Lumbar Puncture for Diagnosis of Idiopathic Intracranial Hypertension in Typical Patients

Background: Patients with typical features of pseudotumor cerebri syndrome (PTCS) must undergo lumbar puncture (LP) to demonstrate elevated opening pressure and cerebrospinal fluid (CSF) analysis to rule out alternative diagnoses. As LP may be associated with significant morbidity, this study aims to determine its necessity in diagnosing typical PTCS. Methods: Retrospective chart review at 3 university-based neuro-ophthalmology practices included women aged 18-45 years with body mass index >25, papilledema, negative neuroimaging, and who met criteria for PTCS or probable PTCS. Results: One hundred fifty-six patients were enrolled. Seven (4.5%) had clinically insignificant CSF abnormalities. No diagnoses or management changed based on LP/CSF results. Conclusion: LP may not be routinely required in the initial evaluation of typical patients with PTCS evaluated by experienced clinicians We caution, however, that further prospective study is required to determine potential risks and benefits of LP as a tool in the diagnosis of IIH before recommending general practice changes.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Lumbar Puncture for Diagnosis of Idiopathic Intracranial Hypertension in Typical Patients Mathew S. Margolis, MD, Adam A. DeBusk, DO, Mark L. Moster, MD, Julie M. Falardeau, MD, Eric R. Eggenberger, DO, Robert C. Sergott, MD, Gregory P. Van Stavern, MD Background: Patients with typical features of pseudotumor cerebri syndrome (PTCS) must undergo lumbar puncture (LP) to demonstrate elevated opening pressure and cerebrospinal fluid (CSF) analysis to rule out alternative diagnoses. As LP may be associated with significant morbidity, this study aims to determine its necessity in diagnosing typical PTCS. Methods: Retrospective chart review at 3 university-based neuro-ophthalmology practices included women aged 18–45 years with body mass index .25, papilledema, negative neuroimaging, and who met criteria for PTCS or probable PTCS. Results: One hundred fifty-six patients were enrolled. Seven (4.5%) had clinically insignificant CSF abnormalities. No diagnoses or management changed based on LP/CSF results. Conclusion: LP may not be routinely required in the initial evaluation of typical patients with PTCS evaluated by experienced clinicians We caution, however, that further prospective study is required to determine potential risks and benefits of LP as a tool in the diagnosis of IIH before recommending general practice changes. Journal of Neuro-Ophthalmology 2021;41:375–378 doi: 10.1097/WNO.0000000000001319 © 2021 by North American Neuro-Ophthalmology Society I diopathic intracranial hypertension (IIH), a disorder of increased intracranial pressure, affects 2 per 100,000 Department of Ophthalmology and Visual Sciences (MSM), Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois; Department of Ophthalmology and Visual Sciences (GVS), Washington University School of Medicine, St. Louis, Missouri; Department of Neuro-Ophthalmology (AD, MLM, RCS), Wills Eye Hospital; Department of Ophthalmology (JF), Oregon Health and Science University; and Department of Neurology (EE), Mayo Clinic, Jacksonville, Florida. A. DeBusk: Research support: GenSight; M. L. Moster: Research support: GenSight and Regenera and speaker: Sanofi Genzyme. The authors report no conflicts of interest. Address correspondence to Gregory Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110; E-mail: [e-mail] Margolis et al: J Neuro-Ophthalmol 2021; 41: 375-378 people in the general population and can occur at a rate up to 15 times higher in overweight and obese women of reproductive age (1,2). The syndrome of intracranial hypertension with normal brain parenchyma without ventriculomegaly, mass lesion, venous sinus thrombosis, underlying infection, or malignancy has been generally referred to as IIH or primary pseudotumor cerebri syndrome (PTCS) (3). This syndrome classically presents with headache (84%), transient visual obscurations (64%), pulsatile tinnitus (52%), and papilledema with a potential for vision loss (34%) (1). Although vision loss is often reversible, severe and permanent visual loss can occur in up to 10% of PTCS cases (4). Several hypotheses are currently under investigation to explain the underlying pathophysiology resulting in “idiopathic” intracranial hypertension. Competing theories include sex, endocrine, and fat hormone imbalances, as well as those related to the overproduction or underabsorption of cerebrospinal fluid (CSF) (2). Regardless of pathophysiology, the phenotype of typical IIH is easily identifiable and treatment has been well described. A subset of IIH defined as “atypical” included prepubescent, men, nonobese, and elderly patients, as well as those with atypical features. These patients generally require a much more extensive workup screening for a secondary cause (5). Currently accepted criteria for the diagnosis of IIH are based on clinical examination findings (papilledema or cranial nerve [CN] VI palsy and no other CN deficits), neuroimaging (normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on MRI, as well as neuroimaging features suggestive of IIH and/or papilledema), lumbar puncture (LP) results including opening pressure (OP) .25 cm H2O, and CSF studies not suggestive of alternative etiologies. Patients who have normal or borderline OP but meet all other criteria may be diagnosed with “probable” IIH (3). This is in part due to the fact that 375 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the normal range of OP is