Natural History and Management Options of Idiopathic Intracranial Hypertension

14 Natural History and Management Options of Idiopathic Intracranial Hypertension

Kevin Liu and Helen V. Danesh-Meyer

Abstract

Idiopathic intracranial hypertension is a disease of raised intracranial pressure causing headache and visual changes.

Epidemiology: Incidence rate of 0.5-2 per 100,000 person years in the general population with higher rates seen in obese women of childbearing age.

Natural History: Vision loss can manifest both early or late in the disease course and often does so without the patient realising. Visual field defects can be observed in up to 87% of patients, though 67% of patients can be asymptomatic with mild/minimal defects. Visual prognosis is good with treatment in up to 60% of patients and only 10% experience worsening visual function. Rate of blindness or severe visual impairment range between 1 and 10%. Recurrence rates vary between 8.3 and 52% and more commonly associated with treatment nonadherence, pregnancy, or weight gain. Three percent patients have a fulminant variant with rapid vision loss from symptom onset, have poor visual prognosis, and often require surgical intervention.

Management: Weight loss is a successful treatment associated with improvement in vision and reduction in headaches. This can also be achieved through bariatric surgery especially in cases where regaining of weight is associated with relapse of disease.

Medical treatment includes acetazolamide with the strongest evidence followed by topiramate and furosemide as alternatives. Corticosteroids are not recommended as long term or routine therapy as withdrawal is associated with rebound in intracranial pressure as well as weight gain. Serial lumbar punctures are not routinely recommended but have a role for those awaiting surgery or avoiding medical treatment in pregnant patients.

Surgical treatment includes optic nerve sheath fenestration, ventriculoperitoneal shunts or lumboperitoneal shunts, and venous sinus stenting. They are generally more indicated in patients in whom vision loss is rapid, have severe symptoms, or the disease is uncontrolled by medical management. There is no evidence to suggest clear superiority of one over another, though choice often depends on individual patient presentation and expertise of the center.

Keywords: idiopathic intracranial hypertension pseudotumor cerebri papilloedema bariatric surgery optic nerve sheath fenestration venitriculoperitoneal shunt lumboperitoneal shunt venous sinus stenting

14.1 Introduction

Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a condition characterized by (1) clinical features of raised intracranial pressure (ICP), (2) normal cerebrospinal fluid (CSF) composition, and (3) absence of abnormal findings on neuroimaging.1

IIH typically affects young obese women, often with menstrual irregularities.²^, ³ The overall incidence is between 0.5 and 2.0 per 100,000 person-years. The rate is higher among obese women of childbearing age (incidence between 12 and 20 per 100,000 person-years).² This incidence is predicted to worsen in parallel with increasing future rates of obesity globally as they have both already demonstrated to have done so for 25 years since 1990.³^, ⁴

Patients usually present with a variety of symptoms indicative of elevated ICP, the more common ones being headache, transient visual obscurations, and pulsatile tinnitus.⁵^, ⁶^, ⁷ Patients with IIH may develop diplopia secondary to unilateral or bilateral sixth nerve palsy (a false localizing sign). Other common nonvisual symptoms include nausea, vomiting, dizziness, and neck and back pain. Less common visual symptoms are retrobulbar pain and sustained visual loss.

Clinical examination reveals papilledema with an otherwise normal neurological examination. The importance of papilledema is that it raises the possibility of damage to optic nerve function if the disc swelling is sustained. It is important to remember that visual acuity is preserved in early papilledema. Visual field testing may reveal an enlarged blind spot, which reflects the papilledema rather than decreased optic nerve function. However, prolonged or extremely elevated ICP may result in optic nerve compromise. This manifests as visual field defects in the early stages. With progression of optic nerve damage, there is decreased visual acuity and loss of color vision.⁵ The most important long-term sequela of IIH is visual loss; therefore, it is critical to perform regular assessment of optic nerve function, which includes visual acuity, visual field (formal automated testing), color vision, and fundus examination.

The diagnosis of IIH requires normal neuroimaging, which includes either a computed tomography (CT) venogram or magnetic resonance (MR) venogram so that venous sinus stenosis/thrombosis can be excluded. In addition, it is important to exclude space-occupying lesion or abnormal meningeal enhancement. Neuroimaging findings that are consistent with elevated ICP include flattening of the globes, fluid in the subarachnoid space around the optic nerves, an empty sellae, and small ventricles (Fig. 14.1). Venous sinus narrowing may also be a sign of raised ICP, although in some cases it may be the underlying cause.

