5987 TAN0010.

1177/1756285616635987Therapeutic Advances in Neurological DisordersRH Jensen, A Radojicic

Therapeutic Advances in Neurological Disorders Review

The diagnosis and management of idiopathic

Ther Adv Neurol Disord

2016, Vol. 9(4) 317326

intracranial hypertension and the associated DOI: 10.1177/

1756285616635987

headache
The Author(s), 2016.
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Rigmor Hjland Jensen, Aleksandra Radojicic and Hanne Yri

Abstract: Idiopathic intracranial hypertension (IIH) is a challenging disorder with a rapid

increasing incidence due to a close relation to obesity. The onset of symptoms is often
insidious and patients may see many different specialists before the IIH diagnosis is settled.
A summary of diagnosis, symptoms, headache characteristics and course, as well as
existing evidence of treatment strategies is presented and strategies for investigations and
management are proposed.

Keywords: acetazolamide, headache, idiopathic intracranial hypertension, visual loss

Introduction 2004; Durcan etal. 1988]. Visual loss can occur Correspondence to:
Rigmor Hjland Jensen,
Idiopathic intracranial hypertension (IIH), or anytime along the course of the disease but is MD, PhD
pseudotumor cerebri, formerly called benign often insidious and as central vision is spared Danish Headache Center,
Department of Neurology,
intracranial hypertension, is a challenging condi- until late in the course of the illness the visual loss Rigshospitalet-Glostrup,
tion with raised intracranial pressure (ICP) in the is often asymptomatic until profound. In addi- University of Copenhagen,
Denmark
absence of identifiable cause [Friedman et al. tion, diagnosis is often delayed as the general rigmor.jensen@regionh.
2013; Mollan etal. 2014; Friedman, 2014]. knowledge of IIH is limited and multiple doctors dk

In the literature, IIH primarily affects young
obese women and the estimated incidence in this
population is 20 per 100,000 which is 20-fold
higher than in normal-weight individuals [Durcan
et al. 1988; Radhakrishnan et al. 1993]. Due to
the close relationship with obesity, which has
been reported to have increased three-fold over
just 15 years in Western countries [WHO, 2013],
the incidence of IIH is expected to increase rap-
idly. As obesity affects children and males to a
similar degree as in females, and as the reports of
IIH in these groups are accumulating [Bruce etal.
2009; Standridge, 2010] it can be hypothesized
that obesity is the main underlying causative fac-
tor, and not gender or age. Still, case-control
studies with male and female patients matched by
weight are needed to clarify the role of gender.
At time of diagnosis various degrees of visual
impairment are present in up to 90% of patients
with IIH [Craig etal. 2001] and in prior studies
an estimated rate of 1024% progressed to severe
and permanent visual impairment [Carta et al.
from various specialties have been consulted Hanne Yri, MD, PhD
Danish Headache Center,
before patients are identified. In a new series from Department of Neurology,
our group the visual prognosis after one year was University of Copenhagen,
Rigshospitalet-Glostrup,
good, probably due to earlier diagnosis, more 2600 Glostrup, Denmark
awareness, a dedicated team effort or a close fol- Aleksandra Radojicic,
MD, MSc
low-up [Yri etal. 2012]. Neurology Clinic,
Clinical Center of Serbia,
Belgrade, Serbia
Clinical presentation and diagnosis
In most patients IIH manifests with severe head-
ache, visual disturbances and bilateral papilledema
[Carta et al. 2004; Mollan et al. 2014; Yri and
Jensen, 2015; Yri etal. 2012]. The symptoms are
clearly summarized [Wall etal. 2014a] (Figure 1)
and were confirmed in the recent field testing of
diagnostic criteria [Yri and Jensen, 2015].
Headache is present in around 93% of patients at
the time of diagnosis, usually being constant or
occurring daily or nearly daily [Craig etal. 2001;
Yri etal. 2012]. It lacks specific features and may
mimic chronic migraine, chronic tension-type
headaches or both. Headache related to IIH is
more likely to be focal than holocranial, and often

http://tan.sagepub.com 317
Therapeutic Advances in Neurological Disorders 9(4)

Figure 1. Percentage of patients and their presenting symptoms in Idiopathic Intracranial Hypertension,
modified from Wall and colleagues [Wall et al. 2014a].

