MEDICATION ASSOCIATED INTRACRA! HYPERTENSION James J. Corbett, MD McCarty Professor and Chairman for Neurology Professor of Ophthalmology University of Mississippi Medical Center Jackson, Mississippi ‘Many drugs are associated with intracranial hypertension (ICH) (Table 1, IA and 1B). ‘These associations have been reported in a variety of ways such as letters to the editor, brief case reports and collections of cases from groups of institutions. The rigor with which these reports have been documented is quite varied. It is common for time relationships between onset of drug use, onset of symptoms and diagnosis of intracranial hypertension to be incompletely documented, Frequently lumbar puncture is not performed to document increased CSF pressure, and if done either pressure or CSF contents are not reported. In infants a bulging fontanelle alone is taken as evidence of elevated CSF pressure. Rarely do reports utilize the WHO criteria for probability of relationship of drug to adverse reaction, (Table 2) Very rarely do they contain evidence of the “Koch’s postulate.” where a drug re-challenge reproduces the same symptoms and signs. The major problem with some reports is that the “offender” medication is picked out of a group of drugs the patient is taking and named arbitrarily as “the cause” of ICH. This is especially true of immune modulating drugs such as cyclosporine and cytarabine which are used with corticosteroids or in complex drug cocktails, ‘The details of the addition of a drug, or the modification of the dose of drug in relation to the others is frequently lacking. Obstacles to the accurate identification of drug induced intracranial hypertension include: 1.) Litigation interference with the completeness of data reported, and the open evaluation of data by drug companies and plaintiff attorneys. 2) The “oh I've seen or heard about it” response to a potential drug-induced event frequently results in no report being filed with the drug company and the FDA. The true incidence of untoward drug side effects is thought to be up to 10 times the reported incidence. 3.) The difficulty in knowing how long intracranial pressure has been elevated, How do we know the intracranial pressure and papilledema has not been present and asymptomatic for a long time before medications were used? 4.) The concurrent or prior use of other medications which have been reported to cause increased intracranial pressure may confound correct identification of the real culprit. 5.) Many physicians don’t know how to use an ophthalmoscope or do know and don’t expend the effort to look, How many patients reported with “drug induced” papilledema had the problem before they ever took the allegedly offending drug?6.) The intracranial hypertension was caused by cerebral venous sinus ‘occlusion which may or may not have been caused by the allegedly offending medication, Patients with hydrocephalus are included in the laundry list of drug induced ICH. 7.) Even when radiologic studies are done, there is no systematic search for evidence of cerebral venous sinus thrombosis. (CVST) VITAMIN A AND OTHER RETINOIDS. Historically, the earliest, clearly recognized, cause of medication-induced elevated intracranial pressure is Vitamin A in the form of polar bear liver. As it turns out, liver of animals is the repository of most of the stored Vitamin A. The livers of fish, calves, bears, sharks and chickens, eaten as liver proper or as liver oil have all been reported to cause elevation of intracranial pressure. Bear liver has huge amounts of Vitamin A and ingestion is associated with development of severe headache in a matter of hours to a day. Of interest, Shackleton and his men, famous Antarctic explorers, ate a stew of penguin meat and liver for months on end but never became ill probably because the Vitamin A had been inactivated by prolonged