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Intracranial Hypertension in Pediatric Patients With Acute Lymphoblastic Leukemia George Vartzelis,1* Donna Lancaster,2 and Penny Fallon1 Acute lymphoblastic leukemia (ALL) remains one of the most common malignancies of childhood. Between April 1999 and August 2004, 9 of 207 patients treated at a Tertiary Oncology Service for ALL presented with Intracranial Hypertension (IH). Seven of the patients met the diagnostic criteria for Idiopathic Intracranial Hypertension (IIH). Four of the patients were treated with cerebro-
Key words:
spinal fluid (CSF) drainage alone and four required Acetazolamide. Two of the four patients who were treated with Acetazolamide required subsequently a lumbar-peritoneal (LP) shunt. One patient succumbed to his disease before receiving any specific treatment. Pediatr Blood Cancer 2009;52:418–420. ß 2008 Wiley-Liss, Inc.
ALL; cerebri; hypertension; idiopathic; intracranial; leukemia; lymphoblastic; pseudotumor
INTRODUCTION Although advances in chemotherapeutic strategies have led to improved long-term event-free survival of patients with Acute Lymphoblastic leukemia (ALL) to over 75%, the condition continues to be associated with various co-morbidities. We observed that 4.3% of patients treated for ALL in a tertiary pediatric oncology center in the United Kingdom developed intracranial hypertension (IH). Only one case has been reported in the literature [1]. The condition has the potential to cause significant adverse events, including visual impairment.
STUDY GROUP Between April 1999 and August 2004, 207 patients were treated at our institution for ALL. From these, nine patients developed IH. The diagnosis was made at different stages of the leukemia treatment, on the basis of increased opening pressure of CSF (>20 cm H2O), measured manometrically under general anesthetic. With regards to leukemia treatment the patients were being treated according the national UKALL 97/01 protocol (Supplemental Appendix). Second line therapy was according to the UKALL R1 or R2 protocol allogenic stem cell transplant as previously described [2]. The medical records of the patients were examined retrospectively and various data regarding demographics, symptoms, and therapy were collected (Table I).
RESULTS One female and eight male patients with ALL presented with IH during the study period. The age of the patients ranged from 2 to 13 years (median 11). Of these, six patients were in complete remission 1 (CR1), two in CR2, and one in CR3. Three patients had a history of CNS disease, one at diagnosis, and two at relapse (one combined bone marrow (BM) and central nervous system (CNS) relapse and one isolated CNS relapse) and had received cranial irradiation. Two of the patients presented during the consolidation phase, one during delayed intensification and the remainder during maintenance therapy. The presenting complaints were headaches or visual symptoms. Of the nine patients, five experienced morning headaches, characteristic of increased intracranial pressure (ICP) and in four patients the headaches were associated with nausea and
ß 2008 Wiley-Liss, Inc. DOI 10.1002/pbc.21861 Published online 4 December 2008 in Wiley InterScience (www.interscience.wiley.com)
