Case
A 22 year old obese but otherwise previously healthy female presents with new onset headaches, pulse synchronous tinnitus, and blurred vision in both eyes (OU). The blood pressure was normal. The visual acuity is 20/20 (6/6) OU. Automated perimetry shows an enlarged blind spot OU. Fundus examination reveals papilledema OU. The remainder of the eye and neurologic exam were normal. Cranial MRI and MR venography are normal except for increased cerebrospinal fluid signal (CSF) in the optic nerve sheaths OU and a partially empty sella. A lumbar puncture showed normal CSF contents but an elevated opening pressure of 35 cm of water.
Introduction
Idiopathic intracranial hypertension (IIH) is a disorder of raised intracranial pressure occurring in women of the childbearing years of undetermined cause. It is characterized by (1) increased intracranial pressure with its attendant symptoms and signs—(2) without localizing neurologic findings in (3) an alert and oriented patient. Neurodiagnostic studies are (4) normal except for increased cerebrospinal fluid pressure. MRI shows smooth-walled venous stenoses, empty sella syndrome and signs related to the unfolded optic nerve sheath such as globe flattening or increased CSF signal in the optic nerve sheaths. In addition, (5) no secondary cause of intracranial hypertension is apparent. These five features comprise the modified Dandy criteria of IIH. IIH can have a self-limited or a life-long chronic course.
Although obesity and weight gain are clearly established as related factors, as is female gender, the cause of the disorder remains unknown. The major morbidity of the disease is visual loss related to papilledema with blindness as a potential outcome of treatment failure. Headache is ubiquitous but various headache syndromes including medication overuse headache can be present. The Idiopathic Intracranial Hypertension Treatment Trial (IIHT) [1], a multicenter, double-masked, randomized, placebo-controlled study of acetazolamide in patients with mild visual loss [1] showed acetazolamide produced significant improvement in visual field function, papilledema grade, quality of life measures and CSF pressure; it gives us an evidence base for treatment strategies in IIH patients.
Etiology (First Evaluate and Treat the Intracranial Hypertension Patient for Secondary Causes)
Studies of conditions associated with IIH are mostly uncontrolled and retrospective. This has led to erroneous conclusions because investigators have reported chance and spurious associations with common medical conditions and medications. Also, there are many case reports of associations with intracranial hypertension where the cases do not meet the modified Dandy criteria of IIH.
For example, pregnancy and oral contraceptive use are reported associations that have been shown to be due to chance alone [2–4]. In case-control studies, no significant association is found between IIH and multivitamin, oral contraceptive or antibiotic use [3, 4]. A case-control study has found strong associations between IIH and obesity and weight gain during the 12 months before diagnosis [4]. A discussion of cases that meet the modified Dandy criteria except that a cause of ICP is found can be found in another publication [5].
Treatment
Once intracranial hypertension is discovered, as discussed above, one should first eliminate presumed causal factors such as excessive vitamin A or tetracyclines and begin a low-sodium weight-reduction diet. Therapy aimed at reversing and preventing visual loss should then be instituted. Then, symptomatic headache treatment can be instituted if this symptom persists in the face of intracranial pressure–lowering agents and procedures.
Many treatments have been used for IIH with varying success. Visual loss is the only serious complication and it may occur anywhere from the time of first appearance to many years later. We therefore recommend tailoring the treatment primarily to the presence and progression of visual loss. Also important is to factor in the severity of papilledema grade and non-headache symptoms such as pulse synchronous tinnitus and transient visual obscurations.
Medical Therapy
Treatment of raised intracranial pressure can be both medical and surgical. It is aimed at lowering of intracranial pressure and treating symptoms directly such as headache.
Weight loss: Weight loss has been used to treat IIH for many years. Newborg in 1974 reported remission of papilledema in all nine patients placed on a low-calorie adaptation of Kempner’s rice diet. The patients’ intake was 400–1000 cal/day by fruits, rice, vegetables and occasionally 1–2 oz. of meat. Fluids were limited to 750–1250 mL/day and sodium to less than 100 mg/day. All patients had reversal of their papilledema. Unfortunately, there was no mention of the patients’ visual testing [6]. Others have also documented successful outcomes associated with weight loss [7–9], and it appears that only modest degrees of weight loss in the range of 5–10% total body weight are needed for reversal of symptoms and signs. Other studies have confirmed weight loss as a useful treatment that lowers intracranial pressure and IIHTT [1, 10].
Since marked recent weight gain is associated with visual deterioration [11] and papilledema can resolve with modest weight loss as the only treatment, we strongly encourage our patients to pursue a supervised weight-loss program. Institution of a low-salt diet and mild fluid restriction appear to be beneficial for many IIH patients. This may be especially true in patients who lose only 5–10% of their total body mass yet have resolution of their papilledema. It is not yet clear whether improvement occurs because of weight loss per se or other changes in diet such as fluid or sodium restriction or decrease in the intake of a molecule such as vitamin A.
Lumbar puncture: Use of repeated lumbar punctures is controversial and not generally recommended. Lumbar puncture has only a short-lived effect on CSF pressure [12] with a return of pressure to pre-tap level after only 82 min. Lumbar puncture measures CSF pressure at only one point in time. Since CSF pressure fluctuates, this information has only limited clinical use for modifying treatment plans. However, since transverse sinus collapse (smooth-walled venous stenoses) can resolve immediately with lowering pressure [13], CSF circulatory dynamics may be restored with this procedure and may give temporary relief until the sinus recollapses.