cooking. People who are avid liver eaters tend to be food faddists and are very rare. When asked about eating liver, most patients wrinkle up their noses or look at you in wonder at such a silly questions Large doses of vitamin A (>0,000 U) daily have been used for skin disorders in the past, but this has been largely supplanted by 13 cis-retinoic acid. The concomitant use of minocycline or tetracyclines is discouraged but is still done and confuses the identification of which of the two drugs is the real trouble maker, if not both. Smith reports that 35% to 50% of individuals with known, hypervitaminosis A develop ICH. Uremia is associated with an uncommonly high incidence of ICH and renal faihure results in reduction of retinol binding protein (RBP) excretion. This produces a higher serum retinol level both bound to RBP and free retinol. This produces hypervitaminosis A. Whether given in chronic low dose (10.000 IU daily for years) or doses of 50 to 100,000 IU daily for skin diseases, or in other forms such as tretinoin, aciretim, etretinate and isoretinoin for acne and other skin diseases (psoriasis, mycosis fungoides), Vitamin A and its congeners have all been associated with ICH. ‘The more recent Vitamin A compounds, All-trans retinoic acid (ATRA) and 9 cis retinoic (9CRA) have shown great prot in the treatment of malignanci acute promyelocytic leukemia in children (ATRA) and “refractory cancer” in children (9CRA). The dose-limiting toxicity of 9CRA was ICH and ATRA has frequent ICH side effects but both are such a potent drugs that the ICH and swollen nerves are dealt with separately. ‘Thus, a number of currently availableVitamin A analogues, when used for skin disease or cancers, orally or topically, should be considered highly likely candidates for producing the ICH. Beta carotene is a retinoid which is composed of two molecules of Vitamin A joined by an aldehyde bond. All Vitamin A that is ingested, enters the blood directly at the brush border of the small intestine; thus the more you eat of Vitamin A, the more that is absorbed. Beta carotene, by contrast, has to be enzymatically cleaved into two molecules of Vitamin A at the brush border. Thus this gate keeper enzyme prevents all beta carotene ingested from being cleared and absorbed as Vitamin A. Beta carotene is also completely absorbed, but once absorbed it cannot be further cleaved to 2 Vitamin A molecules. If enough beta carotene is eaten it will produce hpercarotenemia but not hypervitaminosis A. There is a single case report of hypercarotenemia producing ICH and tested by a re-challenge of carotene. Overall, Vitamin A is a tempting target for further investigation as a model for jiopathic” intracranial hypertension since it is a naturally occurring compound which is derived from directly absorbed Vitamin A A rate limiting enzyme cleaves beta carotene into two molecules of retinol at the brush border of the small intestine. The mechanism by which Vitamin A produces elevated intracranial pressure has not been elucidated but it could be an effect on increasing the production of CSF or interfering with CSF absorption. The current data on the metabolism of Vitamin A in the production of intracranial hypertension is far from complete but strongly suggests a causal relationship exists. STEROIDS Most of the reports of intracranial hypertension (ICH) and corticosteroid use relate the development of ICH to withdrawal, not excessive use of steroids. A review of 25 cases of ICH after withdrawal of steroids in treatment of asthma revealed resolution of the problem when steroids were reinstated. ‘This has also been reported in inflammatory bowel disease. The evidence for the use of corticosteroids inducing ICH is very weak. While topical treatment of skin conditions with triamcinolone is listed as @ cause of ICH, however, the symptoms actually became