OVERVIEW: What every practitioner needs to know

Are you sure your patient has pseudotumor cerebri? What are the typical findings for this disease?

The Pseudotumor Cerebri syndrome may be idiopathic or arise from a secondary cause. Prompt diagnosis and treatment are needed to prevent permanent visual loss.

Symptoms:

  • Most common: Headaches (often with nausea and vomiting), transient visual obscurations, diplopia

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  • Next most common: shimmering lights, visual loss, pulsatile tinnitus, neck pain, back pain, torticollis, ataxia

  • Some children are asymptomatic with papilledema discovered on a routine eye examination

Signs:

  • Most common: Papilledema (Figure 1,
    Figure 2, Figure 3, Figure 4), visual acuity loss, visual field loss, esotropia, abducens palsy

  • Next most common: Stiff neck, cranial nerve palsies (III, IV, VII, XII), torticollis, ataxia, enlarged and poorly reactive pupils

Figure 1.n

Mild papilledema of the left eye. The optic nerve borders are indistinct. The vessels crossing the disc margins are visible in their entirety. There is a dark peripapillary halo with engorgement of the retinal veins.

Figure 2.n

Chronic papilledema, left eye. Note that the optic nerve seems to bulge forward with a dark peripapillary halo. There is increased vascularity of the optic nerve, rendering a “hyperemic” appearance.

Figure 3.n

Magnified view of the exudate in the papillomacular bundle in the patient with severe papilledema.

Figure 4.n

Severe (Frisen grade 5) papilledema in an adolescent with minocycline-induced pseudotumor cerebri. The optic disc margins are not apparent and major vessels are obscured by the edematous nerve fiber layer as they cross the disc margin. There are nerve fiber layer hemorrhages, and edema in the papillomacular bundle producing a star formation.

What other disease/condition shares some of these symptoms?

  • Medication-induced pseudotumor cerebri (see medications below)

  • Impaired cerebral venous outflow: cerebral venous sinus thrombosis, jugular vein thrombosis

  • Meningitis (infectious, inflammatory, malignant)

  • Brain tumor

  • Chronic migraine

  • Chronic tension-type headache

  • Post traumatic increased intracranial pressure

What caused this disease to develop at this time?

  • Incidence 1/100,000 in the general population

  • More common in children over age 10

  • Prior to puberty, boys and girls are equally affected

  • Girls are more frequently affected after puberty

  • Predisposing factors:

    Obesity, particularly in adolescents

    Polycystic ovarian syndrome

    Medications: Vitamin A, tetracycline/minocycline/doxycycline, human growth hormone, corticosteroid withdrawal, thyroxine replacement, levonorgestrel implants, desmopressin nasal spray

    No known genetic abnormality although familial cases have been reported

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Lumbar puncture with opening pressure measurement following neuroimaging: There is a wide variation of normal opening pressure in children. Pressures greater than 280 mm CSF are considered abnormally elevated and suspicious for pseudotumor cerebri. Unless the child develops a post-spinal headache, the headache and other symptoms often improve (at least transiently) after the lumbar puncture. The cerebrospinal fluid contents (glucose, protein, cell count) should be normal. CSF cytology and other testing may be warranted on the diagnostic lumbar puncture.

Ophthalmological exam, including perimetry if the child is able to perform it. The important aspects of the examination are best corrected visual acuity, pupillary reactions, ocular motility, visual field testing and examination of the optic fundus. Visual acuity is generally preserved initially; loss of central acuity at presentation warrants aggressive management. A relative afferent pupillary defect indicates asymmetrical optic neuropathy; large and sluggishly dilated pupils are often present in the setting of severe visual loss. An enlarged physiologic blind spot is the most common visual field defect and is sometimes symptomatic. Other visual field abnormalities include inferonasal field loss, generalized constriction, and inferior or superior arcuate defects. A central scotoma generally accompanies loss of central visual acuity.

Automated perimetry has been successfully performed in children as young as age 4 but is often unsuccessful in children under age 12. Goldmann perimetry is often successfully performed when automated perimetry is not possible.

The lumbar puncture should be performed with the child in the lateral decubitus position with legs extended. Sedation, although often required in younger children, should be avoided when possible to avoid false elevation of the cerebrospinal fluid pressure reading. The subarachnoid space may need to be entered with the patient in the sitting position in very obese children; however, the patient must be moved to the lateral decubitus position to measure the opening pressure.

If the pressure is elevated, remove enough cerebrospinal fluid to bring the pressure into the normal range (approximately 150-170 mm CSF). It is possible to develop a post-spinal headache after the lumbar puncture, so over-drainage is not generally recommended.

Would imaging studies be helpful? If so, which ones?

