- Email: [email protected]
Is there sentinel demyelination before development of primary CNS lymphoma?
Correspondence / Journal of Clinical Neuroscience 15 (2008) 1069–1070
his neurological condition worsened despite this therapy, with the MMT decreasing to 2/5. The patient was transferred to our hospital. On transfer, staining for acid-fast bacilli (AFB), PCR, and culture for tuberculosis from multiple specimens including CSF were negative. The patient did not consent to spinal cord biopsy for a definitive diagnosis. The ADA in the CSF was highly elevated (31.5 pg/mL), which supported a clinical diagnosis of tuberculous myelitis. Treatment with antituberculous medications produced a marked response. The CSF ADA normalized 10 days after treatment started. At 3 months following initiation, motor power had improved diffusely by MMT to 4/5. The abnormal intensity on the MRI had resolved almost completely. Although PCR has proven more sensitive and rapid than staining for AFB or culture for the diagnosis of tuberculosis, it can still produce false-negative results.3 Tuberculosis must then be suspected on the basis of other features such as a compatible history, clinical abnormalities, and typical radiographic findings. Our patient, who showed no evidence of systemic tuberculosis, had a recent infection with Herpes Zoster, which can cause transverse myelitis. The AFB stain, PCR, and culture for tuberculosis were negative. Moreover, MRI findings typical for CNS tuberculosis such as meningeal or ring enhancement were absent.4 Therefore, initial diagnosis was difficult. In our patient, measurement of CSF ADA was useful for diagnosis. Some authors suggest CSF cutoff values of 9 U/L, 15 U/L, or 20 U/L for differentiating tuberculous from non-tuberculous meningitis.5–7 These reports demonstrate a sensitivity of ADA for tuberculous meningitis of >90% and a specificity of about 80%. In contrast, CSF PCR in tuberculous meningitis has a high specificity (90%–100%) but a relatively low sensitivity (32%–85%).3,8 Some reports have found that PCR is less sensitive for tuberculous meningitis than ADA in direct comparisons.9,10 The present case illustrates the dangers of overreliance on PCR for a differential diagnosis when tuberculous myelitis is suspected clinically. In conclusion, markedly elevated ADA in CSF can be considered a useful alternative diagnostic finding in tuber-
1069
culous myelitis even when CSF AFB stain, cultures, and PCR are negative and MRI findings typical for tuberculosis are absent. References 1. Citow JS, Ammirati M. Intramedullary tuberculoma of the spinal cord: case report. Neurosurgery 1994;35:327–30. 2. Jaiswal AK, Jaiswal S, Gupta SK, et al. Intramedullary tuberculoma of the conus. J Clin Neurosci 2006;13:870–2. 3. DeBiasi RL, Tyler KL. Polymerase chain reaction in the diagnosis and management of central nervous system infections. Arch Neurol 1999;56:1215–9. 4. Tayfun C, Ucoz T, Tasar M, et al. Diagnostic value of MRI in tuberculous meningitis. Eur Radiol 1996;6:380–6. 5. Segura RM, Pascual C, Ocana I, et al. Adenosine deaminase in body fluids: a useful diagnostic tool in tuberculosis. Clin Biochem 1989;22:141–8. 6. Pettersson T, Klockars M, Weber TH, et al. Diagnostic value of cerebrospinal fluid adenosine deaminase determination. Scand J Infect Dis 1991;23:97–100. 7. Choi SH, Kim YS, Bae IG, et al. The possible role of cerebrospinal fluid adenosine deaminase activity in the diagnosis of tuberculous meningitis in adults. Clin Neurol Neurosurg 2002;104:10–5. 8. Nguyen LN, Kox LF, Pham LD, et al. The potential contribution of the polymerase chain reaction to the diagnosis of tuberculous meningitis. Arch Neurol 1996;53:771–6. 9. Kim BJ, Park MH, Koh SB, et al. Polyradiculomyelitis associated with clinically diagnosed tuberculous meningitis. Eur Neurol 2001;46:156–7. 10. Ohtake H, Shibasaki Y, Idezuka J, et al. Validity of adenosine deaminase activity in cerebrospinal fluid for early diagnosis of tuberculous meningitis. Shinkeinaika 2001;54:359–62.