Table 1. International Classification of Headache Disorders, third edition beta (ICHD-3-beta) criteria for
headache attributed to IIH [Headache Classification Subcommittee of the International Headache Society,
2013].
A Any headache fulfilling criterion C
B Idiopathic intracranial hypertension (IIH) has been diagnosed, with cerebrospinal fluid (CSF) pressure
>250 mm
CSF (measured by lumbar puncture performed in the lateral decubitus position, without
sedative medications, or by epidural or intraventricular monitoring)
C Evidence of causation demonstrated by at least two of the following
1. Headache has developed in temporal relation to IIH, or has led to its discovery
2. Headache is relieved by reducing intracranial hypertension
3. Headache is aggravated in temporal relation to increase in intracranial pressure
D Not better accounted for by another ICHD-3 beta diagnosis
IIH, idiopathic intracranial hypertension; CSF, cerebrospinal fluid.

with pulsating elements. Aggravation by cough-
ing, straining and physical activity is reported by
the majority of patients [Yri and Jensen, 2015; Yri
et al. 2014b]. The current diagnostic criteria for
headache attributed to IIH given by the
International Classification of Headache Disorders
(ICHD-III beta) [Headache Classification
Subcommittee of the International Headache
Society, 2013] are presented in Table 1. Recently,
these criteria have been field tested and new vali-
dated criteria have been proposed [Yri and
Jensen, 2015]. Still, the headache attributed to
IIH is scarcely studied and none of the existing
trials elucidated the effects of current headache
treatments. The headaches may also determine
the impaired quality of life reported in a study of
IIH patients from the Birmingham group [Mulla
etal. 2015].
Characteristic for the condition is the presence of
a pulsatile tinnitus that is believed to arise from
intensified vascular pulsation occurring with high
ICP. Although very common, it is often not
reported by the patients unless specifically que-
ried about it.
Patients with papilledema often present with tran-
sitory visual obscurations which can be a manifes-
tation of increased bulb pressure, retinal ischemia
or transient ischemia at the optic nerve caused by
papilledema. Increased ICP without papilledema
has been reported in unresponsive chronic migraine
patients suggesting a diagnosis of IIH without
papilledema [De Simone etal. 2014; Mathew etal.
1996; Wang etal. 1998]. However, such a diagno-
sis is challenging and requires caution with addi-
tional clinical or neuroradiological confirmation as

318 http://tan.sagepub.com
 RH Jensen, A Radojicic et al.

Table 2. Diagnostic criteria for pseudotumor cerebri syndrome [Friedman et al.2013].

1. Required for diagnosis of pseudotumor cerebri syndromea
A. Papilloedema
B. Normal neurologic examination except for cranial nerve abnormalities
C. Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass, or structural
lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical
patients (female and obese), and MRI, with and without gadolinium, and magnetic resonance
venography for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used
D. Normal CSF composition
E. Elevated lumbar puncture opening pressure (250 mm CSF in adults and 280 mm CSF in children
[250 mm CSF if the child is not sedated and not obese]) in a properly performed lumbar puncture
2. Diagnosis of pseudotumor cerebri syndrome without papilloedema
In the absence of papilloedema, a diagnosis of pseudotumor cerebri syndrome can be made if BE from
above are satisfied, and in addition the patient has a unilateral or bilateral abducens nerve palsy.
In the absence of papilloedema or sixth nerve palsy, a diagnosis of pseudotumor cerebri syndrome can
be suggested but not made if BE from above are satisfied, and in addition at least three of the following
neuroimaging criteria are satisfied:
i. Empty sella
ii. Flattening of the posterior aspect of the globe
iii. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve
iv. Transverse venous sinus stenosis
aAdiagnosis of pseudotumor cerebri syndrome is definite if the patient fulfills criteria AE. The diagnosis is considered
probable if criteria AD are met but the measured CSF pressure is lower than specified for a definite diagnosis.
CSF, cerebrospinal fluid; CT, computerized tomography; MRI, magnetic resonance imaging.

