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Pseudotumor Cerebri Associated With Corticosteroid Withdrawal in Inflammatory Bowel Disease
Pseudotumor Cerebri Associated With Corticosteroid Withdrawal in Inflammatory Bowel Disease Grant T. Liu, M.D., M a t t h e w D . Kay, M.D., D o n C. Bienfang, M.D., and N o r m a n J. Schatz, M . D . We treated two patients with Crohn's dis ease and one patient with ulcerative colitis who developed headache, papilledema, and intracranial hypertension (pseudotumor cere bri) during corticosteroid withdrawal. One had four separate episodes with corticosteroid withdrawal, which suggested a causal rela tionship. This association between pseudo tumor cerebri and corticosteroid withdrawal has been documented in children, but is rare in adults with inflammatory bowel disease. PSEUDOTUMOR CEREBRI (idiopathic intracranial hypertension) has been related to several drugs including amiodarone, nalidixic acid, and vita min A.1 Its association with reduction in dosage of chronic corticosteroids, typically in children with respiratory, renal, or dermatologie disor ders, has been described but rarely well docu mented. 2 Often these patients fail to satisfy the modified Dandy criteria for the diagnosis of pseudotumor cerebri (signs and symptoms re lated to increased intracranial pressure; normal results of neurologic examination except for abducens paresis; modern neuroimaging; and cerebrospinal fluid with increased intracranial pressure but normal constituents). 1 We treated three patients (two adults and one adolescent) with inflammatory bowel disease who devel oped classic pseudotumor cerebri during corti costeroid withdrawal.
Accepted for publication Nov. 29, 1993. From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida (Drs. Liu, Kay, and Schatz), and the Division of Ophthalmology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr. Bienfang). Reprint requests to Grant T. Liu, M.D., Neuro-ophthalmology Unit, Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce St., Phila delphia, PA 19104.
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Case Reports Case 1 was evaluated at the Children's Hospi tal and Brigham and Women's Hospital in Bos ton, and Cases 2 and 3 were evaluated at the Bascom Palmer Eye Institute in Miami. Case 1
A 16-year-old boy was examined for his fourth episode of headache and vomiting asso ciated with a corticosteroid taper. In 1980, at age 6 years, a fever of 104 F and painful knee swelling suggested a presumptive diagnosis of juvenile rheumatoid arthritis. Six months later he developed anorexia, weight loss, a lowgrade fever, and guaiac-positive diarrhea. Radi ologie studies and colonoscopy, including a biopsy, confirmed the diagnosis of Crohn's dis ease. Treatment with oral prednisone, 40 mg daily, resolved the arthritis and gastrointestinal symptoms. However, each taper resulted in recurrent abdominal pain, lethargy, and diar rhea, and he remained corticosteroid-dependent. In April 1987, at age 13 years, the patient had an ileocolectomy. In December 1987, during a prednisone taper from 20 mg every other day to 17.5 mg every other day, he developed head aches and photophobia. Cerebrospinal fluid opening pressure was 500 mm H 2 0 . He was treated with an increase in corticosteroid dose, acetazolamide, and multiple lumbar punctures, and the symptoms resolved. Identical episodes occurred in 1988 during another taper from 20 to 17.5 mg every other day and then again in 1989 during a taper from 17.5 to 15 mg every other day. The Crohn's disease was stable dur ing these episodes. In November 1990, after a taper from 20 to 10 mg every other day over two months, the pa tient developed difficulty in focusing, blurry vision while sitting, anorexia, headache, and nausea and vomiting. He was thin and short,
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and an examination by one of us (G.T.L.) docu mented normal visual acuity measurements, bilateral papilledema, and normal results of neurologic testing. Results of computed tomog raphy of the head were normal. Cerebrospinal fluid opening pressure was 540 mm H 2 0 . Labo ratory studies showed a white blood cell count of 1 cell/mm 3 , a red blood cell count of 0 cell/mm 3 , a protein level of 17.2 m g / d l , and a glucose level of 58 m g / d l . Acetazolamide was administered. His headache and vomiting worsened, however, and a repeat lumbar punc ture showed an opening pressure of 540 mm H 2 0. Kinetic perimetry showed marginally en larged blind spots bilaterally. The dosage of prednisone was increased to 25 mg every other day and acetazolamide to 500 mg three times a day. Continued headaches responded to the addition of furosemide (10 mg), followed by 5 mg daily for five days without a change in the dosage of acetazolamide. Thereafter the patient remained asymptomat ic with best-corrected visual acuity of 20/20 and normal results of kinetic perimetry testing bilaterally. On Jan. 18, 1991, the disk swelling had resolved, and spontaneous venous pulsa tions were noted. Azathioprine was adminis tered. In May 1991 prednisone was decreased to 20 mg every other day; in September 1991 to 17.5 mg every other day; in October 1991 to 15 mg every other day; and in December 1991 to 12.5 mg every other day. The patient's gastroin testinal symptoms have precluded further ta pering, and as of November 1992 he continues taking acetazolamide 500 mg three times a day and prednisone 15 mg every other day. Case 2 A 21-year-old woman was examined for headaches and blurry vision. At age 18 years she had developed severe left lower abdominal pain that lasted weeks and spontaneously re solved without treatment. Radiologie evalua tion and rectal biopsy established a diagnosis of Crohn's disease. At age 20 years (November 1991) the abdomi nal pain recurred, accompanied by loose, bloody bowel movements, and sigmoidoscopy disclosed colonie ulcérations with a rectal skip area. The symptoms continued despite treat ment with sulfasalazine, and on Nov. 26, 1991, diphenoxylate-atropine and prednisone, 40 mg daily, were administered for seven weeks. Per sistent abdominal pain and hematochezia re quired increases in prednisone to 50 mg daily
