Case Reports / Journal of Clinical Neuroscience 21 (2014) 701–704
burnetii against phase II were still high (1:128). Antibiotics were continued for another 6 months and the serum IgG titer decreased to 1:32. Most of the neurological symptoms resolved except for intermittent diplopia. 3. Discussion Brainstem encephalitis can be caused by a group of inflammatory diseases that result in cranial nerve paresis, ataxia, and long tract signs with CSF pleocytosis, sometimes with abnormal imaging findings. The etiologic categories include infectious, autoimmune, and paraneoplastic causes [4,5]. We diagnosed our patient based on clinical manifestations and laboratory findings. The patient had brainstem manifestations. The CSF showed pleocytosis, and MRI revealed an increased signal intensity lesion in the brainstem on T2-weighted and FLAIR images. Multiple tests for detecting diverse pathogens were negative except for C. burnetii. After initiating antibiotic treatment against C. burnetii, the patient’s neurologic symptoms slowly improved. Neurological complications in the course of Q fever are rare. In a report of 1269 patients with acute Q fever, neurologic involvement was documented in only 29 patients (2.2%) [2]. In another series of 121 patients with Q fever, 40.5% suffered from headaches, 4.1% complained of confusion, and meningitis was confirmed in 0.8% [3]. Meningitis and meningoencephalitis are the most common clinical syndromes in regards to the neurologic effects of Q fever, but brain imaging findings are usually normal or nonspecific, such as diffuse cerebral edema or bilateral periventricular edema [1,6,7]. One patient with acute cerebellitis caused by C. burnetii was previously reported to have a high signal intensity on T2-weighted images in the right cerebellar hemisphere [8]. This report describes brainstem encephalitis presumably caused by Coxiella burnettii in an otherwise healthy man. The
701
patient had a positive response to treatment with antibiotics against C. burnetii, which was administered based on the serologic tests. To the best of our knowledge, this is the first reported patient with brainstem encephalitis associated with Q fever. Brain MRI showed a characteristic asymmetrical high signal intensity brainstem lesion involving the pons, medulla, and upper cervical cord. Therefore, Q fever should be considered a possible etiology of brainstem encephalitis. Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgment This study was supported by Ministry of Health and Welfare, Republic of Korea (A111393–1202–0000100). References [1] Parker N, Barralet J, Bell A. Q fever. Lancet 2006;367:679–88. [2] Bernit E, Pouget J, Janbon F, et al. Neurological involvement in acute Q fever: a report of 29 cases and review of the literature. Arch Intern Med 2002;162:693–700. [3] Kofteridis DP, Mazokopakis EE, Tselentis Y, et al. Neurological complications of acute Q fever infection. Eur J Epidemiol 2004;19:1051–4. [4] Jubelt B, Mihai C, Li TM, et al. Rhombencephalitis/brainstem encephalitis. Curr Neurol Neurosci Rep 2011;11:543–52. [5] Moragas M, Martinez-Yelamos S, Majos C, et al. Rhombencephalitis: a series of 97 patients. Medicine 2011;90:256–61. [6] Schuil J, Richardus JH, Baarsma GS, et al. Q fever as a possible cause of bilateral optic neuritis. Br J Ophthalmol 1985;69:580–3. [7] Gomez-Aranda F, Pachon Diaz J, Romero Acebal M, et al. Computed tomographic brain scan findings in Q fever encephalitis. Neuroradiology 1984;26:329–32. [8] Sawaishi Y, Takahashi I, Hirayama Y, et al. Acute cerebellitis caused by Coxiella burnetii. Ann Neurol 1999;45:124–7.
http://dx.doi.org/10.1016/j.jocn.2013.07.031
Temozolomide-related acute lymphoblastic leukemia with translocation (4;11)(q21;q23) in a glioblastoma patient Kuan-Nien Chou a, Yu-chieh Lin b, Ming-Ying Liu a, Ping-Ying Chang c,⇑ a
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC c Department of Internal Medicine, Division of Hematology & Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC b
a r t i c l e
i n f o
Article history: Received 26 April 2013 Accepted 12 July 2013
Keywords: Glioblastoma multiforme Secondary acute lymphoblastic leukemia Temozolomide Therapy-related acute lymphoblastic leukemia
a b s t r a c t Temozolomide (TMZ), an alkylating agent, is widely used for treating high-grade gliomas. TMZ has been reported to cause secondary myelodysplastic syndrome and acute myeloid leukemia. However, TMZrelated acute lymphoblastic leukemia is rare. Here we describe a 54-year-old woman with glioblastoma multiforme, who developed precursor-B acute lymphoblastic leukemia with translocation (4;11)(q21;q23) after 15 months of TMZ treatment. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction ⇑ Corresponding author. Tel.: +886 8792 7177; fax: +886 8792 7178. E-mail address: [email protected] (P.-Y. Chang).
