Publications

Published: January 2001
ADR update

Tetracyclines and Benign Intracranial Hypertension - a headache rare but real

Prescriber Update 21: 33–36
January 2001

Helen Kingston, FRNZCGP, GP, Takaka

Benign intracranial hypertension (BIH) is a rare but potentially serious condition. BIH has been documented in association with a variety of medicines, particularly the tetracyclines.
A case has been reported to CARM of benign intracranial hypertension with minocycline, recurring on rechallenge.
The common presenting feature of BIH is headache. The signs are papilloedema and sometimes sixth nerve palsy. Raised intracranial pressure confirms the diagnosis. If associated with a medicine, the condition may resolve totally on stopping it. Treatment includes therapeutic lumbar punctures and acetazolamide. Complications of BIH can be lasting visual defects or even blindness, so discontinue the medicine and refer promptly if suspected.
Doctors should regularly enquire about headache when prescribing a tetracycline, even for a short period. The combination of a tetracycline and isotretinoin should be avoided.

Case report: BIH recurred on rechallenge with minocycline

The New Zealand Centre for Adverse Reactions Monitoring (CARM) has received its second report of benign intracranial hypertension (BIH) related to minocycline. It involved a 14 year old female who was being treated with minocycline for acne. Other prescribed medicines were fluticasone and salbutamol inhalers. She presented with headache unrelieved by analgesics, and had intermittent vomiting. Her signs on admission to hospital included slurred speech, reduced sensation and left sided weakness, with mild lateral rectus palsy on the right. The minocycline, which she had taken for thirteen days, was discontinued. A diagnosis of hemiplegic migraine was made, and she recovered from this episode. The headache then recurred after restarting minocycline. Papilloedema was observed and the diagnosis of benign intracranial hypertension (with hemiplegic migraine) was made. Treatment included four lumbar punctures and acetazolamide. The patient had not yet fully recovered at the time of reporting.

BIH is associated with various medical conditions and medicines

Benign intracranial hypertension (also known as pseudotumor cerebri, or idiopathic intracranial hypertension) is a rare condition of unknown cause with an annual incidence of 0.9/100,000 in the general population. It is likely that there is a genetic predisposition.1 It is significantly more common in adolescent and young adult women, but can occur in children. In case control studies, obesity and weight gain have been demonstrated as risk factors for BIH.2 Other medical conditions linked to BIH include migraine, thyroid and parathyroid disorders, Addison's and Cushing's diseases, systemic lupus erythematosis, HIV/AIDS, and sarcoidosis.

Medicines reported to be associated with BIH include vitamin A analogues, tetracyclines, steroids (especially in withdrawal), nalidixic acid, sulphonamides, lithium, thyroxine, growth hormone, amiodarone and tamoxifen.3

Benign intracranial hypertension presents with headache

The predominant presenting symptom is daily headache (90% of cases), pulsatile in quality. Less frequent symptoms are visual disturbances and pulsatile tinnitus. BIH can be completely asymptomatic. The mechanism is not fully understood but current opinion favours impaired reabsorption of cerebrospinal fluid (CSF).

Papilloedema without lateralising signs is diagnostic

The diagnostic criteria are:

BIH appears to occur most frequently with minocycline

Of the medicines associated with BIH, minocycline is most frequently reported in the literature. The WHO adverse reactions database documents 188 cases of intracranial hypertension with minocycline, 31 with tetracycline and 27 with doxycycline. One review of 162 cases of medicine-related BIH found that 9% were linked to minocycline, 5.5% to tetracycline and 1.2% to isotretinoin.4 The lipophilic properties of minocycline may be the explanation for the higher number of reported cases. It is possible that the incidence of BIH may increase if two or more drugs which might cause BIH are used together. For this reason tetracyclines should not be prescribed concomitantly with retinoids (e.g. isotretinoin).4

In contrast to the truly idiopathic cases, minocycline-related BIH occurs more often in patients of normal weight than in the obese. Minocycline-induced cases tend to resolve on stopping the medicine, without recurrence, strengthening the cause and effect hypothesis.5

The above case is the second report of benign intracranial hypertension from a total of 172 adverse reaction reports for minocycline on the CARM database. Australia's Adverse Drug Reactions Advisory Committee figures for minocycline are 463 (all adverse reactions) and 24 (cases of BIH) from 1974 to 1999. A prospective trial describes 14 probable cases out of 700 treated patients.6 There was no association with dosage, so the effect is likely to be idiosyncratic. Most cases occurred in the first four weeks of treatment, but two happened after 6 and 12 months, respectively.6

It is not always benign

Active intervention may not be needed in the absence of visual defects and if there is an association with a medicine which has been discontinued. Treatment includes weight loss if indicated, repeated lumbar punctures until the intracranial pressure returns to normal, and oral acetazolamide. Short-term systemic steroids are advocated by some authorities. Neurosurgical decompression techniques are sometimes used for intractable headache or progressive visual field loss. Although most patients recover fully, the epithet "benign" is misleading as complications include irreversible visual field defects, and, occasionally, blindness.

Ask about headache when prescribing tetracyclines

Minocycline and other tetracyclines are commonly prescribed for acne. Prescribers should be aware that benign intracranial hypertension has been associated with their use, as delay in its diagnosis can lead to serious consequences. Acne treatment may not even be considered as a medicine by patients when asked what medicines they are taking.7 Active enquiry about headache, visual disturbances and tinnitus is advised at each visit. Because the onset of BIH can be insidious or asymptomatic, some authorities also recommend regular fundoscopy of every person taking tetracyclines. When BIH is suspected, the medicine must be stopped and a neurological opinion promptly sought. The same precautions should be observed when prescribing tetracyclines of any kind for malaria prophylaxis (an unapproved use in New Zealand).

Address correspondence to Dr Helen Kingston, Golden Bay Medical Centre, PO Box 173, Takaka. Fax (03) 525 8169

References
  1. Gardner K, Cox T, Digre KB. Idiopathic intracranial hypertension associated with tetracycline use in fraternal twins. Neurology 1995; 45:6-10.
  2. Friedman DI. Pseudotumor cerebri. Neurosurg Clin N Am 1999; 10(4):609-621.
  3. Ramadan NM. Headache caused by raised intracranial pressure and intracranial hypotension. Curr Opin Neurol 1996; 9:214-218.
  4. Lee AG. Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Cutis 1995; 55:165-168.
  5. Chiu AM, Chuenkongkaew WL et al. Minocycline treatment and pseudotumor cerebri syndrome. Am J Ophthalmol 1998; 126(1):116-121 (ISSN: 0002-9394).
  6. Goulden V, Glass D, Cunliffe WJ. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol 1996; 134(4):693-695.
  7. Nagarajan L; Lam GC. Tetracycline-induced benign intracranial hypertension. J Paediatr Child Health 2000; 36(1):82-83.