suggested in the revised diagnostic criteria for
pseudotumor cerebri syndrome (Table 2)
[Friedman etal. 2013]. Other symptoms and clini-
cal signs include dizziness, nausea, reduced mem-
ory and concentration and horizontal diplopia due
to sixth nerve palsy [Carta etal. 2004; Mollan etal.
2014; Yri and Jensen, 2015; Yri et al. 2012].
Recent studies demonstrated a marked cognitive
dysfunction [Kharkar etal. 2011; Yri etal. 2014a;
Zur etal. 2015] and indicated that impaired execu-
tive function, working memory, processing speed
and reaction time remained after normalization of
ICP and alleviation of the headache and the visual
symptoms [Yri etal. 2014a]. It is likely that such
cognitive dysfunction could contribute to the sub-
stantial loss of work capacity and life quality in
patients with IIH and increased focus of the under-
lying pathophysiology and of their rehabilitation
are highly relevant.
Examination
The first step in the neurological examination of a
suspected IIH patient is fundoscopy. Although
assessment of papilledema may be limited by con-
siderable intra- and inter-observer variability and
lack of experience in junior doctors, is it still a
quick, simple and accessible bedside test in the
emergency room. Test of vision and especially
visual field by perimetry are also essential [Carta
etal. 2004; Mollan etal. 2014; Skau etal. 2011a]
but the test method should be standardized and
in most cases needs ophthalmological expertise.
Use of optical coherence tomography (OCT) is
recommended for quantification of papilledema
and the method has been demonstrated to be a
valuable additional tool for identification and
monitoring of papilledema over time [Skau etal.
2011a; El-Dairi et al. 2007; Rebolleda and
Munoz-Negrete, 2009].
The next step is neuroimaging, preferably a mag-
netic resonance imaging (MRI) scan of the brain.
Supplemental MR/CT venography to rule out
sinus venous occlusions is essential, since sinus
venous occlusions may manifest clinically as iso-
lated intracranial hypertension syndrome in more
than one-third of patients [Biousse et al.1999].
Bilateral transverse sinus stenosis, but not occlu-
sions, are frequently reported in IIH patients
[Fera etal. 2005; Farb etal. 2003; Higgins etal.
2004]; still, it remains unclear whether this plays
a role in the pathogenesis of IIH or just serves as
a radiological marker of raised ICP. The other
neuroimaging abnormalities of IIH include empty
sella, flattening of the posterior aspect of the globe
and perioptic subarachnoid space enlargement
[Friedman etal. 2013].