evident when the topical steroids were withdrawn and in one case, the ICH improved when oral corticosteroids were given. Anabolic steroids including testosterone, danazol, stanozolol and androgenic steroids used by weight-lifters have all been reported to cause ICH but there is no large series. The procoagulant properties of the anabolic steroids may predispose to cerebral venous sinus thrombosis in some cases and proved to be the cause of ICH in one report.GONADAL HORMONES Progesterone in the form of levonorgestel (Norplant®) is a subcutaneous implanted contraceptive that has been associated with intracranial pressure. There are over forty cases reported to the FDA and at least three of those were successfully treated by removal of the implant, At least one case of ICH recurred when the implant was replaced. Even when the implants were removed, many patients continued to have ICH, however in four patients ICH resolved without removal of the implant. Lupron® — synthetic gonadotrophin relaxing hormone has been reported as causing ICH in 2 brief reports, however the supporting data is weak. Beta human chorionogonadotrophin (BHCG) has been reported to cause ICH in two patients; one treated for undecended testicle and the other for testicular teratoma, In both of these reports documentation is weak. Oral contraceptives (OC) have been implicated in ICH since their early use. No large studies of the occurrence of ICH related to oral contraceptive use have been carried out, however, two small case control studies showed no difference in the use of OC in ICH cases and controls, ANTIBIOTICS Tetracyelines, especially minocycline and doxyciycline have been reported to cause ICH. Many individual cases and groups of cases have been reported. Attribution of ICH to tetracyclines must exclude cases where there is concomitant or prior use of Vitamin A or retinoid analogues for acne, This two drug scenario is typicaly where the waters are muddied by incomplete reports. A number of cases have been reported where stopping the drug led to remission and a couple of cases had re-challenge and recurrence. It is very likely that tetracycline is a firm causal relationship, particularly since there is one report that points to a genetic mechanism in fraternal twins. Nitrofuran, used in urinary tract infections has had a sprinkling of reports. One report was of a patient who also had paroxysmal noctumal hemoglobinemia, a condition reported to cause ICH due to cerebral venous thrombosis. wole-trimethoprim_and_sulfenazone - have been reported to cause ICH but reports are rare and not well documented. Many of these cases are infants under the age of one and young children. Fluoroquinolone Reports of ICH due to naladixie acid are almost all in children less than 12 rs of age. Many are reported to have seizures and focal neurologic findings. No mechanism has been proposed but withdrawal of the drug provides rapid reliefand re-challenge has been shown to elevate CSF pressure again. Ofloxacin and ciprofloxacin have had brief case reports of ICH. In one report of 20 cases of nalidixic acid intracranial hypertension, almost all the children were given the medication in excessive doses. SPECIAL CIRCUMSTANCES, Renal, hepatic, cardiac_and bone marrow transplants have been reported associated with the development of ICH. ICH may occur much more frequently than recognized. Isolating the causative agent may be very difficult because these patients are on a multitude of medications, frequently in the midst of changing medication doses (especially oral or IV corticosteroid) and finally the use of Human Growth Hormone especially in renal transplants. Another contributing factor is excess weight gain that occurs due to corticosteroid use and lack of exercise. Cardiac transplant is a special circumstance where use of extracorporeal, nonpulsatile