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Bardzo tanie apteki z dostawą w całej Polsce kupic cialis i ogromny wybór pigułek.
Haematologica 1996; 81:152-154
ALL-TRANS-RETINOIC ACID AND PSEUDOTUMOR CEREBRI
IN A YOUNG ADULT WITH ACUTE PROMYELOCYTIC LEUKEMIA:
A POSSIBLE DISEASE ASSOCIATION
Giuseppe Visani,* Giovanni Bontempo,° Silvia Manfroi,* Alberto Pazzaglia,# Roberto D'Alessandro,°
*Institute of Hematology “L. & A. Seragnoli”, University of Bologna; °Servizio di Neurologia, Policlinico S.Orsola-Malpighi,Bologna; #Clinica Oculistica I, University of Bologna, Italy ABSTRACT
Pseudotumor cerebri or idiopathic intracranial hypertension is a neurological syndrome charac-
terized by signs and symptoms of intracranial hypertension without clinical or radiological evi-
dence of infective or space occupying lesions. Iatrogenic factors are frequent; in particular, cases of
pseudotumor cerebri associated with all-trans-retinoic acid treatment in acute promyelocytic
leukemia (APL) have been frequently described in pediatric patients. We report on a case observed
in an older patient (young adult age) and give diagnostic and therapeutic guidelines.
Key words: pseudotumor cerebri, all-trans-retinoic acid, acute promyelocytic leukemia, therapy, retinoids All-trans-retinoic acid (ATRA) is able to µg/mL. Bone marrow biopsy, karyotype exami- nation and molecular biology were compatible with a diagnosis of APL.4 The patient was treat- than 80% of cases both in adults and in chil- ed with ATRA 45 mg/m2 p.o. (80 mg/day, total dren.1-3 ATRA is considered a safe agent.
dose) plus daunorubicin 100 mg/day for three Nevertheless, adverse reactions have been observed to affect various organs and districts Thirty-one days after beginning treatment the (skin, liver, lung, blood, metabolism, heart and patient started complaining of headache, diplop- vascular system, central nervous system).1-3 ia and tinnitus. WBC count was 5.8ϫ109/L and Some of these have been described only in sub- platelets were 197ϫ109/L; bone marrow biopsy jects affected by APL, whereas others, such as and karyotype confirmed achievement of com- pseudotumor cerebri (PTC), are possible in plete remission. Neurological examination was other conditions. In this context, we describe a negative. Ophthalmological examination docu- case of PTC occurring in a young adult patient mented a visual acuity of 9/10 in both eyes.
Pupillary reactions were normal and slitlampexamination results were normal. Fundus oculiexamination showed that both optic disks were Case Report
blurred and elevated; in addition, we observed R.S., a 16-year-old male presented in January venous engorgement, tortuous vessels and scat- 1994 with bleeding, macrohematuria and fever tered, flame-shaped peripapillary hemorrhages.
(38.5°C). Blood tests showed: hemoglobin 8.6 Golman perimetry revealed bilateral enlarge- g/dL; platelets 23ϫ109/L; WBC 1.09ϫ109/L, dif- ment of the blind spot and a concentric contrac- ferential count: 60% blast cells (promyelocytes tion of the peripheral field. Visual evoked poten- with Auer rods), 6% neutrophils, 34% lympho- tials (pattern reversal) were normal.5 A cerebral computed tomography (CT) examination per- Correspondence: Giuseppe Visani, MD, Institute of Hematology “Seràgnoli”, University of Bologna, Policlinico S. Orsola, via Massarenti 9, 40138Bologna, Italy.
Acknowledgments: supported in part by MURST 40%-60%.
Received September 13, 1995; accepted February 7, 1996. ATRA and pseudotumor cerebri
formed the same day and 15 days later failed to detect the presence of space occupying lesions or (NMR) is not considered a mainstay for the ventricular space enlargement. Diagnosis of PTC diagnosis of PTC since the shape of ventricular was therefore made. ATRA was stopped on the enlargement is adequately described by CT.
