Review Article

Idiopathic intracranial hypertension

Cephalalgia
2015, Vol. 35(3) 248261
! International Headache Society 2014
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DOI: 10.1177/0333102414534329
cep.sagepub.com

BR Wakerley1, MH Tan2 and EY Ting3

Abstract
Background: Idiopathic intracranial hypertension or pseudotumour cerebri is primarily a disorder of young obese women
characterised by symptoms and signs associated with raised intracranial pressure in the absence of a space-occupying
lesion or other identifiable cause.
Summary: The overall incidence of idiopathic intracranial hypertension is approximately two per 100,000, but is considerably higher among obese individuals and, given the global obesity epidemic, is likely to rise further. The pathophysiology
of this condition is poorly understood, but most theories focus on the presence of intracranial venous hypertension and/
or increased cerebrospinal fluid outflow resistance and how this relates to obesity. A lack of randomised clinical trials has
resulted in unsatisfactory treatment guidelines and although weight loss is important, especially when used in conjunction
with drugs that reduce cerebrospinal fluid production, resistant cases remain difficult to manage and patients invariably
undergo neurosurgical shunting procedures. The use of transverse cerebral sinus stenting remains contentious and longterm benefits are yet to be determined.
Conclusion: An understanding of the clinical features, diagnostic work-up and therapeutic options available for patients
with idiopathic intracranial hypertension is important both for neurologists and ophthalmologists as visual loss maybe
permanent if untreated.
Keywords
Idiopathic intracranial hypertension, benign intracranial hypertension, pseudotumour cerebri, raised intracranial pressure
Date received: 15 September 2013; revised: 16 December 2013; 24 January 2014; 4 March 2014; accepted: 22 March 2014

Introduction
Recently, the umbrella term pseudotumour cerebri
syndrome (PTCS) has appeared in the literature (1,2)
to describe what is currently understood by most physicians as pseudotumour cerebri, benign intracranial
hypertension or idiopathic intracranial hypertension
(IIH). Further classication, according to aetiology,
in to primary PTCS (or IIH) and secondary PTCS, in
which there is an identiable underlying cause, provides
a useful means of dening such patients. In order to
avoid confusion, in this review we use the term IIH to
dene all patients except when discussing risk factors.
IIH is characterised by symptoms and signs associated with raised intracranial pressure (ICP) in the
absence of a space-occupying lesion or other identiable cause. Its association with obesity has raised
questions about the underlying pathophysiological
mechanism which currently focus on the presence of
intracranial venous hypertension and/or increased cerebrospinal uid (CSF) outow resistance. In contrast
to its previous namesake, benign intracranial hypertension is certainly not benign. In one study it was predicted that approximately 1% to 2% of new patients

with IIH become blind in a given year (3), highlighting

the need for early diagnosis and appropriate eective
treatment.
In this narrative review we discuss the principal clinico-pathological features of IIH and consider currently
available therapeutic options and prognosis in longterm disease. We investigate the important role of
weight loss and examine the use of dierent drugs to
reduce CSF production and lower ICP. We also discuss
the risks and benets associated with more invasive
strategies, including CSF shunting, optic nerve sheath
fenestration (ONSF) and the placement of cerebral
transverse sinus stents. In addition, we highlight
1
The Oxford Headache Centre, Department of Neurology, John Radcliffe
Hospital, UK
2
Department of Ophthalmology, Royal Perth Hospital, Australia
3
Diagnostic Imaging, National University Hospital, Singapore

Corresponding author:
Benjamin Wakerley, Department of Neurology, John Radcliffe Hospital,
Headley Way, Headington, Oxford OX3 9DU, UK.
Email: benwakerley@fastmail.fm

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Wakerley et al.
recent suggested changes to IIH diagnostic criteria (2),
in which patients without papilloedema can still be
diagnosed, providing neuroimaging supports evidence
of chronically raised ICP in the absence of any other
structural cause.

Epidemiology
IIH is primarily a disorder of young women (<45 years
old), although it may occur at any age, and is less frequent in males, especially after the onset of puberty.
The overall annual incidence among the general population is approximately two per 100,000 (4), but is especially high among young women suering from obesity,
which remains the single most important risk factor. A
recent retrospective study in the United Kingdom (UK)
found the incidence of IIH among obese women to be
11.9 per 100,0000 (5), while a prospective study in the
United States (US) among obese women being evaluated for bariatric surgery calculated the incidence to be
as high as 323 per 100,000 (6). Given the current predicted trends in obesity levels (Figure 1), the incidence
of IIH is also likely to rise (7,8).