heart-lung machine leads to edema of the brain almost invariably. How offen this results in venous sinus occlusion of persistent ICH is unknown. Nonetheless, caution must be exercised in attributing ICH to any one element of treatment in the complex setting of organ transplantation, OTHER DRUGS ‘Amiodarone has caused ICH with papilledema PION and AION. Withdrawal of the drug has resulted in resolution of ICH. Axoplasmic flow is compromised with the use of amiodarone. Phenytoin ~ single case report with little specific information. Nitroglycerine ~ causes temporary elevation ICP and reports brain swelling, continuous CSF recordings and coma hardly n ICH. of patients with Dandy criteria Ketoprofen_and Indomethacin — in Bartter's Syndrome. Bartters syndrome is a congenital block to renal tubular absorption of K+. There are five different genetic varieties of Bartter syndrome and individual genetic characterization is needed to know whether one specific genetic subtype was more likely to cause ICH than another, Lithium Small numbers of patients with ICH related to the use of lithium have been reported and in at least two, re-challenge resulted in reappearance of ICH. While there are few cases reported, they were well documented.DRUGS OF DUBIOUS CAUSAL MERIT information to make an informed judgment. Cyclosporine Cytosine arabimoside Oxytocin Thioridazine Imipramine too few cases or confounding Chlorpromazine Sinemet | Cimetidine Tacrolimus Mycophenylate mofetil |Medications Associated with Intracranial Hypertension Slave T Amiodarone Amphotericin _ Chronic gonadotropin _Cimetidine Corticosteroids — prolonged use _| Corticosteroids - withdrawal | Cyclosporine ____| Cytosine arabinoside el Danaz« Fluoroquinolone _Growth hormone | _Indomethacin = Isotretinoin _Ketoprofen, Leuprorelin _Lithium Minocycline —_ Nitrofurantoin Ofloxacin Oxytocin __ - Pancreatic enzyme “Stanozol | Sulfonamides iL _Tamoxifen fel Testosterone _ Tetracycline pet Trimethoprim-sulfamethoxazole Vitamin A _ —Drug-related Headache Reports (n = 9733) to WHO from Australia, New Zeland, Sweden, United States and UK 1972-1987 a _Table IA — Most Frequently Reported Drugs Number of Reports Indomethacin 57 ——aeieR-———}- as Cimetidine =——st—S~=«@Y 238 Atenolol ale a5 Trimethoprim-sulfamethoxazole | 2i1 ~Zimeldine SSCS 182 Glyceryltrinitrate tit tttst~*«i Isosorbide dinitrate =| a - Zomepirac BB a ~~~ Ranitidine =" 116 Isotretinoin 1 7 Captopril ft 108 Piroxicam ~ 107 Metoprolol 106 ~— Diflofenac 105 Methyldopa 98 Terfenadine T o4 "Propranolol 86 Benoxaprofensseseeeasea! seamen 83Drug-related Intracranial Hypertension Reports (n = 162) to WHO from Australia, New Zealand, Sweden, United States and United Kingdom 1972-1978 Table IB Mos: Feuenty Reported gs | ‘Namberof Reet Minocycline ar 15 etn | a” - Nalidixic acid ie 10 7 _ a | 9 -—imeopimsufanetoazole | 2 —— = 5 Preto | | ‘ — = — _ Methylprednisolone 4 Tamoxifen 4 _ Beclomethasone 3World Health Organization Definitions: Causality Assessment of Suspected Adverse Reactions CERTAIN PROBABLE/ LIKELY POSSIBLE UNLIKELY CONDITIONAL UNCLASSIFIED UNASSESSIBLE/ UNCLASSIFIABLE A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and that cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary A clinical event, including laboratory test abnormality, occurring within a reasonable time sequence from administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and following a clinically reasonable response on withdrawal (dechallenge).. Rechallenge information is not required to fulfill this definition A clinical event, including a laboratory test abnormality, occurring within a reasonable time: sequence from administration of the drug, but ‘one that could also be explained by concurrent disease or the presence of other drugs or chemicais. Information on drug withdrawal may be lacking or unclear. A clinical event, including