Idiopathic Intracranial
Hypertension: Report of Seven Cases
NEELUJAIN, M.D., BKVIX, New York, FREDROSNER,M.D., Jamaica, New York, andBronx,
We describe seven patients with idiopathic intracranial hypertension (HH), a disorder, mostly in young women, characterized by papilledema, elevated cerebrospinal fluid (CSF) pressure, normal CSF composition, and normal neuroradiologic studies, Obe&y, the most consistent etiologic association was present in two of our patients. Hypothalamic compression in IIH may induce increased appetite and retmlt in weight gab Use of trimethoprim/t3ulfamethoxazole has beenreportedtobeasaociatedwithIIHandwas seen in one of our patients. III3 is an important diagnostic consideration in the differential diagnosis for a patient with headache, visual dieturbances, and papilledema.
New York
I
diopathic intracranial hypertension (IIH), also known as pseudotumor cerebri and benign intracranial hypertension, is a disorder of intracerebral pressure regulation that may result in a loss of vision due to papilledema. In a recent prospective study, more than 90% of patients had some visual loss, excluding blind spot enlargement, in at least one eye as detected by perimetry [l]. In order to prevent permanent visual loss, it is important for the physician to diagnose and treat IIH. We describe seven patients diagnosed with IIH.
PATIENTS AND METHODS The medical records of seven patients with the diagnosis of IIH admitted to Queens Hospital Center between 1986 and 1990 were reviewed. The following information was obtained for each patient: sex, age, race, clinical symptoms, clinical signs, etiologic associations, and history of medical illnesses. Also obtained were cerebrospinal (CSF) opening pressure, CSF chemistry and blood cell count, results of neuroradiologic studies, treatments given, and hospital course/outcome. Patients were selected based on the diagnosis at discharge. The diagnosis of IIH was made based on the absence of mass lesions on computerized tomographic (CT) findings, elevated CSF opening pressure (greater than 250 mm HsO), normal CSF composition, clinical symptoms of headache and visual loss, and the clinical sign of papilledema.
RESULTS
From the Department of Medicine (FR), Queens Hospital Center Affiliation of the Long island Jewish Medical Center, Jamaica, New York: and the Albert Einstein College of Medicine of Yeshiva University (NJ, FR), Bronx, New York. Requests for reprints should be addressed to Fred Rosner, M.D., Queens Hospital Center, 8268 164 Street, Jamaica, New York 11432. Manuscript submitted December 2, 1991, and accepted in revised form March 23, 1992.
All seven patients were women ranging in age from 20 to 51 years. One patient was 51, and all other patients were between the ages of 20 and 37 years (Table I). Five of the seven women were black, one was Guyanese, and one was white. All patients except Patient 7 presented with headache and blurred vision or diplopia. Patient 6 had an episode of transient visual loss, and Patient 5 complained of photopsia. Three patients complained of dizziness, two of tinnitus, and two also had episodes of nausea and vomiting. One patient presented with neck stiffness. One patient had decreased appetite, and another patient had abdominal discomfort and back pain. On physical examination, all seven patients had bilateral papilledema, and five of the seven had paralysis of cranial nerve VI. Three of the nerve palOctober
1992
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Journal
of Medicine
Volume
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TABLE I Clinical Characteristicsof Seven Patients With Idiopathic Intracranial Hypertension Patient No.
Sex
Age
Etiologic
1
F
37
Haitian
Headache, dizziness, blurred vision
Bilateral papilledema, (L) eye hemorrhage, increased blind spot
None
Seizures
2
F
20
AfricanAmerican
Headache, diplopia, pressure behind (L) eye, stiff neck, tinnitus
Papilledema, hyperemic fundi, (L) CN VI palsy
Obesity
None
3
F
25
White
Headache, diplopia
Bilateral papilledema, ?CN VI palsy
Oral contraceptive pills, tetracycline x 7 d
Microcytic/hypochromic anemia
4
F
37
Guyanese
Headache, dizziness, blurred vision especially on lateral gaze, decreased appetite
Papilledema L > R, (L) CN VI palsy, cotton-wool spots, eye hemorrhage
None
Follicular adenoma of the thyroid
5
F
27
AfricanAmerican
Headache, photopsia, blurry vision, nausea, vomiting, abdominal discomfort, back pain
Papilledema, flame-shaped hemorrhage, exudates, cotton-wool spots, decreased visual acuity
None
Renal artery stenosis, acute renal failure, malignant hypertension
6
F
23
AfricanAmerican
Headache, dizziness! blurred vision, transient visual obscurations, tinnitus, nausea, vomlbng
Bilateral papilledema, (L) CN VI palsy
Trimethoprimlsulfamethoxazole use, obesity
Urinary tract infection, 5-mo amenorrhea, recent weight gain, increased sweating, increased skin pigmentation, swelling of feet, increased acne
7
F
51
AfricanAmerican
Light perception only in both eyes
Bilateral papilledema, microhemorrhages, bilateral CN VI palsy
None
Multiple myeloma, hypertension, insulin-dependent diabetes
Race
ClinicalSymptoms
Signs
Other Medical Illnesses
Associations
4 = cranial nerve; L = left; R = right.
