Pharmacist's guide to pseudotumor cerebri: A review of the condition and its management

INTRODUCTION

Pseudotumor cerebri is a rare neuro-ophthalmologic syndrome with an estimated incidence of 0.9 per 100,000 persons in the general population.¹ As its name implies, pseudotumor cerebri is a condition of increased intracranial pressure with a clinical presentation similar to that of a cerebral tumor, yet it is void of any intracranial masses.² Because the associated symptoms arise from increased intracranial pressure, but are not the result of structural changes, lesions, cerebral spinal fluid composition abnormalities, or hydrocephalus, the condition is often referred to as idiopathic intracranial hypertension (IIH).^2–5 While this name descriptively characterizes the underlying pathology, it implies the condition lacks a clear etiology. The literature, however, suggests that in a small percentage of patients, the change in intracranial pressure is secondary to a medical condition or medication.⁴ For this reason, the term pseudotumor cerebri will be used throughout this article in order to include situations with such suspected etiologies, which are the cases where pharmacy input may be most instrumental. While pharmacists seldom encounter patients with pseudotumor cerebri, it is important that they be familiar with the symptoms, risk factors, and treatment options so that they may be prepared to offer insight into the medication-related factors involved in the pathophysiology and management of the condition.

DIAGNOSTIC CRITERIA

The diagnosis of this clinical syndrome was originally based on four main factors referred to as the Modified Dandy Criteria.⁵⁶ These criteria have since been expanded to include more detail, but retain the original essence (Table 1). The first two criteria require that, if present, signs and symptoms should be consistent with those of elevated intracranial pressure. These signs and symptoms should be generalized, with the exception of abducens nerve palsy, which is a localized sign that may be present in some patients. Fundoscopic examination revealing signs of papilledema is classical for this condition.⁴⁵⁷ The next criterion requires that patients be in the lateral decubitus position during a lumbar puncture and that the measured cerebral spinal fluid (CSF) opening pressure be greater than 250 mm of water. According to the fourth criterion, the CSF collected during the lumbar puncture must be normal. A fifth requirement is that imaging studies do not reveal the presence of a tumor, structural abnormality, or vascular lesion which could explain the patient's symptoms. An additional criterion, specific to the diagnosis of IIH, states there may not be an identifiable cause of the elevated intracranial pressure.⁴⁵⁷ Revised diagnostic criteria have recently been proposed, which outline criteria for a definite and probable diagnosis of pseudotumor cerebri. Similar to the traditional approach, a definitive diagnosis requires the presence of a relatively normal neurologic exam, normal CSF with increased pressure, and the absence of abnormal findings on brain imaging. In addition, patients must also have papilledema or abducens nerve palsy to meet all five required criteria for diagnosis (Table 1). A probable diagnosis may be made if the same criteria are met, yet the patient has an opening CSF pressure of less than 250 mm of water. Patients lacking either papilledema or abducens nerve palsy who have at least three neuroimaging abnormalities may also receive a probable diagnosis. Such abnormalities include an empty sella, globe flattening, swelling of the perioptic subarachnoid space, and transverse venous sinus stenosis.⁸

Table 1. Diagnostic Criteria for Pseudotumor Cerebri

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SYMPTOMS

Although not required by the aforementioned diagnostic criteria, patients with pseudotumor cerebri typically present with a constellation of neurologic symptoms (Table 2). Almost all patients report the presence of headache, with pressure-like, pulsatile pain behind the eyes.³⁴⁷ While headache duration is variable among patients, the intensity is often severe.³⁷ Visual obscurations, or brief periods of blurred vision in one or both eyes, are also common among patients with pseudotumor cerebri and may be the result of intracranial pressure causing temporary optic nerve ischemia.³⁴ While this symptom is transient, patients may experience more persistent symptoms, including visual field loss, which is one of the most worrisome sequelae of pseudotumor cerebri.³⁴ Although most patients experience this symptom, the extent of loss varies, and is associated with the degree of papilledema present.³ If left untreated for a prolonged period, papilledema may also result in changes in visual acuity.³ Other, non-neurologic symptoms may also be present including nausea and vomiting attributable to the severe headache, and neck, back, or shoulder pain.³⁵

