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Idiopathic intracranial hypertension (IIH) is increased intracranial pressure (ICP) with normal cerebrospinal fluid (CSF) contents, in the absence of an intracranial mass, hydrocephalus, or other identifiable causes. The current knowledge of the treatment outcome of IIH is limited, and the data on the natural history of this entity are scant.
The objective of the study is to study the treatment response of IIH by serially measuring the CSF opening pressure and to delineate the factors influencing the same.
A prospective observational study in a cohort of fifty patients with IIH in whom CSF opening pressure was serially measured at pre-specified intervals.
The mean CSF opening pressure at baseline was 302.4 ± 51.69 mm of H2O (range: 220–410). Even though a higher body mass index (BMI) showed a trend toward a higher CSF opening pressure, the association was not significant (P = 0.168). However, the age of the patient had a significant negative correlation with the CSF pressure (P = 0.006). The maximum reduction in CSF pressure occurred in the first 3 months of treatment, and thereafter it plateaued. Remission was attained in 12 (24%) patients. BMI had the strongest association with remission (P = 0.001).
In patients with IIH, treatment response is strongly related to BMI. However, patients with normal BMI are also shown to relapse and hence should have continuous, long-term follow-up. The reduction in CSF pressure attained in the first 3 months could reflect the long-term response to treatment.
Idiopathic intracranial hypertension (IIH) is increased intracranial pressure (ICP) with normal cerebrospinal fluid (CSF) contents, in the absence of an intracranial mass, hydrocephalus, or other identifiable causes. The incidence is approximately 0.9/100,000/year rising to 13/100,000/year in women between 20 and 44 years of age, who are 10% above ideal body weight.[2,3] The incidence of IIH among obese women is 20/100,000, and with the global epidemic of obesity, its prevalence is predicted to rise in coming years.
The pathophysiology of IIH remains poorly understood. Although IIH is known to produce a prolonged or recurrent course, data on the long-term rate of recurrence and prognosis are limited.[5,6] As highlighted in a 2015 Cochrane review the current knowledge of the treatment outcome of IIH is inadequate and evidence to guide therapeutic strategies is also scant. There are no large prospective series that describe the natural history of this entity either.
The aim of our study was to determine the long-term course of IIH by serially measuring the CSF opening pressure and to delineate the factors influencing the same.
This is a prospective observational study conducted in the Department of Neurology of a tertiary care hospital in South India from August 2011 to July 2014.
All patients with features of raised ICP fulfilling Modified Dandy criteria were included in the study after obtaining a written informed consent. These criteria included (1) symptoms and signs of generalized intracranial hypertension such as headache, papilledema, sixth nerve palsies; (2) documented elevated ICP; (3) normal CSF composition; and (4) no evidence of hydrocephalus, mass, or structural or vascular lesion on brain magnetic resonance (MR) imaging, specifically, no evidence of cerebral venous thrombosis. The exclusion criteria included (1) other ocular disease causing visual loss; (2) systemic conditions or medications that may be associated with intracranial hypertension; and (3) alternative plausible mechanisms of visual loss other than IIH.
The study protocol was approved by the hospital institutional review boards.
Demographic features, presenting symptoms, duration of symptoms, presence of any systemic disease, and relevant drug history (corticosteroids, vitamins) were noted. All patients underwent focused neurological examination with particular attention to optic disc examination. The body mass index (BMI) was calculated (calculated as weight in kilograms divided by height in meters squared) and patients were classified according to the World Health Organization (WHO) definition as normal weight, overweight, and obese (BMI <25 kg/m2, 25–29.9 kg/m2, and ≥30 kg/m2, respectively).
Routine hematological and biochemical tests including thyroid function test, antinuclear antibody, serum calcium, and serum cortisol were done. Neuroimaging protocol included 1.5 Tesla MR imaging (MRI) scan with MR venography and angiography. Lumbar puncture (LP) with a recording of opening pressure was performed in all patients in the left lateral decubitus position; legs extended more than 90° at the hip with patient breathing steadily. All patients were treated with acetazolamide and frusemide.
