Idiopathic intracranial hypertension is not benign: A long-term outcome study

Abstract

Idiopathic intracranial hypertension (IIH) primarily affects young obese females, and potentially causes visual loss and severe headache. The aim of this experiment is to examine relapse rate and long-term outcome in IIH patients. The methods involved in this experiment include a prospective controlled study of 18 newly diagnosed IIH patients followed for a mean observation period of 21.1 (±8.0) months. Treatment regime included diuretics, dietary recommendations and check-up visits at a dietician. Baseline and follow-up included neurological examination, detailed headache history and comprehensive neuro-ophthalmological examination, including fundus photography, Humphrey visual fields, and measurement of the retinal thickness (RT) and retinal nerve fiber layers (RNFL) by optical coherence tomography (OCT). Relapse was defined as recurrence of either: (1) papilledema or (2) symptoms and demonstrated raised ICP. The result of this experiment is that relapse was found in 28%. Visual function improved from baseline to follow-up and was generally favorable. In patients without relapse of papilledema RT and RNFL were significantly thinner than in healthy controls (p = 0.003 and 0.02), although atrophy was clinically detectable in only one patient. Headache was still present in 67% of the patients at follow-up. Headache was heterogenic and unrelated to relapse. After an initial reduction, weight increased again in the relapse group compared to reduced weight in the non-relapse group (p = 0.013). Thus, the conclusions drawn are that headache was persistent, difficult to classify, and equally represented in relapse and non-relapse patients. Headache was thus a poor marker of active disease. Relapse rate was high and clinically undetectable optic disc atrophy was discovered in apparently well treated IIH patients.

Full text

ORIGINAL COMMUNICATION
Idiopathic intracranial hypertension is not benign: a long-term
outcome study
Hanne M. Yri •Marianne Wegener •
Birgit Sander •Rigmor Jensen
Received: 30 July 2011 / Revised: 28 September 2011 / Accepted: 1 October 2011
ÓSpringer-Verlag 2011
Abstract Idiopathic intracranial hypertension (IIH) pri-
marily affects young obese females, and potentially causes
visual loss and severe headache. The aim of this experi-
ment is to examine relapse rate and long-term outcome in
IIH patients. The methods involved in this experiment
include a prospective controlled study of 18 newly
diagnosed IIH patients followed for a mean observation
period of 21.1 (±8.0) months. Treatment regime included
diuretics, dietary recommendations and check-up visits at a
dietician. Baseline and follow-up included neurological
examination, detailed headache history and comprehensive
neuro-ophthalmological examination, including fundus
photography, Humphrey visual fields, and measurement of
the retinal thickness (RT) and retinal nerve fiber layers
(RNFL) by optical coherence tomography (OCT). Relapse
was defined as recurrence of either: (1) papilledema or (2)
symptoms and demonstrated raised ICP. The result of this
experiment is that relapse was found in 28%. Visual
function improved from baseline to follow-up and was
generally favorable. In patients without relapse of papil-
ledema RT and RNFL were significantly thinner than in
healthy controls (p=0.003 and 0.02), although atrophy
was clinically detectable in only one patient. Headache was
still present in 67% of the patients at follow-up. Headache
was heterogenic and unrelated to relapse. After an initial
reduction, weight increased again in the relapse group
compared to reduced weight in the non-relapse group
(p=0.013). Thus, the conclusions drawn are that head-
ache was persistent, difficult to classify, and equally rep-
resented in relapse and non-relapse patients. Headache was
thus a poor marker of active disease. Relapse rate was high
and clinically undetectable optic disc atrophy was discov-
ered in apparently well treated IIH patients.
Keywords Headache Idiopathic intracranial
hypertension OCT Papilledema Relapse Recurrence
Introduction
Idiopathic Intracranial Hypertension (IIH) is a condition of
raised intracranial pressure (ICP) in the absence of space
occupying lesions or other known etiology. Symptoms
include severe headache, pulsatile tinnitus, transient visual
obscuration (TVO), blurred vision and diplopia [15,31,41].
