PEDIATRICS Vol. 108 No. 2 August 2001, pp. 519-520

Minocycline and Pseudotumor cerebri: The Well-Known but Well-Kept Secret

To the Editor.

Minocycline, a synthetic derivative of tetracycline, is the most widely prescribed oral systemic antibiotic for acne vulgaris because it does not appear to induce resistance in Propionobacterium acnes and can be administered only once or twice a day. Interestingly, minocycline is lipophilic and penetrates the blood-brain barrier more readily than other tetracyclines, thus attaining higher cerebrospinal fluid (CSF) levels. Despite its widespread use among adolescents, it does not appear that adequate prospective studies have been published to investigate its specific effects on the maturing teenager.

Recent personal experience allowed for more careful study of the effects of minocycline. Specifically, our then 12-year-old son initiated minocycline (100 mg twice a day) by mouth for the treatment of moderately severe acne. Four weeks later, he was examined by a senior pediatric ophthalmologist for his annual assessment of myopia. An entirely normal examination (including pupil dilation and fundoscopic assessment) was documented, but 4 weeks later he complained of a global headache that was modestly relieved by an oral analgesic (day 1). The next day (day 2) he developed vomiting and diarrhea with a low-grade temperature. By day 3, the vomiting and diarrhea had improved, he had defervesced, but he began to complain of visual glare. Although he noticed slight double vision, he did not mention it until late on day 4. On day 5, he was seen by his pediatric ophthalmologist to assess the new symptoms of glare and the double vision. On examination he was noted to have right 6th cranial nerve weakness, bilateral papilledema with focal retinal splinter hemorrhages, and enlarged blind spots. A brain/brainstem computed tomography scan and magnetic resonance imaging the same day failed to identify a cause for the apparent increase in intracranial pressure; thus, a decision was made that minocycline accounted for the symptoms compatible with Pseudotumor cerebri. The minocycline was immediately discontinued. A spinal tap was deferred and Diamox (250 mg every 8 hours) was initiated. Within 24 hours of the last dose of minocycline, his headache was resolving and his double vision slightly improved. Because of sustained double vision 48 hours later, the Diamox was increased to 250 mg every 6 hours, and a potassium-enriched diet was initiated. Within 4 weeks of the diagnosis of Pseudotumor cerebri and discontinuation of the minocycline/initiation of Diamox, the papilledema had resolved, the blind spots had returned to normal size, and our son was virtually symptom-free (aside from the fatigue and shortness of breath with exertion induced by the metabolic acidosis effect of Diamox). The Diamox was tapered then discontinued over days 28 to 30, and the ophthalmologic examination followed closely with sustained normality documented over the next 6 months.

In the process of this alarming experience we made several observations. First, we noted that information about minocycline and Pseudotumor cerebri is lacking in common resources accessible to pediatricians. Specifically, Pseudotumor cerebri is not listed in the current edition of the Harriet Lane Handbook as a complication of minocyclinejust nausea, vomiting, allergy, photophobia, injury to developing teeth, and vestibular dysfunction. The 2001 Physicians' Desk Reference reports Pseudotumor cerebri as a rare complication in adults and notes that bulging fontanelle can occur in babies, but mentions nothing about children or adolescents. The Pediatric Dosage Handbook (commonly used by pediatric residents for medication dosages) does not even list minocycline. Finally, the package insert on the actual minocycline prescription from the pharmacy did not list Pseudotumor cerebri as a complication, nor did it provide an adequate symptom list that might equate with Pseudotumor cerebri. Second, we found that the literature is full of case reports or small series about minocycline and Pseudotumor cerebri (at least 19 reports were located) and tetracycline and Pseudotumor cerebri (at least 10 reports), but they are published primarily in the dermatology and ophthalmology literature. The first report of tetracycline/Pseudotumor cerebri in a child appeared in the Journal of the American Medical Association in 1971.¹ The first report of minocycline/Pseudotumor cerebri in a child appeared in European Neurology in 1978.² Yet, the only original report in the Journal of Pediatrics was a "Clinical Note" published in 1978 as a letter by Stuart and Litt³ regarding tetracycline, and then a letter to the editor citing previous publications.⁴ No reports were found in Pediatrics. The only large prospective study looking for the incidence of side effects of minocycline is in the dermatology literature⁵ and was based on symptom report and blood chemistries, without corroboration on physical or ophthalmologic exam. Finally, the rationale for performing the initial and serial spinal taps, with full recognition that more CSF would soon be produced, was less than clearly stated in the literature.

As a result of this first-hand experience, we have identified 3 key areas where we as pediatricians can prevent the above-described scenario. First, it is our responsibility as investigators to ensure that drugs to be used in children are studied prospectively before FDA approval. In the case of minocycline, an examination by an experienced pediatric ophthalmologist before the initial prescription and then every 2 to 4 weeks thereafter in combination with a patient questionnaire would be appropriate. Only then will the true incidence of Pseudotumor cerebri be known and its relationship to specific "side effects" be clarified. As initially proposed by Maroon and Mealy,¹ it is quite possible that Pseudotumor cerebri occurs more frequently than published reports would suggest. They proposed that many patients likely discontinue use of the offending agent when they experience the ill-defined side effects, before the symptoms progress to the full clinical manifestations. As a result, Pseudotumor cerebri would be unrecognized and therefore unreported. Further, even if the parent seeks medical attention, this would quite likely include examination by the dermatologist or pediatrician who could easily miss the subtle early signs of papilledema. Second, it is our responsibility as pediatricians to insist that all side effects, particularly the most serious ones, of widely dispensed drugs be clearly listed in detail on the package insert and in the texts commonly used by pediatric residents and pediatricians, with no room for ambiguity. If a serious side effect has been identified, this should be reported clearly in these locations with specific references provided. Finally, it is our responsibility as educators to ensure that each child and parent is instructed to look for specific symptoms and serious side effects of any drugs we prescribe before they leave our offices so that we can encourage parents to be knowledgeable and proactive and ensure that the next generation will be well-educated in their own health and well-being.

Debra E. Weese-Mayer, MD
Pediatric Respiratory Medicine
Rush Children's Hospital at Rush-Presbyterian- St Luke's Medical Center
Chicago, IL 60612

Renee J. Yang, MD
Northwestern University Medical School
Chicago, IL

Jonathan R. Mayer
Latin School of Chicago
Chicago, IL

Zibute Zaparackas, MD
Department of Ophthalmology
Northwestern University
Chicago, IL

REFERENCES

1. Maroon JC, Mealy J Jr Benign intracranial hypertension. Sequel to tetracycline therapy in a child. JAMA. 1971; 216:1479-1480 [Abstract/Free Full Text]
2. Monaco F, Agnetti V, Mutani R Benign intracranial hypertension after minocycline therapy. Eur Neurol. 1978; 17:48-49 [Medline]
3. Stuart BH, Litt IF Tetracycline-associated intracranial hypertension in an adolescent: a complication of systemic acne therapy [clinical note]. J Pediatr. 1978; 92:679-680 [Medline]
4. Jay WM, Jay S Benign intracranial hypertension with tetracycline therapy [letter]. J Pediatr. 1978; 93:901 [Medline]
5. Goulden V, Glass D, Cunliffe WJ Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol. 1996; 134:693-695 [Medline]