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for one week then to 60 mg daily the next week. The symptoms improved after admission to the hospital in mid-February 1992, at which time she received parenteral corticosteroids and hyperalimentation, and the prednisone dosage was decreased to 30 mg daily for six weeks. An iron-deficiency anemia with a hemoglobin level of 7.5 g/dl was treated with two units of packed red blood cells, resulting in a hemoglobin level of 11.4 g/dl. On a routine ocular examination in February 1992, the patient reportedly had normal vision, and photographs documented normal fundi. The gastrointestinal symptoms remitted, allow ing a slow taper beginning on March 27, 1992. By mid-July 1992, the dosage was 15 mg daily alternating with 10 mg daily. On July 24, 1992, she had a return of symptoms related to Crohn's disease, and the dosage was increased to 30 mg daily. On July 28, 1992, the regimen was tapered to 30 mg daily, alternating with 25 mg daily, then on Aug. 4, 1992, to 20 mg daily. Subsequently she developed right-sided pain ful sharp headaches, vomiting, and "distorted vision," and on Aug. 11, 1992, her optometrist observed new optic disk edema. Results of magnetic resonance imaging of the head were normal, and cerebrospinal fluid opening pres sure was 450 mm H 2 0. Laboratory testing showed a white blood cell count of 0 cell/mm 3 , a red blood cell count of 0 cell/mm 3 , a glucose level of 62 m g / d l , and a protein level of 16 m g / d l . Results of routine cultures, cryptococcal antigen, india ink, and acid-fast stain test ing were negative. Hemoglobin level was 8.6 g/dl. Prednisone was increased to 25 mg daily, and a regimen of acetazolamide, 250 mg three times a day, was initiated. On Aug. 20, 1992, the patient was examined at the Bascom Palmer Eye Institute, and she complained of new "whooshing noises" and transient visual obscurations. She appeared thin and malnourished and had a cushingoid faciès and intercapsular deposition of adipose tissue ("buffalo" hump). Best-corrected visual acuity was R.E.: 20/25 and L.E.: 20/30. A nerve fiber defect was noted in the visual field of the right eye and mild supranasal depression in the visual field of the left eye (Fig. 1). Results of testing for color vision, pupils, and motility and of slit-lamp and neurologic examinations were all normal. The optic disks were swollen with peripapillary serous retinal detachment (Fig. 2). The prednisone dosage was increased to 30 mg daily, and the acetazolamide to 500 mg
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Fig. 1 (Liu and associates). Case 1. Kinetic perimetry testing demonstrated mild superonasal constriction in the left eye and a nerve fiber defect in the right.
three times a day. The next day, two units of packed red blood cells were transfused, and the hemoglobin level increased to 11.5 g/dl. Because of intolerable extremity numbness, acetazolamide was decreased to 250 mg three times a day. The headache, subjective auditory bruit, and visual obscurations resolved. On Sept. 3, 1992, she underwent a colectomy, which showed histopathologic results consis tent with Crohn's disease, and ileosigmoid anastomosis. By Oct. 8, 1992, the prednisone
dosage had been slowly tapered to 20 mg daily. Visual acuity was R.E.: 20/20 and L.E.: 20/25, results of static perimetry testing using a visual field analyzer were essentially normal, but the optic disks were still swollen. On Oct. 29, 1992, while taking prednisone, 10 mg daily, and acet azolamide, 500 mg twice a day, visual acuity was R.E.: 20/20 and L.E.: 20/25 +2 with nor mal results of static perimetry testing. The papilledema was improved with resolution of the peripapillary fluid. On Dec. 11, 1992, the
Fig. 2 (Liu and associates). Case 1. The right (left) and left (right) optic nerves were swollen with peripapillary serous retinal detachment.
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prednisone dosage was 5 mg daily, and the patient had neither visual nor gastrointestinal symptoms. Case 3 A 55-year-old man with a one-year history of bloody diarrhea, abdominal pain, and weight loss was examined for papilledema. Colonoscopy with multiple biopsies demonstrated chronic inflammation without skip lesions, which was consistent with ulcerative colitis. Prednisone, 80 mg daily, was initiated in June 1992, then slowly tapered over the next ten months. Additional medications included fer rous sulfate and folate. Because of a hemoglo bin level of 6.0 m g / d l in June 1992, the patient was given a transfusion in August 1992, and subsequently the hemoglobin level stabilized at approximately 10.0 g/dl. In late May 1993, three weeks after uncompli cated bilateral cataract extractions, the patient developed an intermittent headache and no ticed "white bubbles" lasting seconds in the lower visual fields of both eyes, often associat ed with positional changes. The prednisone dosage was 7.5 mg daily alternating with 5 mg daily. Bilateral disk edema was noted by his ophthalmologist. Results of magnetic reso nance imaging of the brain were unremarkable, and cerebrospinal fluid opening pressure was 240 mm H 2 0. Laboratory studies showed a white blood cell count of 1 cell/mm 3 , a red blood cell count of 3 cells/mm 3 , and normal glucose and protein levels. Hemoglobin level was 10.0 g/dl. The prednisone was tapered further to 2.5 mg every other day by July 8, 1993, when the patient underwent neuro-ophthalmic examina tion. He was thin but appeared healthy. Results of testing for visual acuity, color vision, pupils, and motility were normal, and static perimetry demonstrated mild nasal steps bilaterally. The results of slit-lamp examination were unre markable except for bilateral posterior chamber intraocular lens implants, and intraocular pres sure was 15 mm Hg in each eye. Bilateral chronic disk edema was noted, with two nerve fiber layer hemorrhages nasal to the disk in the right eye.
