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Review Article
Idiopathic intracranial hypertension
Cephalalgia 0(0) 1–14 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414534329 cep.sagepub.com
BR Wakerley1, MH Tan2 and EY Ting3 Abstract Background: Idiopathic intracranial hypertension or pseudotumour cerebri is primarily a disorder of young obese women characterised by symptoms and signs associated with raised intracranial pressure in the absence of a space-occupying lesion or other identifiable cause. Summary: The overall incidence of idiopathic intracranial hypertension is approximately two per 100,000, but is considerably higher among obese individuals and, given the global obesity epidemic, is likely to rise further. The pathophysiology of this condition is poorly understood, but most theories focus on the presence of intracranial venous hypertension and/ or increased cerebrospinal fluid outflow resistance and how this relates to obesity. A lack of randomised clinical trials has resulted in unsatisfactory treatment guidelines and although weight loss is important, especially when used in conjunction with drugs that reduce cerebrospinal fluid production, resistant cases remain difficult to manage and patients invariably undergo neurosurgical shunting procedures. The use of transverse cerebral sinus stenting remains contentious and longterm benefits are yet to be determined. Conclusion: An understanding of the clinical features, diagnostic work-up and therapeutic options available for patients with idiopathic intracranial hypertension is important both for neurologists and ophthalmologists as visual loss maybe permanent if untreated. Keywords Idiopathic intracranial hypertension, benign intracranial hypertension, pseudotumour cerebri, raised intracranial pressure Date received: 15 September 2013; revised: 16 December 2013; 24 January 2014; 4 March 2014; accepted: 22 March 2014
Introduction Recently, the umbrella term ‘pseudotumour cerebri syndrome (PCTS)’ has appeared in the literature (1,2) to describe what is currently understood by most physicians as pseudotumour cerebri, benign intracranial hypertension or idiopathic intracranial hypertension (IIH). Further classification, according to aetiology, in to primary PCTS (or IIH) and secondary PCTS, in which there is an identifiable underlying cause, provides a useful means of defining such patients. In order to avoid confusion, in this review we use the term IIH to define all patients except when discussing risk factors. IIH is characterised by symptoms and signs associated with raised intracranial pressure (ICP) in the absence of a space-occupying lesion or other identifiable cause. Its association with obesity has raised questions about the underlying pathophysiological mechanism which currently focus on the presence of intracranial venous hypertension and/or increased cerebrospinal fluid (CSF) outflow resistance. In contrast to its previous namesake, ‘benign’ intracranial hypertension is certainly not benign. In one study it was predicted that approximately 1% to 2% of new patients
with IIH become blind in a given year (3), highlighting the need for early diagnosis and appropriate effective treatment. In this narrative review we discuss the principal clinico-pathological features of IIH and consider currently available therapeutic options and prognosis in longterm disease. We investigate the important role of weight loss and examine the use of different drugs to reduce CSF production and lower ICP. We also discuss the risks and benefits associated with more invasive strategies, including CSF shunting, optic nerve sheath fenestration (ONSF) and the placement of cerebral transverse sinus stents. In addition, we highlight 1 The Oxford Headache Centre, Department of Neurology, John Radcliffe Hospital, UK 2 Department of Ophthalmology, Royal Perth Hospital, Australia 3 Diagnostic Imaging, National University Hospital, Singapore
Corresponding author: Benjamin Wakerley, Department of Neurology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. Email: [email protected]
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recent suggested changes to IIH diagnostic criteria (2), in which patients without papilloedema can still be diagnosed, providing neuroimaging supports evidence of chronically raised ICP in the absence of any other structural cause.
Epidemiology IIH is primarily a disorder of young women (90%) of patients with IIH compared to few in body mass index (BMI)-matched controls (21,22). In a recent study, 90% of 51 IIH patients displayed evidence of bilateral transverse sinus stenosis on MR venography (23). Interestingly the degree or location of stenosis in this study did not correlate with CSF opening pressure, visual field testing or the clinical course of disease. Similar findings were observed in 14 IIH patients with bilateral transverse sinus stenoses, who underwent repeated lumbar puncture and MR venography over a six-year-period (24). During follow-up transverse sinus stenoses persisted in all patients, despite ICP normalisation in 64% of 14 cases. This suggested that sinus calibre did not correlate with ICP. Whether such lesions truly cause venous hypertension or merely serve as radiological surrogates of raised ICP is unclear (25,26). In contrast to unilateral transverse sinus stenosis, however, which was observed in 30% of 111 patients with normal CSF opening pressure, bilateral stenosis occurred in only 1.8% of individuals and is therefore a better surrogate of raised ICP (27). Prolonged venous hypertension is thought to interfere with passive absorption of CSF via the arachnoid granulations, which results in increased ICP and further venous sinus compression (28). The term ‘self-sustained venous collapse’ has been used to describe the cyclical mechanism which links these physiological processes (sinus stenosis ! venous hypertension ! reduced CSF absorption ! raised ICP ! sinus stenosis) and may explain the occurrence of chronically raised ICP in patients with IIH (Figure 2) (21). Furthermore, it has been proposed that a wide range of triggers that cause raised ICP have the potential to initiate this cycle in predisposed individuals. Similarly, this may explain why reducing ICP with a single lumbar puncture may break the cycle and lead to long-term remission of IIH (29,21). A recent study showed a significant reduction in sinus diameter following lumbar puncture in IIH patients (30). This is further supported by other studies
which demonstrate reversal of venous sinus stenoses after lumbar puncture or CSF shunting (26,31). Endovascular stenting of transverse sinus stenoses results in decreased venous pressure gradients and improved CSF absorption. In the largest cohort of 52 IIH patients who had stenting, the mean pressure gradient across the stenosis dropped from 19.1 mmHg to 0.6 mmHg post-stenting (32). Similar reductions have been observed in other studies (33–36) and appear to correlate with symptomatic improvement in more than 80% of patients. The significance of stenoses in the pathogenesis of IIH and the role of stenting in the management of such patients, however, remains controversial as stenoses may occur in patients with no evidence of raised ICP (22) and have been shown to persist in IIH patients with normalised ICP following medical treatment (24).
Venous sinus microthombi It has been proposed that the presence of venous sinus microthrombi in patients with thrombophilia may reduce CSF absorption by interfering with arachnoid granulations (37). Such patients should probably not be classified as having classical IIH, and sinus thrombosis should always be excluded.
Abnormal vitamin A metabolism Vitamin A (retinol) is thought to interfere with CSF absorption. There is conflicting evidence as to whether
Figure 2. Predisposed individuals may enter a state of ‘selfsustained venous collapse’. Raised ICP (of any cause) is postulated to induce transverse sinus stenosis (venous collapse). The resultant outflow obstruction then leads to venous hypertension and reduced absorption of CSF at arachnoid granulation. It has been proposed that by breaking this cycle, long-lasting remission may be achieved in some patients (21). ICP: intracranial pressure; CSF: cerebrospinal fluid.
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4 abnormalities of vitamin A metabolism or intoxication cause IIH, with no new studies appearing in the literature over the past five years. Retinol binding protein and retinol were shown to be elevated in some patients with IIH (38,39) and when in excess also transported into the CSF of some patients (40–43). In one study, 24% of 21 patients with elevated ICP secondary to IIH demonstrated high (>25 nM) vitamin A levels compared to 0% of 19 patients with elevated ICP due to other causes and 2.5% of 40 patients with normal ICP (42). Overall 83% of six patients with elevated CSF vitamin A had IIH and indicated a strong association. Furthermore one patient with IIH had two lumbar punctures and demonstrated elevated CSF vitamin A levels only when ICP was high. In the case of IIH it remains unclear whether elevated CSF retinol is toxic to the arachnoid granulation reabsorption mechanisms or simply a marker of excess CSF production by the choroid plexus.
Obesity hypothesis We need to consider why the majority of patients with IIH are young obese females. BMI is equal to weight (kilogram) divided by height (meter) squared. The normal range for BMI is 18.5–25 kg/m2, with those >30 kg/m2 being considered obese and those >40 kg/m2 as morbidly obese. Only a small proportion of females classified as overweight develop IIH, but of these a greater proportion accumulate adipose tissue on their lower bodies (44) compared to those with upper body adiposity, in whom diabetes and hypertension are more common. Furthermore, the hormonal and biological functions of adipose tissue are site dependent (45). For example, muscular deposition is associated with insulin resistance, whereas visceral fat may influence systemic inflammatory processes. Fat cells or adipocytes secrete a variety of so-called adipokines (pro-inflammatory and anti-inflammatory cytokines) and hormones, which are thought to play an important role in the pathogenesis of IIH (46). Several studies have attempted to answer this question by profiling adipocyte and hormone levels in CSF and serum samples taken from IIH- and BMI-matched controls. Of particular interest is the hormone leptin, which is involved in energy metabolism. While one study found elevated CSF leptin levels in IIH patients compared to controls (47), another suggested no such difference (48). Although it remains unclear whether leptin plays a role in the pathogenesis of IIH, hypothalamic leptin resistance is associated with obesity (49). Of note, in contrast to other races, only a minority of Asian patients with IIH are classified as obese (BMI >30 kg/m2), suggesting that obesity may not play a
Cephalalgia 0(0) major role in the aetiology of IIH in Asians (50) and other non-obese patients.