Satoshi Suda Masayuki Ueda Yuichi Komaba Mineo Yamazaki Toshiya Katsumata Yasuo Katayama Divisions of Neurology, Nephrology, and Rheumatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku 113-8602, Tokyo, Japan Tel.: +81 3 3822 2131; fax: +81 3 3822 4865 E-mail address: [email protected] (S. Suda)
doi:10.1016/j.jocn.2007.10.006
Is there sentinel demyelination before development of primary CNS lymphoma? Dear Professor Kaye, We have read with great interest the paper by Ng and colleagues, recently published in the Journal of Clinical Neuroscience.1 The authors have reported a young female patient who initially experienced an episode of neurological
symptoms caused by a histologically proven demyelinating lesion, and who, after four years of remission, developed primary central nervous system lymphoma (PCNSL). The authors concluded that demyelinating lesions of the central nervous system (CNS) may precede development of PCNLS by more than four years.
1070
Correspondence / Journal of Clinical Neuroscience 15 (2008) 1069–1070
We agree with the authors’ statement that PCNSL should be considered in patients presenting with spaceoccupying lesions even if the histology shows classical perivascular cuffing of small lymphocytes and extensive myelin destruction. However, we think that the connection in this particular patient is not fully explored. First, demyelinating lesions of the CNS can be caused by many diseases, other than multiple sclerosis.2,3 The initial evaluation of these patients should include CSF examination for cell counts, atypical lymphoma cells, oligoclonal bands, serology for Borrelia, immunological tests such as antinuclear antibodies (ANA), cardiolipin antibodies or SS-A and SS-B antibodies, and visual evoked potentials to look for demyelination of the optic nerve. Data on preceding viral illness or tick bite can also be very useful. This is of special importance because these diseases, such as acute disseminated encephalomyelitis or neuroborreliosis, can give similar findings on biopsy pathology. We think that adding these data to the first clinical presentation of the patient can help greatly in evaluation of the first lesion. Location of the lesion is also important: although possible, basal ganglia demyelination is rare, but this is a typical location for PCNSL.4 The initial MRI may also be atypical both for tumefactive MS plaques and for Balo’s concentric sclerosis.5 The nodular type of post-gadolinium enhancement is more suggestive of tumor etiology. Second, corticosteroid treatment was given before the initial biopsy was performed. Corticosteroid treatment can mask the clinical, CT or MRI appearance of PCNSL, and this is also true for the histopathological findings. Another important question is whether the specimen was taken by stereotactic biopsy from tissue surrounding the PCNSL, or from the PCNSL itself. These factors can make histopathological examination very difficult to interpret. Third, although authors acknowledge the possibility that the initial lesion was steroid-treated PCNSL, this is not fully explored. There are well-documented reports of spontaneous remission of PCNSL: in some, remission was for more than three years, was not influenced by corticosteroid therapy, and the recurrent tumor had a different location to the previous one.6,7 A possible explanation is that some kind of immune trigger leads to an increased ratio of natural killer cells to lymphoma cells, resulting in remission.6 Also interesting is that many remissions, especially in Burkitt’s lymphoma, are triggered by incision biopsy.8 This is a possibility in the reported patient, as the initial lesion was diagnosed with stereotactic biopsy. Finally, infection with the Epstein–Barr virus (EBV) is implicated in the pathogenesis of PCNSL,4 systemic lymphoma9 and multiple sclerosis10 (MS, representing the most frequent demyelinating disease of the CNS). Our group has recently described a patient with Hodgkin’s lymphoma, doi:10.1016/j.jocn.2007.12.004