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Therapeutic Advances in Neurological Disorders 9(4)
In the clinical setting IIH is documented by a
lumbar puncture with manometry. To minimize
false positive values a standardized procedure is
essential with patients placed in a lateral decubi-
tus position on a flat bed, as relaxed as possible,
with legs stretched before pressure measurements
[King etal. 2002; Whiteley etal. 2006]. Opening
pressure values above 25 cm H2O are considered
abnormal [Headache Classification Subcommittee
of the International Headache Society, 2013;
Friedman etal. 2013]. However, it is only a point
measurement and with high diurnal ICP variabil-
ity repeated pressure measurements may be
required in patients presenting with an atypical
phenotype or with only marginally increased
opening pressure.
Based on the existing evidence and clinical expe-
rience the following diagnostic plan has now been
developed in our academic center and can be rec-
ommended for systematic testing in other settings
(Figure 2).
Management
The target of IIH management is to reduce ICP
with the main goals of preservation of vision and
relief of headache. Over the years the manage-
ment strategy for IIH has been based on clinical
experience, but in recent times, well designed
clinical trials assessing acetazolamide and weight
loss have been published [Ball etal. 2011; Sinclair
etal. 2010; Wall etal. 2014b].
Weight reduction
Weight loss plays a significant role in IIH man-
agement. Originally, this was based on case
reports and small open series but was recently
confirmed in a prospective cohort trial [Sinclair
etal. 2010]. Twenty-five patients with IIH were
treated with a very low calorie diet (425 kcal/day)
for three months following a three-month obser-
vational control period. Upon diet, patients
reduced their weight dramatically (15% of body
weight) resulting in a significant reduction in
ICP, headaches and papilledema. In another
open-labeled design study of newly diagnosed
IIH, the CSF pressure decreased markedly in
patients with 3.5% reduction of body mass
index (BMI), in contrast to patients with no
weight loss [Skau etal. 2011b]. Large scale rand-
omized controlled studies with long-term follow
up are still warranted to verify these findings.
320 http://tan.sagepub.com
Bariatric surgery can be offered to these over-
weight patients for the faster weight reduction
and a review of case reports or small case series
has been published [Fridley et al. 2011].
Altogether, the 62 included patients reported
92% resolution of IIH symptoms postsurgery.
Specifically, papilloedema regressed in 34 of 35
subjects and a mean ICP reduction of 25 cm H2O
was reported. The average weight loss was impres-
sive with a 45.4 kg decrease and the BMI was
reduced by 16 kg/m2 [Fridley etal. 2011]. On the
indication of severe IIH with rapid loss of vision
and morbid obesity, bariatric surgery appears
promising; but the complication rate has been
very high and randomized controlled trials with
at least some years of follow-up protocols are
required to establish the long-term outcome and
the side effects.
Drug treatments
The first drug of choice in IIH management is
acetazolamide, an old diuretic with a significant
carbonic anhydrase inhibitor effect. The efficacy
of acetazolamide in IIH has been investigated in
two randomized studies. The first by Ball and col-
leagues was an open-label randomized pilot study
of acetazolamide versus no acetazolamide, includ-
ing 25 patients in each arm [Ball et al. 2011].
However, 48% of patients in the active group
could not to tolerate the medication and stopped
or reduced the planned dose up to a maximum of
1500 mg. The authors concluded that a very large
controlled study was needed to demonstrate a
moderate treatment effect. The reported side
effects were acroparesthesia, dysgeusia, fatigue,
gastrointestinal symptoms, and nephrolithiasis.
The other study was a multicenter, randomized,
double-masked, placebo-controlled study of
acetazolamide in 165 participants with IIH and
showed a small but significant beneficial effect of
acetazolamide on visual function [Wall et al.
2014b]. For obvious ethical reasons only patients
with mild visual loss were included which may
explain that only a limited effect of treatment
could be demonstrated. The clinical significance
of the shown visual improvement and of other
symptoms thus remains to be determined.
Furosemide and other diuretics are sometimes
used in IIH, either alone or in combination with
acetazolamide but there are no randomized con-
trolled trials supporting its effect. Further evi-
dence is thus required before furosemide or other