Sodium and water retention For many years it was thought that IIH was caused by abnormalities in sodium and water retention. This has since been disproved and there is no histological evidence of brain oedema in patients with IIH postmortem (51). Furthermore, antibodies against aquaporin-4, a transmembrane channel that regulates brain water homeostasis, have not been observed in this patient group (52,53).
Sleep apnoea Apnoeic episodes are associated with retention of carbon dioxide, cerebral vasodilation and subsequent raised ICP. Sleep apnoea is common among obese individuals, especially males, and may exacerbate rather than cause IIH (14,54).
Clinical symptoms The majority (>90%) of patients with IIH present with headache, which may mimic migraine or tension-type headache (Table 1) (10). Lateralised throbbing pain associated with nausea, vomiting, visual disturbance and photopsia is frequently described and can be exacerbated by a change in posture, for example, bending over or lying down. Headache is frequently but not always present on waking. Pulsatile tinnitus is more specific and less common in other primary headache disorders (55). Retrobulbar, cervical and facial pains are also encountered. Relief often comes with rest or non-steroidal anti-inflammatory drugs, with patients habitually becoming dependent on analgesics and developing superimposed medication-overuse headache (56). Visual disturbance is common (>70%) and worrying for patients (16). Transient visual obscurations, described as monocular or binocular blurring lasting
Table 1. Common symptoms in idiopathic intracranial hypertension (IIH). Headache Transient visual obscurations Intracranial noises Photopsia Retrobulbar pain Diplopia Sustained visual loss Source: Adapted from Wall and George (10).
92% 72% 60% 54% 44% 38% 26%
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Wakerley et al. for a few seconds, usually occur when standing, and are thought to reflect momentary ischaemia of the already compressed optic nerve microvasculature. Their frequency does not correlate with the degree of raised ICP or the severity of papilloedema and is not predictive of future sustained visual loss (57). Raised ICP may cause unilateral or bilateral sixth nerve palsies, resulting in horizontal diplopia.
Clinical signs Stereotypically, the patient will be young, female and obese. As a direct consequence of raised ICP, optic disc swelling or papilloedema (Figure 3(a)) is commonly present and considered to be the hallmark sign of IIH. This is usually symmetrical, although can occasionally be unilateral (58) or rarely even absent (59) and if long-standing leads to secondary optic atrophy. In very early disease, prior to the appearance of disc oedema, there may be loss of venous pulsations, which are best observed in the venous segment that transverses the optic nerve head. Venous pulsations are absent in 10% of normal individuals (60). Typically, early papilloedema does not affect acuity, colour vision or pupillary function and the patient may not complain of any visual symptoms. If present, however, the blind spot is usually enlarged and there is evidence of peripheral visual field loss. Deterioration of central vision and acuity is usually gradual, but may be abrupt in the case of fulminant disease and more likely to be permanent. The earliest false localising sign associated with raised ICP is sixth nerve palsy, although other cranial nerves (III, IV, V, VII and VIII) may also rarely be involved (61).
Differential diagnosis Other causes of raised ICP and optic disc swelling should be considered before a diagnosis of IIH is
made. Many secondary causes of intracranial hypertension (e.g. intracranial mass lesion, obstructive hydrocephalus, venous sinus thrombosis (62), venous sinus obstruction secondary to arachnoid granulations (63) and choroid plexus papilloma (64)) can be excluded radiologically, but occasionally IIH may be mistaken for conditions which cause elevation of the optic nerve head without raised ICP. These include malignant hypertension, which may be accompanied by retinal haemorrhages and exudates; optic disc drusen (Figure 3(b), (c)), caused by calcified deposits at the optic nerve head, which do not affect visual acuity or central venous pulsations (65) and can be distinguished from papilloedema by computed tomography (CT) or ultrasound imaging of the optic nerve head (66); and diabetic papillopathy (67), a rare complication of diabetes thought to be secondary to diabetic microangiopathy.
Diagnosis A diagnosis of IIH is frequently made on the basis of clinical history and ophthalmological findings alone, although neuroradiological exclusion of other causes of raised ICP, especially venous sinus thrombosis, is mandatory before proceeding to confirmatory CSF manometry. Criteria for the diagnosis of IIH were first established by Dandy in 1937 (68), but have since been modified (69,2). The most recent criteria in children and adults (2) also take account of patients who don’t develop papilloedema, yet have neuroimaging suggestive of chronically raised ICP (Table 2). As outlined in the recently published ‘International Classification of Headache Disorders, third edition (beta version)’, headache attributed to IIH should be diagnosed only if there is a clear temporal relationship with raised ICP and should resolve when ICP normalises (70). Formal visual field testing, dilated fundus examination and photographs of the optic discs are indicated if
Figure 3. (a) Optic disc swelling (papilloedema, Frise´n grade IV) compared with different degrees ((b), mild; (c), severe), of optic disc drusen (pseudopapilloedema), which are not associated with raised intracranial pressure.
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6 Table 2. Diagnostic criteria for pseudotumour cerebri syndrome. 1.
Required for diagnosis of pseudotumour cerebri syndromea A. Papilloedema B. Normal neurologic examination except for cranial nerve abnormalities C. Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (female and obese), and MRI, with and without gadolinium, and magnetic resonance venography for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used D. Normal CSF composition E. Elevated lumbar puncture opening pressure (250 mm CSF in adults and 280 mm CSF in children (250 mm CSF if the child is not sedated and not obese)) in a properly performed lumbar puncture 2. Diagnosis of pseudotumour cerebri syndrome without papilloedema In the absence of papilloedema, a diagnosis of pseudotumour cerebri syndrome can be made if B–E from above are satisfied, and in addition the patient has a unilateral or bilateral abducens nerve palsy. In the absence of papilloedema or sixth nerve palsy, a diagnosis of pseudotumour cerebri syndrome can be suggested but not made if B–E from above are satisfied, and in addition at least three of the following neuroimaging criteria are satisfied: i. Empty sella ii. Flattening of the posterior aspect of the globe iii. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve iv. Transverse venous sinus stenosis a A diagnosis of pseudotumour cerebri syndrome is definite if the patient fulfils criteria A–E. The diagnosis is considered probable if criteria A–D are met but the measured CSF pressure is lower than specified for a definite diagnosis. Source: Reproduced with permission of Wolters Kluwer from Friedman et al. (2). MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; CT: computed tomography.
there is any doubt to the presence of papilloedema and provide important baseline observations for monitoring disease course and treatment effects. Papilloedema can be objectively graded (I to V) according to the Frise´n scale (71,72). Although MR imaging/MR venography is the preferred imaging modality (73), especially in young patients, those presenting acutely often undergo CT brain and CT venography in order to exclude spaceoccupying lesions and sinus thrombosis quickly (74). Some radiologists prefer CT venograms as in-plane signal loss in two-dimensional (2D) time-of-flight MR
Cephalalgia 0(0) venography may occur and mimic thrombosis (75,76). Neither modality is diagnostic of IIH, but subtle features suggestive of raised ICP are well described, including flattening of the posterior sclera, and the presence of an empty sella, which are present in the majority of patients (Figure 4) (77,78). Less commonly seen are protrusion and/or enhancement (with gadolinium) of the optic nerve (79). Once a space-occupying lesion has been excluded, CSF manometry via lumbar puncture in the lateral decubitus position is performed. In adults the accepted upper limit of normal is 25 cm H2O (80), while in children this is less clear, with some authors suggesting an upper limit of 18 cm H2O in those under the age of 8 years (81). Some studies suggest that raised pressures may occur in obese patients (82) in the absence of IIH, but opening pressures above 28 cm H2O should always be regarded as abnormal. Pain and sedation may give rise to false positives and repeated manometry is sometimes indicated. CSF constituents (cell count, glucose and protein) are normal in IIH. Non-invasive measurement of ICP using transcranial Doppler ultrasonography may be available in the future as a means of monitoring IIH patients in the outpatient setting or during acute exacerbations (83–85). Visual field testing with computer-assisted static perimetry (Figure 5) is frequently used to assess the severity of optic nerve involvement and can be repeated at each clinic visit to monitor disease course (86). Enlargement of the blind spot, visual field constriction and inferonasal vision loss are more commonly observed than scotomas. The role in assessing the severity of papilloedema with confocal scanning laser tomography (87) is not entirely clear (88).