Temozolomide (TMZ) has been increasingly reported to cause secondary myelodysplastic syndrome (MDS) and acute myeloid
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Case Reports / Journal of Clinical Neuroscience 21 (2014) 701–704
Fig. 1. (A) Peripheral blood smear showing blasts with scant cytoplasm (Wright–Giemsa; original magnification 200) (circles). (B) Bone marrow biopsy showing hypercellularity of 60% (hematoxylin and eosin stain; original magnification 200). (C) Bone marrow biopsy showing no terminal deoxynucleotidyl transferase reactivity of the blasts (original magnification 400). (D) Bone marrow biopsy showing no immunoreactivity for CD20 (original magnification 400). (E) Bone marrow biopsy showing CD79a expression (original magnification 400).
Fig. 2. Cytogenetic study of the bone marrow with G-banding, indicating translocation involving chromosomes 4q21 and 11q23, t (4;11) (q21;q23) (arrow).
leukemia (AML) [1]. However, TMZ-related acute lymphoblastic leukemia (ALL) has rarely been reported [2–5]. We describe a 54year-old woman with glioblastoma multiforme (GBM) who developed precursor-B–ALL with translocation (4;11)(q21;q23) after 15 months of TMZ treatment.
2. Case report A 54-year-old Taiwanese woman was diagnosed with a GBM tumor in the left frontoparietal lobe by stereotactic biopsy in August 2011. However, she refused to undergo surgery after the diagnosis.
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Case Reports / Journal of Clinical Neuroscience 21 (2014) 701–704 Table 1 Characteristics of temozolomide-related secondary acute lymphoblastic leukemia reported in the literature Patient
Sex/ Age
Diagnosis
Chemoradiation strategy
Latency
Immunophenotype
Cytogenetics
Leukemiarelated death
1 [2]
M/40
Glioblastoma multiforme
4 months
Pre-B ALL
F/12
Anaplastic astrocytoma
13 months
Pre-B ALL
45, XY, 7, der(9) (p12) t(9;22) Normal
No data
2 [3] 3 [4]
M/26
17 months
Pre-B ALL
Normal
No data
4 [5]
F/49
Astrocytoma and oligodendroglioma WHO grade II WHO grade II astrocytoma
60 cGy with 70 mg/m2/daily, 200 mg/m2/daily 1 cycle 60 cGy with 75 mg/m2/daily, 150 mg/m2/daily 8 cycles 60 cGy with 75 mg/m2/daily, 150 mg/m2/daily 6 cycles
57 months
Pre-T ALL
Normal
No data
Present patient
F/54
Glioblastoma multiforme
15 months
Pre-B ALL
t (4;11)(q21;q23)
1 month
80 cGy with 75 mg/m2/daily, 150 mg/m2/daily 6 cycles 60 cGy with 75 mg/m2/daily, 150 mg/m2/daily 11 cycles
8 months
ALL = acute lymphoblastic leukemia, der = derivative chromosome, F = female, M = male, t = translocation, WHO = World Health Organization.
She received TMZ-based concurrent chemoradiation (total dose of 6000 cGy in 30 fractions and TMZ 75 mg/m2/day for 42 days) and TMZ maintenance therapy (150 mg/m2/day for 5 days in a 28 day cycle) for eight cycles. Disease progression was observed in July 2012, and she underwent an operation to remove the brain tumor. The patient received three cycles of TMZ maintenance therapy after the surgery. She developed leukopenia with anemia, which began in August 2012 and persisted. She remained stable until November 2012, following which she presented with rapid progression of generalized weakness and drowsiness. Brain MRI showed tumor recurrence. Moreover, complete blood count showed marked leukocytosis (white blood cell count, 104 103/ lL, [normal range, 4.5–11 103/lL] including 1% neutrophils, 2% lymphocytes, and 97% blasts), anemia (hemoglobin 8.0 g/dL [normal range, 13.5–18.0 g/dL), and thrombocytopenia (platelet count 54 103/lL [normal range, 150–400 103/lL]). A diffuse growth pattern of blasts with scant cytoplasm and nuclear hyperchromatism was detected after bone marrow biopsy. Peripheral blood flow cytometry revealed CD19 and HLA-DR expression; immunohistochemistry of the bone marrow biopsy specimen revealed CD79a expression. CD34, CD3, CD5, CD10, CD20, kappa/lambda, and terminal deoxynucleotidyl transferase were negative in both examinations (Fig. 1). Consequently, precursor-B–ALL was diagnosed. Bone marrow cytogenetics revealed translocation (4;11)(q21;q23) but was negative for Philadelphia chromosome (Fig. 2). Dexamethasone was administered to alleviate the peritumoral edema and B-ALL related leukocytosis. We provided supportive care only to the patient due to her poor performance status. She died of profound sepsis in one month later. The total cumulative dose of TMZ in this patient was 11,400 mg/m2.