The crux of the study is the LPs performed with recording of CSF opening pressure at baseline, 3, 9, 15, and 21 months. If the CSF opening pressure came down to ≤200 mm of H2O at any of the follow-up LPs, medications (acetazolamide and frusemide) were withheld till the next scheduled LP. If in the next LP, the CSF pressure was found to be >200 mm of H2O, medications were restarted. On the other hand, if the CSF pressure remained ≤200 mm of H2O in the next LP also, the patient was deemed to have attained remission, the drugs were withdrawn, and the patient was kept under follow-up without further LPs and on any further symptoms of raised ICP drugs were reinstituted.
Quantitative variables were summarized as mean and standard deviation while the qualitative variables were represented as frequency and percentages. Quantitative variables were compared between the two groups using Student's t-test, while qualitative variables were tested using Chi-square test. Quantitative variables were correlated using Pearson correlation coefficient, and it was graphically represented as scatter plots. P < 0.05 was considered as statistically significant.
Fifty-eight patients who fulfilled the inclusion were enrolled during the study. Of these, eight patients were later excluded as four of them withdrew the consent, two were lost for follow-up, and one patient was later diagnosed to have systemic lupus erythematosus. There were 47 females and 3 males (female:male ratio [15.7:1]). The mean age was 32.16 ± 9.56 years (range 13–60). A total of 46% were <30 years, 32% between 30 and 39 years of age, and only 22% were more than 40 years.
The mean BMI was 27.71 ± 6.12 kg/m2 (range 18.1–48). A total of 32 patients (64%) were in the overweight (n = 16) or obese (n = 16) (i.e., BMI ≥25 kg/m2) category.
The most common presenting symptom was a headache (82%). Other symptoms were blurring of vision 70%, transient visual obscuration 68%, tinnitus 56%, diplopia 22%, CSF rhinorrhea 2%, and vertigo 2%. In two asymptomatic patients (4%), IIH was diagnosed following incidental detection of papilledema on routine ophthalmologic evaluation.
The ocular findings included papilledema 46 (92%), lateral rectus palsy 11 (22%), and optic atrophy 2 (4%). Four patients (8%) did not have papilledema at presentation.
Duration of symptoms ranged from 1 week to 6 years.
The most common radiological abnormality detected was an empty sella (66%). Other abnormalities detected were flattening of the posterior sclera (58%), distension of the perioptic subarachnoid space (52%), and vertical tortuosity of the optic nerve (38%). The MRI was normal in 13 (26%) patients.
The mean CSF opening pressure at presentation was 302.4 ± 51.69 mm of H2O (range: 220–410). Even though a higher BMI showed a trend toward a higher CSF opening pressure, the association was not significant (P = 0.168). However, the age of the patient had a significant negative correlation with the CSF pressure (P = 0.006); older patients having less opening pressure [Figure 3].
During the follow-up LPs at 3, 9, 15, and 21 months the mean CSF pressures were 227.94, 230.10, 222.39, and 223.57 mm of H2O, respectively. The maximum reduction in CSF pressure occurred in the first 3 months of treatment, and thereafter it plateaued [Figure 4]. Remission (CSF pressure ≤200 mm of H2O on two consecutive measurements with the second one while off medications) was attained in 12 (24%) patients. In 22 (44%) patients, the CSF pressure decreased to ≤200 mm of H2O in any one of the follow-up LPs but increased again to >200 mm of H2O on withdrawal of medications. Sixteen (32%) patients had persistently elevated CSF pressures of >200 mm of H2O throughout the study period [Table 1].
BMI had the strongest association with remission (P = 0.001). While ten patients (55.6%) with a BMI of <25 attained remission, only two patients (12.5%) with a BMI of 25–30 did so. At the same time, none of the patients with a BMI of more than thirty attained remission.
This prospective observational study of fifty patients with IIH is one of the largest series of IIH from India. This is also the largest study on the natural history of IIH employing CSF pressure measurement to monitor the response to treatment rather than surrogate markers of raised ICP such as papilledema or visual field defects. The basic clinical denominator in IIH being the raised ICP, the observations of our study has important implications.
