Idiopathic intracranial hypertension (IIH) is a condition characterized by increased
intracranial pressure (ICP) of unknown cause, papilledema with the risk of permanent
visual impairment, and severe headaches that profoundly impair quality of life, often
becoming irreversible despite resolution of the IIH and disappearance of the papilledema.
IIH is diagnosed using the modified Dandy criteria,based on increased ICP (>25 cm H2O on
lumbar puncture (LP) performed in the lateral decubitus), papilledema, normal
cerebrospinal fluid (CSF) and brain imaging that rules out all other causes of
intracranial hypertension.
IIH is attracting growing interest among clinicians as its incidence and prevalence
increases. IIH predominates in women of childbearing age with increased body mass index
(BMI) . In the United Kingdom its incidence has doubled in 14 years, rising from 3.5 per
100,000 to 7.69 per 100,000 in the female population between 2002 and 2016 (+ 108%)
To date, the exact pathophysiology of IIH remains unknown. IIH is considered to be a
complex neurometabolic and neuroendocrine disorder favored by female gender and obesity.
Hypothesized mechanisms include inflammatory, autoimmune and hormonal abnormalities, of
notably androgens.
In the majority of patients (80% of the cases) IIH is associated with obstruction of
cerebral venous drainage with bilateral stenosis of the transverse sinus. This stenosis
may be the main underlying cause in the so-called "venogenic" form of IIH. Equally, in
the absence of a stenosis, obstruction may occur when otherwise normal venous sinuses are
compressed by the increased ICP, the so-called "non-venogenic" form of IIH.
The therapeutic management of IIH has a triple objective: i) to treat the underlying
cause(s); ii) to protect vision, and iii) to reduce the impact of headaches.
Unfortunately, current treatments (weight loss, drug therapy with acetazolamide or
Diamox, and/or anti-migraine treatment) are not very effective. It has been argued to
favor treatments targeted directly at the cause of the increased ICP, and therefore at
its etiology. A promising innovative treatment of venogenic IIH includes stenting of the
transverse sinus stenosis. It has been associated with papilledema and ICP reduction
rates up to 80% .
However, venous stenosis is probably not the only underling mechanism of increased ICP.
Accordingly, the role of metabolic, hormonal and inflammatory mechanisms requires further
investigation. It has been found that serum levels of tumor necrosis factor-alpha (TNF-α)
were significantly higher in patients with IIH compared with healthy controls . The serum
TNF-α level was a significant predictor of the severity of visual field disease.
Interestingly, by evaluating adipokine and cytokine levels to identify possible serum
markers of inflammation in the pathophysiology of IIH, it was observed that interleukin
(IL)-1β levels were significantly higher in the IIH group compared to the control group,
whereas IL-8 and TNF-α levels were significantly lower. Although the latter seems in
contrast with previous findings, the presence of recurrent relapses - known to enhance
chronic inflammatory protective mechanisms and thus increased TNF- α levels, may explain
this difference. Serum levels seem thus to be altered (IL-1β, IL-8 and TNF-α) and may be
associated with the pathogenesis of IIH. Cytokines might be valuable as prognostic
markers in IIH to predict possible relapse.
Given the established association between increased perivascular expression of the water
channel aquaporin-4 (AQP4), degeneration of pericytes, capillary basement membranes, and
blood-brain barrier (BBB) dysfunction in patients with IIH, the BBB function was
investigated by determining the prevalence of extravasation of endogenous proteins such
as fibrinogen. Signs of BBB dysfunction, measured by the surface area of extravasated
fibrinogen/fibrin, were significantly more pronounced in IIH patients than in reference
subjects and demonstrated BBB dysfunction. The increased degree of BBB dysfunction was
associated with increased perivascular AQP4 immunoreactivity. AQP4 appears to play a
major role in "flushing" brain parenchyma through interstitial fluid, thus also affecting
inflammation-generating substances including fibrinogen extravasation.
Given the obesity of IHH patients, the involvement of leptin, a hormone associated with
the sensation of hunger, was also investigated and found to be elevated. Its regulation
mechanism of Na/K ATPase in the choroid plexus and CSF secretion has been postulated . It
is also important to point out that between 40%-50% of women with IIH suffer from
polycystic ovary syndrome, which is characterized by dysregulation of sex hormones .
Finally, mineralocorticoids, such as 11β-hydroxysteroid dehydrogenase, have been studied
in the pathogenesis of IIH following their potential role in the regulation of Na/K
ATPase at the level of the choroid plexus .
Taken together, these studies seem to highlight a wide range of processes for which
biomarkers associated with IIH are starting to emerge, but that are still poorly
understood. The lack of prospective studies and the small number of patients included in
most of the studies carried out so far, impedes conclusions on the role of these factors
in the etiology of IIH.
Nevertheless, improvement of IIH treated with acetazolamide and/or stenting seems to
correlate with a reduction in ICP, but the association of this reduction with metabolic
changes in peripheral, central blood and/or CSF needs to be clarified. The identification
of specific inflammatory, immunological and hormonal biomarkers in patients with IIH and
their variation in relation to ICP variation should provide a better understanding of its
etiology. Biomarkers related to disease severity should allow, in the longer term,
proposing alternative treatments.
Advances in endovascular techniques have made it possible to measure ICP at the level of
the intracerebral venous system, and to take biological samples at the central
(intracerebral) level in order to identify biomarkers associated with clinical severity,
and to study their variation as a function of i) normalization of intracranial pressure
after treatment with stenting or Diamox, ii) changes in ophthalmological symptoms and
headaches.
To date, there are very few prospective cohorts analyzing the biology of patients with
IIH. This study will help in the search for biomarkers of the pathology's severity, with
a dual aim: 1) to stimulate understanding of the pathophysiology of IIH, which to date
remains largely unknown; 2) to develop new drug treatments targeting the mechanisms of
increased ICP.