vomiting. Three patients developed visual problems during the course of their disease (Table I). All patients had cranial imaging and all but one underwent detailed investigations including full blood count, basic biochemistry, levels of vitamins A and E, and tests for prothrombotic state and thyroid function. Seven patients met the criteria of idiopathic intracranial hypertension (IIH), defined as increased intracranial pressure in the absence of a space-occupying lesion and apparent obstruction in the CSF pathways [3]. One patient had meningeal infiltration with leukemic cells, thus presenting a mechanism of CSF pathway obstruction. Indirect CSF pathway obstruction could also be the etiology of IH in one patient who suffered recurrent ear infections with evidence of previous venous sinus thrombosis. Another patient had a history of sub-clavian vein thrombosis however brain MRI/V was normal. Seven patients had been receiving dexamethasone and two prednisolone prior to developing symptoms. In two of the patients, a likely association of the symptoms with the administration of steroids was identified, while in three others the above association was possible. In these patients a significant exacerbation of their headaches was noted either during or approximately 1 week after the administration of steroids. Four patients receiving dexamethasone were switched to prednisolone and two of them had some improvement in symptoms. Four of the patients were treated with CSF drainage alone which proved to be successful therapy (n ¼ 3) or because they could not tolerate acetazolamide (n ¼ 1). Four of the remaining patients were —————— Additional supporting information may be found in the online version of this article. Abbreviations: UK ALL 97/01, United Kingdom acute lymphoblastic leukemia 97/01 Trial; R1, United Kingdom R1 protocol for relapsed acute lymphoblastic leukemia; R2, United Kingdom R2 protocol for relapsed acute lymphoblastic leukemia; Allo SCT, allogeneic stem cell transplant; Mini Allo SCT, reduced intensity allogeneic stem cell transplant; CSF, cerebrospinal fluid; CR, complete remission; BFM, Berlin-Frankfurt-Mu¨nster group protocol. 1
Department of Pediatric Neurology, St George’s Hospital, London, UK; 2Department of Pediatric Oncology, Royal Marsden Hospital, London, UK *Correspondence to: George Vartzelis, 3 Zarifi St, Athens 152 37, Greece. E-mail:
[email protected] Received 13 February 2008; Accepted 15 October 2008
CSF drainage Acetazolamide for 2 months No No Yes 24
No No 35
CR2 Subsequent CNS relapse 6 months later CR1
CR3
1. UK ALL XI 2. R1 þ Allo SCT (Aug 95) 3. R2 þ mini Allo SCT (Dec 91) 1. UK ALL XI 2. ALL R2 Maintenance cycle 5 R2 þ Cranial Irradiation UK ALL 97/01 (Regimen C) Delayed intensification 2
CR1
13 9
M
10 8
M
11 7
M 2 6
M
Augmented BFM consolidation Off treatment
CR1 CR1 Maintenance cycle 7 Maintenance cycle 4
UK ALL 97/01 (Regimen A) UK ALL 97/01 (Regimen B) þ cranial irradiation UK ALL 97/01 (Regimen C) 5 11 4 5
M F
CR2 Maintenance cycle 7 11 3
M
R2 Protocol þ cranial irradiation
CR1 CR1 Interim maintenance 1 Interim maintenance 2 UK ALL 97/01 (Regimen B) UK ALL 97/01(Regimen B) 10 13 1 2
M M
No
Repeated CSF drainage Acetazolamide for 2 years LP shunt No treatment Yes No Yes 30 (Subsequently up to 48)
CSF drainage X2 No No No 36
Yes No No Mild visual field loss and chronic papilledema Yes No 37 40
30
No
Bilateral optic disk atrophy, loss of acuity and visual fields
No
CSF drainage X2 Repeated CSF drainage Acetazolamide for 12 months Repeated CSF drainage Acetazolamide for 17 months LP shunt Repeated CSF drainage Repeated CSF drainage Yes Yes No Bilateral papilledema Yes Yes 36 31
Visual problems Remission status Phase of treatment on IH presentation Treatment protocol Gender Age Patient
TABLE I. Summary of Patient Characteristics, ALL, and IH Treatment Details
Opening CSF pressure (mm/Hg)
Morning headaches
Clinical characteristics
Nausea vomiting
Treatment of IH
Brief Reports
Pediatr Blood Cancer DOI 10.1002/pbc
419
treated with acetazolamide and two of them went on to have a lumbar-peritoneal (LP) shunt sited, which eventually relieved their symptoms. One patient did not receive any specific treatment as he subsequently died from his leukemia.