day of onset of intracranial hypertension symp- Lumbar puncture could be helpful to confirm toms and the patient was treated with acetazo- diagnosis. The case described here is a typical lamide. Because of a scarce response to the phar- example of PTC arising in a young adult (16 macological treatment, a lumbar puncture was years old) following treatment with ATRA, performed after 15 days. It showed a strong ele- without the simultaneous use of other drugs vation of cerebrospinal fluid (CSF) pressure (310 with a potential risk of inducing PTC; further- mm of water), and the fluid was clear and color- more, clinical and instrumental documentation less in appearance. Cytochemical and microbio- satisfied all accepted criteria for a diagnosis of logical evaluation was negative. A total amount of 28 cc of CSF were removed, leaving final CSF The pathogenesis of ATRA-induced PTC still pressure of 150 mm of water. This procedure was remains to be established. It could be seen as a followed by prompt clinical improvement. No manifestation of vitamin A overdose; high doses recurrence of symptoms was noted and no other of ATRA induce an over stimulation of RAR-␣ ATRA-related side effects were observed. The (retinoic acid receptor), which proves to be help- patient has been in continuous complete remis- ful in gaining control over the leukemic myeloid sion for 17 months; he completed the chemo- clone (in which the receptor is expressed in an therapy protocol, including autologous bone aberrant form) but which is frankly pathological marrow transplantation, without any neurologic in other tissues, including the central nervous system. In fact, the existence of retinoid recep- tors and related cytoplasmic binding proteinshas been demonstrated in the nervous system.7,8 Discussion
The retinoids seem to have a fundamental mor- PTC is a diagnosis of exclusion and a con- phological action in the nervous system.9 In par- firmed diagnosis requires the following widely ticular, ATRA is involved in fundamental aspects of the development of the central nervous sys- 1. signs and symptoms of intracranial hyper- tem.9 A change in the metabolic pathways related to retinoids after embryonic development, or an action exerted by retinoids not at the level of the 3. lack of focal neurological signs except for nerve cells – neurons and glial cells – but on the those referable to intracranial hypertension structures of the blood-brain barrier or on the and those lacking in locational value, such as drainage of cerebrospinal fluid (choroid plexuses 4. normally-sized and shaped cerebral ventri- and arachnoid villi, respectively) could be postu- cles and absence of space occupying lesions small ventricles and of empty sella is, howev- previously described in ten pediatric patients treated for APL with ATRA at doses ranging 5. documented elevation of cerebrospinal fluid from 45 to 80 mg/m2/day.10-12 PTC was also pressure (200 mm of water in non obese and reported in children treated with ATRA for neo- plasms other than APL, whereas clinical trials 6. normal composition of cerebrospinal fluid; performed on young adults or adults treated 7. no other identifiable causes of intracranial with higher dosages (up to 150 mg/m2/day) for pathologies other than APL did not show any A correct diagnostic approach consists of evidence of toxicity on the central nervous sys- physical examination and computerized tomo- tem. At present, the appropriate management G. Visani et al.
2. Degos L, Chomienne C, Daniel MT, et al. Treatment of first of patients who experience this syndrome is still relapse in acute promyelocytic leukemia with all-trans unclear. Major analgesic drugs, such as codeine retinoic acid. Lancet 1990; 336:1440-1.
or morphine sulphate, or temporary ATRA dis- 3. Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelo- continuation in non responding cases may help cytic leukemia. I. Clinical results. Blood 1990; 76:1704-9.
in reducing the severe headache, nausea and 4. Diverio D, Riccioni R, Mandelli F, Lo Coco F. The PML/RAR␣ vomiting; acetazolamide or furosemide is rec- fusion gene in the diagnosis and monitoring of acutepromyelocytic leukemia. Haematologica 1995, 80:155-60.
ommended to reduce CSF pressure, as is lum- 5. Spoor TC, Ramocki JM, Madion MP, Wilkinson MJ.
bar puncture with removal of CSF in order to Treatment of pseudotumor cerebri by primary and secondaryoptic nerve sheath decompression. Am J Ophtalmol 1991; maintain a final CSF pressure of no more than 6. Radhakrishnan K, Ahlskog JE, Cross SA, Kurland LT, O’Fallon WM. Idiopathic intracranial hypertension -Descriptive epidemiology in Rochester, Minn, 1976 to 1990, retinoid stimulation in the central nervous sys- tem, or a progressive age-related reduction of 7. Maden M, Ong DE, Chytil F. Retinoid-binding protein dis- RAR expression in the central nervous system tribution in the developing mammalian nervous system.
Development 1990; 109:75-80.
could be postulated. However, the case described 8. Ruberte E, Friederich V, Chambon P, Morris-Kay G. Retinoic highlights the possibility of a diagnosis of PTC in acid receptors and cellular retinoid binding proteins. III.
Their differential transcript distribution during mouse ner- APL patients no longer in the pediatric age, sug- vous system development. Development 1993; 118:267-82.
gesting that PTC should be considered at all ages Maden M, Holder N. The involvement of retinoic acid in the in the diagnostic procedure for APL patients development of the vertebrate central nervous system,Development 1991; 11(Suppl. 2):87-94.
10. Smith MA, Adamson PC, Balis FM, et al. Phase I and phar- macokinetic evaluation of all-trans-retinoic acid in pediatricpatients with cancer, J Clin Oncol 1992; 10:1666-73.
11. Warrell RP, Frankel SR, Miller WH. Jr, et al. Differentiation References
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1. Huang ME, Ye YC, Chen SR. et al. Use of all-trans retinoic 12. Mahmoud HH, Hurwitz CA, Roberts WM, Santana VM, acid in the treatment of acute promyelocytic leukemia. Blood Ribeiro RC, Krance RA. Tretinoin toxicity in children with acute promyelocytic leukaemia. Lancet 1993; 342:1394-5.
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