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Elevation of CSF Tumor Necrosis Factor α Levels in New Daily Persistent Headache and Treatment Refractory Chronic Migraine


  • Todd Rozen MD,

  • Sahar Z. Swidan PharmD

  • From the Michigan Head Pain and Neurological Institute–Neurology, Ann Arbor, MI (Dr. Rozen); and Michigan Head Pain and Neurological Institute–Pharmacy, Ann Arbor, MI (Dr. Swidan).

Address all correspondence to Dr. Todd Rozen, Michigan Head Pain and Neurological Institute – Neurology, 3120 Professional Drive, Ann Arbor, MI, 48104.


Objective.—To determine if patients with new daily persistent headache (NDPH) have elevated levels of tumor necrosis factor α (TNF α) in the CSF.

Background.—NDPH is considered one of the most treatment resistant of all headache syndromes. This reflects a lack of understanding of its pathogenesis. As a certain percentage of NDPH patients have their headaches start after an infection, the possibility of a persistent state of systemic or CNS inflammation comes into question. TNF α is a proinflammatory cytokine involved in brain immune and inflammatory activities, as well as in pain initiation. The goal of this study was to look at TNF α levels in the CSF of NDPH patients, to determine if CNS inflammation may play some role in the pathogenesis of this condition.

Methods.—CSF TNF α levels were studied in 38 patients: 20 with NDPH and a control population of 16 patients with chronic migraine (CM), and 2 with post-traumatic headache (PT).

Results.—CSF TNF α levels were elevated in 19 of 20 NDPH patients, 16 of 16 CM patients, and both PT patients. Serum TNF α levels were normal in most of the study subjects.

Conclusion.—An elevation of CSF TNF α levels was found in almost all NDPH patients and suggest a role for TNF α in the pathogenesis of this condition. Surprisingly, all CM and PT patients tested had elevated CSF TNF α levels. In most patients with elevated CSF levels, serum TNF α levels were normal. All of these syndromes may be manifestations of CNS inflammation. As most of the positive-tested patients showed minimal to no improvement during aggressive inpatient treatment, persistent elevation of CSF TNF α levels may be one of the causes of treatment refractory CDH.