Fig. 14.1 Neuroimaging features of idiopathic intracranial hypertension (IIH). (a) Magnetic resonance imaging (MRI) venography showing narrowing of the left transverse sinus (arrows). (b) T2-weighted MRI, axial, and flattening of the globes (vertical arrows) and distension of optic nerve sheaths (horizontal arrows).

If papilledema is present in the presence of normal neuroimaging, then a lumbar puncture is required to both measure the opening pressure and to evaluate the CSF composition. The diagnosis of IIH requires normal CSF composition and elevated opening pressure (1) greater than 250 mm H₂O in adults; (2) greater than 280 mm H₂O in children and adolescents; or (3) 250 mm H₂O for nonobese, nonsedated children.⁸

There have been multiple secondary causes for pseudotumor cerebri noted in the literature. There is a long list of medications that have been reported to be associated with or causative of IIH. Of these, the most common and relevant include tetracycline antibiotics and vitamin A and its metabolites. Tetracycline has been suggested as a precipitant to IIH with between 7 and 9% of patients found to be taking tetracycline concurrently. Withdrawal of the medication may result in resolution of the IIH in some cases; however, persistent IIH has also been reported.⁹^, ¹⁰^, ¹¹ Excess vitamin A and its metabolites (retinoids) have been suggested in multiple reports to also act as another secondary cause; however, the recent IIH Treatment Trial (IIHTT) with the Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC) Idiopathic Intracranial Hypertension Study Group produced conflicting evidence where toxicity from vitamin A and retinoids is unlikely to be contributory based on their measurements of vitamin A metabolites in the serum and CSF of their study patients.¹² Other medications have also included thyroxine, growth hormone, tamoxifen, corticosteroids, lithium, and ciclosporin.² Nitrofurantoin, sulfonamides, and nalidixic acid have been reported as a secondary cause for children.²^, ¹³^, ¹⁴

For medical disorders associated with pseudotumor cerebri, chronic anemia has been shown to have an incidence association of 10.3% with resolution of this illness upon correction of anemia.15 Other disorders include Addison’s disease, obstructive sleep apnea, and systemic lupus erythematous.²^, ¹⁶^, ¹⁷

14.2 Selected Papers on Natural History

●Corbett JJ, Savino PJ, Thompson HS, et al. Visual loss in pseudotumor cerebri. Follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol 1982;39(8):461–474

●Wall M, George D. Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain 1991;114(Pt 1A):155–180

●Shah VA, Kardon RH, Lee AG, Corbett JJ, Wall M. Long-term follow-up of idiopathic intracranial hypertension: the Iowa experience. Neurology 2008;70(8):634–640

●Wall M, Kupersmith MJ, Thurtell MJ, Moss HE, Moss EA, Auinger P; NORDIC Idiopathic Intracranial Hypertension Study Group. The longitudinal idiopathic intracranial hypertension trial: outcomes from months 6–12. Am J Ophthalmol 2017;176:102–107

14.3 Natural History of Idiopathic Intracranial Hypertension

There are no prospective series of large study size evaluating the natural history of IIH. There are only relatively small retrospective reviews with selected populations, for example, males with IIH. There is a recent multicenter trial of IIH, the Idiopathic Intracranial Hypertension Trial (IIHT), which is a randomized prospective multicenter trial recruiting 165 participants with mild IIH. Natural history data are beginning to emerge from this study although they remain limited at this stage. The data summarized below are based on the available evidence as depicted in Fig. 14.2.

Fig. 14.2 Fundus photographs and optical coherence tomography (OCT) can contribute to diagnosis and monitoring of idiopathic intracranial hypertension (IIH) and papilledema. (a) Fundal photograph of the right eye and (b) fundal photograph of the left eye with corresponding OCT scans of the (c) right and (d) left eyes. Humphrey visual fields of the same (e) left and (f) right eyes. (a) and (b) show optic disc swelling with elevated discs and peripapillary haloes. (c) and (d) show increases in retinal nerve fiber layer thickness (RNFL). Both (e) and (f) show enlarged blind spots and (d) shows early stages of generalized constriction of the visual field.