aiee were left-sided, one was bilateral, and one was not reported to be unilateral or bilateral. Ophthalmoscopic findings were as follows: one patient each had unilateral eye hemorrhage; hyperemic fundi; eye hemorrhage and cotton wool spots; flameshaped hemorrhage, cotton wool spots, and exudates; and microhemorrhages. One patient had an increased blind spot, and one patient had decreased visual acuity. , Only three of the seven patients had any etiologic associations. Patients 2 and 6 were obese. Patient 3 had microcytic/hypochromic anemia and had received a 7-day course of tetracycline therapy approximately 2 months earlier. She also was taking oral contraceptives until 1 month prior to hospitalization. Patient 6 had started trimethoprim/sulfamethoxazole for a urinary tract infection when she developed neurologic symptoms. All but two patients had a history of other medical illness. These included one patient with seizure disorder and one with thyromegaly (discovered to be follicular adenoma). One patient had renal artery stenosis, malignant hypertension, and acute renal failure. One patient was amenorrheic for 5 months prior to hospitalization with associated weight gain, increased sweating, increased pigmentation, increased acne, and swollen feet. Another 392
October 1992 The American Journal of Medicine
patient had multiple myeloma and also had a history of hypertension and insulin-dependent diabetes. All patients had high CSF opening pressures ranging from 310 to 610 mm HzO) (Table II). CSF chemistries and cell counts were within normal ranges for all patients. Each patient had a head CT scan to rule out any mass lesions, and Patient 1 also underwent magnetic resonance imaging to rule out venous thrombosis. All scans were negative for masses, but Patient 4 had small ventricles, Patient 5 had an empty sella, and Patient 7 had mild cortical atrophy and lytic skull lesions (consistent with multiple myeloma). Therapies included acetazolamide in six of the seven patients, dexamethasone in two, repeated lumbar punctures in two, and furosemide in one. Patient 5 underwent optic nerve sheath decompression after medical treatment failed. Six patients were discharged with clinical improvement, and one was discharged unchanged.
COMMENTS IIH is a condition or syndrome of abnormal CSF pressure regulation, which was initially described by Quincke [2] in 1897. Typically, patients are young obese women of childbearing age. The peak incidence of IIH is at age 30 [3]. IIH occurs with an
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/ JAIN AND ROSNER
TABLE II Laboratory Findings, Treatment, and Outcome in Seven PatientsWith Idiopathic Intracranial Hypertension Patient No. 1
CSF Opening Pressure
(mm HzO) 500
CSF Chemistry and Cell Count*
10 RBC, 1 WBC, 57 glucose,
Head CT Scan Results Normal; MRI-normal
Dexamethasone, acetazolamide, repeated lumbar punctures
Discharged unchanged
Normal
Acetazolamide
Discharged with clinical improvement
36 protein, 123 chloride
2
310
4 RBC, 0 WBC, 57 glucose, 27
Outcome (Hospital Course)
Treatment
protein
3
320
1 WBC, 70 glucose, 24 protein, 130 chloride
Normal
Acetazolamide
Discharged with clinical improvement
4
500
5 RBC, 3 WBC, 63 glucose, 22 protein, 116 chloride
No mass lesions, small ventricles
Acetazolamide, furosemide
Discharged with clinical improvement
5
610
0 RBC, 0 WBC, 101 glucose, 30 protein, 121 chloride
No mass lesions, empty sella
Acetazolamide, repeated lumbar punctures, optic nerve sheath decompression
Discharged with clinical improvement
6
High
0 RBC, 2 WBC, 60 glucose, 21 protein, 125 chloride
Normal
Acetazolamide
Discharged with clinical improvement
7
500
15 RBC, 0 WBC, 87 glucose,
Mild atrophy, lytic skull lesions Glycerol, dexamethasone 17 protein, 132 chloride (from myeloma) rd u,hlN-“i b=,,=, rdlc. wmRt,x- -- ,ru ..uv -- ,r,hi,. .,,,,.r hlnnrl u>- IIdc. bc,,a, PPE uv, -- r.mh,ncnin.l ‘L,CwwV,\,Y, fl,,iA. ,,uw, PT u, -- m”ln,,+.d b’y,,,Fu.cu+nmnn..nhir. wwus,+w~, MD, w,,\, -- m.nndir ,,,u6,,cw ,nmn,nra ,caw,a,,cc im.oinn ,,,,m6,,,6
Discharged with clinical improvement
*Protein, glucose, and chloride units are mg/dL, mg/dL, and mEq/L, respectively; RBCand WBC are per milliliter.
incidenceof approximately 1 of 100,000per year in the generalpopulation. In obesefemalesbetween20 and 44yearsof age,the incidenceis asmuch as19of 100,000[4]. The syndrome of IIH is characterized by increasedCSF pressure(greaterthan 200 mm Hz0 in nonobesepatients and greaterthan 250mm Hz0 in obesepatients [5]), normal CSF chemistry and cell countsbut with CSF protein content being either normal or low (less than 20 mg/dL), and symptoms and signsdue only to increasedintracranial pressure.There is no alteration of consciousness [3]. Symptoms most commonly reported by patients with IIH are daily headaches(94%),transient visual obscurations (seconds-long visual blackouts) (68%),pulsatile intracranial noises/tinnitus (58%),photopsia (54%),and retrobulbar pain (44%)increasedwith eye movement (22%) [6]. In addition, patients complain of diplopia, visual loss, nausea, and vomiting. Headache, the most frequently encounteredsymptom, is usually generalized, episodic,and throbbing and worsenedby the Valsalvamaneuverand headmovement.Lastly, radiologic studiesare generallynormal, with no intracranial mass lesion on CT and no ventricular dilation. CT scans are completely normal in 90% of cases; however, enlarged optic nerve sheaths (46.7%),empty sellae (45.7%),and small slit-like ventriclessuggestiveof brain edema(11.4%)may be seen [7]. On physical examination, patients may show involvement of the oculomotor, trochlear, abducens,
or facial nerves [8]. Abducens nerve palsy is the most common causeof diplopia and is a result of increasedpressureon this nerve [9]. A rare caseof complete external ophthalmoplegia with IIH has been described [8]. Most patients have bilateral papilledema, consideredto be a halhnark of IIH, although rare caseswithout papilledema havebeen reported [lo]. Permanent visual loss is the major complication of IIH and is due to damageto the optic disk asa result of papilledema[ll]. Therefore, patients without papilledema are in no danger of visual loss [lo-121. Pathogenesis
The precisepathogenesisof IIH is unknown but the following are postulated mechanisms [3]: (1) increasedrate of CSF production; (2) decreasein CSF absorption; (3) increase in cerebral venous pressure;and (4) brain parenchymal edema. Currently, the most acceptedhypothesisis that of reduced CSF absorption [3,13]. In addition, there is evidenceof interstitial edema,which may reduce brain compliance,thereby preventing hydrocephalus [3,14]. Etiologic Associations
