- Email: [email protected]
Isotretinoin-associated intracranial hypertension
Isotretinoin-Associated Intracranial Hypertension Frederick W. Fraunfelder, MD,1,3,4 Frederick T. Fraunfelder, MD,1,4 James J. Corbett, MD2 Purpose: To evaluate the association between intracranial hypertension (IH) and isotretinoin use. Design: Observational case series. Methods: In this retrospective study, approximately 1950 case reports of adverse ocular side effects related to isotretinoin were received from spontaneous reporting systems. Reports were evaluated as to the occurrence of IH with isotretinoin use. A survey was mailed to all members of the North American Neuro-ophthalmology Society soliciting their opinions on whether isotretinoin caused IH. Results: One hundred seventy-nine reports of IH were associated with isotretinoin use. The mean time from drug exposure to IH diagnosis was 2.3 months. There were 6 cases of positive rechallenge; 5 new cases are reported here, along with 1 previously published report. Of neuro-ophthalmologists surveyed (62% response rate), 6% believed an association between IH and isotretinoin use was certain; 32%, probable; 52%, possible; and 10%, unlikely. Twelve respondents (4%) had personally seen one or more cases of positive rechallenge with isotretinoin causing IH. Conclusions: Based on the number and pattern of rapid IH onsets after isotretinoin exposure and the 6 cases of positive rechallenge, along with the probable similarity in metabolic pathways of this agent and vitamin A (a known cause of IH), it seems certain that there is a direct correlation between IH and isotretinoin use. Ophthalmology 2004;111:1248 –1250 © 2004 by the American Academy of Ophthalmology.
Isotretinoin, 13-cis retinoic acid (Accutane, Roche Pharmaceuticals, Nutley, NJ), is the only effective therapy for severe recalcitrant nodular acne and has been used for various dermatologic conditions for 2 decades. This drug has numerous major systemic side effects that have prompted 20 changes in the package insert since it was first put on the market in the United States in 1982. In the 2003 package insert, intracranial hypertension (IH) is listed in bold under adverse reactions. The insert also warns against taking isotretinoin in conjunction with tetracycline.1 However, this adverse reaction warning is less prominent than the black box warning that was used to highlight IH before 1999. Our prior publication indicated only a “possible” Originally received: June 30, 2003. Accepted: September 3, 2003. Manuscript no. 230423. 1 Casey Eye Institute, Oregon Health & Science University, Portland, Oregon. 2 University of Mississippi School of Medicine Neurology Department, Jackson, Mississippi. 3 Collaborating Center for International Drug Monitoring, World Health Organization, Uppsala, Sweden. 4 National Registry of Drug Induced Ocular Side Effects, Casey Eye Institute, Portland, Oregon. The authors are indebted to the national centers mentioned in this study that contributed data. The opinions and conclusions, however, are not necessarily those of the various centers or of the World Health Organization. The authors have no proprietary interest in these materials. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, New York, New York. Reprint requests to F. W. Fraunfelder, MD, Casey Eye Institute, 3375 SW Terwilliger Boulevard, Portland, OR 97239-4197. E-mail: [email protected].
1248
© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
association between isotretinoin and IH using the World Health Organization (WHO) Causality Classification Guide.2 Then only one case of positive rechallenge of IH secondary to isotretinoin use was in the literature; yet, positive rechallenge is a necessary factor in a “certain” association.3 Five new cases with positive rechallenge data associating IH with isotretinoin use are included here, along with a review of 179 additional cases. It is hoped clinicians will better understand the pattern of onset and the clinical characterisitics of this adverse drug reaction. Based on this data, we feel there is a “certain” association between isotretinoin and resultant IH in rare instances.
Design In this observational case series, reports were collected from centers receiving spontaneous reports of adverse drug reactions, and analyzed as to a possible association between IH and isotretinoin use.
