Pseudotumor Cerebri, a.k.a. Idiopathic Intracranial Hypertension

I. What every physician needs to know.

Pseudotumor cerebri (PTC), now more commonly referred to as Idiopathic Intracranial Hypertension (IIH), is a syndrome of elevated intracranial pressure (ICP) in the absence of a secondary cause of intracranial hypertension such as a mass lesion, vascular lesion, or structural abnormality.

IIH is most often seen in obese women of childbearing age, but can affect individuals of any sex, age, or weight. The cause and pathogenesis are unknown. Diagnosis depends upon demonstrating elevated cerebrospinal fluid (CSF) opening pressure, normal CSF composition, normal cranial imaging, and the exclusion of other causes of elevated intracranial pressure. Treatment options include medical therapy to reduce CSF production, CSF diversion procedures, and optic nerve sheath fenestration. The major morbidity is visual loss, though the most common is continued chronic headache.

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II. Diagnostic Confirmation: Are you sure your patient has Idiopathic Intracranial Hypertension?

A. History Part I: Pattern Recognition.

The most common presenting complaint is headache, the description of which can be highly variable. Often patients will complain of daily headache that is bilateral, frontal, or retro-ocular.Some may also complain of symptoms that mimic migraine, including unilateral throbbing, nausea, and photophobia. Less commonly, patients may complain of retrobulbar pain (sometimes exacerbated by eye movements) or pain in the neck and upper back.

Visual complaints are common and may precede the onset of headache. Transient visual obscurations (TVO), which are episodes of visual blurring/loss lasting seconds, are the most common visual symptom occurring in 60-70% of patients. Diplopia occurs in one third to two thirds of patients with IIH. It is typically horizontal and binocular. Other non-visual symptoms may include pulsatile tinnitus, dizziness, and paresthesias.

The typical patient with IIH is an overweight woman between the ages of 15 and 45. It is unusual for IIH to occur in males, elderly, or thin patients; in such cases an aggressive workup for a secondary cause of elevated ICP must be undertaken.

B. History Part 2: Prevalence.

Obesity, recent weight gain, and female sex increase the risk of IIH. Obese women of childbearing age are at highest risk. Incidence is estimated at 12 to 28 per 100,000 in this population, compared to 1 to 3 per 100,000 in the general population.

C. History Part 3: Competing diagnoses that can mimic Idiopathic Intracranial Hypertension.

The differential diagnosis of IIH includes secondary causes of intracranial hypertension. Conditions which impede CSF or intracranial venous outflow may mimic IIH. CSF outflow can be impaired by scarring to the arachnoid granulations from previous inflammation from meningitis or prior subarachnoid hemorrhage. Venous outflow can be impaired by venous sinus thrombosis, intracranial mass lesions which impinge upon a venous sinus, venous sinus ligation, jugular vein ligation (as in radical neck dissection), superior vena cava syndrome, thrombosis of a central venous catheter in the chest or neck, glomus jugulare tumor, or increased right heart pressure.

Exogenous agents such as tetracyclines, vitamin A, and human growth hormone have all been associated with elevated ICP, as has corticosteroid withdrawal. Likewise, associations have been drawn between various systemic diseases and intracranial hypertension. These include systemic lupus erythematosus, hypoparathyroidism, obstructive sleep apnea, Cushing’s disease, Addison’s disease, and renal failure.

Optic nerve abnormalities such as tilted optic discs and optic nerve drusen may give the false appearance of papilledema (“pseudo-papilledema”) erroneously suggesting elevated ICP. When papilledema is absent, IIH may be misdiagnosed as a primary headache syndrome such as chronic daily headache or medication overuse headache.

D. Physical Examination Findings.

Papilledema on ophthalmoscopy is the cardinal exam feature of IIH. Papilledema is typically bilateral in IIH, but may be asymmetric. Cases without papilledema do occur, but this is rare. Visual field defects occur in >90% of cases of IIH. These defects may be noted on confrontational testing at the bedside, though more often formal perimetry is necessary to adequately detect and characterize the defects. The types of defects are those associated with papilledema, most commonly enlargement of the physiologic blindspot, inferonasal defects, and the presence of scotomas. Visual acuity may be depressed, but is more often normal. Impairment of eye abduction, indicative of a CN VI palsy, may be present.

Papilledema is the cardinal exam finding in IIH; it is usually bilateral but may be asymmetric. It is uncommonly unilateral and even more rarely absent in IIH. Visual field deficits may be noted on confrontational testing at the bedside or formal perimetry. Defects often include enlargement of the blind spot and the presence of scotomas. Visual acuity may be depressed but is often normal. Cranial nerve (CN) VI (and rarely CN VII) palsies are found in 10-20%, but other focal neurologic deficits should prompt consideration of an alternative diagnosis.