Risk factors
The majority of patients with IIH are overweight (9).
Interestingly, a signicant proportion of newly aected

individuals report rapid weight gain over the preceding

few months (10) and weight reduction remains the most
eective treatment option (11). A number of systemic
diseases and medications have been linked with
the development of PTCS, although it remains
unclear whether these are true risk factors or conditions
associated with obesity (12) (e.g. polycystic ovary
syndrome (13) and obstructive sleep apnoea (14)).
Hypercoagulable states, including systemic lupus
erythematosus (15), pregnancy and the use of oral
contraception, do not confer signicant risk to developing IIH (16).
There are, however, clear associations between
commencement of growth hormone (17), especially in
children, tetracyclines (e.g. doxycyline) (18) and retinoids (e.g. vitamin A) (19) and the development of
secondary PTCS, with apparent improvement of symptoms when the oending agent is reduced or stopped.

Pathogenesis
The exact pathogenesis of IIH remains unknown,
although most theories focus on the presence of intracranial venous hypertension and/or increased CSF outow resistance. There is no evidence that CSF
production is excessive in patients with IIH. Other
mechanisms include: venous microthombi, abnormal
vitamin A metabolism, fat metabolism and endocrine

80%

Proportion overweight

70%

60%

Canada

50%
USA

England
Spain

40%

Austria
Italy
Australia

30%

France
korea

20%
1970

1980

1990

2000

2010

2020

Year

Figure 1. Past and future trends in global obesity (7). The proportion of people overweight is projected by the OECD to rise a
further 5% during the next 10 years.
OECD: Organization for Economic Co-operation and Development.

250
dysregulation, altered sodium and water retention, and
sleep apnoea.

Intracranial venous hypertension

The clinical presentation of IIH is similar to that of
sinus thrombosis (20), which has led to the suggestion
that IIH is caused by venous hypertension. Here,
instead of thrombus obstructing venous blood ow,
venous hypertension is thought to result from stenosis
of distal portions of the transverse sinus. This is
supported by several imaging studies and symptom improvement following endovascular stenting.
Magnetic resonance (MR) venography and conventional angiography have identied the presence of
venous sinus stenoses in a large majority (>90%) of
patients with IIH compared to few in body mass
index (BMI)-matched controls (21,22). In a recent
study, 90% of 51 IIH patients displayed evidence of
bilateral transverse sinus stenosis on MR venography
(23). Interestingly the degree or location of stenosis in
this study did not correlate with CSF opening pressure,
visual eld testing or the clinical course of disease.
Similar ndings were observed in 14 IIH patients with
bilateral transverse sinus stenoses, who underwent
repeated lumbar puncture and MR venography over
a six-year-period (24). During follow-up transverse
sinus stenoses persisted in all patients, despite ICP normalisation in 64% of 14 cases. This suggested that sinus
calibre did not correlate with ICP. Whether such lesions
truly cause venous hypertension or merely serve as
radiological surrogates of raised ICP is unclear
(25,26). In contrast to unilateral transverse sinus stenosis, however, which was observed in 30% of 111
patients with normal CSF opening pressure, bilateral
stenosis occurred in only 1.8% of individuals and is
therefore a better surrogate of raised ICP (27).
Prolonged venous hypertension is thought to interfere
with passive absorption of CSF via the arachnoid
granulations, which results in increased ICP and further
venous sinus compression (28). The term self-sustained
venous collapse has been used to describe the cyclical
mechanism which links these physiological processes
(sinus stenosis ! venous hypertension ! reduced
CSF absorption ! raised ICP ! sinus stenosis) and
may explain the occurrence of chronically raised ICP in
patients with IIH (Figure 2) (21). Furthermore, it has
been proposed that a wide range of triggers that cause
raised ICP have the potential to initiate this cycle in
predisposed individuals. Similarly, this may explain
why reducing ICP with a single lumbar puncture may
break the cycle and lead to long-term remission of IIH
(29,21). A recent study showed a signicant reduction
in sinus diameter following lumbar puncture in IIH
patients (30). This is further supported by other studies

Cephalalgia 35(3)
which demonstrate reversal of venous sinus stenoses
after lumbar puncture or CSF shunting (26,31).
Endovascular stenting of transverse sinus stenoses
results in decreased venous pressure gradients and
improved CSF absorption. In the largest cohort of
52 IIH patients who had stenting, the mean pressure
gradient across the stenosis dropped from 19.1 mmHg
to 0.6 mmHg post-stenting (32). Similar reductions
have been observed in other studies (3336) and
appear to correlate with symptomatic improvement in
more than 80% of patients. The signicance of stenoses
in the pathogenesis of IIH and the role of stenting in the
management of such patients, however, remains controversial as stenoses may occur in patients with no
evidence of raised ICP (22) and have been shown to
persist in IIH patients with normalised ICP following
medical treatment (24).

