Journal of Neuro-Ophthalmology, June 2004, Volume 24, Issue 2

Chronic Intracranial Hypertension with Unexplained Cerebrospinal Fluid Pleocytosis

In a retrospective review of all cases with a diagnosis of idiopathic intracranial hypertension in two academic departments of neurology over a nine-year period, the authors identified six patients with a clinical course typical of idiopathic intracranial hypertension (IIH) except for the finding of cerebrospinal fluid pleocytosis. There were five women and one man with a mean age at presentation of 25.7 years (range, 25-32 yr). All were obese but had no other associated medical conditions or identifiable risk factors for IIH. In five patients, all or most cerebrospinal fluid cells were lymphocytes. Cerebrospinal fluid pleocytosis persisted for several months in all patients. Patients underwent a thorough laboratory and neuroimaging evaluation that did not reveal a primary cause. Medical treatment directed solely at lowering intracranial pressure was effective in five patients; one patient required lumboperitoneal shunting. Ophthalmic manifestations of increased intracranial pressure stabilized or remitted after treatment was withdrawn with a mean follow-up period of 33 months (range, 14-55 mo). Some patients may present with idiopathic chronic meningitis and elevated intracranial pressure that responds to treatment used for IIH.

ORIGINAL CONTRIBUTION Chronic Intracranial Hypertension with Unexplained Cerebrospinal Fluid Pleocytosis Yaniv Barkana, MD, Neta Levin, MD, Yochanan Goldhammer, MD, and Israel Steiner, MD Abstract: In a retrospective review of all cases with a di­agnosis of idiopathic intracranial hypertension in two aca­demic departments of neurology over a nine- year period, the authors identified six patients with a clinical course typical of idiopathic intracranial hypertension ( IIH) except for the finding of cerebrospinal fluid pleocytosis. There were five women and one man with a mean age at presen­tation of 25.7 years ( range, 25- 32 yr). All were obese but had no other associated medical conditions or identifiable risk factors for IIH. In five patients, all or most cerebrospi­nal fluid cells were lymphocytes. Cerebrospinal fluid pleo­cytosis persisted for several months in all patients. Patients underwent a thorough laboratory and neuroimaging evalu­ation that did not reveal a primary cause. Medical treatment directed solely at lowering intracranial pressure was effec­tive in five patients; one patient required lumboperitoneal shunting. Ophthalmic manifestations of increased intracra­nial pressure stabilized or remitted after treatment was withdrawn with a mean follow- up period of 33 months ( range, 14- 55 mo). Some patients may present with idio­pathic chronic meningitis and elevated intracranial pressure that responds to treatment used for IIH. ( JNeuro- Ophthalmol 2004; 24: 106- 108) diopathic intracranial hypertension ( IIH), or pseudotumor cerebri, is a clinical syndrome characterized by headache and increased intracranial pressure, with no focal neuro­logic signs except for abducens nerve paresis and without any evidence on neuroimaging of structural brain disease, including the lack of ventriculomegaly ( 1- 3). One of the accepted diagnostic criteria strictly specifies normal cere­brospinal fluid ( CSF) composition. If white blood cells are From the Department of Neurology, Sheba Medical Center, Tel Hashomer, Tel Aviv ( YB, YG), and the Department of Neurology, Hadas-sah- Hebrew University Hospital, Jerusalem ( NL), Israel. Dr. Barkana is currently with the Department of Ophthalmology, As-saf Harofe Medical Center, Beer Yaacov, Zerifin, Israel. Address correspondence to Yaniv Barkana, MD, Department of Ophthalmology, Assaf Harofe Medical Center, Beer Yaacov, Zerifin 70300, Israel. E- mail: idityaniv@ yahoo. com found in the CSF, the working diagnosis is meningitis and diagnostic efforts are focused on finding a primary cause for the intracranial hypertension to introduce specific treat­ment. Although IIH has been associated with diverse etio-logic factors, in many instances the association is circum­stantial rather than causal, and the mechanism responsible for this condition remains elusive ( 2). In the majority of patients with IIH, no cause