a laboratory test abnormality, with a temporal relationship to drug administration that makes a causal relationship improbable and for which other drugs, chemicals, or underlying disease provide plausible explanations. A clinical event, including a laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment or the additional data are under examination. A report suggesting an adverse reaction that cannot be judged because information is insufficient or contradictory, and that cannot be supplemented or verifiedMedication Associated Intracranial Hypertension James J. Corbett, MD University of Mississippi Criteria used to relate drugs t0 clinical conditions + Close relationship of signs and symptoms to use of medication + Remission of symptoms/signs when drug is withdeawat + Reoceurrence of symptoms/‘signs when drug is reinstated + Optimally some mechanism i identified Problems with identification of drug side effects Tend wo be rare ' Once reported itis assumed to be a firm relationship 1 RSponv ef alee lbasipsto FDA ae oF 1 The “On I've heard of that” effect 1 Were the Dandy ertria fulilled?Problems with identification of drug side effects 1 How waste side effect Hw long ws the side ‘denied? lec presen? * Wat he sells b= New sympeoms ‘nme? tecidenal finding on 1 Howlong deste physical examination pplena ode + Hohn dis the SUBIC heat TO, Sy Problems with identification of drug side effects ‘The Issue of Mukiple Drugs ‘= Transplantation = Chemotherapy for tumor 1 Were conicostervids used? 1 When were the various drugs used relative to the discovery of IOP Vitamin A and Analogues f Liverof avasityof a Tretinoin (tiny smile palate, Resi AP) © Boisrtinoic acid a Vaan A(35 20 50% of (Gowrerinoin, Accutane") pattems wih fyperviaminosis A) Alla retinoic acid (TRA) cian) 1 Scisretnoi acid @CRA) © Bea CaroteneCorticosteroids and Other Hormones 4 Wikdewlofondand Levon! Nope?) moaleem * Leptin ape.) Senna + tea + Dinwel EE _ + Hm pono = Abo nie cect comb ED ee ‘trnindes) + Ontaamnerpis Antibiotics ee o Teacines 1 Phoromilones Gprfleacn 1 Minoytne Naik Acid Ofiacin 1 Doneycne Sonar 1 Nirofratoin “Tinethapsin salfetinaole seas eee Sufenazone Other Drugs ee Lith Siena? * Pheroicines 1 Ginetiine — ——— ® Amiodarone © Cyclosporine 1 Petenene Mle Phen * GyorinesabinosidePotential Mechanisms Toxic effect on CSF drainage 1 Sudden increase of CSF production fect on clotting fect on central venous pressure Criteria for Viable Causal Association A. The Dandy erteria are observed 2, LP includes CSF pressure measurement protein, glicose and cll count. &-MRU/MRV bas been done Withdrasel produces improvernent E. Rechallenge reproduces symptoms What should be done? 1 A commitce of NANOS shouldbe convened oases ihe ong lind bt of causes of ICEL 1 Using the WHO definitions of CausalyAgessment of snopected Adverse Drag Reactions ~ chsstyall od pores Ase of criteria oe the dagnoss of cg related 1H thould be uted Chased (Newology aa), taologs IMRT. MQ), sn Lboraory (CSF pressure "Sxl contr) should Be wel 0 judge the rearreVITAMIN A Adamson PC, Reaman C, Finkelstein JI, etal Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on intermittent schedule in combination with interferon x2 a in pediatric patients with refractory cancer. J Clin Oncology 1997;15: 3330-37. Farris WA, Edman JW. Protracted hypervitaminosis A following long term low intakes. JAMA 1982; 247:1317-18. Goodman DS. Vitamin A and retinoids in health and disease, NEJM 1984;310:1023-31 Joseph HW. Hypervitaminosis A and carotenemia, A J Dis Child 1954;87:731-36. Lambert A, Carlon H. Benign intracranial hypertension due to A hypervitaminosis in adults and adolescents. Eur Neurol 1976;14:340-50. Mahmond HH, Hanitz CA, Roberts WM et al. tretinoin toxicity in children with acute promyelocytic leukemia, Lancet 1993; 342:1394-95, Marie J, See G, Acute hypervitaminosis A of the