Some reports of dizziness [10,25] or cognitive deficits [3,
38] have also been published. Signs are papilledema [5,20,
21] and occasionally sixth nerve palsy. The papilledema may
be asymmetric, unilateral or in some cases even absent [23].
The main morbidity of IIH is the risk of visual impairment
and high recurrence rates have been reported [17]. If treated,
visual prognosis is usually good [12]. Untreated the papil-
ledema may cause a progressive and irreversible visual loss
due to secondary optic disc atrophy. Unfortunately, visual
loss may be insidious and asymptomatic until irreversible
damage has occurred. Mainly visual fields are affected while
visual acuity and color-vision are relatively spared [32,33].
IIH primarily affects young obese women. The estimated
incidence is this group is 20 times higher (19.4/100.000) than
in the general population (0.9–1.0/100.000) [11,28,29]. As
the worldwide prevalence of obesity is rapidly increasing the
H. M. Yri (&)R. Jensen
Danish Headache Center, Glostrup Hospital,
University of Copenhagen, Nordre Ringvej 67,
DK-2600 Glostrup, Denmark
e-mail: HAMAYR01@glo.regionh.dk
M. Wegener B. Sander
Department of Ophthalmology, Glostrup Hospital,
University of Copenhagen, Glostrup, Denmark
123
J Neurol
DOI 10.1007/s00415-011-6273-9

incidence of IIH is likely to follow. Even though the inci-
dence at this point is relatively low, the socio-economic
consequences of the disease are substantial [13].
A standardization of the acute and long term manage-
ment of IIH patients is lacking, and further information on
the natural history of the disorder is needed to establish a
sufficient clinical follow-up regime. The aim of the present
study was to investigate the relapse rate and long term
clinical outcome, with respect to visual function and
headache, in a prospective case–control study of 18
patients with confirmed IIH.
Materials and methods
A prospective long-term follow-up study of 20 newly
diagnosed IIH patients, were consecutively recruited
among patients referred to the Danish Headache Center
from Dec 2006 to Dec 2008. All met the diagnostic criteria
of IIH according to the International Headache classifica-
tion (criteria B, Table 1 [1]). Exclusion criteria were other
significant medical, psychiatric or ocular disorders. A
group of 20 healthy individuals, matched in terms of age,
gender and body mass index (BMI) served as control [37].
The Danish Headache Center is a tertiary referral
resource for patients with rare or severe headache disorders
referred from private neurologists, outpatient neurology
clinics and hospitals. IIH patients are diagnosed and treated
in close collaboration with the Department of Ophthal-
mology, Glostrup Hospital, a tertiary eye care center
receiving patients from other Danish ophthalmological
departments and private ophthalmologists.
At baseline patients underwent a detailed interview on
headache symptoms and had a standardized neurological
and ophthalmological examination including pressure
measurement by lumbar puncture, Humphrey visual field
testing (30-2 SITA standard), measurement of RNFL and
RT by peripapillary and macular OCT (Stratus OCT 3000,
fast RNFL 3.4 protocol) and fundus photography (Zeiss, FF
450 plus, red and red-free light). Baseline results are
described in previous publications [36,37].
Treatment regime included dietary recommendations to
induce weight loss and medication with per oral acetazol-
amide in individualized dosages (maximum 2,250 mg/
day). The treatment goal was to reduce papilledema and
eliminate visual dysfunction, and to relieve symptoms
while minimizing medical side-effects. If acetazolamide
alone was insufficient, a dose of furosemide (40–120 mg/
day) combined with potassium was added. Topiramate
served as a second-line treatment and replaced acetazola-
mide in case of intolerable side-effects.
During the follow-up period patients were seen at reg-
ular neuro-ophthalmological and neurological control
visits. Number of visits varied depending on the severity of
the disease and patient compliance. The neuro-ophthal-
mological evaluation included best corrected visual acuity
(Snellen), Ishihara color vision test, assessment of pupillary
function and eye motility, slit-lamp examination, Goldman
intraocular pressure measurement, dilated fundoscopy,
fundus photography and Humphrey visual field testing. At
final follow-up the examination program was similar to the
one at baseline (except from pressure measurement that
was only repeated in two patients).