conventional external beam radiotherapy does not increase the risk of acute leukemia compared with chemotherapy alone in patients with malignant glioma [10]. In the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) archive of adult acute leukemia, 5.1% (200 out of 3934) of patients had secondary AML and ALL, and 77 of the evaluated 148 patients had undergone previous chemotherapy and/or radiotherapy. Only two patients had primary central nervous system malignancy [11,12]. Therefore, cranial radiotherapy seems to have limited influence, and we believe that TMZ plays a major role in the pathogenesis of secondary acute leukemia. Villano et al. reported that 17 of 3490 patients treated with TMZ developed leukemia [13]. TMZ-related ALL has been increasingly reported in the literature (Table 1) [2–5]. Interestingly, the latency between previous cancer treatment and leukemia development is long after treatment with most alkylating agents (3–8 years) [7]. However, TMZ-related ALL seems to have a shorter latency (4– 57 months). 4. Conclusion TMZ is a mainstay treatment for high-grade gliomas and other malignancies; however, physicians should monitor the therapeutic efficacy and myelotoxicity of TMZ closely and be aware of treatment-related leukemogenesis. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
3. Discussion References Alkylating therapeutic agents are clearly related to secondary AML/MDS and are associated with deletions or loss of the long arms of chromosomes 5 and 7 [6]. Alkylating agent-induced leukemia is generally preceded by MDS [7]. Translocation (4;11)(q21;q23) leads to MLL-AF4 fusion gene formation and accounts for approximately 10% of newly diagnosed B-cell ALL in adult patients [8]. Chromosomal 11q23 rearrangements are the most common karyotypic alterations in therapy-related ALL, and most of these abnormalities are caused by previous topoisomerase II inhibitor exposure [9]. Translocation (4;11)(q21;q23) has been reported in secondary ALL, but most are case reports. However, it has not been reported in TMZ-related acute leukemia. To our knowledge, this is the first report to describe TMZ-related ALL with translocation (4;11)(q21;q23). Cranial radiotherapy is the standard treatment after surgery for high-grade glioma. The clinical review by Perry et al. proposed that
[1] Baehring JM, Marks PW. Treatment-related myelodysplasia in patients with primary brain tumors. Neuro Oncol 2012;14:529–40. [2] De Vita S, De Matteis S, Laurenti L, et al. Secondary Ph+ acute lymphoblastic leukemia after temozolomide. Ann Hematol 2005;84:760–2. [3] Momota H, Narita Y, Miyakita Y, et al. Acute lymphoblastic leukemia after temozolomide treatment for anaplastic astrocytoma in a child with a germline TP53 mutation. Pediatr Blood Cancer 2010;55:577–9. [4] Shaikh AJ, Masood N. Acute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report. J Med Case Rep 2010;4:274. [5] Ogura M, Todo T, Tanaka M, et al. Temozolomide may induce therapy-related acute lymphoblastic leukaemia. Br J Haematol 2011;154:663–5. [6] Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 2002;99:1909–12. [7] Leone G, Mele L, Pulsoni A, et al. The incidence of secondary leukemias. Haematologica 1999;84:937–45. [8] Marchesi F, Girardi K, Avvisati G. Pathogenetic, clinical, and prognostic features of adult t(4;11)(q21;q23)/MLL-AF4 positive B-cell acute lymphoblastic leukemia. Adv Hematol 2011;2011:621627.
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Case Reports / Journal of Clinical Neuroscience 21 (2014) 704–706
[9] Chen W, Wang E, Lu Y, et al. Therapy-related acute lymphoblastic leukemia without 11q23 abnormality: report of six cases and a literature review. Am J Clin Pathol 2010;133:75–82. [10] Perry JR, Brown MT, Gockerman JP. Acute leukemia following treatment of malignant glioma. J Neurooncol 1998;40:39–46. [11] Pagano L, Pulsoni A, Tosti ME, et al. Acute lymphoblastic leukaemia occurring as second malignancy: report of the GIMEMA archive of adult acute leukaemia.
Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. Br J Haematol 1999;106:1037–40. [12] Pagana L, Pulsoni A, Tosti ME, et al. Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia. Br J Haematol 2001;112:109–17. [13] Villano JL, Letarte N, Yu JM, et al. Hematologic adverse events associated with temozolomide. Cancer Chemother Pharmacol 2012;69:107–13.
http://dx.doi.org/10.1016/j.jocn.2013.07.032
Acute inflammatory demyelinating polyradiculoneuropathy following malaria Aaron L. Berkowitz a,⇑, Kiran T. Thakur b a b
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
a r t i c l e
i n f o
Article history: Received 13 July 2013 Accepted 15 July 2013
Keywords: Acute inflammatory demyelinating polyneuropathy Guillain–Barré syndrome Malaria Tropical neurology
a b s t r a c t Among the neurologic complications of malaria, acute inflammatory demyelinating polyradiculoneuropathy is a rarely reported phenomenon. We describe a patient with acute inflammatory demyelinating polyradiculoneuropathy following malaria in a 26-year-old traveler to an endemic area and review the clinical features of all 23 previously reported patients. Malarial infection should be considered as a potential preceding trigger in patients residing in or travelers returning from malaria-endemic areas presenting with the clinical features of acute inflammatory demyelinating polyradiculoneuropathy in the setting of a recent or ongoing febrile illness. Ó 2013 Elsevier Ltd. All rights reserved.
1. Case report A 26-year-old previously healthy American volunteer living in Malawi developed fevers, malaise, nausea, vomiting, and diarrhea 9 months into her stay. Her rapid malaria diagnostic test for Plasmodium falciparum was positive, and she was treated with 4 days of artemether and lumefantrine. She made a complete recovery such that she was cycling and hiking 1 week after completion of anti-malarial treatment. Two weeks following her initial malaria symptoms, she developed painful paresthesias in the soles of her feet. Over several days, these symptoms ascended to her proximal legs as well as her hands bilaterally. She had difficulty walking over the following 5 days and presented for evaluation. She reported no headaches, visual difficulties, respiratory symptoms, neck or back pain, nor bowel or bladder symptoms. She had never experienced symptoms of this nature previously, had no preceding illnesses aside from her recent malaria infection, and had no recurrence of malaria symptoms since her treatment 2 weeks prior to the onset of neurologic symptoms. Her neurologic examination was normal with the exception of subtle hip flexion weakness bilaterally, absent bilateral patellar and ankle reflexes (with preserved reflexes in the upper extremities), and a waddling gait suggestive of proximal lower extremity weakness. Her clinical history and examination were felt to be consistent with acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Cerebrospinal fluid (CSF) evaluation showed cytoalbuminologic dissociation with a protein of 60 mg/dl and no white blood cells. As her symptoms were mild 1 week into her illness, no immunomodulatory treatment was initiated, and she
⇑ Corresponding author. Tel.: +1 617 732 7432; fax: +1 617 278 6083. E-mail address: [email protected] (A.L. Berkowitz).
made a complete recovery with respect to her gait within 3 weeks of the onset of her symptoms, though she had residual painful paresthesias for several months.