Treatment Patients with IIH are best managed jointly by neurologists and ophthalmologists, although a multidisciplinary approach, involving clinical psychologists, personal trainers and dieticians, may be of use in certain cases (Table 3). Successful treatment requires motivation and an understanding that permanent visual loss is likely if ICP is poorly controlled. In obese patients, weight reduction in conjunction with diuretics remains the principal management strategy. In more resistant or fulminant cases, CSF shunts offer the only hope in controlling raised ICP. Controlled weight loss has been shown to be of benefit in obese patients at lowering ICP and improving papilloedema (88), but is notoriously difficult to maintain. In one study, 25 patients were restricted to a lowcalorie diet (425 kcal/day, equivalent to four bananas) for three months and lost an average of 15.7 kg and saw an 8 cm H2O reduction in ICP (11). Bariatric surgery
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Figure 4. Radiological features seen in IIH. (a) Axial T2-weighted brain MRI demonstrates severe scleral flattening (black arrow) and widening of the perioptic spaces (white arrow), which are barely visible in healthy individuals. Flattening of the anterior pituitary gland by increased CSF pressure results in an empty sella (black star), which is best appreciated on saggital T1-weighted brain MRI ((b), saggital views of brain stem; normal; abnormal, white arrow). It remains undecided whether transverse sinus stenosis ((c), white arrow), demonstrated here with MRI venography is involved in the pathogenesis of IIH or a secondary compressive phenomenon. IIH: idiopathic intracranial hypertension; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid.
may be a viable option in some patients. A review of 62 obese patients with IIH showed that bariatric surgery was effective in terms of symptom resolution and visual outcome (99). In 97% of 35 patients who had pre- and postoperative funduscopy, papilloedema resolved. Similarly, 92% of 12 patients were also found to have marked improvement on formal visual field testing postoperatively. Weight loss takes time and therefore medical treatment is indicated at presentation. Acetazolamide, a carbonic anhydrase inhibitor, is the initial drug of choice and has been shown to lower CSF pressure in IIH patients, possibly by reducing CSF production (89). Acetazolamide controls symptoms in approximately half of patients and appears to prevent relapses if continued long term. However, it is frequently not tolerated. Common side effects include digital and oral paraesthesia, metallic taste and anorexia. Patients should also be warned about kidney stones and the relative contraindication in pregnancy due to teratogenicity. Improved compliance in adult patients can be achieved if started at lower doses (e.g. 125 mg
daily) and slowly titrated up to 1 or 2 g per day. In some patients the sustained release formulation (Diamox sequels) is better tolerated. Methazolamide can be used as an alternative. Topiramate is an anticonvulsant, but also inhibits carbonic anhydrase. One unblinded study suggested similar efficacy to acetazolamide with respect to symptom improvement (90). Patients should be warned about weight loss, cognitive impairment and kidney stones. Fetal malformations have been reported in approximately 4% of pregnancies exposed to topiramate, and women of childbearing age should therefore be counselled (100). Patients should also be warned that the efficacy of oral contraception is reduced with topiramate doses above 200 mg per day. Angle closure glaucoma and myopia may also rarely occur acutely (usually within the first two weeks) in patients commenced on topiramate and may be difficult to differentiate clinically from high ICP-related symptoms (101). Loop diuretics, e.g. furosemide, are sometimes used and have been shown to be of benefit in children when used in conjunction with acetazolamide (102).
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Figure 5. Visual fields and blind spot can be assessed using Humphrey’s perimetry. Left eye; normal blind spot (a), enlarged (b).
Table 3. Treatment options in idiopathic intracranial hypertension (IIH). Lifestyle Medical management
Intervention
a
Weight loss (11) Acetazolamide (89) Topiramate (90) Ferosemide (89) Intravenous methylprednisolonea (91) Repeated lumbar punctureb (92,93) Cerebral transverse sinus stenting (94) Shunts (95–97) Ventriculoperitoneal Lumboperitoneal Lumbar drain Optic nerve fenestration (98)
Not recommended unless sight-threatening fulminant disease. Should be used only if no alternatives are available, for example, during pregnancy. b
The use of corticosteroids in IIH is controversial. One small series showed benefit in patients with severe acute visual loss when used in conjunction with acetazolamide (103) but long-term use is associated with weight gain and salt retention, which may worsen symptoms. Venous stenting of the transverse sinuses, in patients with proven stenosis or obstruction on cerebral venography, has been postulated to relieve venous hypertension but remains controversial and long-term outcomes remain unknown. Retrospective group analysis of 143 cases (104) from 15 studies (32–36), with mean followup of 22.3 months, showed promising results. Stents were placed in the right (69%) or left (27%) or both (4%) transverse or sigmoid sinuses using an endovascular approach (99% of cases). Headache improved in 88% of 112 patients, vision in 87% of 67 patients and papilloedema resolved in 97% of 113 patients. No deaths were reported during or immediately after the procedure, although major complications occurred in
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Wakerley et al. three patients (subdural haemorrhage) and minor complications in six patients. Many patients with IIH continue to have chronic daily headache despite normalisation of their CSF pressure and this can be complicated by medication-overuse headaches. Frequently patients with IIH also develop what appears to be chronic migraine and this can sometimes be difficult to distinguish from high-pressure headaches. Drugs used for migraine prophylaxis should be used including, but not limited to, anticonvulsants, tricyclic antidepressants, and beta blocker medications (94). Some of these medications can be associated with weight gain and should be introduced cautiously.
Acute management of IIH Patients presenting with worsening headaches or visual disturbance often receive benefit from ICP lowering following a therapeutic lumbar puncture. In some cases this can induce lasting remission (21), despite 1 ml of CSF being produced approximately every five minutes and therefore CSF volume returning to normal within a few hours. The long-term benefits associated with serial lumbar punctures in patients with IIH, however, remain unknown, although it appears to be effective when treating exacerbations during pregnancy (92,93). The procedure itself can be technically challenging in obese patients, who often find it uncomfortable. Repeated lumbar puncture is also more likely to result in complications, including: low-pressure headache, CSF leak or infection. The use of intravenous indomethacin to lower ICP in some patients with severe head injury has been debated for over two decades (105), although its use in IIH remains controversial and is not widespread. Unlike other cyclo-oxygenase inhibitors, indomethacin causes cerebral vasoconstriction, which reduces cerebral blood flow and has an ICP lowering effect (106,107). In one study, all seven IIH patients showed a significant reduction (mean 14.4, range 8.0–20.0 cm CSF) in CSF opening pressure one minute after a 50 mg infusion of indomethacin over one minute (108). On follow-up all patients reported an improvement in headache symptoms and showed some resolution of papilloedema. Rebound increase in ICP has been reported following discontinuation of indomethacin and further trials in IIH patients are therefore required to determine both the short- and long-term benefits. In patients with rapid deterioration of vision more invasive techniques are often required. CSF shunting or ONSF are the most commonly used surgical procedures although it remains unclear whether one is superior to the other (109). CSF shunting works directly by lowering CSF pressure and poses no direct risk to vision, while ONSF is less invasive and directly treats
9 papilloedema, but offers less headache relief, at least in the short term. The type of surgical intervention adopted therefore appears to be driven by local preferences and expertise, as there are no trial data comparing the two. CSF pressure can also be lowered by placing a permanent drainage shunt between the ventricles or subarachnoid space in the lumbar region and the peritoneal cavity (ventriculoperitoneal and lumboperitoneal shunts, respectively) (110). Ventriculoperitoneal shunts are thought to be less prone to obstruction than lumboperitoneal shunts, but both types fail in nearly half of cases and surgical revisions are therefore common. In one retrospective series, 82% of 30 IIH patients experienced symptom improvement following ventriculoperitoneal shunting (95). Here, papilloedema improved in 96% of patients and visual acuity improved by at least two lines in 71% of patients. There were a total of 126 shunt revisions, although 87 occurred in four patients and when excluded the overall revision rate was 2.5 per patient. Similarly, another series showed that 95% of 42 IIH patients reported significant improvement in headache symptoms postshunting (96). Although the majority of IIH patients appear to report initial symptom relief when CSF pressure is lowered, the long-term benefits of shunting remain less clear. In the largest retrospective study (97), symptoms and signs of elevated ICP were characterised in 53 patients pre-shunt and at six, 12 and 24 months post-shunt. Papilloedema was present in 92% of patients at baseline and 44% by two years, while headache was present in 96% at baseline and 79% by two years. Visual deficits were noted in 78% of patients at baseline and 32% by two years, while tinnitus was present in 80% at baseline and 67% at two years. From the available data, shunting therefore appears to improve visual symptoms in approximately 50% of patients and headaches in only 20% over the first two years. Fifty-one per cent of these patients also required shunt revision and 31% multiple revisions, indicating that neurosurgical intervention should probably be considered only as a last resort when medical therapy and/or weight loss have failed or if vision is rapidly deteriorating. ONSF is favoured in some centres and has been shown to improve or at least stabilise vision in 70%– 90% of cases (98,111), and has a significantly lower complication and failure rate compared to CSF shunting. Headache symptoms, however, may not dissipate and usually require additional medical treatment. The efficacy and safety of ONSF were examined retrospectively in 158 eyes of 86 IIH patients (98). Improvement in visual acuity and improvement or stabilisation in visual fields were reported in 94% and 88%, respectively. Furthermore, vision-limiting surgical
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10 complications were reported in less than 1% of cases. Headache symptoms, however, improved in only 31% of cases and ONSF probably does not reduce ICP significantly. Fulminant IIH is rare, but devastating if not recognised and treated early. This was highlighted recently in the case of an 18-year-old female with a CSF opening pressure of 60 cm H2O, who developed complete lightperception blindness over four days. The authors hypothesised that a rapid increase in pressure in the perineural space of the optic nerve resulted in ischemic optic neuropathy (91). On day 1 ICP was lowered by inserting a lumbar drain and she was commenced on intravenous methylprednisolone sodium succinate and furosemide. Later, a ventriculoperitoneal drain was inserted and after one month visual acuity had improved to 20/30 in both eyes.
