Idiopathic Intracranial Hypertension
Michael Wall, M.D.
The University of Iowa
Department of Neurology and
Department of Ophthalmology and Visual Sciences
Medical Treatment of IIH
(written for physicians only)
Treatment of raised intracranial pressure is both medical and surgical. It is aimed mainly at lowering of intracranial pressure and secondarily at treating symptoms directly, for example headache. Unfortunately, all reports to date are anecdotal as there have not been any controlled clinical treatment trials for idiopathic intracranial hypertension. While there is no evidence based treatment to guide medical therepy there is currently an ongoing National Eye Institute sponsored trial, the Idiopathic Intracranial Hypertension Treatment Trial. The trial has two aims. One is to determine if acetazolamide (Diamox) with a low sodium weight reduction diet is superior to placebo with the diet. The second aim is to investigate the cause of idopathic intracranial hypertension. Further information can be found at the NORDIC website.
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 strict diet. She used a low calorie adaptation of Kempner’s rice diet. The patient’s intake was 400-1000 calories per 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.1
The beneficial effects of weight loss have also been reported more recently. Kupersmith and colleagues retrospectively reviewed the charts of 250 IIH medically treated IIH patients from two centers and tabulated results on 56 patients that had at least 6 months of follow-up and otherwise met entry criteria.2 The mean time to improve one papilledema grade was about 4 months in patients with weight loss compared with about 1 year in patients without weight loss. Papilledema resolved in 28/38 patients with weight loss compared with 8/20 without weight loss.
Johnson and coworkers retrospectively studied 15 IIH patients treated with acetazolamide and weight loss for 24 weeks.3 They reported 3.3% weight loss in patients having one grade of improvement in their papilledema grade. Nine of 10 patients that improved took acetazolamide as did the four patients that did not lose weight and had no improvement in papilledema grade. Our experience from a pilot study with 29 patients has also been that improvement often occurs with only modest degrees of weight loss. Greer however, reported a group of six obese patients that became asymptomatic without weight loss.4 Sinclair and coworkers, have shown diet over a three month period lowers intracranial pressure.
Resolution of IIH in a patient following surgically induced weight loss (gastric exclusion procedure) was first reported by Amaral.5 Sugarman and coworkers performed gastric weight reduction surgery in 24 morbidly obese women with IIH.6 Five patients were lost to follow-up. Symptoms resolved in all but one patient within 4 months of the procedure. Two patients regained weight associated with return of their symptoms. There were significant but treatable surgically-related complications.
Since marked recent weight gain is a predictor of visual deterioration7 and we have observed papilledema resolve with weight loss as the only treatment, we strongly encourage our patients to pursue a supervised weight loss program. As Friedman and colleagues have shown, there is a subset of IIH patients with orthostatic edema.8 Low salt diets and fluid restriction may also be beneficial for IIH patients. This may be especially true in patients that lose only a few percent of their total body mass yet have resolution of their optic disc edema. 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.
Repeated lumbar puncture, although still used by some neurologists, leaves much to be desired as a treatment. Lumbar puncture has only a short-lived effect on CSF pressure; Johnston and Paterson9 found a return of pressure to pre-tap level after only 82 minutes. Interestingly, Weisberg10 reported 6 of 28 patients treated with serial lumbar punctures symptomatically improved.
Repeated lumbar punctures also raise the risk of developing intraspinal epidermoid tumors presumably caused by implantation of epidermal cells. Lastly, repeated lumbar punctures to measure CSF pressure do so at only one point in time. Since CSF pressure fluctuates widely throughout the day, this information has only limited clinical use for modifying treatment plans. Following the patient’s papilledema (which reflects the mean intracranial pressure) is a superior index of the mean intracranial pressure.
Paterson13 first reported the efficacy of corticosteroids for treating IIH in five of six consecutive patients. Weisberg10 has documented prompt beneficial initial responses to steroids. Corticosteroids are still used to treat this disease but their mechanism of action remains unclear. The side effects of weight gain, striae, and acne are particularly unfortunate for these obese patients. Although patients treated with steroids often respond well, there may be recurrence of papilledema with rapid tapering of the dose. This may be accompanied by severe worsening of visual function. A prolonged tapering may prevent return of symptoms and signs in some patients. Use of corticosteroids to treat IIH patients has largely been abandoned by most neuro-ophthalmologists.