DISCUSSION Idiopathic Intracranial Hypertension or Pseudotoumor Cerebri is a condition of multi-factorial etiology and the annual incidence in the pediatric as well as the general population is estimated to 0.9 per 100,000 persons [3–6]. For the purposes of our study, we used the commonly accepted value of 20 cm H2O as the defining pressure for the diagnosis of IIH, although a value of 25 cm H2O has been suggested as more appropriate in a previous report [7]. Eight of our patients had a CSF opening pressure of 30 cm H2O or more with only one having a relatively lower pressure of 24 cm H2O. Radhakrishnan et al. [8] suggested that patients, who demonstrate IH as a result of intracranial or other venous thrombosis, should be regarded separately. We have included such patients in the IIH population, as their management remains the same regardless of the IH etiology. For the same reason we are reporting the patient with meningeal infiltration, despite not meeting the criteria for IIH. Acute Lymphoblastic leukemia predisposes for conditions with a causative potential for idiopathic as well as secondary IH, such as prothrombotic and hyperviscocity states, infections, and malnourishment. Furthermore the treatment of the condition can be implicated in the genesis of IH. Withdrawal from treatment with steroids has been shown to constitute a certain etiology [9,10]. Although the role of chemotherapy agents in the pathogenesis of IH is not clear, the use of busulfan, cyclophosphamide, etoposide, cytarabine, and All-Trans Retinoic Acid has been considered responsible in patients who developed IH [11–14]. Intrathecal methotrexate has also been shown to cause arachnoiditis, which could in theory affect the absorption of the CSF [15]. Asparaginase has the best-established potential for IH by causing imbalance of the anticoagulating systems [16]. Most of our patients were treated with the MRC ALL97/01 protocol, which includes asparaginase, cytarabine, and intrathecal methotrexate. Three patients had received prior cranial irradiation and one total body irradiation. Although we are not aware of any association of IH with irradiation, the latter could theoretically alter the CSF flow. Intracranial hypertension has an impact on the quality of life of leukemic patients in the form of headaches, visual problems, and the associated treatment. The headaches are usually worse in the morning and are occasionally difficult to differentiate from the background headaches of chronic disease. Of the nine patients, all but one had chronic headaches while five also had morning headaches. The visual problems undoubtedly pose the major threat to the health of patients with IH. They occur mainly as a result of edema of the optic nerves and present as decreased acuity, enlarged blind spot, restricted visual fields, and altered perception of colors. Despite earlier beliefs that visual problems do not occur as often in pediatric patients, there are a number of patients who are left with visual sequele [17]. From our patients three had visual problems as a result of their IH, in two of them persisting after completion of treatment. In view of the retrospective nature of the study, factors that could influence the measurement of the CSF pressure during the LP could not be eliminated. Such possible factors are a pCO2 above the normocarbic range of 4–6 kPa, or whether the legs were flexed
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causing increased abdominal pressure. Our patients received propofol and fentanyl by intravenous injection for induction anesthesia followed by inhalation with oxygen, nitrous oxide and sevoflurane for maintenance anesthesia up until 2003. From 2003 onwards, propofol and remifentanil by intermittent injection have been used. We are not aware of any association between these agents and increased ICP. As all of our patients (those with and without IH) likely received the same anesthetic, there is no reason why only a small percentage would have developed IH. As it is known, anesthesia does not cause IH, although hypoventilation during anesthesia could result to increased ICP. We believe that all our patients had IH, based on the relevant signs and symptoms as well as the improvement that was achieved with treatment. To date there is little reported in the literature on the occurrence of IH in children with ALL. The apparent increased incidence of IH in these patients with ALL, compared to the general pediatric population, highlights this as a potential problem. Clinicians should have a high index of suspicion in such patients with persistent symptoms indicative of IH and treatment should be decisive in order to protect their vision.
REFERENCES 1. Sastry J, Karandikar SS, English MW. Benign intracranial hypertension in association with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2003;20:157–160. 2. Roy A, Cargill A, Love S, et al. Outcome after first relapse in childhood acute lymphoblastic leukaemia—lessons from the United Kingdom R2 trial. Br J Haematol 2005;130:67–75. 3. Aicardi J. Diseases of the nervous system in childhood. London: Mc Keith Press; 1998. 4. Durcan FJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri. Population studies in Iowa and Louisiana. Arch Neurol 1988;45:875–877.
