Journal of Neuro-Ophthalmology, December 1994, Volume 14, Issue 4

Association of multiple sclerosis and intracranial hypertension.

Three patients fulfilled the diagnostic criteria for both multiple sclerosis and pseudotumor cerebri. Although coincidence is possible, intracranial hypertension may be a manifestation of demyelinating disease.

Journal of Neuro- Ophthalmology 14( 4): 189- 192, 1994. ) 1994 Raven Press, Ltd., New York Association of Multiple Sclerosis and Intracranial Hypertension Nancy J. Newman, M. D., Kenneth A. Selzer, M. D., and Raymond A. Bell, M. D. Abstract: Three patients fulfilled the diagnostic criteria for both multiple sclerosis and pseudotumor cerebri. Although coincidence is possible, intracranial hypertension may be a manifestation of demyelinating disease. Key Words: Pseudotumor cerebri- Idiopathic intra­cranial hypertension- Raised intracranial pressure- Multiple sclerosis- Demyelinating disease. Multiple sclerosis and idiopathic intracranial hy­pertension ( pseudotumor cerebri) are both dis­eases found with higher frequency among women in their childbearing years. We report three pa­tients in whom these two diseases coexisted clini­cally. Although coincidence is possible, several features of these cases raise the possibility of an association between these two clinical entities. CASE REPORTS Casel From the Departments of Ophthalmology, Neurology and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia; the Department of Neurology, Vanderbilt Medical School, Nashville, Tennessee; and the Departments of Oph­thalmology and Neurology, the Medical College of Georgia, Augusta, Georgia, U. S. A. This work was supported in part by a departmental grant from Research to Prevent Blindness, Inc., New York, New York, and NIH grant # P30 EY06360 ( Emory University, Oph­thalmology). Address correspondence and reprint requests to Dr. Nancy J. Newman, Neuro- Ophthalmology Unit, Emory Eye Center, 1327 Clifton Rd., N. E., Atlanta, GA 30322, U. S. A. At age 31, a previously healthy, thin white woman experienced intermittent paresthesias from the waist down. A myelogram was normal. She did well until age 39 when she experienced daily episodes of vertigo lasting 30- 45 minutes for several months, followed by left- sided numbness that lasted 4 weeks, then gradually resolved. Workup included magnetic resonance imaging ( MRI) with periventricular white matter abnormal­ities consistent with demyelinating disease and normal four- vessel cerebral arteriography. Two lumbar punctures with the patient relaxed re­vealed opening pressures of greater than 300 mm of water, no white blood cells, normal protein lev­els, and no oligoclonal bands. At age 40, she de­veloped ataxia. Neurologic examination revealed bilateral disc edema, normal visual acuity, and left-sided ataxia. She was diagnosed with multiple sclerosis and treated with prednisone, 60 mg/ day, for 4 days, but this was discontinued secondary to insomnia. Several subsequent lumbar punctures all had elevated opening pressures ( none lower than 290 mm of water), no white blood cells, and normal protein levels. Oligoclonal banding was documented on at least one occasion. She was treated with acetazolamide. Approximately 3 months after the disc edema was first appreciated, 189 190 N. J. NEWMAN ET AL. the patient began to have severe headaches that improved after lumbar puncture and with increas­ing the dosage of acetazolamide. Medication side effects ultimately required the acetazolamide be discontinued, and a lumboperitoneal shunt was performed with resolution of her headache and papilledema. At age 41, she had an exacerbation of her multiple sclerosis, manifested as right- sided weakness. She was treated with intravenous sol-umedrol, 1000 mg/ day for 5 days, with improve­ment of her hemiplegia. Four days after the dis­continuation of intravenous corticosteroids, she developed recurrence of her severe headaches, worse in the morning and with lying flat. She also complained of transient visual obscurations with changes in posture, as well as pulsatile tinnitus. Neuro- ophthalmic examination revealed mild bi­lateral disc edema but normal visual function. The lumboperitoneal shunt was revised and symptoms resolved. Case 2 At 45 years of age, a previously healthy, thin white woman developed numbness of her left hand and difficulty in holding objects. She under­went carpal tunnel surgery, but the numbness and clumsiness of the left hand persisted intermit­tently. She also complained of some problems with her right lower leg, causing her to trip when she walked, as well as some intermittent pain in the neck and both arms. When she was 47 years old, an MRI demonstrated several bright T2 periven­tricular white matter lesions compatible with de­my elinating disease. At age 49, she began to com­plain of early morning occipital headaches that would frequently wake her from sleep, occasional episodes of horizontal diplopia, and bilateral, sec­onds- long, transient visual obscurations. Neuro-ophthalmic examination revealed vision of 20/ 25 - OD