Subjects and Methods Approximately 1950 spontaneous reports of possible adverse ocular events reported with isotretinoin were sent to the Food and Drug Administration (FDA), the WHO Sponanteous Reporting System, or the National Registry of Drug-Induced Ocular Side Effects at the Casey Eye Institute before May 2002. Efforts were made to prevent duplication of cases, because reporting systems may overlap. In some instances, the National Registry contacted the reporting physician to obtain further data. The FDA information is available to the public through the Freedom of Information ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.09.044
Fraunfelder et al 䡠 Isotretinoin-Associated Intracranial Hypertension Table 1. Intracranial Hypertension and Isotretinoin Use, Positive Rechallenge Data
Case No.
Age (yrs)
Gender
Indications
1 2
26 38
F F
Acne Acne
3
23
F
Acne
4 5 6*
34 14 14
F M F
Acne Acne Acne
Other Drugs None Fiorinal (caffeine, butalbital, acetylsalicylic acid), alprazolam daily Oral contraceptives (continued through dechallenge and rechallenge) None None Triple-dose isotretinoin (120 mg/day) Minocycline (100 mg twice a day) (short term) (length unknown)
Time from Usage to Onset of First Pseudotumor
Positive Dechallenge
Positive Rechallenge
None Anxiety, hypertension
4 wks 6 wks
Yes Yes
Yes Yes
Colitis, hyperlipidemia, abnormal hepatic function Chronic sinusitis None None
8 wks
Yes
Yes
5 mos 2 mos 5 wks
Yes Yes Yes
Other Disorders
Yes Yes Yes (rechallenge only with isotretinoin)
*Visani G, Manfroi S, Tosi P, Martinelli G. All-trans-retinoic acid and pseudotumor cerebri. Leuk Lymphoma 1996;23:437– 42.
Act. The National Registry data are accessed by the authors as proprietors, and the WHO data are provided by Dr F. W. Fraunfelder in his role as a consultant to the WHO. Data were garnered regarding age, gender, dosage, route of administration, other medications, duration of therapy, time to onset of adverse reaction, and dechallenge and rechallenge of the medication dating back to the initial FDA approval of isotretinoin. In addition, a written survey was sent by mail to the 490member North American Neuro-ophthalmology Society asking their opinion as to (1) an association between isotretinoin and IH and (2) whether they had personally seen positive rechallenge cases of IH secondary to isotretinoin use. Responses were collected at the Casey Eye Institute after a single mailing. Sixty-one drugs have been reported to cause IH.4 The case reports collected were classified using the WHO Causality Assessment Guide of Suspected Adverse Reactions.5 The 5 new cases of positive rechallenge arose from the spontaneous reporting systems of the National Registry, the FDA, and the WHO.
Results The databases revealed 179 cases of IH associated with isotretinoin use. Cases involved 134 females aged 11 to 68 years, 42 males aged 12 to 37, and 3 patients whose gender was not reported. Average ages were 21.9 years (females) and 18.7 years (males). From the spontaneous reports, 24% (43 patients) had taken drugs that have also been associated with IH (i.e., tetracycline, doxycyline, or minocycline). These drugs were usually started and stopped before starting isotretinoin therapy; however, in years past, some were given in conjunction with isotretinoin. The median time from the start of isotretinoin therapy to IH diagnosis was 2.3 months. There were 86 cases (48%) of positive dechallenge, with the IH resolving in a matter of a few weeks to a few months after stopping the drug. No follow-up was obtained in the remaining cases. Reports included 6 cases (3%) of positive rechallenge with isotretinoin (Table 1).
The return mail survey of the 490-member North American Neuro-ophthalmology Society had a 62% (304 persons) response rate. Of the respondents, 6% (18) felt that an association between IH and isotretinoin usage was certain; 32% (97) felt it was probable; 52% (158), possible; and 10% (30), unlikely. Twelve respondents (4%) stated that they had seen a positive rechallenge of isotretinoin in association with IH (11 respondents saw one case each, whereas a single respondent saw multiple cases).
