Download The syndrome of pseudotumour cerebri and idiopathic intracranial

The syndrome of pseudotumour cerebri and idiopathic
intracranial hypertension
Clare Frasera and Gordon T. Plantb
a
Fellow in Neuro-Ophthalmology, Moorfields Eye
Hospital, City Road, London and bThe National
Hospital for Neurology and Neurosurgery, Queen
Square, London, UK
Correspondence to Dr Gordon T. Plant, Box 93, The
National Hospital for Neurology and Neurosurgery,
Queen Square, London WC1N 3BG, UK
E-mail: [email protected]
Current Opinion in Neurology 2011, 24:12–17
Purpose of review
Idiopathic intracranial hypertension (IIH) is a condition in which raised intracranial
pressure is associated with a high body mass index, and in those societies in which the
prevalence of obesity is increasing the disorder is of increasing importance. It is one
cause of the syndrome of pseudotumour cerebri but the cause and the link with a rise in
body weight are not understood. Furthermore the treatment of the more severe, sightthreatening cases is controversial.
Recent findings
A major theme in recent years has been an attempt to identify the underlying mechanism of
IIH. Some theories – such as the dural sinus stenosis theory – seem to ignore the
relationship with weight gain; others have proposed a direct link between obesity and
raised intracranial pressure through a specific fat distribution in the body; others through
the production of lipokines; and yet others have suggested a converse causation with
raised intracranial pressure giving rise to obesity. Uncontrolled case series continue to
demonstrate the success of interventions such as cerebrospinal fluid diversion
procedures, venous sinus stenting and bariatric surgery but there are no level 1 clinical
trials.
Summary
Interest in IIH is increasing and currently generating numerous studies but there is no
consensus view on either cause or management.
Keywords
dural sinus stenosis, dural sinus thrombosis, intracranial hypertension, papilloedema,
pseudotumour cerebri
Curr Opin Neurol 24:12–17
ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540
Introduction
Idiopathic intracranial hypertension (IIH) is a disorder
characterized by increased intracranial pressure (ICP)
of unknown cause, predominantly seen in women of
childbearing age and associated with a history of recent
weight gain [1]. The concept of raised intracranial
pressure in the absence of a space occupying lesion
was first introduced by Nonne [2] as ‘pseudotumour
cerebri’ (PTC). The article in which the term was
coined refers to a number of other conditions causing
raised intracranial pressure in the absence of an intracranial tumour, such as communicating hydrocephalus,
which would not now be classified as PTC. Later the
term ‘benign intracranial hypertension’ became popular and was often used interchangeably with PTC. The
condition was considered ‘benign’ in comparison with
cases of tumour [3] but it has been argued that loss of
visual function in up to 25% of cases and progression to
blindness if untreated means that it should not be
considered ‘benign’ as far as visual function is concerned. Hence the term IIH is now generally used.
1350-7540 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
The authors contend that PTC remains a useful term to
describe patients with raised ICP who have neither
hydrocephalus nor a mass lesion but in whom either a
cause has been established (often a cause of intracranial
venous hypertension such as dural sinus thrombosis or a
dural fistula) or the patient does not have an elevated
body mass index (BMI) as a potential underlying cause.
There is of course a difficulty here in that the causal
relationship between weight gain and the development
of IIH is unknown and an increase in body mass may act
synergistically with other pathogenic mechanisms such as
obstructive sleep apnoea. A set of criteria, now known as
the modified Dandy criteria [4], can be used to establish a
diagnosis of IIH after a thorough search for an identifiable
cause of PTC (see Table 1). As stated above the authors
prefer to reserve the term IIH for cases associated with a
high BMI but without evidence of obstructive sleep
apnoea.