Venous sinus microthombi

It has been proposed that the presence of venous sinus
microthrombi in patients with thrombophilia may
reduce CSF absorption by interfering with arachnoid
granulations (37). Such patients should probably not be
classied as having classical IIH, and sinus thrombosis
should always be excluded.

Abnormal vitamin A metabolism

Vitamin A (retinol) is thought to interfere with CSF
absorption. There is conicting evidence as to whether

Figure 2. Predisposed individuals may enter a state of selfsustained venous collapse. Raised ICP (of any cause) is postulated to induce transverse sinus stenosis (venous collapse). The
resultant outflow obstruction then leads to venous hypertension
and reduced absorption of CSF at arachnoid granulation. It has
been proposed that by breaking this cycle, long-lasting remission
may be achieved in some patients (21).
ICP: intracranial pressure; CSF: cerebrospinal fluid.

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Wakerley et al.
abnormalities of vitamin A metabolism or intoxication
cause IIH, with no new studies appearing in the literature over the past ve years. Retinol binding protein
and retinol were shown to be elevated in some patients
with IIH (38,39) and when in excess also transported
into the CSF of some patients (4043). In one study,
24% of 21 patients with elevated ICP secondary to IIH
demonstrated high (>25 nM) vitamin A levels compared to 0% of 19 patients with elevated ICP due to
other causes and 2.5% of 40 patients with normal ICP
(42). Overall 83% of six patients with elevated CSF
vitamin A had IIH and indicated a strong association.
Furthermore one patient with IIH had two lumbar
punctures and demonstrated elevated CSF vitamin A
levels only when ICP was high. In the case of IIH it
remains unclear whether elevated CSF retinol is toxic to
the arachnoid granulation reabsorption mechanisms or
simply a marker of excess CSF production by the choroid plexus.

Obesity hypothesis
We need to consider why the majority of patients
with IIH are young obese females. BMI is equal to
weight (kilogram) divided by height (meter) squared.
The normal range for BMI is 18.525 kg/m2, with
those >30 kg/m2 being considered obese and those
>40 kg/m2 as morbidly obese. Only a small proportion of females classied as overweight develop IIH,
but of these a greater proportion accumulate adipose
tissue on their lower bodies (44) compared to those
with upper body adiposity, in whom diabetes and
hypertension are more common. Furthermore, the
hormonal and biological functions of adipose tissue
are site dependent (45). For example, muscular
deposition is associated with insulin resistance,
whereas visceral fat may inuence systemic inammatory processes. Fat cells or adipocytes secrete a variety of so-called adipokines (pro-inammatory and
anti-inammatory cytokines) and hormones, which
are thought to play an important role in the pathogenesis of IIH (46). Several studies have attempted to
answer this question by proling adipocyte and hormone levels in CSF and serum samples taken from
IIH- and BMI-matched controls. Of particular interest is the hormone leptin, which is involved in energy
metabolism. While one study found elevated CSF
leptin levels in IIH patients compared to controls
(47), another suggested no such dierence (48).
Although it remains unclear whether leptin plays a
role in the pathogenesis of IIH, hypothalamic leptin
resistance is associated with obesity (49). Of note, in
contrast to other races, only a minority of Asian
patients with IIH are classied as obese (BMI
>30 kg/m2), suggesting that obesity may not play a

major role in the aetiology of IIH in Asians (50) and

other non-obese patients.

Sodium and water retention

For many years it was thought that IIH was caused by
abnormalities in sodium and water retention. This
has since been disproved and there is no histological
evidence of brain oedema in patients with IIH postmortem (51). Furthermore, antibodies against aquaporin-4, a transmembrane channel that regulates
brain water homeostasis, have not been observed in
this patient group (52,53).

Sleep apnoea
Apnoeic episodes are associated with retention of
carbon dioxide, cerebral vasodilation and subsequent
raised ICP. Sleep apnoea is common among obese individuals, especially males, and may exacerbate rather
than cause IIH (14,54).