Discussion Postmarketing surveillance systems suffer from underreporting, incomplete information, and lack of follow-up. Survey data suffer from incomplete reporting and the potential of bias both from physicians who do choose to submit completed surveys and in the absence of pertinent information from physicians who fail to complete and return surveys. However, these systems do provide information as to a temporal relationship, a pattern of presentation, and dechallenge and rechallenge data that may suggest possible, probable, or certain causation of an adverse drug event.5 In the evaluation of adverse drug reactions, positive rechallenge data are most compelling for categorization as “certain” under the WHO guidelines. Data from spontaneous reporting systems in combination with the WHO classification system have recently resulted in a series of articles2,6 –9 that help guide clinicians as to drug-induced ocular side effects. We believe isotretinoin is a causative factor in the development of IH primarily because of the large number of reports of IH occurring soon (mean, 2.3 months) after isotretinoin administration and the 6 documented cases of positive rechallenge. In addition, more than 80 cases of positive dechallenge have occurred within a few weeks to a few months of stopping treatment with isotretinoin. The
1249
Ophthalmology Volume 111, Number 6, June 2004 survey of the North American Neuro-ophthalmology Society reinforces this notion, as 12 neuro-ophthalmologists reported cases of positive rechallenge of IH after isotretinoin exposure. The retinoid family includes vitamin A and synthetic derivatives such as isotretinoin, etretinate, and retinoin. Vitamin A has been well documented as a cause of IH, and other retinoids such as all-trans-retinoic acid can cause IH.10,11 In fact, 9% of patients taking tretinoin develop IH.12 The mechanism of how retinoids cause IH is unclear, but it is felt to be part of a common pathway.10 It is possible that high doses of this class of drug induce a secretion of cerebrospinal fluid and alter the lipid constituents of the arachnoid villi. This may then disrupt the normal transport systems and impede the absorption of cerebrospinal fluid at the arachnoid villi.13 According to the Intracranial Hypertension Research Foundation (Vancouver, Washington), the incidence of IH associated with isotretinoin has significantly decreased (Tanne E, personal communication, 2003). This is confirmed by a decreased number of reports of IH with isotretinoin use to the National Registry of Drug-Induced Ocular Side Effects and by the removal of the black box warning of IH in the isotretinoin package insert of the Physician’s Desk Reference. The reason for fewer reports may be that more subspecialized physicians are the primary prescribers. At the first signs of unexplained visual changes or headaches, consultation is obtained or the drug is discontinued. We have few data as to the onset of IH for patients taking drugs in the tetracycline family, although the properties of these agents may be additive. Patients with the 5 new cases of positive rechallenge with isotretinoin and IH were not taking concomitant tetracycline preparations. Few neuro-ophthalmologists thought that there was a direct causal relationship between isotretinoin and IH, because there was only one previously reported case of positive rechallenge in the literature.3 It is impressive that 12 neuro-ophthalmologists (4%) had seen a case of positive rechallenge with isotretinoin causing IH. Using the WHO causality assessment guide to drugs and their side effects, the present report places isotretinoin’s association with IH in the “certain” category. This is based on positive dechallenge–positive rechallenge cases, a strong temporal relationship between drug exposure and IH, a large
1250
series of 179 cases, and isotretinoin’s belonging to a class of compounds known to cause IH. Data in the Physician’s Desk Reference and in the National Registry of DrugInduced Ocular Side Effects suggest that the more recently released retinoid, acitretin, also has the potential to cause IH. Patients taking oral retinoids who complain of unexplained headaches or visual symptoms should either stop the medication or be monitored closely for possible IH.
References 1. Vesanoid. In: Physician’s Desk Reference. 57th ed. Montvale, NJ: Medical Economics; 2002:2950 –2. 2. Fraunfelder FT, Fraunfelder FW, Edwards R. Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol 2001;132:299 –305. 3. Spector RH, Carlisle J. Pseudotumor cerebri caused by a synthetic vitamin A preparation. Neurology 1984;34:1509 – 11. 4. Fraunfelder FT, Fraunfelder FW. Drug-Induced Ocular Side Effects. 5th ed. Boston: Butterworth-Heinemann; 2001:824. 5. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994;10:93–102. 6. Hartmann K, Doser AK, Kuhn M. Postmarketing safety information: how useful are spontaneous reports? Pharmacoepidemiol Drug Saf 1999;8(suppl):S65–71. 7. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramateassociated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 2004;111:109 –11. 8. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular side effects. N Engl J Med 2003;348:1187– 8. 9. Fraunfelder FW, Fraunfelder FT, Jensvold B. Scleritis associated with pamidronate disodium use. Am J Ophthalmol 2003;135:219 –22. 10. Morrice G, Havener WH, Capetansky F. Vitamin A intoxication as a cause of pseudotumor cerebri. JAMA 1960;173: 1802–5. 11. Jacobson DM, Berg R, Wall M, et al. Serum vitamin A concentration is elevated in idiopathic intracranial hypertension. Neurology 1999;53:1114 – 8. 12. Visani G, Manfroi S, Tosi P, Martinelli G. All-trans-retinoic acid and pseudotumor cerebri. Leuk Lymphoma 1996;23:437– 42. 13. Roytman M, Frumkin A, Bohn TG. Pseudotumor cerebri caused by isotretinoin. Cutis 1988;42:399 – 400.
