Case Review
Subacute Progressive Paraneoplastic Necrotizing Myelopathy: A Rare Presentation of Lymphoma
Michaël Mayette, MD, Jean Rivest, MD, Bassem Sawan, MD
About the Authors
Michaël Mayette is a third-year internal medicine resident, Jean Rivest is professor of neurology, and Bassem Sawan is an associate professor and director of the Pathology Division, all at the University of Sherbrooke, Sherbrooke, Quebec. Correspondence may be directed to Michaël Mayette at michael.mayette@usherbrooke.ca.
Case Report
An 84-year-old right-handed man presented to our hospital with complaints of recurrent falls. He was known to have longstanding seronegative rheumatoid arthritis (RA), well controlled on hydroxychloroquine therapy, and a recent inferior wall myocardial infarction. His falls were associated with recent-onset distal right leg weakness and bilateral symmetrical lower extremity hypoesthesia. He had no other neurological complaints, no recent febrile illness, and no symptoms suggestive of collagen-vascular disease. His arthritis was not active. He had not travelled outside of Quebec. Upon examination, his mentation was normal, his visual fields were intact, and his cranial nerves were normal. Upper extremity sensory and motor examination was unremarkable. However, lower extremity examination revealed asymmetrical distal paresis, particularly in dorsiflexion of the ankle and hallux, and to a lesser extent in the knee and foot flexors. These findings were initially limited to the right leg. Flaccidity was apparent, without fasciculation. On sensory examination, there was loss of proprioception and severely diminished vibratory sense to the mid-thigh in both legs. Pain sensation was initially normal.
Results of a routine blood workup were unremarkable, with a normal complete blood count, B12, and folic acid levels, thyroid function tests, and stable renal function. Initial findings on head computed tomography (CT) and magnetic resonance imaging (MRI) were normal. Full-spine MRI (Figure 1A) revealed three foci of an intramedullary hypersignal in T2 and STIR (lower cervical, lower thoracic, and conus medullaris). There was no medullary edema, evidence of extrinsic compression, or contrast-induced enhancement. Lumbar puncture revealed mild pleocytosis, normal glucose, elevated proteins, and elevated immunoglobulin G. Results of all cultures, viral PCR, fungi, tuberculosis stains, Lyme, Venereal Disease Research Laboratory, cytomegalovirus, and human immunodeficiency virus (HIV) tests, and hepatitis B and C studies were negative. Serological testing revealed a past Epstein-Barr virus (EBV) infection. Screening for acute inflammatory conditions (including ANA, ANCA, RF, and complement dosing) was negative.
Over the course of 3 weeks, paresis progressed in an ascending fashion to complete plegia of both legs, with the pinprick sensory level rising to T5, and the development of urinary and fecal incontinence. Symptoms failed to respond to high-dose intravenous (IV) steroid therapy and to a 5-day course of IV gamma globulins. Repeat spine MRI (Figure 1B) revealed the progression of the lesions previously described to confluent hypersignal from C7 down to the conus medullaris.
Figure 1. Magnetic resonance imaging (MRI) scan of the spine, STIR acquisition. A, Initial MRI scan showing three lesions (two seen here, arrows). Lesions extended respectively from C6 to T3, T5 to T7, and T12 to the conus medullaris. B, Control MRI scan 3 weeks later shows progression to confluent lesions.
With most of the other etiologies of severe subacute progressive myelopathy being ruled out, paraneoplastic necrotizing myelopathy was suspected, despite the absence of symptoms suggestive of cancer, such as weight loss, night sweats, or findings of lymphadenopathy. Chest radiographs and thoracic CT scans were normal. Abdominal CT revealed a 3.4 × 2.2 × 2.1 cm lesion in the liver, possibly a metastatic lesion. Positron emission tomography was performed and revealed a single hypermetabolic intrahepatic lesion with no evidence of adenopathies or distant metastasis. A percutaneous biopsy of the lesion confirmed a diagnosis of malignant non-Hodgkin’s lymphoma, diffuse large B-cell, post-germinal type (Figure 2).