Table 2. Reported Neurologic and Psychiatric Symptoms

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While the classic presentation of pseudotumor cerebri involves predominantly neuro-ophthalmologic symptoms, literature also suggested that patients may experience psychiatric symptoms (Table 2). There have been case reports of patients with untreated pseudotumor cerebri experiencing symptoms ranging from anxiety to delusions.^9–11 Although no causal relationship between pseudotumor cerebri and psychiatric symptoms can be derived from these reports, they do raise questions as to whether the condition may be exacerbating symptoms of an underlying psychiatric disorder or whether the condition shares risk factors with mental illnesses.⁹¹²¹³ Two studies further explored the possibility of such a relationship, and found patients with IIH experienced more anxiety than case-controls without the condition.¹²¹³ Similarly, one of the studies reported higher rates of depression among patients as compared to case-controls.¹³ Again, no causal relationship can be supported by this data, but it does illustrate the need to monitor patients for psychiatric symptoms.

RISK FACTORS

In addition to considering what symptoms patients may experience with pseudotumor cerebri, it is important to consider which patients may be at high risk for developing the syndrome. Despite the mechanism not being fully elucidated, many studies demonstrated overweight and obese women of child-bearing age are at increased risk for being diagnosed with pseudotumor cerebri.^1–4714 A study done in 1988 reported that the incidence increased from 0.9 per 100,000 people among the general population to 3.5 per 100,000 people among women of child bearing age (15–44 years). Incidence further increased to 14 per 100,000 people among women who were more than 10% over their ideal body weight (IBW) and to 19.3 per 100,000 people among women who were greater than 20% of their IBW.¹ Such a strong association with weight raises concern for the possibility of an increasing incidence of pseudotumor cerebri to mirror the ever growing rates of obesity throughout the country. A more recent study added to the knowledge concerning weight and risk of developing pseudotumor cerebri by exploring whether weight gain imparted any additional risk.¹⁴ Results from the study supported the concept that patients with a higher body mass index were at higher risk. It also showed patients whose weight increased between 5 and 15% within a one year period were at significantly greater risk for developing pseudotumor cerebri. This held true even for patients who were not obese.¹⁴ Understanding that moderate weight gain, not just obesity, significantly changes a patient's risk for pseudotumor cerebri reinforces the importance of counseling patients on proper diet and exercise. It also highlights the need to consider the weight gain profiles of medications recommended for at risk patients. This is especially relevant among patients treated for psychiatric or neurologic conditions, as significant weight gain is a well-documented adverse effect of many medications used to treat these populations.

Patient characteristics are not the only factors to consider when assessing the risk for pseudotumor cerebri, as various medications have also been implicated in the development of the condition. Retinols, both natural and synthetic, are among the medications most strongly linked to increased intracranial pressure, especially when used at high doses (>25,000 units vitamin A daily).⁴¹⁵ Tetracycline, minocycline, and, to a lesser extent, doxycycline have also been documented as being associated with pseudotumor cerebri. Often, symptoms begin within weeks of therapy, resolve after medication discontinuation, and return if re-challenged.¹⁵ Withdrawal from long-term corticosteroid use may also induce elevations in intracranial pressure, supporting the need for gradual taper after prolonged exposures.³⁴¹⁵ Lithium has been listed among possible causes of pseudotumor cerebri.⁴¹⁵ Case reports describe patients who developed pseudotumor cerebri after years of lithium monotherapy maintained within the normal therapeutic range, and patients using lithium in combination with divalproex sodium, quetiapine and venlafaxine, and minocycline for more acute management of manic symptoms.^16–19 Other medications have been associated with pseudotumor cerebri (Table 3), although less evidence exists to support their relationship.⁴⁷¹⁵ It is unclear whether these medications have independent mechanisms by which they elevate intracranial pressure or if their effects are mediated by the impact they have a patient's weight. Regardless, it is important to consider the potential for worsening a patient's condition should they be started on one of these medications while their intracranial pressure is elevated, or the possibility that a patient with new onset of symptoms may have pseudotumor cerebri secondary to a medication.