Neuroimaging: magnetic resonance imaging (MRI) of the brain with and without gadolinium, magnetic resonance (MR)-venogram. MRI may be normal or show cerebellar tonsillar descent, empty sella, distention of perioptic subarachnoid space, protrusion of optic nerve papilla into the vitreous, flattening of posterior sclerae. MR venogram may reveal transverse sinus stenosis.

Computed tomography (CT) of the brain with contrast may be performed, but sagittal views are less satisfactory than MRI, and radiation exposure occurs with CT.

Confirming the diagnosis

  • See attached algorithm (Figure 5). There are no randomized, clinical trials upon which to base treatment guidelines.

Figure 5.n

Treatment algorithm (reproduced with permission) Friedman DI. Pseudotumor Cerebri. Neurol Clin 2004;22:99-131

If you are able to confirm that the patient has pseudotumor cerebri, what treatment should be initiated?

  • Note: No randomized, controlled clinical trials have been performed. Recommendations are based on experience, case series, and generally accepted standards of care. Medical and surgical treatment options are summarized in Table I.

  • Discontinue causative agent if applicable, then treat as follows:

  • Mild visual loss

    Acetazolamide 15 mg/kg/day in 2-3 divided doses or methazolamide

    Weight loss if child is overweight

  • Moderate visual loss

    Acetazolamide 15 mg/kg/day in 2-3 divided doses or methazolamide

    Repeat lumbar puncture(s)

    Topiramate (1.5-3 mg/kg/day in 2 divided doses) may be helpful if there is prominent headache

    Weight loss if the child is overweight

  • Severe visual loss

    Optic nerve sheath fenestration and/or

    Lumboperitoneal or ventriculoperitoneal shunt

    Acetazolamide 15 mg/kg/day in 2-3 divided doses IV or PO

    Adjunctive or temporizing treatments: repeated lumbar punctures, lumbar drain, corticosteroids

  • Long-term treatments

    Weight loss of at least 6% total body weight if child is overweight. Excessive weight gain is associated with disease recurrence

    Continue acetazolamide or methazolamide

  • Headache management if acetazolamide not effective

    Topiramate

    Amitriptyline or nortriptyline (monitor for weight gain)

  • Allergy or intolerance of acetazolamide

    Methazolamide (50-100 mg BID – TID)*

    Furosemide (2 mg/kg/day, may gradually increase to 6 mg/kg/day as needed)

    Triamterene*

    Spironolactone*

    (* There is little experience with these agents in treating children)

Table I.
Treatment Dose Advantages Disadvantages
Acetazolamide 15 mg/kg/day in 2-3 divided doses.Starting dose in adolescents 1 gm daily in 2-4 divided doses (maximum 4 gm daily) Likely mechanism of action is decreased CSF secretion by choroid plexus mediated by carbonic anhydrase inhibition. May improve headaches.May be given IV. Common side effects: paresthesias, altered taste sensation, fatigue, gastric upsetRare side effects: Elevated liver function tests, renal stones, allergyNOTE: Allergy to sulfa antibiotics is not a contraindication to acetazolamide use
Methazolamide 25 BID up to 100 mg TID (Dosage not established in children) Proposed mechanism similar to acetazolamide.May be better tolerated than acetazolamide although generally not used first-line Same as acetazolamide
Topiramate 1.5 – 3 mg/kg/day in 2 divided doses Mild carbonic anhydrase inhibition. Efficacy for visual loss not established.Most beneficial for patients with headache as major manifestation. May be used concurrently with acetazolamide in low doses. Common side effects: Paresthesias, fatigue, gastric upset, weight lossUncommon side effects: cognitive dysfunction, alopecia.Rare side effects: Renal stones, hypohidrosis, allergy.May interfere with oral contraceptive efficacy in doses over 200 mg/day
Furosemide 2 mg/kg/day starting dose, increase gradually to 6 mg/kg/day if needed Inhibits CSF secretion at choroid plexus. More potent systemic diuretic than acetazolamide. Requires electrolyte monitoring for hypokalemia
Triamterene Well tolerated, potassium-sparing diuretic. No known action at choroid plexus
Spironolactone Well tolerated, potassium-sparing diuretic No known action at choroid plexus
Lumbar drain May be used to monitor pressure when diagnosis uncertain.May be used to urgently or temporarily lower CSF pressure if definitive surgery not possible Incorrect placement, catheter migration or occlusion may preclude functioning system.Rare complications: infection, radiculopathy
Optic nerve sheath fenestration Preferred treatment for patients with visual loss as major morbidity.May be performed unilaterally or bilaterally.Generally halts or reverses visual loss.Unilateral surgery may improve vision in both eyes.Well tolerated and no hardware required.Should not be performed primarily for treatment of headache, although headaches often improve after surgery. Requires experienced oculoplastic surgeon.Common side effects: ocular discomfort, diplopia (usually transient), eyelid edemaRare side effects: worsened vision or blindness
Ventriculoperitoneal shunt Immediately lowers CSF pressure.Treats headaches and visual loss, assuming patent and contiguous perioptic subarachnoid space. Stereotactic placement may be needed as the procedure is technically difficult in the presence of normal-sized ventricles.Common complications: Shunt failure is common and may occur at any time.Shunt revision may be required as the child grows.Rare complications: intracranial hemorrhage, shunt migration, infection, abdominal complications from distal catheter
Lumboperitoneal shunt Same as ventriculoperitoneal shunt Technically easier to perform in non-obese patient.Common complications: shunt failure is common and may occur at any time.Rare complications: Radicular pain, acquired Chiari malformation from over-shunting, infection, abdominal complications from distal catheter

