Abstract

Peripheral neuropathies, especially those with atypical features, remain a diagnostic challenge. In this case, a 60-year-old patient presented with acute-onset weakness starting in the right hand then sequentially involving the left leg, left hand, and right leg over 5 days. The asymmetric weakness was accompanied by persistent fever and elevated inflammatory markers. Subsequent development of rashes combined with careful review of the history led us to the final diagnosis and targeted treatment. This case highlights clinical pattern recognition with the help of electrophysiologic studies in peripheral neuropathies, which provide shortcuts to narrow the differential diagnosis. We also illustrate the important pitfalls from history taking to ancillary testing in diagnosing the rare but treatable cause of peripheral neuropathy (eFigure 1, links.lww.com/WNL/C541).

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.

Questions for Consideration:

How would you localize the patient's symptoms?

What is the differential diagnosis?

GO TO SECTION 2

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).

Table

Results of Nerve Conduction Studies and Needle Electromyogram Studies

Questions for Consideration:

What is the interpretation of the NCS/EMG results in the Table?

What further investigations should be considered?

GO TO SECTION 3

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.

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).

Questions for Consideration:

What is your diagnosis given the new-onset rash and ancillary testing results?

How would you treat the patient?

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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.

Discussion

EGPA, which manifests as nonspecific symptoms in the early phase, presents a diagnostic challenge. Previously known as Churg-Strauss syndrome, it is an AAV subtype histologically defined by eosinophil-rich, necrotizing granulomatous inflammation mainly affecting the small-sized arteries.3 According to recently updated criteria,3,4 3 core features, that is, peripheral eosinophilia, obstructive airway disease, and nasal polyps, constitute the hallmarks of EGPA diagnosis. Mononeuritis multiplex and eosinophilic inflammation on biopsy serve as important discriminant classifiers.3 By contrast, cANCA/anti-PR3 positivity and hematuria are red flags indicative of an alternative diagnosis.3 Neurologic complications of EGPA are common, including PNS involvement in 53%–78% of patients.5 Our patient presented with an acute-onset mononeuritis multiplex with concomitant systemic findings. Despite an extensive workup, the diagnosis was only unveiled after he developed diffuse rashes all over the body, leading to the biopsy that revealed small-vessel vasculitis. The diagnosis of EGPA was further confirmed with the history of pulmonary granuloma and repeated episodes of peripheral eosinophilia.

The 3 atypical characteristics of neuropathy, that is, the onset, distribution, and associated systemic features (ODSs), have guided our investigation. Fulfillment of any of the ODS criteria, that is, an acute or subacute onset, a nonlength-dependent pattern of distribution, or systemic features, allows rapid diagnosis of immune-mediated neuropathies with a sensitivity of 96% and specificity of 85%.6 NCS/EMG is especially valuable to establish the diagnosis, which helps confirm the pattern of nerve/muscle involvement and determine the axonal/demyelinating nature of the neuropathy. Electrodiagnostic studies are also important in excluding vasculitis mimics which may also fulfill the ODS criteria, including hereditary neuropathy with liability to pressure palsies (slowing across sites of entrapment), multifocal motor neuropathy (motor nerve conduction block), and the Lewis-Sumner syndrome (motor and sensory nerve conduction block).1

Notably, several diagnostic pitfalls should be considered. First, EGPA is the AAV subtype characterized by a low prevalence of ANCA positivity (only 40%–60%).3 A negative ANCA testing should not exclude the diagnosis of AAV. Second, by the time of evaluation, the confluence of sequential neuropathies may falsely lead to a clinical impression of generalized axonal polyneuropathies. The focal nature of disease onset, often affecting the territory of a single nerve, and an asymmetric pattern of disease progression may be evident only by history. Thirdly, EGPA typically develops in sequential phases, with the upper/lower airway involvement and peripheral eosinophilia preceding the ultimate systemic vasculitic phase.7 A comprehensive review of the history is important to identify previous eosinophilia or respiratory involvement. Last, a tissue biopsy is helpful to confirm the diagnosis but not always necessary. A nerve biopsy can miss the vasculitis because of the patchy nature of the disease (sensitivity for definite vasculitis approximately 30%–50%).8

Early and aggressive treatments are essential to prevent irreversible nerve damage for AAV including EGPA. Multidisciplinary management of systemic vasculitis is essential, especially when choosing between the various treatment options. First-line therapy includes high-dose systemic glucocorticoid, along with rituximab or cyclophosphamide.9 A steroid-sparing agent, such as methotrexate, azathioprine, mycophenolate mofetil, or rituximab, is often required for remission maintenance in AAV with PNS involvement.9

Study Funding

This study was supported by the National Natural Science Foundation of China (Grant number 82201607; 82071443), the Natural Science Foundation of Zhejiang Province (Q23H090002), and the Medical Science and Technology Project of Zhejiang Province (Grant number 2019KY482; 2020KY686).

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Acknowledgment

We gratefully acknowledge the cooperation and patience of the patient, who made this work possible.

Appendix AuthorsFootnotes

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Submitted and externally peer reviewed. The handling editor was Resident and Fellow Deputy Editor Ariel Lyons-Warren, MD, PhD.

Received July 25, 2022.Accepted in final form November 1, 2022.© 2022 American Academy of Neurology