It has already been established that IIH typically occurs in obese, young women of the childbearing age group. In our cohort, females constituted the vast majority of the patients (94%). Most large IIH trials report a preponderance of females usually in the 90% range.[6,12,13,14]
The prevalence of obesity in most large series ranges from 70.5% to 94%.[15,16,17] However, in our study, only 64% of the patients belonged to the overweight (BMI 25–<30) and obese (BMI ≥30) categories. We applied the WHO definitions of BMI classes and obesity to maintain uniformity of definitions across the studies. The revised consensus BMIs for Asian Indians was proposed to address the higher prevalence of diabetes and cardiovascular diseases and the differing associations of BMI with body fat in this population.[18,19,20,21,22] As per this, the patients are categorized as underweight (<18.5 kg/m2), normal or lean BMI (18.5–22.9 kg/m2), overweight (23.0–24.9 kg/m2), and obese (≥25 kg/m2). It is interesting to note that, when the revised consensus criteria of BMI for India was applied, 82% of patients in our cohort fell into the overweight/obese category, indicating that for all obesity-related health problems, ethnic-specific BMI cutoff values need to be applied.
The highlight of our study is that response to treatment was assessed by serially measuring the CSF opening pressure. When the opening pressure decreased to ≤200 mm of H2O the medications (acetazolamide and frusemide) were withheld, and if a repeat LP 6 months later showed an opening pressure of ≤200 mm of CSF again, the patient was considered to be in remission. Applying this criterion, 24% of patients achieved remission. In 32% of patients, the target CSF opening pressure of ≤200 mm of CSF could never be attained, and the remaining 44% had a fluctuating course with values of ≤200 mm of CSF while on medications and values >200 mm of CSF while medications were withheld.
BMI was strongly correlated with response to treatment. In our study, 55.6% of patients with BMI <25 kg/m2, 12.5% of the patients with BMI 25–30 kg/m2, and 0% of the patients with BMI >30 kg/m2 attained remission. It has been well established that obesity predisposes to IIH, but our study clearly demonstrates that the response of CSF pressure to treatment is also significantly associated with the BMI values.
In a previous prospective study conducted in a cohort of 25 women with BMI >25 kg/m2 diagnosed with chronic IIH (defined as diagnosis >3 months) followed for 9 months, subjects were placed on a nutritionally complete, low energy diet (425 kcal/day) for 3 months. Patients achieved a mean weight loss of 15.7 ± 8 kg. Significantly reduced ICP was noted compared with the pressure measured in the 3 months before diet. In our study, the mean CSF pressure touched the nadir at the 3rd month of treatment and thereafter it remained static indicating that a CSF pressure measurement performed at the 3rd month of starting treatment would be an important prognostic indicator. Even though the mean CSF pressure in normal population has been estimated to be 80-180 mm of CSF; it remained >220 mm of H2O in our cohort throughout the study period especially in patients with a higher BMI. In a previous study, even though the ICP remained above 25 cm H2O in 16 out of 20 women, 13 became asymptomatic for tinnitus, visual loss, diplopia, and visual obscuration after weight loss, compared with four at baseline.
Put together, these data could mean it might not be necessary for people with IIH to reduce their ICP to below defined normal levels to achieve measurable symptomatic relief. Considering the fact that a higher BMI has a marginal though clinically insignificant influence on CSF pressure, one can hypothesize that perhaps the equilibrium of CSF dynamics in resolving IIH might be kept at a higher set point so that apparent normality occurs at higher pressures.
This prospective study from South India shows that the epidemiological parameters of IIH follow a remarkably homogeneous pattern throughout the world. The role of obesity in the pathophysiology of IIH is well known, but geographical and ethnic differences have to be taken into account while defining BMI classes not only in diabetes and cardiovascular diseases but also in IIH. Treatment response is also strongly related to BMI in patients with IIH. However, patients with normal BMI are also shown to relapse and hence should have continuous, long-term follow-up. The reduction in CSF pressure attained in the first 3 months could reflect the long-term response to treatment.
Future studies combining drug therapy with structured weight-reduction strategies might provide a better insight into the management of this chronic condition. Hopefully, data from the IIH treatment trial will provide more information regarding the benefits of weight loss and the relationship between obesity and IIH.
There are no conflicts of interest.