Isotretinoin, 13-cis retinoic acid (Accutane, Roche Pharmaceuticals, Nutley, NJ), is the only effective therapy for severe recalcitrant nodular acne and has been used for various dermatologic conditions for 2 decades. This drug has numerous major systemic side effects that have prompted 20 changes in the package insert since it was first put on the market in the United States in 1982. In the 2003 package insert, intracranial hypertension (IH) is listed in bold under adverse reactions. The insert also warns against taking isotretinoin in conjunction with tetracycline.1 However, this adverse reaction warning is less prominent than the black box warning that was used to highlight IH before 1999. Our prior publication indicated only a “possible” Originally received: June 30, 2003. Accepted: September 3, 2003. Manuscript no. 230423. 1 Casey Eye Institute, Oregon Health & Science University, Portland, Oregon. 2 University of Mississippi School of Medicine Neurology Department, Jackson, Mississippi. 3 Collaborating Center for International Drug Monitoring, World Health Organization, Uppsala, Sweden. 4 National Registry of Drug Induced Ocular Side Effects, Casey Eye Institute, Portland, Oregon. The authors are indebted to the national centers mentioned in this study that contributed data. The opinions and conclusions, however, are not necessarily those of the various centers or of the World Health Organization. The authors have no proprietary interest in these materials. This study was supported in part by an unrestricted grant from Research to Prevent Blindness, New York, New York. Reprint requests to F. W. Fraunfelder, MD, Casey Eye Institute, 3375 SW Terwilliger Boulevard, Portland, OR 97239-4197. E-mail: [email protected].
1248
© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
association between isotretinoin and IH using the World Health Organization (WHO) Causality Classification Guide.2 Then only one case of positive rechallenge of IH secondary to isotretinoin use was in the literature; yet, positive rechallenge is a necessary factor in a “certain” association.3 Five new cases with positive rechallenge data associating IH with isotretinoin use are included here, along with a review of 179 additional cases. It is hoped clinicians will better understand the pattern of onset and the clinical characterisitics of this adverse drug reaction. Based on this data, we feel there is a “certain” association between isotretinoin and resultant IH in rare instances.
Design In this observational case series, reports were collected from centers receiving spontaneous reports of adverse drug reactions, and analyzed as to a possible association between IH and isotretinoin use.
Subjects and Methods Approximately 1950 spontaneous reports of possible adverse ocular events reported with isotretinoin were sent to the Food and Drug Administration (FDA), the WHO Sponanteous Reporting System, or the National Registry of Drug-Induced Ocular Side Effects at the Casey Eye Institute before May 2002. Efforts were made to prevent duplication of cases, because reporting systems may overlap. In some instances, the National Registry contacted the reporting physician to obtain further data. The FDA information is available to the public through the Freedom of Information ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.09.044
Fraunfelder et al 䡠 Isotretinoin-Associated Intracranial Hypertension Table 1. Intracranial Hypertension and Isotretinoin Use, Positive Rechallenge Data
Case No.
