The aim of this work was to describe the structure and methods of the VIIH database and to characterize a population-based real-world IIH cohort, which is the largest European IIH cohort presented to date.
Our main findings align well with previously published literature: IIH is a rare disease, mainly affecting young overweight women. Most common symptoms at first admittance are headaches resembling a migraine or tension-type headache as well as visual disturbances. A multimodal treatment concept of weight loss and pharmacological therapy can improve disease course, but long-term sequelae of IIH may be substantial.
Acknowledging the limitations of retrospective data collected before the official establishment of the VIIH database, this study provides a comprehensive overview of demographics, clinical presentations, and disease courses of IIH in middle Europe. The VIIH cohort characterized in this study will provide the base of prospective studies analyzing the value of diagnostic procedures, prognostic/predictive markers and efficacy, tolerability, and safety of therapeutic interventions in patients with IIH.
Cohort characteristics and symptoms
Demographic characteristics of the VIIH cohort (mean age about 32 years, 90% female, 85% overweight) are in line with previously published cohorts [30].
At initial presentation headache was present in 84% resembling migraine in 43% and tension-type headache in 17%. Reported rates of headache types vary within the literature. While Friedman et. al initially described that about 30% of treated IIH patients suffer from a tension headache type and 20% from migraine-like headaches, the IIHTT cohort showed a prevalence of 52% migraine-like headaches and 22% tension-type headaches [10, 11]. Our results support a representation in between those findings but confirm migraine-like headache to be the most common phenotype among IIH patients.
Visual symptoms were present in 76% at initial presentation and 95% had papilledema, while 5% were classified as IIH-WOP. Previous reports have also indicated a 5% proportion of patients with IIH without papilledema [18, 31]. In a prospective clinical trial of 50 IIH patients, abducens palsy was found in approximately 10% of patients, which is about double the rate in the VIIH cohort (5.3%) [16]. A possible explanation for this gap might the retrospective study design in our cohort. Abducens palsy often can be very subtle, and some cases might have been missed.
The prevalence of pulsatile tinnitus was documented in 24%, while other groups found a prevalence up to 58% [32, 33]. However, we only classified a pulsatile tinnitus as such if it was explicitly documented in clinical reports, which likely has led to a lower frequency.
Paraclinical findings
MRI findings most frequently reported in our cohort were empty sella sign (40%), transverse sinus stenosis (29%), and optic nerve sheath distension (27%). These frequencies are lower than in a recent study by Brodsky et. al, which can likely be explained by the retrospective design of our study, where MRI reports are not standardized and depend on the indication of MRI, especially whether radiologists are specifically asked for signs of IIH [34]. Lumbar puncture opening pressure in our cohort (median 31 cmH2O) aligns well with findings from other studies [17, 21]. Proportions of abnormalities in visual acuity and visual fields (16% and 67%, respectively) are also similar to previous studies with ranges of 10-25% and 61-92%, respectively [16, 35]. As well, OCT findings (Median pRNFL thickness: 199µm, median GCL volume: 1.13 mm3) in our cohort are comparable to reported findings from other groups [36, 37]. Also, ultrasonography showed similar ONSD (median 5.4 mm) compared to previously published studies using standardized A-scan echography in IIH, but slightly lower values than studies measuring ONSD from B-scans (approximately 6.5 mm) [38–40]. B-scan ultrasound has limited resolution that depends on the used frequency, and since standardized settings are not available, caliper measurements in the images are influenced by the applied signal gain due to a blooming effect. Standardized A-scan echography avoids these drawbacks and makes it a more accurate measure for ONSD.