Discussion Pseudotumor cerebri is characterized by headache, papilledema, and intracranial hyper
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tension without a mass lesion on neuroimaging or abnormal cerebrospinal fluid contents. Ex cept for a lateral rectus muscle palsy, results of neurologic examination are normal. 3 Our three patients satisfied all these criteria. Our patients developed pseudotumor cerebri during decreases in corticosteroid dosage. The patient in Case 1 had four episodes, which suggests a causal relationship. He was an ado lescent, and the patients in Cases 2 and 3 were adults. The usual risk factors for pseudotumor cerebri, such as obesity or history of recent weight gain, 1 were notably absent, and two patients were male. Each was taking predni sone chronically, in Case 1 for seven years, in Case 2 for eight months, and in Case 3 for 11 months. All patients had mild visual field ab normalities consistent with papilledema. 1 We treated the patients in Cases 1 and 2 successful ly with acetazolamide, an increase in predni sone dosage, and slower subsequent predni sone tapers. Others authors have reported the association between pseudotumor cerebri and chronic cor ticosteroid use, typically in young children. Although in rare instances increases in cortico steroid dosage resulted in pseudotumor cere bri, 4 most patients (like ours) developed symp toms during dosage reduction. Greer 5 described five patients with either eczema, asthma, ne phritis, or arthritis undergoing withdrawal from prednisone, triamcinolone, or both. Weisberg and Chutorian 6 added two more chil dren with asthma and one with eczema, and Lessell and Rosman 7 documented another pa tient with asthma. Several authors described other patients; however, the diagnosis of pseudotumor cerebri in these patients must be considered suspect because they failed to fulfill the modified Dandy criteria. 13 Some of these patients had abnormal neurologic findings in cluding decreased mental status, ataxia, hemiparesis, third-nerve palsy, asymmetric reflexes, and extensor plantar responses. 811 Other pa tients, including one with ulcerative colitis, 12 lacked either cerebrospinal fluid examinations or adequate neuroradiologic studies.12"15 Intracranial hypertension may develop in pa tients taking chronic corticosteroids because of adrenal insufficiency during tapering, although this is uncertain. Greer 5 found normal urinary 17-ketosteroid and 17-hydroxycorticoid levels in his patients, which suggests no adrenal ab normalities. However, reports of pseudotumor cerebri occurring in corticosteroid-deficient states, such as Addison's disease, 16 adrenocorti-
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cotropic h o r m o n e deficiency, 1 7 a n d after r e m o v al of a n a d r e n o c o r t i c o t r o p i c h o r m o n e — s e c r e t ing pituitary adenoma, 1 8 , 1 9 s u b s t a n t i a t e this h y p o t h e s i s . The c o m b i n a t i o n of t h e s e s t u d i e s , our experience, a n d the r e p o r t s t h a t corticosteroids effectively treat p s e u d o t u m o r cerebri 1 suggest t h a t corticosteroids have an effect o n cerebrospinal fluid d y n a m i c s . The chronic inflammatory b o w e l d i s e a s e s are divided into two major g r o u p s : C r o h n ' s r e g i o n al enteritis, w i t h s e g m e n t a i , t r a n s m u r a l , a n d g r a n u l o m a t o u s features, a n d ulcerative colitis, w h i c h is c h a r a c t e r i z e d b y diffuse i n f l a m m a t i o n , usually i n v o l v i n g the rectum. 2 0 P a t i e n t s w i t h either d i s o r d e r typically p r e s e n t w i t h a b d o m i nal p a i n , fistulas, strictures, a n d d i a r r h e a or b l o o d y diarrhea. 2 0 The origin of t h e s e d i s e a s e s is unclear. A l t h o u g h possible, we d o u b t o u r p a t i e n t s ' i n t r a c r a n i a l h y p e r t e n s i o n w a s c a u s e d b y their inflammatory b o w e l d i s e a s e . A p p r o x i m a t e l y 10% of p a t i e n t s w i t h C r o h n ' s d i s e a s e a n d a smaller p e r c e n t a g e of t h o s e w i t h ulcerative co litis d e v e l o p ocular complications, 2 1 w h i c h in clude k e r a t o p a t h y , iridocyclitis, episcleritis, uveitis, a n d m a c u l a r e d e m a b u t n o t p s e u d o t u m o r cerebri. 2 2 Rare i n s t a n c e s of optic disk swelling caused by optic neuritis 2 3 a n d p e r i p a p illary scleritis 2 2 in association w i t h i n f l a m m a t o ry bowel disease have b e e n r e p o r t e d . We c a n n o t exclude the role of iron-deficiency a n e m i a , a r e c o g n i z e d association, 1 in t h e p s e u d o t u m o r cerebri in Cases 2 or 3. P a t i e n t s w i t h in tracranial h y p e r t e n s i o n associated w i t h c h r o n ic b l o o d loss, however, t e n d to b e m o r e severely a n e m i c t h a n ours. 2 4 2 7 Our patients demonstrate that pseudotumor cerebri associated w i t h steroid w i t h d r a w a l can occur in inflammatory b o w e l d i s e a s e , can h a p p e n in a d u l t s as well as in c h i l d r e n , a n d is m o r e t h a n a c h a n c e association.