Prognosis Disease course in IIH is poorly defined, with some patients appearing to stabilise early with occasional relapses, while others develop more progressive disease (56,112). Recurrence of IIH is frequently associated with additional weight gain. In one study of 50 patients previously diagnosed with IIH, 26 experienced disease recurrence (113). BMI in those with disease recurrence was significantly higher than at diagnosis (34.5 kg/m2 vs 32.7 kg/m2), while in patients without recurrence, BMI was significantly less than at diagnosis (35.8 kg/m2 vs 43.6 kg/m2). Overall 6% weight gain was observed in patients with recurrence compared to 0% without recurrence, highlighting the importance of weight loss in the treatment of IIH. Despite some patients remaining asymptomatic, disturbances in CSF hydrodynamics probably persist for many years (114). The effects of chronically raised CSF pressure on the optic nerve are well described (57), but there is also evidence which suggests that it may lead to osseous erosion of the skull base. Widening of the foramen ovale was observed in 50% of patients on CT (115) and it has also been postulated that in some cases, such bony erosion may cause CSF otorrhoea and rhinorrhoea. Interestingly, patients presenting with spontaneous CSF leak are also often middle-aged, obese and of female gender. In one study of 16 patients presenting with spontaneous CSF leak, 50% fulfilled Dandy criteria (68) for IIH (116). The majority were female and obese, and also complained of headache in addition to pulsatile tinnitus. In another series of 17 patients presenting with spontaneous CSF otorrhea, all 12 females had BMI >30 kg/m2 and two were diagnosed previously as having IIH (117). Similarly, 18 patients presenting with spontaneous rhinorrhoea also displayed evidence of raised ICP, and the majority had other
Cephalalgia 0(0) features suggestive of IIH (118). It has been postulated that CSF leak may keep some patients with IIH symptom free, and that symptoms and signs associated with raised ICP may re-emerge if the leak is corrected without addressing the underlying cause of raised ICP (119). Whether spontaneous CSF leak in these patients represents a variant of IIH in predisposed individuals or a consequence of chronically raised CSF pressure is uncertain, and highlights the need for more long-term studies.
The IIH Treatment Trial (IIHTT) The Neuro-ophthalmological Research Disease Investigator Consortium (NORDIC) is currently performing the IIHTT and has recruited 166 IIH patients with mild visual loss (120). This multi-centre, randomised, double-blind, placebo-controlled study is examining whether dieting coupled with acetazolamide is superior to treatment with dieting and placebo in IIH patients. The primary outcome is improvement in visual perimetry (perimetric mean deviation) from baseline to six months. Other outcomes include the change in papilloedema grade, ICP measurements, other visual field measurements and quality of life measures. Recruitment is now complete, although not all patients have been followed for six months. Preliminary analysis indicated that dieting and lifestyle modifications have resulted in 6% weight loss in almost half of patients recruited. High doses of acetazolamide also appeared to be safe and well tolerated if given twice daily with food, although 2% of patients developed kidney stones. There are many unanswered questions regarding the pathogenesis of IIH which this trial hopes to address by studying proteomic and genetic risk factors in IIH patients compared to controls. This will determine further investigations into serum and CSF levels of potential IIH mediators, the results of which are eagerly awaited.
Conclusion Given the global obesity epidemic, the incidence of IIH is likely to rise, although it should not be overlooked in non-obese individuals, especially males. Patients who fail conservative management strategies, including weight loss and the use of drugs that reduce CSF production, present a particular problem to neurologists and ophthalmologists and invariably undergo neurosurgical intervention, which is often unsatisfactory in the long term. A better understanding of the underlying pathophysiological processes in IIH and the advent of new clinical trials will lead to the development of more treatment options, which are currently lacking in this disease of unknown aetiology.
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Literature search methods English-language publications were searched for in PubMed between January 2003 and December 2013. The following search terms were used: ‘pseudotumo(u)r cerebri’, ‘benign idiopathic hypertension’ and ‘idiopathic intracranial hypertension’. A total of 741 publications
11 were identified and individually assessed according to their relevance and publication date. Specific exclusion criteria included: publications on paediatric patients; single case reports, unless of exceptional importance; letters; editorials; and other review articles. The reference lists of identified publications were also scrutinised for further relevant publications.
Clinical implications . Given the global obesity epidemic, the incidence of idiopathic intracranial hypertension is likely to rise. . At present non-surgical treatment options for lowering intracranial pressure in such patients are limited and often poorly tolerated. . Understanding the pathophysiological mechanisms associated with developing idiopathic intracranial hypertension and obesity may lead to the development of new treatment strategies. . New evidence suggests that idiopathic intracranial hypertension may exist as a chronic disease in some individuals, even in the absence of headache. Funding This research was funded by the Oxford Headache Centre, UK.
Conflict of interest None declared.
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8. Karnik S and Kanekar A. Childhood obesity: A global public health crisis. Int J Prev Med 2012; 3: 1–7. 9. Szewka AJ, Bruce BB, Newman NJ, et al. Idiopathic intracranial hypertension: Relation between obesity and visual outcomes. J Neuroophthalmol 2012; 33: 4–8. 10. Wall M and George D. Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain 1991; 114: 155–180. 11. Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: Prospective cohort study. BMJ 2010; 341: c2701. 12. Barness LA, Opitz JM and Gilbert-Barness E. Obesity: Genetic, molecular, and environmental aspects. Am J Med Genet A 2007; 143: 3016–3034. 13. Cosar E, Cosar M, Ko¨ken G, et al. Polycystic ovary syndrome is related to idiopathic intracranial hypertension according to magnetic resonance imaging and magnetic resonance venography. Fertil Steril 2008; 89: 1245–1246. 14. Marcus DM, Lynn J, Miller JJ, et al. Sleep disorders: A risk factor for pseudotumor cerebri? J Neuroophthalmol 2001; 21: 121–123. 15. Dave S, Longmuir R, Shah VA, et al. Intracranial hypertension in systemic lupus erythematosus. Semin Ophthalmol 2008; 23: 127–133. 16. Giuseffi V, Wall M, Siegel PZ, et al. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): A case-control study. Neurology 1991; 41: 239–244. 17. Blethen SL. Complications of growth hormone therapy in children. Curr Opin Pediatr 1995; 7: 466–471. 18. Friedman DI, Gordon LK, Egan RA, et al. Doxycycline and intracranial hypertension. Neurology 2004; 62: 2297–2299. 19. Fraunfelder FW, Fraunfelder FT and Corbett JJ. Isotretinoin-associated intracranial hypertension. Ophthalmology 2004; 111: 1248–1250.
