Pseudotumor cerebri syndrome (PTCS) is a disorder associated with increased intracranial pressure in the absence of clinical, laboratory, or radiologic evidence of an intracranial space-occupying lesion (1–4). The diagnosis is established according to the modified Dandy criteria (1). The annual incidence among adults in the United States seems to be 0.9 per 100,000; 3.5 per 100,000 females; and 13–19 per 100,000 obese females (5). In a Canadian study, the prevalence in the pediatric population was found to be 1/100,000 with equal sex distribution (6).
The precise terminology for PTCS remains unsettled (7). If the disorder occurs without any identifiable risk factors, the terms primary PTCS or idiopathic intracranial hypertension (IIH) are applied. In contrast, if a predisposing factor is present (e.g. minocycline use, cerebral venous sinus thrombosis), it is designated secondary PTCS. Previous studies have reported that the clinical profile of pediatric PTCS differs from that of adults, suggesting that the precipitating factors and the outcome may be different in children (8–10).
In addition to appropriate management of any risk factors, acetazolamide is the mainstay of the medical treatment of PTCS (11). Disease relapse during and after discontinuation of treatment was reported to be 20% in one study (7). Indications for surgical intervention in the treatment of PTCS include deterioration in vision and incapacitating headaches or relapse of headaches despite aggressive medical management. Two surgical procedures, optic nerve sheath fenestration and cerebrospinal fluid shunting (lumboperitoneal and ventriculoperitoneal shunt), have a place in the treatment of PTCS. Unlike adult patients with PTCS, in whom the procedure choice is generally dictated by the predominant complaint (visual deterioration or headache), in pediatric patients, the guidelines for surgical intervention are less clear (11).
The natural history of PTCS in childhood is poorly understood. Of the few studies on treatment, most were focused on visual acuity, visual fields, and papilledema (5,7,8). Our aim was to investigate the response to treatment and relapse in pediatric patients with PTCS 2 years after diagnosis. We included those with both the primary and secondary forms.
This study was a retrospective follow-up of pediatric patients, who were treated for PTCS between 2000 and 2007 in the pediatric and the pediatric neurology departments at our institution. Their medical charts were reviewed for demographic and clinical data. In addition, a phone survey was conducted to complete the missing data. The study population included children diagnosed with PTCS, according to the modified Dandy criteria. All children were under 18 years of age at the time of diagnosis. As the purpose of the investigation was to shed light on patient outcomes, we included only children with at least 2 years of follow-up in the pediatric neurology clinic.
Demographic and clinical data collected included: age at onset of symptoms; symptom/complaint (headache, vomiting, blurred vision etc); presence of papilledema; amount overweight (defined as BMI [body mass index] >25 kg/m2) at presentation; medical history of recent drug therapies; abnormal findings on neurological examination; neuroimaging studies; cerebrospinal fluid opening pressure measured during lumbar puncture; response to drug treatment (defined as relief of symptoms and improvement in the neuro-ophthalmological findings); duration of drug therapy; duration of follow-up; duration of symptoms before the diagnosis and after beginning drug therapy; disease relapse after cessation of drug therapy; and surgical intervention. The study was conducted with the approval of the hospital institutional review board.
Data analysis was performed using SPSS version 13 for Windows (SPSS for Windows; SPSS Inc, Chicago, IL). The student t test and χ2 test were used to compare the variables, including age of disease onset, sex, overweight, and cerebrospinal fluid opening pressure between the responders and nonresponders groups, as well as between the relapse and nonrelapse groups. For sex and for the presence of being overweight, contingency tables were used to compare between the prepubertal and pubertal groups. Puberty was defined by age at presentation (pubertal group > 11 years) (12).
Fisher exact test was used when appropriate. Logistic regression was used by backward conditional removal of variables to estimate the predictors of response to therapy and the risk factors for relapse in the cohort.
The study group included 60 children with PTCS (36 females; 24 males). Onset of symptoms was at a mean age of 10.8 years (range: 2–18 years) and the mean duration of follow-up was 3.47 years (range: 2–13.5 years). Twenty-four patients were prepubertal (2–11 years), and 36 patients were pubertal (11–18 years). There was a distinct female predominance in the pubertal group (n = 26, 72.2%), whereas in the prepubertal group 41.7% were females, with a female male ratio of 10:14 (χ2 = 5.6, P < 0.05).