References 1. Wall, M.: Idiopathic intracranial hypertension. Neurol. Clin. 9:73, 1991. 2. Lesseil, S.: Pédiatrie pseudotumor cerebri (idio pathic intracranial hypertension). Surv. Ophthalmol. 37:155, 1992. 3. Smith, J. L.: Whence pseudotumor cerebri? J. Clin. Neuro. Ophthalmol. 5:55, 1985. 4. Vyas, C. K., Talwar, K. K., Bhatnagar, V., and Sharma, B. K.: Steroid-induced benign intracranial hypertension. Postgrad. Med. J. 57:181, 1981.
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5. Gréer, M.: Benign intracranial hypertension. II. Following corticosteroid therapy. Neurology 13:439, 1963. 6. Weisberg, L. A., and Chutorian, A. M.: Pseudo tumor cerebri of childhood. Am. J. Dis. Child. 131:1243, 1977. 7. Lesseil, S., and Rosman, N. P.: Permanent visu al impairment in childhood pseudotumor cerebri. Arch. Neurol. 43:801, 1986. 8. Dees, S. C , and McKay, H. W.: Occurrence of pseudotumor cerebri (benign intracranial hyperten sion) during treatment of children with asthma by adrenal steroids. Report of three cases. Pediatrics 23:1143, 1959. 9. Walker, A. E., and Adamkiewicz, J. J.: Pseudo tumor cerebri associated with prolonged corticoster oid therapy. Reports of four cases. JAMA 188:779, 1964. 10. Gordon, R. C , and Kelsey, W. M.: Pseudo tumor cerebri in congenital adrenal hyperplasia. Am. J. Dis. Child. 113:727, 1967. 11. Grant, D. N.: Benign intracranial hyperten sion. A review of 79 cases in infancy and childhood. Arch. Dis. Child. 46:651, 1971. 12. Neville, B. G., and Wilson, J.: Benign intracra nial hypertension following corticosteroid withdraw al in childhood. Br. Med. J. 3:554, 1970. 13. Calcagno, P. L., and Rubin, M. I.: Physiologic considerations concerning corticosteroid therapy and complications in the nephrotic syndrome. J. Pediatr. 58:686, 1961. 14. Cohn, G. A.: Pseudotumor cerebri in children secondary to administration of adrenal steroids. J. Neurosurg. 20:784, 1963. 15. Rose, A., and Maison, D. D.: Benign intracra nial hypertension in children. Pediatrics 39:227, 1967. 16. Walsh, F. B.: Papilledema associated with in creased intracranial pressure in Addison's disease. Arch. Ophthalmol. 47:86, 1952. 17. Aanderud, S., and Jorde, R.: ACTH deficiency, hyperprolactinemia and benign intracranial hyper tension. A case report. Acta Endocrinol. (Copenh.) 118:346, 1988. 18. Martin, N. A., Linfoot, J., and Wilson, C. B.: Development of pseudotumor cerebri after the re moval of an adrenocorticotropic hormone-secreting pituitary adenoma. Case report. Neurosurgery 8:699, 1981. 19. Weissman, M. N., Page, L. K., and Bejar, R. L.: Cushing's disease in childhood. Benign intracranial hypertension after trans-sphenoidal adenomectomy. Neurosurgery 13:195, 1983. 20. Glickman, R. M.: Inflammatory bowel disease. Ulcerative colitis and Crohn's disease. In Braunwald, E., Isselbacher, K. J., Petersdorf, R. G., Wilson, J. D., Martin, J. B., and Fauci, A. S. (eds.): Harrison's Principles of Internal Medicine, ed. 11. New York, McGraw-Hill, 1987, pp. 1277-1290. 21. Knox, D. L.: Inflammatory bowel disease. In Gold, D. H., and Weingeist, T. A. (eds.): The Eye in
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Systemic Disease. Philadelphia, J. B. Lippincott, 1990, pp. 103-105. 22. Knox, D. L., Schachat, A. P., and Mustonen, E.: Primary, secondary and coincidental ocular com plications of Crohn's disease. Ophthalmology 91:163, 1984. 23. Sedwick, L. A., Klingele, T. G., Bürde, R. M., and Behrens, M. M.: Optic neuritis in inflammatory bowel disease. J. Clin. Neuro. Ophthalmol. 4:3, 1984. 24. Lübeck, M. J.: Papilledema caused by iron-
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deficiency anemia. Trans. Am. Acad. Ophthalmol. 63:306, 1959. 25. Schwaber, J. R., and Blumberg, A. G.: Papille dema associated with blood loss anemia. Ann. In tern. Med. 55:1004, 1961. 26. Capriles, L. F.: Intracranial hypertension and iron-deficiency anemia. Report of four cases. Arch. Neurol. 9:147, 1963. 27. Ikkala, E., and Laitinen, L.: Papilloedema due to iron deficiency anemia. Acta Haematol. 29:368, 1963.