Clinical symptoms
The majority (>90%) of patients with IIH present with
headache, which may mimic migraine or tension-type
headache (Table 1) (10). Lateralised throbbing pain
associated with nausea, vomiting, visual disturbance
and photopsia is frequently described and can be exacerbated by a change in posture, for example, bending
over or lying down. Headache is frequently but not
always present on waking. Pulsatile tinnitus is more
specic and less common in other primary headache
disorders (55). Retrobulbar, cervical and facial pains
are also encountered. Relief often comes with rest or
non-steroidal anti-inammatory drugs, with patients
habitually becoming dependent on analgesics and
developing superimposed medication-overuse headache
(56). Visual disturbance is common (>70%) and worrying for patients (16). Transient visual obscurations,
described as monocular or binocular blurring lasting

Table 1. Common symptoms in idiopathic

intracranial hypertension (IIH).
Headache
Transient visual obscurations
Intracranial noises
Photopsia
Retrobulbar pain
Diplopia
Sustained visual loss
Source: Adapted from Wall and George (10).

92%
72%
60%
54%
44%
38%
26%

252
for a few seconds, usually occur when standing, and are
thought to reect momentary ischaemia of the already
compressed optic nerve microvasculature. Their frequency does not correlate with the degree of raised
ICP or the severity of papilloedema and is not predictive of future sustained visual loss (57). Raised ICP may
cause unilateral or bilateral sixth nerve palsies, resulting
in horizontal diplopia.

Clinical signs
Stereotypically, the patient will be young, female and
obese. As a direct consequence of raised ICP, optic disc
swelling or papilloedema (Figure 3(a)) is commonly
present and considered to be the hallmark sign of
IIH. This is usually symmetrical, although can occasionally be unilateral (58) or rarely even absent (59)
and if long-standing leads to secondary optic atrophy.
In very early disease, prior to the appearance of disc
oedema, there may be loss of venous pulsations, which
are best observed in the venous segment that transverses the optic nerve head. Venous pulsations are
absent in 10% of normal individuals (60). Typically,
early papilloedema does not aect acuity, colour
vision or pupillary function and the patient may not
complain of any visual symptoms. If present, however,
the blind spot is usually enlarged and there is evidence
of peripheral visual eld loss. Deterioration of central
vision and acuity is usually gradual, but may be abrupt
in the case of fulminant disease and more likely to be
permanent. The earliest false localising sign associated
with raised ICP is sixth nerve palsy, although other
cranial nerves (III, IV, V, VII and VIII) may also
rarely be involved (61).

Differential diagnosis
Other causes of raised ICP and optic disc swelling
should be considered before a diagnosis of IIH is

Cephalalgia 35(3)
made. Many secondary causes of intracranial hypertension (e.g. intracranial mass lesion, obstructive hydrocephalus, venous sinus thrombosis (62), venous sinus
obstruction secondary to arachnoid granulations (63)
and choroid plexus papilloma (64)) can be excluded
radiologically, but occasionally IIH may be mistaken
for conditions which cause elevation of the optic nerve
head without raised ICP. These include malignant
hypertension, which may be accompanied by retinal
haemorrhages and exudates; optic disc drusen (Figure
3(b), (c)), caused by calcied deposits at the optic nerve
head, which do not aect visual acuity or central
venous pulsations (65) and can be distinguished from
papilloedema by computed tomography (CT) or ultrasound imaging of the optic nerve head (66); and diabetic papillopathy (67), a rare complication of diabetes
thought to be secondary to diabetic microangiopathy.

Diagnosis
A diagnosis of IIH is frequently made on the basis of
clinical history and ophthalmological ndings alone,
although neuroradiological exclusion of other causes
of raised ICP, especially venous sinus thrombosis, is
mandatory before proceeding to conrmatory CSF
manometry. Criteria for the diagnosis of IIH were
rst established by Dandy in 1937 (68), but have since
been modied (69,2). The most recent criteria in children and adults (2) also take account of patients who
dont develop papilloedema, yet have neuroimaging
suggestive of chronically raised ICP (Table 2). As
outlined in the recently published International
Classication of Headache Disorders, third edition
(beta version), headache attributed to IIH should be
diagnosed only if there is a clear temporal relationship
with raised ICP and should resolve when ICP normalises (70).
Formal visual eld testing, dilated fundus examination and photographs of the optic discs are indicated if

Figure 3. (a) Optic disc swelling (papilloedema, Frisen grade IV) compared with different degrees ((b), mild; (c), severe), of optic disc
drusen (pseudopapilloedema), which are not associated with raised intracranial pressure.

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Wakerley et al.
Table 2. Diagnostic criteria for pseudotumour cerebri
syndrome.
1.