Various conditions, diseasestates, and medications havebeenreported to be associatedand even causally related to IIH. Steroid withdrawal [15,16] and Addison’s disease[17] are establishedassociations. In addition, other endocrinologicdisorders
October
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such as hyperthyroidism [ 181, hypothyroidism [ 191, and hypoparathyroidism [20] may be associated with IIH. Use of various medications has been linked to IIH. In a recent survey of drug-related headache, the drugs most frequently reported in intracranial hypertension include minocycline, isotretinoin, nalidixic acid, tetracycline, and trimethoprim/sulfamethoxazole [21]. Hypervitaminosis A [22] and excess isotretinoin [23], a synthetic vitamin A derivative, have been reported to cause IIH. Danazol, a drug used in treating disorders such as endometriosis and menorrhagia, has also been implicated [24]. Greer described IIH occurring at menarche [25] and during pregnancy [26], and other authors have found associations with menstrual irregularities and oral contraceptive use [3]. More recent studies suggest that pregnancy itself does not predispose to IIH [27,28], and oral contraceptive use and menstrual abnormalities appear not to be linked with IIH [6,28]. Many of the purported associations may, in reality, be chance associations. The most commonly reported association with IIH is obesity and significant weight gain prior to diagnosis [6,28,29], perhaps related to extraovarian estrone production (in adipocytes), which is thought to stimulate CSF formation [30]. This increase in estrone may account for the association of IIH with menstrual irregularities, its occurrence at menarche, and its association with oral contraceptive use. In addition, certain medical illnesses such as bronchitis, sinusitis, gastroenteritis, and urinary tract infections have been associated with IIH but may be chance occurrences [31]. Iron deficiency anemia is also known to be associated with IIH [32]. Patients have been described who became hyperphagic and gained weight due to intermittent increases in CSF pressure [33]. Their hyperphagia was eliminated by decreasing CSF pressure [29]. Mabel and associates [33] demonstrated that increases in CSF pressure in rats result in hyperphagia due to compression of the ventromedial (VM) nuclei of the hypothalamus. Similarly, in humans, bilateral lesions in the VM portion of the hypothalamus can cause hyperphagia and resultant obesity [34]. Polyphagia and weight gain following hypothalamic sarcoidosis were recently reported [35]. Other eating disorders such as bulimia may be associated with increased intracranial pressure [36] and more specifically with IIH [37]. Since patients with IIH are typically obese, one can postulate that the elevated intracerebral pressure compresses the hypothalamus, resulting in obesity. Hyperphagia may actually be an early manifestation of elevated CSF 394
October 1992 The American Journal of Medicine
pressure [37]. Furthermore, in certain patients, endocrinologic abnormalities may be a consequence of pituitary compression from elevated intracranial pressure [7]. Medical Management When IIH is diagnosed, associated diseases should be sought and treated. Patients should be followed monthly for 6 to 12 months to check for visual field loss, visual acuity, and intraocular pressure [12]. Perimetry should be used to follow the course of therapy since visual evoked potential is not a sensitive measure of peripheral visual loss [14]. Patients who are obese should be urged to lose weight since weight reduction can eliminate signs and symptoms of IIH [38]. Other medical treatments include acetazolamide, which decreases CSF formation [12]. Corticosteroids, alone or with other drugs, are sometimes used, but side effects and recurrence after tapering may limit their usefulness [14]. Furosemide, chlorthalidone, glycerol, and digoxin have all been used, but no one drug appears to be clearly superior to another [12,14], and no randomized controlled study assessing different medical treatments has been done. Repeated lumbar punctures with removal of 30 mL of fluid or 50% reduction of initial CSF opening pressure has been recommended [39]. CSF is produced at 0.35 mL/min and is thus quickly replenished after removal; however, some patients obtain symptomatic relief after a single lumbar tap, perhaps due to a persistent leak of CSF [3]. Surgical Treatment The decision to intervene surgically depends mainly on the status of the patient’s visual field and acuity. Intractable severe headache may also necessitate surgery [ 121. Subtemporal decompression is no longer used due to complications such as seizures and strokes [14]. Lumboperitoneal shunting is still used, but high failure rates and low-pressure headache limit its effectiveness [40]. Optic nerve sheath decompression involves excision of a tiny portion of dura and arachnoid from the optic nerve [41]. This technique is becoming more widely used to prevent visual loss in patients with IIH. How optic nerve sheath fenestration improves the signs and symptoms of IIH is not entirely clear. Perhaps the procedure acts as a filtering mechanism. Unilateral decompression may lead to resolution of papilledema bilaterally, and, unless bilateral decompression is indicated, a unilateral procedure is recommended [42]. Gastric exclusion surgery may play a role in treating morbidly obese patients in whom all medical treatments have failed [43].
Volume 93
IDIOPATHIC
CONCLUSION IIH is a syndrome of unclear pathogenesis with various possible etiologies. It has a predilection for obese women of childbearing age but has also been reported in the pediatric population [44]. Although severe permanent visual loss occurs in 11% to 24% of patients [11,45], IIH has a good prognosis. Recurrence rates vary from 10% to 37% [45,46], and chronic IIH occurs in up to 25% of patients [47]. Patients with IIH should be followed concurrently by an ophthalmologist and a neurologist. In addition, the patient should be urged to comply with follow-up visits and cautioned about the danger of permanent visual damage.
to Siamak Bakhshian
HYPERTENSION
/ JAIN AND ROSNER
19. Press OW. Ladenson PW. Pseudotumor cerebri and hypothyroidism. Arch Intern Med 1983; 143: 167-8. 29. Sheldon RS, Becker WJ, Hanley DA, Culver RL. Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association. Can J Neurol Sci 1987;
14: 622-5. 21.Askmark
H, Lundberg
PO, Olsson S. Drug related
headache.