who subsequently developed MS.11 This association is particularly interesting because EBV is implicated in the pathogenesis of lymphomas and it is considered a trigger for the development of MS. It would be interesting to explore this association on the patient presented by the authors, especially EBV seropositivity in the initial stages of the disease. To conclude, although sentinel demyelination has occasionally been reported in patients with PCNSL, there is no convincing evidence to suggest that this is a true association or a previously unrecognised case of PCNSL. References 1. Ng S, Butzkueven H, Kalnins R, et al. Prolonged interval between sentinel pseudotumoral demyelination and development of primary CNS lymphoma. J Clin Neurosci 2007. doi:10.1016/ j.jocn.2006.05.003, Sep 21. 2. Brinar VV, Poser CM. The spectrum of disseminated encephalomyelitis. Clin Neurol Neurosurg 2006;108:295–310. 3. Brinar VV, Habek M, Brinar M, et al. The differential diagnosis of acute transverse myelitis. Clin Neurol Neurosurg 2006;108:278–83. 4. Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract Neurol 2007;3:24–35. 5. Guilfoyle MR, Kirollos RW. Tumefactive demyelinating lesion. Neurology 2007;68:2155. 6. Al-Yamany M, Lozano A, Nag S, et al. Spontaneous remission of primary central nervous system lymphoma: report of 3 cases and discussion of pathophysiology. J Neurooncol 1999;42:151–9. 7. Kon T, Kakita A, Koide A, et al. A primary CNS lymphoma in spontaneous remission for 3.5 years after initial detection of the lesions by MRI. Brain Tumor Pathol 2003;20:27–31. 8. Ziegler JL. Spontaneous remission in Burkitt’s lymphoma. Natl Cancer Inst Monogr 1976;44:61–5. 9. Tzankov A, Dirnhofer S. Pathobiology of classical Hodgkin lymphoma. Pathobiology 2006;73:107–25. 10. Haahr S, Hollsberg P. Multiple sclerosis is linked to Epstein-Barr virus infection. Rev Med Virol 2006;16:297–310. 11. Habek M, Brinar VV, Hajnsek S. The association of multiple sclerosis and Hodgkin’s disease: the role of Epstein–Barr virus infection. Mult Scler 2008, doi:10.1177/1352458507082600.
Mario Habek Vesna V. Brinar University Department of Neurology, Zagreb School of Medicine and University Hospital Center, Kisˇpatic´eva 12, HR-10000 Zagreb, Croatia Tel.: +38 5988 83323; fax: +38 5124 21891 E-mail address: [email protected] (M. Habek) ˇ arkovic´ Kamelija Z University Department of Neuropathology, Zagreb School of Medicine and University Hospital Center, Zagreb, Croatia David Ozretic´ University Department of Neuroradiology, Zagreb School of Medicine and University Hospital Center, Zagreb, Croatia
his neurological condition worsened despite this therapy, with the MMT decreasing to 2/5. The patient was transferred to our hospital. On transfer, staining for acid-fast bacilli (AFB), PCR, and culture for tuberculosis from multiple specimens including CSF were negative. The patient did not consent to spinal cord biopsy for a definitive diagnosis. The ADA in the CSF was highly elevated (31.5 pg/mL), which supported a clinical diagnosis of tuberculous myelitis. Treatment with antituberculous medications produced a marked response. The CSF ADA normalized 10 days after treatment started. At 3 months following initiation, motor power had improved diffusely by MMT to 4/5. The abnormal intensity on the MRI had resolved almost completely. Although PCR has proven more sensitive and rapid than staining for AFB or culture for the diagnosis of tuberculosis, it can still produce false-negative results.3 Tuberculosis must then be suspected on the basis of other features such as a compatible history, clinical abnormalities, and typical radiographic findings. Our patient, who showed no evidence of systemic tuberculosis, had a recent infection with Herpes Zoster, which can cause transverse myelitis. The AFB stain, PCR, and culture for tuberculosis were negative. Moreover, MRI findings typical for CNS tuberculosis such as meningeal or ring enhancement were absent.4 Therefore, initial diagnosis was difficult. In our patient, measurement of CSF ADA was useful for diagnosis. Some authors suggest CSF cutoff values of 9 U/L, 15 U/L, or 20 U/L for differentiating tuberculous from non-tuberculous meningitis.5–7 These reports demonstrate a sensitivity of ADA for tuberculous meningitis of >90% and a specificity of about 80%. In contrast, CSF PCR in tuberculous meningitis has a high specificity (90%–100%) but a relatively low sensitivity (32%–85%).3,8 Some reports have found that PCR is less sensitive for tuberculous meningitis than ADA in direct comparisons.9,10 The present case illustrates the dangers of overreliance on PCR for a differential diagnosis when tuberculous myelitis is suspected clinically. In conclusion, markedly elevated ADA in CSF can be considered a useful alternative diagnostic finding in tuber-