2. Discussion Cerebral malaria characterized by encephalopathy and/or seizures is the most common and severe neurologic manifestation of malaria [1]. AIDP following malaria is a rarely reported phenomenon, with 23 documented patients in the literature to our knowledge (Table 1) [2–12]. Considering all reported cases including our patient, three (13%) were caused by Plasmodium vivax infection and 20 (87%) by Plasmodium falciparum. The mean age of all patients was 34 years (range 1–63, standard deviation [SD] 14.3; with no significant difference between patients infected by P. falciparum or P. vivax [p = 0.13]). The average time from initial malaria symptoms to the onset of AIDP was 12 days (range 5–30, SD 6.16; with no significant difference between P. falciparum and P. vivax infected patients [p = 0.99]). All patients had weakness, 11 out of the 14 (79%) for whom sensory examination was reported had sensory symptoms and/or signs, and 11 (48%) had cranial nerve palsies (including one out of the three patients infected with P. vivax). Nine patients (39%) had respiratory failure, all of whom were infected with P. falciparum, and seven of these patients died; the two who survived both received immunomodulatory therapy (intravenous immunoglobulin in one, plasma exchange in the other). All 14 patients without respiratory failure survived, only two of whom received therapy directed at AIDP (steroids in both patients). In patients who survived, the average time until full recovery was 8 weeks (range 9 days to 6 months, SD 6.5; with no significant difference between P. falciparum and P. vivax infected patients [p = 0.40]). Cytoalbuminologic dissociation was present
burnetii against phase II were still high (1:128). Antibiotics were continued for another 6 months and the serum IgG titer decreased to 1:32. Most of the neurological symptoms resolved except for intermittent diplopia. 3. Discussion Brainstem encephalitis can be caused by a group of inflammatory diseases that result in cranial nerve paresis, ataxia, and long tract signs with CSF pleocytosis, sometimes with abnormal imaging findings. The etiologic categories include infectious, autoimmune, and paraneoplastic causes [4,5]. We diagnosed our patient based on clinical manifestations and laboratory findings. The patient had brainstem manifestations. The CSF showed pleocytosis, and MRI revealed an increased signal intensity lesion in the brainstem on T2-weighted and FLAIR images. Multiple tests for detecting diverse pathogens were negative except for C. burnetii. After initiating antibiotic treatment against C. burnetii, the patient’s neurologic symptoms slowly improved. Neurological complications in the course of Q fever are rare. In a report of 1269 patients with acute Q fever, neurologic involvement was documented in only 29 patients (2.2%) [2]. In another series of 121 patients with Q fever, 40.5% suffered from headaches, 4.1% complained of confusion, and meningitis was confirmed in 0.8% [3]. Meningitis and meningoencephalitis are the most common clinical syndromes in regards to the neurologic effects of Q fever, but brain imaging findings are usually normal or nonspecific, such as diffuse cerebral edema or bilateral periventricular edema [1,6,7]. One patient with acute cerebellitis caused by C. burnetii was previously reported to have a high signal intensity on T2-weighted images in the right cerebellar hemisphere [8]. This report describes brainstem encephalitis presumably caused by Coxiella burnettii in an otherwise healthy man. The
701
patient had a positive response to treatment with antibiotics against C. burnetii, which was administered based on the serologic tests. To the best of our knowledge, this is the first reported patient with brainstem encephalitis associated with Q fever. Brain MRI showed a characteristic asymmetrical high signal intensity brainstem lesion involving the pons, medulla, and upper cervical cord. Therefore, Q fever should be considered a possible etiology of brainstem encephalitis. Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgment This study was supported by Ministry of Health and Welfare, Republic of Korea (A111393–1202–0000100). References [1] Parker N, Barralet J, Bell A. Q fever. Lancet 2006;367:679–88. [2] Bernit E, Pouget J, Janbon F, et al. Neurological involvement in acute Q fever: a report of 29 cases and review of the literature. Arch Intern Med 2002;162:693–700. [3] Kofteridis DP, Mazokopakis EE, Tselentis Y, et al. Neurological complications of acute Q fever infection. Eur J Epidemiol 2004;19:1051–4. [4] Jubelt B, Mihai C, Li TM, et al. Rhombencephalitis/brainstem encephalitis. Curr Neurol Neurosci Rep 2011;11:543–52. [5] Moragas M, Martinez-Yelamos S, Majos C, et al. Rhombencephalitis: a series of 97 patients. Medicine 2011;90:256–61. [6] Schuil J, Richardus JH, Baarsma GS, et al. Q fever as a possible cause of bilateral optic neuritis. Br J Ophthalmol 1985;69:580–3. [7] Gomez-Aranda F, Pachon Diaz J, Romero Acebal M, et al. Computed tomographic brain scan findings in Q fever encephalitis. Neuroradiology 1984;26:329–32. [8] Sawaishi Y, Takahashi I, Hirayama Y, et al. Acute cerebellitis caused by Coxiella burnetii. Ann Neurol 1999;45:124–7.
http://dx.doi.org/10.1016/j.jocn.2013.07.031
Temozolomide-related acute lymphoblastic leukemia with translocation (4;11)(q21;q23) in a glioblastoma patient Kuan-Nien Chou a, Yu-chieh Lin b, Ming-Ying Liu a, Ping-Ying Chang c,⇑ a
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC c Department of Internal Medicine, Division of Hematology & Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC b
a r t i c l e
i n f o
Article history: Received 26 April 2013 Accepted 12 July 2013
Keywords: Glioblastoma multiforme Secondary acute lymphoblastic leukemia Temozolomide Therapy-related acute lymphoblastic leukemia
a b s t r a c t Temozolomide (TMZ), an alkylating agent, is widely used for treating high-grade gliomas. TMZ has been reported to cause secondary myelodysplastic syndrome and acute myeloid leukemia. However, TMZrelated acute lymphoblastic leukemia is rare. Here we describe a 54-year-old woman with glioblastoma multiforme, who developed precursor-B acute lymphoblastic leukemia with translocation (4;11)(q21;q23) after 15 months of TMZ treatment. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction ⇑ Corresponding author. Tel.: +886 8792 7177; fax: +886 8792 7178. E-mail address: [email protected] (P.-Y. Chang).