OPHTHALMIC MINIATURE
"Wrong? The eyes, I mean, sir? All we know for certain is that he wears sunglasses at nighttime. Could mean anything or nothing. Could be a fad. Maybe he fancies himself in them. Maybe, as Dekker suggested, he thinks sunglasses are de rigueur for the better-class villain. Maybe, like the American President's Secret Service bodyguards, he wears them because any potential malefactor in a crowd can never know whether the agent's eyes are fixed on him or not, thereby inhibiting him from action. Or he might be suffering from nyctalopia." Alistair, MacLean, Floodgate Garden City, New York, Doubleday & Company, Inc., 1983, p. 21
Accepted for publication Nov. 29, 1993. From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida (Drs. Liu, Kay, and Schatz), and the Division of Ophthalmology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr. Bienfang). Reprint requests to Grant T. Liu, M.D., Neuro-ophthalmology Unit, Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce St., Phila delphia, PA 19104.
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Case Reports Case 1 was evaluated at the Children's Hospi tal and Brigham and Women's Hospital in Bos ton, and Cases 2 and 3 were evaluated at the Bascom Palmer Eye Institute in Miami. Case 1
A 16-year-old boy was examined for his fourth episode of headache and vomiting asso ciated with a corticosteroid taper. In 1980, at age 6 years, a fever of 104 F and painful knee swelling suggested a presumptive diagnosis of juvenile rheumatoid arthritis. Six months later he developed anorexia, weight loss, a lowgrade fever, and guaiac-positive diarrhea. Radi ologie studies and colonoscopy, including a biopsy, confirmed the diagnosis of Crohn's dis ease. Treatment with oral prednisone, 40 mg daily, resolved the arthritis and gastrointestinal symptoms. However, each taper resulted in recurrent abdominal pain, lethargy, and diar rhea, and he remained corticosteroid-dependent. In April 1987, at age 13 years, the patient had an ileocolectomy. In December 1987, during a prednisone taper from 20 mg every other day to 17.5 mg every other day, he developed head aches and photophobia. Cerebrospinal fluid opening pressure was 500 mm H 2 0 . He was treated with an increase in corticosteroid dose, acetazolamide, and multiple lumbar punctures, and the symptoms resolved. Identical episodes occurred in 1988 during another taper from 20 to 17.5 mg every other day and then again in 1989 during a taper from 17.5 to 15 mg every other day. The Crohn's disease was stable dur ing these episodes. In November 1990, after a taper from 20 to 10 mg every other day over two months, the pa tient developed difficulty in focusing, blurry vision while sitting, anorexia, headache, and nausea and vomiting. He was thin and short,
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and an examination by one of us (G.T.L.) docu mented normal visual acuity measurements, bilateral papilledema, and normal results of neurologic testing. Results of computed tomog raphy of the head were normal. Cerebrospinal fluid opening pressure was 540 mm H 2 0 . Labo ratory studies showed a white blood cell count of 1 cell/mm 3 , a red blood cell count of 0 cell/mm 3 , a protein level of 17.2 m g / d l , and a glucose level of 58 m g / d l . Acetazolamide was administered. His headache and vomiting worsened, however, and a repeat lumbar punc ture showed an opening pressure of 540 mm H 2 0. Kinetic perimetry showed marginally en larged blind spots bilaterally. The dosage of prednisone was increased to 25 mg every other day and acetazolamide to 500 mg three times a day. Continued headaches responded to the addition of furosemide (10 mg), followed by 5 mg daily for five days without a change in the dosage of acetazolamide. Thereafter the patient remained asymptomat ic with best-corrected visual acuity of 20/20 and normal results of kinetic perimetry testing bilaterally. On Jan. 18, 1991, the disk swelling had resolved, and spontaneous venous pulsa tions were noted. Azathioprine was adminis tered. In May 1991 prednisone was decreased to 20 mg every other day; in September 1991 to 17.5 mg every other day; in October 1991 to 15 mg every other day; and in December 1991 to 12.5 mg every other day. The patient's gastroin testinal symptoms have precluded further ta pering, and as of November 1992 he continues taking acetazolamide 500 mg three times a day and prednisone 15 mg every other day. Case 2 A 21-year-old woman was examined for headaches and blurry vision. At age 18 years she had developed severe left lower abdominal pain that lasted weeks and spontaneously re solved without treatment. Radiologie evalua tion and rectal biopsy established a diagnosis of Crohn's disease. At age 20 years (November 1991) the abdomi nal pain recurred, accompanied by loose, bloody bowel movements, and sigmoidoscopy disclosed colonie ulcérations with a rectal skip area. The symptoms continued despite treat ment with sulfasalazine, and on Nov. 26, 1991, diphenoxylate-atropine and prednisone, 40 mg daily, were administered for seven weeks. Per sistent abdominal pain and hematochezia re quired increases in prednisone to 50 mg daily
