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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In January of 2012, 14 year old Ellie came down with a routine sinus infection. Her sinus infection seemed typical: fever, congestion, headache, fatigue. The symptoms eventually resolved, all, except the headache. A constant, 24/7 persistent headache that was “whole head” “whole hairline and upper neck”. Days turned into weeks, weeks into months, months into a year. Multiple doctor visits, all without much relief or explanation. The only thing that seemed to bring the pain down some was Topamax, but the side effects were difficult, no appetite and serious mood changes.
She eventually ended up at the Michigan Head & Neurological Institute with Dr. Joel Saper. Ellie was diagnosed with New Daily Persistent Headache which was described as a subset of Chronic Migraine.
Two weeks inpatient at MHNI with intravenous administration of various medications trying to break the headache brought no relief. Prior to discharge a series of nerve blocks were administered and a detectable, not substantial, but detectable, temporary lowering of her head pain was noted.
Two and a half years into Ellie’s headache, her father was researching other possible treatments including nerve decompression surgery and implanted nerve stimulators.
A 2014 article described an all too familiar story of a teenage girl named Meredith who missed two years of high school due to a debilitating constant headache. Meredith's journey started much like Ellie’s, dozens of specialists looking for infections or allergies. Trying nearly 50 different medications. Botox, nerve blocks and several week long hospital stays. All without relief. In June 2013 Meredith had life changing nerve decompression surgery by Dr. Bardia Amirlak.
Dr. Bardia Amirlak is a plastic surgeon at University of Texas Southwestern Medical Center in Dallas.
I had a chance to talk with Dr. Amirlak recently. I found him to be very candid with a cautious demeanor. “Nerve decompression surgery is not for everyone with a Chronic Migraine or New Daily Persistent Headache” he said. “We like to demonstrate nerve involvement by nerve blocks and/or botox. If we don’t detect any connection, surgery is probably not a good choice”
But for those who do demonstrate some connection, the results can be dramatic. Dr. Amirlak has operated on hundreds of chronic headache patients. About 60% of these patients get complete relief. Of the remaining 40%, nearly 90% of those experience at least a 50% reduction in pain.
Nerve decompression surgery for migraine was stumbled upon much like how botox was discovered for migraine. Plastic surgeons had patients who anecdotally found migraine relief after a plastic surgery procedure.
Dr. Amilak took this seriously and has become one of the pioneers in nerve decompression surgery.
In June of 2015, Ellie went to see Dr. Amilak. After extensive consultations and administrations of nerve blocks. Dr. Amirlak determined surgery was a promising option. Ellie woke from her surgery headache free. This was the first time in two and a half years she was without pain.
I spoke with Ellie’s mom Debra recently. Ellie is doing great, working full time, headache free. She gets normal headaches now from time to time. Headaches that respond to diclofenac.
For some, headaches like: chronic migraine, occipital neuralgia, new daily persistent headache and even some episodic headache patients can benefit from this kind of surgery.
In Ellie’s case, it appears that an infection left material inflamed or innervated causing compression along her nerves. Others speculate that there may be the possibility that the nerves get innervated and became hypersensitized. For some, these nerves may not have persistent compression around them, but by relieving normal pressure, allows these “hypersensitized” nerves to settle back to homeostasis..
For folks with new daily persistent headache that have not responded to nerve blocks or botox administered by their neurologist, is surgery not an option? Not always. Dr. Amilak has had patients respond to his nerve blocks that did not respond to nerve blocks by others.
Eventually, I believe we will find that NDPH is not a one size fits all headache. We will most likely find several subtypes that are driven by different onsets and pathways. For some, this innervated nerve pathway is diagnosable and treatable.
In the Summer of 2016, 14 year old Ashley was healthy and happy. Looking forward to vacationing with family friends. By mid July Ashley suddenly felt very different. Nausea, aches, pains and horrible head pressure. A headache like she had never experienced. Deep intracranial pressure, unrelenting, day & night. A local hospital tested Ashley for Lyme. The results were negative. That was that, it was a hospital test after all. A pediatric neurologist in Manhattan was the first to mention a difficult headache called New Daily Persistent Headache. Ashley’s mom finally felt maybe they were getting somewhere, a diagnosis. Elavil, a nerve pain medication and Tizanidine, a muscle relaxer were prescribed. Months and no change, the headache was constant. The doctor discontinued the Elavil and put Ashley on Topiramate. Topiramate is also a nerve pain medication and also an anticonvulsant used for treating seizures and migraine. Ashley's mom Tina had been doing her homework. Pouring over articles online, Tina learned that Lyme disease can often produce the symptoms that Ashley was haunted with and that Lyme tests were often inconclusive and false.