Temozolomide (TMZ) has been increasingly reported to cause secondary myelodysplastic syndrome (MDS) and acute myeloid
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Case Reports / Journal of Clinical Neuroscience 21 (2014) 701–704
Fig. 1. (A) Peripheral blood smear showing blasts with scant cytoplasm (Wright–Giemsa; original magnification 200) (circles). (B) Bone marrow biopsy showing hypercellularity of 60% (hematoxylin and eosin stain; original magnification 200). (C) Bone marrow biopsy showing no terminal deoxynucleotidyl transferase reactivity of the blasts (original magnification 400). (D) Bone marrow biopsy showing no immunoreactivity for CD20 (original magnification 400). (E) Bone marrow biopsy showing CD79a expression (original magnification 400).
Fig. 2. Cytogenetic study of the bone marrow with G-banding, indicating translocation involving chromosomes 4q21 and 11q23, t (4;11) (q21;q23) (arrow).
leukemia (AML) [1]. However, TMZ-related acute lymphoblastic leukemia (ALL) has rarely been reported [2–5]. We describe a 54year-old woman with glioblastoma multiforme (GBM) who developed precursor-B–ALL with translocation (4;11)(q21;q23) after 15 months of TMZ treatment.
2. Case report A 54-year-old Taiwanese woman was diagnosed with a GBM tumor in the left frontoparietal lobe by stereotactic biopsy in August 2011. However, she refused to undergo surgery after the diagnosis.
703
Case Reports / Journal of Clinical Neuroscience 21 (2014) 701–704 Table 1 Characteristics of temozolomide-related secondary acute lymphoblastic leukemia reported in the literature Patient
Sex/ Age
Diagnosis
Chemoradiation strategy
Latency
Immunophenotype
Cytogenetics
Leukemiarelated death
1 [2]
M/40
Glioblastoma multiforme
4 months
Pre-B ALL
F/12
Anaplastic astrocytoma
13 months
Pre-B ALL
45, XY, 7, der(9) (p12) t(9;22) Normal
No data
2 [3] 3 [4]
M/26
17 months
Pre-B ALL
Normal
No data
4 [5]
F/49
Astrocytoma and oligodendroglioma WHO grade II WHO grade II astrocytoma
60 cGy with 70 mg/m2/daily, 200 mg/m2/daily 1 cycle 60 cGy with 75 mg/m2/daily, 150 mg/m2/daily 8 cycles 60 cGy with 75 mg/m2/daily, 150 mg/m2/daily 6 cycles
57 months
Pre-T ALL
Normal
No data
Present patient
F/54
Glioblastoma multiforme
15 months
Pre-B ALL
t (4;11)(q21;q23)
1 month
80 cGy with 75 mg/m2/daily, 150 mg/m2/daily 6 cycles 60 cGy with 75 mg/m2/daily, 150 mg/m2/daily 11 cycles
8 months
ALL = acute lymphoblastic leukemia, der = derivative chromosome, F = female, M = male, t = translocation, WHO = World Health Organization.
She received TMZ-based concurrent chemoradiation (total dose of 6000 cGy in 30 fractions and TMZ 75 mg/m2/day for 42 days) and TMZ maintenance therapy (150 mg/m2/day for 5 days in a 28 day cycle) for eight cycles. Disease progression was observed in July 2012, and she underwent an operation to remove the brain tumor. The patient received three cycles of TMZ maintenance therapy after the surgery. She developed leukopenia with anemia, which began in August 2012 and persisted. She remained stable until November 2012, following which she presented with rapid progression of generalized weakness and drowsiness. Brain MRI showed tumor recurrence. Moreover, complete blood count showed marked leukocytosis (white blood cell count, 104 103/ lL, [normal range, 4.5–11 103/lL] including 1% neutrophils, 2% lymphocytes, and 97% blasts), anemia (hemoglobin 8.0 g/dL [normal range, 13.5–18.0 g/dL), and thrombocytopenia (platelet count 54 103/lL [normal range, 150–400 103/lL]). A diffuse growth pattern of blasts with scant cytoplasm and nuclear hyperchromatism was detected after bone marrow biopsy. Peripheral blood flow cytometry revealed CD19 and HLA-DR expression; immunohistochemistry of the bone marrow biopsy specimen revealed CD79a expression. CD34, CD3, CD5, CD10, CD20, kappa/lambda, and terminal deoxynucleotidyl transferase were negative in both examinations (Fig. 1). Consequently, precursor-B–ALL was diagnosed. Bone marrow cytogenetics revealed translocation (4;11)(q21;q23) but was negative for Philadelphia chromosome (Fig. 2). Dexamethasone was administered to alleviate the peritumoral edema and B-ALL related leukocytosis. We provided supportive care only to the patient due to her poor performance status. She died of profound sepsis in one month later. The total cumulative dose of TMZ in this patient was 11,400 mg/m2.