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for one week then to 60 mg daily the next week. The symptoms improved after admission to the hospital in mid-February 1992, at which time she received parenteral corticosteroids and hyperalimentation, and the prednisone dosage was decreased to 30 mg daily for six weeks. An iron-deficiency anemia with a hemoglobin level of 7.5 g/dl was treated with two units of packed red blood cells, resulting in a hemoglobin level of 11.4 g/dl. On a routine ocular examination in February 1992, the patient reportedly had normal vision, and photographs documented normal fundi. The gastrointestinal symptoms remitted, allow ing a slow taper beginning on March 27, 1992. By mid-July 1992, the dosage was 15 mg daily alternating with 10 mg daily. On July 24, 1992, she had a return of symptoms related to Crohn's disease, and the dosage was increased to 30 mg daily. On July 28, 1992, the regimen was tapered to 30 mg daily, alternating with 25 mg daily, then on Aug. 4, 1992, to 20 mg daily. Subsequently she developed right-sided pain ful sharp headaches, vomiting, and "distorted vision," and on Aug. 11, 1992, her optometrist observed new optic disk edema. Results of magnetic resonance imaging of the head were normal, and cerebrospinal fluid opening pres sure was 450 mm H 2 0. Laboratory testing showed a white blood cell count of 0 cell/mm 3 , a red blood cell count of 0 cell/mm 3 , a glucose level of 62 m g / d l , and a protein level of 16 m g / d l . Results of routine cultures, cryptococcal antigen, india ink, and acid-fast stain test ing were negative. Hemoglobin level was 8.6 g/dl. Prednisone was increased to 25 mg daily, and a regimen of acetazolamide, 250 mg three times a day, was initiated. On Aug. 20, 1992, the patient was examined at the Bascom Palmer Eye Institute, and she complained of new "whooshing noises" and transient visual obscurations. She appeared thin and malnourished and had a cushingoid faciès and intercapsular deposition of adipose tissue ("buffalo" hump). Best-corrected visual acuity was R.E.: 20/25 and L.E.: 20/30. A nerve fiber defect was noted in the visual field of the right eye and mild supranasal depression in the visual field of the left eye (Fig. 1). Results of testing for color vision, pupils, and motility and of slit-lamp and neurologic examinations were all normal. The optic disks were swollen with peripapillary serous retinal detachment (Fig. 2). The prednisone dosage was increased to 30 mg daily, and the acetazolamide to 500 mg
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Fig. 1 (Liu and associates). Case 1. Kinetic perimetry testing demonstrated mild superonasal constriction in the left eye and a nerve fiber defect in the right.
three times a day. The next day, two units of packed red blood cells were transfused, and the hemoglobin level increased to 11.5 g/dl. Because of intolerable extremity numbness, acetazolamide was decreased to 250 mg three times a day. The headache, subjective auditory bruit, and visual obscurations resolved. On Sept. 3, 1992, she underwent a colectomy, which showed histopathologic results consis tent with Crohn's disease, and ileosigmoid anastomosis. By Oct. 8, 1992, the prednisone
dosage had been slowly tapered to 20 mg daily. Visual acuity was R.E.: 20/20 and L.E.: 20/25, results of static perimetry testing using a visual field analyzer were essentially normal, but the optic disks were still swollen. On Oct. 29, 1992, while taking prednisone, 10 mg daily, and acet azolamide, 500 mg twice a day, visual acuity was R.E.: 20/20 and L.E.: 20/25 +2 with nor mal results of static perimetry testing. The papilledema was improved with resolution of the peripapillary fluid. On Dec. 11, 1992, the
Fig. 2 (Liu and associates). Case 1. The right (left) and left (right) optic nerves were swollen with peripapillary serous retinal detachment.
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prednisone dosage was 5 mg daily, and the patient had neither visual nor gastrointestinal symptoms. Case 3 A 55-year-old man with a one-year history of bloody diarrhea, abdominal pain, and weight loss was examined for papilledema. Colonoscopy with multiple biopsies demonstrated chronic inflammation without skip lesions, which was consistent with ulcerative colitis. Prednisone, 80 mg daily, was initiated in June 1992, then slowly tapered over the next ten months. Additional medications included fer rous sulfate and folate. Because of a hemoglo bin level of 6.0 m g / d l in June 1992, the patient was given a transfusion in August 1992, and subsequently the hemoglobin level stabilized at approximately 10.0 g/dl. In late May 1993, three weeks after uncompli cated bilateral cataract extractions, the patient developed an intermittent headache and no ticed "white bubbles" lasting seconds in the lower visual fields of both eyes, often associat ed with positional changes. The prednisone dosage was 7.5 mg daily alternating with 5 mg daily. Bilateral disk edema was noted by his ophthalmologist. Results of magnetic reso nance imaging of the brain were unremarkable, and cerebrospinal fluid opening pressure was 240 mm H 2 0. Laboratory studies showed a white blood cell count of 1 cell/mm 3 , a red blood cell count of 3 cells/mm 3 , and normal glucose and protein levels. Hemoglobin level was 10.0 g/dl. The prednisone was tapered further to 2.5 mg every other day by July 8, 1993, when the patient underwent neuro-ophthalmic examina tion. He was thin but appeared healthy. Results of testing for visual acuity, color vision, pupils, and motility were normal, and static perimetry demonstrated mild nasal steps bilaterally. The results of slit-lamp examination were unre markable except for bilateral posterior chamber intraocular lens implants, and intraocular pres sure was 15 mm Hg in each eye. Bilateral chronic disk edema was noted, with two nerve fiber layer hemorrhages nasal to the disk in the right eye.