Required for diagnosis of pseudotumour 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 pseudotumour cerebri syndrome
without papilloedema
In the absence of papilloedema, a diagnosis of pseudotumour 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 pseudotumour 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

venography may occur and mimic thrombosis (75,76).

Neither modality is diagnostic of IIH, but subtle features suggestive of raised ICP are well described,
including attening of the posterior sclera, and the
presence of an empty sella, which are present in the
majority of patients (Figure 4) (77,78). Less commonly
seen are protrusion and/or enhancement (with gadolinium) of the optic nerve (79).
Once a space-occupying lesion has been excluded,
CSF manometry via lumbar puncture in the lateral
decubitus position is performed. In adults the accepted
upper limit of normal is 25 cm H2O (80), while in children this is less clear, with some authors suggesting an
upper limit of 18 cm H2O in those under the age of 8
years (81). Some studies suggest that raised pressures
may occur in obese patients (82) in the absence of IIH,
but opening pressures above 28 cm H2O should always
be regarded as abnormal. Pain and sedation may give
rise to false positives and repeated manometry is sometimes indicated. CSF constituents (cell count, glucose
and protein) are normal in IIH.
Non-invasive measurement of ICP using transcranial Doppler ultrasonography may be available in the
future as a means of monitoring IIH patients in the outpatient setting or during acute exacerbations (8385).
Visual eld testing with computer-assisted static perimetry (Figure 5) is frequently used to assess the severity of optic nerve involvement and can be repeated
at each clinic visit to monitor disease course (86).
Enlargement of the blind spot, visual eld constriction
and inferonasal vision loss are more commonly
observed than scotomas. The role in assessing the severity of papilloedema with confocal scanning laser
tomography (87) is not entirely clear (88).

A diagnosis of pseudotumour cerebri syndrome is definite if the patient

fulfils 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.
Source: Reproduced with permission of Wolters Kluwer from Friedman
et al. (2).
MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; CT: computed
tomography.

there is any doubt to the presence of papilloedema and

provide important baseline observations for monitoring
disease course and treatment eects. Papilloedema can
be objectively graded (I to V) according to the Frisen
scale (71,72).
Although MR imaging/MR venography is the preferred imaging modality (73), especially in young
patients, those presenting acutely often undergo CT
brain and CT venography in order to exclude spaceoccupying lesions and sinus thrombosis quickly (74).
Some radiologists prefer CT venograms as in-plane
signal loss in two-dimensional (2D) time-of-ight MR

Treatment
Patients with IIH are best managed jointly by neurologists and ophthalmologists, although a multidisciplinary approach, involving clinical psychologists, personal
trainers and dieticians, may be of use in certain cases
(Table 3). Successful treatment requires motivation and
an understanding that permanent visual loss is likely if
ICP is poorly controlled. In obese patients, weight
reduction in conjunction with diuretics remains the
principal management strategy. In more resistant or
fulminant cases, CSF shunts oer the only hope in
controlling raised ICP.
Controlled weight loss has been shown to be of benet in obese patients at lowering ICP and improving
papilloedema (88), but is notoriously dicult to maintain. In one study, 25 patients were restricted to a lowcalorie diet (425 kcal/day, equivalent to four bananas)
for three months and lost an average of 15.7 kg and saw
an 8 cm H2O reduction in ICP (11). Bariatric surgery

254

Cephalalgia 35(3)

Figure 4. Radiological features seen in IIH.

(a) Axial T2-weighted brain MRI demonstrates severe scleral flattening (black arrow) and widening of the perioptic spaces (white
arrow), which are barely visible in healthy individuals. Flattening of the anterior pituitary gland by increased CSF pressure results in an
empty sella (black star), which is best appreciated on saggital T1-weighted brain MRI ((b), saggital views of brain stem; normal;
abnormal, white arrow). It remains undecided whether transverse sinus stenosis ((c), white arrow), demonstrated here with MRI
venography is involved in the pathogenesis of IIH or a secondary compressive phenomenon.
IIH: idiopathic intracranial hypertension; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid.