Visual fields were graded from grade 0 (normal) to
grade 4 (extensive defects) on a visual field grading scale.
The grading scale is based on the presence of nerve fiber
layer type of visual field defects and mean deviation values
(see the Iowa experience [34]). Papilledema was graded
according to the Frise
´n grading scale [14].
Relapse of IIH was defined as (1) recurrence of previ-
ously resolved papilledema or (2) recurrence of clinical
symptoms (e.g. headache, TVO, tinnitus) and increased
ICP measured by repeated lumbar puncture.
Statistics
Demographic data were summarized. Differences between
controls and patients were evaluated by t-test for age and
Mann–Whitney test for BMI. Wilcoxon sign test for mat-
ched pairs compared BMI at baseline and follow-up.
Weight-changes and duration of treatment in the relapsing
and non-relapsing group were tested by Mann–Whitney
test for unrelated groups.
As papilledema is often asymmetric, follow-up evalua-
tion and treatment in clinical practice is based on the most
affected eye. Thus, statistical analyses of OCT in this study
were based on measurements of the eye presenting with the
thickest RNFL and RT at baseline.
The RNFL and RT from baseline to follow-ups were
analyzed by the Wilcoxon sign test for matched pairs.
RNFL and RT values for patients and controls were com-
pared by Mann–Whitney test. In non-parametric tests
immeasurable eyes were assigned a value above the highest
measurable value. Data are expressed as mean ±SD.
p-Level \0.05 was chosen as the level of significance.
Results
Demographics
Baseline
Two of the 20 patients included at baseline were lost to
follow-up. Eighteen patients were re-evaluated. Fourteen
had IIH with papilledema (IIHWP) and four were
J Neurol
123

diagnosed with IIH without papilledema (IIHWOP).
Baseline ICP exceeded measure limits ([50 cmH
2
O) in
three patients. Mean ICP in the remaining 15 patients was
32.1(±6.4) cmH
2
O. The demographic characteristics are
shown in Table 2.
Mean follow-up time was 21.1 ±8.0 months. Mean
number of visits between baseline examination and follow-
up was 8.5 (range from 4 to 16 visits). An average of
1.9 ±2.4 telephone consultations were offered.
Follow-up
At final follow-up five IIHWP patients (28%) presented
with papilledema. Four patients had relapse of a papille-
dema previously reported to be resolved. One patient had a
persistent papilledema from baseline examination to final
follow-up. In one IIHWOP patient relapse was suspected
by recurrence of headache and cognitive symptoms.
Relapse was confirmed by lumbar puncture (opening ICP
of 30 cmH
2
O). In total, relapse was found in five of 18
patients (28%). All IIH relapses occurred among patients in
whom medical treatment was discontinued due to clinical
remission.
The remaining 12 patients had no signs of relapse at
final follow-up. Nine had IIHWP and remission was sup-
ported by normal optic nerve heads. Of the three IIHWOP
patients, one had severe continuous headache and signifi-
cant visual field defects. Relapse was ruled out by 24-h
continuous ICP measurement showing a pressure of
5–9 mmHg (7–12 cmH
2
O).
Systematic ICP measurement was not repeated at fol-
low-up, but performed only in those two IIHWOP patients
with suspected relapse. Neither duration of treatment nor
medication free interval differed significantly between the
relapsing and non-relapsing group. Mean duration of
treatment in the relapsing group was 9.5 (±4.4) months
versus 11.7 (±5.9) months in the non-relapsing group
(p=0.6). The five relapsing patients had been off medi-
cation for an average at 11.6 (±5.3) months. Seven of 12
patients in the non-relapsing group were off medication
[mean time 14 (±11) months (p=0.9)].
Headache
Baseline
At baseline headache was present in 17 of 18 patients
(94%) (Table 3). The single patient without headache
reported a mild pressure (but no pain) above the right orbit.