Recent publications have looked again at the question of
weight gain in IIH, some suggesting pathogenic mechanisms which may explain how weight gain can lead to
DOI:10.1097/WCO.0b013e328341f94a
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Syndrome of pseudotumour cerebri and IIH Fraser and Plant 13
raised ICP, others suggesting the reverse – that raised
ICP is the cause of weight gain. We do, however, have
further convincing evidence that weight loss results in a
lowering of ICP. There are further observations regarding
the possible role of narrowing of the dural sinuses, either
as a primary stenosis or secondary compression.
Diagnosis and investigations
The diagnosis of IIH is made by the exclusion of other
causative pathologies. However, there are some recent
reports of features and tests that can assist in the diagnosis
and monitoring of IIH.
Ophthalmic features
A cross-sectional analysis and comparison of the features of
IIH patients with and without papilloedema has been
carried out. Among 353 patients studied, the prevalence
of those without papilloedema was 5.7% (n ¼ 20). Patients
without papilloedema reported photopsias (20%) and were
found to have spontaneous venous pulsation (75%) and
nonphysiologic visual field constriction (20%) more often
than did those with papilloedema. Mean opening pressure,
although above normal, was lower in patients without
papilloedema (309 versus 373 cmH2O), but visual acuities
were similar between groups [5]. A case report of a patient
with IIH and monocular papilloedema documents progressive optic atrophy and central field loss in the eye
without papilloedema. Despite this, the authors caution
against attributing vision loss to raised ICP when there is
no papilloedema [6]. Another case this year emphasizes
that optic nerve sheath fenestration may yield initial
improvement in vision and reduction in papilloedema
yet not prevent subsequent visual loss in IIH despite
the improvement in the optic disc appearance and resolution of transient visual obscurations. If there is further
visual loss, a cerebrospinal fluid (CSF) diversion procedure
should be considered if ICP is high [7].
When there are visual field changes in IIH without
papilloedema, nonphysiological visual loss may be the
underlying problem. In one review of functional visual
loss (FVL) and IIH, 65% of patients had FVL at pres-
Key points
Idiopathic intracranial hypertension is a condition
in which raised intracranial pressure is associated
with a high body mass index, and in those societies
where the prevalence of obesity is increasing the
disorder is of increasing importance.
A study from Birmingham has shown that women
who followed a low-energy diet for 3 months had
significantly reduced signs and symptoms of idiopathic intracranial hypertension and that these
reductions persisted for 3 months after they stopped
the diet.
Controversy remains as to whether venous sinus
stenosis is consequent upon or is causative of the
raised intracranial pressure.
Uncontrolled cases series continue to demonstrate
the success of interventions such as cerebrospinal
fluid diversion procedures, venous sinus stenting
and bariatric surgery but there are no level 1
clinical trials.
Pseudotumour cerebri remains a useful term to
describe patients with raised intracranial pressure
who have neither hydrocephalus nor a mass lesion
but in whom either a cause has been established
(such as dural sinus thrombosis or a dural fistula) or
the patient does not have an elevated body mass
index as a potential underlying cause.
entation and all had tubular or nonphysiological constriction of visual fields. The majority had significant psychiatric, psychosocial, or other medical comorbidities. Of
concern is that 53% were managed surgically at some
point, having nerve decompression, shunt, or both [8].
Disc imaging and visual field analysis
Optical coherence tomography (OCT) gives clinicians
the ability to quantify the thickness of the retinal nerve
fibre layer (RNFL) at the optic disc. The data from a
recent study support the possible use of OCT as a
noninvasive quantitative method of monitoring the
severity and evolution of papilloedema in IIH. In a cohort
of patients with mild papilloedema associated with IIH,
the RNFL thickness was 75% (78.5 micron) greater than
Table 1 Modified Dandy criteria
Symptoms of raised intracranial pressure
No localizing signs
The patient is awake and alert
Normal CT and MRI findingsc
Lumbar puncture opening pressure >25 cmH2O
No other explanation for raised intracranial pressured
Headache, nausea, vomiting, transient visual obscurations or papilloedemaa
With the exception of abducens (CN VI) palsyb
With no evidence of cerebral thrombosis
With normal CSF biochemical and cytological composition
Data from [4].
