Idiopathic Intracranial Hypertension with Papilledema

Idiopathic intracranial hypertension (IIH) is becoming an increasingly common health care concern as global obesity rates rise. Physicians need to be familiar with the salient clinical features of this condition to improve the quality of lives of patients, reduce related health care costs, and optimize visual outcomes. The focus of this review is IIH with papilledema, because the potential for vision loss is a dire concern that drives urgency in diagnosis and management. We will discuss potential pathogenic mechanisms, describe the expanding clinical spectrum, highlight emerging diagnostic biomarkers, and explore established and emerging treatment options for people with IIH.

Key points

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To discuss current concepts regarding the pathogenesis of idiopathic intracranial hypertension (IIH).
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To review the expanding clinical spectrum of IIH.
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To highlight emerging ocular imaging techniques and artificial intelligence (AI) approaches used in the diagnosis and management of IIH with papilledema.
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To summarize contemporary medical and surgical treatment approaches for IIH with papilledema.

Abbreviations

AI	artificial intelligence
AUC	area under the curve
BMI	body mass index
BONSAI	Brain and Optic nerve Study with an AI
CI	Confidence Interval
CTV	CT venography
DVSS	dural venous sinus stenting
EDI-OCT	enhanced depth OCT
GCL	ganglion cell layer
GLP	Glucagon-like peptide
ICP	intracranial pressure
IIH	idiopathic intracranial hypertension
IIHTT	IIH Treatment Trial
LP	lumbar puncture
LPS	lumboperitoneal shunt
PMD	pattern mean deviation
pwIIH	people with IIH
OCT	optical coherence tomography
ONH	optic nerve head
ONSF	optic nerve sheath fenestration
OSA	obstructive sleep apnea
PCOS	polycystic ovarian syndrome
pRNFL	peripapillary retinal nerve fiber layer
RPE/BM	retinal pigment epithelium/Bruch’s membrane
VPS	ventriculoperitoneal shunt

Introduction

Idiopathic intracranial hypertension (IIH) is an enigmatic syndrome of raised intracranial pressure (ICP) with variable clinical manifestations. Traditionally, IIH has been considered a condition of overweight young women, but men and children may also be affected. People with IIH (pwIIH) are often plagued by headaches, although 1 in every 4 individuals may be asymptomatic. Sadly, 24% of pwIIH experience permanent visual impairment. For this reason, it is important for physicians to recognize features of IIH, identify signs of visual compromise, and implement effective therapies in a timely manner to optimize outcomes.

Etiology and Potential Pathogenic Mechanisms

Idiopathic intracranial hypertension is a multifaceted syndrome with distinct neurologic, metabolic, and psychological features. While its cause is yet to be elucidated, IIH is believed to arise from an interplay between abnormal cerebrospinal fluid (CSF) dynamics, glymphatic system dysregulation, and increased venous pressure in the central nervous system ( Table 1 ). The impact of adipocyte dysfunction, hormonal influences, and inflammatory mechanisms in the pathobiology of IIH is being rigorously explored. Understanding factors that drive disease manifestations will be key to identifying potential therapeutic targets for IIH (see Table 1 ).