larger than previously described and the variability of positions used to measure OP, which may undermine the validity of the pressure measurement (6). Therefore, in a typical patient with IIH (overweight or obese women of reproductive age with bilateral optic disc edema) with classic neuroimaging features, the treatment and management may be identical regardless of the OP. In many such cases, the role of LP is primarily to exclude meningitis. Although rare meningeal complications may potentially masquerade as IIH, a recent retrospective analysis of 60 participants with typical PTCS at the Wills Eye Hospital found no such cases. Six patients (10%) had CSF findings that necessitated follow-up; however, all those were deemed clinically insignificant. All patients were diagnosed with probable IIH and followed a typical treatment course without alternative diagnoses or change in outcome for an average follow-up of 26 months (7). Although LP and CSF results currently are a part of the IIH diagnostic criteria, they are not without risk. The LP is an invasive procedure that has been associated with patient discomfort and severe headache due to intracranial hypotension (8,9). Recent prospective studies have found a postLP headache rate of 17.5%–32.2% (10–12), and a recent retrospective review found that 10% of patients with IIH who received LP required a blood patch to treat post-LP headache (13). Other rare complications include cerebral herniation, cord compression, nerve injury, infection, and epidermoid tumors (14,15). In addition, LP is increasingly performed under fluoroscopy, resulting in radiation exposure and increased cost (16). Given the morbidity associated with LP, this study was designed to determine the need for such a diagnostic procedure as part of the initial diagnostic workup in patients presenting with typical demographic and clinical features of IIH to experienced neuroophthalmology services. features indicative of alternative etiologies; and follow-up less than one year or before resolution of symptoms. Data Collection Approval for this study was obtained from the Washington University Human Research Protection Office, the Wills Eye Hospital Institutional Review Board (IRB), and the Oregon Health and Science University IRB before data accumulation. All HIPAA regulations regarding the use of personal health information were strictly followed. The data below were collected. Demographics Age and sex. Clinical History and Examination Patient-reported symptoms of headache, transient visual obscurations, pulsatile tinnitus, diplopia, medication use, height, weight (and recent changes), and CN abnormalities. Diagnostic Testing Visual field data, imaging findings on any radiologic test used in diagnosis of IIH, and LP and CSF results including OP, cell count, protein and glucose, culture results if available, and any other CSF tests obtained. Main Outcome Measures The main outcome measures included OP on LP, CSF abnormalities, and change in diagnosis or management of participants with a diagnosis of “probable” IIH or CSF abnormalities. Statistical Analysis This study is limited to descriptive statistics. RESULTS METHODS Study Population A retrospective observational chart review was conducted at 3 university-based neuro-ophthalmology practices. Each institution’s database was interrogated for patients presenting with papilledema who were diagnosed with IIH or “probable” IIH (for those participants with LP OPs ,25 cm H2O) using established diagnostic criteria (3). Patients selected were consecutive cases who met the following inclusion criteria: female sex, body mass index .25, of reproductive age (18–45 years). Exclusion criteria included lack of LP or neuroimaging; participants with atypical presentations (history suggestive of alternate etiology including but not limited to medication induced), examination with atypical neurologic findings (including CN abnormalities beyond CN VI palsy), or neuroimaging 376 One hundred fifty-six patients with a mean age of 29.3 ± 7.4 years were included in this study. One hundred thirtysix patients (87.2%) had a diagnosis of IIH, and 20 patients (12.8%) were diagnosed with “probable” IIH due to OP ,25 cm. The median participant OP was 32.5 cm H2O with an STDV of 11.4 (range; 12.2–70). One hundred forty-nine CSF samples (95.5%) had no abnormalities, whereas 7 samples (4.5%) had CSF abnormalities. Of those 7, 4 had mildly elevated protein, 2 had mildly elevated white blood cell counts, and one had atypical lymphocytes. In those with OP ,25, 2 of the 20 (10%) had CSF abnormalities, whereas in those with OP $25, 5 of the 156 (3.2%) had CSF abnormalities (x (2) = 1.63; P = 0.20). All participants were followed for a minimum of 12 months or until complete resolution of symptoms. Participants with CSF abnormalities were followed for a Margolis et al: J Neuro-Ophthalmol 2021; 41: 375-378 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution mean of 27 mo (4–55 mo). All CSF abnormalities were found to be clinically insignificant with follow-up yielding no alternative diagnosis. No patients had changes in diagnosis or management based on LP results. Fifteen participants (9.6%) did require subsequent surgical procedures because of the progressive nature of their disease despite best medical management; however, no patients with CSF abnormalities required surgical treatment or had significant visual loss during the duration of follow-up. CONCLUSIONS In this retrospective review of 156 patients with typical signs and symptoms of IIH, diagnostic LP and CSF analysis did not alter diagnosis or management. No