a
It is now well established that IIH can occur without headache and indeed without papilloedema.
b
Although others can occur rarely such as conjugate gaze palsies and facial palsy.
c
In most cases the imaging is not normal but shows changes secondary to raised intracranial pressure such as intra-sellar arachnoid herniation,
distension of the optic nerve sheaths and flattening of the posterior aspect of the globe. These changes are not specific to IIH.
d
Syndromically, in adults, most IIH patients are females with a high body mass index and a history of recent weight gain. The authors recommend
putting cases who do not have this phenotype in a different category (for example a slim male). These patients can be said to have the ‘pseudotumour
cerebri syndrome’ but not IIH as the diagnosis must remain under permanent review in such patients.
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14 Neuro-ophthalmology and neuro-otology
in control eyes and correlated significantly with Humphrey visual field indices of mean deviation and pattern
standard deviation. Regression analysis showed that for
every 10 micron of mean RNFL thickness increase at
baseline, there was a 0.6-dB decrease in mean deviation
at the last follow-up [9]. However, in more severe
examples of papilloedema becoming atrophic it would
be expected that thinning of the nerve fibre layer would
be associated with visual loss.
Dural venous sinus stenosis and compression
A ‘self-sustained venous collapse’ is proposed as a crucial
causative mechanism in predisposed patients, leading to
intracranial hypertension in the presence of a wide range
of triggering factors. The proposed mechanisms predict
the long-term remission of IIH syndromes frequently
observed after a single or few serial CSF subtractions
by lumbar puncture [10]. Controversy remains as to
whether venous sinus stenosis is consequent upon or is
causative of the raised ICP.
Imaging
Sinus venous stenoses have been found at magnetic
resonance venography (MRV) in the large majority of
IIH patients in one study [10]. However, a Spanish group
reports that only 58% of PTC patients showed filling
defects in the transverse sinus [11]. These stenoses may
have various conformations, ranging from functional
smooth narrowing of sinus segments associated or not
with definite flow gaps, to segmental hypoplasia or aplasia
of one or more central venous collectors.
Anatomical variations must be considered when interpreting these images. Computed tomographic venography demonstrates both the morphology of the venous
system and the adjacent bony grooves so provides an
insight into the cause of observed narrowings of the
transverse sinuses. A study from King’s College Hospital
in 2008 was able to demonstrate a strong correlation of
bony groove height with venous sinus height at the
largest portions of the transverse sinus in both IIH
patients and non-IIH individuals. They concluded that
transverse sinus tapered narrowing in individuals without
IIH and in the majority of patients with IIH were
associated with proportionately small or absent grooves,
and these were postulated to be primary or fixed. Some
patients with IIH demonstrated tapered transverse sinus
stenoses with disproportionately large bony grooves,
suggesting a secondary or acquired narrowing [12]. This
observation has important implications as it indicates that
we need to consider three possible reasons why a dural
sinus such as the lateral sinus may appear narrow in a
patient with PTC: it may be congenitally narrow, it may
be compressed secondarily to the ICP itself, or it may be
an acquired stenosis.
In addition there are structures that may result in MRI
venographic filling defects, such as trabeculae/septa and
arachnoid granulations, all of which could ultimately lead
to increased intracranial dural sinus venous hypertension.
However, in normal individuals, over 50% were found to
have structures in their transverse sinuses that could be
potential venous filling defects [13].
Intervention
With the recent emphasis on the significant number of
patients with IIH found to have associated nonthrombotic dural venous sinus stenosis there has been renewed
interest in endovascular stenting as a treatment option.
However, the assumption that venous stenosis leads to a
high-pressure gradient that decreases CSF resorption
through arachnoid villi requires further evidence.