The phenotypical presentation resembled migraine in eight
and tension-type headache in six patients. Three patients
had an underlying tension-type like headache with inter-
mittent migraine-like attacks. Of the headache patients, 16
reported continuous headaches while the remaining patient
reported intermittent headache (1–2 days/week). Mean
headache intensity of continuous headaches was 6.3 on a
0–10 VAS-scale. In addition they suffered intermittent
peak intensities of 6–10, 2–4 days/week.
Headache location was holocranial in eight patients
while the remaining nine patients reported a single frontal
(4), temporal (5) and occipital (4) location or in a combi-
nation. In two patients (non-migraineurs) the headache was
strictly unilateral. Specific retrobulbar pain/pressure was
present in eight patients. All 17 patients reported a press-
ing/tightening quality of their headache; in addition, five
reported intermittent pulsatile aggravations. Only three
patients reported aggravation of their headache in the
morning and/or on bending forward.
Table 1 Diagnostic criteria of IIH
Idiopathic intracranial hypertension, ICHD-II criteria B [1]
1. Alert patient with neurological examination that either is normal
or demonstrates any of the following abnormalities:
a) Papilledema
b) Enlarged blind spot
c) Visual field defect (progressive if untreated)
d) Sixth nerve palsy
2. Increased CSF pressure ([200 mmH
2
O [non-obese],
[250 mmH
2
O [obese]) measured by lumbar puncture in the
recumbent position or by epidural or intraventricular pressure
monitoring
3. Normal CSF chemistry (low CSF protein acceptable) and
cellularity
4. Intracranial diseases (including venous sinus thrombosis) ruled
out by appropriate investigations
5. No metabolic, toxic or hormonal cause of intracranial
hypertension
Table 2 Demographic data of IIH patients (at baseline and follow-
up) and healthy controls
Baseline
(n=18)
Follow-up
(n=18)
Controls
(n=20)
IIHWP/IIHWOP 14/4 14/4
Age (y) 25.7 ±7.9 27.4 ±7.9 35.5 ±12.5
Sex (F/M) 16/2 16/2 19/1
BMI (kg/m
2
) 36.4 ±7.1
a
35.7 ±8.8
b
30.6 ±3.8
c
ICP (cmH
2
O) 32.1 (±6.4)* 17.1 (±2.4)
IIHWP Idiopathic intracranial hypertension with papilledema;
IIHWOP Idiopathic intracranial hypertension without papilledema
*n=15 (ICP values were above measurable limits ([50 cmH
2
O) in
three patients. These were not included in calculation of mean value)
Difference in BMI from baseline to follow-up:
ab
p=0.8. Baseline
BMI compared to controls:
ac
p=0.01. Follow-up BMI compared to
controls:
bc
p=0.06
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123

Five patients had a history of episodic headache,
respectively migraine (2), tension-type headache (2) or
post-traumatic headache type (1) prior to symptoms of IIH.
In addition two patients had suffered from chronic tension-
type headaches and chronic migraine on a daily basis
during [4 years prior to the diagnosis of IIH. The
remaining 11 patients reported no headaches prior to debut
of IIH.
Follow-up
At follow-up six patients were completely headache free.
Twelve patients still experienced headaches, 8 of which
had no headache history prior to IIH. One patient had
suffered from a constant headache since baseline. One
patient had a relapse of continuous headache the last month
prior to follow-up after a period of 19 headache-free
months. A daily although intermittent headache was
reported in three, episodic headache (1–4 days/week) in
five and infrequent headache 2–4 days/month in two
patients. Totally, the mean intensity of headache (VAS-
scale 0–10) was decreased from 6.8 at baseline to 5 at
follow-up. Location of pain was very variable. Holocranial
in three, frontal alone or in combination with other loca-
tions in six, and retrobulbar, parietal and temporal,
respectively in the remaining three. In respect to quality,
nine and five patients reported, respectively, tightening
and/or pulsatile, widely unchanged from baseline.
Headache was reported in four of six (67%) patients
with relapse, and in eight of 12 (67%) patients without
relapse. Neither duration nor intensity of headaches dif-
fered between the groups.