Headache
1989; 29: 441-4. 22. Lombaert A, Carton H. Benign intracranial hypertension due to A-hypervitaminosis in adults and adolescents. Eur Neurol 1976; 14: 340-50. 23. Spector RH. Carlisle J. Pseudotumor cerebri caused by a syntheticvitamin A preparation. Neurology 1984; 34: 1509-l 1. 24. Shah A, Roberts T. McQueen INF. Graham JG. Danazol and benign intracranial hypertension [short report]. BMJ 1987; 294: 1325. 25. Greer M. Benign intracranial hypertension. IV: Menarche. Neurology 1964;
14: 569-73. 26. Greer M. Benign intracranial
hypertension.
Ill: Pregnancy.
Neurology
1963;
13: 670-2. 27. Kassam SH, Hadi HA, Fade1 HE, et al. Benign intracranial hypertension in pregnancy: current diagnosis and therapeutic approach. Obstet Gynecol Surg
ACKNOWLEDGMENT We are indebted
INTRACRANIAL
1983; 38: 314-21. for technical
28. Ireland B, Corbett cerebri: a preliminary
assistance.
REFERENCES 1. Wall M, George D. Idiopathic intracranial hypertension: a prospective study of 50 patients. Brain 1991; 114: 155-80. 2 Quincke H. Uber meningitis serosa and verwandte zustande. Dtsch 2 Nervenheilkd 1897; 9: 149-68. 3.Ahlskog JE. O’Neill BP. Pseudotumor cerebri. Ann Intern Med 1982; 97: 249-56. 4. Durcan FJ. Corbett JJ, Wall M. The incidence of pseudotumor cerebri. Population studies in Iowa and Louisiana. Arch Neurol 1988; 45: 875-7. 5. Corbett JJ, Mehta MP. Cerebrospinal fluid pressure in normal obese subjects and patients with pseudotumor cerebri. Neurology 1983; 33: 1386-8. 6. Giuseffi V, Wall M, Siegel PZ. Rojas PB. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case control study. Neurology 1991; 41: 239-44. 7. Wessel K, Thron A, Linden D, Petersen D. Dichgans J. Pseudotumor cerebri: clinical and neuroradiological findings. Eur Arch Psychiatry Neurol Sci 1987; 237: 54-60. 8. Landan I, Policherla H, McLaurin J. Complete external ophthalmoplegia in a case of pseudotumor cerebri. Headache 1982; 27: 573-4. 9. Corbett JJ. Problems in the diagnosis and treatment of pseudotumor cerebri. Can J Neurol Sci 1983: 10: 221-9. 10. Marcelis J, Silberstein SD. Idiopathic intracranial hypertension without papilledema. Arch Neurol 1991; 48: 392-9. 11. Corbett JJ, Savino PJ, Thompson S, et al. Visual loss in pseudotumor cerebri. Follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol 1982; 39: 461-74. 12 Corbett JJ. Thompson S. The rational management of idiopathic intracranial hypertension. Arch Neurol 1989; 46: 1049-51. 13. Fishman RA. The pathophysiology of pseudotumor cerebri. An unsolved puzzle. Arch Neurol 1984; 41: 257-8. 14. Wall M. Idiopathic intracranial hypertension. Neurol Clin 1991; 9: 73-94. 15. Greer M. Benign intracranial hypertension. II: Following corticosteroid therapy. Neurology 1963; 13: 439-41. 16. Neville BG, Wilson J. Benign intracranial hypertension following corticosteroid withdrawal in childhood. BMJ 1970: 3: 554-6. 17. Walsh FB. Papilledema associated with increased intracranial pressure in Addison’s disease. Arch Ophthalmol 1952; 47: 86. 18. Dickman MS. Somasundaram M, Brzozowski L. Pseudotumor cerebri and hyperthyroidism. N Y State J Med 1980; 80: 1118-20.
JJ, Wallace RB. The search for causes of pseudotumor case-control study. Arch Neurol 1990; 47: 315-20.
29. Greer M. Benign intracranial 382-8. 39. Donaldson JO. Pathogenesis
hypertension.
VI: Obesity.
of pseudotumor
Neurology
cerebri syndromes.
1965; 15: Neurology
1981; 31: 877-80. 31. Lehman LB. Pseudotumor
cerebri:
an enigmatic process.
Hosp Pratt
1988;
127-30. 32. Stoebner R, Kiser R, Alperin JB. Iron deficiency J Dig Dis 1970; 15: 919-22.
anemia and papilledema.