1069
culous myelitis even when CSF AFB stain, cultures, and PCR are negative and MRI findings typical for tuberculosis are absent. References 1. Citow JS, Ammirati M. Intramedullary tuberculoma of the spinal cord: case report. Neurosurgery 1994;35:327–30. 2. Jaiswal AK, Jaiswal S, Gupta SK, et al. Intramedullary tuberculoma of the conus. J Clin Neurosci 2006;13:870–2. 3. DeBiasi RL, Tyler KL. Polymerase chain reaction in the diagnosis and management of central nervous system infections. Arch Neurol 1999;56:1215–9. 4. Tayfun C, Ucoz T, Tasar M, et al. Diagnostic value of MRI in tuberculous meningitis. Eur Radiol 1996;6:380–6. 5. Segura RM, Pascual C, Ocana I, et al. Adenosine deaminase in body fluids: a useful diagnostic tool in tuberculosis. Clin Biochem 1989;22:141–8. 6. Pettersson T, Klockars M, Weber TH, et al. Diagnostic value of cerebrospinal fluid adenosine deaminase determination. Scand J Infect Dis 1991;23:97–100. 7. Choi SH, Kim YS, Bae IG, et al. The possible role of cerebrospinal fluid adenosine deaminase activity in the diagnosis of tuberculous meningitis in adults. Clin Neurol Neurosurg 2002;104:10–5. 8. Nguyen LN, Kox LF, Pham LD, et al. The potential contribution of the polymerase chain reaction to the diagnosis of tuberculous meningitis. Arch Neurol 1996;53:771–6. 9. Kim BJ, Park MH, Koh SB, et al. Polyradiculomyelitis associated with clinically diagnosed tuberculous meningitis. Eur Neurol 2001;46:156–7. 10. Ohtake H, Shibasaki Y, Idezuka J, et al. Validity of adenosine deaminase activity in cerebrospinal fluid for early diagnosis of tuberculous meningitis. Shinkeinaika 2001;54:359–62.
Satoshi Suda Masayuki Ueda Yuichi Komaba Mineo Yamazaki Toshiya Katsumata Yasuo Katayama Divisions of Neurology, Nephrology, and Rheumatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku 113-8602, Tokyo, Japan Tel.: +81 3 3822 2131; fax: +81 3 3822 4865 E-mail address: [email protected] (S. Suda)
doi:10.1016/j.jocn.2007.10.006
Is there sentinel demyelination before development of primary CNS lymphoma? Dear Professor Kaye, We have read with great interest the paper by Ng and colleagues, recently published in the Journal of Clinical Neuroscience.1 The authors have reported a young female patient who initially experienced an episode of neurological
symptoms caused by a histologically proven demyelinating lesion, and who, after four years of remission, developed primary central nervous system lymphoma (PCNSL). The authors concluded that demyelinating lesions of the central nervous system (CNS) may precede development of PCNLS by more than four years.
1070
Correspondence / Journal of Clinical Neuroscience 15 (2008) 1069–1070
We agree with the authors’ statement that PCNSL should be considered in patients presenting with spaceoccupying lesions even if the histology shows classical perivascular cuffing of small lymphocytes and extensive myelin destruction. However, we think that the connection in this particular patient is not fully explored. First, demyelinating lesions of the CNS can be caused by many diseases, other than multiple sclerosis.2,3 The initial evaluation of these patients should include CSF examination for cell counts, atypical lymphoma cells, oligoclonal bands, serology for Borrelia, immunological tests such as antinuclear antibodies (ANA), cardiolipin antibodies or SS-A and SS-B antibodies, and visual evoked potentials to look for demyelination of the optic nerve. Data on preceding viral illness or tick bite can also be very useful. This is of special importance because these diseases, such as acute disseminated encephalomyelitis or neuroborreliosis, can give similar findings on biopsy pathology. We think that adding these data to the first clinical presentation of the patient can help greatly in evaluation of the first lesion. Location of the lesion is also important: although possible, basal ganglia demyelination is rare, but this is a typical location for PCNSL.4 The initial MRI may