were more suggestive of systemic immune-mediated or infectious causes, rather than neoplastic or genetic diseases.

To further examine the PNS pathology, nerve conduction studies (NCS) and needle electromyogram (EMG) were performed soon after admission (Table).

Section 3

On NCS, the most striking finding was a significant reduction in compound muscle action potential (CMAP) amplitude and an absent response in multiple nerves, suggesting a severe axonal loss. The prolonged latency and slowed conduction velocity were present but relatively mild, indicating a secondary demyelinating pathology. EMG revealed abnormal spontaneous activities and reduced recruitment of the first dorsal interosseous, further confirming the primary axonal damage. Taken together, the NCS/EMG studies were suggestive of axonal neuropathy in a multiple mononeuropathy distribution, which narrows the differential to certain immune-mediated causes including axonal GBS, sarcoidosis, vasculitis, or infectious neuropathies because of rare pathogens.

Ancillary studies including serum antinuclear antibodies and antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factors, and antiganglioside antibodies were unremarkable. Cerebral spinal fluid analysis was normal. To further exclude infectious causes, we performed metagenomic next-generation sequencing and blood cultures, which were negative. Chest CT scan revealed only postoperative fibrosis of the right lung. Other tests including echocardiogram, renal, and abdominal ultrasound were nonrevealing.

Given that immune-mediated neuropathies were the most likely diagnosis based on available data, empiric treatment with intravenous immunoglobulin (2g/kg) was administered over 5 days. However, the weakness progressed further and fever persisted, rendering the patient practically bedbound. Repeated NCS showed a remarkable reduction of amplitudes in multiple nerves. Adding to the neurologic deterioration, the patient developed pruritic rashes as waxing and waning papules on the extremities, abdomen, and back (Figure, A). Based on these rashes, we investigated histopathology by performing muscle biopsy of the right biceps, which revealed transmural inflammation of the vessel wall with granulomatous inflammation (Figure, B). The findings of palpable rash with leukocytoclastic vasculitis in the context of mononeuritis multiplex highly suggested systemic vasculitis as the underlying cause of the asymmetric neuropathy.

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Figure Skin Rash and Pulmonary Granulomas

(A) Papules on the trunk and bilateral extremities of the patient, which seem as pruritic, tiny, and raised bumps. (B) Leukocytoclastic vasculitis in the dermis showing multinucleated giantcells (arrow) with eosinophilic infiltration (arrowhead) (Hematoxylin & Eosin [H&E] stain, ×100). (C) Chest CT scan 4 years ago showed 2 pulmonary nodules (triangle) in the right upper and lower lobe, respectively, both with spiculated and unclear margins. (D) Surgical biopsy of the right upper nodule demonstrated necrotizing noncaseous granulomatous inflammation (H&E stain, ×20) with small-vessel vasculitis (asterisk, H&E stain, ×100).

Section 4

The most common type of systemic vasculitis associated with peripheral neuropathy includes ANCA-associated vasculitis (AAV), polyarteritis nodosa, cryoglobulinemia, or vasculitis secondary to rheumatoid arthritis and other connective tissue diseases.² For further classification, we recalled the history of the pulmonary nodule 4 years ago (Figure, C). A review of medical records unveiled prominent eosinophilia (white blood cells: 18.2 × 10⁹/L, eosinophils: 2.57 × 10⁹/L, 14.1%) in the middle of that hospitalization. Pathology of the pulmonary nodule showed noncaseous granulomatous inflammation (Figure, D). According to the 2022 AAV classification criteria (eTable 1, links.lww.com/WNL/C542), the presence of mononeuritis multiplex and episodes of peripheral eosinophilia qualified the patient for the diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA).³

Corticosteroid was initiated (80 mg/d, i.v), resulting in a remarkable improvement in weakness and fever, as well as a reduction of peripheral eosinophils (0.2 × 10⁹/L, 1.4%). However, the weakness relapsed on oral tapering to 15 mg/d. We initiated rituximab (RTX) with 2 initial infusions of 500 mg, given a fortnight apart for remission induction and subsequent infusions of 500 mg every 6 months for maintenance. At the latest follow-up 1 year after RTX treatment, the patient remained relapse-free. He was even able to ride a bicycle without assistance despite residual claw-hand and claw-toe deformities because of irreversible nerve damage.