Correspondence

Levonorgestrel Implants and Intracranial Hypertension

N Engl J Med 1995; 332:1720-1721June 22, 1995

Article

To the Editor:

Levonorgestrel (Norplant, Wyeth–Ayerst Laboratories, Philadelphia) is a subdermally implanted synthetic progestin that has been available in the United States since 1991. Intracranial hypertension developed in two women seen at the Oregon Health Sciences University after the insertion of this implant. We reviewed data from the national Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, Oreg.), the Food and Drug Administration's Spontaneous Reporting System (Rockville, Md.), and the World Health Organization's Collaborating Center for International Drug Monitoring (Uppsala, Sweden) for a possible association between levonorgestrel use and intracranial hypertension. A total of 56 cases of intracranial hypertension or disk edema were found. Most cases were reported by physicians who believed the events may have been drug-related. The patients were female, with a mean age of 22 years (range, 16 to 34), and they had been treated with levonorgestrel for a mean of 206 days (range, 9 to 616) before the onset of the syndrome. We have no data about the weight of these women. Visual-field defects were reported in seven patients, and diplopia in six. Levonorgestrel has been associated with intracranial hypertension in two other patients.1

Our patients were a 16-year-old white girl and a 19-year-old Hispanic woman in whom disk edema occurred four to five months after the implantation of levonorgestrel. Neither was obese, had prior medical problems, or used other medications that have been associated with intracranial hypertension. Both had normal results on neuroimaging studies (magnetic resonance imaging or computed tomography), and both had lumbar-puncture opening pressures that exceeded 550 mm of water with normal chemical and cellular analysis. Presenting symptoms consisted of transient visual obscurations, severe headaches, or emesis. Ocular findings included visual acuity in the range of 20/20 to 20/25 and florid bilateral papilledema with enlarged blind spots. Intracranial hypertension resolved in the 19-year-old patient; she remains free of symptoms after 28 months of follow-up. The 16-year-old patient has had three recurrences over a period of 18 months, each of which was controlled with acetazolamide.

The cause of intracranial hypertension is not known. This condition has been reported in association with the use of a wide range of medications.2 The Physicians' Desk Reference lists a possible association under the heading “Precautions.”3 The manufacturer suggests that patients be screened for papilledema if the following occurs: “headache (associated with a change in the frequency, pattern, severity, or persistence; of particular importance are those headaches that are unremitting in nature) and visual disturbances.”3 If papilledema is present, referral to a neurologist is recommended.

In the general population of females between the ages of 15 and 44 years, idiopathic intracranial hypertension occurs at a rate of 3.3 per 100,000 per year.4 Headaches are among the most commonly reported nongynecologic side effects of levonorgestrel implants.5 Removal of the implants may help relieve this symptom. Such factors may confound this possible association, and it remains unclear whether the drug causes intracranial hypertension. One of our patients had recurrences requiring medication to control. Levonorgestrel may have contributed to the onset of intracranial hypertension, or it may have had nothing to do with it. Until more information is available, we concur with the manufacturer's recommendation to examine the ocular fundus in selected patients with visual symptoms or changes in the pattern of their headaches and to remove the implant in patients in whom intracranial pressure increases.

John B. Alder, M.D.
F.T. Fraunfelder, M.D.
Oregon Health Sciences University, Portland, OR 97201

Ralph Edwards, M.D.
World Health Organization, S-75103 Uppsala, Sweden

5 References

1. 1

   Sunku AJ, O'Duffy AE, Swanson JW. Benign intracranial hypertension associated with levonorgestrel implants. Ann Neurol 1993;34:299-299 abstract.
   Web of Science

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   Fraunfelder FT. Drug-induced ocular side effects and drug interactions. 3rd ed. Philadelphia: Lea & Febiger, 1989:595.
   

3. 3

   Physicians' Desk Reference. 49th ed. Montvale, N.J.: Medical Economics Data Production, 1995:2696-700.
   

4. 4

   Radhakrishnan K, Ahlskog JE, Cross SA, Kurland LT, O'Fallon WM. Idiopathic intracranial hypertension (pseudotumor cerebri): descriptive epidemiology in Rochester, Minn, 1976 to 1990. Arch Neurol 1993;50:78-80
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   Shaaban MM, Salah M, Zarzour A, Abdullah SA. A prospective study of NORPLANT implants and the Tcu 380AgIUD in Assiut, Egypt. Stud Fam Plann 1983;14:163-169
   CrossRef | Web of Science | Medline

Author/Editor Response

Spokespersons for Wyeth–Ayerst Laboratories reply:

To the Editor: The 70 reports of idiopathic intracranial hypertension received by Wyeth–Ayerst are recorded without regard to causality. Obesity, a known risk factor, was noted in 38 of 49 reports in which information about weight was available. For women 20 to 44 years of age who are 20 percent or more above their ideal body weight, the mean annual incidence of idiopathic intracranial hypertension is 19.3 per 100,000.1

Since its introduction in 1991, the Norplant system has been inserted in nearly one million women. Assuming a highly conservative annual discontinuation rate of 20 percent, we calculated an observed reporting rate for idiopathic intracranial hypertension of 4.1 per 100,000 patient-years in this population. This rate is similar to the expected annual incidence rate of 3.3 per 100,000 for all females 15 to 44 years of age, and lower than the rate expected for obese women.

In 24 of the 44 reports in which information on follow-up was available, idiopathic intracranial hypertension did not abate after the implant was removed. This further confounds the issue of a causal relation.

Margaret E. Weber, M.D.
Howard E. Rofsky, M.D.
Marc W. Deitch, M.D.
Wyeth–Ayerst Laboratories, Philadelphia, PA 19101-8299

1 References

1. 1

   Durcan FJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri: population studies in Iowa and Louisiana. Arch Neurol 1988;45:875-877
   Web of Science | Medline

Citing Articles (9)

Citing Articles

1. 1

   Lubaina M. Rangwala, Grant T. Liu. (2007) Pediatric Idiopathic Intracranial Hypertension. Survey of Ophthalmology 52:6, 597-617
   CrossRef

2. 2

   J W Chan. (2006) Idiopathic intracranial hypertension associated with depot medroxyprogesterone. Eye 20:12, 1396-1397
   CrossRef

3. 3

   Deborah I Friedman. (2005) Medication-Induced Intracranial Hypertension in Dermatology. American Journal of Clinical Dermatology 6:1, 29-37
   CrossRef

4. 4

   Deborah I. Friedman. (2005) A Practical Approach to Intracranial Hypertension. Headache Currents 2:1, 1-10
   CrossRef

5. 5

   Deborah I Friedman. (2004) Pseudotumor cerebri. Neurologic Clinics 22:1, 99-131
   CrossRef

6. 6

   Stephen Silberstein. (2001) Current Opinion in Neurology 14:3, 323
   CrossRef

7. 7

   K MECKSTROTH, P DARNEY. (2000) IMPLANTABLE CONTRACEPTION. Obstetrics and Gynecology Clinics of North America 27:4, 781-815
   CrossRef

8. 8

   K. Gwan Go. (2000) Pseudotumour Cerebri. CNS Drugs 14:1, 33-49
   CrossRef

9. 9

   &NA;. (1995) Levonorgestrel. Reactions Weekly &NA;:557, 8
   CrossRef