What are the adverse effects associated with each treatment option?

Please refer to Table I.

What are the possible outcomes of pseudotumor cerebri?

Most children with mild-to-moderate optic nerve swelling and visual field defects have resolution of their condition with prompt diagnosis and treatment. Papilledema resolves in 4.7 months, on average, in the pediatric population. Permanent visual acuity loss occurs in up to 10% of cases, with permanent visual field loss in 17%. Profound visual loss, including blindness may occur; most cases of fulminant IIH are associated with high-grade papilledema, early loss of visual acuity, and rapid progression despite medical intervention. Recurrence rate is 6%-22% and is associated with weight gain.

What will you tell the family about prognosis?

The most worrisome complication of idiopathic intracranial hypertension (IIH) is visual loss; the efforts to treat IIH are primarily directed at preserving vision. Although most children do well, a small percentage will lose vision despite our best efforts. It important for the child to take medications as prescribed and return for follow-up visits. Management is directed by the visual status; the treatment team incorporates a neurologist, an ophthalmologist (or neuro-ophthalmologist), pediatrician and possibly other specialists (e.g., endocrinologist, neurosurgeon). Any perceived worsening of vision should be investigated immediately.

There is some evidence that pubertal children are at higher risk for a poor visual outcome than younger children. The child should avoid eating foods with a high salt content. He/she should avoid taking vitamin A and related medications, many of which are used to treat acne. If the child is overweight, weight loss must be achieved and maintained. The child will probably not require life-long treatment. In most cases, the medications can be tapered and discontinued once it is certain that the optic disc swelling has resolved and there is no evidence of recurrence. Some children will continue having headaches even though the disease is controlled; they are generally managed medically.

What will you tell the family about the risks-benefits of treatment?

The medications used to treat IIH all have side effects, which are usually tolerable. Acetazolamide (off-label use) commonly produces tingling in the extremities and makes carbonated beverages taste bad. It may also cause stomach upset and fatigue. Some children are allergic to it (watch for skin rash).

If acetazolamide cannot be used, other diurectics may be effective. Topiramate may be helpful for headache prevention (off-label use). Surgical procedures are employed when vision is threatened. Shunts often fail in the long term; one should have a shunt placed with the expectation that it will need to be replaced at least once in the future. Therefore, shunts are not generally recommended for the treatment of headache. Optic nerve sheath decompression carries a low risk of visual loss, but is generally effective for reversing visual loss or stabilizing vision.

What causes this disease and how frequent is it?

  • Epidemiology:

    The disorder may occur at any age. It most frequently occurs in obese females of childbearing age. Obesity is less frequently encountered In prepubertal children with pseudotumor cerebri.

    No infectious agents are known. Symptoms may occasionally follow a viral illness or mild head trauma.

    Pseudotumor cerebri has been associated with the following medications: Vitamin A, isotretinoin, tetracycline, minocycline, doxycycline, human growth hormone, corticosteroid withdrawal. Less frequent associations include lithium, thyroxine supplementation, anabolic steroids (body building), chlordecone, levonorgestrel implants, desmopressin nasal spray.

    Polycystic ovarian syndrome is associated with pseudotumor cerebri. It is rarely reported with Addison disease. No definite association exists with oral contraceptives or pregnancy.

  • There is no known genetic component. Familial cases have been reported but it is uncertain whether there is truly a genetic factor versus other factors common among family members (e.g., obesity).

How do these pathogens/genes/exposures cause the disease?

It is unknown how these pathogens/genes/exposures cause increased intracranial pressure.

Other clinical manifestations that might help with diagnosis and management

What complications might you expect from the disease or treatment of the disease?

Complications from the disease:

  • Permanent visual loss, visual field loss, rarely legal or complete blindness

  • Headaches

  • Double vision (usually correctable by strabismus surgery)

  • Depression and anxiety

  • Missed school days from disease-related disability and appointments

Complications from the treatment:

  • Shunt failure requiring revision

  • Side effects of medication (See Table I)

  • Small risk of worsening vision following optic nerve sheath fenestration

Are additional laboratory studies available; even some that are not widely available?