One patient from the non-relapsing group reported a
constant high intensity headache. Relapse was out ruled by
24-h continuous ICP measurement. In another patient
presenting with a constant headache at follow-up, the
headache was classified as chronic tension-type headache
and resolved almost completely after physiotherapy.
Papilledema
Baseline
Fourteen of 18 patients had clinically detectable papille-
dema at baseline, bilateral in 13 and unilateral in one.
Mean edema grade was 2 on the Frise
´n scale [14]. In one
case the edema was very subtle and upon the subsequent
grading (fundus photography) both optic discs were graded
as normal.
Follow-up
At final follow-up a complete resolution was found in nine
patients. Mild papilledema grade 1–2 (mean 1.7) was found
in five cases, two bilateral and three unilateral. Four of these
were relapses of a previously resolved papilledema. All had
been off medical treatment for at least 3 months
(3–14 months). One patient had persistent papilledema from
baseline examination to final follow-up. During the obser-
vation period of 24 months this patient had 10 clinical fol-
low-up visits. Complete resolution was never detected
despite an initial improvement. Deterioration was observed
4 months before the final follow-up visit after a period of
12 months with poor compliance, self-administered tapering
of acetazolamide to 250 mg/day and no clinical controls.
Mean time from diagnosis of papilledema to clinical
resolution (as documented in the medical records) was
5.4 ±2.6 months. In three cases the edema resolved
within 3 months, in another six cases within 6 months. In
two cases the exact time of clinical resolution was uncer-
tain due to a tight optic nerve head structure complicating
the distinction between genuine edema and blurred disc
margins due to congenital optic disc morphology.
OCT
OCT data are displayed in Table 4. In the relapse group
RNFL and RT values were above the 97.5 percentile of the
Table 3 Headache and other symptoms at baseline and follow-up
Baseline total
n(%)
n=18
Follow-up
Relapse
n(%)
n=6
Non-relapse
n(%)
n=12
Headache 17 (94) 4 (67) 8 (67)
Throbbing 5 (29) 2 (50) 3 (38)
Pressing 17 (100) 2 (50) 7 (88)
Related to
position
3 (18) 1 (25) 2 (25)
Photophobia 11 (65) 1 (25) 3 (38)
Phonophobia 7 (41) 0 3 (38)
Pulsatile tinnitus 12 (67) 3 (50) 5 (42)
Visual disturbances
Diplopia 8 (44) 1 (17) 0
Blurred vision 12 (67) 1 (17) 1 (8)
TVO 8 (44) 2 (33) 1 (8)
Other
Retrobulbar
pain
8 (44) 1 (17) 0
Dizziness 10 (56) 0 5 (42)
Symptoms at baseline and follow-up. At follow-up symptoms are
displayed according to occurrence in, respectively, relapse and non-
relapse patients.
* Data from the patient with continuous disease is included in the
relapse group
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123

healthy controls in seven eyes. Papilledema was detectable
clinically in only six eyes.
IIHWP patients with resolved papilledema at follow-up
had a significant reduction in RNFL and RT values from
the 3-month follow-up visit to the final follow-up (RT:
p=0.011 and RNFL: p=0.03). At final follow-up RNLF
and RT were significantly thinner than in healthy controls
(RT: p=0.003 and RNFL: p=0.02) although atrophy
was clinically detectable in only one patient.
Visual fields
Visual fields from six (baseline) and three eyes (follow-up)
were excluded due to poor cooperation.
Baseline
Normal visual fields (grade 0) were found in 15 eyes
(48%). Eleven eyes (35%) graded C2 and three eyes (10%)
graded 3 or 4 (Table 5).
Follow-up
Visual fields were normal in and 26 eyes (79%). Thirty of
33 eyes (91%) graded B1 and no eyes rated higher than
grade 2. In eyes of IIHWP without relapse at follow-up
visual fields were normal (grade 0) in 15 eyes and grade 1
in 2 eyes.
Peripheral visual field defects in 11 eyes resolved com-
pletely during the observation period. Eyes with peripheral
visual field defects at follow-up had similar or even higher
graded defects at baseline. Thus, no deterioration was seen in
visual fields from baseline to final follow-up.
