Copyright 2007 The Authors Journal compilation 2007 Blackwell Munksgaard
Acta Neurol Scand 2007: 116: 322–327 DOI: 10.1111/j.1600-0404.2007.00905.x
ACTA NEUROLOGICA SCANDINAVICA
Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study C¸elebisoy N, Go¨kc¸ay F, S¸irin H, Akyu¨rekli O¨. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand 2007: 116: 322–327. 2007 The Authors Journal compilation 2007 Blackwell Munksgaard. Objectives – To assess the efficacy of topiramate in the treatment of idiopathic intracranial hypertension (IIH) and to compare it with acetazolamide. Methods – Fourty patients diagnosed as IIH and randomly assigned to treatment with either acetazolamide or topiramate were assessed prospectively. Improvement in the visual fields at the end of third, sixth and twelfth months were taken into consideration. Results – The demographic, clinical features and the cerebrospinal fluid (CSF) pressure of the two treatment groups were similar at the beginning of the study. When the follow-up visual field grades were compared with the visual field grades at the beginning of the study in each group a statistically significant improvement was detected with both drugs. When the results of the two treatment groups were compared with each other no statistically significant difference was present. Prominent weight loss was recorded in the topiramate group. Conclusions – Topiramate seems to be effective in the treatment of IIH. Weight reduction as well as the reduction of the CSF formation is the possible mechanism of action.
Introduction
Idiopathic intracranial hypertension (IIH) is the clinical syndrome of raised intracranial pressure without clinical, laboratory or radiological evidence of intracranial pathology. Diagnostic criteria were first published by Dandy in 1937 (1). With the advent of neuroimaging techniques some conditions previously diagnosed as IIH, such as intracranial venous thrombosis have been identified and the diagnostic criteria have undergone several modifications. The most recent formulation of the criteria has been published in the International Headache SocietyÕs (IHS) classification of headache disorders second edition (2). IIH is a relatively common condition with an annual incidence of 1–2 per 100,000 of population, with an incidence of up to 21 per 100,000 in obese women in the childbearing age (3–5). No gender difference occurs in children (6) whereas the female-to-male ratio is 322
N. elebisoy, F. GçkÅay, H. S¸ irin, . Akyrekli Department of Neurology, Ege University Medical School, Bornova, _Izmir, Turkey
Key words: acetazolamide; idiopathic intracranial hypertension; topiramate Nes¸ e elebisoy, Department of Neurology, Ege University Medical School, Bornova, _Izmir, 35100, Turkey. Tel. ⁄ Fax: +90 232 3880980 e-mail:
[email protected] Accepted for publication June 19, 2007
between 3:1 and 10:1 in adults (3–5). Headache is the most prominent manifestation; it is the presenting symptom in 75–100% of patients (4, 7). Disturbance of vision is the second most prevalent symptom. Monocular or binocular transient visual obscurations (TVO) have been reported in up to 72% of the patients. Other less common visual abnormality is diplopia with sixth nerve palsy. Unilateral or bilateral pulsatile tinnitus has been reported in up to 60% of the patients (7). Papilledema is the cardinal finding of the visual examination and it is almost always bilateral but can be asymmetric (8). Visual field defects appear in up to 96% of patients during the course of IIH (7). Enlargement of the blind spot is frequent and is found nearly in all patients with papilledema. Peripheral rim constriction, nasal steps and arcuate scotomas are the other most typical defects (9). Reduction in visual acuity is less frequent. However, it may deteriorate rapidly in severe cases (7).
Idiopathic intracranial hypertension Idiopathic intracranial hypertension is a diagnosis of exclusion. Magnetic resonance imaging (MRI) has become the investigation of choice. Magnetic resonance venography (MRV) must also be performed in order to rule out cerebral venous thrombosis (10–12). The diagnostic criteria require elevated cerebrospinal fluid (CSF) pressure with normal constituents. Management of patients includes a combination of medical therapy associated with weight reduction where appropriate, and surgical intervention for the severe cases. Carbonic anhydrase inhibitor acetazolamide is the drug most commonly used to treat IIH. It reduces the CSF production. Patients taking acetazolamide usually complain about nausea, fatigue, tingling of the hands and feet and altered taste. The other alternatives for treatment are diuretics such as furosemide, which seems to be much less potent than acetazolamide; its mechanism of action in reducing increased intracranial pressure, however is not clear (10, 11, 13). There are only two case reports with topiramate showing favorable results (14, 15). The aim of the present study was to investigate the effect of topiramate in IIH and to compare it with acetazolamide treatment. Materials and methods
The study was conducted in the specialized neuroophthalmology clinic in Department of Neurology, _ Ege University Medical School, Izmir, Turkey. The study protocol was approved by the local ethics committee. From September 2002 to January 2007 patients with the diagnosis of IIH were assessed prospectively. The histories were taken directly from the patients, who were asked if they had headache, TVO diplopia, and ⁄ or tinnitus. Secondary causes of IIH including known systemic diseases and medications were also questioned. All patients underwent a complete general, neurological and ophthalmologic examination including Snellen visual acuities, ophthalmoscopy and automated perimetry. The degree of papilledema was graded by using FrisenÕs scheme (16). Grade 0 defines an optic nerve head without swelling and Grade V severe papilledema. Marco MS 30 (Marco Ophthalmic Inc., Jacksonville, FL, USA) was used for perimetry testing tresholding 98 points in the central 30 of the visual field. Visual fields with loss of fixation, false positive and false negative errors over 30% were accepted unreliable and repeated. The perimetry grading was performed according to the criteria of Wall and George (7) given for automated perimetry. Grade 0 defines normal visual field and Grade III moderate visual loss.