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12 20. Paciaroni M, Palmerini F and Bogousslavsky J. Clinical presentations of cerebral vein and sinus thrombosis. Front Neurol Neurosci 2008; 23: 77–88. 21. De Simone R, Ranieri A and Bonavita V. Advancement in idiopathic intracranial hypertension pathogenesis: Focus on sinus venous stenosis. Neurol Sci 2010; 31(Suppl 1): S33–S39. 22. Farb RI, Vanek I, Scott JN, et al. Idiopathic intracranial hypertension: The prevalence and morphology of sinovenous stenosis. Neurology 2003; 60: 1418–1424. 23. Riggeal BD, Bruce BB, Saindane AM, et al. Clinical course of idiopathic intracranial hypertension with transverse sinus stenosis. Neurology 2013; 80: 289–295. 24. Bono F, Giliberto C, Mastrandrea C, et al. Transverse sinus stenoses persist after normalization of the CSF pressure in IIH. Neurology 2005; 65: 1090–1093. 25. Rohr A, Bindeballe J, Riedel C, et al. The entire dural sinus tree is compressed in patients with idiopathic intracranial hypertension: A longitudinal, volumetric magnetic resonance imaging study. Neuroradiology 2012; 54: 25–33. 26. Stienen A, Weinzierl M, Ludolph A, et al. Obstruction of cerebral venous sinus secondary to idiopathic intracranial hypertension. Eur J Neurol 2008; 15: 1416–1418. 27. Bono F, Lupo MR, Lavano A, et al. MR venography of transverse sinuses in subjects with normal CSF pressure. Neurology 2003; 61: 1267–1270. 28. Biousse V, Bruce BB and Newman NJ. Update on the pathophysiology and management of idiopathic intracranial hypertension. J Neurol Neurosurg Psychiatry 2012; 83: 488–494. 29. De Simone R, Marano E, Fiorillo C, et al. Sudden reopening of collapsed transverse sinuses and longstanding clinical remission after a single lumbar puncture in a case of idiopathic intracranial hypertension. Pathogenetic implications. Neurol Sci 2005; 25: 342–344. 30. Horev A, Hallevy H, Plakht Y, et al. Changes in cerebral venous sinuses diameter after lumbar puncture in idiopathic intracranial hypertension: A prospective MRI study. J Neuroimaging 2013; 23: 375–378. 31. Lee SW, Gates P, Morris P, et al. Idiopathic intracranial hypertension; immediate resolution of venous sinus ‘‘obstruction’’ after reducing cerebrospinal fluid pressure to
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Idiopathic intracranial hypertension
Cephalalgia 0(0) 1–14 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414534329 cep.sagepub.com
BR Wakerley1, MH Tan2 and EY Ting3 Abstract Background: Idiopathic intracranial hypertension or pseudotumour cerebri is primarily a disorder of young obese women characterised by symptoms and signs associated with raised intracranial pressure in the absence of a space-occupying lesion or other identifiable cause. Summary: The overall incidence of idiopathic intracranial hypertension is approximately two per 100,000, but is considerably higher among obese individuals and, given the global obesity epidemic, is likely to rise further. The pathophysiology of this condition is poorly understood, but most theories focus on the presence of intracranial venous hypertension and/ or increased cerebrospinal fluid outflow resistance and how this relates to obesity. A lack of randomised clinical trials has resulted in unsatisfactory treatment guidelines and although weight loss is important, especially when used in conjunction with drugs that reduce cerebrospinal fluid production, resistant cases remain difficult to manage and patients invariably undergo neurosurgical shunting procedures. The use of transverse cerebral sinus stenting remains contentious and longterm benefits are yet to be determined. Conclusion: An understanding of the clinical features, diagnostic work-up and therapeutic options available for patients with idiopathic intracranial hypertension is important both for neurologists and ophthalmologists as visual loss maybe permanent if untreated. Keywords Idiopathic intracranial hypertension, benign intracranial hypertension, pseudotumour cerebri, raised intracranial pressure Date received: 15 September 2013; revised: 16 December 2013; 24 January 2014; 4 March 2014; accepted: 22 March 2014
Introduction Recently, the umbrella term ‘pseudotumour cerebri syndrome (PCTS)’ has appeared in the literature (1,2) to describe what is currently understood by most physicians as pseudotumour cerebri, benign intracranial hypertension or idiopathic intracranial hypertension (IIH). Further classification, according to aetiology, in to primary PCTS (or IIH) and secondary PCTS, in which there is an identifiable underlying cause, provides a useful means of defining such patients. In order to avoid confusion, in this review we use the term IIH to define all patients except when discussing risk factors. IIH is characterised by symptoms and signs associated with raised intracranial pressure (ICP) in the absence of a space-occupying lesion or other identifiable cause. Its association with obesity has raised questions about the underlying pathophysiological mechanism which currently focus on the presence of intracranial venous hypertension and/or increased cerebrospinal fluid (CSF) outflow resistance. In contrast to its previous namesake, ‘benign’ intracranial hypertension is certainly not benign. In one study it was predicted that approximately 1% to 2% of new patients
with IIH become blind in a given year (3), highlighting the need for early diagnosis and appropriate effective treatment. In this narrative review we discuss the principal clinico-pathological features of IIH and consider currently available therapeutic options and prognosis in longterm disease. We investigate the important role of weight loss and examine the use of different drugs to reduce CSF production and lower ICP. We also discuss the risks and benefits associated with more invasive strategies, including CSF shunting, optic nerve sheath fenestration (ONSF) and the placement of cerebral transverse sinus stents. In addition, we highlight 1 The Oxford Headache Centre, Department of Neurology, John Radcliffe Hospital, UK 2 Department of Ophthalmology, Royal Perth Hospital, Australia 3 Diagnostic Imaging, National University Hospital, Singapore
Corresponding author: Benjamin Wakerley, Department of Neurology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. Email: [email protected]
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recent suggested changes to IIH diagnostic criteria (2), in which patients without papilloedema can still be diagnosed, providing neuroimaging supports evidence of chronically raised ICP in the absence of any other structural cause.
Epidemiology IIH is primarily a disorder of young women (90%) of patients with IIH compared to few in body mass index (BMI)-matched controls (21,22). In a recent study, 90% of 51 IIH patients displayed evidence of bilateral transverse sinus stenosis on MR venography (23). Interestingly the degree or location of stenosis in this study did not correlate with CSF opening pressure, visual field testing or the clinical course of disease. Similar findings were observed in 14 IIH patients with bilateral transverse sinus stenoses, who underwent repeated lumbar puncture and MR venography over a six-year-period (24). During follow-up transverse sinus stenoses persisted in all patients, despite ICP normalisation in 64% of 14 cases. This suggested that sinus calibre did not correlate with ICP. Whether such lesions truly cause venous hypertension or merely serve as radiological surrogates of raised ICP is unclear (25,26). In contrast to unilateral transverse sinus stenosis, however, which was observed in 30% of 111 patients with normal CSF opening pressure, bilateral stenosis occurred in only 1.8% of individuals and is therefore a better surrogate of raised ICP (27). Prolonged venous hypertension is thought to interfere with passive absorption of CSF via the arachnoid granulations, which results in increased ICP and further venous sinus compression (28). The term ‘self-sustained venous collapse’ has been used to describe the cyclical mechanism which links these physiological processes (sinus stenosis ! venous hypertension ! reduced CSF absorption ! raised ICP ! sinus stenosis) and may explain the occurrence of chronically raised ICP in patients with IIH (Figure 2) (21). Furthermore, it has been proposed that a wide range of triggers that cause raised ICP have the potential to initiate this cycle in predisposed individuals. Similarly, this may explain why reducing ICP with a single lumbar puncture may break the cycle and lead to long-term remission of IIH (29,21). A recent study showed a significant reduction in sinus diameter following lumbar puncture in IIH patients (30). This is further supported by other studies
which demonstrate reversal of venous sinus stenoses after lumbar puncture or CSF shunting (26,31). Endovascular stenting of transverse sinus stenoses results in decreased venous pressure gradients and improved CSF absorption. In the largest cohort of 52 IIH patients who had stenting, the mean pressure gradient across the stenosis dropped from 19.1 mmHg to 0.6 mmHg post-stenting (32). Similar reductions have been observed in other studies (33–36) and appear to correlate with symptomatic improvement in more than 80% of patients. The significance of stenoses in the pathogenesis of IIH and the role of stenting in the management of such patients, however, remains controversial as stenoses may occur in patients with no evidence of raised ICP (22) and have been shown to persist in IIH patients with normalised ICP following medical treatment (24).
Venous sinus microthombi It has been proposed that the presence of venous sinus microthrombi in patients with thrombophilia may reduce CSF absorption by interfering with arachnoid granulations (37). Such patients should probably not be classified as having classical IIH, and sinus thrombosis should always be excluded.