How can pseudotumor cerebri be prevented?

It is uncertain why some children develop increased intracranial pressure in response to various medications or weight gain when most children do not. There are no known effective preventive measures.

What is the evidence?

Avery, RA, Shah, SS, Licht, DJ. “Reference range for cerebrospinal fluid opening pressure in children”. NEJM. vol. 363. 2010. pp. 891-3. (Perhaps the most important study related to IIH. One hundred nintey-seven children without infection, inflammation or ischemia having a lumbar puncture for their clinical care were studied prospectively to determine a threshold for abnormally elevated opening pressure [90th percentile or higher]. The threshold for abnormal opening pressure was 28 cm of water. Subjects having the procedure done using moderate to deep sedation had a slighter higher opening pressure than those performed without sedation. There was a small relationship between BMI and opening pressure.)

Avery, RA, Licht, DJ, Shah, SS. “CSF opening pressure in children with optic nerve head edema”. Neurology. vol. 76. 2011. pp. 1658-61. (In a follow-up study to the above study by the same group, 41 opening pressure measurements were obtained on 33 subjects with optic nerve head edema and no evidence of infection, inflammation or ischemia. The mean pressure was 41.4 cm CSF (range 22-56) compared to control subjects (mean 18.9, range 9-29). Forty of the 41 patients with optic nerve head edema had opening pressures > 28 cm CSF, supporting the conclusions of the previous study.)

Balcer, LJ, Liu, GT, Forman, S. “Idiopathic intracranial hypertension: relation of age and obesity in children”. Neurology. vol. 52. 1999. pp. 870-2. (This retrospective study of 45 consecutive children with newly diagnosed IIH showed that younger children were less likely to be obese than older children [43% of ages 3-11 years, 81% of 12-14 year-olds, 91% of 15-17 year olds].)

Weig, SG. “Asymptomatic idiopathic intracranial hypertension in young children”. J Child Neurol. vol. 17. 2002. pp. 239-41. (Case series of children diagnosed with IIH after finding asymptomatic papilledema on a routine eye exam.)

Ko, MW, Liu, GT. “Pediatric idiopathic intracranial hypertension (pseudotumor cerebri)”. Horm Res Paediatr. vol. 74. 2010. pp. 381-9. (Review of IIH diagnosis and treatment in children [Note that normal values for opening pressure on lumbar puncture were established after this paper was published].)

Tibussek, D, Schneider, DT, Vandemeulebroecke, N. “Clinical spectrum of the pseudotumor cerebri complex in children”. Childs Nerv System. vol. 26. 2010. pp. 313-21. (Retrospective series of 53 patients, including symptoms, characterization of headaches, CSF pressure, treatment, comorbidities and medications at presentation. This article emphasizes the heterogeneous nature of the disorder.)

Stiebel-Kalish, H, Kalish, Y, Lusky, M. “Puberty as a risk factor for less favorable visual outcome in idiopathic intracranial hypertension”. Am J Ophthalmol. vol. 142. 2006. pp. 279-83. (The authors analyzed outcome data for 96 patients [prepubertal, pubertal, teenage, adult], incorporating medical risk factors commonly associated with a poor prognosis [hypertension, renal failure, anemia]. Puberty was significantly associated with a moderate to poor visual outcome, compared with the other age groups.)

Thuente, DD, Buckley, EG. “Pediatric optic nerve sheath decompression”. Ophthalmology. vol. 112. 2005. pp. 724-7. (Visual outcomes from 17 eyes in 12 children under age 16 years were retrospectively evaluated following optic nerve sheath fenestration. All patients had improvement in disc edema with improvement or stabilization of acuity in all surgical eyes. No patient had visual loss, infection or strabismus. One patient required a lumboperitoneal shunt and 2 required acetazolamide therapy postoperatively. Five patients subsequently had the procedure performed in the other eye.)

Soiberman, U, Stolovitch, C, Balcer, LJ. “Idiopathic intracranial hypertension in children: visual oucome and risk of recurrence”. Childs Nerv Syst. vol. 27. 2011. pp. 1913-8. (A retrospective study of 90 children under age 18 with a mean follow-up of 30.65 months showed an improvement in visual acuity overall. The highest risk of recurrence was within the first 18 months after diagnosis.)

Ongoing controversies regarding etiology, diagnosis, treatment

There are no randomized clinical treatment trial results to guide therapy in children or adults. Therefore, many controversies exist:

Which surgical treatment is best: shunting or optic nerve sheath fenestration?

What is the correct dose of acetazolamide?

What is the role for venous sinus stenting in the treatment of IIH?

There are many obese children and adults in the world – why is IIH a rare disease?

If IIH is associated with weight gain and venous hypertension, why isn’t it more common during pregnancy?

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