The mean duration of complaints during the acute phase was 1.7 ± 2.2 months (range: few days–12 months). Eight patients (13%) were asymptomatic and they were diagnosed because of the incidental discovery of papilledema. Of the patients with recorded symptoms, 50 had headaches (83.3%), 21 complained of blurred vision (35%), 12 suffered from vomiting (20%), 6 had diplopia due to sixth cranial nerve palsy (10%), and 3 complained of paresthesias (5%).
All patients had normal neuroimaging, either brain MRI (48.3%) or computed tomography (52.7%). The mean opening pressure on lumbar puncture was 38.4 ± 10.8 cm H2O (range: 20–60 cm H2O).
Four patients (6.7%) had conditions previously associated with increased intracranial pressure: 2 patients (3.3%) had polycystic ovary syndrome and 2 (3.3%) were treated with minocycline. In addition, 1 patient was treated for hypothyroidism and 1 patient was given a homeopathic drug before admission. Fifty-six (93.3%) patients had no relevant medical history, but 29 patients had a BMI >25 kg/m2. The prevalence of being overweight was higher in the pubertal group (2–11 years: 29.2%, 11–18 years: 61.1%; χ2 = 5.8, P < 0.05). Patients with PTCS but BMI ≤25 kg/m2 were significantly younger (8.4 ± 4.7 vs 12.6 ± 3.1 years, P < 0.001).
All the patients received acetazolamide as first line therapy. Fourteen patients (23.3%) were treated with second line therapy because of acetazolamide treatment failure. Among them, 7 patients (11.6%) received topiramate, 4 (6.6%) were treated with acetazolamide and corticosteroids, 2 (3.3%) received acetazolamide, corticosteroids, and topiramate and 1 patient (1.6%) was treated with acetazolamide, corticosteroids, and furosemide.
Treatment Course and Outcome
Forty-six patients (76.6%) responded to acetazolamide with complete resolution of headache within an average of 3.8 weeks (range: 1 week–4 months) from initiation of therapy and with resolution of papilledema.
The duration of drug therapy among the 46 patients who responded to acetazolamide ranged from 1 month to 5 years. In 27 patients (59%) treatment lasted less than 6 months, in 7 (15%) between 6 months and 1 year, in 5 (11%) 1–2 years and 7 (15%) were treated for more than 2 years. Thus, most responders (74%) received treatment for less than a year. One patient had their medication switched to topiramate because of side effects of acetazolamide.
Among the 14 (23.4%) nonresponders to acetazolamide, 9 patients (15%) required surgical intervention: 6 (10%) underwent lumboperitoneal shunt; 2 (3.3%) underwent foramen magnum decompression; 1 (1.7%) required 3 spinal taps. The indications for surgical intervention included intractable headaches despite pharmacological therapy, or headache relapse. No patient in our study underwent optic nerve sheath fenestration.
Table 1 summarizes the clinical data of the acetazolamide-responders vs the nonresponders. The only statistically significant difference between the 2 groups was age at onset. The nonresponders tended to present with PTCS at a younger age than the acetazolamide responders (8.7 ± 4.8 vs 11.5 ± 4.1 years, P = 0.04).
To identify the risk factors for nonresponse to drug therapy, we applied a logistic regression model that included the following variables: sex, age of onset, presence of etiology (vs idiopathic), BMI, duration of complaints, headache, blurred vision, vomiting, diplopia, paresthesia, tinnitus, opening pressure on LP (lumbar puncture), papilledema, and puberty. Using backward stepwise variable selection, we found that (with 95% CI [confidence interval]) male sex (odds ratio = 5.59 [0.67, 46.57], P = 0.112), older age of onset (odds ratio = 1.64 [1.19, 2.25], P = 0.02), idiopathic (odds ratio = 0.83 [0.008, 0.83], P = 0.034) and no headaches (odds ratio = 0.64 [0.003, 1.21], P = 0.67) were predictors of good response to medical treatment.
Of the responders, 3 patients were still under treatment during our study. Thirty-one out of the 43 responders (72%) remained asymptomatic after discontinuation of drug therapy, but 12 patients (26%) had a relapse of symptoms. We found that overall, 51.6% of patients with PTCS responded to the initial acetazolamide therapy with no relapse of symptoms (n = 31) and another 20% (n = 12) who had relapse of symptoms after discontinuation of acetazolamide, required longer periods of therapy to achieve a good response. Table 2 summarizes the differences between the relapse vs the nonrelapse subgroups among the responders group. On comparing these 2 subgroups, we found that the only statistically significant difference was younger age at onset in the relapse group than in nonrelapse group (8.9 ± 4.5 vs 12.1 ± 3.7 years, P < 0.05). The presence of BMI >25 kg/m2 or headaches did not significantly predict the rate of relapse (Table 2). It is important to note that all the patients with a relapse after acetazolamide discontinuation responded well to renewal of treatment and none required surgical intervention.
