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Journal of Clinical Oncology, Vol 24, No 30 (October 20), 2006: pp. 4942-4944 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.5920
Encephalopathy in a Patient After Long-Term Treatment With ThalidomideUniversity Hospital, Institute of Hematology/Oncology/Immunology, Marburg, Germany
University Hospital, Department of Neurosurgery, Marburg, Germany
University Hospital, Department of Neuroradiology, Marburg, Germany
University Hospital, Department of Neurosurgery, Marburg, Germany
University Hospital, Department of Neuropathology, Marburg, Germany
University Hospital, Institute of Hematology/Oncology/Immunology, Marburg, Germany A 60-year-old man with a 4.3-year history of multiple myeloma presented with an impairment of cerebral function and personality changes. Over a time period of 12 weeks this patient developed partial amnesia, amnesic aphasia, defects in spelling and calculation, inability to read a watch, as well as emotional disturbance with an increasingly aggressive behavior. The symptoms appeared intermittently and partially resolved in between. Four years earlier in 1999, a diagnosis of a multiple myeloma stage IIIA, according to Durie and Salmon, with an IgA-lambda paraprotein was made. Surgical stabilization of vertebral body fractures and radiation therapy of the osteolytic bone lesions had been carried out. Subsequently, combination chemotherapy with four cycles of vincristine, doxorubicin, and dexamethasone (VAD; over a period of 4 days) was started, followed by stem-cell mobilization and tandem high-dose therapy with melphalan supported by autologous stem-cell transplantation. After 1 year of stable disease the patient presented with a systemic progress including infiltration of the CSF as demonstrated by cytology. He was treated with four courses thalidomide, cyclophosphamide, etoposide, and dexamethasone (TCED) and intrathecal methotrexate (MTX). Thalidomide monotherapy (200 mg per day) was continued over 21 months and a complete remission of the myeloma was maintained. By the time when the first neurologic symptoms occurred, thalidomide therapy was stopped immediately. CSF investigation revealed normal white cell count (lymphocytes), slightly increased protein, and a glucose level within the normal range. There was no evidence for cytomegalovirus or varicella virus infection on analysis of CSF. Magnetic resonance imaging showed multiple lesions in the cerebrum and cerebellum, which were characterized by contrast enhancement and partial ring enhancement in T1-weighted spin echo sequence (Fig 1) and multiple lesions with hyperintensity in T2-weighted fast spin echo sequence (Fig 2). A systemic progression of the multiple myeloma was excluded by standard laboratory parameters and x-ray procedures. However, due to the therapeutic relevance of a potential cerebral manifestation of the myeloma a frontal microsurgical biopsy of one lesion was carried out under image guidance. Histopathology showed severe reactive astrogliosis (Fig 3A; Klüver-Barrera, Fig 3B; GFAP) and microglial activation. Only few foamy macrophages were seen (Fig 3C, anti-CD68) and immunohistochemistry for lymphocytes was negative. Subsequently, high doses of steroids were administered, but no improvement of the neurologic symptoms occurred. Six months after the first symptoms, the patient's mental situation deteriorated dramatically. He developed a severe dementia and the need of constant care.
The diagnostic findings excluded a cerebral infiltration of the myeloma or of any other malignant tumor, septic lesions were also ruled out. Thus, we hypothesize that the patient suffered from a thalidomide-induced encephalopathy as a consequence of long-term use of this drug over a period of 21 months. Thalidomide is a glutamic acid derivative, which was administered in the 1950s as a sedative and withdrawn from the market in the 1960 due to its teratogenic effects. In recent years new uses for the drug, including treatment of erythema nodosum leprosum, systemic and cutaneous lupus erythematosus, wasting syndrome associated with HIV infection, graft-versus-host disease and multiple myeloma, were discovered. The mechanism of action and antineoplastic activity are complex and not yet completely understood. Proposed mechanisms are antiangiogenic potency,1 immunomodulatory effects due to induction of interferon-  and interleukin-2 secretion by T-helper cells type 1,2,3 and inhibition of tumor necrosis factor alpha production.3 Moreover, a proapoptotic activity by inhibiting nuclear factor–kappa B has been described.4 In the literature, the most common adverse effects of thalidomide are sedation, fatigue, skin rash, constipation, and peripheral neurotoxicity. Peripheral neuropathy is a potentially irreversible adverse effect, often responsible for withdrawing thalidomide. No other neurotoxic manifestation has been described under thalidomide treatment so far. Peripheral neuropathy seems to be a common adverse effect of long-term use (> 12 months) of this drug occurring in approximately 30% to 75% of patients.5-11 A prior therapy with vincristine and also disease duration were associated with a higher incidence. The two most important differential diagnoses in this case are viral encephalitis and chronic neurotoxicity after intrathecal MTX therapy. Viral encephalitis, such as progressive multifocal leukencephalopathy or Herpes virus encephalitis, is accompanied by progressive signs of cerebral dysfunction and may have a rapidly fatal course. Usually it presents as an acute illness occurring with fever, headache, possible seizures, and focal neurologic deficits.12 Here, the negative CSF cytology and the lack of lymphocytic infiltration and viral inclusions in the brain biopsy made viral encephalitis unlikely. Chronic neurotoxicity of MTX may develop months to years after MTX therapy. Characteristic symptoms are confusion, somnolence, ataxia, seizures, dementia, and also in severe cases with quadriparesis, coma, or even death can occur. The incidence is less than 2% given MTX intrathecally alone and increases up to 45% after a combination of intrathecal MTX and cranial radiation.13,14 In this case, there are some facts that made MTX as the causative agent of the encephalopathy very unlikely. First, the neurologic symptoms appeared a long time (4 years) after MTX intrathecally. Second, the patient never underwent cerebral radiation. Third, 1 year after diagnosis of the encephalopathy and stopping thalidomide he is still alive with a stable clinical picture. To our knowledge this patient is the first described case, where long-term use of thalidomide may have caused a relevant central neurotoxicity. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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