Discussion Pseudotumor cerebri is characterized by headache, papilledema, and intracranial hyper
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tension without a mass lesion on neuroimaging or abnormal cerebrospinal fluid contents. Ex cept for a lateral rectus muscle palsy, results of neurologic examination are normal. 3 Our three patients satisfied all these criteria. Our patients developed pseudotumor cerebri during decreases in corticosteroid dosage. The patient in Case 1 had four episodes, which suggests a causal relationship. He was an ado lescent, and the patients in Cases 2 and 3 were adults. The usual risk factors for pseudotumor cerebri, such as obesity or history of recent weight gain, 1 were notably absent, and two patients were male. Each was taking predni sone chronically, in Case 1 for seven years, in Case 2 for eight months, and in Case 3 for 11 months. All patients had mild visual field ab normalities consistent with papilledema. 1 We treated the patients in Cases 1 and 2 successful ly with acetazolamide, an increase in predni sone dosage, and slower subsequent predni sone tapers. Others authors have reported the association between pseudotumor cerebri and chronic cor ticosteroid use, typically in young children. Although in rare instances increases in cortico steroid dosage resulted in pseudotumor cere bri, 4 most patients (like ours) developed symp toms during dosage reduction. Greer 5 described five patients with either eczema, asthma, ne phritis, or arthritis undergoing withdrawal from prednisone, triamcinolone, or both. Weisberg and Chutorian 6 added two more chil dren with asthma and one with eczema, and Lessell and Rosman 7 documented another pa tient with asthma. Several authors described other patients; however, the diagnosis of pseudotumor cerebri in these patients must be considered suspect because they failed to fulfill the modified Dandy criteria. 13 Some of these patients had abnormal neurologic findings in cluding decreased mental status, ataxia, hemiparesis, third-nerve palsy, asymmetric reflexes, and extensor plantar responses. 811 Other pa tients, including one with ulcerative colitis, 12 lacked either cerebrospinal fluid examinations or adequate neuroradiologic studies.12"15 Intracranial hypertension may develop in pa tients taking chronic corticosteroids because of adrenal insufficiency during tapering, although this is uncertain. Greer 5 found normal urinary 17-ketosteroid and 17-hydroxycorticoid levels in his patients, which suggests no adrenal ab normalities. However, reports of pseudotumor cerebri occurring in corticosteroid-deficient states, such as Addison's disease, 16 adrenocorti-
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cotropic h o r m o n e deficiency, 1 7 a n d after r e m o v al of a n a d r e n o c o r t i c o t r o p i c h o r m o n e — s e c r e t ing pituitary adenoma, 1 8 , 1 9 s u b s t a n t i a t e this h y p o t h e s i s . The c o m b i n a t i o n of t h e s e s t u d i e s , our experience, a n d the r e p o r t s t h a t corticosteroids effectively treat p s e u d o t u m o r cerebri 1 suggest t h a t corticosteroids have an effect o n cerebrospinal fluid d y n a m i c s . The chronic inflammatory b o w e l d i s e a s e s are divided into two major g r o u p s : C r o h n ' s r e g i o n al enteritis, w i t h s e g m e n t a i , t r a n s m u r a l , a n d g r a n u l o m a t o u s features, a n d ulcerative colitis, w h i c h is c h a r a c t e r i z e d b y diffuse i n f l a m m a t i o n , usually i n v o l v i n g the rectum. 2 0 P a t i e n t s w i t h either d i s o r d e r typically p r e s e n t w i t h a b d o m i nal p a i n , fistulas, strictures, a n d d i a r r h e a or b l o o d y diarrhea. 2 0 The origin of t h e s e d i s e a s e s is unclear. A l t h o u g h possible, we d o u b t o u r p a t i e n t s ' i n t r a c r a n i a l h y p e r t e n s i o n w a s c a u s e d b y their inflammatory b o w e l d i s e a s e . A p p r o x i m a t e l y 10% of p a t i e n t s w i t h C r o h n ' s d i s e a s e a n d a smaller p e r c e n t a g e of t h o s e w i t h ulcerative co litis d e v e l o p ocular complications, 2 1 w h i c h in clude k e r a t o p a t h y , iridocyclitis, episcleritis, uveitis, a n d m a c u l a r e d e m a b u t n o t p s e u d o t u m o r cerebri. 2 2 Rare i n s t a n c e s of optic disk swelling caused by optic neuritis 2 3 a n d p e r i p a p illary scleritis 2 2 in association w i t h i n f l a m m a t o ry bowel disease have b e e n r e p o r t e d . We c a n n o t exclude the role of iron-deficiency a n e m i a , a r e c o g n i z e d association, 1 in t h e p s e u d o t u m o r cerebri in Cases 2 or 3. P a t i e n t s w i t h in tracranial h y p e r t e n s i o n associated w i t h c h r o n ic b l o o d loss, however, t e n d to b e m o r e severely a n e m i c t h a n ours. 2 4 2 7 Our patients demonstrate that pseudotumor cerebri associated w i t h steroid w i t h d r a w a l can occur in inflammatory b o w e l d i s e a s e , can h a p p e n in a d u l t s as well as in c h i l d r e n , a n d is m o r e t h a n a c h a n c e association.