Am
33. Mabel JA, Baile CA, Mayer J. Hyperphagia induced by ventricular pressure and pentobarbitone in normal and hypothalamic obese rats. Lancet 1966; 2: 472-3. 34. Celesia GG, Archer CR, Chung HD. Hyperphagia and obesity. Relationship to medial hypothalamic lesions. JAMA 1981; 246: 151-3. 35. Vesely DL. Hypothalamic sarcoidosis: a new cause of morbid obesity. South Med J 1988; 82: 758-61. 36. Krahn DD, Mitchell JE. Case report of bulimia associated with increased intracranial pressure. Am J Psychiatry 1984; 141: 1099-100. 37. Pelosi Al, David A. Bulimia associated with increased intracranial pressure [letter]. Am J Psychiatry 1985; 142: 1128. 38. Newborg B. Pseudotumor cerebri treated by rice/reduction diet. Arch Intern Med 1974; 133: 802-7. 39. Susman JL. Benign intracranial hypertension, J Fam Pratt 1990; 30: 290-2. 49. Rosenberg M, Smith C, Beck R, eta/. The efficacy of shunting procedures in pseudotumor cerebri [abstract]. Neurology 1989; 39 Suppl: 209. 41. Tse DT, Nerad JA. Anderson RL, Corbett JJ. Optic nerve sheath fenestration in pseudotumor cerebri: a lateral oribitotomy approach. Arch Ophthalmol1988,
106: 1458-62. 42. Keltner JL. Optic nerve sheath decompression. How does it work? Has its time come? [editorial]. Arch Ophthalmol 1988; 106: 1365-9. 43. Amaral JF, Tsiaris W, Morgan T, Thompson WR. Reversal of benign intracranial hypertension by surgically induced weight loss. Arch Surg 1987; 122: 946-9. 44. Baker RS. Baumann RJ, Buncic JR. Idiopathic intracranial hypertension (pseudotumor cerebri) in pediatric patients. Pediatr Neurol 1989; 5: 5-l 1. 45. Rush JA. Pseudotumor cerebri: clinical profile and visual outcome in 63 patients. Mayo Clin Proc 1980; 55: 541-6. 46. Weisberg IA. Benign intracranial hypertension. Medicine (Baltimore) 1975; 54: 197-207. 47. Sorensen PS, Krogsaa B, Gjerris F. Clinical course and prognosis of pseudotumor cerebri. A prospective study of 24 patients. Acta Neurol Stand 1988; 77:
October
164-72.
1992
The American
Journal
of Medlclne
Volume
93
395
Hypertension: Report of Seven Cases
NEELUJAIN, M.D., BKVIX, New York, FREDROSNER,M.D., Jamaica, New York, andBronx,
We describe seven patients with idiopathic intracranial hypertension (HH), a disorder, mostly in young women, characterized by papilledema, elevated cerebrospinal fluid (CSF) pressure, normal CSF composition, and normal neuroradiologic studies, Obe&y, the most consistent etiologic association was present in two of our patients. Hypothalamic compression in IIH may induce increased appetite and retmlt in weight gab Use of trimethoprim/t3ulfamethoxazole has beenreportedtobeasaociatedwithIIHandwas seen in one of our patients. III3 is an important diagnostic consideration in the differential diagnosis for a patient with headache, visual dieturbances, and papilledema.
New York
I
diopathic intracranial hypertension (IIH), also known as pseudotumor cerebri and benign intracranial hypertension, is a disorder of intracerebral pressure regulation that may result in a loss of vision due to papilledema. In a recent prospective study, more than 90% of patients had some visual loss, excluding blind spot enlargement, in at least one eye as detected by perimetry [l]. In order to prevent permanent visual loss, it is important for the physician to diagnose and treat IIH. We describe seven patients diagnosed with IIH.
PATIENTS AND METHODS The medical records of seven patients with the diagnosis of IIH admitted to Queens Hospital Center between 1986 and 1990 were reviewed. The following information was obtained for each patient: sex, age, race, clinical symptoms, clinical signs, etiologic associations, and history of medical illnesses. Also obtained were cerebrospinal (CSF) opening pressure, CSF chemistry and blood cell count, results of neuroradiologic studies, treatments given, and hospital course/outcome. Patients were selected based on the diagnosis at discharge. The diagnosis of IIH was made based on the absence of mass lesions on computerized tomographic (CT) findings, elevated CSF opening pressure (greater than 250 mm HsO), normal CSF composition, clinical symptoms of headache and visual loss, and the clinical sign of papilledema.
RESULTS
From the Department of Medicine (FR), Queens Hospital Center Affiliation of the Long island Jewish Medical Center, Jamaica, New York: and the Albert Einstein College of Medicine of Yeshiva University (NJ, FR), Bronx, New York. Requests for reprints should be addressed to Fred Rosner, M.D., Queens Hospital Center, 8268 164 Street, Jamaica, New York 11432. Manuscript submitted December 2, 1991, and accepted in revised form March 23, 1992.
All seven patients were women ranging in age from 20 to 51 years. One patient was 51, and all other patients were between the ages of 20 and 37 years (Table I). Five of the seven women were black, one was Guyanese, and one was white. All patients except Patient 7 presented with headache and blurred vision or diplopia. Patient 6 had an episode of transient visual loss, and Patient 5 complained of photopsia. Three patients complained of dizziness, two of tinnitus, and two also had episodes of nausea and vomiting. One patient presented with neck stiffness. One patient had decreased appetite, and another patient had abdominal discomfort and back pain. On physical examination, all seven patients had bilateral papilledema, and five of the seven had paralysis of cranial nerve VI. Three of the nerve palOctober
1992
The American
Journal
of Medicine
Volume
93
391
TABLE I Clinical Characteristicsof Seven Patients With Idiopathic Intracranial Hypertension Patient No.