Figure 2. Proposal of a diagnostic work-up and strategy in patients with possible idiopathic intracranial
hypertension.
diuretics can be recommended. Topiramate, an
antiepileptic and a migraine prophylactic, has
become increasingly popular as a management
option in IIH [Celebisoy etal. 2007; Linde etal.
2013]. The appeal for this drug stems from the
combined effect as carbonic anhydrase inhibitor,
although weaker than acetazolamide, a migraine
preventive, and its positive side effect of appetite
suppression and weight loss. Reported adverse
effects are very similar to acetazolamide with par-
esthesia, fatigue, and gastrointestinal symptoms
in addition to dizziness, coordination, and gait
problems.
The effect of topiramate and acetazolamide was
compared in an open-label study of 40 IIH
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RH Jensen, A Radojicic et al.
patients, with a main focus on visual fields
[Celebisoy et al. 2007]. Both drugs showed an
improvement over time with no significant differ-
ence between them with respect to visual func-
tion. However, the effect of topiramate could be
explained by a greater weight loss in this group.
As headache is such a predominant and disabling
feature in patients with IIH, topiramate is appeal-
ing to prescribe as a monotherapy or in combina-
tion with acetazolamide. However, treatments are
often hampered by the marked side effects. In
migraine treatment the adherence to topiramate
is under 50% [Linde etal. 2013]. In addition cog-
nitive symptoms may occur even with low doses
of topiramate, and it is a highly undesirable
adverse effect in a patient population already
Therapeutic Advances in Neurological Disorders 9(4)
hampered by severe headaches and various
degrees of cognitive dysfunction.
So far, there are no guidelines or relevant studies
that would provide recommendations for drug
treatment duration. Our clinical practice is to
taper the medication slowly down when the visual
symptoms and papilledema are improved, the
CSF-pressure is normalized, and 510% weight
loss is achieved. We recommend regular follow-
up visits of the patients, so an eventual relapse
can be identified and medication reinstituted.
Other interventions
Several surgical procedures for IIH have been
reported but none of them have been subjected to
randomized controlled trials and the evidence is
still lacking. Neurosurgical intervention with
insertion of a ventriculoperitoneal shunt (VPS) is
not indicated in the vast majority of IIH-cases but
should be reserved for cases with rapid or malig-
nant loss of vision (i.e. fulminant or malignant
IIH) [Thambisetty etal. 2007]. A recent system-
atic review summarizing the effect and the com-
plications of different surgical options and
stenting for IIH concluded that no evidence was
available to support the use of any technique in
particular [Lai etal. 2014]. Considering a risk of
various complications associated with surgical
interventions, in many settings repeated spinal
taps are employed with daily or weekly intervals
but the evidence is entirely clinical. The choice of
procedure is therefore largely dependent on local
expertise, resources, and preference.
Optic nerve sheath fenestration
Studies assessing the safety and efficacy of optic
nerve sheath fenestration (ONSF) are small and
uncontrolled and there have been no prospective
trials. Chandrasekaran and colleagues reviewed 32
patients in an observational case series including
13 diagnosed with IIH. Visual function improved
significantly post-operatively, but in 11 of 32
patients additional CSF diversion was required
after the ONSF procedure [Chandrasekaran etal.
2006]. Another series of 78 patients with ONSF,
62 of which had a unilateral diversion [Alsuhaibani
etal. 2011] suggested that a unilateral procedure
may be sufficient in relief of pressure in both eyes.
Complications to ONSF include traumatic optic
neuropathy, retinal vascular occlusion, pupil dila-
tation, and diplopia [Spitze et al. 2014]. Overall
322 http://tan.sagepub.com
outcome on headache and quality of life are not
reported.
CSF diversion
Types of CSF diversion include: lumboperitoneal
shunts (LPS) or VPS. In earlier days also ven-
triculojugular and ventriculoatrial shunting have
been performed. There are no prospective con-
trolled trials to guide procedure choice but shunts
with variable flow valves are reported to be supe-
rior [Hickman etal. 2014].
In one of the largest retrospective case note
reviews of LPS and VPS shunts, including 53 IIH
patients, improvements from baseline were noted
in VAs after 6 months and 12 months. However,
at 6 month follow up, 68% of patients still
reported persistent or recurrent headache and
after 12 months this number was increased to
77% [Sinclair et al. 2011]. Other reported IIH
symptoms, such as tinnitus and diplopia remained
unchanged in 28% of patients and low pressure
headaches were also reported post-procedurally.
Although appearing effective in reducing the early
ICP-related signs and symptoms, complications
included shunt blockage, infection, abdominal
and back pain, intracranial hypotension and ton-
sillar herniation. Shunt revisions were required in
51% with multiple revisions needed in 30%
[Sinclair etal. 2011].
Dural venous sinus stenting
The causal role of venous sinus compression in
IIH is debated and stenting of the dural venous
system is controversial. Several smaller case series
and retrospective studies have been published
and no prospective, randomized controlled trials
have yet been performed, probably due to the
ethical considerations. Resolution of tinnitus,
improvements in headaches, visual function, and
papilledema is commonly reported after dural
venous sinus stenting, but none of these end-
points are statistically confirmed [Higgins et al.
2002; Radvany etal. 2013; Riggeal etal. 2013].
However, in a larger study of 52 patients immedi-
ate, and in most cases longstanding, amelioration
of signs and symptoms was obtained [Ahmed
etal. 2011]. Complications reported in the litera-
ture include stent migration, stent thrombosis,
restenosis, and vessel perforation [Ahmed et al.
2011; Higgins et al. 2002; Radvany et al. 2013;
Riggeal etal. 2013].