References 1. Wall, M.: Idiopathic intracranial hypertension. Neurol. Clin. 9:73, 1991. 2. Lesseil, S.: Pédiatrie pseudotumor cerebri (idio pathic intracranial hypertension). Surv. Ophthalmol. 37:155, 1992. 3. Smith, J. L.: Whence pseudotumor cerebri? J. Clin. Neuro. Ophthalmol. 5:55, 1985. 4. Vyas, C. K., Talwar, K. K., Bhatnagar, V., and Sharma, B. K.: Steroid-induced benign intracranial hypertension. Postgrad. Med. J. 57:181, 1981.
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5. Gréer, M.: Benign intracranial hypertension. II. Following corticosteroid therapy. Neurology 13:439, 1963. 6. Weisberg, L. A., and Chutorian, A. M.: Pseudo tumor cerebri of childhood. Am. J. Dis. Child. 131:1243, 1977. 7. Lesseil, S., and Rosman, N. P.: Permanent visu al impairment in childhood pseudotumor cerebri. Arch. Neurol. 43:801, 1986. 8. Dees, S. C , and McKay, H. W.: Occurrence of pseudotumor cerebri (benign intracranial hyperten sion) during treatment of children with asthma by adrenal steroids. Report of three cases. Pediatrics 23:1143, 1959. 9. Walker, A. E., and Adamkiewicz, J. J.: Pseudo tumor cerebri associated with prolonged corticoster oid therapy. Reports of four cases. JAMA 188:779, 1964. 10. Gordon, R. C , and Kelsey, W. M.: Pseudo tumor cerebri in congenital adrenal hyperplasia. Am. J. Dis. Child. 113:727, 1967. 11. Grant, D. N.: Benign intracranial hyperten sion. A review of 79 cases in infancy and childhood. Arch. Dis. Child. 46:651, 1971. 12. Neville, B. G., and Wilson, J.: Benign intracra nial hypertension following corticosteroid withdraw al in childhood. Br. Med. J. 3:554, 1970. 13. Calcagno, P. L., and Rubin, M. I.: Physiologic considerations concerning corticosteroid therapy and complications in the nephrotic syndrome. J. Pediatr. 58:686, 1961. 14. Cohn, G. A.: Pseudotumor cerebri in children secondary to administration of adrenal steroids. J. Neurosurg. 20:784, 1963. 15. Rose, A., and Maison, D. D.: Benign intracra nial hypertension in children. Pediatrics 39:227, 1967. 16. Walsh, F. B.: Papilledema associated with in creased intracranial pressure in Addison's disease. Arch. Ophthalmol. 47:86, 1952. 17. Aanderud, S., and Jorde, R.: ACTH deficiency, hyperprolactinemia and benign intracranial hyper tension. A case report. Acta Endocrinol. (Copenh.) 118:346, 1988. 18. Martin, N. A., Linfoot, J., and Wilson, C. B.: Development of pseudotumor cerebri after the re moval of an adrenocorticotropic hormone-secreting pituitary adenoma. Case report. Neurosurgery 8:699, 1981. 19. Weissman, M. N., Page, L. K., and Bejar, R. L.: Cushing's disease in childhood. Benign intracranial hypertension after trans-sphenoidal adenomectomy. Neurosurgery 13:195, 1983. 20. Glickman, R. M.: Inflammatory bowel disease. Ulcerative colitis and Crohn's disease. In Braunwald, E., Isselbacher, K. J., Petersdorf, R. G., Wilson, J. D., Martin, J. B., and Fauci, A. S. (eds.): Harrison's Principles of Internal Medicine, ed. 11. New York, McGraw-Hill, 1987, pp. 1277-1290. 21. Knox, D. L.: Inflammatory bowel disease. In Gold, D. H., and Weingeist, T. A. (eds.): The Eye in
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Systemic Disease. Philadelphia, J. B. Lippincott, 1990, pp. 103-105. 22. Knox, D. L., Schachat, A. P., and Mustonen, E.: Primary, secondary and coincidental ocular com plications of Crohn's disease. Ophthalmology 91:163, 1984. 23. Sedwick, L. A., Klingele, T. G., Bürde, R. M., and Behrens, M. M.: Optic neuritis in inflammatory bowel disease. J. Clin. Neuro. Ophthalmol. 4:3, 1984. 24. Lübeck, M. J.: Papilledema caused by iron-
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deficiency anemia. Trans. Am. Acad. Ophthalmol. 63:306, 1959. 25. Schwaber, J. R., and Blumberg, A. G.: Papille dema associated with blood loss anemia. Ann. In tern. Med. 55:1004, 1961. 26. Capriles, L. F.: Intracranial hypertension and iron-deficiency anemia. Report of four cases. Arch. Neurol. 9:147, 1963. 27. Ikkala, E., and Laitinen, L.: Papilloedema due to iron deficiency anemia. Acta Haematol. 29:368, 1963.
OPHTHALMIC MINIATURE
"Wrong? The eyes, I mean, sir? All we know for certain is that he wears sunglasses at nighttime. Could mean anything or nothing. Could be a fad. Maybe he fancies himself in them. Maybe, as Dekker suggested, he thinks sunglasses are de rigueur for the better-class villain. Maybe, like the American President's Secret Service bodyguards, he wears them because any potential malefactor in a crowd can never know whether the agent's eyes are fixed on him or not, thereby inhibiting him from action. Or he might be suffering from nyctalopia." Alistair, MacLean, Floodgate Garden City, New York, Doubleday & Company, Inc., 1983, p. 21