infant. Am J Dis Child 1954;73:73 1- 36. Mikkelson B, Ehlero N, Thomason HG. Vitamin A intoxication causing papilledema simulating acute encephalitis. Acta Neurol Scand 1974;50:642-50, Muenter MD, Perry HO, Ludwig J. Chronic vitamin A intoxication in adults: Herpatic, neurologic and dermatologic complications. Am J Med 1971;50:129-36. Roytman M, Franklin A, Bohn TG. Pseudotumor cerebri caused by isorctinoin, Ceitis 1990;42:399-400. Selhost JB, Worybright EA, Jennings S, etal. Liver lovers headache; pseudotumor cerebri and Vitamin A intoxication. JAMA 1984;252:3365, Smith FR, Goodman DS. Vitamin A transport in human Vitamin A toxicity. NEM 1976;294:805-8, Smith JE, Goodman DS. Retinol-binding protein and regulation of Vitamin A transport. Federation Pre 1979; 38:2504-09. Sepetor RH, Carlisle J. Pseudotumor cerebri caused by a synthetic Vitamin A preparation. Neurol 1984:34:1509-11. Viraben R, Mathieu C, Fontan B. Benign intracranial hypertension during etretinate therapy for mycosis fungeides, J AM Acad Dermatol 1985;13:515-17Visani G, Manfoi S, Tosi P, etal. All-trans retinoic acid and pseudotumor cerebri. Leuk Lymphoma 1996;23:437-42 Yatzidis H, Digenis P, Founsa P. Hypervitaminosiis A. accompanying advanced chronic renal failure. BMJ 1975;3:352-3. Zwiacier K, etal. Low plasma levels of vitamin A and E during weight reduction. Acta Pediatr: Second. 1988;77:760-761. Sano F, Tsiji K, Kumika N, et al. Pseudotumor cerebri in a patient with acute promyelocytic leukemia during treatment with all-trans retinoic acid. Intern Med 1998;37:546-9. Fraunfelder FW, Fraunfelder FT. Evidence for a probable causal relationship between tretinoin, acitretin and etretinate and intracranial hypertension. J Neuro Ophthalmol 2004;24:214-6. Fraunfelder FW, Fraunfelder FT, Corbett JJ. Isotretinoin associated intracranial hypertension. Ophthalmology 2004;111:1248-50. Donahue SP. Recurrence of idiopathic intracranial hypertension after weight loss: the carrot craver, Am J Ophthalmol 2000;130:850-1 Adamson PC, Widemann BC, Reaman GH, etal. A phase I trial and pharmacokinetic study of 9-cis-retinoic acid (ALRT1057) in pediatric patients with refractory cancer. Clinical Cancer Res 2005;7:3034-9. Sacchi S, Russo D, Avvisati, etal, All-trans retinoic acid in hematological malignancies an update. Hematologica 1997;82:106-121. de Bolton S, Coiteux V, Chevret $ et al. Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Ongol 2004 Apr 15:22 1404-12 ANTIBIOTICS Quinotones + Nalidixic acid = Ofloxacin * Ciprofloxacin Sulfa © Sulfamethoxazole-Trimethoprim + SulfenazoneWinrow AP, Supramaniam G, Benign intracranial hypertension afier ciprofloxacin administration. Arch Dis Child 1990 Oct; 65:1165-6. Getenet JC, Croisile B, Vighetto A, et al. Idiopathic intracranial hypertension after ofloxacin treatment, Acta Neurol Scand 1993 Jun; 87:503-4 Jain N, Rosner F. Idiopathic intracranial hypertension: report of seven cases. Am J Med 1994 Aug; 97:200-1 Murgia S, Del Curto E, Zecca G. Benign intracranial hypertension caused by sulfenazone, BPediatr Med Chir 1989 Sept-Oct; 11:541-2. Digre KB, Not so benign intracranial hypertension. BMJ 2003;326:613-14. Gardner D, Cox T, Digre KB. Idiopathic intracranial hypertension associated with tetracycline use in fraternal twins: case report and review. Neurology 1994:45:6-10. Chiu AM, Chuenkongkaew WL, Comblath WT, etal, Minocycline treatment and pseudotumor cerebri syndrome. AM J Ophthalmol 1998 Jul;126:116-21 Monaco F, Agnetti V, Martani R, Benign intracranial hypertension after minocycline therapy. Eur Neurol 1978;17:48-9, Kesler A, Goldhammer Y, Hadayer A. etal. The outcome of pseudotumor verebri induced by tetracycline therapy. Acta Neurologica Scandanavia 2004;110:408-11 Friedman DI, Gordon LK, Egan RA, etal, Doxycycline and intracranial hypertension. Neurology 2004:62:2297-99. Lochhead J, Elston JS. Doxyeycline