All patients had blood examinations including complete blood count, blood biochemistry, thyroid and parathyroid function tests to exclude disorders reported to cause raised intracranial pressure such as iron deficiency anemia, thyroid disease, hypoparathyroidism and renal failure. CSF examinations other than pressure measurement, including cell count, biochemistry, cultures for bacteria, fungi and tuberculosis were grown and cytological analysis were performed to rule out infectious and infiltrative meningitis. All patients had MRI and MRV to rule out intracranial pathology including sinus thrombosis. MRI examination was performed with a 1.5 T unit (Magnetom Vision, Siemens, Erlangen, Germany). Forty-one patients diagnosed as IIH were assigned to treatment with either acetazolamide or topiramate. The first patient was given acetazolamide and the second topiramate and this alternating choice of drugs was continued. Snellen visual acuities, ophthalmoscopy and automated perimetry testing were made every second week in the first month increasing to one in every third month to judge the treatment efficacy. The results of the third, sixth and twelfth months were taken into consideration. There were 36 women and 5 men with age ranging from 16 to 51 years. One patient was dropped out as the visual fields were deteriorated very rapidly within the first week when she was using topiramate 50 mg ⁄ day; a lumboperitoneal shunt was performed on her. The results of 20 patients on topiramate were compared with the results of the 20 patients on acetazolamide. Treatment of topiramate was administered at doses ranging from 100 to 150 mg daily. Daily doses of acetazolamide ranged from 1000 to 1500 mg. Topiramate was started at a dose of 50 mg ⁄ day and gradually titrated to the efficacious dose. A titration schedule that started with 500 mg ⁄ day was used for acetazolamide. Statistical analyses were performed by Statistical Package for Social Sciences (SPSS) 14.0 for Windows (SPSS Inc., Chicago, IL, USA). The demographic and the clinical features including visual acuity, papilledema grades and visual field grades of the two treatment groups at the initial visit and the visual field grades at the end of the third, sixth and twelfth months of the two groups were compared by using the Mann–Whitney U-test (for non-parametric data). Statistical significance level was set at P < 0.05. Friedman test was used for the analysis of improvement in visual field grades under therapy in each group. Wilcoxon signed ranks test was used for further comparison of the visual field grades at the initial visit with the 323
C¸elebisoy et al. visual field grades at the end of the third, sixth and twelfth months. After the Friedman test Bonferroni, correction was performed for Wilcoxon signed ranks test and the P-value was set at 0.0167. Results
Of the 40 patients taken into consideration, 35 were women, of which 17 were in the acetazolamide and 18 in the topiramate group. The median age at onset of symptoms was 35 years in the acetazolamide and 32 years in the topiramate group. Median weight in the acetazolamide group was 70 kg whereas it was 73.5 kg in the topiramate group. Median CSF pressure recorded at the beginning of the study was 300 mm H2O in the acetazolamide and 342.5 mm H2O in the topiramate group. The demographic features including sex, age at onset and weight as well as the CSF pressure recorded in two groups are given in Table 1. When the demographic features of the two treatment groups were compared with each other, no statistically significant difference was found (P > 0.05). The most frequent symptom was headache recorded in all 40 patients (100%). Eighteen patients (45%) complained about TVO (11 in the acetazolamide and seven in the topiramate group). Intracranial noises were reported by 12 patients (30%) (seven in the acetazolamide and five in the topiramate group). Diplopia associated with abducens palsy was present in seven patients (17.5%; two using acetazolamide and five using topiramate). The symptoms of the patients are listed in Table 2. The best corrected Snellen visual acuity at the initial visit was normal in 36 of the 40 patients. There were four patients (10%) with the loss of at least two lines in Snellen visual acuity at the beginning of the study. Three were in the topiramate and one in the acetazolamide group. All of the 40 patients had papilledema. Automated perimetry was abnormal in all 40 patients at the initial visit. The most common defects were constriction of the visual field and nasal loss. Clinical features of the patients are given in Table 2. When these
Table 1 Demographic features and the CSF pressure values of the two treatment groups
Sex (M ⁄ F) Age (median) Weight (kg) (median) CSF pressure (mmH2O) (median)
324
Acetazolamide
Topiramate
3 ⁄ 17 35 (16–49) 70 (63–95) 300 (225–700)
2 ⁄ 18 32 (16–51) 73.5 (60–95) 342.5 (250–850)
Table 2 Symptoms and the clinical features of the two treatment groups Acetazolamide (number of patients) Headache TVO Intracranial noises Diplopia Snellen visual acuity Normal Loss of at least two lines Papilledema grades at the initial visit Grade 3 Grade 4 Grade 5 Visual field grades at the initial visit Grade 1 Grade 2 Grade 3
Topiramate (number of patients)
20 11 7 2
20 7 5 5
19 1
17 3
3 14 3
2 13 5
1 5 14
7 13
features including Snellen visual acuity, papilledema grades, visual field grades as well as the CSF pressure of the two treatment groups at the beginning of the study was compared, a statistically significant difference could not be found (P > 0.05). Visual field grade was the main criterion to assess clinical improvement. When the visual field grades at the beginning of the study were compared with the visual fields at the end of the third, sixth and twelfth months, a statistically significant difference was present (P < 0.0167), indicating prominent improvement in both of the treatment groups. Median visual field grades at the initial visit and at the end of the third, sixth and twelfth months in the two groups are given in Table 3a, b. Table 3 Mean and median visual field grades at the initial visit and at the end of the third, sixth and twelfth months in the two treatment groups (a) right eye (b) left eye Visual field grade (topiramate) Median (min–max) (a) Right eye Initial visit Third month Sixth month Twelfth month (b) Left eye Initial visit Third month Sixth month Twelfth month
Pa
Visual field grade (acetazolamide) Median (min–max)
Pa
Pb
3 2 2 1
(2–3) (1–3) (1–3) (0–3)
0.008
