Chronic demyelinating polyneuropathy preceding T-cell lymphoma: differentiation between primary neurolymphomatosis and paraneoplastic neuropathy

Background

Various neuropathies are associated with lymphoma. Neuropathy preceding lymphoma diagnosis can be broadly divided into neurolymphomatosis and paraneoplastic neuropathy. Neurolymphomatosis is the infiltration of lymphoma cells into the peripheral nerves, nerve roots, plexuses or cranial nerves. Primary neurolymphomatosis exclusively involves the peripheral nervous system, whereas secondary neurolymphomatosis is defined as the invasion of lymphoma cells into the peripheral nervous system from other tissues or organs.

It is difficult to differentiate between neurolymphomatosis and paraneoplastic neuropathy as both conditions can present as axonal neuropathy with multiple mononeuropathies, demyelinating polyneuropathy or a complex mixture of demyelinating and axonal changes.1 We have reported a rare case of chronic demyelinating polyneuropathy diagnosed as primary neurolymphomatosis 16 months after symptom onset.

Case presentation

A 49-year-old man presented to our centre in August 2019 with pain and weakness in both feet and left finger. The patient had experienced severe right-sided plantar pain in February 2019 which progressed to involve the left foot and fifth digit of his left hand. The patient was previously healthy and denied any previous medical problems, including diabetes mellitus, hypertension and allergic diseases. Further, the patient had no family history of neuromuscular disease. Neurological examination showed weak finger abduction/adduction in the left hand (Medical Research Council (MRC) grade 2) and left ankle dorsiflexion (MRC grade 2) with sensory changes in the corresponding areas. Other neurological examination findings, including cranial nerve function, were within normal ranges.

Investigations and differential diagnosis

Electrodiagnostic tests conducted in August 2019 revealed bilateral tibial and peroneal neuropathy with relative asymmetry and left ulnar neuropathy. Nerve conduction studies revealed a conduction block in more than two nerves (table 1). Serological test findings for vasculitis, including antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme level, viral markers, vitamin B₁₂ level and thyroid function, were within normal ranges, and there was no monoclonal gammopathy. The patient was negative for antiganglioside antibodies but tests for antibodies associated with paraneoplastic syndrome such as anti-Hu, anti-Yo and others were not performed. Cerebrospinal fluid analysis revealed a normal white blood cell count (<5/mm³) and total protein level (43 mg/dL). Nerve biopsy of the left superficial peroneal nerve showed myelin destruction without an active inflammatory reaction, suggesting chronic demyelinating neuropathy (figure 1A,B). The result of electrodiagnostic tests was not fulfil European Federation of Neurological Societies (EFNS) criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) but based on result of nerve biopsy, this case was attempted to be treated as CIDP. The patient was administered intravenous immunoglobulin (0.4 g/kg/day for 5 days) from September 24th to 28th. However, the weakness progressed to the proximal leg, and the patient experienced difficulty in standing from a squatting position in October 2019. Neurological examination revealed progressive weakness in left finger abduction/adduction (MRC grade 0), bilateral wrist extension (MRC grade 4 on the right side and MRC grade 3 on the left side), bilateral foot dorsiflexion (MRC grade 3 on the right side and MRC grade 0 on the left side), bilateral knee extension (MRC grade 3 on both sides) and bilateral hip flexion (MRC grade 3 on the right side and MRC grade 3 on the left side). Electrodiagnostic tests revealed aggravated bilateral lower extremity neuropathy and left ulnar, median, and radial neuropathies in October 2019. A conduction block in the median nerve was also observed (table 1).

Due to the presence of asymmetrical weakness associated with severe pain, treatment for vasculitic neuropathy was initiated. The treatment included methylprednisolone pulse therapy (1000 mg/day for 5 days) from October 4 to 8 and then oral steroids (60 mg/day). The patient’s severe pain alleviated with the steroid therapy. However, the patient complained of progressive weakness and could not perform activities of daily living due to bilateral hand and lower extremity weakness. Electrodiagnostic tests performed in November 2019 revealed aggravated lower extremity neuropathy and bilateral ulnar, median, and left radial neuropathies (table 1). A second nerve biopsy was performed on the right sural nerve. Histopathology revealed diffuse infiltration of lymphocytic cells with mild atypia (figure 1C,D). T-cell receptor gamma gene rearrangement analysis of the biopsied specimen showed monoclonality. ¹⁸F-2 fluoro-2-deoxy-glucose positron emission tomography (FDG-PET)/CT revealed hypermetabolic lesions on both the sciatic and left axillary nerves (figure 1E). The patient was transferred to another hospital for further evaluation, and a bone marrow biopsy was performed in January 2020. Normocellular marrow (cellularity 50%–60%) without abnormal lymphoid aggregates was observed, with no evidence of bone marrow involvement of lymphoproliferative disorder.

Treatment, outcome and follow-up

The patient was administered low-dose oral steroids (7.5–30 mg/day), tacrolimus (4 mg) and methotrexate (20 mg/week) for T-cell suppression. However, his symptoms did not improve. The patient experienced dysphonia on March 7 and diplopia and dysphagia in April 2020. The patient revisited our centre because of dysphagia and dyspnoea. Neurological examination revealed quadriplegia (MRC grade 3 on the right upper extremity and MRC grade 0–1 on all other extremities) and multiple cranial nerve palsies (left VII, right VI and right X). FDG-PET/CT showed intense FDG uptake in almost the entire bone marrow, stomach, bowel and left lower leg in June 2020 (figure 1F). The patient was diagnosed with T-cell lymphoma and was treated with cyclophosphamide, vincristine and prednisolone, but died 2 months later because of lymphoma progression.