Central nervous system or meningeal involvement in chronic lymphocytic leukemia (CLL) is uncommon (1-4). Its neurologic manifestations usually consist of neurocognitive dysfunction, cerebellar signs, and cranial nerve palsies (1,5,6). Optic neuropathy in CLL is rare and has been treated successfully with irradiation (2).
This is the first reported case of optic neuropathy in CLL to be successfully treated with intrathecal methotrexate alone.
A 68-year-old woman presented with a 10-week history of right periocular pain and reduced vision OD. She had stage A chronic lymphocytic leukemia diagnosed 10 years earlier that had progressed to stage C within 2 years. However, it had been in remission for 7 years.
At her first assessment by our Neuro-Ophthalmology Unit, visual acuity was counting fingers OD and 20/30 OS. The patient had a marked color deficit and a relative afferent pupil defect OD. The OS was normal. Goldmann visual field testing revealed a centrocecal scotoma OD (Fig. 1). Ophthalmoscopic examination and ultrasonography revealed normal optic discs.
Laboratory studies included hemoglobin 11 g/dL, white blood cell count 75.8 × 109/L, and platelets 89 × 109/L. Cerebrospinal fluid (CSF) analysis revealed small lymphocytes and no evidence of organisms. Immunophenotyping of CSF revealed a predominance of lymphocytes, two-thirds of which belonged to a neoplastic clone of B cells that was positive for CD20, CD5, and lambda, a phenotype consistent with B-cell CLL.
After 3 days of treatment with intravenous methylprednisolone 1 g/d, there was no improvement in vision, so the patient was begun on chlorambucil 5 mg three times daily orally for 6 days and four weekly doses of methotrexate 12.5 mg intrathecally. At completion of treatment, visual acuity had improved to 20/80 OD. She had a persistent relative afferent pupil defect and temporal optic disc pallor OD. Repeat CSF analysis revealed no leukemic cells. Complete blood count showed hemoglobin 11.3 g/L, white blood cell count 6.7 × 109/L, and platelets 99 × 109/L.
Six months after treatment, visual acuity had improved to 20/30 OD. At 18 months, visual acuity remained 20/30 OD with a residual central scotoma OD (Fig. 2). Four years later, there has been no change in her ophthalmic status and hematological and CSF parameters remain normal.
Invasion of the brain, spinal cord, leptomeninges, and dura by B-cell CLL is found in 33% of autopsies of CLL patients but clinical cases are rare (3). Central nervous system and meningeal involvement is generally thought to be a manifestation of advanced CLL, but it may occur early in the disease and even as a presenting manifestation (2-5). From 16 autopsies of CLL patients with CNS involvement, Cramer et al (1) demonstrated that it may occur across all stages of the CLL. In one series of three cases, optic neuropathy was the first clinical manifestation of previously asymptomatic CLL and the precursor of worsening of the CLL (2).
Factors associated with central nervous system involvement include transformation to a more aggressive variant of CLL (Richter syndrome) (1), thrombocytopenia, and a T-cell variant, which is relatively aggressive (7). Our patient was noted to be consistently thrombocytopenic, although she was not symptomatic from this condition.
Optic nerve involvement is more commonly a feature of acute leukemia than of CLL. It is characteristically associated with hematological relapses (8), unlike our case. The optic neuropathy may occur with or without optic disc edema. Reduction in vision is postulated to result from distension of the optic nerve septae by leukemic cells, causing axonal compression and impairment of axoplasmic flow (9,10).
CSF analysis and immunophenotyping is necessary to confirm the diagnosis. It is critical in differentiating CLL infiltration from opportunistic infections caused by Herpes viruses, Candida, or Cryptococcus, which may cause a polyclonal B-cell response, and from radiation optic neuropathy. CSF phenotyping is also valuable in confirming the resolution of meningeal CLL after treatment (2).
Currie et al (2) described three cases of optic neuropathy as an early clinical manifestation of CLL and that responded favorably to optic nerve irradiation. Improvement of visual acuity and visual fields occurred at first with the use of high-dose corticosteroid therapy in two of these cases, but the effect diminished as the medication was tapered. All three patients underwent 24 to 30 Gy irradiation to the orbital area. Some visual improvement was noted within 2 weeks of treatment (2).
However, because of the many complications associated with brain and spinal cord x-irradiation, treatment with intrathecal methotrexate alone has its advantages (11-13). In one series of patients with central nervous system involvement in CLL, intrathecal chemotherapy alone produced longer survival than intrathecal chemotherapy combined with cranial irradiation (1). In that series, there were two long-term survivors who had been treated with cranial irradiation alone and had persistent disease localized to the optic nerve, suggesting that irradiation alone may not be effective for optic nerve infiltration (1).
In view of these facts, we elected to treat our patient with intrathecal methotrexate. She displayed a dramatic and sustained visual recovery without any systemic complications. After 4 years, she remains in hematologic remission. To our knowledge, this is the first reported case of optic neuropathy in CLL to be successfully treated with intrathecal methotrexate without cranial irradiation.
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