Table 1

IIH: Potential pathogenic mechanisms and therapeutic target s

Mechanism	Possible Role in IIH	Management Considerations	Therapeutic Considerations
Increased CSF Secretion	Hypersecretion of CSF at the level of the choroid plexus may cause raised ICP.	The CSF volume in adults (90–150 mL) is replaced 3–4 times a day. Removing CSF via LP or lumbar drain may improve manifestations of raised ICP.	Carbonic anhydrase inhibitors (acetazolamide) and GLP-1 receptor agonists (exenatide) lower CSF secretion.
AG/CSF and venous outflow obstruction	AGs are projections of the arachnoid membrane that extend to the dural venous sinuses. AGs may affect CSF absorption.	pwIIH often have intracranial venous sinus stenosis involving the transverse and sigmoid sinuses. Abnormal venous sinuses may impact CSF flow dynamics.	Venous stenting may alleviate effects of raised ICP.
Altered glymphatic function	The glymphatic system transports fluid in the brain through periarterial channels, perivenous spaces, and lymphatics.	Congestion in the glymphatic system may impact CSF outflow and contribute to raised ICP.	Further studies are needed to determine whether glymphatic dynamics impact IIH.
Altered adipocyte function/fat distribution/and obesity	Omental adipocyte activity may drive lipogenesis in IIH.	Truncal obesity impacts risk for type 2 DM, insulin resistance and possibly IIH. The confluence of these factors may contribute to raised ICP.	GLP-1 increases satiety and delays gastric emptying, thus contributing to weight loss which is known to ameliorate effects of IIH.
Hormonal influences	Female hormones have been hypothesized as a causal factor in IIH since women are disproportionately affected.	Testosterone alterations have been noted in the CSF of pwIIH, and hormonal therapy may impact IIH risk in transgender patients	Better understanding of hormonal influences may lead to potential therapies and improved management strategies for pwIIH.
Chronic inflammation	Obesity creates a proinflammatory state and increased cytokine production (in particular adipokines) which may impact risk for IIH.	Markers of inflammation (leptin, interleukin 8, interleukin 1β, and tumor necrosis factor α) may differ in pwIIH patients	Ongoing research is exploring how inflammatory responses related to obesity may contribute to the development of IIH.
Genetic links	Familial cases of IIH have been reported	Having relatives(s) may increase risk for IIH, or alternatively shared lifestyle factors may also drive familial links.	The role of genetics and epigenetics may be an area of future research in IIH.

Abbreviations : AG, Arachnoid Granulations; CSF, cerebrospinal fluid; DM, diabetes mellitus; ICP, intracranial pressure; IIH, idiopathic intracranial hypertension; LP, lumbar puncture.

Epidemiology

Idiopathic intracranial hypertension was once considered a rare condition, with an estimated annual incidence of 0.5 to 2 in 100,000. In the modern era, however, IIH has emerged as a formidable health care challenge. Mollan and colleagues showed that the incidence of IIH increased by 108% over a 14 year interval, rising from 2.26 per 100, 000 in 2022 to 4.69 per 100,000 in 2016. In this English study, 23,182 new IIH cases were diagnosed and health care costs increased from £9.2 to £50 million per annum during the study interval. Female sex, increased body mass index (BMI), and social deprivation (for women) were factors associated with increased risk for IIH. Similar findings were noted in a recent Welsh retrospective cohort study, in which Miah and colleagues analyzed 35 million patient-years of data and 1765 cases of IIH (85% female). The prevalence (76/100,000/year [y] vs 12/100,000/y) and incidence (7.8/100,000/y vs 2.3/100,000/y) of IIH increased by six fold and three fold respectively, in 2017 relative to 2003. During this time period, calculated obesity rates rose from 29% to 40%. Moving forward, the influence of social deprivation and low income as social determinants of care on IIH risk and severity warrants further study.

Clinical Manifestations of Idiopathic Intracranial Hypertension

While the clinical spectrum of IIH continues to expand ( Table 2 ), headaches, pulsatile tinnitus, and transient visual obscurations remain common complaints. Unfortunately, a year after diagnosis, 68% of pwIIH still harbor headaches, despite normalization of ICP. This modest treatment effect may mean that medical management is suboptimal, or alternatively indicate that pwIIH frequently harbor more than one headache subtype. Given the ubiquitous nature of primary headache subtypes and rising prevalence of IIH, primary care providers and general neurologists need to be comfortable with managing IIH patients and play integral roles in their multidisciplinary care teams.