conventional external beam radiotherapy does not increase the risk of acute leukemia compared with chemotherapy alone in patients with malignant glioma [10]. In the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) archive of adult acute leukemia, 5.1% (200 out of 3934) of patients had secondary AML and ALL, and 77 of the evaluated 148 patients had undergone previous chemotherapy and/or radiotherapy. Only two patients had primary central nervous system malignancy [11,12]. Therefore, cranial radiotherapy seems to have limited influence, and we believe that TMZ plays a major role in the pathogenesis of secondary acute leukemia. Villano et al. reported that 17 of 3490 patients treated with TMZ developed leukemia [13]. TMZ-related ALL has been increasingly reported in the literature (Table 1) [2–5]. Interestingly, the latency between previous cancer treatment and leukemia development is long after treatment with most alkylating agents (3–8 years) [7]. However, TMZ-related ALL seems to have a shorter latency (4– 57 months). 4. Conclusion TMZ is a mainstay treatment for high-grade gliomas and other malignancies; however, physicians should monitor the therapeutic efficacy and myelotoxicity of TMZ closely and be aware of treatment-related leukemogenesis. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
3. Discussion References Alkylating therapeutic agents are clearly related to secondary AML/MDS and are associated with deletions or loss of the long arms of chromosomes 5 and 7 [6]. Alkylating agent-induced leukemia is generally preceded by MDS [7]. Translocation (4;11)(q21;q23) leads to MLL-AF4 fusion gene formation and accounts for approximately 10% of newly diagnosed B-cell ALL in adult patients [8]. Chromosomal 11q23 rearrangements are the most common karyotypic alterations in therapy-related ALL, and most of these abnormalities are caused by previous topoisomerase II inhibitor exposure [9]. Translocation (4;11)(q21;q23) has been reported in secondary ALL, but most are case reports. However, it has not been reported in TMZ-related acute leukemia. To our knowledge, this is the first report to describe TMZ-related ALL with translocation (4;11)(q21;q23). Cranial radiotherapy is the standard treatment after surgery for high-grade glioma. The clinical review by Perry et al. proposed that
[1] Baehring JM, Marks PW. Treatment-related myelodysplasia in patients with primary brain tumors. Neuro Oncol 2012;14:529–40. [2] De Vita S, De Matteis S, Laurenti L, et al. Secondary Ph+ acute lymphoblastic leukemia after temozolomide. Ann Hematol 2005;84:760–2. [3] Momota H, Narita Y, Miyakita Y, et al. Acute lymphoblastic leukemia after temozolomide treatment for anaplastic astrocytoma in a child with a germline TP53 mutation. Pediatr Blood Cancer 2010;55:577–9. [4] Shaikh AJ, Masood N. Acute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report. J Med Case Rep 2010;4:274. [5] Ogura M, Todo T, Tanaka M, et al. Temozolomide may induce therapy-related acute lymphoblastic leukaemia. Br J Haematol 2011;154:663–5. [6] Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 2002;99:1909–12. [7] Leone G, Mele L, Pulsoni A, et al. The incidence of secondary leukemias. Haematologica 1999;84:937–45. [8] Marchesi F, Girardi K, Avvisati G. Pathogenetic, clinical, and prognostic features of adult t(4;11)(q21;q23)/MLL-AF4 positive B-cell acute lymphoblastic leukemia. Adv Hematol 2011;2011:621627.
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[9] Chen W, Wang E, Lu Y, et al. Therapy-related acute lymphoblastic leukemia without 11q23 abnormality: report of six cases and a literature review. Am J Clin Pathol 2010;133:75–82. [10] Perry JR, Brown MT, Gockerman JP. Acute leukemia following treatment of malignant glioma. J Neurooncol 1998;40:39–46. [11] Pagano L, Pulsoni A, Tosti ME, et al. Acute lymphoblastic leukaemia occurring as second malignancy: report of the GIMEMA archive of adult acute leukaemia.