E. What diagnostic tests should be performed?

Once papilledema is seen on exam, brain imaging should be performed. The preferred test is an MRI of the head and orbits with IV contrast, along with MR or CT venography. Imaging is mainly indicated to exclude space-occupying lesions, obstructive hydrocephalus, and cerebral sinus venous thrombosis as underlying causes of increased ICP.

Once these diagnoses have been ruled out, the next necessary step is a lumbar puncture. The procedure should be performed in the lateral decubitus position with manometer attached for measurement of opening pressure. Diagnosis of IIH is made with pressure > 250 mmH2O.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

CSF obtained during the LP should be analyzed for cell counts with differential, protein, glucose, cytology, and basic cultures to exclude infection, inflammation, or malignancy. In IIH, the CSF profile is typically normal, though protein may occasionally be low.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Cranial imaging is mandatory in patients with suspected elevated ICP and must be performed prior to LP. Brain magnetic resonance imaging (MRI) with gadolinium is the preferred modality for the evaluation of patients with suspected IIH. Computed tomography (CT) can exclude hydrocephalus, mass lesions, and hemorrhage in patients with contraindications to MRI. Common MRI findings in IIH include an empty sella, optic nerve sheath dilatation, and optic disc elevation.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Serial LPs for monitoring ICP are unnecessary and should generally be avoided. Most patients require only the initial diagnostic LP.

III. Default Management.

A. Immediate management.

Any patient suspected of IIH should be evaluated by a neurologist and either a neuro-ophthalmologist or ophthalmologist. The main goals of both acute and chronic management of IIH are the prevention of vision loss and the reduction of long-term headache disability.

Treatment decisions are primarily based on visual function. Evaluation of visual function (visual acuity, color vision, ocular motility, pupillary function, visual perimetry, and dilated fundoscopic examination) must be performed immediately to establish baseline function. If severe visual impairment is noted, acetazolamide should be started and urgent surgical consultation should be sought for consideration of a shunting procedure or optic nerve sheath fenestration. If mild to moderate visual impairment is present, acetazolamide should be started (in the absence of contraindications such as severe renal insufficiency, liver failure, etc.); using the extended release sequels capsules, one may start with 500 mg orally every night for 3 days, then increase to 500 mg twice daily dosing.

If no visual impairment is identified, emergent interventions are not necessary (see Long-Term Management) and symptoms can be monitored. If headache is present, agents such as acetaminophen, non-steroidal anti-inflammatories, calcium channel blockers, beta-blockers, or tricyclic anti-depressants may be used symptomatically.

Steroids should not be used for headache management. The unfavorable side effect profile of long-term steroids for headache make the other agents preferable for management of headache. In addition, steroids may promote further weight gain and have the potential to further increase intracranial pressure.

B. Physical Examination Tips to Guide Management.

Vision must be monitored closely during management. The degree of papilledema can be followed with fundoscopic examination. Adequate examination may be difficult with a direct ophthalmoscope and regular monitoring should be performed by an ophthalmologist or neuro-ophthalmologist. These specialists are able to perform a dilated exam using a slit-lamp biomicroscope which provides a stereoscopic view of the fundus permitting a more accurate assessment of optic disc swelling and contour. Additionally, slit-lamp biomicroscopy utilizes a much brighter light source than direct ophthalmoscopy which can allow for better visualization of fundus structures in the presence of media opacities, such as cataracts or corneal damage.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There are no specific laboratory tests to monitor in the management of IIH.

D. Long-term management.

Weight loss is recommended for all overweight non-pregnant patients and referral to a nutritionist should be considered. Symptomatic improvement has been reported with reduction of 5-10% of total body weight.

There are no FDA-approved medications for the treatment of IIH, thus all medications used in the treatment of IIH are used in an “off-label” fashion. Acetazolamide, a carbonic-anhydrase inhibitor, reduces CSF production and is used as a first-line therapy in IIH. Using the extended release sequels capsules, patients are typically started at a dose of 500 mg orally each night for 3 days to ensure tolerability; the dose is then increased to 500 mg twice daily. Further titrations can be made slowly as necessary/tolerated up to 2-4 g/day total dose. Response of visual signs and symptoms guides the need for titration. Patients should be informed of the potential side effects of acetazolamide including paresthesias (particularly of the perioral region, fingers, and toes), metallic taste, fatigue, loss of appetite, kidney stones, nausea/vomiting, and changes in electrolytes.

Topiramate may also be effective and is tried in many patients if acetazolamide is ineffective or not tolerated. Topiramate can cause weight-loss which may provide additional therapeutic benefit in overweight patients. Other side effects are similar to those of acetazolamide, with the notable addition of adverse cognitive effects. Given the role of topiramate in migraine prevention, it can be an effective choice for those patients with IIH who also experience migraine headaches.