and 20/ 25 OS. There was a 0.2 log unit right relative afferent pupillary defect. Motility was full. There was bilateral disc edema, right greater than left. Visual fields were constricted in both eyes, right greater than left. The remainder of her neu­rologic examination was notable for mild weakness and reduced sensation to all modalities in the left upper extremity, a right upgoing toe, and de­creased sensation in both hands. MRI demon­strated bilateral, bright T2, deep, periventricular white matter lesions, consistent with multiple scle­rosis. Lumbar puncture revealed an opening pres­sure of 420 mm of water, 5 white cells, normal protein and glucose levels, negative cultures, neg­ative cytology, and no oligoclonal bands. Two sub­sequent lumbar punctures had opening pressures of 280 and 270 mm of water, normal protein levels, and no oligoclonal bands. She was treated with oral acetazolamide and intravenous, then oral, cor­ticosteroids. Her headaches and blurred vision im­proved over the subsequent 2 weeks. Corticoste­roids were tapered off over 1 month. Her head­aches recurred 2 weeks later, and the opening pressure was 260 mm of water. Her acetazolamide dosage was increased, and she was given a 3- week course of steroids. Symptoms resolved, and she was maintained on acetazolamide. Follow- up lum­bar puncture 2 months later revealed an opening pressure of 185 mm of water and normal cerebro­spinal fluid. On examination 1 month later, vision was 20/ 20 OU, there was no relative afferent pu­pillary defect, papilledema had resolved, and her visual fields were expanded. Case 3 At 26 years of age, an obese white woman, com­plaining of 2 years of severe headaches, was noted to have bilateral disc edema. Two computed to­mography ( CT) scans of the brain were normal. Lumbar punctures on three separate occasions documented opening pressures of 250- 350 mm of water. The cerebrospinal fluid was otherwise com­pletely normal, including normal protein levels, < 5 white blood cells, and no oligoclonal bands. She was diagnosed with pseudotumor cerebri and treated with a regimen of prednisone 20 mg every other day, acetazolamide 250 mg twice per day, and furosemide 20 mg/ day. Her headaches per­sisted, and 6 months after the initiation of therapy she also complained of progressive blurred vision in the left eye, diplopia, and decreased sensation of the left hand. On examination, visual acuity was 20/ 30 OU. There was a 0.3 log unit left relative afferent pupillary defect. Ophthalmoscopic exam­ination revealed bilateral optic disc pallor, left worse than right. There was decreased hearing on the right. She had patchy decreased sensation of the left hand. Gait was wide- based and unsteady. Repeat lumbar puncture revealed an opening pres­sure of 280 mm of water, 1 white blood cell, normal protein and glucose, and no oligoclonal bands. Sedimentation rate was 38, thyroid function tests were normal, ANA, RPR, ACE levels, and Lyme titer were negative. MRI of the brain demonstrated multiple, nonenhancing, bright T2 periventricular lesions consistent with demyelinating disease. Her acetazolamide dosage was increased, and her prednisone and furosemide was discontinued. The patient's symptoms gradually improved. Follow- J Neuro- Ophthalmol, Vol. 14, No. 4, 1994 Multiple Sclerosis and Intracranial Hypertension 191 up lumbar puncture 3 months later revealed an opening pressure of 210 mm of water and normal cerebrospinal fluid. Approximately 6 months later, the patient complained of " blind spots in the left eye," vertigo, increased difficulty with balance, and numbness over the distal left upper extremity and the occipital area of the scalp. Repeat MRI demonstrated periventricular white matter lesions without change. Lumbar puncture revealed an opening pressure of 180 mm of water, and the cerebrospinal fluid was positive for oligoclonal bands. DISCUSSION These three patients had papilledema, docu­mented elevation of intracranial pressure, other­wise unremarkable cerebrospinal fluid, and no ev­idence of hydrocephalus or encephalopathy, all compatible with the diagnosis of idiopathic intra­cranial hypertension or pseudotumor cerebri ( 1,2). They also had experienced episodes of neurologic dysfunction separated in time and space, best lo­calized to lesions in central nervous system white matter, consistent with demyelinating disease and the diagnosis of multiple sclerosis ( MS) ( 3- 5). In further support of the diagnosis of MS, all three patients had MRI periventricular white matter ab­normalities, and two had oligoclonal bands in their cerebrospinal fluid ( 3). While no feature alone is specific for MS, case 1 would meet the criteria for clinically definite multiple sclerosis, cases 2 and 3 for at least clinically probable MS and laboratory-supported definite MS. Is the association of pseudotumor cerebri and MS in these three patients coincidental? The over­all incidence of pseudotumor cerebri in the general population is estimated at approximately 1/ 100,000 ( 6). Among women ages 15 to 44 years, the inci­dence