induced intracranial hypertension. BMJ 2003:326: 641-42. GROWTH HORMONE Schowengerdt KO Jr., Gajarski RJ, Denefield §. Progressive visual deterioration leading to blindness afier pediatric heart transplant. Tex Heart Inst J. 1993;20299-303. Wingenfeld P, Schmidt B, Hoppe B, etal. Acute glaucoma and intracranial hypertension in a child onlong-term peritoneal dialysis treated with growth hormone. Pediatr Nephrol 1995 Dec;9:742-5. Malozowski 8, Tannaer LA, Wysowski DK, etal. Benign intracranial hypertension in childrenwith growth hormone deficiency treated with growth hormone. J Pediatr. 1995 June; 126:996-9.Francois 1, Castells 1, Silberstein J, etal. Empty sella, growth hormone deficiency and pseudotumor cerebri: effect of initiation, withdrawal and resumption of growth hormone therapy. Eur J Pediatr. 1997 Jan;156:69-70, Katz B. Disk edema subsequent to renal transplantation. Surv Ophthalmol. 1997 Jan- Feb; 41:315-20, Hauffa BP. One-year results of growth hormone treatment of short stature in Prader- Willi syndrome, Acta Paediatr Suppl. 1997 Nov; 423:63-5 Koller BA, Stadel BV, Malozowski SN. Papilledema in 15 renally compromised patients treated with growth hormone. Pediatr Nephrol. 1997;11:451-54. Crock PA, MeKenzie JD, Nicoll AM, etal. Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand. Acta Paediatr. 1998 Apr; 87:381-6. Rogers AH, Rogers CL, Bremer DL, McGregor MD. Pseudotumor cerebri in children receiving ecombinant human growth hormone. Ophthalmology 1999;106:1 186-89, Reeves GD, Doyle DA. Growth hormone treatment and pseudotumor cerebri: coincidence or close relationship? J Pediatr Endocrinol Metab 2002 May; 15 Suppl 2:723-30. Fine RN, Ho M, Tejani A, et al. Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease. J Pediatr. 2003 May;142:539- 45, Francis PJ, Haywood S, Rigden S, et al. Benign intracranial hypertension in children following renal transplantation. Pediatr Nephrol. 2003 Dec:18:1265-9, Chamberlin CE, Fitzgivvon E, Wasserman EM et al. Idiopathic intracranial hypertension following kidney transplantation: a case report and review of the literature Pediatr Transplant, 2005 Aug; 9:545-50. OTHER DRUGS Lithium Saul RF, Hamburger HA, Selhorst JB. Pseudotumor cerebri secondary to lithium carbonate, JAMA, 1985 May 17: 253; 2869-70. Levine SH, Puchalski C, Pseudotumor cerebri associated with lithium therapy in two patients. Journal of Clinical Psychiatry, 1990:52:239.Amiodarone ten Tusscher, MPM, Jacobs PJC, Busch M, de Graff L, et al. Bilateral anterior toxic neuropathy and the case of infliximab. BMJ, 326;579. Macaluso DC, Shults, WT, Fraunfelder FT. Features of aminodarone induced optic neuropathy. Arch Ophthalmology, 1999;127:610-2. Borat FX, Regli F. Pseudotumor cerebri as a complication of amiodarone therapy. Am J Ophthalmology 1993;116:776-7 Grogan WA, Narlean DM. Pseudotumor cerebri with amiodarone. JNNP 1986; 49: 1463-4. Van Zandijeke M, Dewachter A. Pseudotumor cerebri with amiodarone. JNNP 1986;49 1463-4 Fikkers BG, Bogousslavsky J, Regli F, etal... Pseudotumor cerebri with aminodarone. JINNP 1986;49:606. Johnson LN, Krohel GB, Thomas ER. The clinical spectrum of amiodarone optic neuropathy. J Natl Med Assoc 2004;96:1477-91 Cyclosporine Buscher R, Vijo, Huddet, etal. Pseudotumor cerebri following Cyclosporine A treatment in a boy with tubulointerstitial nephritis associated with ureitis. Pediatrie Nephrol 2004; 19:558-60 Aery R, Jabs DA Wingard JR, et al. Optic disc edema after bone marrow transplantation. Possible role of cyclosporine toxicity. Ophthalmology 1991 Aug; 98:1294-301 Cytarabine Fort JA, Smith LD. Pseudotumor cerebri secondary to intermediate dose cytarabine HCL. Ann Pharmacotherapy 1999:33:576-8 Schutta HS, Corbett 1J. Intracranial Hypertension Syndromes. In: Joynt RU, Griggs RC (Ed.): Clinical Neurology. Lippincott-Raven, Philadelphia, PA. Ch. 23B:1-57, 1997,