Other headache preventive medications such as valproic acid, calcium-channel blockers, beta-blockers, or tricyclic anti-depressants may be helpful for symptomatic management of headache in IIH. Abortive therapy for headache may include acetaminophen (for example, 1000 mg PO every 6 hours as needed not to exceed 4 grams per day) or non-steroidal anti-inflammatories (for example, ibuprofen 400 mg PO every 4-6 hours as needed or naproxen 220 mg PO every 12 hours as needed). Regular daily use of analgesics should be avoided as frequent use of these medications may result in medication overuse headache.

Surgical treatment options, such as CSF shunting procedures – lumboperitoneal (LP) shunt or ventriculoperitoneal (VP) shunt – and optic nerve sheath fenestration (ONSF), are available to patients with severe visual loss at presentation or those that continue to experience visual decline despite medical management. Surgery should also be considered in patients who are non-compliant with medications, patients who cannot perform visual field perimetry testing, and patients with headache refractory to medical therapies.

CSF shunting procedures aim to reduce CSF volume, thereby reducing intracranial pressure and the associated signs and symptoms of IIH. Shunting procedures carry the risk of overdrainage, low-pressure headache, shunt infection, and shunt failure requiring shunt revisions. VP shunting appears to carry a lower risk of shunt failure. ONSF aims to prevent or improve visual loss associated with papilledema in IIH. Dural venous sinus stenting in IIH patients with venous sinus stenosis has been reported though remains controversial.

There are no formal guidelines regarding the frequency of monitoring of visual function in patients with IIH. Monitoring should be individualized based on the severity of vision loss. In patients newly diagnosed with IIH and those with moderate to severe visual loss, monitoring of visual function (most importantly visual field perimetry, and fundoscopic examination with retinal photographs) should be performed more frequently, weekly or bi-weekly initially, until visual function improves or stabilizes at which point monitoring intervals can be lengthened. In stable patients with more long-standing diagnoses, monitoring can be performed less frequently such as every 3 months. Typically, patients should be monitored for 6-12 months following taper of medications.

E. Common Pitfalls and Side-Effects of Management.

Sulfa allergy is not an absolute contraindication to acetazolamide as cross-reactivity is likely more theoretical.

Corticosteroids should generally be avoided in the treatment of IIH because of weight gain and the potential for increased ICP which can occur with tapering steroid doses. There are instances where corticosteroids may have a role in the treatment of IIH such as when there is sudden severe visual loss, or if surgical treatments are necessary but not immediately available.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Acetazolamide is excreted in the urine. For patients with mild to moderate renal dysfunction, dosage frequency may need to be adjusted. For patients with creatinine clearances less than 10 mL/min, acetazolamide should be avoided.

B. Liver Insufficiency.

Acetazolamide should be used with caution in hepatic disease as it may induce encephalopathy or coma.

C. Systolic and Diastolic Heart Failure.

Right-sided heart failure can cause elevated ICP and should be ruled out as the cause of intracranial hypertension before the diagnosis of IIH is made.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

Acetazolamide can cause alterations in serum glucose levels and should be used with caution in patients with pre-diabetes or diabetes. Other electrolyte imbalances which can occur with acetazolamide include hypokalemia, hyponatremia, and metabolic acidosis. In children, acetazolamide can result in growth retardation.

F. Malignancy.

Metastatic CNS disease must be carefully excluded as secondary cause of elevated ICP in the setting of known systemic malignancy.

G. Immunosuppression (HIV, chronic steroids, etc).

Steroid withdrawal has been associated with IIH. There may also be an association between systemic lupus erythematosis and IIH.

H. Primary Lung Disease (COPD, Asthma, ILD).

Acetazolamide use should be avoided in severe obstructive pulmonary disease.

I. Gastrointestinal or Nutrition Issues.

Acetazolamide can cause taste alteration (particularly with carbonated beverages), decreased appetite, nausea/vomiting, diarrhea, and melena. Possible hepatic side effects include cholestatic jaundice, hepatic insufficiency, abnormal liver function tests, or fulminant hepatic necrosis.

J. Hematologic or Coagulation Issues.

Acetazolamide can rarely cause aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and thrombocytopenic purpura. Generally, monitoring of CBC is not necessary but should be considered in patients with pre-existing hematologic derangements.

K. Dementia or Psychiatric Illness/Treatment.

Carbonic anhydrase inhibitors may decrease the excretion of memantine. They may also decrease the serum concentrations of lithium, and enhance the orthostatic hypotensive effects of MAO inhibitors. In these situations, monitoring of therapy is required.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Headaches should be managed symptomatically and steroids should generally be avoided. If vision deteriorates acutely and deficits become severe, neuro-ophthalmology or ophthalmology and possibly neurosurgery should be consulted on an urgent basis for consideration for surgical intervention (ONSF, or shunting procedure). If urgent consultation is unavailable, or there is a delay to surgical intervention, treatment with IV methylprednisolone 250 mg four times daily for 5 days (followed by prednisone 80 mg daily tapered over 4 weeks) combined with acetazolamide may be considered as a temporizing measure until definitive treatment can be initiated.