may be a viable option in some patients. A review of

62 obese patients with IIH showed that bariatric surgery was eective in terms of symptom resolution and
visual outcome (99). In 97% of 35 patients who had
pre- and postoperative funduscopy, papilloedema
resolved. Similarly, 92% of 12 patients were also
found to have marked improvement on formal visual
eld testing postoperatively.
Weight loss takes time and therefore medical treatment is indicated at presentation. Acetazolamide, a carbonic anhydrase inhibitor, is the initial drug of choice
and has been shown to lower CSF pressure in IIH
patients, possibly by reducing CSF production (89).
Acetazolamide controls symptoms in approximately
half of patients and appears to prevent relapses if continued long term. However, it is frequently not tolerated. Common side eects include digital and oral
paraesthesia, metallic taste and anorexia. Patients
should also be warned about kidney stones and the
relative contraindication in pregnancy due to teratogenicity. Improved compliance in adult patients can
be achieved if started at lower doses (e.g. 125 mg

daily) and slowly titrated up to 1 or 2 g per day. In

some patients the sustained release formulation
(Diamox sequels) is better tolerated. Methazolamide
can be used as an alternative. Topiramate is an anticonvulsant, but also inhibits carbonic anhydrase. One
unblinded study suggested similar ecacy to acetazolamide with respect to symptom improvement (90).
Patients should be warned about weight loss, cognitive
impairment and kidney stones. Fetal malformations
have been reported in approximately 4% of pregnancies exposed to topiramate, and women of childbearing
age should therefore be counselled (100). Patients
should also be warned that the ecacy of oral contraception is reduced with topiramate doses above 200 mg
per day. Angle closure glaucoma and myopia may also
rarely occur acutely (usually within the rst two weeks)
in patients commenced on topiramate and may be difcult to dierentiate clinically from high ICP-related
symptoms (101).
Loop diuretics, e.g. furosemide, are sometimes used
and have been shown to be of benet in children when
used in conjunction with acetazolamide (102).

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Wakerley et al.

(a)

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Figure 5. Visual fields and blind spot can be assessed using Humphreys perimetry. Left eye; normal blind spot (a), enlarged (b).

Table 3. Treatment options in idiopathic intracranial

hypertension (IIH).
Lifestyle
Medical management

Intervention

Weight loss (11)

Acetazolamide (89)
Topiramate (90)
Ferosemide (89)
Intravenous methylprednisolonea (91)
Repeated lumbar punctureb (92,93)
Cerebral transverse sinus stenting (94)
Shunts (9597)
Ventriculoperitoneal
Lumboperitoneal
Lumbar drain
Optic nerve fenestration (98)

Not recommended unless sight-threatening fulminant disease.

Should be used only if no alternatives are available, for example, during
pregnancy.
b

The use of corticosteroids in IIH is controversial.

One small series showed benet in patients with
severe acute visual loss when used in conjunction with
acetazolamide (103) but long-term use is associated
with weight gain and salt retention, which may
worsen symptoms.
Venous stenting of the transverse sinuses, in patients
with proven stenosis or obstruction on cerebral venography, has been postulated to relieve venous hypertension but remains controversial and long-term outcomes
remain unknown. Retrospective group analysis of 143
cases (104) from 15 studies (3236), with mean followup of 22.3 months, showed promising results. Stents
were placed in the right (69%) or left (27%) or both
(4%) transverse or sigmoid sinuses using an endovascular approach (99% of cases). Headache improved
in 88% of 112 patients, vision in 87% of 67 patients
and papilloedema resolved in 97% of 113 patients. No
deaths were reported during or immediately after the
procedure, although major complications occurred in

256
three patients (subdural haemorrhage) and minor complications in six patients.
Many patients with IIH continue to have chronic
daily headache despite normalisation of their CSF pressure and this can be complicated by medication-overuse
headaches. Frequently patients with IIH also develop
what appears to be chronic migraine and this can sometimes be dicult to distinguish from high-pressure headaches. Drugs used for migraine prophylaxis should be
used including, but not limited to, anticonvulsants, tricyclic antidepressants, and beta blocker medications
(94). Some of these medications can be associated with
weight gain and should be introduced cautiously.

Acute management of IIH

Patients presenting with worsening headaches or visual
disturbance often receive benet from ICP lowering following a therapeutic lumbar puncture. In some cases
this can induce lasting remission (21), despite 1 ml of
CSF being produced approximately every ve minutes
and therefore CSF volume returning to normal within a
few hours. The long-term benets associated with serial
lumbar punctures in patients with IIH, however,
remain unknown, although it appears to be eective
when treating exacerbations during pregnancy (92,93).
The procedure itself can be technically challenging in
obese patients, who often nd it uncomfortable.
Repeated lumbar puncture is also more likely to
result in complications, including: low-pressure headache, CSF leak or infection.
The use of intravenous indomethacin to lower ICP in
some patients with severe head injury has been debated
for over two decades (105), although its use in IIH
remains controversial and is not widespread. Unlike
other cyclo-oxygenase inhibitors, indomethacin causes
cerebral vasoconstriction, which reduces cerebral blood
ow and has an ICP lowering eect (106,107). In one
study, all seven IIH patients showed a signicant reduction (mean 14.4, range 8.020.0 cm CSF) in CSF opening pressure one minute after a 50 mg infusion of
indomethacin over one minute (108). On follow-up all
patients reported an improvement in headache symptoms and showed some resolution of papilloedema.
Rebound increase in ICP has been reported following
discontinuation of indomethacin and further trials in
IIH patients are therefore required to determine both
the short- and long-term benets.
In patients with rapid deterioration of vision more
invasive techniques are often required. CSF shunting or
ONSF are the most commonly used surgical procedures
although it remains unclear whether one is superior to
the other (109). CSF shunting works directly by lowering CSF pressure and poses no direct risk to vision,
while ONSF is less invasive and directly treats