Abnormal vitamin A metabolism Vitamin A (retinol) is thought to interfere with CSF absorption. There is conflicting evidence as to whether
Figure 2. Predisposed individuals may enter a state of ‘selfsustained venous collapse’. Raised ICP (of any cause) is postulated to induce transverse sinus stenosis (venous collapse). The resultant outflow obstruction then leads to venous hypertension and reduced absorption of CSF at arachnoid granulation. It has been proposed that by breaking this cycle, long-lasting remission may be achieved in some patients (21). ICP: intracranial pressure; CSF: cerebrospinal fluid.
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4 abnormalities of vitamin A metabolism or intoxication cause IIH, with no new studies appearing in the literature over the past five years. Retinol binding protein and retinol were shown to be elevated in some patients with IIH (38,39) and when in excess also transported into the CSF of some patients (40–43). In one study, 24% of 21 patients with elevated ICP secondary to IIH demonstrated high (>25 nM) vitamin A levels compared to 0% of 19 patients with elevated ICP due to other causes and 2.5% of 40 patients with normal ICP (42). Overall 83% of six patients with elevated CSF vitamin A had IIH and indicated a strong association. Furthermore one patient with IIH had two lumbar punctures and demonstrated elevated CSF vitamin A levels only when ICP was high. In the case of IIH it remains unclear whether elevated CSF retinol is toxic to the arachnoid granulation reabsorption mechanisms or simply a marker of excess CSF production by the choroid plexus.
Obesity hypothesis We need to consider why the majority of patients with IIH are young obese females. BMI is equal to weight (kilogram) divided by height (meter) squared. The normal range for BMI is 18.5–25 kg/m2, with those >30 kg/m2 being considered obese and those >40 kg/m2 as morbidly obese. Only a small proportion of females classified as overweight develop IIH, but of these a greater proportion accumulate adipose tissue on their lower bodies (44) compared to those with upper body adiposity, in whom diabetes and hypertension are more common. Furthermore, the hormonal and biological functions of adipose tissue are site dependent (45). For example, muscular deposition is associated with insulin resistance, whereas visceral fat may influence systemic inflammatory processes. Fat cells or adipocytes secrete a variety of so-called adipokines (pro-inflammatory and anti-inflammatory cytokines) and hormones, which are thought to play an important role in the pathogenesis of IIH (46). Several studies have attempted to answer this question by profiling adipocyte and hormone levels in CSF and serum samples taken from IIH- and BMI-matched controls. Of particular interest is the hormone leptin, which is involved in energy metabolism. While one study found elevated CSF leptin levels in IIH patients compared to controls (47), another suggested no such difference (48). Although it remains unclear whether leptin plays a role in the pathogenesis of IIH, hypothalamic leptin resistance is associated with obesity (49). Of note, in contrast to other races, only a minority of Asian patients with IIH are classified as obese (BMI >30 kg/m2), suggesting that obesity may not play a
Cephalalgia 0(0) major role in the aetiology of IIH in Asians (50) and other non-obese patients.
Sodium and water retention For many years it was thought that IIH was caused by abnormalities in sodium and water retention. This has since been disproved and there is no histological evidence of brain oedema in patients with IIH postmortem (51). Furthermore, antibodies against aquaporin-4, a transmembrane channel that regulates brain water homeostasis, have not been observed in this patient group (52,53).
Sleep apnoea Apnoeic episodes are associated with retention of carbon dioxide, cerebral vasodilation and subsequent raised ICP. Sleep apnoea is common among obese individuals, especially males, and may exacerbate rather than cause IIH (14,54).
Clinical symptoms The majority (>90%) of patients with IIH present with headache, which may mimic migraine or tension-type headache (Table 1) (10). Lateralised throbbing pain associated with nausea, vomiting, visual disturbance and photopsia is frequently described and can be exacerbated by a change in posture, for example, bending over or lying down. Headache is frequently but not always present on waking. Pulsatile tinnitus is more specific and less common in other primary headache disorders (55). Retrobulbar, cervical and facial pains are also encountered. Relief often comes with rest or non-steroidal anti-inflammatory drugs, with patients habitually becoming dependent on analgesics and developing superimposed medication-overuse headache (56). Visual disturbance is common (>70%) and worrying for patients (16). Transient visual obscurations, described as monocular or binocular blurring lasting
Table 1. Common symptoms in idiopathic intracranial hypertension (IIH). Headache Transient visual obscurations Intracranial noises Photopsia Retrobulbar pain Diplopia Sustained visual loss Source: Adapted from Wall and George (10).
92% 72% 60% 54% 44% 38% 26%
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Wakerley et al. for a few seconds, usually occur when standing, and are thought to reflect momentary ischaemia of the already compressed optic nerve microvasculature. Their frequency does not correlate with the degree of raised ICP or the severity of papilloedema and is not predictive of future sustained visual loss (57). Raised ICP may cause unilateral or bilateral sixth nerve palsies, resulting in horizontal diplopia.
Clinical signs Stereotypically, the patient will be young, female and obese. As a direct consequence of raised ICP, optic disc swelling or papilloedema (Figure 3(a)) is commonly present and considered to be the hallmark sign of IIH. This is usually symmetrical, although can occasionally be unilateral (58) or rarely even absent (59) and if long-standing leads to secondary optic atrophy. In very early disease, prior to the appearance of disc oedema, there may be loss of venous pulsations, which are best observed in the venous segment that transverses the optic nerve head. Venous pulsations are absent in 10% of normal individuals (60). Typically, early papilloedema does not affect acuity, colour vision or pupillary function and the patient may not complain of any visual symptoms. If present, however, the blind spot is usually enlarged and there is evidence of peripheral visual field loss. Deterioration of central vision and acuity is usually gradual, but may be abrupt in the case of fulminant disease and more likely to be permanent. The earliest false localising sign associated with raised ICP is sixth nerve palsy, although other cranial nerves (III, IV, V, VII and VIII) may also rarely be involved (61).
Differential diagnosis Other causes of raised ICP and optic disc swelling should be considered before a diagnosis of IIH is
made. Many secondary causes of intracranial hypertension (e.g. intracranial mass lesion, obstructive hydrocephalus, venous sinus thrombosis (62), venous sinus obstruction secondary to arachnoid granulations (63) and choroid plexus papilloma (64)) can be excluded radiologically, but occasionally IIH may be mistaken for conditions which cause elevation of the optic nerve head without raised ICP. These include malignant hypertension, which may be accompanied by retinal haemorrhages and exudates; optic disc drusen (Figure 3(b), (c)), caused by calcified deposits at the optic nerve head, which do not affect visual acuity or central venous pulsations (65) and can be distinguished from papilloedema by computed tomography (CT) or ultrasound imaging of the optic nerve head (66); and diabetic papillopathy (67), a rare complication of diabetes thought to be secondary to diabetic microangiopathy.
Diagnosis A diagnosis of IIH is frequently made on the basis of clinical history and ophthalmological findings alone, although neuroradiological exclusion of other causes of raised ICP, especially venous sinus thrombosis, is mandatory before proceeding to confirmatory CSF manometry. Criteria for the diagnosis of IIH were first established by Dandy in 1937 (68), but have since been modified (69,2). The most recent criteria in children and adults (2) also take account of patients who don’t develop papilloedema, yet have neuroimaging suggestive of chronically raised ICP (Table 2). As outlined in the recently published ‘International Classification of Headache Disorders, third edition (beta version)’, headache attributed to IIH should be diagnosed only if there is a clear temporal relationship with raised ICP and should resolve when ICP normalises (70). Formal visual field testing, dilated fundus examination and photographs of the optic discs are indicated if
Figure 3. (a) Optic disc swelling (papilloedema, Frise´n grade IV) compared with different degrees ((b), mild; (c), severe), of optic disc drusen (pseudopapilloedema), which are not associated with raised intracranial pressure.
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6 Table 2. Diagnostic criteria for pseudotumour cerebri syndrome. 1.
