Idiopathic intracranial hypertension (IIH) is a rare but important disease associated with significant morbidity.
The pathophysiology of IIH is incompletely characterised; suggested underpinning mechanisms include the role of cerebrospinal fluid regulation as well as metabolic and endocrinological perspectives
This review will provide an up-to-date discussion on the potential pathogenic mechanisms and management of IIH.
The underlying pathogenesis of IIH is uncertain. Raised ICP is a uniform characteristic, but the mechanism by which ICP is elevated in IIH is not clear.
It is also questionable whether a single unifying mechanism elevates ICP in these individuals (figure 1). Secondary causative factors which lead to elevation of ICP may be mechanistically distinct from truly idiopathic causes.
Figure 1: Schematic diagram of the possible pathophysiological mechanisms in idiopathic intracranial hypertension (IIH).
Cerebrospinal fluid (CSF) is produced mainly by the choroid plexus epithelial cells, with a small amount being secreted by ependymal cells that line the ventricular system.
Classically, CSF was thought to drain predominantly through the subarachnoid space through arachnoid granulations into the superior sagittal sinus.
Evidence also suggests CSF drains through the cribriform plate along cranial nerves into the nasal lymphatics (yellow).
The most recent hypothesis proposes bulk flow of fluid along perivascular routes (glymphatic pathway) which is cleared from the brain into the subarachnoid CSF, bloodstream or cervical lymphatics. Supporting this concept is the recent discovery of lymphatic vessels (yellow) in the dura that drain into the deep cervical lymph nodes.
Role of altered CSF dynamics
Changes in the volume of blood, CSF and brain tissue influence ICP. IIH likely represents a disorder of CSF regulation, potentially through CSF hypersecretion or reduced drainage.
- Increased CSF production
- Reduced CSF drainage
- Role of obesity
- Role of gender
Improvements in brain venography imaging reveal that most patients with IIH have anatomical abnormalities of the cerebral venous sinus system
These include stenosis of the dominant (figure 2) or both transverse sinuses. There are two recognised morphological types of venous stenosis, and a combination of both can occur in one patient
Reducing ICP has led to resolution of stenosis in some patients, suggesting that the stenoses are a result of raised ICP externally deforming the venous sinuses, and not a primarily cause
Additionally, elevated venous sinus pressure in the setting of venous sinus stenosis, may impair CSF drainage at the arachnoid granulation tissue further exacerbating a cycle of intracranial hypertension
Table 1 Diagnostic criteria for idiopathic intracranial hypertension (IIH) adapted from Friedman et al1
Additionally, they have recognised that IIH may occur in the absence of symptoms of elevated ICP and rarely in the absence of papilloedema, so-called IIH without papilloedema (IIHWOP).
There are a number of identifiable causes that give rise to secondary intracranial hypertension such as anaemia, obstruction to venous drainage and exposure to various pharmacological agents, for example, tetracyclines, hypervitaminosis vitamin A and retinoids (table 2). Neuroimaging, either MRI or CT or MRI, must exclude hydrocephalus, structural lesions, abnormal meningeal enhancement and cerebral venous sinus thrombosis.
Pharmacological agents Systemic conditions Antibiotics: tetracycline and derivatives, vitamin A derivatives: isotretinoin, all-trans-retinoic acid (for acute promyelocytic leukaemia)
Hormonal agents: corticosteroid withdrawal, growth hormone, thyroxine replacement in children
Other agents: lithium, nalidixic acid, rofecoib, cimetidine
Respiratory: obstructive sleep apnoea
Renal: renal failure
Endocrine: obesity, weight gain, polycystic ovarian syndrome, Cushing’s disease, Addison’s disease, hypoparathyroidism
Genetic: turner syndrome
Autoimmune: systemic lupus erythematosus
Nutritional: hypervitaminosis A
Venous: cerebral venous sinus thrombosis, superior vena cava obstruction, increased right-sided heart pressure
Table 2 Conditions that may cause intracranial hypertension
Polycystic ovarian syndrome (PCOS) is a chronic endocrine condition characterised by menstrual irregularities, ovarian dysfunction, hyperandrogenism and hirsutism. The prevalence of PCOS in women with IIH is reported to be as high as 39–57%,46 compared to 7–18% in the general population.
Assessment and investigations
The 2015 Cochrane review concluded that there is no current consensus on the best management strategy for IIH.12 The two key approaches in IIH are to preserve visual function, and to reduce long-term headache disability. The treatments employed depend largely on the patient’s level of visual function and rate of progression. Accepted medical interventions range from dietary therapy (eg, responsible and sustainable weight loss, lifestyle modification, low-salt diet) to medications and surgical treatment.
Treatment of headache
Headache is the most common presenting feature in IIH and leads to significant morbidity
Many patients do not have the classical headache phenotype attributed to raised ICP and the International Classification of Headache Disorders, which does not specify a particular headache phenotype (ICHD 3) has poor specificity (53%) in IIH.
Many patients with IIH have daily headache (86%) that often resembles migraine or tension-type headache.
IIH headache improves post-LP in 72%, but an improvement also occurs in 25% of those with headache without IIH or a pressure syndrome.
Headaches outcomes are poor even in those with no prior history of headache, with 57% having headaches at 12 months
Accurate headache phenotyping is key, and mixed headache types frequently coexist (high pressure, migraine, tension-type, low pressure in those with a shunt). Medication overuse headaches often occur and are underdiagnosed.
Our practice is to treat the predominant headache phenotype, typically using migraine-preventative strategies
It is worthy of note that some of the commonest medications here can cause weight gain.
Health-related quality of life
For patients with IIH, the journey is typically extremely challenging
The diagnostic process with urgent brain imaging and LP is frightening and painful
For many, the reality is a long-term illness dominated by drug side effects, headaches, potential depression and in some surgery, which can be recurrent. The impact on their family life, occupation and earning potential is great.
Studies verify that IIH has a significant effect on health-related quality of life (QOL) patients with IIH have also been found to have higher levels of anxiety, depression and fatigue than controls
A number of factors could impact on cognitive function in IIH (depression, headaches, sleep apnoea, obesity, medications and raised ICP)
One study reported reduced reaction time and processing speed in patients with acute IIH
Another cross-sectional study has also demonstrated multidomain mild cognitive impairment in IIH, with lowest scores in visuospatial, attention and global indices
Cognitive dysfunction may contribute to the patient morbidity, however, it is largely uncertain whether the deficits are chronic or related to treatment effects.
IIH without papilloedema
In patients with chronic daily headache, raised CSF pressure has been identified in some patients, particularly in the obese, despite the lack of papilloedema.
Isolated, single LP measures are not ideal in assessing patients with chronic headaches as ICP fluctuates diurnally. In some cases, a period of prolonged CSF monitoring, ideally while the patient is ambulatory is helpful
As patients with IIHWOP do not have papilloedema and do not develop papilloedema, they do not develop visual loss
For clinicians managing patients with IIH, questions remain about the optimal evidence-based approach for management
IIH is a multisystem disorder encompassing neuroscience, ophthalmology and endocrinology and cross-specialty collaboration will be integral to advance our understanding of IIH. In the clinical environment, multidisciplinary input is essential to optimise patient care.