In one case report, authors describe a patient with IIH who
was found at venography to have a giant arachnoid granulation in the left dominant transverse sinus and in whom
venous sinus stenting reduced the cerebral spinal fluid
opening pressure with immediate symptomatic improvement, suggesting a causal relationship between venous
outflow obstruction and IIH [14]. Another Australian report
describes a woman with IIH in whom a repeatedly demonstrated venous obstruction on MRV partially resolved
when the CSF pressure was reduced to 11 cmH2O and
completely resolved when reduced to 8 cmH2O. These
findings support the view that raised pressure is the cause
rather than the outcome of venous obstruction [15].
In a more recent publication, 13 patients with refractory
IIH were evaluated for venous sinus stent placement.
Moderate sinus stenoses with normal intra-sinus pressures were found in three patients and therefore stent
placement was not performed. Ten patients had elevated
pressure gradient across a stenosis (11–50 mmHg), which
decreased following unilateral transverse sinus stent placement. Headaches improved or resolved in all stented
patients. Papilloedema resolved completely or almost
completely in eight patients and significantly improved
in two patients. There were no major periprocedural
complications [16].
A review of published cases to date found 78% had
complete relief or improvement of their main presenting
symptoms after endovascular stenting. Resolution or
improvement in papilledoema was seen in 85.1% of
patients. The study concluded by saying that endovascular stenting should be considered whenever venous
sinus stenosis is diagnosed in patients with IIH [17].
Other pathophysiological advances
Other disorders of venous circulation, such as jugular
valve insufficiency, have also been investigated in recent
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Syndrome of pseudotumour cerebri and IIH Fraser and Plant 15
years, based on reflux duration during a controlled valsalva manoeuvre. Jugular valve insufficiency was found to
be significantly more frequent in patients with IIH (70%
as opposed to 30% in a control group) and may facilitate
pressure transmission from increased intra-abdominal
pressure in obesity into the intracranial venous system [18].
Waist-to-hip ratio (WHR) is a descriptive measure of
body fat distribution approximately reflecting upper to
lower body fat ratio. In a study of IIH patients compared
with two obese control groups, WHR was 0.79 in IIH
versus 0.84 and 0.91 in the controls. The authors concluded that in IIH, fat tends to preferentially accumulate
in the lower body relative to other obese women of the
same BMI range. Whereas most complications of obesity,
such as hypertension, diabetes, dyslipidaemia, and the
metabolic syndrome, are linked to upper body adiposity,
IIH may represent a unique condition potentially
induced by nonvisceral fat-related mechanisms [19].
Contrary to the obesity hypothesis, one group reported
findings of similar BMI in chronic tension type headache
patients and IIH patients, who did differ significantly in
lumbar CSF pressure (20 as opposed to 35 cmH2O). They
concluded that this refutes the hypothesis that obesity
precedes, and is the cause of, intracranial hypertension in
IIH. Since a relationship between raised ICP and obesity
is established it is therefore necessary to propose that
intracranial hypertension is the primary cause of weight
increase in IIH [20]. Also, in the Asian population only
7.1% of IIH patients classify as obese according to BMI,
suggesting that obesity may not play a major role in the
pathogenesis of IIH in Asians [21].
Recent studies have linked obesity with abnormalities in
circulating inflammatory and adiposity-related cytokines
[22]. Obesity is also related to dysregulation of cortisol
production by the prereceptor enzyme, 11beta-hydroxysteroid dehydrogenase, and this may have a role in
pathogenesis [23]. In a study of 26 patients, CSF leptin
was significantly higher in patients with IIH compared to
controls. In the control population, BMI correlated with
serum and CSF leptin, but this was not the case for the
IIH population. This suggests that CSF leptin may be
important in the pathogenesis of IIH and that obesity in
IIH may occur as a result of hypothalamic leptin resistance [24]. However, another study found there was no
alteration in leptin levels but did show an elevation in
CSF cytokine CCL2 [25]. Yet another study found that
no significant differences in the serum and CSF concentrations of cytokines IL-1beta, tumour necrosis factor
(TNF) and IP-1 were observed between the IIH and
controls, suggesting these cytokines do not contribute to
pathogenesis [25]. Both natriuretic peptides and aquaporin-4 were proposed as potential factors in vascular
dysregulation affecting the CSF; however, studies
recently published have failed to find an association with
IIH [26,27].
