Pseudotumor cerebri (idiopathic intracranial hypertension)

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Pseudotumor cerebri (idiopathic intracranial hypertension)
Classification and external resources
DiseasesDB 1331


Pseudotumor cerebri and idiopathic intracranial hypertension (IIH) are synonyms however the former is usually the preferred term. It is a disease entity in which patients present with signs and symptoms of increased intracranial pressure (ICP) of unknown cause. It predominantly affects obese women of childbearing age. Papilledema is the primary ocular finding and may progressively lead to optic atrophy and blindness if no treatment is provided. Variable treatment options are available however to date there are no formal guidelines provided with regards to the therapeutic approach.

Disease

Epidemiology and Risk factors

Among studies performed in the United States, the incidence of IIH was found to be 0.9 to 1.0 per 100,000 in the general population, increasing to 1.6-3.5 per 100,000 in women and to 7.9-20 per 100,000 in overweight women. The disease incidence is variable throughout the world mainly because its occurrence varies according to the incidence of obesity in the region. The disease may be seen in any age group but has a high predilection among women especially those of childbearing age. Men however despite having lower incidence rate are more likely to sustain worse visual prognosis. In the prepubertal age group, IIH has no particular predilection to obesity or female gender. Finally, race has been shown to impact visual prognosis rather than disease prevalence.

Among other possible risk factors, certain systemic illnesses have also been reported to be associated with IIH such: obstructive sleep apnea, hypothyroidism, anemia, Addison disease, systemic lupus erythematosus, Behçet's syndrome, polycystic ovary syndrome, coagulation disorders, uremia. The underlying pathogenic mechanism of these associations is not yet fully understood. Other possible causative factors includes medication use such oral contraceptive pills, tetracycline, nalidixic acid, cyclosporine and vitamin A.

Pathophysiology

The pathophysiology remains unclear but multiple hypotheses have been suggested.

Cerebral edema was one of the earliest proposed pathological mechanisms for IIH. However, it was quickly criticized as the elevated ICP was not associated with altered levels of alertness, cognitive impairments, or focal neurologic findings typically seen with cerebral edema. Furthermore, no pathologic signs of cerebral edema were documented in these patients.

A current hypothesis that has received substantial interest involves stenosis of the distal portion of the transverse cerebral sinuses. A study performed by Farb et al demonstrated evidence of narrowing in the transverse sinus among 29 patients with IIH whereas none of the 59 control subjects had these findings. Based on these results the authors proposed that elevated ICP initially causes the narrowing which consequently further exacerbates the pressure elevation by increasing the venous pressure in the superior sagital sinus (Figure 1). However, some evidence at present suggests that apparent venous sinus narrowing is secondary to increased intracranial pressure and is not the primary cause in most cases.

Other suggested theories

Some suggested that an increase in intraabdominal pressure, secondary to obesity, causes increased cardiac filling pressure which impedes venous return from the brain and subsequently leads to an elevated intracranial venous pressure and IIH. However, this hypothesis is unable to explain its presence among the non-obese population group.

Other studies have suggested a role of vitamin A in the pathogenesis based on elevated serum and CSF vitamin A, retinol, and retinol binding protein levels reported in patients with IIH. Although the implication of these findings remains unclear, one theory suggests that excess retinol or retinol binding protein in the CSF interferes with CSF resorption. A major study on vitamin A remains to be done, however an ongoing trial (US IIH trial) may provide useful data once completed.

It has also been proposed that there may be microthrombosis in the sagittal sinus, of insufficient size to be seen on neuroimaging studies, which is blocking CSF absorption in the arachnoid granulations. However, against this theory is the absence of hydrocephalus which is usually seen with impaired CSF absorption or overproduction.

Few studies have examined the potential role of sex hormones in IIH and the latter remains to be further investigated.