is 3.5/ 100,000. In obese women of this age who are more than 20% above ideal weight, the incidence increases to approximately 19/ 100,000. Our cases 1 and 2 were not obese and were 40 and 50 years of age, respectively, when papilledema was first noted. The incidence of multiple sclerosis among white women is estimated at approxi­mately 7/ 100,000 ( 7). The prevalence of both pseu­dotumor cerebri and MS would be greater than the reported incidence rates. In order to estimate the prevalence of pseudotumor cerebri, however, we would need to know the average duration of this disease. Unfortunately, there are no adequate studies that report the duration of pseudotumor cerebri, and those that do show great variability ( 8- 11). The prevalence of multiple sclerosis among white women has been estimated at 247/ 100,000 ( 7), although recent revised estimates suggest the prevalence may be somewhat greater ( 12). If not coincidental, how might these two dis­eases be related? One explanation is that the dis­ease process involved in multiple sclerosis some­how also causes an elevation of the intracranial pressure. There have been several reports of a " pseudotumoral" form of multiple sclerosis in which large demyelinating plaques with surround­ing edema act as mass lesions, often with a rapidly malignant course ( 13). The clinical course and neu-roimaging features mimic those of true brain tu­mors, and raised intracranial pressure would be expected. However, our three patients demon­strated neither the clinical features nor the neu-roimaging findings characteristic of this form of demyelinating disease. Butler and Gilligan ( 14) reported a 32- year- old man with laboratory- supported definite multiple sclerosis and obstructive hydrocephalus secondary to the mass effect of a plaque of acute demyelina-tion in the brainstem. Our patients showed no ev­idence of hydrocephalus or potentially obstructing plaques. The theory that a small, neuroradiologi-cally undetected plaque in some way transiently obstructed normal cerebrospinal fluid circulation was used by David and colleagues ( 15) to explain why intracranial hypertension was seen among the initial findings in a 45- year- old man presenting with his first manifestations of multiple sclerosis. Brainstem signs were accompanied by papillede­ma, headache, and vomiting. CT scanning re­vealed " slight bilateral ventricular enlargement." His condition improved with treatment with corti­costeroids and osmotic agents. He subsequently had two further episodes of neurologic dysfunc­tion consistent with multiple sclerosis and unac­companied by papilledema. Although our three cases appear somewhat unique in the English literature in their association of multiple sclerosis and raised intracranial pres­sure, the Russian literature refers to cerebrospinal fluid hypertension in the setting of MS exacerba­tion as if it were a commonly accepted association ( 16). A total of 40 patients, 29 women and 11 men, ages 24- 44, were studied during an exacerbation of MS. All of them had raised intracranial pressure ( 220- 380 mm of water) and symptoms of head­ache, nausea, and sometimes vomiting and changes in mentation. In 33 patients there was widening of the third ventricle by " echoencepha-lography." Although most patients had an in­creased number of T lymphocytes in the cerebro­spinal fluid, no specific details are given regarding the number of white blood cells or the protein lev- / Neuro- Ophthalmol, Vol. 14, No. 4, 1994 192 N. J. NEWMAN ET Ah. els within the spinal fluid. No mention is made of papilledema. The authors hypothesize that, dur­ing the flares of multiple sclerosis, the increased IgG and oligoclonal bands cause changes in the osmotic and oncotic pressures within the cerebro­spinal fluid, thereby disturbing the blood brain barrier and elevating the intracranial pressure. Other theories to explain a causal relationship would need to explore ways the multiple sclerosis process could decrease cerebrospinal fluid resorp­tion or increase production. None of our three pa­tients had elevated spinal fluid protein levels or significant cellular content. It would be highly un­likely that raised intracranial pressure alone would cause the episodic neurologic symptoms and signs as well as the MRI findings in our cases. However, it is conceivable that autoimmune triggers could result in both diseases. Finally, the treatment of presumed demyelinating disease frequently in­volves the use of corticosteroids, agents whose use as well as whose rapid withdrawal have been as­sociated with raised intracranial pressure. All of our patients had papilledema noted prior to any corticosteroid treatment. The association of demyelinating disease and in­tracranial hypertension may be missed in patients with concurrent or presumed papillitis. Alterna­tively, those patients with multiple sclerosis and optic atrophy secondary to previous episodes of optic neuritis may fail to exhibit disc edema even if the intracranial pressure is elevated. 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