Table 2

IIH: Clinical features and co-associated condition s ^,^,^,

Clinical Feature (Symptom or Sign)	Relevance to IIH	Management Considerations	Key Pearls
Neurologic
Headache	In the IIHTT 84% of participants had headache at presentation. Notably, 68% of pwIIH may have persistent headaches a year after diagnosis and despite CSF pressure normalization.	The features of headache in pwIIH may mimic primary headache disorders and may be exacerbated by medication overuse. Headache severity does not correlate with CSF opening pressure.	IIH patients may have more than one headache subtype. It is important to not undertreat headache manifestations of IIH but also not overtreat nonIIH headaches with acetazolamide or more aggressive CSF diversion procedures.
Cranial Nerve Dysfunction	pwIIH may report binocular intermittent or persistent horizonal diplopia due to abducens nerve dysfunction.	Abducens nerve dysfunction is the most common cranial nerve deficit seen in IIH. Occasionally facial nerve and other cranial nerve palsies occur.	Diplopia in pwIIH often resolves with CSF pressure lowering effects. Patients with multiple cranial nerve palsies should be evaluated for other potential causes.
Neck Pain	Neck, back, and radicular pain may occur in pwIIH.	Using medications to reduce ICP may alleviate these symptoms.	It is important, particularly in atypical IIH cases, to consider other causes of neck pain which may be cervicogenic or meningeal in origin.
Altered cognition	IIH patients may have cognitive deficits in attention, visual-spatial, and global indices of function.	Cognitive impairment may affect standard perimetry performance. Medications, OSA, headache severity, depression, anxiety, poor sleep, and fatigue are other factors to consider.	Cognitive function may improve with CSF pressure lowering interventions. It is also important to address other modifiable factors such as OSA with treatment.
Ophthalmic
TVOs	TVOs are common (68%) in IIH, particularly for patients with high grades of optic disc edema. TVOs worsen with postural changes or Valsalva maneuvers. They are thought to result from transient ischemia of the edema of the optic nerve head.	TVOs may occur in conditions like optic disc drusen that mimic papilledema. This symptom is therefore not reliable in distinguishing papilledema from pseudopapilledema secondary to drusen.	In pwIIH, TVOs may herald treatment failure as a surrogate measure of papilledema severity. Similarly, improvement in TVOs can be a sign of treatment efficacy as papilledema improves.
Papilledema	Papilledema is the most important sign seen in IIH patients because it may herald permanent vision loss.	Papilledema arises from axoplasmic flow stasis and edema of the retinal nerve fibers emanating from the optic disc. Papilledema may be symmetric or asymmetric, unilateral or bilateral. High grades of papilledema are associated with greater risk of vision loss.	The severity of optic disc edema may be determined with the modified Frisen scale and OCT measures.
Pseudodrusen Deposits ( Fig. 4 )	Pseudodrusen are small white refractile deposits overlying the optic disc that can develop in patients with long-standing papilledema.	Pseudodrusen look different than superficial optic disc drusen, which appear as larger yellow refractile bodies arising from the optic disc itself.	Pseudodrusen may be confused with superficial optic disc drusen, and it is important to remember that patients may have IIH and drusen.
Retinal and subretinal hemorrhages	Hemorrhages in the pRNFL occur in IIH and are associated with severity of papilledema.	Hemorrhages related to IIH will resolve with treatment and normalization of ICP	Subretinal hemorrhages may occur with pseudopapilledema and are less helpful in discriminating cases of papilledema from pseudopapilledema.
CWS and retinal exudates	CWS represent retinal nerve fiber layer infarcts. Together with retinal exudates they can be found in patients with more severe grades of papilledema	CWS and retinal exudates resolve with treatment and regression of elevated ICP.	It is important to exclude other causes of papilledema, CWS, and retinal exudates including malignant hypertension, hypertensive retinopathy and vasculitis.
Hyperopic Shift and Choroidal Folds	Patients may develop vision loss from hyperopic shift and choroidal folds.	Choroidal folds often persist even with effective treatment of IIH.	It is important to obtain the best corrected visual acuity with refraction, to avoid confusing optic nerve compromise with other modifiable causes of vision loss in pwIIH.
PPW and RF	Patients with PPW and/or RF may describe positive visual phenomena (sparkles) metamorphopsia (distorted central vision) and visual blurring.	PPW and RF may help distinguish cases of papilledema from pseudopapilledema and are easily identified with enface OCT techniques.	PPW and RF are outer retinal causes of vision loss that often respond to medical management.