Best corrected visual acuity (BCVA)
BCVA at follow-up was[0.8 in all eyes, and[1.0 in 34 of
36 eyes. Five eyes had improved from a BCVA of 0.8–0.9
at baseline to [1.0. Two eyes remained stable at 0.8 and
0.9, respectively (Table 5). BVCA at baseline was only
affected in one of the 10 eyes that presented with a high-
grade edema (Frise
´n grade 4, BCVA =0.9).
At follow-up BCVA was [1.0 in all 10 eyes. In total,
mean BCVA improved from baseline to follow-up
(p=0.01) and none decreased in BCVA.
Other signs
Color vision was not significantly affected. Apart from two
patients suspected of functional vision loss, only two
patients presented with errors in the Ishihara test (B2
errors) at baseline and follow-up. No relative afferent pupil
deficit (RAPD) was found.
Six patients presented with sixth nerve palsy at baseline.
All were resolved at follow-up. In two cases without initial
sixth nerve palsy a subtle bilateral abduction deficit was
suspected at follow-up. Only one of these had other signs
of raised ICP.
Other symptoms
Pulsatile tinnitus was reported in three of the six (50%)
patients with relapse and in five of the 12 (42%) non-
relapsed patients. A clear reduction of other symptoms was
noted (Table 3). TVO was only reported by three patients
(two with and one without papilledema). One patient in
each group reported blurred vision.
Table 4 OCT from baseline to final follow-up
OCT Baseline 3-month follow-up Final
follow-up
Controls
ac
p
bc
p
cd
p
Non-relapse
Eyes 9 9 9 20
RNFL (lm) 256.1 ±112.1
a
104.8 ±13.4
b
94.4 ±8.8
c
101.1 ±7.5
d
0.008 0.03 0.02
RT (lm) 521.3 ±222.1
a
282.7 ±31.1
b
258.9 ±14.9
c
278.9 ±9.9
d
0.008 0.01 0.003
Relapse
a
Eyes 5 5 5 20
RNFL (lm) 307.6 ±84.6
a
136.1 ±38.4
b
183.4 ±46.0
c
101.1 ±7.5
d
0.08 0.08 0.001
RT (lm) 824.3 ±235.9
a
318.7 ±42.0
b
415 ±122.0
c
278.9 ±9.9
d
0.08 0.1 0.01
Data are expressed as mean ±SD.
The table shows RNFL and RT values of healthy controls and IIHWP patients with and without relapse of papilledema at final follow-up. OCT
values were immeasurable due to extensive edema in respectively six (RNFL) and four (RT) eyes at baseline and one (RNFL and RT) eye at final
follow-up. Immeasurable eyes were assigned to values above highest measurable value
a
The patient with continuous papilledema was included in the relapse group.
ac
pdifference from baseline to final follow-up;
bc
pdifference from
3-month follow-up to final follow-up;
cd
pfinal follow-up compared to healthy controls
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123

Weight and BMI
At baseline 15 patients were obese and three were over-
weight. Mean BMI was 36.7 kg/m
2
. At follow-up mean
BMI had not changed significantly (Table 2). Only one
patient had achieved a normal BMI (\24.9 kg/m
2
). Three
patients were overweight with BMI between 24.9 and
29.9 kg/m
2
. Fourteen patients were obese with BMI [
30 kg/m
2
. Only five had lost [5 kg (or 5% of body
weight). Two of these had major weight loss of 45 kg
(37.5%) and 24 kg (20.3%) due to Bariatric surgery and
major depression, respectively.
In the relapse group three of five patients had gained
weight of 17.5, 18 and 24.8 kg, respectively (13.8–17.3%
of body weight). All of these were now morbidly obese
with BMI [40 kg/m
2
. The one patient with prolonged
disease course had a weight gain of 5 kg (4.6%). In the 12
patients without signs of relapse seven had lost weight
(2.2–37.5%), one was stable and four had had minor weight
gains (1.1–5.7%). In total the relapsed patients have had a
significant weight gain (in % of body weight) compared to
the non-relapsed patients (p=0.013) (Fig. 1).
