Continuing Education Activity

Pseudotumor cerebri (PTC), also known by the name idiopathic intracranial hypertension (IIH), is a disorder with increased intracranial pressure (ICP) and associated headaches, papilledema, vision changes, or pulsatile tinnitus in the setting of normal imaging and cerebrospinal fluid (CSF) studies. It mainly affects overweight women of child-bearing age, This activity reviews the cause and pathophysiology of pseudotumor cerebri and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the etiology of pseudotumor cerebri.
• Review the presentation of pseudotumor cerebri.
• Outline the treatment and management options available for pseudotumor cerebri.
• Describe interprofessional team strategies for improving care coordination and outcomes in patients with pseudotumor cerebri.

Introduction

Pseudotumor cerebri (PTC), also known by the name idiopathic intracranial hypertension (IIH), is a disorder with increased intracranial pressure (ICP) and associated headaches, papilledema, vision changes, or pulsatile tinnitus in the setting of normal imaging and cerebrospinal fluid (CSF) studies. It mainly affects overweight women of child-bearing age,[1] however women of all ages, men, and children of both sexes may also be affected.[2] There are multiple hypotheses about the etiology of PTC including decreased CSF absorption and/or increased CSF production.[1] Regardless of the etiology, this disorder can become debilitating and may lead to permanent vision loss. Thus timely diagnosis and treatment is a must.

Etiology

The primary etiology is an accumulation of cerebrospinal fluid (CSF) either through decreased resorption and/or increased production; this leads to an elevated intracranial pressure, the source of the associated symptoms and signs.[3] There is no proven cause for either the decreased resorption or increased production (hence the term idiopathic intracranial hypertension); however, descriptions of the proposed mechanisms are under the pathophysiology section.

Epidemiology

The condition most commonly affects women aged 20-44 years with an annual incidence of 19.3/100,000 in those who weigh 20% or more than their ideal body weight. The annual incidence in all women aged 15 to 44 years is 3.5 per 100,000. The annual incidence of PTC in the general populace is 0.9 per 100,000.[1] It disproportionately affects women, and when considering only post-pubertal patients, 90% of all cases occur in females. A positive relationship exists between the female sex, elevated BMI, and risk of PTC.[4]

Children of both genders are affected equally before puberty (defined as an age of under 12 years old). Obesity less commonly correlates with the pre-pubertal patient.[2] Males aged 12 to 15 years have an annual incidence of 0.8 per 100,000; females aged 12 to 16 years have an annual incidence of 2.2 per100,000.[5]

Pathophysiology

Proposed mechanisms involve the vascular, hormonal, and cellular systems.

Vascular: One of the most common radiologic findings, transverse sinus stenosis, suggests a vascular component. However, the consensus is that this is likely secondary to the increased pressure rather than the cause of the increased pressure; this results in a feed-forward cycle that is relieved by removal of CSF.[4] Hormonal: Aldosterone excess (associated with obesity and PCOS) commonly correlates with PTC and is suggested to affect the mineralocorticoid receptor of the choroid plexus leading to increased CSF production.[6] Unfortunately, this has not yet achieved validation.[3]

Cellular: Increased outflow resistance to CSF has been demonstrated in multiple experimental studies and is the leading theory for causation of PTC. The outflow resistance could be due to an effect of estrogen or retinoic acid (both elevated by increased adiposity) on epithelial cells leading to less outflow of CSF. Finally, the predilection of PTC for younger populations could be explained by decreased CSF production with aging.  Approximately 600 milliliters is produced daily but decreases with increasing age.[3]

History and Physical

The classic historical findings include:

• Headache: any location (bilateral, frontal, retrobulbar), often daily, and sometimes associated with increased severity in the morning and with Valsalva.[7][8] Associated symptoms include nausea, vomiting, and photophobia as well as neck and back pain. Headaches occur in up to 98% of cases.[9]
• Transient vision loss: can be monocular or binocular, partial or complete, and typically lasts for a few seconds at a time. Vision loss is likely due to optic disc edema leading to temporary ischemia of the optic nerve. Transient vision loss occurs in up to 70% of cases.
• Diplopia: binocular and horizontal due to cranial nerve VI (abducens) palsy.[1]
• Pulsatile tinnitus: described as a heartbeat or whooshing sound. Tinnitus can be unilateral or bilateral.[10]  This tinnitus is hypothesized to be due to transmission of vascular pulsations by CSF under increased pressure to the walls of the venous sinuses.[9] Tinnitus occurs in up to 60% of cases.[7]
• Photopsia: described as sudden flashes of light; occurs in up to 54% of cases.[11]
• Persistent vision loss: occurs in up to 32% of cases, most of whom are untreated.[12]

The classic physical exam findings include:

• Papilledema: due to increased intracranial pressure.[8]
• Cranial nerve VI (abducens)/lateral rectus palsy: may result in esotropia. The patient may experience horizontal diplopia.[1]
• Visual field loss: occurs more frequently than changes in visual acuity.[13] One study found 96% of patients have vision loss of differing severities. The most common types of vision loss include increased physiologic blind spot and the loss of inferonasal portions of the visual field.[9]

Evaluation

Patient evaluation of those presenting with signs and symptoms of PTC includes neuroimaging, lumbar puncture with opening pressures and CSF analysis, ophthalmoscopy, visual acuity testing, perimetry testing, and complete blood count (CBC). 

Neuroimaging

• Magnetic resonance imaging (MRI) with venography (MRV) is the preferred imaging modality and is used to rule out other secondary causes of intracranial hypertension. Imaging reveals normal parenchyma and ventricles.[1] Other findings on MRI that can suggest PTC but are nondiagnostic include transverse sinus stenosis,[3] flattening of the posterior sclera, distension of the perioptic subarachnoid space, empty sella, and vertical tortuosity of the orbital optic nerve.[14]
• Computed tomography (CT) can be performed if there are contraindications to MRI but is less sensitive and specific.[9]

Lumbar puncture

• An opening pressure greater than 25cm H2O in adults and greater than 28cm H2O in children aged 1 to 18 years, in the setting of normal CSF studies and negative neuroimaging, is suggestive for PTC.[2][4]
• CSF analysis should include cell count and differential, glucose, protein, gram stain, and culture. 

Ophthalmologic evaluation

• Ophthalmoscopy: evaluates for optic disc edema, known as papilledema. Typically, a higher the grade of papilledema corresponds to more severe vision loss.
• Visual acuity testing: assesses for visual sequelae of the disease. 
• Perimetry testing: more sensitive regarding the degree of vision loss in comparison to visual acuity testing.[9]

Complete blood count

• To rule out anemia or lymphoproliferative causes of papilledema.[15]

Diagnosis involves utilization of the Modified Dandy Criteria [16]:

1. Signs and symptoms of increased ICP

2. The absence of localizing findings on neurologic examination

3. The absence of deformity, displacement, or obstruction of the ventricular system with otherwise normal neurodiagnostic studies, except for evidence of increased cerebrospinal fluid pressure (greater than 200 mm water). Abnormal neuroimaging apart from empty sella turcica, optic nerve sheath with filled out CSF spaces, and smooth-walled non-flow-related venous sinus stenosis or collapse should lead to another diagnosis.

4. Awake and alert

5. No other causes of increased intracranial pressure present with CSF opening pressure of 20cm to 25 cm water, required at least one of the following:

• Pulse-synchronous tinnitus (pulsatile tinnitus)
• Cranial nerve VI palsy
• Frisen Grade II papilledema
• Echography for drusen negative and no other disc anomalies mimicking disc edema present
• MRV (Magnetic Resonance Venography) with lateral sinus collapse/stenosis preferably using ATECO technique
• Partially empty sella on coronal or sagittal views and optic nerve sheaths with filled out CSF spaces next to the globe on T2 weighted axial scans

Treatment / Management

The mainstays of medical treatment include:

• Diagnostic lumbar puncture: can transiently relieve symptoms or, in some cases, lead to a complete resolution.
• Weight loss: weight loss of 5 to 10% of total body weight has been found to cause remission.[4]
• Carbonic anhydrase inhibitors (acetazolamide): decreases CSF production (up to 50%) and functions as a diuretic.[17]
• Topiramate: classically used for migraine prophylaxis. This medication is useful because it has weak carbonic anhydrase activity and can lead to weight loss.
• Diuretics (furosemide, chlorthalidone): less effective at symptom reduction than carbonic anhydrase (CA) inhibitors. When used with CA inhibitors, can lead to severe hypokalemia.[4]
• Steroids: can rapidly lower ICP. Caution recommended as these can cause weight gain and rebound elevated ICP when tapered off. Steroid therapy should only be in cases with severe vision loss or in cases refractory to other medical treatments.[1]

For cases refractory to medical treatment, surgery can be an option:

• Optic nerve sheath defenestration (optic nerve sheath decompression): involves making slits in the dura and arachnoid posterior to the globe leading to an increased outflow of CSF and decreasing pressure on the optic nerve. This operation is mainly reserved for severe vision loss that is refractory to medical management.[4]
• CSF diversion: via either a ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt.[18] CSF diversion has been found to mainly be effective in reducing headache symptoms and less effective for correcting vision loss.[4]

Differential Diagnosis

The differential diagnosis for PTC includes etiologies that can lead to elevated ICP.

• Cerebral venous sinus thrombosis
• Intracranial mass
• Obstructive hydrocephalus
• Jugular vein compression
• Superior vena cava syndrome
• Decreased CSF absorption (secondary to meningitis or following a subarachnoid hemorrhage)
• Malignant hypertension

Prognosis

The disease prognosis depends on several factors including:

• The rapidity of onset of symptoms: a more rapid onset requires more aggressive treatment
• Amount of vision loss at presentation: significant loss at the time of presentation suggests a higher risk of permanent vision loss.[19]
• The grade of papilledema at presentation: higher grades suggest a greater risk of permanent vision.[20]

It is not uncommon for this condition to cause symptoms for from months to years even with prompt treatment. Some patients will have continued papilledema, increased ICPs, and even residual visual field deficits.[13]

Complications

The most concerning complication of PTC is permanent vision loss because of compression of the optic nerve secondary to elevated intracranial pressure.[1] Other complications are mainly related to side effects from treatment of the disease.

• Acetazolamide: hypokalemia, paresthesias of the extremities, and dysgeusia.
• Steroids: weight gain, refractory ICP increase when tapered, and fluid retention.
• Diuretics (furosemide, chlorthalidone): hypokalemia, hypomagnesemia (Furosemide), and ototoxicity. 
• Lumbar puncture: infection, damage to surrounding structures, and post-lumbar puncture headache.[4]
• Surgery: infection, diplopia (transient or permanent), and transient or permanent visual loss secondary to central retinal artery occlusion or ischemic optic neuropathy.[18]

Deterrence and Patient Education

Pseudotumor cerebri/idiopathic intracranial hypertension more commonly affects women of child-bearing age and the obese. The symptoms involve headaches, vision loss (transient or persistent), pulsatile tinnitus (a whooshing sound in the ears), and/or diplopia (blurry or double vision). Treatment involves weight loss paired with medications that can reduce production of cerebrospinal fluid such as acetazolamide or reduce overall body fluids such as loop diuretics (furosemide, chlorthalidone). In severe cases steroids and/or surgery are an option. 

Deterrence can involve:

• Weight loss
• Avoidance of certain medications including retinoic acids (vitamin A), tetracyclines, growth hormone, corticosteroids, and lithium.[1]

Enhancing Healthcare Team Outcomes

Pseudotumor cerebri/idiopathic intracranial hypertension is a disease that can be missed or misdiagnosed given its overlapping features with many other disease processes. Therefore, it is essential for the diagnosing physician to work closely with neurology, ophthalmology, and radiology to provide patient-centered, evidence-based care. Nurses should be aware of pupillary changes that often occur with an elevation of intracranial pressure - a prompt referral to a neurologist/neurosurgeon is necessary when the patient has unequal pupils, papilledema and/or focal neurological deficits.