Diagnosis

Clinical Presentation

Although the presentation of IIH is usually non-specific, the following symptoms are among those usually reported:

  • Headache: the most commonly reported symptom. It is usually diffuse, non-specific, and may be associated with vomiting. It may also occur with retro-ocular pain.
  • Transient episodes of visual loss (usually lasting seconds): often following changes in posture or Valsava-maneuvers
  • Pulsatile tinnitus: a pulse-synchronus sound classically described as a unilateral "whooshing" sound exacerbated with positional changes. It is considered to be specific for the diagnosis.
  • Visual disturbance: typically involves the peripheral visual field with an infero-nasal defect, arcuate defect, or severe visual field constriction. Visual acuity is not usually affected and is more a sign of fulminant or advanced disease. Central visual field loss may occur in cases when concomitant macular pathology is present.
  • Horizontal diplopia: occurs among patients with associated unilateral or bilateral sixth nerve palsy


Upon ocular examination, papilledema is the hallmark sign of IIH. It is typically bilateral and symmetric, however unilateral or asymmetrical cases may also occur. The Frisén scale may be used to grade severity of the papilledema. Interestingly, the literature describes a few cases of IIH with absent papilledema among patients presenting with intractable headache and elevated opening pressure on lumbar puncture.

The following may also be present on fundoscopic examination: choroidal compression across macula, choroidal neovascularisation, and retinal elevation around optic nerve head. Finally, 6th nerve palsy may also be present secondary to compression effect from the increased intracranial pressure.

Clinical diagnosis

IIH is a diagnosis of exclusion. Nonetheless, definitive diagnostic criteriawere established by Dandy in 1937. However, over the years some modifications were provided and the new criteria are now known as the modified Dandy criteria:

  1. Signs and symptoms of increased ICP
  2. No localizing neurologic signs, except for unilateral or bilateral sixth nerve palsy
  3. Increased CSF opening pressure but normal CSF composition
  4. No evidence of hydrocephalus, mass, structural, or vascular lesion (including venous sinus thrombosis) on imaging
  5. No other cause of increased ICP identified

Diagnostic procedures

When evaluating a patient for IIH, a complete ocular examination including a dilated fundus examination, visual field examination, and optic nerve photographs is required. Subsequently, neuroimaging is needed to exclude secondary causes of intracranial hypertension. MRI, including MR venography, is usually the imaging of choice. It may show abnormalities suggestive of IIH that are however not specific as they may be seen with other causes of increased ICP. The findings include:

  • Flattening of the posterior pole
  • Distension of perioptic subarachnoid space
  • Enhancement (with gadolinium) of the prelaminar optic nerve
  • Empty sella
  • Intraocular protrusion of the prelaminar optic nerve
  • Vertical tortuosity of the orbital optic nerve
  • Stenosis of one or both transverse cerebral venous sinuses


Furthermore, a lumbar puncture is mandatory for all patients who are suspected of having IIH. The diagnosis is based upon an elevated opening pressure greater than 250 mm water taken with the patient lying in the lateral decubitus position. Values between 200 and 250 mm water are considered equivocal. The CSF must also be studied to rule-out inflammation, tumour-cells, and infection. Patients with IIH usually have normal or low protein level, normal glucose levels and a normal cell count.

Differential diagnosis

IIH is usually a diagnosis of exclusion. The term papilledema usually suggests disc edema/swelling secondary to elevated intracranial pressure, which can have many etiologies in addition to IIH. Therefore, among causes of papilledema the following disease entities must be considered:

  • Intracranial mass lesions (tumor, abscess)
  • Increased cerebrospinal fluid (CSF) production, eg, choroid plexus papilloma
  • Decreased CSF absorption, eg, arachnoid granulation adhesions after bacterial or other infectious meningitis, subarachnoid hemorrhage
  • Obstructive hydrocephalus
  • Obstruction of venous outflow, eg, venous sinus thrombosis, jugular vein compression, neck surgery


Furthermore, the differential diagnosis of IIH also includes disease entities which lead to unilateral or bilateral disc edema such:

  • Pseudopapilledema
  • Papillitis
  • Hypertensive optic neuropathy
  • Central retinal vein occlusion
  • Ischemic optic neuropathy
  • infiltration of optic disc
  • Leber hereditary optic neuropathy
  • Orbital optic nerve tumours
  • Diabetic papillopathy
  • Thyroid-related optic neuropathy

Management

General treatment

The goal of treatment is to alleviate symptoms of ICP and preserve vision. Although diagnostic lumbar puncture may provide symptom relief the latter is often transient and requires combination with further long-term therapy.

All obese patients should be encouraged to lose modest amount of weight. Among patients who are obese or overweight, weight loss of about 5-10% has been found to improve symptoms and signs. In a recent study, weight loss allowed a decrease in headaches, papilledema, and ICP. However, the latter option is not effective for acute symptomatic relief and management and therefore needs to be combined with further acute treatment. It is important to ensure preservation of weight loss and avoidance of weight fluctuation in order to minimize the risk of recurrence. Bariatric surgery may be an option among morbidly obese patients. In cases where weight loss alone is insufficient other treatment modalities should be used simultaneously on the long-term.