Treatment
In the VIIH cohort, significant weight loss as the basic principle of IIH treatment was achieved in 57% of patients with a median reduction of about 7% from weight at initial presentation, while 43% had not achieved significant weight loss. All but one patient received acetazolamide therapy, while therapeutic lumbar punctures were necessary in 56% and surgical treatment (mostly ventricular peritoneal/atrial shunt) in 13%. Achieved weight loss, average maximum acetazolamide dosage and proportion of lumbar punctures were largely in line with the therapeutic strategy of the acetazolamide + weight loss treatment arm of IIHTT. However, additional lumbar punctures in the IIHTT were performed electively after 6 months in a selected subpopulation. Furthermore, use of other medication such as topiramate was prohibited and no surgical interventions have been performed [21].
Outcome
Long-term follow-up after almost 4 years, showed persistent headache in 76% of the patients. Headache had improved in 76% and 24% were headache-free. In the IHTT cohort as well as in our cohort, 84% of patients had headaches at baseline. Regardless of the IIHTT’s treatment group (acetazolamide or placebo), prevalence decreased to about 68%. Also, both treatment groups showed an equivalent improvement of headache disability at 6 months follow-up.
At final follow-up the proportion of patients with abnormal visual acuity had not changed compared to baseline remaining at 15%. This aligns with the assumption that visual acuity as a measure of central vision function is largely unaffected by moderately increased ICP [12]. Comparing initial presentation to follow-up, perimetry was abnormal in 67% vs. 50% (8% worsened, 24% improved). Visual fields showed a slight improvement (+2.1 dB) from baseline, which is comparable to the improvement of +1.4 dB found in the IIHTT acetazolamide + weight loss group [21]. Fundoscopy was still abnormal in 59% (compared to 95% at baseline). The acetazolamide + weight loss treatment group in the IIHTT achieved an investigator rated Frisén-Scale change of -1.55, from 2.60 at baseline to 0.85 at 6 months follow-up [21]. Hence, the majority of treated patients in the IIHTT had an investigator rated Frisén-Scale outcome of 0 or 1. Given the additional inclusion of severe cases in our study, the changes observed in our cohort seem to support these findings [12].
In OCT, pRNFL thickness was significantly reduced by a median 105µm resulting in apparently normal pRNFL thickness at last follow-up (99µm). While pRNFL cannot distinguish between real resolution of papilledema and pseudonormalization caused by atrophy, the corresponding finding of very moderate loss of GCL volume (-0.05 mm3 over nearly 4 years) strongly indicates a small degree of neuroaxonal damage. These results confirm the significant effect of weight loss and acetazolamide as described in the IHHTT OCT substudy [40]. In ultrasonography, 65% still displayed an ONSD above 4.5mm and/or a bat sign compared to 87% at baseline. Median ONSD improved from 5.4mm to 4.9mm, which is comparable to other studies that reported an average decrease of 0.2-0.7 mm after 6 months of treatment [13, 41, 42].
Strengths and Limitations
The strengths of the VIIH database are the large number of patients and the close-meshed, standardized follow-up over a long-term period. Duration of follow-up close to 4 years, which is significantly longer than in prospective trials such as the IIHTT, enables characterization of long-term sequelae. Also, our cohort comprises the whole clinical spectrum of IIH, whereas e.g. the IIHTT only included patients with mild visual loss and patients were excluded if progression of visual symptoms was observed [21].
However, there are some limitations. The retrospective analyses of data collected in clinical routine creates a variety of possible biases, although these are mitigated by the standardized data collection and thorough quality control applied within in the VIIH.
Considering the IIH prevalence in the geographic area, VIIH seems to have caught most of its IIH patients. Still, a potential selection bias towards more benign courses and/or severely disabled patients, who both tend to stop attending clinics, cannot be completely excluded.
Although acquired in a real-world cohort, OCT and echography scans were meticulously controlled for quality and confounding factors were ruled out rigorously, e.g., severe myopia, optic disc drusen or previous diagnoses of ophthalmological, neurological, systemic or drug-related causes of vision loss or retinal damage not attributable to IIH. Biological variability and measurement errors were also minimized by a homogeneous single-center data set. These sources of errors might be increased when protocols and devices vary, and multicenter data sets are used.