Corticosteroids: Steroids are still occasionally used to treat IIH but their mechanism of action remains unclear. The side effects of weight gain, striae, and acne are especially unfortunate for these obese patients. Although patients treated with steroids often respond well, there usually is recurrence of papilledema with rapid tapering of the dose. This may be accompanied by marked deterioration of visual function. A prolonged tapering may prevent return of symptoms and signs in some patients. Use of long-term steroids to treat IIH has largely been abandoned. We may use steroids as the patient awaits surgery.
Acetazolamide: McCarthy and Reed [14] showed acetazolamide (Diamox®) decreases CSF flow but not until over 99.5% of choroid plexus carbonic anhydrase was inhibited. The IIHTT [1] showed statistically significant improvements in visual field function, quality of life measures, papilledema grade and CSF pressure in the acetazolamide-plus diet compared to the placebo-plus diet group. Acetazolamide was well tolerated and safe at the maximally tolerated dosage (up to 4 g/day). We recommend using the maximally tolerated dosage of acetazolamide along with a low sodium weight reduction diet in IIH patients with mild visual loss—especially in those with high grade papilledema.
We start with ½–1 g/day of acetazolamide in divided doses and gradually increase the dose until either symptoms and signs regress, side effects become intolerable or a dose of 3–4 g/day is reached.
The mechanism of action of acetazolamide is likely multifactorial. It has been found to reduce CSF production; also, it changes the taste of foods and sometimes causes anorexia, aiding in weight loss; however, the IIHTT showed acetazolamide’s effect on visual improvement was independent of weight loss. Patients nearly always experience tingling in the fingers, toes, and perioral region, and less commonly have malaise. Renal stones occur in a few percent of patients. Metabolic acidosis, evidenced by lowered serum bicarbonate, is a good measure of compliance. A rare but serious side effect is aplastic anemia. It occurs in one in 15,000 patient-years of treatment with acetazolamide and usually occurs in the first 6 months of therapy. Aplastic anemia from acetazolamide has been reported most often in the elderly and is probably less common in younger idiopathic intracranial hypertension patients. Since this side effect is so rare and finding the case and stopping the medication does not necessarily cure the patient, repeated blood testing is not usually performed [15].
Topiramate (Topamax®) has also been used to treat IIH since it has carbonic anhydrase activity and weight loss commonly occurs. In studies to date, it appears comparable to acetazolamide but has more sedative side effects that limit is use [16, 17].
Furosemide: Furosemide has also been used to treat IIH [18]. It has been well documented that furosemide (Lasix®) can lower intracranial pressure [19]. It appears to work by both diuresis and reducing sodium transport into the brain. It may work synergistically with acetazolamide [20, 21]. We initiate furosemide at a dose of 20 mg p.o. b.i.d. and gradually increase the dose, if necessary, to a maximum of 80 mg p.o. b.i.d. Potassium supplementation is given as needed.
Treatment Overview
Medical and surgical treatment of patients with idiopathic intracranial hypertension is often challenging, requiring integration of the history, examination and clinical course. Many factors are involved and each is weighted in creating individualized therapy. The most important factor is usually the amount and progression of visual loss followed closely by the degree of the papilledema (high grade papilledema of Frisén grade 3 or more is a risk factor for visual loss). Next in importance is the severity of the patient’s symptoms with regard to how much they are interfering with the patient’s activities of daily living. Headache is the most problematic symptom to treat and may not improve with reduction in CSF pressure [22]. Strategies for medication overuse headache may need to be employed.
Patients with IIH and mild visual loss are treated with weight loss and sodium restriction with the addition of acetazolamide given in the maximal tolerated dosage up to 4 g/day. Furosemide may be added if there is not adequate treatment. If progressive visual loss occurs inspite of maximal medical therapy, CSF shunting or optic nerve sheath fenestration is used. If intractable headache dominates the course, a CSF shunting procedure is recommended realizing only half of the patients will have headache relief at 2 years [22].
Treatment of Headache
Headache in IIH patients may improve after a lumbar puncture, but may remain as a management problem even after medications have been given to reduce edema. We have had success treating these patients with standard prophylactic vascular headache remedies. However, we try to avoid medications that cause hypotension, such as beta blockers or calcium channel blockers, because they may cause reduced perfusion of the optic nerve head. Tricyclic antidepressants can be problematic because of their side effect of weight gain. We use tricyclics in very low doses such as amitriptyline 10–25 mg at bedtime. Non-steroidal anti-inflammatory agents are used as an adjunct but their use is limited to 2 days per week to prevent the development of rebound (medication overuse) headaches. Topiramate may be useful both for its migraine prophylaxis, side effect of weight loss and for carbonic anhydrase inhibition.
Global Perspective
Idiopathic intracranial hypertension is characterized by elevated CSF pressure of unknown cause. The first step is to be certain the patient has the idiopathic form of IH. Once the modified Dandy criteria are met, patients with up to mild/moderate visual loss are started on a weight reduction program and gradually increasing dosages of acetazolamide—the mainstay of therapy. The maximally tolerated dosage of acetazolamide up to 4 g/day should be used. Headaches usually becomes manageable with treatment, papilledema regresses, and vision improves in most patients. Those that fail medical therapy are candidates for surgical treatment.