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http://dx.doi.org/10.1016/j.jocn.2013.07.032
Acute inflammatory demyelinating polyradiculoneuropathy following malaria Aaron L. Berkowitz a,⇑, Kiran T. Thakur b a b
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
a r t i c l e
i n f o
Article history: Received 13 July 2013 Accepted 15 July 2013
Keywords: Acute inflammatory demyelinating polyneuropathy Guillain–Barré syndrome Malaria Tropical neurology
a b s t r a c t Among the neurologic complications of malaria, acute inflammatory demyelinating polyradiculoneuropathy is a rarely reported phenomenon. We describe a patient with acute inflammatory demyelinating polyradiculoneuropathy following malaria in a 26-year-old traveler to an endemic area and review the clinical features of all 23 previously reported patients. Malarial infection should be considered as a potential preceding trigger in patients residing in or travelers returning from malaria-endemic areas presenting with the clinical features of acute inflammatory demyelinating polyradiculoneuropathy in the setting of a recent or ongoing febrile illness. Ó 2013 Elsevier Ltd. All rights reserved.
1. Case report A 26-year-old previously healthy American volunteer living in Malawi developed fevers, malaise, nausea, vomiting, and diarrhea 9 months into her stay. Her rapid malaria diagnostic test for Plasmodium falciparum was positive, and she was treated with 4 days of artemether and lumefantrine. She made a complete recovery such that she was cycling and hiking 1 week after completion of anti-malarial treatment. Two weeks following her initial malaria symptoms, she developed painful paresthesias in the soles of her feet. Over several days, these symptoms ascended to her proximal legs as well as her hands bilaterally. She had difficulty walking over the following 5 days and presented for evaluation. She reported no headaches, visual difficulties, respiratory symptoms, neck or back pain, nor bowel or bladder symptoms. She had never experienced symptoms of this nature previously, had no preceding illnesses aside from her recent malaria infection, and had no recurrence of malaria symptoms since her treatment 2 weeks prior to the onset of neurologic symptoms. Her neurologic examination was normal with the exception of subtle hip flexion weakness bilaterally, absent bilateral patellar and ankle reflexes (with preserved reflexes in the upper extremities), and a waddling gait suggestive of proximal lower extremity weakness. Her clinical history and examination were felt to be consistent with acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Cerebrospinal fluid (CSF) evaluation showed cytoalbuminologic dissociation with a protein of 60 mg/dl and no white blood cells. As her symptoms were mild 1 week into her illness, no immunomodulatory treatment was initiated, and she
⇑ Corresponding author. Tel.: +1 617 732 7432; fax: +1 617 278 6083. E-mail address: [email protected] (A.L. Berkowitz).
made a complete recovery with respect to her gait within 3 weeks of the onset of her symptoms, though she had residual painful paresthesias for several months.
2. Discussion Cerebral malaria characterized by encephalopathy and/or seizures is the most common and severe neurologic manifestation of malaria [1]. AIDP following malaria is a rarely reported phenomenon, with 23 documented patients in the literature to our knowledge (Table 1) [2–12]. Considering all reported cases including our patient, three (13%) were caused by Plasmodium vivax infection and 20 (87%) by Plasmodium falciparum. The mean age of all patients was 34 years (range 1–63, standard deviation [SD] 14.3; with no significant difference between patients infected by P. falciparum or P. vivax [p = 0.13]). The average time from initial malaria symptoms to the onset of AIDP was 12 days (range 5–30, SD 6.16; with no significant difference between P. falciparum and P. vivax infected patients [p = 0.99]). All patients had weakness, 11 out of the 14 (79%) for whom sensory examination was reported had sensory symptoms and/or signs, and 11 (48%) had cranial nerve palsies (including one out of the three patients infected with P. vivax). Nine patients (39%) had respiratory failure, all of whom were infected with P. falciparum, and seven of these patients died; the two who survived both received immunomodulatory therapy (intravenous immunoglobulin in one, plasma exchange in the other). All 14 patients without respiratory failure survived, only two of whom received therapy directed at AIDP (steroids in both patients). In patients who survived, the average time until full recovery was 8 weeks (range 9 days to 6 months, SD 6.5; with no significant difference between P. falciparum and P. vivax infected patients [p = 0.40]). Cytoalbuminologic dissociation was present
