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Myelomatous meningitis: A rare neurological involvement in complete remission of Multiple Myeloma
Journal of the Neurological Sciences 340 (2014) 241–242
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Myelomatous meningitis: A rare neurological involvement in complete remission of Multiple Myeloma Keywords: Myeloma meningitis Multiple myeloma Relapse Leptomeningeal dissemination
To the Editor Neurological manifestations of Multiple Myeloma (MM) are relatively common and often secondary to medullary compression, hypercalcemia, hyperviscosity or peripheral neuropathies [1]. Leptomeningeal dissemination causing Myelomatous meningitis (MyM) is one of the rarest complications of MM [1]. The mechanisms underlying leptomeningeal spreading of plasma cells in MM are not yet determined. Hematogenous spread or direct extension through the adjacent affected bone are possible mechanisms [2]. Treatment of MyM is seldom curative and essentially palliative, with attempted preservation of neurologic function [2]. We present a rare fatal case of MyM occurring after treatment and complete remission of MM. A 64-year-old female, without any relevant medical antecedents, presented a two-month history of right hip joint pain. A lytic lesion in the proximal right femur was identified on X-ray. B2 microglobulin levels and serum creatinine were 2.17 and 1.2, respectively. A biopsy was performed leading to the diagnosis of plasmacytoma (Fig. 1A). Serum protein electrophoresis revealed a monoclonal spike of gamma globulin. Serum immunofixation identified immunoglobulin (Ig) G kappa-type M protein and urine immunofixation electrophoresis revealed the presence of Bence–Jones proteinuria (kappa light-chain). Bone marrow examination showed 14% infiltration by plasma cells in aspirate; 30% of plasma cells; mitosis, and pleomorphism in biopsy. MM stage IA by Durie–Salmon staging system and stage I by International Staging System, was diagnosed and the patient was treated with surgery and radiotherapy (30 Gy) in bone lesion. The remaining metabolic, hematological, and imagiological studies were normal. Her clinical status improved steadily for the following 4 months, when she complained of persistent dorsal back pain. A new bone CT showed multiple osteolytic lesions of the skull base, spine and ribs. Bone marrow biopsy again revealed the presence of neoplastic plasma cells, CD38 +, representing 60% of the cells. Karyotype analysis showed complex structure and OncoFISH detected the presence of deletion in chromosome 13q. She was treated with bortezomib, (2 mg on days 1, 4, 8, 11 of each cycle) with dexamethasone (40 mg with the same schema as bortezomib), and radiotherapy in dorsal spine. No clinical or radiological improvement occurred after 4 cycles of treatment. After the second cycle of a rescue treatment with lenalidomide (25 mg/day, for 21 days, completing 6 cycles) and dexamethasone, complete remission was achieved. The paraprotein became unquantifiable, bone marrow showed less than 5%
http://dx.doi.org/10.1016/j.jns.2014.03.015 0022-510X/© 2014 Elsevier B.V. All rights reserved.
plasma cells, and the patient was proposed for autologous bone marrow transplantation (ABMT). Between the second salvage chemotherapy and ABMT the patient was asymptomatic and without treatment. At the programmed time for ABMT (5 months later), she presented right eye ptosis, right hemifacial paresthesia, dysphagia, dysphonia and right limb ataxia. No meningeal signs were present and fundoscopy was normal. The study for systemic MM was wholly negative; brain CT was normal. The lumbar puncture showed: leukocytes 185/ul and total protein 53.2; cerebrospinal liquor cytological examination revealed the presence of malignant plasma cells (Fig. 1B). Immunophenotyping showed CD138 +, CD38 +, CD56 + cells (Fig. 2). A diagnosis of MyM was made. Due to displaying only leptomeningeal infiltration without structural lesions, it was decided to perform just intrathecal chemotherapy.
Fig. 1. 1A: HE (40×) Right femur lesion with infiltration by monoclonal plasma cells; 1B: Papanicolau technique (20×) LCR product with cytological findings consistent with atypical plasma cells.
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Letter to the Editor
Fig. 2. Immunophenotyping of cerebrospinal fluid presents cells of small size and low granularity. Show CD38+, CD56+, CD138+, CD45−and CD19− cells.