Vision loss can manifest both early and late in the disease course and often does so without the patient realizing it.¹⁸^, ¹⁹ Such vision loss commonly occurs over a long course of months to years and can range from mild defects with enlarged blind spots, nasal defects, and generalized depressions to permanent blindness, which is the main morbidity associated with IIH.⁶ Visual field defects were observed in monitored patients (75-87% on Goldmann perimetry and 56-80% on automated perimetry). Sixty-seven percent of these defects were mild/minimal and patients were reportedly asymptomatic with these defects.¹⁹ In general, visual prognosis appears to be good with treatment, with 51 to 60% of patients found to have stable or improved visual fields and only 10% experiencing worsening visual function.⁶^, ¹⁸ However, the risk of blindness is variable depending on the population and the treatment. Corbett¹⁸ found that 24.6% developed blindness in one or both eyes, with 78% of those with persistent vision loss at initial assessment found to be blind on follow-up. Other more recent studies report lower rates of blindness/severe visual impairment or treatment failure, occurring in 1 to 13.8% of observed patients.⁶^, ²⁰^, ²¹^, ²²^, ²³ The NORDIC IIHTT showed a treatment failure rate of 1% in patients on acetazolamide and a weight loss diet compared to 10% on weight loss diet only.²¹^, ²⁴

Recurrence of IIH has been found to occur in patients after resolution of symptoms and recovery from the first episode or after stability of months and years at a reported rate of between 8.3 and 52%.²⁵^, ²⁶^, ²⁷^, ²⁸ Recurrence mainly occurred in the context of cessation of acetazolamide treatment due to noncompliance or intolerance of the medication.²⁵ In some studies, weight gain has also been shown to have an association with recurrence.²⁷^, ²⁸

Approximately 3% of patients with IIH experience a fulminant variant of the disease with rapid vision loss within 4 weeks of symptom onset, requiring surgical intervention, but unfortunately this group of patients have been shown to have very poor visual outcomes with 50% blindness in a study’s patients, particularly in those with greater surgical delay, and 100% of patients left with severe visual field defects.29

14.3.1 Factors Predicting Blindness or Poor Visual Outcome

Patients at initial assessment who were found to have persistent vision loss with poor visual acuity and those with high-grade papilledema were found to be at greater risk of vision loss.21^, ²⁴ Papilledema and treatment effect were best found to be monitored by photographic disc area from fundus photos and volume on optical coherence tomography (OCT) rather than the Frisén score (a clinical score for papilledema).³⁰ Papilledema can also be monitored with the assistance of OCT, which is a noninvasive technique that measures the peripapillary retinal nerve fiber layer thickness.³¹^, ³² This allows a quantitative measure of optic nerve head swelling. One caveat is that the nerve swelling may resolve for two reasons¹: resolution of the papilledema or² death of ganglion cells, which results in loss of retinal nerve fiber layer; therefore, there is less nerve fiber tissue to become swollen.

Men who make up less than 10% of IIH patients have greater risk of treatment failure and severe visual impairment in one or both eyes with the risk found to be up to 26 times that of women.²¹^, ³³ Obesity is well known to be associated with a greater risk of IIH; in addition, a higher percentage of weight gain in the year prior to symptom onset in both obese and nonobese patients was reported to have a greater risk.³⁴ Szewka et al, in a study of 414 patients, found that those who were morbidly obese were likely to have severe papilledema on initial assessment, which is associated with greater risk of severe vision loss and every increase in 10 kg/m² of body mass index (BMI) increased the risk of severe vision loss by 1.4 times.³⁵ Patients of black race were also found to have increased risk of blindness and worse visual outcomes despite equal access to health care and treatment than nonblacks with relative risk of 3.5 for blindness in one eye and 4.8 in both eyes.²² Systemic hypertension has been observed as another risk factor for poor visual outcomes, with between 62 and 80% of patients who developed blindness having systemic hypertension.¹⁸^, ²² Onset of IIH during puberty was associated with greater moderate to poor visual outcomes compared to prepubescent, teenage/young adult, and adult age groups.³⁶ The results of the IIHTT) showed that the presence nerve fiber layer hemorrhages in at least one eye correlated with the severity of papilledema and with failed treatment outcomes/poorer visual outcomes.³⁷ Another finding from the IIHTT trial also showed that patients with more than 30 transient visual obscurations per month were 10.59 times more likely to have treatment failure compared to those with less than 30 per month.²¹