can be identified. Within the past few years, we have encountered sev­eral patients who have fulfilled the criteria required for the diagnosis of IIH except for the presence of CSF pleocytosis. An extensive workup for the cause or origin of the disease did not yield any underlying abnormality, and the patients followed a clinical course typical of IIH. All responded to pharmacological or surgical therapies recommended for the treatment of IIH. The aim of the present report is to draw attention to a disorder of chronic meningitis that mimics the course of IIH and, despite intense diagnostic efforts, re­mains idiopathic and resolves with treatment that is neither anti- infectious nor anti- inflammatory. METHODS We reviewed the files of all patients who were hospi­talized with the diagnosis of IIH from January 1991 to De­cember 1999 in the departments of neurology of Sheba Medical Center, Tel Hashomer ( Tel Aviv, Israel) and Ha-dassah- Hebrew University Hospital ( Jerusalem, Israel). All patients who had CSF pleocytosis were identified and included in the present study. For these patients, data were collected from patient charts, including gender, age at presentation, obesity, symptoms and signs, CSF findings on presentation, results of diagnostic workup, and clini­cal course. RESULTS Over a nine- year period, six patients were identified with a clinical picture typical of IIH except for the presence of CSF pleocytosis. There were five women and one man. Mean age at presentation was 25.7 years ( range, 17- 32 yr). Mean follow- up was 33 months ( range, 14- 55 mo). Clinical data are summarized in Table 1. All patients were obese, as defined by body mass in­dex greater than 30 kg/ m2. Otherwise, none had associated 106 J Neuro- Ophthalmol, Vol. 24, No. 2, 2004 Chronic Intracranial Hypertension JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 TABLE 1 Patient no 1 2 3 4 5 6 Patient no. . Clinical course A Glucose ( mg/ dL) ge( y) 25 32 29 17 26 25 and outcome Sex M F F F F F Opening CSF pressure ( mm H20) Obesity Yes Yes Yes Yes Yes Yes Presenting symptoms TVOs Headache, TVOs, nausea and vomiting TVOs Headache, TVOs, nausea and vomiting Headache Headache, vomiting, horizontal diplopia CSF cells/| iL (% lymphocytes) 125 ( 100) 152 ( 90) 66 ( few) 38( 100) 16( 100) 65 ( 100) Treatment Outcome Protein ( mg %) 55 31 45 46 46 43 Follow- up ( mo) 50 > 400 2 3 4 5 6 56 48 52 59 55 > 400 > 470 500 310 380 Acetazolamide for 3 mo, then prednisone 60 mg/ d for 3 mo, then open lumbar drain for 3 d, then LP shunt Acetazolamide for 4 mo Acetazolamide for 12 mo Acetazolamide for 6 mo Acetazolamide for 5 mo Acetazolamide for 6 mo Stabilized following LP shunt; irreversible inferior visual field defects in both eyes; bilateral optic disc pallor; visual acuity: 20/ 25 both eyes Remained normal after therapy stopped Remained normal after therapy stopped Remained normal after therapy stopped Remained normal after therapy stopped Remained normal after therapy stopped 55 14 29 33 31 36 CSF, cerebrospinal fluid; LP, lumboperitoneal; TVOs, transient visual obscurations. medical conditions or identifiable risk factors for IIH. All were afebrile throughout the clinical course. Upon presen­tation, all patients but one had bilateral swollen discs. All patients had elevated opening CSF pressures ( range, 380- 500 mm H20) and normal CSF glucose and protein values. The average number of white blood cells in the CSF on presentation was 77 cells/ uL ( range, 16- 152 cells/ uL). In # 1,4, 5, and 6, all cells were lymphocytes; in one patient (# 2), 90% were lymphocytes; and in one patient (# 3), the CSF contained predominantly polymorphonuclear leuko­cytes and a few lymphocytes. Five of the six patients had at least one additional CSF examination performed one to seven weeks after the initial spinal tap and performed as late as sevenmonths after presentation (# 1). Cerebrospinal fluid pleocytosis persisted in all repeated examinations, with a tendency to decrease in magnitude over time. All patients underwent a thorough laboratory evalu­ation ( Table 2). In none of the patients did it reveal a pri­mary central nervous system or a systemic cause for the clinical picture. Computed tomography scans of the brain and orbits were normal in all patients. Brain