A logistic regression model was applied to identify risk factors that could predict relapse. The variables entered were: sex, age of onset, presence or absence of risk factors, BMI, duration of complaints, headache, blurred vision, vomiting, diplopia, paresthesia, tinnitus, opening pressure in LP, papilledema, and puberty. The only selected variable for the model (with 95% CI) in backward stepwise was puberty (odds ratio = 0.182 [0.04, 0.77], P = 0.021), meaning that prepubertal children had higher risk of relapse.
The aim of our study was to investigate the response to treatment in pediatric patients with PTCS. For this purpose, we examined duration of treatment required to achieve complete symptoms remission, response rate for initial drug therapy, relapse rate after discontinuation of drug treatment, the need for neurosurgical intervention, and potential predictors for worse outcome.
All patients were treated with acetazolamide as first line therapy with a response rate characterized by resolution of symptoms and papilledema as high as 76.6%. Only 1 patient reported side effects related to acetazolamide treatment. We found that the nonresponders in our series were significantly younger than acetazolamide responders. The relationship between younger age at presentation and treatment-resistant PTCS has been reported previously (13). The response to second line therapy was poor among the 14 nonresponders, 9 patients requiring surgical intervention.
Of the 46 patients with good response to acetazolamide, 12 patients (26%) experienced relapse after discontinuation of drug therapy, but all responded after resuming treatment, with no need for neurosurgical intervention. Comparison between the relapse and nonrelapse subgroups also found that patients with relapse presented with PTCS at a younger age.
Our study revealed that 51.6% of patients with PTCS responded to initial acetazolamide therapy with no relapse of symptoms after an average of 1 year of treatment. Patients with initial response to treatment and relapse after drug discontinuation (20% of patients) required longer periods of therapy after resuming the medication, but all eventually responded to therapy.
Compared with our results, the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) of adult patients found no significant change in headache disability score compared with baseline after 6 months of acetazolamide treatment and low-sodium diet, whereas the improvement in visual field with treatment was modest compared with controls (14). We assume that a possible reason, besides different age groups and ocular vs nonocular prominent symptomatology, may be the dissimilarity in the profile of the studied population (15). Although in the IIHTT the typical patient profile was a young overweight female, in the present study 40% of the children were males, 40% prepubertal and 53% of the prepubertal group were not overweight. This confirms earlier reported observations in pediatric patients with PTCS (16).
The demographic pattern in our series demonstrating female predominance in the postpubertal subgroup is similar to that seen in PTCS study on adult population (15) and in other pediatric series (9,17). Moreover, we found an increased prevalence of overweight individuals in the pubertal subgroup in accordance with previous reports (18–20).
Only 9 patients (15%) in our series were asymptomatic, much less when compared with other studies that reported approximately 25%–33% of patients with PTCS being asymptomatic (21,22). A possible explanation for this difference may be the fact that in previous series, which were mainly reported by neuro-ophthalmologic teams, the presenting symptom was the incidental finding of papilledema.
In conclusion, the treatment outcome in most patients (76.6%) in our PTCS series was favorable, with complete remission of symptoms with acetazolamide therapy and a low rate of side effects. However, for the subgroup of nonresponders the outcome was poor. A younger age at presentation was found to be associated with a poorer prognosis as it was a predictor of drug treatment failure, need for surgical intervention, and relapse after discontinuation of medical therapy.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: E. Tovia, S. Reif, and A. Fattal-Valeski; b. Acquisition of data: E. Tovia, A. Oren, and A. Mitelpunkt; c. Analysis and interpretation of data: A. Fattal-Valevski, A. Mitelpunkt, and S. Reif; Category 2: a. Drafting the manuscript: E. Tovia, A. Oren, and A. Fattal-Valevski; b. Revising it for intellectual content: A. Oren, S. Reif, A. Mitelpunkt, and A. Fattal-Valevski; Category 3: a. Final approval of the completed manuscript: E. Tovia, S. Reif, A. Oren, A. Mitelpunkt, and A. Fattal-Valevski.
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