NDPH Research

TNF-alpha has long been suspected as a player in some cases of New Daily Persistent Headache.  Todd Rozen recorded elevated TNF-a in the CSF, but not serum, in a group of NDPH patients back in 2007.  Doxycycline, a known TNF-a antagonist has been trialed with mixed results.  This case report of a 24 year old male with a 6-year-long headache chases the elevated TNF-a theory with a new approach.

Case Report Summary: “A 24-year-old male presented with a 6-year-long continuous headache characterized by constant, bilateral pressure emanating from his temple. There was no family or pertinent past medical history. The pain had a pulsatile nature, and pain intensity was mostly constant at 8–9, on a self-reported numerical pain scale, with periods of increased pain reaching up to a 10. The pain was associated with exhaustion, nausea but not vomiting, position sensitivity, or photophobia. His symptoms led to difficulty in schoolwork and social interactions. From onset, the headache took a day to reach both 24/7 constancy and peak intensity. He could specifically recall the moment of headache onset, noting that it slowly built in intensity over a 24 h, making it inconsistent with a thunderclap onset. The patient sought medical evaluation and treatment from over 12 medical professionals including several headache specialists.

The patient self-administered Excedrin, Ibuprofen, and Acetaminophen without any benefit prompting a visit to his local neurologist. He was then administered Topiramate which was ineffective. The constancy of headache and associated nausea prompted a magnetic resonance imaging (MRI) study with contrast, in order to rule out any brain abnormalities, and found nothing of note. A sleep study was also conducted in order to rule out sleep apnea, which has been associated with chronic daily headache, and found no sleep abnormalities. Eventually, the patient sought out a headache specialist who found potentially elevated cerebral spinal fluid (CSF) pressure (24 cm H₂O) via lumbar puncture. A second puncture did not find elevation, and neither puncture improved the patient’s headache. Both punctures were taken in the lateral decubitus position. CSF analysis showed no evidence of meningitis, encephalitis, or any other abnormalities. Fundoscopic examination identified no papilledema which in conjunction with both lumbar punctures ruled out pseudotumor cerebri. Failure of headache responsiveness to Indomethacin ruled out hemicrania continua. Sustained pain and continued difficulty in school work led to a neuropsychiatric evaluation. Two areas of significant impairment were identified including immediate and delayed recall within stories (Wechsler Memory Scale-Revised (WMS-R)) and notably slow manual speed and dexterity in non-dominant left hand. Based on this history, he met the criteria for NDPH as outlined by International Classification of Headache Disorders (ICHD-3) beta.  Further physical examination identified cervical hypermobility, a trait associated with NDPH irrespective of triggering event.   Patient also exhibited discomfort over the auriculotemporal nerve distribution and tenderness over the greater occipital nerve region.

The patient cited a stressful life event as the triggering factor of the headache. Unlike other reported cases, our patient identified a prolonged period of stress associated with his transition to college life, rather than a singular triggering event. He was also heavily involved in academic research work, adding another layer of stress and workload. Directly prior to onset, patient reported period of biphasic sleep, high stress, and long “work” hours. The patient denied usage of alcohol or any illicit drug. There was no associated fever or chills. Patient also denies usage of any medications prior to onset or during treatment, other than those prescribed ruling out a medication-overuse headache. In total, over 20 medications/treatments were administered with no long-term benefit to headache pain.  However, we found that daily administration of Venlafaxine resulted in reduction of pain along with improving other symptoms such as nausea, exhaustion, and neuropsychiatric deficiencies.

The patient was administered 37.5 mg of Venlafaxine and instructed to incrementally increase dosage by 37.5 mg every week if no adverse side effects occurred. We found that a dosage of 300 mg resulted in a predictable attenuation of headache pain with the average pain score decreasing to a 3. After 3 months of treatment, we tried to see if removal of Venlafaxine would allow for retention of improvement. Following a 3 week washout, there was a rise in headache pain back to baseline along with accompanying symptoms. Readministration and titration of Venlafaxine once again ameliorated symptoms. Interestingly, 6 more months of Venlafaxine treatment resulted in resolution of pain.

In another case of NDPH, a patient with a proposed thunderclap onset subset of NDPH had complete remission of headache following administration of Nimodipine.  Nimodipine is a calcium channel blocker traditionally used in treating cardiovascular diseases, but now mostly used in the management of subarachnoid hemorrhage. It also appears to inhibit TNF-α production by microglial cells, through inhibition of NADPH preventing superoxide production.   In addition, Nimodipine inhibits cerebral artery vasospasm, a known downstream effect of TNF-α.

This patient was administered Nimodipine, but found no major relief. To some, this may point to a non-TNF-α method of activity for Venlafaxine treatment. However, the mechanism of action for both drugs is different. We speculate that NDPH is a cluster of diseases driven by chronic inflammation via TNF-α within the CSF explaining heterogeneity in specific drug responsiveness, but homogeneity in ultimate drug activity. Other NDPH case reports also suggest an inflammatory pathogenesis.”

This case report is important for several reasons.  The patient presents with classic NDPH including observed joint hypermobility that has been noted in multiple reports.  The significance of joint hypermobility seems apparent, yet, no hypothesis for a hypermobile/NDPH relationship has yet surfaced.  The trial of Venlafaxine in headache management is not extraordinary, however, most anecdotal reports that this author has observed from headache specialists, rarely achieve doses above 150mg.  This case report demonstrates attenuation at a dosage of 300mg. The general consensus is, 300mg could be difficult to reach due to adverse events, side effects.   An extremely conservative titration regimen may reduce AE’s.

The presented hypothesis of venlafaxine acting as an antagonist to TNF-a certainly seems reasonable, considering their washout and reintroduction period.  Yet, I suppose some other action of Venlafaxine not considered could have been responsible.  Venlafaxine is also known to have unique anti-pathogenic properties through bacterial efflux pump inhibition.  A case could be made that some NDPH is some sort of persistent infection and that if a case report hypothesized such and presented venlafaxine attenuating via it’s anti-pathogenic effects, a different conclusion could be inferred.   Until future research better elucidates the etiology of NDPH, we just don’t know.

NDPH Research Foundation is interested in supporting the following studies:

Cytokine, TNF-a CSF levels in a group of patients and controls.

Venlafaxine trial with TNF-a CSF levels before and after.

PCR -  blood serum , CSF & temporal artery tissue

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