Age (yrs)
Gender
Indications
1 2
26 38
F F
Acne Acne
3
23
F
Acne
4 5 6*
34 14 14
F M F
Acne Acne Acne
Other Drugs None Fiorinal (caffeine, butalbital, acetylsalicylic acid), alprazolam daily Oral contraceptives (continued through dechallenge and rechallenge) None None Triple-dose isotretinoin (120 mg/day) Minocycline (100 mg twice a day) (short term) (length unknown)
Time from Usage to Onset of First Pseudotumor
Positive Dechallenge
Positive Rechallenge
None Anxiety, hypertension
4 wks 6 wks
Yes Yes
Yes Yes
Colitis, hyperlipidemia, abnormal hepatic function Chronic sinusitis None None
8 wks
Yes
Yes
5 mos 2 mos 5 wks
Yes Yes Yes
Other Disorders
Yes Yes Yes (rechallenge only with isotretinoin)
*Visani G, Manfroi S, Tosi P, Martinelli G. All-trans-retinoic acid and pseudotumor cerebri. Leuk Lymphoma 1996;23:437– 42.
Act. The National Registry data are accessed by the authors as proprietors, and the WHO data are provided by Dr F. W. Fraunfelder in his role as a consultant to the WHO. Data were garnered regarding age, gender, dosage, route of administration, other medications, duration of therapy, time to onset of adverse reaction, and dechallenge and rechallenge of the medication dating back to the initial FDA approval of isotretinoin. In addition, a written survey was sent by mail to the 490member North American Neuro-ophthalmology Society asking their opinion as to (1) an association between isotretinoin and IH and (2) whether they had personally seen positive rechallenge cases of IH secondary to isotretinoin use. Responses were collected at the Casey Eye Institute after a single mailing. Sixty-one drugs have been reported to cause IH.4 The case reports collected were classified using the WHO Causality Assessment Guide of Suspected Adverse Reactions.5 The 5 new cases of positive rechallenge arose from the spontaneous reporting systems of the National Registry, the FDA, and the WHO.
Results The databases revealed 179 cases of IH associated with isotretinoin use. Cases involved 134 females aged 11 to 68 years, 42 males aged 12 to 37, and 3 patients whose gender was not reported. Average ages were 21.9 years (females) and 18.7 years (males). From the spontaneous reports, 24% (43 patients) had taken drugs that have also been associated with IH (i.e., tetracycline, doxycyline, or minocycline). These drugs were usually started and stopped before starting isotretinoin therapy; however, in years past, some were given in conjunction with isotretinoin. The median time from the start of isotretinoin therapy to IH diagnosis was 2.3 months. There were 86 cases (48%) of positive dechallenge, with the IH resolving in a matter of a few weeks to a few months after stopping the drug. No follow-up was obtained in the remaining cases. Reports included 6 cases (3%) of positive rechallenge with isotretinoin (Table 1).
The return mail survey of the 490-member North American Neuro-ophthalmology Society had a 62% (304 persons) response rate. Of the respondents, 6% (18) felt that an association between IH and isotretinoin usage was certain; 32% (97) felt it was probable; 52% (158), possible; and 10% (30), unlikely. Twelve respondents (4%) stated that they had seen a positive rechallenge of isotretinoin in association with IH (11 respondents saw one case each, whereas a single respondent saw multiple cases).