Figure 2. A, Hematoxylin and eosin stain shows multiple large tumoral cells. B, CD20 expression on the cell surface confirms their lymphoid B-cell lineage. C, MUM-1 nuclear expression confirms their origin from post-germinal cells.
The patient refused surgery or chemotherapy. He died of respiratory insufficiency after 6 weeks’ evolution of neurological symptoms. No autopsy was performed, as expressed in patient’s and family’s wishes.
Discussion
Primary hepatic lymphoma (PHL) is a rare tumour, representing 0.4% of extranodal and 0.016% of all non-Hodgkin’s lymphomas.1 The vast majority are of B-cell lineage. Clinical associations have been made with HIV infection, hepatitis B and C, liver cirrhosis, autoimmune disease (particularly RA), and immunosuppressive medications. In RA, the lymphoma risk usually correlates with disease activity. Those risk factors are additive, as with the multiple case reports of rheumatoid patients treated with methotrexate. To our knowledge, no association has been established between PHL and hydroxychloroquine therapy. Multiple explanations have been proposed for this association, including CD5+ clonal expansion and decreased counts and function of T suppressor lymphocytes and natural killer cells.2
Evidence is accumulating linking EBV infection with lymphoproliferative disorders, particularly in rheumatoid patients: up to 41% of patients with RA-induced lymphoma on methotrexate were found to be EBV positive.3 Depressed T-cell function in RA explains the high prevalence of latent infection, and the pro-oncogenic properties of EBV may explain its association with lymphoma.
Paraneoplastic necrotizing myelopathy is a rare disease of the spinal cord of uncertain pathophysiology, possibly caused by cross-reactivity of autoantibodies to spinal axons or by a necrotizing vasculitis. It was originally described in 1964,4 and case reports have associated it with lymphoma (Hodgkin’s disease), small cell pulmonary neoplasm, and renal cell adenocarcinoma. Myelopathy is most frequently a manifestation of advanced disease but rarely can be the presenting symptom,5 as in this case. Disease progression is usually subacute, unremitting, and progressive, as opposed to the salutary evolution of idiopathic necrotizing myelopathy.6 It presents as ascending sensory deficits, progressing flaccid paresis, and sphincter dysfunction.
It is usually considered a diagnosis of exclusion since the imaging is nonspecific and there is no reliable serological test (as opposed to other neurological paraneoplastic diseases for which specific autoantibodies are detectable). Important differential diagnoses include B12-related combined spinal degeneration, extrinsic medullary compression from any cause, infectious diseases such as HIV, HTLV, and zoster-associated myelopathy, poliomyelitis, neurosyphilis, and multiple others. Guillain-Barré syndrome and neuromyelitis optica can usually be excluded on clinical grounds. A rare syndrome, Foix-Alajouanine, must be differentiated; it is characterized by focal medullary necrosis secondary to stasis or thrombosis of arteriovenous malformations in the lower spine. Contrast-enhanced MRI of the spine is an essential addition to serological and microbiological assessment.
Cases have reported partial response to high-dose steroid therapy, intrathecal dexamethasone administration, IV immunoglobulins, or plasmapheresis.7 In most cases, treatment is ineffective, and the vast majority of patients develop respiratory failure and succumb. Even treatment of the underlying neoplasm fails to halt the progression of symptoms, except in one case report of myelopathy associated with bronchial carcinoma.8
In conclusion, paraneoplastic necrotizing myelopathy is a rare entity, presenting a major diagnostic challenge because of the vast differential, the absence of a reliable diagnostic test, and the possibility of neurological symptoms preceding the associated neoplasm. This case highlights the importance of considering myelopathy as a paraneoplastic syndrome, thus helping direct diagnostic assessment and prognostication.
Acknowledgments
I would like to thank Dr. Luc Lanthier for reviewing the manuscript.
References
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8. Lins H, Kanakis D, Dietzmann K, et al. Paraneoplastic necrotizing myelopathy with hypertrophy of the cauda equine. J Neurol 2003;250:1388–9.
Article citation: Mayette M, Rivest J, Sawan B. Subacute progressive paraneoplastic necrotizing myelopathy: A rare presentation of lymphoma. Can J Gen Intern Med 2008;3(3):131-133 |