Required for diagnosis of pseudotumour cerebri syndromea A. Papilloedema B. Normal neurologic examination except for cranial nerve abnormalities C. Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (female and obese), and MRI, with and without gadolinium, and magnetic resonance venography for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used D. Normal CSF composition E. Elevated lumbar puncture opening pressure (250 mm CSF in adults and 280 mm CSF in children (250 mm CSF if the child is not sedated and not obese)) in a properly performed lumbar puncture 2. Diagnosis of pseudotumour cerebri syndrome without papilloedema In the absence of papilloedema, a diagnosis of pseudotumour cerebri syndrome can be made if B–E from above are satisfied, and in addition the patient has a unilateral or bilateral abducens nerve palsy. In the absence of papilloedema or sixth nerve palsy, a diagnosis of pseudotumour cerebri syndrome can be suggested but not made if B–E from above are satisfied, and in addition at least three of the following neuroimaging criteria are satisfied: i. Empty sella ii. Flattening of the posterior aspect of the globe iii. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve iv. Transverse venous sinus stenosis a A diagnosis of pseudotumour cerebri syndrome is definite if the patient fulfils criteria A–E. The diagnosis is considered probable if criteria A–D are met but the measured CSF pressure is lower than specified for a definite diagnosis. Source: Reproduced with permission of Wolters Kluwer from Friedman et al. (2). MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; CT: computed tomography.
there is any doubt to the presence of papilloedema and provide important baseline observations for monitoring disease course and treatment effects. Papilloedema can be objectively graded (I to V) according to the Frise´n scale (71,72). Although MR imaging/MR venography is the preferred imaging modality (73), especially in young patients, those presenting acutely often undergo CT brain and CT venography in order to exclude spaceoccupying lesions and sinus thrombosis quickly (74). Some radiologists prefer CT venograms as in-plane signal loss in two-dimensional (2D) time-of-flight MR
Cephalalgia 0(0) venography may occur and mimic thrombosis (75,76). Neither modality is diagnostic of IIH, but subtle features suggestive of raised ICP are well described, including flattening of the posterior sclera, and the presence of an empty sella, which are present in the majority of patients (Figure 4) (77,78). Less commonly seen are protrusion and/or enhancement (with gadolinium) of the optic nerve (79). Once a space-occupying lesion has been excluded, CSF manometry via lumbar puncture in the lateral decubitus position is performed. In adults the accepted upper limit of normal is 25 cm H2O (80), while in children this is less clear, with some authors suggesting an upper limit of 18 cm H2O in those under the age of 8 years (81). Some studies suggest that raised pressures may occur in obese patients (82) in the absence of IIH, but opening pressures above 28 cm H2O should always be regarded as abnormal. Pain and sedation may give rise to false positives and repeated manometry is sometimes indicated. CSF constituents (cell count, glucose and protein) are normal in IIH. Non-invasive measurement of ICP using transcranial Doppler ultrasonography may be available in the future as a means of monitoring IIH patients in the outpatient setting or during acute exacerbations (83–85). Visual field testing with computer-assisted static perimetry (Figure 5) is frequently used to assess the severity of optic nerve involvement and can be repeated at each clinic visit to monitor disease course (86). Enlargement of the blind spot, visual field constriction and inferonasal vision loss are more commonly observed than scotomas. The role in assessing the severity of papilloedema with confocal scanning laser tomography (87) is not entirely clear (88).
Treatment Patients with IIH are best managed jointly by neurologists and ophthalmologists, although a multidisciplinary approach, involving clinical psychologists, personal trainers and dieticians, may be of use in certain cases (Table 3). Successful treatment requires motivation and an understanding that permanent visual loss is likely if ICP is poorly controlled. In obese patients, weight reduction in conjunction with diuretics remains the principal management strategy. In more resistant or fulminant cases, CSF shunts offer the only hope in controlling raised ICP. Controlled weight loss has been shown to be of benefit in obese patients at lowering ICP and improving papilloedema (88), but is notoriously difficult to maintain. In one study, 25 patients were restricted to a lowcalorie diet (425 kcal/day, equivalent to four bananas) for three months and lost an average of 15.7 kg and saw an 8 cm H2O reduction in ICP (11). Bariatric surgery
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Figure 4. Radiological features seen in IIH. (a) Axial T2-weighted brain MRI demonstrates severe scleral flattening (black arrow) and widening of the perioptic spaces (white arrow), which are barely visible in healthy individuals. Flattening of the anterior pituitary gland by increased CSF pressure results in an empty sella (black star), which is best appreciated on saggital T1-weighted brain MRI ((b), saggital views of brain stem; normal; abnormal, white arrow). It remains undecided whether transverse sinus stenosis ((c), white arrow), demonstrated here with MRI venography is involved in the pathogenesis of IIH or a secondary compressive phenomenon. IIH: idiopathic intracranial hypertension; MRI: magnetic resonance imaging; CSF: cerebrospinal fluid.
may be a viable option in some patients. A review of 62 obese patients with IIH showed that bariatric surgery was effective in terms of symptom resolution and visual outcome (99). In 97% of 35 patients who had pre- and postoperative funduscopy, papilloedema resolved. Similarly, 92% of 12 patients were also found to have marked improvement on formal visual field testing postoperatively. Weight loss takes time and therefore medical treatment is indicated at presentation. Acetazolamide, a carbonic anhydrase inhibitor, is the initial drug of choice and has been shown to lower CSF pressure in IIH patients, possibly by reducing CSF production (89). Acetazolamide controls symptoms in approximately half of patients and appears to prevent relapses if continued long term. However, it is frequently not tolerated. Common side effects include digital and oral paraesthesia, metallic taste and anorexia. Patients should also be warned about kidney stones and the relative contraindication in pregnancy due to teratogenicity. Improved compliance in adult patients can be achieved if started at lower doses (e.g. 125 mg
daily) and slowly titrated up to 1 or 2 g per day. In some patients the sustained release formulation (Diamox sequels) is better tolerated. Methazolamide can be used as an alternative. Topiramate is an anticonvulsant, but also inhibits carbonic anhydrase. One unblinded study suggested similar efficacy to acetazolamide with respect to symptom improvement (90). Patients should be warned about weight loss, cognitive impairment and kidney stones. Fetal malformations have been reported in approximately 4% of pregnancies exposed to topiramate, and women of childbearing age should therefore be counselled (100). Patients should also be warned that the efficacy of oral contraception is reduced with topiramate doses above 200 mg per day. Angle closure glaucoma and myopia may also rarely occur acutely (usually within the first two weeks) in patients commenced on topiramate and may be difficult to differentiate clinically from high ICP-related symptoms (101). Loop diuretics, e.g. furosemide, are sometimes used and have been shown to be of benefit in children when used in conjunction with acetazolamide (102).
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Figure 5. Visual fields and blind spot can be assessed using Humphrey’s perimetry. Left eye; normal blind spot (a), enlarged (b).
Table 3. Treatment options in idiopathic intracranial hypertension (IIH). Lifestyle Medical management
Intervention
a
Weight loss (11) Acetazolamide (89) Topiramate (90) Ferosemide (89) Intravenous methylprednisolonea (91) Repeated lumbar punctureb (92,93) Cerebral transverse sinus stenting (94) Shunts (95–97) Ventriculoperitoneal Lumboperitoneal Lumbar drain Optic nerve fenestration (98)
Not recommended unless sight-threatening fulminant disease. Should be used only if no alternatives are available, for example, during pregnancy. b
The use of corticosteroids in IIH is controversial. One small series showed benefit in patients with severe acute visual loss when used in conjunction with acetazolamide (103) but long-term use is associated with weight gain and salt retention, which may worsen symptoms. Venous stenting of the transverse sinuses, in patients with proven stenosis or obstruction on cerebral venography, has been postulated to relieve venous hypertension but remains controversial and long-term outcomes remain unknown. Retrospective group analysis of 143 cases (104) from 15 studies (32–36), with mean followup of 22.3 months, showed promising results. Stents were placed in the right (69%) or left (27%) or both (4%) transverse or sigmoid sinuses using an endovascular approach (99% of cases). Headache improved in 88% of 112 patients, vision in 87% of 67 patients and papilloedema resolved in 97% of 113 patients. No deaths were reported during or immediately after the procedure, although major complications occurred in
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Wakerley et al. three patients (subdural haemorrhage) and minor complications in six patients. Many patients with IIH continue to have chronic daily headache despite normalisation of their CSF pressure and this can be complicated by medication-overuse headaches. Frequently patients with IIH also develop what appears to be chronic migraine and this can sometimes be difficult to distinguish from high-pressure headaches. Drugs used for migraine prophylaxis should be used including, but not limited to, anticonvulsants, tricyclic antidepressants, and beta blocker medications (94). Some of these medications can be associated with weight gain and should be introduced cautiously.