A recent study has looked again at the question of
thrombophilia in IIH. In a cohort of 51 patients with
obesity-related IIH, the presence of antiphospholipid
antibodies was significantly associated, as were elevated
levels of factor VIII, plasminogen activator inhibitor-1
and lipoprotein(a). How these results should be interpreted is difficult to say as any evidence of thrombosis
per se is outwith the clinical definition of IIH [28].
Management
Dural venous sinus stenting has shifted management
focus in some institutions, but this should be considered
on balance with other options for normalizing ICP.
Lifestyle
It has long been taught that acetazolamide is used to
protect patients from the potential harm of IIH while
they are losing enough weight to reverse the pathological
process, with little top-level evidence. However, results
from the first formal study of lifestyle intervention were
published this year. In this study, 25 women with a BMI
above 25, who had papilloedema and intracranial pressure
greater than 25 cmH2O for over 3 months, underwent a
dietary modification. The protocol followed three stages,
each of 3 months duration:
(1) Stage 1: no new intervention
(2) Stage 2: nutritionally complete low calorie diet
(425 kcal/day)
(3) Stage 3: follow-up period after the diet.
All measures of weight, IIH symptoms and visual function remained stable over stage 1. During stage 2, there
were significant reductions in weight (mean 15.7 kg), ICP
(mean 8.0 cmH2O), score on headache impact test (7.6),
and papilloedema. Mean deviation of the Humphrey
visual field remained stable, and in five patients the
Log MAR visual acuity improved by one line. Fewer
women reported symptoms including tinnitus, diplopia,
and obscurations. Re-evaluation at 3 months after the diet
showed no significant change in weight, and all outcome
measures were maintained. This study shows for the first
time that women who followed a low-energy diet for
3 months had significantly reduced signs and symptoms
of IIH and that these reductions persisted for three
months after they stopped the diet [29].
Medical
Reducing the production rate of CSF can be achieved
using acetazolamide (a carbonic anhydrase inhibitor), and
this still the mainstay of medical therapy. Frusemide,
bendroflumethiazide and topiramate may also be used, in
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16 Neuro-ophthalmology and neuro-otology
those intolerant of acetazolamide. The use of corticosteroids is debatable. There have been no updates in the
literature for 2009 and 2010 concerning the use of any of
these medications.
A 2007 study compared topiramate versus acetazolamide
in IIH, and found no statistically significant difference in
outcome, except for prominent weight loss in those given
topiramate [30]. A 2010 review of electronic medical
records found the use of topiramate in IIH is seen
particularly in patients with co-existent obesity, depression or bipolar disorder with the average dose being
100 mg per day [31].
In 2007 there was a study of the use of octreotide in the
management of IIH [32]. However, there have been no
subsequent publications in Medline listed journals.
Surgical
To date, no prospective, randomized study has been
performed comparing lumbo-peritoneal shunt, ventriculo-peritoneal shunt and optic nerve sheath fenestration. Procedure choice appears to be based on local
availability and the prominence of presenting symptoms.
Well designed, multicentred clinical trials to clarify
which intervention best suits particular patients are
needed [33].
In a single-centre review of adjustable lumbo-peritoneal
shunts, 77% had improvement of their headache and 86%
had no ongoing visual problems postoperatively. Spontaneous readjustment of the valve occurred in one patient
causing over-drainage headache, and this resolved when
the valve was reset. Distal obstruction meant 35%
required shunt exploration or revision procedures [34].
In another study of four patients treated with lumboperitoneal flow-regulated shunts, the device was found to
be a satisfactory treatment for those who require surgical
therapy [35]. Further experience is required to address
the long-term outcome of adjustable shunts, balancing
sufficient drainage while preventing over-drainage [36].