Discussion
In general IIH is considered a benign condition with a
favorable long-term outcome. It may, however, be com-
plicated by severe visual loss [9]. An overall rate of visual
impairment between 10 and 20% is indicated by prior
studies [9,29]. As the disease and associated progressive
visual loss can be asymptomatic for a long time, it poses a
challenge in patient follow-up. Signs and symptoms at time
of diagnosis cannot predict the risk of recurrence or visual
deterioration [41] and further knowledge is thus needed to
establish recommendations for future disease management
and follow-up.
The relapse rate in this prospective long-term study of
18 IIH patients was 28%. This is somewhat less than a
relapse rate of 38.4% reported by Kesler et al. [17]. The
mean observation period in their study, however, was
6.2 years compared to 21.1 months in our study. In another
retrospective study by Shah et al. covering an observation
period of 10 years the recurrence rate was only 15% [34].
The lower rate can probably, and at least partly, be
explained by a more strict definition of relapse. Shah et al.
defined relapse as a return of signs and symptoms after
resolution of papilledema and being off medication for at
Table 5 Neuro-ophthalmological signs at baseline and final follow-up
Baseline total
eyes (n=36)
Follow-up
Relapse eyes
(n=12)
Non-relapse eyes
(n=24)
Papilledema 22 7 0
Frise
´n
grade 0
12 5 24
Frise
´n
grade 1
320
Frise
´n
grade 2
750
Frise
´n
grade 3
400
Frise
´n
grade 4
10 0 0
Frise
´n
grade 5
000
Visual fields
Grade 0 15 7 19
Grade 1 4 2 2
Grade 2 8 1 2
Grade 3 2 0 0
Grade 4 1 0 0
Snellen visual acuity
C1,0 28 12 22
0.8–0.9 7 0 2
\0.8 1 0 0
Ishihara
17 24 10 19*
C15 9 2 3
\14 3 0 0
RAPD 0 0 0
Ishihara: number of correctly identified plates out of 17 possible. *
One patient (non-relapse) was not re-tested at follow-up
Visual fields are graded according to the IOWA grading scale
Autoperimetry result from, respectively six and three eyes at baseline
and follow-up were excluded due to poor cooperation
Fig. 1 Weight changes in kg from baseline to follow-up. Mean body
weight (kg) at baseline, 3-month and final follow-up displayed for
respectively relapse and non-relapse patients. The patient with
continuos disease is included in the relapse group
J Neurol
123

least 6 months. The present study and the one by Kesler
et al. did not request any medication free period in the
relapse definition. Relapse rates of IIH have been reported
in yet other and older studies (1966–1990) (with less well
defined criteria of relapse) at levels between 6 and 19% [2,
9,22,43].
Among the five patients with relapse in our study only
one experienced symptoms (relapse of continuous head-
ache of moderate to high intensity and deficits in memory
and concentration) at a level that caused the patient to
consult a physician. Two patients were completely
asymptomatic and the remaining two had paid no attention
to their symptoms (intermittent headaches and episodes of
TVO).
In contrast daily or frequent headaches were reported by
42% of patients in the non-relapse group as was pulsatile
tinnitus. Unfortunately, the headache profile of IIH is not
pathognomic as it mimics the primary headaches. Like
previous studies [24,40,42] we found no features that
separated the initial IIH-headaches from episodic migraine
or chronic tension-type headache. Detailed characteristics
of headache in prior follow-up studies are lacking. We
hypothesize that headache and other symptoms are poor
markers of disease activity.
IIH is closely associated with obesity, and weight
reduction has been shown to improve the rate of recovery
and prognosis in overweight patients [18,26,35,41,44].