also be atypical both for tumefactive MS plaques and for Balo’s concentric sclerosis.5 The nodular type of post-gadolinium enhancement is more suggestive of tumor etiology. Second, corticosteroid treatment was given before the initial biopsy was performed. Corticosteroid treatment can mask the clinical, CT or MRI appearance of PCNSL, and this is also true for the histopathological findings. Another important question is whether the specimen was taken by stereotactic biopsy from tissue surrounding the PCNSL, or from the PCNSL itself. These factors can make histopathological examination very difficult to interpret. Third, although authors acknowledge the possibility that the initial lesion was steroid-treated PCNSL, this is not fully explored. There are well-documented reports of spontaneous remission of PCNSL: in some, remission was for more than three years, was not influenced by corticosteroid therapy, and the recurrent tumor had a different location to the previous one.6,7 A possible explanation is that some kind of immune trigger leads to an increased ratio of natural killer cells to lymphoma cells, resulting in remission.6 Also interesting is that many remissions, especially in Burkitt’s lymphoma, are triggered by incision biopsy.8 This is a possibility in the reported patient, as the initial lesion was diagnosed with stereotactic biopsy. Finally, infection with the Epstein–Barr virus (EBV) is implicated in the pathogenesis of PCNSL,4 systemic lymphoma9 and multiple sclerosis10 (MS, representing the most frequent demyelinating disease of the CNS). Our group has recently described a patient with Hodgkin’s lymphoma, doi:10.1016/j.jocn.2007.12.004
who subsequently developed MS.11 This association is particularly interesting because EBV is implicated in the pathogenesis of lymphomas and it is considered a trigger for the development of MS. It would be interesting to explore this association on the patient presented by the authors, especially EBV seropositivity in the initial stages of the disease. To conclude, although sentinel demyelination has occasionally been reported in patients with PCNSL, there is no convincing evidence to suggest that this is a true association or a previously unrecognised case of PCNSL. References 1. Ng S, Butzkueven H, Kalnins R, et al. Prolonged interval between sentinel pseudotumoral demyelination and development of primary CNS lymphoma. J Clin Neurosci 2007. doi:10.1016/ j.jocn.2006.05.003, Sep 21. 2. Brinar VV, Poser CM. The spectrum of disseminated encephalomyelitis. Clin Neurol Neurosurg 2006;108:295–310. 3. Brinar VV, Habek M, Brinar M, et al. The differential diagnosis of acute transverse myelitis. Clin Neurol Neurosurg 2006;108:278–83. 4. Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract Neurol 2007;3:24–35. 5. Guilfoyle MR, Kirollos RW. Tumefactive demyelinating lesion. Neurology 2007;68:2155. 6. Al-Yamany M, Lozano A, Nag S, et al. Spontaneous remission of primary central nervous system lymphoma: report of 3 cases and discussion of pathophysiology. J Neurooncol 1999;42:151–9. 7. Kon T, Kakita A, Koide A, et al. A primary CNS lymphoma in spontaneous remission for 3.5 years after initial detection of the lesions by MRI. Brain Tumor Pathol 2003;20:27–31. 8. Ziegler JL. Spontaneous remission in Burkitt’s lymphoma. Natl Cancer Inst Monogr 1976;44:61–5. 9. Tzankov A, Dirnhofer S. Pathobiology of classical Hodgkin lymphoma. Pathobiology 2006;73:107–25. 10. Haahr S, Hollsberg P. Multiple sclerosis is linked to Epstein-Barr virus infection. Rev Med Virol 2006;16:297–310. 11. Habek M, Brinar VV, Hajnsek S. The association of multiple sclerosis and Hodgkin’s disease: the role of Epstein–Barr virus infection. Mult Scler 2008, doi:10.1177/1352458507082600.
Mario Habek Vesna V. Brinar University Department of Neurology, Zagreb School of Medicine and University Hospital Center, Kisˇpatic´eva 12, HR-10000 Zagreb, Croatia Tel.: +38 5988 83323; fax: +38 5124 21891 E-mail address: [email protected] (M. Habek) ˇ arkovic´ Kamelija Z University Department of Neuropathology, Zagreb School of Medicine and University Hospital Center, Zagreb, Croatia David Ozretic´ University Department of Neuroradiology, Zagreb School of Medicine and University Hospital Center, Zagreb, Croatia