Acute management of IIH Patients presenting with worsening headaches or visual disturbance often receive benefit from ICP lowering following a therapeutic lumbar puncture. In some cases this can induce lasting remission (21), despite 1 ml of CSF being produced approximately every five minutes and therefore CSF volume returning to normal within a few hours. The long-term benefits associated with serial lumbar punctures in patients with IIH, however, remain unknown, although it appears to be effective when treating exacerbations during pregnancy (92,93). The procedure itself can be technically challenging in obese patients, who often find it uncomfortable. Repeated lumbar puncture is also more likely to result in complications, including: low-pressure headache, CSF leak or infection. The use of intravenous indomethacin to lower ICP in some patients with severe head injury has been debated for over two decades (105), although its use in IIH remains controversial and is not widespread. Unlike other cyclo-oxygenase inhibitors, indomethacin causes cerebral vasoconstriction, which reduces cerebral blood flow and has an ICP lowering effect (106,107). In one study, all seven IIH patients showed a significant reduction (mean 14.4, range 8.0–20.0 cm CSF) in CSF opening pressure one minute after a 50 mg infusion of indomethacin over one minute (108). On follow-up all patients reported an improvement in headache symptoms and showed some resolution of papilloedema. Rebound increase in ICP has been reported following discontinuation of indomethacin and further trials in IIH patients are therefore required to determine both the short- and long-term benefits. In patients with rapid deterioration of vision more invasive techniques are often required. CSF shunting or ONSF are the most commonly used surgical procedures although it remains unclear whether one is superior to the other (109). CSF shunting works directly by lowering CSF pressure and poses no direct risk to vision, while ONSF is less invasive and directly treats
9 papilloedema, but offers less headache relief, at least in the short term. The type of surgical intervention adopted therefore appears to be driven by local preferences and expertise, as there are no trial data comparing the two. CSF pressure can also be lowered by placing a permanent drainage shunt between the ventricles or subarachnoid space in the lumbar region and the peritoneal cavity (ventriculoperitoneal and lumboperitoneal shunts, respectively) (110). Ventriculoperitoneal shunts are thought to be less prone to obstruction than lumboperitoneal shunts, but both types fail in nearly half of cases and surgical revisions are therefore common. In one retrospective series, 82% of 30 IIH patients experienced symptom improvement following ventriculoperitoneal shunting (95). Here, papilloedema improved in 96% of patients and visual acuity improved by at least two lines in 71% of patients. There were a total of 126 shunt revisions, although 87 occurred in four patients and when excluded the overall revision rate was 2.5 per patient. Similarly, another series showed that 95% of 42 IIH patients reported significant improvement in headache symptoms postshunting (96). Although the majority of IIH patients appear to report initial symptom relief when CSF pressure is lowered, the long-term benefits of shunting remain less clear. In the largest retrospective study (97), symptoms and signs of elevated ICP were characterised in 53 patients pre-shunt and at six, 12 and 24 months post-shunt. Papilloedema was present in 92% of patients at baseline and 44% by two years, while headache was present in 96% at baseline and 79% by two years. Visual deficits were noted in 78% of patients at baseline and 32% by two years, while tinnitus was present in 80% at baseline and 67% at two years. From the available data, shunting therefore appears to improve visual symptoms in approximately 50% of patients and headaches in only 20% over the first two years. Fifty-one per cent of these patients also required shunt revision and 31% multiple revisions, indicating that neurosurgical intervention should probably be considered only as a last resort when medical therapy and/or weight loss have failed or if vision is rapidly deteriorating. ONSF is favoured in some centres and has been shown to improve or at least stabilise vision in 70%– 90% of cases (98,111), and has a significantly lower complication and failure rate compared to CSF shunting. Headache symptoms, however, may not dissipate and usually require additional medical treatment. The efficacy and safety of ONSF were examined retrospectively in 158 eyes of 86 IIH patients (98). Improvement in visual acuity and improvement or stabilisation in visual fields were reported in 94% and 88%, respectively. Furthermore, vision-limiting surgical
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10 complications were reported in less than 1% of cases. Headache symptoms, however, improved in only 31% of cases and ONSF probably does not reduce ICP significantly. Fulminant IIH is rare, but devastating if not recognised and treated early. This was highlighted recently in the case of an 18-year-old female with a CSF opening pressure of 60 cm H2O, who developed complete lightperception blindness over four days. The authors hypothesised that a rapid increase in pressure in the perineural space of the optic nerve resulted in ischemic optic neuropathy (91). On day 1 ICP was lowered by inserting a lumbar drain and she was commenced on intravenous methylprednisolone sodium succinate and furosemide. Later, a ventriculoperitoneal drain was inserted and after one month visual acuity had improved to 20/30 in both eyes.
Prognosis Disease course in IIH is poorly defined, with some patients appearing to stabilise early with occasional relapses, while others develop more progressive disease (56,112). Recurrence of IIH is frequently associated with additional weight gain. In one study of 50 patients previously diagnosed with IIH, 26 experienced disease recurrence (113). BMI in those with disease recurrence was significantly higher than at diagnosis (34.5 kg/m2 vs 32.7 kg/m2), while in patients without recurrence, BMI was significantly less than at diagnosis (35.8 kg/m2 vs 43.6 kg/m2). Overall 6% weight gain was observed in patients with recurrence compared to 0% without recurrence, highlighting the importance of weight loss in the treatment of IIH. Despite some patients remaining asymptomatic, disturbances in CSF hydrodynamics probably persist for many years (114). The effects of chronically raised CSF pressure on the optic nerve are well described (57), but there is also evidence which suggests that it may lead to osseous erosion of the skull base. Widening of the foramen ovale was observed in 50% of patients on CT (115) and it has also been postulated that in some cases, such bony erosion may cause CSF otorrhoea and rhinorrhoea. Interestingly, patients presenting with spontaneous CSF leak are also often middle-aged, obese and of female gender. In one study of 16 patients presenting with spontaneous CSF leak, 50% fulfilled Dandy criteria (68) for IIH (116). The majority were female and obese, and also complained of headache in addition to pulsatile tinnitus. In another series of 17 patients presenting with spontaneous CSF otorrhea, all 12 females had BMI >30 kg/m2 and two were diagnosed previously as having IIH (117). Similarly, 18 patients presenting with spontaneous rhinorrhoea also displayed evidence of raised ICP, and the majority had other
Cephalalgia 0(0) features suggestive of IIH (118). It has been postulated that CSF leak may keep some patients with IIH symptom free, and that symptoms and signs associated with raised ICP may re-emerge if the leak is corrected without addressing the underlying cause of raised ICP (119). Whether spontaneous CSF leak in these patients represents a variant of IIH in predisposed individuals or a consequence of chronically raised CSF pressure is uncertain, and highlights the need for more long-term studies.
The IIH Treatment Trial (IIHTT) The Neuro-ophthalmological Research Disease Investigator Consortium (NORDIC) is currently performing the IIHTT and has recruited 166 IIH patients with mild visual loss (120). This multi-centre, randomised, double-blind, placebo-controlled study is examining whether dieting coupled with acetazolamide is superior to treatment with dieting and placebo in IIH patients. The primary outcome is improvement in visual perimetry (perimetric mean deviation) from baseline to six months. Other outcomes include the change in papilloedema grade, ICP measurements, other visual field measurements and quality of life measures. Recruitment is now complete, although not all patients have been followed for six months. Preliminary analysis indicated that dieting and lifestyle modifications have resulted in 6% weight loss in almost half of patients recruited. High doses of acetazolamide also appeared to be safe and well tolerated if given twice daily with food, although 2% of patients developed kidney stones. There are many unanswered questions regarding the pathogenesis of IIH which this trial hopes to address by studying proteomic and genetic risk factors in IIH patients compared to controls. This will determine further investigations into serum and CSF levels of potential IIH mediators, the results of which are eagerly awaited.
Conclusion Given the global obesity epidemic, the incidence of IIH is likely to rise, although it should not be overlooked in non-obese individuals, especially males. Patients who fail conservative management strategies, including weight loss and the use of drugs that reduce CSF production, present a particular problem to neurologists and ophthalmologists and invariably undergo neurosurgical intervention, which is often unsatisfactory in the long term. A better understanding of the underlying pathophysiological processes in IIH and the advent of new clinical trials will lead to the development of more treatment options, which are currently lacking in this disease of unknown aetiology.
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Literature search methods English-language publications were searched for in PubMed between January 2003 and December 2013. The following search terms were used: ‘pseudotumo(u)r cerebri’, ‘benign idiopathic hypertension’ and ‘idiopathic intracranial hypertension’. A total of 741 publications
11 were identified and individually assessed according to their relevance and publication date. Specific exclusion criteria included: publications on paediatric patients; single case reports, unless of exceptional importance; letters; editorials; and other review articles. The reference lists of identified publications were also scrutinised for further relevant publications.
Clinical implications . Given the global obesity epidemic, the incidence of idiopathic intracranial hypertension is likely to rise. . At present non-surgical treatment options for lowering intracranial pressure in such patients are limited and often poorly tolerated. . Understanding the pathophysiological mechanisms associated with developing idiopathic intracranial hypertension and obesity may lead to the development of new treatment strategies. . New evidence suggests that idiopathic intracranial hypertension may exist as a chronic disease in some individuals, even in the absence of headache. Funding This research was funded by the Oxford Headache Centre, UK.
Conflict of interest None declared.
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