Medical therapy

Medical therapy is usually considered among patients with mild to moderate disease.

Among the options available, acetazolamide, a carbonic anhydrase inhibitors, is believed to reduce the rate of CSF production and is the first-line medical treatment for IIH. When the latter is inefficient or not tolerated it may be combined with or substituted by:

  • Topiramate, a weak carbonic anhydrase inhibitor usually used as an antiepilepsy agent, is considered as a therapeutic option due to its efficacy at improving headaches and allowing weight loss. However, it has similar efficacy to acetazolamide for visual symptoms.
  • Furosemide, a loop diuretic, may also be of use but is not as effective at reducing ICP.


Although steroids were previously routinely recommended in the treatment of IIH, their use is no longer suggested due to their long-term undesired side-effects (mainly weight gain) and the rebound intracranial hypertension caused following withdrawal. However, high dose intravenous steroids are occasionally used in patients with fulminant IIH causing rapidly progressive visual loss until a more definitive surgical option is chosen.

New emerging studies which are of promising future value are evaluating the effect of octreotide, a growth hormone and insulin-like growth factor inhibitor, for the reduction of ICP.

Surgery

Surgical management should be the option of choice among patients with refractory headaches or more severe/ rapidly progressive visual field loss when all other options have failed to prevent progressive visual loss. Corbett and colleagues have provided potential indications for surgery in patients with IIH

  • Development of a new visual-field defect
  • Worsening of a previous visual field defect
  • Severe visual loss at the time of presentation
  • Anticipated hypotension induced by treatment of high blood pressure of renal dialysis
  • Psychosocial reasons: non-compliance to medication, inability to perform visual field studies
  • Refractory headache


The two most used procedures are CSF diversion via shunt and optic nerve sheath fenestration. The choice of the procedure is based on patients’ signs and symptoms.

Optic nerve sheath fenestration is the preferred surgical procedure for papilledema with associated severe visual loss but no ICP symptoms (such as headache). It has been shown to preserve or restore vision in 80-90% of patients. The procedure involves incisions in the abnormally bulbous anterior dural covering of the optic nerve sheath which creates an outlet for continuous CSF drainage. Consequently, the CSF no longer distends the sheath and axoplasmic flow in the optic nerve is restored. It is also considered to be the safest approach among patients with renal failure requiring hemodialysis and for visual loss occurring during pregnancy

CSF shunting produces rapid reduction in ICP and is therefore most beneficial among patients with visual loss and symptoms of raised ICP. Two types are available lumbo-peritoneal and ventriculo-peritoneal. The former is usually preferred due its lower complication rate.

Over the past years, new surgical approaches have emerged.

Transverse venous sinus stenoses stenting is an emerging procedure based on the hypotheses that patients with IIH may have stenoses of the transverse venous sinus or other cerebral vein. TSS has been shown to decrease cerebral venous pressure, leading to increased CSF absorption and consequent decrease ICP. Some studies have demonstrated improvement in symptoms following this procedure. However, despite its possible beneficial outcomes, the procedure may be associated with serious complications such as stent migration, venous sinus perforation, in-stent thrombosis, subdural hemorrhage and recurrent stenosis formation proximal to the stent. Consequently this procedure should be only reserved for patients with refractory symptoms who are not candidates for other surgical options.

Treatment approach is similar in the pediatric population however surgical intervention should be considered earlier as visual field testing is often inaccurate in this patient population.

Prognosis

The course of the disease is variable and may vary from weeks to years. To date there are no prospective studies that have evaluated the natural history of the disease. Following treatment there is usual improvement and/or disease stabilization. Nonetheless, many patients may not fully recover and demonstrate persistent visual field defect, disc edema or elevated opening pressures on lumbar puncture. Permanent visual loss is the major morbidity and is mostly related to the severity of papilledema. Some studies have identified factors independently associated with a worse visual outcome:

  • Gender (male)
  • Race (Black)
  • Morbid obesity
  • Anemia
  • Obstructive sleep apnea
  • Acute onset of symptoms and signs of raised ICP (fulminant IIH)


Recurrence may occur in 8 to 38% of patients weeks to years following recovery from initial presentation or a prolonged period of stability. Weight gain has been to be associated with disease recurrence.

Additional Resources


References

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