Subretinal fluid	Subretinal fluid extending to the macula may occur in the setting of IIH, particularly with higher grades of papilledema.	Subretinal fluid in the macula may diminish central vision and cause concern for optic nerve injury in pwIIH. It is important to check for this condition because it responds well to medical management.	Subretinal fluid may also occur in case of pseudopapilledema and therefore cannot distinguish these 2 conditions
Choroidal Neovascular Membrane (CNVM)	In rare cases, subretinal hemorrhage can result from peripapillary choroidal neovascularization.	CNVM may reduce central vision and cause concern for optic nerve injury in pwIIH.	This condition may be treated with medical approaches to reduce ICP and antiVEGF receptor inhibitor drugs. A consult with a retinal specialist may be helpful.
RAO	Rarely, papilledema may be complicated by RAOs, particularly in cases of severe optic disc edema.	Unfortunately, RAOs generally cause permanent visual loss, even when papilledema has resolved.	Treating mechanisms of raised ICP aggressively may be necessary to optimize visual recovery.
SecondaryNA-AION	pwIIH may develop persistent vision loss due to secondary NA-AION, particularly if they have coexisting vascular risk factors and an optic disc at risk (crowded optic nerve with small cup).	It may be challenging to distinguish IIH complicated by NA-AION from fulminant IIH at presentation. The swelling from NA-AION resolves within 2 mo.	Treating mechanisms of raised ICP aggressively may be necessary to optimize recovery in pwIIH at risk of secondary ischemic injury to the optic nerve.
Secondary RVO	Rarely, papilledema may be associated with branch or central RVO or venous stasis retinopathy.	In cases of venous stasis retinopathy or RVO disc hemorrhages may be distal from the optic disc, and disproportionate to the amount of optic disc swelling observed.	It is important to treat the ICP and consider referral to a retinal specialist for optimal management.
Visual Field Loss	Enlarged blind spots are the most common visual field defect seen with IIH reflecting the edematous optic nerve heads(s).	Visual fields may be markedly constricted in severe cases of IIH, with preserved central vision. This may lead to delayed diagnosis and poor visual outcomes if the threat to vision is not realized.	Formal perimetry is best means of measuring visual field compromise in pwIIH, and the mainstay of ophthalmic surveillance.
Otorhinolaryngology
PST	Unilateral or bilateral pulse-synchronous tinnitus occurs in 52% to 60% of pwIIH.	The cause of PST is believed to be turbulent blood flow across stenoses in the transverse venous sinuses.	PST may persist even in well managed cases of IIH with resolved papilledema. It is important to reassure patients with PST who are otherwise responding well to treatment.
CSF Rhinorrhea	CSF rhinorrhea may occur in pwIIH.	Defects in the cribriform plate may account for CSF leaks in the setting of chronic raised ICP.	Evaluating and treating raised ICP, and ENT assessment may be considered.
Hearing Loss	Rarely hearing loss has been reported in pwIIH.	Hearing loss has also been associated with obesity and rarely associated with acetazolamide use.	Consider formal audiology testing and explore potential causes of hearing loss in pwIIH since these problems has multiple potential causes.
Endocrine and Obstetric-Gynecologic Health
Pregnancy	Live births are lower in female patients with IIH relative to women in the general population.	Pregnancy complications are higher in pwIIH including preeclampsia (5.3-fold increase) and gestational diabetes (2.7-fold increase), with elective caesarean delivery rates increased by 2.4-fold.	Multidisciplinary care approaches, optimizing disease management, reassurance, and education are needed to optimize care for pregnant pwIIH and their babies.
PCOS	Patients with IIH are 1.5 times more likely to have PCOS relative to the general female population.	Screening for PCOS manifestations (irregular periods, hirsutism, weight gain, acne, male pattern hair loss) might help identify cases.	Checking for ovarian cysts (ultrasound) and involving specialists from Obstetrics-Gynecology can be an important aspect of care.
Psychiatric
Depression and anxiety	Depression and anxiety are common in IIH. Psychiatric comorbidities have been reported in as many as 45% of pwIIH.	Coassociated depression and anxiety may impact test performance (perimetry) and self-reported symptoms.	Addressing components of depression and anxiety are important to understanding disease management and may require referral to appropriate mental health services.
General
OSA	Obesity is a risk factor for both IIH and OSA and the latter has been reported to affect 33%–63% of people with IIH.	Untreated OSA may impact cognition, impact cardiovascular risks, and drive headaches.	Treating OSA may improve papilledema. Screening strategies to consider include questionnaires such as the STOP-BANG questionnaire, and overnight oximetry.