Jefferson and Clark15 treated 30 patients with various types of oral dehydrating agents (chlorthalidone, hydroflumethiazide, glycerol and urea). All patients were also placed on a weight reduction diet. They used blind spot size as their main outcome measure. This measure can be problematic for many reasons including changes in refractive error16 and changes in stimulus speed and reaction times between exams. Fourteen of these patients had reduced visual acuity, and in all, vision improved with therapy. Friedman treated 30 women with IIH with chlorthalidone and spironolactone.8 In 15, dextroamphetamine or phenteramine was added and 18 patients also were treated with acetazolamide. This treatment did not consistently reduce headaches and only four of the 30 patients had improvement in their papilledema. Thiazides are not first line drugs to treat idiopathic intracranial hypertension.
In 1974, McCarthy and Reed17 showed inhibition of CSF flow but not until over 99.5% of choroid plexus carbonic anhydrase was inhibited. Lubow and Kuhr, in 1976, reported a series of IIH patients, many of whom were treated successfully with acetazolamide (Diamox®) and weight reduction.18 An important study was published in 1978 by Gücer and Viernstein.19 They used intracranial pressure monitoring before and after treatment in four IIH patients. They monitored acetazolamide treatment in two of the patients and showed gradual CSF pressure reduction in both. They only reported the dose in one of the patients (four grams of acetazolamide per day). Ten years later, Tomsak et al.,20 documented resolution of papilledema with photographs of the optic disc in four patients treated with one gram of acetazolamide a day. Acetazolamide appeared to be an effective medication in their patients with results occurring over several months.
The mechanism of action of acetazolamide is likely multifactorial. It has been found to reduce CSF production in humans by 6-50%.21 It has been thought to work by inhibition of carbonic anhydrase that causes a reduction in transport of sodium ions across choroid plexus epithelium. Also, it changes the taste of foods and causes carbonated beverages to taste metallic. This may aid the patient in weight loss. Additionally, some patients experience nausea, further helping them to lose weight.
Topiramate (Topamax) is a structurally related medication used for headache. It has weight loss as a side effect! To date, it appears about as effective as acetazolamide but is considerably more expensive.
The most effective dose is not yet determined. In addition to the gustatory side effects, patients commonly experience tingling in the fingers, toes, and perioral region, and less commonly, malaise, nausea and anorexia are reported. Rarely patients will develop renal stones. Metabolic acidosis, evidenced by lowered serum bicarbonate, is a good measure of compliance. Younger patients tolerate acetazolamide better than older ones and the Diamox 500mg sequels appeared to be better tolerated. Aplastic anemia is so rare, some advocate not monitoring complete blood counts. Zimran and Beutler estimate the cost of finding one case would be $1.5 million.22 While it has been suggested that patients that are sulfa allergic should not use acetazolamide because of potential cross reaction, there is no conclusive evidence for withholding the drug in sulfa allergic patients. If patients develop renal stones, one can discontinue the medication or continue usage with periodic ultrasound examinations to see if the renal stones are recurring.
It has been documented that furosemide (Lasix®) can lower intracranial pressure.7,23-25 Furosemide has also been used to treat IIH.26 It appears to work by both diuresis and reducing sodium transport into the brain.28
Based on an assumption by McCarthy and Reed17 that the effects of acetazolamide and furosemide might be additive, Schoeman treated pediatric IIH patients with this combination therapy.29 In a controlled trial of children with tuberculous meningitis, 57 with communicating hydrocephalus were randomly assigned to three treatment groups: antituberculous drugs only; or additional intrathecal hyaluronidase or oral acetazolamide and furosemide in addition to antituberculous treatment. Acetazolamide and furosemide in combination was significantly more effective in achieving normal ICP than antituberculous drugs alone.30
Schoeman then treated eight pediatric IIH patients with oral acetazolamide (37-100 mg/kg) and furosemide (1 mg/kg) until the papilledema cleared. He used continuous 1-hour lumbar cerebrospinal fluid pressure monitoring these children with IIH on admission and at weekly intervals until the baseline pressure became normal. Six children had an increased baseline cerebrospinal fluid pressure, whereas raised intracranial pressure was diagnosed in three children based on an abnormal pulse wave and/or pressure waves. The mean baseline pressure normalized in all patients within 6 weeks of start of therapy. As with all treatments of IIH, all reports to date are anecdotal and recommended treatments vary widely.