5. Gordon K. Pediatric pseudotumor cerebri: Descriptive epidemiology. Can J Neurol Sci 1997;24:219–221. 6. Youroukos S, Psychou F, Fryssiras S, et al. Idiopathic intracranial hypertension in children. J Child Neurol 2000;15:453– 457. 7. Corbett JJ, Mehta MP. Cerebrospinal fluid pressure in normal obese subjects and patients with pseudotumor cerebri. Neurology 1983; 33:1386–1388. 8. Radhakrishnan K, Ahlskog JE, Garrity JA, et al. Idiopathic intracranial hypertension. Mayo Clin Proc 1994;69:169–180. 9. Newton M, Cooper BT. Benign intracranial hypertension during prednisolone treatment for inflammatory bowel disease. Gut 1994; 35:423–425. 10. Vyas CK, Talwar KK, Bhatnagar V, et al. Steroid-induced benign intracranial hypertension. Postgrad Med J 1981;57:181–182. 11. Falchuk SC, Spitzer TR, Deeg HJ. Pseudotumor cerebri after ABMT. Bone Marrow Transplant 1990;6:152–153. 12. Fort JA, Smith LD. Pseudotumor cerebri secondary to intermediate-dose cytarabine HCl. Ann Pharmacother 1999;33:576– 578. 13. Guirgis MF, Lueder GT. Intracranial hypertension secondary to alltrans retinoic acid treatment for leukemia: Diagnosis and management. J Aapos 2003;7:432–434. 14. Visani G, Bontempo G, Manfroi S, et al. All-trans-retinoic acid and pseudotumor cerebri in a young adult with acute promyelocytic leukemia: A possible disease association. Haematologica 1996;81: 152–154. 15. Naiman JL, Rupprecht LM, Tanyeri G, et al. Intrathecal methotrexate. Lancet 1970;1:571. 16. Kieslich M, Porto L, Lanfermann H, et al. Cerebrovascular complications of L-asparaginase in the therapy of acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2003;25:484– 487. 17. Baker RS, Carter D, Hendrick EB, et al. Visual loss in pseudotumor cerebri of childhood. A follow-up study. Arch Ophthalmol 1985; 103:1681–1686.
Severe Vitamin B-12 Deficiency in a Child Mimicking Thrombotic Thrombocytopenic Purpura Andrea Dimond,
1 MD, *
James N. George,
We report a case of severe vitamin B-12 deficiency in a child who had a clinical presentation of hemolysis and thrombocytopenia that suggested the diagnosis of thrombotic thrombocytopenic purpura (TTP) and was associated with decreased ADAMTS13 activity. In this
Key words:
2{ MD,
and Caroline Hastings,
MD
1{
report, we review vitamin B-12 deficiency in children, the relationship between ADAMTS13 activity and TTP and discuss other conditions associated with decreased ADAMTS13 activity. Pediatr Blood Cancer 2009;52:420–422. ß 2008 Wiley-Liss, Inc.
megaloblastic anemia; vitamin B-12 deficiency; thrombotic thrombocytopenic purpura; ADAMTS13; pediatric
——————
INTRODUCTION When the ADAMTS13 metalloprotease was isolated, investigators hoped that the ADAMTS13 activity level might distinguish thrombotic thrombocytopenic purpura (TTP) from other forms of microangiopathic hemolytic anemia. As measurement of ADAMTS13 activity became standardized and widely available, it became clear that a variety of conditions can be associated with decreased activity. We describe the case of a 14-year-old who presented with pancytopenia, elevated LDH, and low ADAMTS13 activity in whom the diagnosis of TTP was suspected. When she did
ß 2008 Wiley-Liss, Inc. DOI 10.1002/pbc.21788 Published online 4 November 2008 in Wiley InterScience (www.interscience.wiley.com)
1
Department of Hematology Oncology, Children’s Hospital Oakland, Oakland, California; 2Departments of Medicine and Biostatistics & Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
{
George Lynn Cross Professor.
{
Fellowship Director.
*Correspondence to: Andrea Dimond, Fellow, Children’s Hospital Oakland, 747 52nd St, Oakland, CA 94609. E-mail:
[email protected] Received 30 May 2008; Accepted 26 August 2008