Sex
Age
Etiologic
1
F
37
Haitian
Headache, dizziness, blurred vision
Bilateral papilledema, (L) eye hemorrhage, increased blind spot
None
Seizures
2
F
20
AfricanAmerican
Headache, diplopia, pressure behind (L) eye, stiff neck, tinnitus
Papilledema, hyperemic fundi, (L) CN VI palsy
Obesity
None
3
F
25
White
Headache, diplopia
Bilateral papilledema, ?CN VI palsy
Oral contraceptive pills, tetracycline x 7 d
Microcytic/hypochromic anemia
4
F
37
Guyanese
Headache, dizziness, blurred vision especially on lateral gaze, decreased appetite
Papilledema L > R, (L) CN VI palsy, cotton-wool spots, eye hemorrhage
None
Follicular adenoma of the thyroid
5
F
27
AfricanAmerican
Headache, photopsia, blurry vision, nausea, vomiting, abdominal discomfort, back pain
Papilledema, flame-shaped hemorrhage, exudates, cotton-wool spots, decreased visual acuity
None
Renal artery stenosis, acute renal failure, malignant hypertension
6
F
23
AfricanAmerican
Headache, dizziness! blurred vision, transient visual obscurations, tinnitus, nausea, vomlbng
Bilateral papilledema, (L) CN VI palsy
Trimethoprimlsulfamethoxazole use, obesity
Urinary tract infection, 5-mo amenorrhea, recent weight gain, increased sweating, increased skin pigmentation, swelling of feet, increased acne
7
F
51
AfricanAmerican
Light perception only in both eyes
Bilateral papilledema, microhemorrhages, bilateral CN VI palsy
None
Multiple myeloma, hypertension, insulin-dependent diabetes
Race
ClinicalSymptoms
Signs
Other Medical Illnesses
Associations
4 = cranial nerve; L = left; R = right.
aiee were left-sided, one was bilateral, and one was not reported to be unilateral or bilateral. Ophthalmoscopic findings were as follows: one patient each had unilateral eye hemorrhage; hyperemic fundi; eye hemorrhage and cotton wool spots; flameshaped hemorrhage, cotton wool spots, and exudates; and microhemorrhages. One patient had an increased blind spot, and one patient had decreased visual acuity. , Only three of the seven patients had any etiologic associations. Patients 2 and 6 were obese. Patient 3 had microcytic/hypochromic anemia and had received a 7-day course of tetracycline therapy approximately 2 months earlier. She also was taking oral contraceptives until 1 month prior to hospitalization. Patient 6 had started trimethoprim/sulfamethoxazole for a urinary tract infection when she developed neurologic symptoms. All but two patients had a history of other medical illness. These included one patient with seizure disorder and one with thyromegaly (discovered to be follicular adenoma). One patient had renal artery stenosis, malignant hypertension, and acute renal failure. One patient was amenorrheic for 5 months prior to hospitalization with associated weight gain, increased sweating, increased pigmentation, increased acne, and swollen feet. Another 392
October 1992 The American Journal of Medicine
patient had multiple myeloma and also had a history of hypertension and insulin-dependent diabetes. All patients had high CSF opening pressures ranging from 310 to 610 mm HzO) (Table II). CSF chemistries and cell counts were within normal ranges for all patients. Each patient had a head CT scan to rule out any mass lesions, and Patient 1 also underwent magnetic resonance imaging to rule out venous thrombosis. All scans were negative for masses, but Patient 4 had small ventricles, Patient 5 had an empty sella, and Patient 7 had mild cortical atrophy and lytic skull lesions (consistent with multiple myeloma). Therapies included acetazolamide in six of the seven patients, dexamethasone in two, repeated lumbar punctures in two, and furosemide in one. Patient 5 underwent optic nerve sheath decompression after medical treatment failed. Six patients were discharged with clinical improvement, and one was discharged unchanged.
COMMENTS IIH is a condition or syndrome of abnormal CSF pressure regulation, which was initially described by Quincke [2] in 1897. Typically, patients are young obese women of childbearing age. The peak incidence of IIH is at age 30 [3]. IIH occurs with an
Volume 93
IDIOPATHIC
INTRACRANIAL
HYPERTENSION
/ JAIN AND ROSNER
TABLE II Laboratory Findings, Treatment, and Outcome in Seven PatientsWith Idiopathic Intracranial Hypertension Patient No. 1
CSF Opening Pressure
(mm HzO) 500
CSF Chemistry and Cell Count*
10 RBC, 1 WBC, 57 glucose,
Head CT Scan Results Normal; MRI-normal
Dexamethasone, acetazolamide, repeated lumbar punctures
Discharged unchanged
Normal
Acetazolamide
Discharged with clinical improvement
36 protein, 123 chloride
2
310
4 RBC, 0 WBC, 57 glucose, 27
Outcome (Hospital Course)
Treatment
protein
3
320
1 WBC, 70 glucose, 24 protein, 130 chloride
Normal
Acetazolamide
Discharged with clinical improvement
4
500
5 RBC, 3 WBC, 63 glucose, 22 protein, 116 chloride
No mass lesions, small ventricles
Acetazolamide, furosemide
Discharged with clinical improvement
5
610
0 RBC, 0 WBC, 101 glucose, 30 protein, 121 chloride
No mass lesions, empty sella
Acetazolamide, repeated lumbar punctures, optic nerve sheath decompression
Discharged with clinical improvement
6
High
0 RBC, 2 WBC, 60 glucose, 21 protein, 125 chloride
Normal
Acetazolamide
Discharged with clinical improvement
7
500
15 RBC, 0 WBC, 87 glucose,
Mild atrophy, lytic skull lesions Glycerol, dexamethasone 17 protein, 132 chloride (from myeloma) rd u,hlN-“i b=,,=, rdlc. wmRt,x- -- ,ru ..uv -- ,r,hi,. .,,,,.r hlnnrl u>- IIdc. bc,,a, PPE uv, -- r.mh,ncnin.l ‘L,CwwV,\,Y, fl,,iA. ,,uw, PT u, -- m”ln,,+.d b’y,,,Fu.cu+nmnn..nhir. wwus,+w~, MD, w,,\, -- m.nndir ,,,u6,,cw ,nmn,nra ,caw,a,,cc im.oinn ,,,,m6,,,6
Discharged with clinical improvement
*Protein, glucose, and chloride units are mg/dL, mg/dL, and mEq/L, respectively; RBCand WBC are per milliliter.