Oral glycerol is a form of cerebral dehydration first recommended in 1963 to reduce intracranial pressure. A single dose of one gram/kg of glycerol will raise serum osmolality from 295 to 320 mOsm/L in 90 minutes, and reduce CSF pressure for 3 to 5 hours. Doses every four hours can cause a reversed osmotic gradient and a rebound increase in intracranial pressure31,32 while a six hour interval is too long and allows the pressure to recur. Together, the added calories the large volume of glycerol needed, the awkwardness for a working person to use this medication, the nauseating side effects, and other side effects make this a cumbersome medication for IIH. It is rarely used today for increased intracranial pressure.
Treatment of Headache
Sometimes, in spite of full medical therapy to reduce CSF pressure, headaches persist. We have success in some patients with standard prophylactic vascular headache remedies. However, caution should be used in patients with visual loss as the hypotension that accompanies many of these medications can accelerate the visual loss.
Patients with idiopathic intracranial hypertension also have other headache syndromes. Especially in patients with a migraine history, analgesic rebound or caffeine rebound headaches may coexist. It may require IV dihydroergotamine to break this troublesome headache syndrome.
Weight loss is the cornerstone of therapy for idiopathic intracranial hypertension. We recommend a low salt, weight reduction diet with loss of about 5 - 10% of body weight followed by stable weight. This goal, of modest weight loss, is more likely to succeed than the usual aggressive weight loss program.
In our experience, acetazolamide appears to be an effective treatment for idiopathic intracranial hypertension. We start the patient with a dose of 250 mg p.o. b.i.d. and increase the dose every four days by 250 mg until a dose of 1 gram a day is reached or the patient becomes intolerant to the side effects. If tolerated we give the medication twice daily with meals. If after one to two months there is no substantial improvement in visual function or symptoms, we gradually increase the dose to two grams per day. Doses of up to four grams a day may be needed but we usually obtain a beneficial effect in the one to two gram a day range. If acetazolamide is not well tolerated we use furosemide or topiramate. Modification of therapy is based on a combination of the patient’s symptoms, visual field examinations and changes in papilledema.
- Newborg B. Pseudotumor cerebri treated by rice reduction diet. Arch Intern Med 1974; 133:802-807.
- Kupersmith MJ, Gamell L, Turbin R, Peck V, Spiegel P, Wall M. Effects of weight loss on the course of idiopathic intracranial hypertension in women. Neurology 1998; 50(4):1094-1098.
- Johnson LN, Krohel GB, Madsen RW, March GA, Jr. The role of weight loss and acetazolamide in the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Ophthalmology 1998; 105(12):2313-2317.
- Greer M. Benign intracranial hypertension. VI. Obesity. Neurology 1965; 15:382-388.
- Amaral JF, Tsiaris W, Morgan T, Thompson WR. Reversal of benign intracranial hypertension by surgically induced weight loss. Arch Surg 1987; 122:946-949.
- Sugerman HJ, Felton WL, III, Sismanis A, Kellum JM, DeMaria EJ, Sugerman EL. Gastric surgery for pseudotumor cerebri associated with severe obesity. Ann Surg 1999; 229(5):634-640.
- Wall M, George D. Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain 1991; 114:155-180.
- Friedman DI, Streeten DH. Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis. Neurology 1998; 50(4):1099-1104.
- Johnston I, Paterson A. Benign intracranial hypertension. II. CSF pressure and circulation. Brain 1974; 97:301-312.
- Weisberg LA. Benign intracranial hypertension. Medicine 1975; 54:197-207.