At baseline patients entered a course of dietary recom-
mendations and follow-up visits resulting in an overall
initial weight loss [37]. Despite continuous information of
the correlation between weight loss and prognosis the long-
term effect was poor. Apart from two patients with major
weight losses due to either bariatric surgery or psychiatric
illness, only another two had a sustained weight loss of
[4%. Only one patient achieved a normal BMI while 14
(78%) were still obese (BMI [30 kg/m
2
). Three patients
presenting with a relapse had even gained significant
weight[17 kg ([13% of body weight). Patients presenting
with relapse at final follow-up had higher baseline BMI and
in addition gained significant weight compared to patients
without relapse. This demonstrates the importance of and
the difficulties in achieving and maintaining long-term
weight loss. Far more detailed and controlled weight
reduction programs are needed if weight loss is aimed to be
a realistic and consistent treatment strategy.
The main risk of IIH is irreversible visual impairment.
Visual loss caused by IIH is often insidious and may appear
months or years after initial symptoms. Long-term studies
report visual impairment at rates between 10 and 20% [9,
29]. In the present study visual function in terms of visual
fields and visual acuity improved from baseline to follow-
up and in general the outcome was good. At follow-up VA
was normal in 94% of eyes and subnormal in the remaining
6%. Visual fields were normal in 79% of eyes and sub-
normal in 12%. In the remaining three eyes (9%) visual
fields were moderately affected. Only one of the eyes were,
however, considered to have true visual field affection, as
defects in one patient (two eyes) were suspected to be
functional.
At final follow-up RNFL and RT of IIHWP patients
without relapse of papilledema were significantly thinner
than in the healthy controls, although optic nerve atrophy
was only clinically detectable in one patient. This impor-
tant finding indicates that axonal loss might be more
widespread than previously suspected and might occur
even in apparently effectively treated IIH.
Axonal nerve fiber loss becomes evident on OCT only
after papilledema resolves. The point at which atrophy
appears is, therefore, difficult to define. Most likely it
appears initially before papilledema has resolved signifi-
cantly. Our study and similar findings reported by Laem-
mer et al. [19], indicating early retinal axonal nerve fiber
loss, suggest that early and aggressive treatment of IIH is
indicated even in cases of unaffected visual parameters.
The present study did not include surgical interventions.
CSF diversion procedures (ventriculoperitoneal and lum-
boperitoneal shunting) and optic nerve sheath fenestration
(ONSF) are currently the mainstay of interventions when
medical therapy is insufficient. In patients with acute visual
deterioration or progressive visual loss unresponsive to
medical therapy surgical interventions should be consid-
ered promptly [39].
The procedures are, however, invasive and associated
with potential complications that may require multiple
additional procedures [4,6–8,16,27,30]. In patients
without detectable visual defects the overall benefit of
surgical intervention thus most likely does not outweigh
the disadvantages.
The present findings with subclinical optic atrophy and
unfavorable prognosis in a subset of IIH patients do,
however, prompt reconsiderations and randomized con-
trolled studies of medical versus surgical treatment are
desirable.
Limitations of the present study are the small patient
cohort and the individualized number of clinical follow-up.
The follow-up did not include systematic ICP measurement
and undetected relapse of intracranial hypertension cannot
be completely excluded. The strength of the study is the
controlled prospective design, the detailed reports of
headache, and the standardized neuro-ophthalmological
examination.
In conclusion, this 21-month prospective follow-up
study of 18 IIH patients showed a high relapse rate.
Prevalence of chronic headache was high whereas the
clinical visual outcome was good. Significant headache
(C14 days/month) persisted in 42% of patients without
J Neurol
123

signs of active disease. Neither headache nor other symp-
toms were reliable indicators of relapse. Patients with
relapse were more obese and had gained weight compared
to patients without relapse.
Although the visual outcome was favorable, subclinical
optic nerve atrophy was detected by OCT in apparently
well treated patients. Along with the high relapse rate, our
findings underline that IIH is not a benign disease and
suggest that intensified medical treatment may be essential
even in the absence of detectable visual field defects.
Furthermore, as symptoms of relapse were vague, long
term follow-up for years after initial remission is
mandatory.
Acknowledgments The studies have been approved by the appro-
priate ethics committee and have been performed in accordance with
the ethical standards laid down in the 1964 Declaration of Helsinki.
Conflict of interest The authors declare that they have no conflict
of interest.
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