incidenceof approximately 1 of 100,000per year in the generalpopulation. In obesefemalesbetween20 and 44yearsof age,the incidenceis asmuch as19of 100,000[4]. The syndrome of IIH is characterized by increasedCSF pressure(greaterthan 200 mm Hz0 in nonobesepatients and greaterthan 250mm Hz0 in obesepatients [5]), normal CSF chemistry and cell countsbut with CSF protein content being either normal or low (less than 20 mg/dL), and symptoms and signsdue only to increasedintracranial pressure.There is no alteration of consciousness [3]. Symptoms most commonly reported by patients with IIH are daily headaches(94%),transient visual obscurations (seconds-long visual blackouts) (68%),pulsatile intracranial noises/tinnitus (58%),photopsia (54%),and retrobulbar pain (44%)increasedwith eye movement (22%) [6]. In addition, patients complain of diplopia, visual loss, nausea, and vomiting. Headache, the most frequently encounteredsymptom, is usually generalized, episodic,and throbbing and worsenedby the Valsalvamaneuverand headmovement.Lastly, radiologic studiesare generallynormal, with no intracranial mass lesion on CT and no ventricular dilation. CT scans are completely normal in 90% of cases; however, enlarged optic nerve sheaths (46.7%),empty sellae (45.7%),and small slit-like ventriclessuggestiveof brain edema(11.4%)may be seen [7]. On physical examination, patients may show involvement of the oculomotor, trochlear, abducens,
or facial nerves [8]. Abducens nerve palsy is the most common causeof diplopia and is a result of increasedpressureon this nerve [9]. A rare caseof complete external ophthalmoplegia with IIH has been described [8]. Most patients have bilateral papilledema, consideredto be a halhnark of IIH, although rare caseswithout papilledema havebeen reported [lo]. Permanent visual loss is the major complication of IIH and is due to damageto the optic disk asa result of papilledema[ll]. Therefore, patients without papilledema are in no danger of visual loss [lo-121. Pathogenesis
The precisepathogenesisof IIH is unknown but the following are postulated mechanisms [3]: (1) increasedrate of CSF production; (2) decreasein CSF absorption; (3) increase in cerebral venous pressure;and (4) brain parenchymal edema. Currently, the most acceptedhypothesisis that of reduced CSF absorption [3,13]. In addition, there is evidenceof interstitial edema,which may reduce brain compliance,thereby preventing hydrocephalus [3,14]. Etiologic Associations
Various conditions, diseasestates, and medications havebeenreported to be associatedand even causally related to IIH. Steroid withdrawal [15,16] and Addison’s disease[17] are establishedassociations. In addition, other endocrinologicdisorders
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such as hyperthyroidism [ 181, hypothyroidism [ 191, and hypoparathyroidism [20] may be associated with IIH. Use of various medications has been linked to IIH. In a recent survey of drug-related headache, the drugs most frequently reported in intracranial hypertension include minocycline, isotretinoin, nalidixic acid, tetracycline, and trimethoprim/sulfamethoxazole [21]. Hypervitaminosis A [22] and excess isotretinoin [23], a synthetic vitamin A derivative, have been reported to cause IIH. Danazol, a drug used in treating disorders such as endometriosis and menorrhagia, has also been implicated [24]. Greer described IIH occurring at menarche [25] and during pregnancy [26], and other authors have found associations with menstrual irregularities and oral contraceptive use [3]. More recent studies suggest that pregnancy itself does not predispose to IIH [27,28], and oral contraceptive use and menstrual abnormalities appear not to be linked with IIH [6,28]. Many of the purported associations may, in reality, be chance associations. The most commonly reported association with IIH is obesity and significant weight gain prior to diagnosis [6,28,29], perhaps related to extraovarian estrone production (in adipocytes), which is thought to stimulate CSF formation [30]. This increase in estrone may account for the association of IIH with menstrual irregularities, its occurrence at menarche, and its association with oral contraceptive use. In addition, certain medical illnesses such as bronchitis, sinusitis, gastroenteritis, and urinary tract infections have been associated with IIH but may be chance occurrences [31]. Iron deficiency anemia is also known to be associated with IIH [32]. Patients have been described who became hyperphagic and gained weight due to intermittent increases in CSF pressure [33]. Their hyperphagia was eliminated by decreasing CSF pressure [29]. Mabel and associates [33] demonstrated that increases in CSF pressure in rats result in hyperphagia due to compression of the ventromedial (VM) nuclei of the hypothalamus. Similarly, in humans, bilateral lesions in the VM portion of the hypothalamus can cause hyperphagia and resultant obesity [34]. Polyphagia and weight gain following hypothalamic sarcoidosis were recently reported [35]. Other eating disorders such as bulimia may be associated with increased intracranial pressure [36] and more specifically with IIH [37]. Since patients with IIH are typically obese, one can postulate that the elevated intracerebral pressure compresses the hypothalamus, resulting in obesity. Hyperphagia may actually be an early manifestation of elevated CSF 394
October 1992 The American Journal of Medicine
pressure [37]. Furthermore, in certain patients, endocrinologic abnormalities may be a consequence of pituitary compression from elevated intracranial pressure [7]. Medical Management When IIH is diagnosed, associated diseases should be sought and treated. Patients should be followed monthly for 6 to 12 months to check for visual field loss, visual acuity, and intraocular pressure [12]. Perimetry should be used to follow the course of therapy since visual evoked potential is not a sensitive measure of peripheral visual loss [14]. Patients who are obese should be urged to lose weight since weight reduction can eliminate signs and symptoms of IIH [38]. Other medical treatments include acetazolamide, which decreases CSF formation [12]. Corticosteroids, alone or with other drugs, are sometimes used, but side effects and recurrence after tapering may limit their usefulness [14]. Furosemide, chlorthalidone, glycerol, and digoxin have all been used, but no one drug appears to be clearly superior to another [12,14], and no randomized controlled study assessing different medical treatments has been done. Repeated lumbar punctures with removal of 30 mL of fluid or 50% reduction of initial CSF opening pressure has been recommended [39]. CSF is produced at 0.35 mL/min and is thus quickly replenished after removal; however, some patients obtain symptomatic relief after a single lumbar tap, perhaps due to a persistent leak of CSF [3]. Surgical Treatment The decision to intervene surgically depends mainly on the status of the patient’s visual field and acuity. Intractable severe headache may also necessitate surgery [ 121. Subtemporal decompression is no longer used due to complications such as seizures and strokes [14]. Lumboperitoneal shunting is still used, but high failure rates and low-pressure headache limit its effectiveness [40]. Optic nerve sheath decompression involves excision of a tiny portion of dura and arachnoid from the optic nerve [41]. This technique is becoming more widely used to prevent visual loss in patients with IIH. How optic nerve sheath fenestration improves the signs and symptoms of IIH is not entirely clear. Perhaps the procedure acts as a filtering mechanism. Unilateral decompression may lead to resolution of papilledema bilaterally, and, unless bilateral decompression is indicated, a unilateral procedure is recommended [42]. Gastric exclusion surgery may play a role in treating morbidly obese patients in whom all medical treatments have failed [43].