- Batnitzky S, Keucher TR, Mealey T, Jr., Campbell RL. Iatrogenic intraspinal epidermoid tumors. JAMA 1977; 237:148-150.
- Manno NJ, Uihlein A, Kernohan JW. Intraspinal epidermoids. J Neurosurg 1962; 19:754-756.
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- Weisberg LA, Chutorian AM. Pseudotumor cerebri of childhood. Am J Dis Child 1977; 131:1243-1248.
- Jefferson A, Clark J. Treatment of benign intracranial hypertension by dehydrating agents with particular reference to the measurement of the blind spot area as a means of recording improvement. J Neurol Neurosurg Psychiatr 1976; 39:627-639.
- Corbett JJ, Jacobson DM, Mauer RC, Thompson HS. Enlargement of the blind spot caused by papilledema. Am J Ophthalmol 1988; 105:261-265.
- McCarthy KD, Reed DJ. The effect of acetazolamide and furosemide on CSF production and choroid plexus carbonic anhydrase activity. J Pharmacol Exp Ther 1974; 189:194-201.
- Lubow M, Kuhr L. Pseudotumor cerebri: comments on practical management. In: Glaser JS, Smith JL, editors. Neuro-ophthalmology, Vol. IX. St. Louis: C.V. Mosby, 1976: 199-206.
- Gucer G, Vierenstein L. Long-term intracranial pressure recording in management of pseudotumor cerebri. J Neurosurg 1978; 49:256-263.
- Tomsak RL, Niffenegger AS, Remler BF. Treatment of pseudotumor cerebri with Diamox (acetazolamide). J Clin Neuro-ophthalmol 1988; 8:93-98.
- Rubin RC, Henderson ES, Ommaya AK, Walker MD, Rall DP. The production of cerebrospinal fluid in man and its modification by acetazolamide. J Neurosurg 1966; 25(4):430-436.
- Zimran A, Beutler E. Can the risk of acetazolamide-induced aplastic anemia be decreased by periodic monitoring of blood cell counts? Am J Ophthalmol 1987; 104(6):654-658.
- Pollay M, Fullenwider C, Roberts PA, Stevens FA. Effect of mannitol and furosemide on blood-brain osmotic gradient and intracranial pressure. J Neurosurg 1983; 59(6):945-950.
- Roberts PA, Pollay M, Engles C, Pendleton B, Reynolds E, Stevens FA. Effect on intracranial pressure of furosemide combined with varying doses and administration rates of mannitol. J Neurosurg 1987; 66:440-446.
- Vogh BP, Langham MR, Jr. The effect of furosemide and bumetanide on cerebrospinal fluid formation. Brain Research 1981; 221(1):171-183.
- Corbett JJ. The 1982 Silversides lecture. Problems in the diagnosis and treatment of pseudotumor cerebri. Can J Neurol Sci 1983; 10:221-229.
- Cottrell JE, Robustelli A, Post K, Turndorf H. Furosemide- and mannitol-induced changes in intracranial pressure and serum osmolality and electrolytes. Anesthesiology 1977; 47(1):28-30.
- Buhrley LE, Reed DJ. The effect of furosemide on sodium-22 uptake into cerebrospinal fluid and brain. Experimental Brain Research 1972; 14(5):503-510.
- Schoeman JF. Childhood pseudotumor cerebri: clinical and intracranial pressure response to acetazolamide and furosemide treatment in a case series. Journal of Child Neurology 1994; 9(2):130-134.
- Schoeman J, Donald P, van Zyl L, Keet M, Wait J. Tuberculous hydrocephalus: comparison of different treatments with regard to ICP, ventricular size and clinical outcome. Developmental Medicine & Child Neurology 1991; 33(5):396-405.
- Guisado R, Tourtellotte WW, Arieff AI, Tomiyasu U, Mishra SK, Schotz MC. Rebound phenomenon complicating cerebral dehydration with glycerol. J Neurosurg 1975; 42:226-228.
- Rottenberg DA, Hurwitz BJ, Posner JB. The effect of oral glycerol on intraventricular pressure in man. Neurology 1977; 27:600-608.