High Incidence of Post–Lumbar Puncture Headaches in Patients With Multiple Sclerosis Treated With Natalizumab: Role of Intrathecal Leukocytes

The reported frequency of post–lumbar puncture headache (PLPH) is as high as 70%.¹ In contrast, the frequency of PLPH with an atraumatic 22-gauge Sprotte needles is 12.2%.²

Natalizumab (Tysabri; Biogen Idec, Cambridge, Massachusetts) is a recombinant humanized monoclonal antibody that binds to the α₄ chain of the α₄β₁ and α₄β₇ integrins. Natalizumab reduces the extravasation of T lymphocytes, B lymphocytes, and plasma cells into the central nervous system.^3,4 We tested the association between lymphocyte numbers in the peripheral blood and cerebrospinal fluid (CSF) and the frequency of PLPH in patients with relapsing-remitting multiple sclerosis who were receiving natalizumab therapy and 14 months after cessation of therapy.

Patients receiving natalizumab therapy were recruited at the University of Texas Southwestern Medical Center at Dallas (UTSW) and at the Multiple Sclerosis Center at Texas Neurology.^3,4 Twenty-one of the patients were female, 2 were male. Fourteen months after cessation of natalizumab therapy, CSF was obtained from 12 of the original patients. Informed consent had been granted.

Only CSF samples that were obtained with 22-gauge Sprotte needles were included in the analysis. Four investigators performed an equal percentage of lumbar punctures at both time points. A total of 30 mL of CSF was obtained. The stylet was replaced before removing the spinal needle. In all patients except 1, CSF was successfully obtained during the initial attempt. In 1 patient, 2 attempts were required. This particular patient did not develop a PLPH. Routine assessment of PLPH was conducted in all patients at the Multiple Sclerosis Center at UTSW. Patients were asked to remain recumbent for 1 hour after the procedure. Patients were provided with additional printed information on PLPH, and they were asked to contact the clinic should they experience symptoms consistent with this diagnosis. All procedures were approved by the UTSW institutional review board. Cells in the CSF and peripheral blood were counted by light microscopy and analyzed by flow cytometry.^3,4

Statistical analysis was performed with a GraphPad Prism 4 (version 4.03; GraphPad Software Inc, San Diego, California). Normally distributed variables were compared by t tests. Not normally distributed samples were compared using the Mann-Whitney U test. To determine nonrandom associations between 2 categorical variables, the 2-sided Fisher exact test was employed. Significance was defined as P<.05. Power analyses were calculated using Stata 9.0 software (StataCorp LP, College Station, Texas).

The patient cohort examined in this study is described elsewhere.^3,4 At either study time point, there was no significant difference between the patients who developed PLPH and those who did not with regard to age and sex (data not shown).

Five of 22 patients (23%) contacted our clinic within 48 hours and reported a PLPH. Three patients (13%) required an epidural blood patch. Fourteen months after cessation of natalizumab therapy, 1 of 9 patients (11%) developed PLPH.

The number of lymphocytes were within normal limits at both time points, and there was no statistical difference between the 2 cohorts. The numbers of total white blood cells in CSF was significantly lower when patients were on natalizumab therapy as compared with 14 months after cessation of natalizumab (P<.001). Cell numbers and phenotypes between patients with and without PLPH could not be statistically analyzed at the second time point as only 1 patient developed a headache.

The frequency of PLPH observed in patients with multiple sclerosis treated with natalizumab was unexpectedly high. The pathogenesis of PLPH is thought to be a prolonged CSF leakage due to compromise of the dural sac and a subsequent decline in CSF pressure. Pain may be triggered by intracranial arterial and venous dilatation. Compensation of volume loss by CSF production and resistance to CSF outflow may prevent PLPH. It was reported in a prospective multicenter trial that leukocyte pleocytosis associated with viral meningitis significantly lowers the frequency of PLPH.⁵ Our data further suggest that the absolute number of leukocytes within the CSF may determine the overall risk of developing PLPH.

At the initial time point, natalizumab had just been withdrawn from the market because of unexpected serious adverse events. It is conceivable that patients on natalizumab therapy may have perceived their illness or the circumstances of the natalizumab withdrawal differently than they did 14 months later. These are factors that could potentially alter the pain threshold of PLPH.

The sample sizes in this study were too small to demonstrate a significant difference in PLPH frequency between the 2 cohorts. Assuming a PLPH frequency that was observed in the 2 patient cohorts in this study, the estimated sample size to show significance for 2-sample comparison of proportions with an α of .05 (2-sided) and a power of 0.90 would be 256 patients per sample.

Correspondence: Dr Stüve, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9036 (olaf.stuve@utsouthwestern.edu).

Author Contributions:Study concept and design: Stüve, Frohman, and Racke. Acquisition of data: Stüve, Cravens, Singh, Frohman, Phillips, Remington, Olek, Monson, and Racke. Analysis and interpretation of data: Stüve, Frohman, Hu, and Hemmer. Drafting of the manuscript: Stüve, Singh, Frohman, Phillips, Remington, Hu, and Hemmer. Critical revision of the manuscript for important intellectual content: Stüve, Cravens, Frohman, Olek, Monson, and Racke. Statistical analysis: Stüve, Cravens, and Hemmer. Obtained funding: Stüve, Frohman, Monson, and Racke. Administrative, technical, and material support: Stüve, Singh, Frohman, Phillips, Remington, Olek, and Racke. Study supervision: Stüve, Frohman, Monson, and Racke.

Financial Disclosure: None reported. Although the AFFIRM monotherapy trial and the SENTINEL add-on trial with interferon beta-1a (Avonex) were sponsored by Biogen Idec Inc and Elan Corp, the manufacturers of natalizumab, the work presented in this study was not.

Funding/Support: This work was supported in part by a start-up grant from the Dallas VA Research Corporation, a New Investigator Award from VISN 17 in the Department of Veterans Affairs, grant RG3427A8/T from the National Multiple Sclerosis Society (NMSS), and a grant from the Viragh Foundation (O.S.). Support also came from grants NS37513 and NS44250 from the National Institutes of Health and grant RG2969-B-7 from the NMSS (M.K.R.). Additional support came from grants He2386/4-1 and He2386/4-2 of the Deutsche Forschungsgemeinschaft (B.H.) and grant NS40993 from the National Institutes of Health (N.L.M.).

Additional Contributions: We thank our patients for participating in this study. Brittney Fort, Jane Lee, Janey Phillips, Jill Fowler, Nancy Perna, and Subir Sinha assisted in data acquisition.