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IDIOPATHIC
CONCLUSION IIH is a syndrome of unclear pathogenesis with various possible etiologies. It has a predilection for obese women of childbearing age but has also been reported in the pediatric population [44]. Although severe permanent visual loss occurs in 11% to 24% of patients [11,45], IIH has a good prognosis. Recurrence rates vary from 10% to 37% [45,46], and chronic IIH occurs in up to 25% of patients [47]. Patients with IIH should be followed concurrently by an ophthalmologist and a neurologist. In addition, the patient should be urged to comply with follow-up visits and cautioned about the danger of permanent visual damage.
to Siamak Bakhshian
HYPERTENSION
/ JAIN AND ROSNER
19. Press OW. Ladenson PW. Pseudotumor cerebri and hypothyroidism. Arch Intern Med 1983; 143: 167-8. 29. Sheldon RS, Becker WJ, Hanley DA, Culver RL. Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association. Can J Neurol Sci 1987;
14: 622-5. 21.Askmark
H, Lundberg
PO, Olsson S. Drug related
headache.
Headache
1989; 29: 441-4. 22. Lombaert A, Carton H. Benign intracranial hypertension due to A-hypervitaminosis in adults and adolescents. Eur Neurol 1976; 14: 340-50. 23. Spector RH. Carlisle J. Pseudotumor cerebri caused by a syntheticvitamin A preparation. Neurology 1984; 34: 1509-l 1. 24. Shah A, Roberts T. McQueen INF. Graham JG. Danazol and benign intracranial hypertension [short report]. BMJ 1987; 294: 1325. 25. Greer M. Benign intracranial hypertension. IV: Menarche. Neurology 1964;
14: 569-73. 26. Greer M. Benign intracranial
hypertension.
Ill: Pregnancy.
Neurology
1963;
13: 670-2. 27. Kassam SH, Hadi HA, Fade1 HE, et al. Benign intracranial hypertension in pregnancy: current diagnosis and therapeutic approach. Obstet Gynecol Surg
ACKNOWLEDGMENT We are indebted
INTRACRANIAL
1983; 38: 314-21. for technical
28. Ireland B, Corbett cerebri: a preliminary
assistance.
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33. Mabel JA, Baile CA, Mayer J. Hyperphagia induced by ventricular pressure and pentobarbitone in normal and hypothalamic obese rats. Lancet 1966; 2: 472-3. 34. Celesia GG, Archer CR, Chung HD. Hyperphagia and obesity. Relationship to medial hypothalamic lesions. JAMA 1981; 246: 151-3. 35. Vesely DL. Hypothalamic sarcoidosis: a new cause of morbid obesity. South Med J 1988; 82: 758-61. 36. Krahn DD, Mitchell JE. Case report of bulimia associated with increased intracranial pressure. Am J Psychiatry 1984; 141: 1099-100. 37. Pelosi Al, David A. Bulimia associated with increased intracranial pressure [letter]. Am J Psychiatry 1985; 142: 1128. 38. Newborg B. Pseudotumor cerebri treated by rice/reduction diet. Arch Intern Med 1974; 133: 802-7. 39. Susman JL. Benign intracranial hypertension, J Fam Pratt 1990; 30: 290-2. 49. Rosenberg M, Smith C, Beck R, eta/. The efficacy of shunting procedures in pseudotumor cerebri [abstract]. Neurology 1989; 39 Suppl: 209. 41. Tse DT, Nerad JA. Anderson RL, Corbett JJ. Optic nerve sheath fenestration in pseudotumor cerebri: a lateral oribitotomy approach. Arch Ophthalmol1988,
106: 1458-62. 42. Keltner JL. Optic nerve sheath decompression. How does it work? Has its time come? [editorial]. Arch Ophthalmol 1988; 106: 1365-9. 43. Amaral JF, Tsiaris W, Morgan T, Thompson WR. Reversal of benign intracranial hypertension by surgically induced weight loss. Arch Surg 1987; 122: 946-9. 44. Baker RS. Baumann RJ, Buncic JR. Idiopathic intracranial hypertension (pseudotumor cerebri) in pediatric patients. Pediatr Neurol 1989; 5: 5-l 1. 45. Rush JA. Pseudotumor cerebri: clinical profile and visual outcome in 63 patients. Mayo Clin Proc 1980; 55: 541-6. 46. Weisberg IA. Benign intracranial hypertension. Medicine (Baltimore) 1975; 54: 197-207. 47. Sorensen PS, Krogsaa B, Gjerris F. Clinical course and prognosis of pseudotumor cerebri. A prospective study of 24 patients. Acta Neurol Stand 1988; 77:
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