participants with CSF abnormalities required surgical treatment or had significant visual loss over an average of two-plus years of follow-up. Twenty (12.8%) participants were diagnosed as probable IIH based on OP; however, this did not change their management or outcome. Participants diagnosed with IIH and probable IIH had a similar rate of CSF abnormalities; none of which were deemed clinically significant. The total percentage of CSF findings above the reference range in our participants (4.5%) without alternative explanation is not much greater than the expected 2.5% of any reference range. Although rare meningeal complications may potentially masquerade as IIH, our study demonstrated no such cases. Although LP complications were not recorded in this retrospective review, rates of post-LP headache are known to range from 17.5% to 32.2% (10–12), and a recent retrospective review found 10% of patients with IIH required a blood patch after LP (13). With an incidence of up to 30 per 100,000 patient years and an estimated 61 million reproductive-age women living in the United States [Centers for Disease Control and Prevention; guttmatcher. org], the number of LPs for diagnosis of IIH may be as great as 18,300 per year. This yields up to 5,900 potentially avoidable cases of post-LP headache and up to 1800 blood patching procedures as part of the IIH diagnostic process per year. Rare adverse events including cerebral herniation, cord compression, nerve injury, infection, and epidermoid tumors occur at significantly lower rates (14,15). In addition to societal cost secondary to days of work lost, the cost to patients is high. One study from 2011 found the cost of IV caffeine infusion, a common treatment for post-LP headache, to be $2,475 for 500-mg dose ($297.90/60-mg vial) and the cost for a blood patch was $1,500. In addition, hospitalization in a neurology inpatient service was $1,209/day (17). LPs are increasingly performed under fluoroscopy and therefore involve exposure to radiation. A review of Medicare data found that although radiologists performed only 11.3% (n = 10,533) of LPs in 1991, they performed 46.6% (n = 45,338) in 2011 (16), now exceeding all other providers in the number of LPs. Although radiation dose is Margolis et al: J Neuro-Ophthalmol 2021; 41: 375-378 highly variable based on the method of fluoroscopy used, one review stated that the amount was comparable to a chest radiograph (18) (20–25 mGy and 4,000–5,000 mGy$cm2), if completed in under 20 seconds. Fluoroscopic guidance also comes at an additional financial cost, with one report citing an additional charge of $356 when LP was performed under fluoroscopy (19). Our study has several limitations including a retrospective and observational design, small sample size, and with all participants coming from tertiary referral centers. In addition, our results are not generalizable to patients with IIH who are atypical (men, normal body habitus, history of malignancy, atypical symptoms, examination, or imaging); do not present with papilledema; have severe disease warranting surgical intervention (shunting, optic nerve sheath fenestrations, and/or venous stenting); respond atypically to treatment; and present with new onset atypical findings during the course of follow-up. We also acknowledge that starting treatment for presumptive IIH before LP may result in overtreatment of patients with migraine, as well as pseudopapilledema, which may be reduced by careful clinical examination, ultrasound, fundus autofluorescence, and optical coherence tomography with enhanced depth imaging. All such patients require careful follow-up, and if they deviate from expected course and/or natural history of IIH, we strongly believe that LP is warranted. We also acknowledge that these results may not apply to patients undergoing evaluation by providers less well versed in the presentation, diagnosis, and management of IIH. The utility of all diagnostic procedures, particularly those of an invasive nature, should always be subject to reevaluation. At our respective institutions, LP has not been shown to change diagnosis or management of typical patients with IIH. When weighed against the significant morbidity induced by unnecessary and expensive medical testing, it is reasonable to question this practice. Under the care of an experienced clinician, defined as an academic, fellowship-trained neuro-ophthalmologist who routinely diagnoses and manages patients with IIH and other causes of papilledema in a clinical setting and can recognize the typical and atypical presentations, clinical and imaging findings, and clinical coarse, we believe LP may not always be warranted. These practitioners must be confident in their diagnosis and must actively use imaging studies to rule out alternative etiologies, such as optic disc drusen masquerading as papilledema, which may otherwise result in overtreatment. We caution, however, that further prospective study is required to determine potential risks and benefits of LP as a tool in the diagnosis of IIH before recommending general practice changes. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. S. Margolis, M. L. Moster, E. Eggenberger, J. Falardeau, and A. DeBusk; b. Acquisition of data: M. S. Margolis, M. L. Moster, E. Eggenberger, J. Falardeau, and A. 377 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution DeBusk; c. Analysis and interpretation of data: M. S. Margolis, M. L. Moster, E. Eggenberger, J. Falardeau, and A. DeBusk. Category 2: a. Drafting the manuscript: M. S. Margolis, M. L. Moster, E. 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