Journal of Neuro-Ophthalmology, June 2005, Volume 25, Issue 2

Sustained Visual Recovery After Treatment with Intrathecal Methotrexate in a Case of Optic Neuropathy Caused by Chronic Lymphocytic Leukemia

A 68-year-old woman with chronic lymphocytic leukemia (CLL) had acute optic neuropathy associated with cerebrospinal fluid evidence of meningeal spread of CLL. There was no evidence of a hematologic relapse. After undergoing four weekly doses of intrathecal methotrexate, vision improved dramatically and spinal fluid became normal. Four years later, she has near normal vision in the affected eye and remains in hematologic remission. This is the first reported case of successful treatment of optic neuropathy in CLL with intrathecal methotrexate alone.

ORIGINAL CONTRIBUTION Sustained Visual Recovery After Treatment With Intrathecal Methotrexate in a Case of Optic Neuropathy Caused by Chronic Lymphocytic Leukemia Lizette Mowatt, FRCS, FRCOphth, Tim Matthews, FRCOphth, and Ioanne Anderson, MBBS, FRANZCO Abstract: A 68- year- old woman with chronic lymphocytic leukemia ( CLL) had acute optic neuropathy associated with cerebrospinal fluid evidence of meningeal spread of CLL. There was no evidence of a hematologic relapse. After undergoing four weekly doses of intrathecal methotrexate, vision improved dramatically and spinal fluid became nor­mal. Four years later, she has near normal vision in the affected eye and remains in hematologic remission. This is the first reported case of successful treatment of optic neu­ropathy in CLL with intrathecal methotrexate alone. ( J Neuro- Ophthalmol 2005; 25: 113- 115) Central nervous system or meningeal involvement in chronic lymphocytic leukemia ( CLL) is uncommon ( 1- 4). Its neurologic manifestations usually consist of neuro-cognitive 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. CASE REPORT 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 Sandwell and West Birmingham NHS Trust ( LM), Birmingham and Midland Eye Center, Birmingham, England and University Hospital of the West Indies, Mona Campus, Jamaica, West Indies; Sandwell and West Birmingham NHS Trust ( TM), Birmingham and Midland Eye Center, Birmingham, England; Sandwell and West Birmingham NHS Trust ( IA), Birmingham and Midland Eye Center, Dudley Road, Birmingham, England and Mater Health Services Raymond Terrace South Brisbane Queensland, Australia. Address correspondence to Dr. Lizette Mowatt, Department of Surgery, Anesthetics, Intensive Care & Radiology, University Hospital of the West Indies, Mona, Kingston 7, Jamaica, West Indies; E- mail: lillenea@ aol. com 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 X 109/ L, and platelets 89 X 109/ L. Cerebrospinal fluid ( CSF) analysis revealed small lymphocytes and no evidence of organisms. Immunophe-notyping 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 phe-notype consistent with B- cell CLL. After 3 days of treatment with intravenous methyl-prednisolone 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 X 109/ L, and platelets 99 X 107L. 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. DISCUSSION 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 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 113 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Mowatt et al FIG. 1. Visual field OD on presenta­tion shows a cecocentral scotoma associated with a visual acuity of finger counting. 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 FIG. 2. Visual field OD 18 months after treatment shows reduction in the size of the scotoma associated with im­provement in visual acuity to 20/ 30. \ - - \ 114 2005 Lippincott Williams & Wilkins Optic Neuropathy Caused by Chronic Lymphocytic Leukemia J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 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. REFERENCES 1. Cramer SC, Glaspy JA, Efird JT, Louis DN. Chronic Lymphocytic Leukemia and the central nervous system. A Clinical and Path­ological Study. Neurology 1996; 46: 19- 25. 2. Currie JN, Lessell S, Lessell IM, et al. Optic Neuropathy in Chronic Lymphocytic Leukemia Arch Ophthalmol 1988; 106: 654- 60. 3. Barcos M, Lane W, Gomez GA et al. An Autopsy Study of 1206 Acute and Chronic Leukemias ( 1958 tol982) Cancer 1987; 60: 827- 37. 4. Cash J, Fehir KM, Pollack MS. Meningeal Involvement in Early Stage Chronic Lymphocytic Leukemia. Cancer 1987; 59: 798- 800. 5. Akintola- Ogunremi O, Whitney C, Mathur SC, Finch CN. Chronic Lymphocytic Leukemia presenting with symptomatic central nervous system involvement. Ann Hematol 2002; 81: 402^ k 6. Miller K, Budke H, Orazi A. 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