Despite intrathecal administration of methotrexate, cytarabine and hydrocortisone, she rapidly progressed to death in less than a month. The estimated incidence of MyM in MM is around 1.1%. The hallmark of MyM diagnosis is the identification of plasma cells in the cerebrospinal fluid [3]. Magnetic resonance can be useful in detecting leptomeningeal disease. However, it lacks specificity, and during the initial phase of MyM, false negatives can occur [3]. In our case, rapid clinical deterioration prevented the realization of magnetic resonance. MM frequently involves the skull base, confounding and possibly delaying the diagnosis of MyM [1]. In our patient, besides the lower cranial nerve lesion that could have been caused by a previous lesion at the skull base, the deficits of upper cranial nerves contributed to the suspicion of MyM. Despite being unpredictable, MyM generally occurs in the context of active MM, mostly in Salmon–Durie stage III [2]. In our patient, an isolated CNS relapse appeared at a time when the disease was in complete remission. Nieuwenhuizen and Biesma, in a review, reported thirty-one cases of MyM in well-controlled MM [2]. The authors suggested that MyM results from the leptomeningeal spread of lymphoid cells and continuous growth of plasma cells in CNS during the course and treatment of MM and occurs due to the inability of most drugs to cross the blood– brain barrier. Median survival time for MyM is approximately 2 months, often shorter when associated with systemic aggressive disease [3]. In spite of the prompt diagnosis, absence of systemic disease, and aggressive intrathecal treatment, the patient died after one month. In conclusion, our case highlights the possibility of MyM occurring even in wellcontrolled MM, and confirms the very poor prognosis of this rare and severe neurological complication.
Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgment We would like to thank Dra. Ana Machado (Clinical Pathology) and Dra. Matilde Gonçalves (Anatomical Pathology) for their support in the diagnosis and providing the figures.
References [1] Chamberlain MC, Glantz M. Myelomatous meningitis. Cancer 2008;112(7):1562–7. [2] Nieuwenhuizen L, Biesma DH. Central nervous system myelomatosis: review of the literature. Eur J Haematol 2008;80(1):1–9. [3] Schluterman KO, Fassas AB, Van Hmert RL, Harik SI. Multiple myeloma invasion of the central nervous system. Arch Neurol 2004;61(9):1423–9.
Marisa Brum⁎ Ana Santo António Rui Guerreiro Hospital São Bernardo, Centro Hospitalar de Setúbal, Setúbal, Portugal ⁎Corresponding author at: Rua Camilo Castelo Branco, 2910-446 Setúbal Portugal. Tel.: +351 912137364; fax: +351 296549050. E-mail address: [email protected] (M. Brum). 15 January 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Myelomatous meningitis: A rare neurological involvement in complete remission of Multiple Myeloma Keywords: Myeloma meningitis Multiple myeloma Relapse Leptomeningeal dissemination
To the Editor Neurological manifestations of Multiple Myeloma (MM) are relatively common and often secondary to medullary compression, hypercalcemia, hyperviscosity or peripheral neuropathies [1]. Leptomeningeal dissemination causing Myelomatous meningitis (MyM) is one of the rarest complications of MM [1]. The mechanisms underlying leptomeningeal spreading of plasma cells in MM are not yet determined. Hematogenous spread or direct extension through the adjacent affected bone are possible mechanisms [2]. Treatment of MyM is seldom curative and essentially palliative, with attempted preservation of neurologic function [2]. We present a rare fatal case of MyM occurring after treatment and complete remission of MM. A 64-year-old female, without any relevant medical antecedents, presented a two-month history of right hip joint pain. A lytic lesion in the proximal right femur was identified on X-ray. B2 microglobulin levels and serum creatinine were 2.17 and 1.2, respectively. A biopsy was performed leading to the diagnosis of plasmacytoma (Fig. 1A). Serum protein electrophoresis revealed a monoclonal spike of gamma globulin. Serum immunofixation identified immunoglobulin (Ig) G kappa-type M protein and urine immunofixation electrophoresis revealed the presence of Bence–Jones proteinuria (kappa light-chain). Bone marrow examination showed 14% infiltration by plasma cells in aspirate; 30% of plasma cells; mitosis, and pleomorphism in biopsy. MM stage IA by Durie–Salmon staging system and stage I by International Staging System, was diagnosed and the patient was treated with surgery and radiotherapy (30 Gy) in bone lesion. The remaining metabolic, hematological, and imagiological studies were normal. Her clinical status improved steadily for the following 4 months, when she complained of persistent dorsal back pain. A new bone CT showed multiple osteolytic lesions of the skull base, spine and ribs. Bone marrow biopsy again revealed the presence of neoplastic plasma cells, CD38 +, representing 60% of the cells. Karyotype analysis showed complex structure and OncoFISH detected the presence of deletion in chromosome 13q. She was treated with bortezomib, (2 mg on days 1, 4, 8, 11 of each cycle) with dexamethasone (40 mg with the same schema as bortezomib), and radiotherapy in dorsal spine. No clinical or radiological improvement occurred after 4 cycles of treatment. After the second cycle of a rescue treatment with lenalidomide (25 mg/day, for 21 days, completing 6 cycles) and dexamethasone, complete remission was achieved. The paraprotein became unquantifiable, bone marrow showed less than 5%
http://dx.doi.org/10.1016/j.jns.2014.03.015 0022-510X/© 2014 Elsevier B.V. All rights reserved.