Table 3. Medications and Pseudotumor Cerebri

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MANAGEMENT

Since pseudotumor cerebri is a condition with documented risk factors, a large part of its treatment entails non-pharmacologic options such as removing the likely cause. If a medication is suspected to be the provoking factor, it can often be discontinued or switched to an alternate agent.³ However, if weight is the likely culprit, even a small amount of weight loss (5–10%) can reverse the neurologic effects and lead to symptom resolution.²²⁰ The main goals in managing pseudotumor cerebri are to relieve symptoms such as headache and prevent vision loss.⁷²⁰ If non-pharmacologic treatment options, such as weight loss or sodium restriction, are not sufficient for achieving such goals, medical interventions may be necessary. A conservative approach is usually recommended, starting with pharmacotherapy. Consideration of more invasive procedures should be reserved for patients who are refractory to medications or experiencing severe visual deficits. In these patients, interventions such as lumbar punctures, surgical procedures to drain CSF, optic nerve sheath fenestration to reduce pressure around the optic nerve, or bariatric surgery to assist patients in losing weight may be used.³²⁰ However, such extreme interventions are rarely required.⁷²⁰

Most often, if patients require treatment intervention, medications are initiated. There are three main categories of medications used in treating pseudotumor cerebri which include carbonic anhydrase inhibitors, diuretics, and steroids (Table 3).²³²¹ Acetazolamide is widely used off-label for this indication. Its role in the management of pseudotumor cerebri is via carbonic anhydrase inhibition, which works to decrease CSF production and therefore helps to decrease intracranial pressure. This medication also causes some degree of taste alteration, nausea, and decreased appetite, which has been suggested to assist with weight loss.³²² There is no standardized dosing for pseudotumor cerebri. However, doses ranging from 500 mg to 4000 mg per day are reported; most commonly between 1000 mg and 2000 mg per day, divided twice-daily.²³²¹ Topiramate has a similar role in managing pseudotumor cerebri. It provides some degree of carbonic anhydrase inhibition to help decrease CSF production, but does this to a lesser extent than acetazolamide. The drug does, however, offer other benefits in that it causes weight loss and may help reduce headache pain.²²¹²² Topiramate dosing is usually initiated at 25 mg daily, and titrated to a dose of 100 mg twice daily.²¹ Although both acetazolamide and topiramate have reported efficacy, it is recommended that the two not be used in combination due to a possible increase in metabolic acidosis and kidney stones.²²²³ However if clinically indicated, low-dose topiramate (25 mg twice daily) may be added to control headaches, if they are not controlled by acetazolamide monotherapy.²² Diuretics including furosemide, bumetanide, and mannitol are also reported to have beneficial effects in managing pseudotumor cerebri, with furosemide most often cited in the literature.³⁷²⁰²² The proposed mechanism by which furosemide reduces intracranial pressure is multifactorial including decreasing the amount of sodium which gets to the brain, reducing CSF production, and promoting general diuresis.³²⁰ Doses may be titrated to effect or to 40 mg twice a day.³ Furosemide can be safely combined with acetazolamide.²¹ Oral and intravenous steroids have also been recommended in treating elevated intracranial pressure, especially as an acute treatment for patients experiencing extensive loss of vision. Long-term, however, steroids can cause weight gain and withdrawal may induce pseudotumor cerebri. For these reasons, oral steroids are not the treatment of choice.²⁷²⁰

CONCLUSION

Pharmacists are not likely to encounter a plethora of pseudotumor cerebri cases throughout their careers; however, it is a condition very likely to elicit drug information questions when it does present. For this reason, pharmacists, especially those working in neurology and psychiatry settings, should become familiar with the disease, the drugs that may cause it, and its possible treatments. Knowledge of medications that may cause weight gain may also offer a new perspective to the patient care team, and help in the development of a well-rounded treatment plan. In all, pseudotumor cerebri is a condition where drugs play a large role, and therefore, pharmacists do too.