Cephalalgia 35(3)
papilloedema, but oers less headache relief, at least
in the short term. The type of surgical intervention
adopted therefore appears to be driven by local preferences and expertise, as there are no trial data comparing the two.
CSF pressure can also be lowered by placing a permanent drainage shunt between the ventricles or subarachnoid space in the lumbar region and the
peritoneal cavity (ventriculoperitoneal and lumboperitoneal shunts, respectively) (110). Ventriculoperitoneal
shunts are thought to be less prone to obstruction than
lumboperitoneal shunts, but both types fail in nearly
half of cases and surgical revisions are therefore
common. In one retrospective series, 82% of 30 IIH
patients experienced symptom improvement following
ventriculoperitoneal shunting (95). Here, papilloedema
improved in 96% of patients and visual acuity
improved by at least two lines in 71% of patients.
There were a total of 126 shunt revisions, although 87
occurred in four patients and when excluded the overall
revision rate was 2.5 per patient. Similarly, another
series showed that 95% of 42 IIH patients reported
signicant improvement in headache symptoms postshunting (96). Although the majority of IIH patients
appear to report initial symptom relief when CSF pressure is lowered, the long-term benets of shunting
remain less clear. In the largest retrospective study
(97), symptoms and signs of elevated ICP were characterised in 53 patients pre-shunt and at six, 12 and 24
months post-shunt. Papilloedema was present in 92%
of patients at baseline and 44% by two years, while
headache was present in 96% at baseline and 79% by
two years. Visual decits were noted in 78% of patients
at baseline and 32% by two years, while tinnitus was
present in 80% at baseline and 67% at two years. From
the available data, shunting therefore appears to
improve visual symptoms in approximately 50% of
patients and headaches in only 20% over the rst two
years. Fifty-one per cent of these patients also required
shunt revision and 31% multiple revisions, indicating
that neurosurgical intervention should probably be
considered only as a last resort when medical therapy
and/or weight loss have failed or if vision is rapidly
deteriorating.
ONSF is favoured in some centres and has been
shown to improve or at least stabilise vision in 70%
90% of cases (98,111), and has a signicantly lower
complication and failure rate compared to CSF shunting. Headache symptoms, however, may not dissipate
and usually require additional medical treatment. The
ecacy and safety of ONSF were examined retrospectively in 158 eyes of 86 IIH patients (98). Improvement
in visual acuity and improvement or stabilisation
in visual elds were reported in 94% and 88%,
respectively. Furthermore, vision-limiting surgical

257

Wakerley et al.
complications were reported in less than 1% of cases.
Headache symptoms, however, improved in only 31%
of cases and ONSF probably does not reduce ICP
signicantly.
Fulminant IIH is rare, but devastating if not recognised and treated early. This was highlighted recently in
the case of an 18-year-old female with a CSF opening
pressure of 60 cm H2O, who developed complete lightperception blindness over four days. The authors
hypothesised that a rapid increase in pressure in the
perineural space of the optic nerve resulted in ischemic
optic neuropathy (91). On day 1 ICP was lowered by
inserting a lumbar drain and she was commenced on
intravenous methylprednisolone sodium succinate and
furosemide. Later, a ventriculoperitoneal drain was
inserted and after one month visual acuity had
improved to 20/30 in both eyes.