Discussion Postmarketing surveillance systems suffer from underreporting, incomplete information, and lack of follow-up. Survey data suffer from incomplete reporting and the potential of bias both from physicians who do choose to submit completed surveys and in the absence of pertinent information from physicians who fail to complete and return surveys. However, these systems do provide information as to a temporal relationship, a pattern of presentation, and dechallenge and rechallenge data that may suggest possible, probable, or certain causation of an adverse drug event.5 In the evaluation of adverse drug reactions, positive rechallenge data are most compelling for categorization as “certain” under the WHO guidelines. Data from spontaneous reporting systems in combination with the WHO classification system have recently resulted in a series of articles2,6 –9 that help guide clinicians as to drug-induced ocular side effects. We believe isotretinoin is a causative factor in the development of IH primarily because of the large number of reports of IH occurring soon (mean, 2.3 months) after isotretinoin administration and the 6 documented cases of positive rechallenge. In addition, more than 80 cases of positive dechallenge have occurred within a few weeks to a few months of stopping treatment with isotretinoin. The
1249
Ophthalmology Volume 111, Number 6, June 2004 survey of the North American Neuro-ophthalmology Society reinforces this notion, as 12 neuro-ophthalmologists reported cases of positive rechallenge of IH after isotretinoin exposure. The retinoid family includes vitamin A and synthetic derivatives such as isotretinoin, etretinate, and retinoin. Vitamin A has been well documented as a cause of IH, and other retinoids such as all-trans-retinoic acid can cause IH.10,11 In fact, 9% of patients taking tretinoin develop IH.12 The mechanism of how retinoids cause IH is unclear, but it is felt to be part of a common pathway.10 It is possible that high doses of this class of drug induce a secretion of cerebrospinal fluid and alter the lipid constituents of the arachnoid villi. This may then disrupt the normal transport systems and impede the absorption of cerebrospinal fluid at the arachnoid villi.13 According to the Intracranial Hypertension Research Foundation (Vancouver, Washington), the incidence of IH associated with isotretinoin has significantly decreased (Tanne E, personal communication, 2003). This is confirmed by a decreased number of reports of IH with isotretinoin use to the National Registry of Drug-Induced Ocular Side Effects and by the removal of the black box warning of IH in the isotretinoin package insert of the Physician’s Desk Reference. The reason for fewer reports may be that more subspecialized physicians are the primary prescribers. At the first signs of unexplained visual changes or headaches, consultation is obtained or the drug is discontinued. We have few data as to the onset of IH for patients taking drugs in the tetracycline family, although the properties of these agents may be additive. Patients with the 5 new cases of positive rechallenge with isotretinoin and IH were not taking concomitant tetracycline preparations. Few neuro-ophthalmologists thought that there was a direct causal relationship between isotretinoin and IH, because there was only one previously reported case of positive rechallenge in the literature.3 It is impressive that 12 neuro-ophthalmologists (4%) had seen a case of positive rechallenge with isotretinoin causing IH. Using the WHO causality assessment guide to drugs and their side effects, the present report places isotretinoin’s association with IH in the “certain” category. This is based on positive dechallenge–positive rechallenge cases, a strong temporal relationship between drug exposure and IH, a large
1250
series of 179 cases, and isotretinoin’s belonging to a class of compounds known to cause IH. Data in the Physician’s Desk Reference and in the National Registry of DrugInduced Ocular Side Effects suggest that the more recently released retinoid, acitretin, also has the potential to cause IH. Patients taking oral retinoids who complain of unexplained headaches or visual symptoms should either stop the medication or be monitored closely for possible IH.
References 1. Vesanoid. In: Physician’s Desk Reference. 57th ed. Montvale, NJ: Medical Economics; 2002:2950 –2. 2. Fraunfelder FT, Fraunfelder FW, Edwards R. Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol 2001;132:299 –305. 3. Spector RH, Carlisle J. Pseudotumor cerebri caused by a synthetic vitamin A preparation. Neurology 1984;34:1509 – 11. 4. Fraunfelder FT, Fraunfelder FW. Drug-Induced Ocular Side Effects. 5th ed. Boston: Butterworth-Heinemann; 2001:824. 5. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994;10:93–102. 6. Hartmann K, Doser AK, Kuhn M. Postmarketing safety information: how useful are spontaneous reports? Pharmacoepidemiol Drug Saf 1999;8(suppl):S65–71. 7. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramateassociated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 2004;111:109 –11. 8. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular side effects. N Engl J Med 2003;348:1187– 8. 9. Fraunfelder FW, Fraunfelder FT, Jensvold B. Scleritis associated with pamidronate disodium use. Am J Ophthalmol 2003;135:219 –22. 10. Morrice G, Havener WH, Capetansky F. Vitamin A intoxication as a cause of pseudotumor cerebri. JAMA 1960;173: 1802–5. 11. Jacobson DM, Berg R, Wall M, et al. Serum vitamin A concentration is elevated in idiopathic intracranial hypertension. Neurology 1999;53:1114 – 8. 12. Visani G, Manfroi S, Tosi P, Martinelli G. All-trans-retinoic acid and pseudotumor cerebri. Leuk Lymphoma 1996;23:437– 42. 13. Roytman M, Frumkin A, Bohn TG. Pseudotumor cerebri caused by isotretinoin. Cutis 1988;42:399 – 400.