Figure 3. Proposal of a stratified treatment strategy for idiopathic intracranial hypertension according to
symptom severity.
Headache management and prognosis
Although headache is the most frequent symptom
in patients with IIH, headache management is a
field yet to be explored, since the existing treat-
ment trials have been focused on ICP changes or
visual outcome rather than a headache relief.
In many patients IIH headache responds well to
management of ICP by cerebrospinal fluid
withdrawal or medical treatment, with most
improvement occurring within the first month
[Yri etal. 2014b]. Immediate headache relief is
typically seen after the diagnostic lumbar punc-
ture with CSF removal [Yri and Jensen, 2015].
In a small prospective acetazolamide study,
headache prevalence was reduced from 68% to
43% in acetazolamide-treated patients, com-
pared to a reduction from 72% to 65% in a con-
trol group [Ball et al. 2011]. However, no
significant treatment effects were noted with
respect to headache disability in a larger, rand-
omized placebo-controlled study of acetazola-
mide [Wall etal. 2014b].
Data on the long-term outcome of headache in
IIH are limited. In a prospective follow-up study
by Yri and colleagues, 43% of patients either
recovered totally or reported only infrequent
headache (1 day/month) after 1 year while
another 43% were left with a persistent chronic
headache even after intracranial hypertension
http://tan.sagepub.com 323
RH Jensen, A Radojicic et al.
and visual symptoms had resolved [Yri et al.
2014b], supporting theories that headache in IIH
is attributed to more complex mechanisms than
ICP elevation alone [Ekizoglu et al. 2012].
Persistent headache has a major impact on qual-
ity of life in IIH but the causes of headache
chronification are yet unknown. Coexisting
migraine and tension-type headache, medication
overuse, depression and anxiety which are com-
mon in IIH, may have a role in chronic post-IIH
headaches, and should be recognized and treated
simultaneously [Friedman and Rausch, 2002;
Kleinschmidt et al. 2000]. In the recent study
predictors for a favorable outcome of headache
12 months after diagnosis were younger age at
onset and a high diagnostic opening pressure.
This may relate to an early diagnosis or fast ini-
tiation of relevant treatment in these patients [Yri
etal. 2014b].
The visual prognosis appears to have improved in
recent years, but IIH is still a complex disorder to
handle, multiple medical specialties need to be
involved and the relapse rate is high at up to 40%
[Best et al. 2013; Kesler et al. 2004; Ko et al.
2011; Shah etal. 2008]. In our IIH populations of
44 and 40 patients, respectively, the visual func-
tion were almost normalized in all subjects after
12 months whereas the major long-term compli-
cations were headache and impaired cognition
[Yri etal. 2014b; Yri etal. 2012].
Therapeutic Advances in Neurological Disorders 9(4)
Despite the severe headache and a potential treat
to visual function, compliance to treatment and
follow-up is surprisingly poor. Therefore, we rec-
ommend patient education and close long term
follow-up with weight control. From a clinical
perspective, we also recommend that the treat-
ment strategy should be stratified according to
disease severity (Figure 3). Other issues such as
patient tolerability, compliance and the available
health care service should also be considered.
Conclusion and recommendations
IIH is a challenging and serious disease with a sig-
nificant burden on the individual and the society.
We suggest organization of specific national IIH
teams for awareness, management and research.
In a setting with a dedicated IIH team consisting
of neuro-ophthalmologist, neurologist and dieti-
cian and an easy access to frequent follow-up vis-
its, it should be possible to adjust the medical
treatment individually depending on disease
course and symptomatology. The number of sur-
gical interventions should be minimized and only
employed for the malignant cases or rapid pro-
gression. The visual prognosis seems to have
improved in recent years while persistent head-
ache still poses a significant long-term problem for
the patients. The incidence of IIH is in rapid pro-
gression in the wake of the global endemic obesity
problem and expertise is absolutely required for
scientific progress and a better outcome.
Funding
The author(s) received no financial support for
the research, authorship, and/or publication of
this article.
Conflict of interest statement
The author(s) declared no potential conflicts of
interest with respect to the research, authorship,
and/or publication of this article.
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