A review of the literature examining the use of bariatric
surgery in IIH was published, reporting on a total of 62
patients. The Roux-en-Y gastric bypass was the most
common bariatric procedure performed. Over 90% had
resolution of their IIH symptoms, and 97% of those with
papilloedema were found to have resolution. The average
postoperative ICP decrease was 25 cmH2O. Prospective,
controlled studies are necessary [37].
The syndrome of pseudotumour cerebri
The following by no means a definitive list of secondary
causes of raised ICP; it does, however, serve to highlight
recently published cases.
The incidence of microcytic anaemia was found to be
10.3% in a review of 80 case notes. On correction of
anaemia alone, the majority of these cases resolved [38].
A review of over 300 presumed IIH cases showed cerebral
venous sinus thrombosis (CVST) was present in 11.4%.
MRI alone identified 68% of CVST, with the addition of
MRV revealing the other cases. Risk factors associated
with CVST were only identifiable in 26% of patients [39].
Pseudotumour cerebri is described after successful
surgery for Cushing’s disease. In a retrospective review
of 941 surgeries, raised ICP was found in seven children
(3%), but no adults, within 1 year of surgery and often
while patients were still undergoing replacement steroid
therapy. There was no correlation between the degrees of
hypercortisolism before surgery [40].
In a review of Behcet’s disease patients with clinical
evidence of neurological involvement, 6% of patients were
found to have PTC [41]. There is also a recently published
review of IIH in systemic lupus erythematosus [42].
Minocycline has been associated with mild and transient
papilloedema due to raised ICP. However, two cases of
severe papilloedema and visual field loss have now been
reported. In these cases treatment of PTC had to be
continued even after discontinuation of the minocycline
[43].
Conclusion
Since the recognition of the condition there have been
limited advances in evidence-based treatments for IIH,
but myriad changes in proposed cause [44]: the publications in past months reviewed above have continued this
bewildering tradition. The authors’ opinion is that weight
gain is of fundamental importance and plays a causal role in
IIH; the observation that weight loss ameliorates the
condition supports this. Some of the articles reviewed
above are at odds with this basic concept, suggesting that
raised ICP may cause weight gain or that the pathogenesis
of IIH may be from stenosis of a dural sinus with no
explanation as to how this might be related to a high
BMI except as a collision of two risk factors.
If normalization of the ICP is achieved (by whatever
means) the condition will be cured. It is essential that this
be brought about before irreversible visual loss has
occurred. With so many potential therapeutic measures
available–weight loss, acetazolamide and other carbonic
anhydrase inhibitors, lumbo-peritoneal and ventriculoperitoneal shunts and dural sinus stenting–the choice
will depend upon, on the one hand, the risk of visual loss
or of continued significant headaches if control of the ICP
is not immediate, against the long-term complications of
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Syndrome of pseudotumour cerebri and IIH Fraser and Plant 17
the various interventions. Unfortunately for our patients
we still cannot advise them, based on class 1 evidence,
which intervention is to be preferred and until such
evidence is available decisions will continue to be based
largely on local practice.
18 Nedelmann M, Kaps M, Mueller-Forell W. Venous obstruction and jugular
valve insufficiency in idiopathic intracranial hypertension. J Neurol 2009;
256:964–969.
19 Kesler A, Kliper E, Shenkerman G, Stern N. Idiopathic intracranial hypertension
is associated with lower body adiposity. Ophthalmology 2010; 117:169–174.
It is often the interesting exceptions that prove the rule and this observation could
also lead to a useful experimental approach to this question.
20 Hannerz J, Ericson K. The relationship between idiopathic intracranial hypertension and obesity. Headache 2009; 49:178–184.
Acknowledgement
Dr Clare Fraser wishes to acknowledge the funding and support of the
Sydney Eye Hospital Alumni Travelling Fellowship.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 89–90).
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