plasma cells, and the patient was proposed for autologous bone marrow transplantation (ABMT). Between the second salvage chemotherapy and ABMT the patient was asymptomatic and without treatment. At the programmed time for ABMT (5 months later), she presented right eye ptosis, right hemifacial paresthesia, dysphagia, dysphonia and right limb ataxia. No meningeal signs were present and fundoscopy was normal. The study for systemic MM was wholly negative; brain CT was normal. The lumbar puncture showed: leukocytes 185/ul and total protein 53.2; cerebrospinal liquor cytological examination revealed the presence of malignant plasma cells (Fig. 1B). Immunophenotyping showed CD138 +, CD38 +, CD56 + cells (Fig. 2). A diagnosis of MyM was made. Due to displaying only leptomeningeal infiltration without structural lesions, it was decided to perform just intrathecal chemotherapy.
Fig. 1. 1A: HE (40×) Right femur lesion with infiltration by monoclonal plasma cells; 1B: Papanicolau technique (20×) LCR product with cytological findings consistent with atypical plasma cells.
242
Letter to the Editor
Fig. 2. Immunophenotyping of cerebrospinal fluid presents cells of small size and low granularity. Show CD38+, CD56+, CD138+, CD45−and CD19− cells.
Despite intrathecal administration of methotrexate, cytarabine and hydrocortisone, she rapidly progressed to death in less than a month. The estimated incidence of MyM in MM is around 1.1%. The hallmark of MyM diagnosis is the identification of plasma cells in the cerebrospinal fluid [3]. Magnetic resonance can be useful in detecting leptomeningeal disease. However, it lacks specificity, and during the initial phase of MyM, false negatives can occur [3]. In our case, rapid clinical deterioration prevented the realization of magnetic resonance. MM frequently involves the skull base, confounding and possibly delaying the diagnosis of MyM [1]. In our patient, besides the lower cranial nerve lesion that could have been caused by a previous lesion at the skull base, the deficits of upper cranial nerves contributed to the suspicion of MyM. Despite being unpredictable, MyM generally occurs in the context of active MM, mostly in Salmon–Durie stage III [2]. In our patient, an isolated CNS relapse appeared at a time when the disease was in complete remission. Nieuwenhuizen and Biesma, in a review, reported thirty-one cases of MyM in well-controlled MM [2]. The authors suggested that MyM results from the leptomeningeal spread of lymphoid cells and continuous growth of plasma cells in CNS during the course and treatment of MM and occurs due to the inability of most drugs to cross the blood– brain barrier. Median survival time for MyM is approximately 2 months, often shorter when associated with systemic aggressive disease [3]. In spite of the prompt diagnosis, absence of systemic disease, and aggressive intrathecal treatment, the patient died after one month. In conclusion, our case highlights the possibility of MyM occurring even in wellcontrolled MM, and confirms the very poor prognosis of this rare and severe neurological complication.
Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgment We would like to thank Dra. Ana Machado (Clinical Pathology) and Dra. Matilde Gonçalves (Anatomical Pathology) for their support in the diagnosis and providing the figures.
References [1] Chamberlain MC, Glantz M. Myelomatous meningitis. Cancer 2008;112(7):1562–7. [2] Nieuwenhuizen L, Biesma DH. Central nervous system myelomatosis: review of the literature. Eur J Haematol 2008;80(1):1–9. [3] Schluterman KO, Fassas AB, Van Hmert RL, Harik SI. Multiple myeloma invasion of the central nervous system. Arch Neurol 2004;61(9):1423–9.
Marisa Brum⁎ Ana Santo António Rui Guerreiro Hospital São Bernardo, Centro Hospitalar de Setúbal, Setúbal, Portugal ⁎Corresponding author at: Rua Camilo Castelo Branco, 2910-446 Setúbal Portugal. Tel.: +351 912137364; fax: +351 296549050. E-mail address: [email protected] (M. Brum). 15 January 2014