magnetic resonance im­aging in four (# 1,3,6, and 7) and magnetic resonance ve­nography in one patient (# 6) did not identify any cerebral or meningeal abnormalities ( including enhancement). Treatment with 250 mg acetazolamide every six hours resulted in prompt symptomatic relief in three pa­tients (# 2,3, and 6) and gradual improvement over a period of several months in two (# 4 and 5). These five patients remained asymptomatic following withdrawal of therapy TABLE 2. Blood serologic and ancillary cerebrospinal fluid studies Substance Studies Blood Cerebrospinal fluid Serologic studies for EBV, HSV, CMV, VDRL, TPA- ABS, Brucella, Borrelia burgdorferi, anti- DNA and anti- nuclear antibodies, ACE level Serologic studies for EBV, HSV, CMV, VDRL, cryptococcus; cultures for bacteria, chlamydia, viruses, and fungi; oligoclonal immunoglobulin G; ACE and ANA level; cytologic examination EBV, Epstein- Barr virus; HSV, herpes simplex vims; CMV, cytomeg­alovirus; VDRL, Venereal Disease Research Laboratories; TPA- ABS, tre-ponema pallidum antigen absorption; ACE, angiotensin- converting en­zyme; ANA, antinuclear factor. 107 JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 Barkana et al after four to 12 months. The one man (# 1) did not respond adequately to medical treatment, requiring lumboperitoneal shunt. DISCUSSION In the present study, we report six patients who had chronic or subacute meningitis with intracranial hyperten­sion and for whom the cause of CSF pleocytosis remained unexplained. Viewed alternatively, for these patients the criteria required for the diagnosis of IIH were met except for CSF pleocytosis because they presented with headache and papilledema without focal neurologic signs and neu-roimaging did not disclose any intracranial abnormality. None of the patients had systemic symptoms or signs of an infectious or an inflammatory process. All underwent a comprehensive workup that did not disclose an infectious, inflammatory, or malignant cause during a mean follow- up period of 33 months. Our patients had age and sex attributes typical for IIH. All had a course that resembles that of IIH, with five patients responding favorably to treatment with acetazol-amide and one patient improving after lumboperitoneal shunt. The pathogenesis of IIH is unknown. The syndrome may be due to an imbalance between the formation and the egress of CSF or a result of inability of intracranial structures, such as brain parenchyma and blood vessels, to accommodate increased volumes of CSF ( 1). Many conditions have been associated with the occurrence of the disorder, and in some, a cause- and- effect relationship has been established by clinical recovery following withdrawal of an exogenous causative agent and relapse upon repeat exposure ( 1). Especially relevant are systemic conditions associ­ated with the occurrence of IIH that are also capable of causing meningitis. Examples of such possible primary causes for IIH include several inflammatory, immune-mediated, or infectious disorders, such as systemic lupus erythematosus ( 4), Behget disease ( 5), human immunode­ficiency virus ( HIV) infection ( 6), and Lyme disease ( 7). IIH has also been reported in epidemics following viral in­fection without meningitis ( 8). However, although all these diseases are recognized causes of meningitis, the cited case reports have not documented CSF pleocytosis. CSF pleocytosis accompanies systemic infections with nervous system involvement in HIV infection ( 9), Lyme disease ( 10), and cryptococcal meningitis ( 11) and in association with sinusitis ( 12), but in none of these condi­tions has IIH been described. The pathogenetic mechanism linking the meningitis in the presented cases and the in­creased intracranial pressure is unclear. Both could be the independent outcome of a primary systemic condition. As an alternative, the meningitis could be the primary event and contribute to the occurrence of IIH by several mecha­nisms ( such as impeding CSF absorption at the arachnoid villi). Considering that all patients were overweight, which is a known risk factor for IIH, it might be possible that obese patients are predisposed to develop IIH in some cases of meningeal inflammation. 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