B. Anticipated Length of Stay.

In patients hospitalized with IIH, length of stay is driven by obtaining the appropriate baseline evaluations (neurology and either neuro-ophthalmology or ophthalmology, brain MRI, LP), baseline assessments of visual function, and the initiation of appropriate management according to the patient’s degree of visual loss. Hospitalized IIH patients with no, mild, or moderate visual loss will be ready for discharge once the above is completed and appropriate follow-up is established. This can usually be accomplished within 24-48 hours. Those patients with severe visual loss must be considered for surgical intervention (ONSF, VP shunt, LP shunt) which is likely to lengthen stay.

C. When is the Patient Ready for Discharge?

Patients are ready for discharge once they have been evaluated by neurology and either neuro-ophthalmology or ophthalmology; MRI and LP have been performed; baseline visual function testing has been performed (including computerized visual field testing and fundoscopic examination with retinal photography); appropriate management has been instituted based on the degree of visual impairment; and appropriate follow-up has been arranged.

D. Arranging for Clinic Follow-up.

1. When should clinic follow-up be arranged and with whom.

IIH should ideally be co-managed by neurologist and either a neuro-ophthalmologist or ophthalmologist. Follow-up with these providers should be arranged in accordance with the acuity and severity of the patient’s visual signs and symptoms. Patients with moderate to severe visual deficits should be evaluated within 1-2 weeks for re-assessment of visual function (with visual fields and fundoscopic examination with retinal photographs) and response to therapy. Newly diagnosed patients with mild visual signs (minor field defects and acuity of 20/30 or better) and symptoms should also have their first outpatient follow-up within 2 weeks of hospital discharge in order to track the trajectory of their visual impairment and assess response to treatment.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Prior to hospital discharge, patients with IIH should undergo brain MRI, lumbar puncture, neurologic evaluation, and formal evaluation by a neuro-ophthamologist or ophthamologist. This should include visual field perimetry testing and fundoscopic exam (with retinal images if possible).

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

If on acetazolamide therapy, patient should have a basic metabolic panel checked, looking for renal dysfunction or electrolyte imbalances. Visual field assessment with manual or automated perimetry should be performed immediately prior to the patient’s first and all subsequent outpatient evaluations.

E. Placement Considerations.

Patients with IIH do not typically require placement following hospitalization. Those with severe visual loss who do not have appropriate support/assistance to function at home may require placement until visual function improves sufficiently for them to function safely at home.

F. Prognosis and Patient Counseling.

Men, African Americans, and the elderly may have worse visual outcomes. Most patients with mild or moderate visual loss recover vision following medical treatment. Papilledema usually resolves over weeks to months. Medical therapy can be tapered upon stabilization of vision and resolution of disc swelling. Typically, further monitoring of visual function in stable patients becomes unnecessary 6-12 months after tapering of medication.

In patients with severe visual loss requiring surgical treatment, residual deficits in visual acuity and fields are not uncommon and can sometimes be debilitating. Recurrence of IIH may occur and is often associated with weight gain; patients should be informed of this risk. Recurrences may be more common in patients with severe visual loss and semi-annual examinations are recommended for several years after stabilization. Rarely, fulminant cases may be seen which are refractory to all modalities of therapy; a chronic form of IIH requiring years of medical therapy may also occur but is rare.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

There are no JCAHO core measures relevant to IIH.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with moderate or severe visual deficits should be placed on fall precautions. Close follow-up with the neuro-ophthalmologist or ophthalmologist should be in place prior to discharge to help prevent readmission.

VII. What’s the evidence?

Biousse, V, Bruce, BB, Newman, NJ. “Update on the pathophysiology and management of idiopathic intracranial hypertension”. J Neurol Neurosurg Psychiatry. vol. 83. 2012. pp. 488-494.

Bruce, BB, Biousse, V, Newman, NJ. “Perspective: update on idiopathic intracranial hypertension”. Am J Ophthal. vol. 152. 2011. pp. 163-169.

Fraser, C, Plant, GT. “The syndrome of pseudotumour cerebri and idiopathic intracranial hypertension”. Curr Opin Neurol. vol. 24. 2011. pp. 12-17.

Mollan, SP, Ali, F, Hassan-Smith, G. “Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management”. J Neurol Neurosurg Psychiatry. vol. 0. 2016. pp. 1-11.

Wall, M. “Idiopathic intracranial hypertension”. Neurol Clin. vol. 28. 2010. pp. 593-617.

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