Prognosis
Disease course in IIH is poorly dened, with some
patients appearing to stabilise early with occasional
relapses, while others develop more progressive disease
(56,112). Recurrence of IIH is frequently associated
with additional weight gain. In one study of 50 patients
previously diagnosed with IIH, 26 experienced disease
recurrence (113). BMI in those with disease recurrence
was signicantly higher than at diagnosis (34.5 kg/m2 vs
32.7 kg/m2), while in patients without recurrence, BMI
was signicantly less than at diagnosis (35.8 kg/m2 vs
43.6 kg/m2). Overall 6% weight gain was observed in
patients with recurrence compared to 0% without
recurrence, highlighting the importance of weight loss
in the treatment of IIH. Despite some patients remaining asymptomatic, disturbances in CSF hydrodynamics
probably persist for many years (114). The eects of
chronically raised CSF pressure on the optic nerve are
well described (57), but there is also evidence which
suggests that it may lead to osseous erosion of the
skull base. Widening of the foramen ovale was
observed in 50% of patients on CT (115) and it has
also been postulated that in some cases, such bony erosion may cause CSF otorrhoea and rhinorrhoea.
Interestingly, patients presenting with spontaneous
CSF leak are also often middle-aged, obese and of
female gender. In one study of 16 patients presenting
with spontaneous CSF leak, 50% fullled Dandy criteria (68) for IIH (116). The majority were female and
obese, and also complained of headache in addition to
pulsatile tinnitus. In another series of 17 patients presenting with spontaneous CSF otorrhea, all 12 females
had BMI >30 kg/m2 and two were diagnosed previously as having IIH (117). Similarly, 18 patients presenting with spontaneous rhinorrhoea also displayed
evidence of raised ICP, and the majority had other

features suggestive of IIH (118). It has been postulated

that CSF leak may keep some patients with IIH symptom free, and that symptoms and signs associated with
raised ICP may re-emerge if the leak is corrected without addressing the underlying cause of raised ICP (119).
Whether spontaneous CSF leak in these patients represents a variant of IIH in predisposed individuals or a
consequence of chronically raised CSF pressure is
uncertain, and highlights the need for more long-term
studies.

The IIH Treatment Trial (IIHTT)

The Neuro-ophthalmological Research Disease
Investigator Consortium (NORDIC) is currently performing the IIHTT and has recruited 166 IIH patients
with mild visual loss (120). This multi-centre, randomised, double-blind, placebo-controlled study is examining whether dieting coupled with acetazolamide is
superior to treatment with dieting and placebo in IIH
patients. The primary outcome is improvement in
visual perimetry (perimetric mean deviation) from baseline to six months. Other outcomes include the change
in papilloedema grade, ICP measurements, other visual
eld measurements and quality of life measures.
Recruitment is now complete, although not all patients
have been followed for six months. Preliminary analysis
indicated that dieting and lifestyle modications have
resulted in 6% weight loss in almost half of patients
recruited. High doses of acetazolamide also appeared
to be safe and well tolerated if given twice daily with
food, although 2% of patients developed kidney stones.
There are many unanswered questions regarding the
pathogenesis of IIH which this trial hopes to address
by studying proteomic and genetic risk factors in IIH
patients compared to controls. This will determine further investigations into serum and CSF levels of potential IIH mediators, the results of which are eagerly
awaited.

Conclusion
Given the global obesity epidemic, the incidence of IIH
is likely to rise, although it should not be overlooked in
non-obese individuals, especially males. Patients who
fail conservative management strategies, including
weight loss and the use of drugs that reduce CSF
production, present a particular problem to neurologists and ophthalmologists and invariably undergo
neurosurgical intervention, which is often unsatisfactory in the long term. A better understanding of the
underlying pathophysiological processes in IIH and
the advent of new clinical trials will lead to the development of more treatment options, which are currently
lacking in this disease of unknown aetiology.

258
Literature search methods
English-language publications were searched for in
PubMed between January 2003 and December 2013.
The following search terms were used: pseudotumo(u)r
cerebri, benign idiopathic hypertension and idiopathic
intracranial hypertension. A total of 741 publications

Cephalalgia 35(3)
were identied and individually assessed according to
their relevance and publication date. Specic exclusion
criteria included: publications on paediatric patients;
single case reports, unless of exceptional importance; letters; editorials; and other review articles. The reference
lists of identied publications were also scrutinised for
further relevant publications.

Clinical implications
. Given the global obesity epidemic, the incidence of idiopathic intracranial hypertension is likely to rise.
. At present non-surgical treatment options for lowering intracranial pressure in such patients are limited and
often poorly tolerated.
. Understanding the pathophysiological mechanisms associated with developing idiopathic intracranial
hypertension and obesity may lead to the development of new treatment strategies.
. New evidence suggests that idiopathic intracranial hypertension may exist as a chronic disease in some
individuals, even in the absence of headache.
Funding
This research was funded by the Oxford Headache Centre,
UK.

Conflict of interest
None declared.

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