A new doctor and new tests, this time with a Lyme Literate Medical Doctor. This doctor, based upon clinical observation put Ashley on Doxycycline. Tests were eventually ordered from a lab called Igenex.
The Igenex tests came back negative for Lyme but positive, “off the charts positive” for Bartonella and positive for Babesia. Both common coinfections of Lyme infection. It is possible to get these co-infections without Lyme. She also tested positive for recent HHV-6 and clinically diagnosed with Mast Cell Activation Syndrome. Bartonella is actually quite common. It is common in the cat population and can easily be transmitted to humans through a scratch, flea or tick. For most people, the immune system is quite capable of suppressing this bacteria. Perhaps for some, maybe a combination of genetics and environment, a perfect storm happens and chronic infection overwhelms the central nervous system. Just prior to getting sick, Ashley received the Gardasil vaccine. There are some who speculate that the aluminum adjuvant nano-particle substrates contained in Gardasil react in those with certain genetic predispositions causing a cascade of excessive inflammation, activating dormant pathogens such as bartonella, babesia, HHV’s, etc. Ashleys doctor still did not dismiss the possibility of Lyme along with these coinfections as Ashley was taking doxycycline which perhaps suppressed the sensitivity of the test. Ashley started a heavy protocol of antibiotics along with an antiviral. Two months of Zithromax. One month of Ceftin. Three months alternating between Zithromax and Tinidazole. Including the Doxycycline, Ashley was on antibiotics for nine months. In February 2018, Ashley said her headache began to “break-up” and by the end of the month, it was pretty much gone. For the past six months Ashley’s big headache is gone. She still takes some supplements, Dolevent. She recognizes she is more prone to headaches now. When she is stressed, dehydrated, not sleeping regularly etc. But, the BIG headache is gone. So was it the pathogen protocol or the Topiramate?
There are other chronic daily headache related reports speculating that bartonella may be involved in some cases. Dr. Daniel Jaller in Rockville, Maryland is not afraid to treat complex chronically ill patients. He is not afraid of scrutiny, he “practices” medicine. He treats: ME/CFS, fibromyalgia, small fibre neuropathy, chronic headache, lyme & lyme related diseases as well as undiagnosed chronically ill patients. In 2014 he shared a clinical observation involving a 25 year old female with a new onset chronic daily headache. An unrelenting headache for over 18 months. The headache began shortly after returning from a camping trip. One year prior she had tested positive EIA and ⅔ Igm Western Blot bands meeting the CDC criteria for positive lyme. She was treated with doxycycline for 4 weeks with no impact on her headache. She was told by her neurologist that lyme disease was not relevant to her condition and an infectious disease specialist felt she was adequately treated. She had tried: topamax, neurontin, imitrex, fioricet and many other medications without effect. Upon physical examination she was completely normal with exception to subtle sensory deficits to cold objects touching her hands and feet. This was dismissed by all others, but Dr. Jaller has noted this phenomenon to be present in a high percentage of his patients with active lyme.
Bartonella species may be the most frequent coinfection in lyme disease. Prior to 1990, there were only two bartonella species named, today there are over 60 known bartonella species. The varied species may very well carry with them their own organ preferred host and unique accompanying symptomatic expression. In 2013 Maggi et al report the ability of bartonella henselae to invade the human brain vascular pericytes. Pericytes are small cells that surround endothelial cells and are an intricate constituent of the blood brain barrier. Again, bartonella can be tricky to test for. My guess is that most folks suffering with NDPH have not had extensive bartonella ePCR testing or treated for bartonella based upon clinical diagnosis.
Dr. Jaller treated her with zithromax, rifampin and tindamax. Within 4 weeks the symptoms had resolved, only to return after 5 days of discontinuation. The medication was reinstated for 3 months and the headache resolved and did not return.
Spend a week of inpatient headache treatment at a prominent headache center and they will likely include a Lyme panel in your workup. Bartonella is often not included. We know, however, Lyme can be tricky to test for. A chronic pathogenic infection plays havoc on the immune system. A disrupted immune system may not properly build the antibodies that the most common Lyme tests are looking for. Getting another opinion from Igenex or Galaxy may be warranted. Galaxy Diagnostics specializes in bartonella testing. Their ePCR test uses a triple serum draw test (draw serum every other day in attempts to catch the cycling bacteria).
New Daily Persistent Headache is rare. If it is merely inherited genetics, coupled with a virus or bacteria etc so many more people would have it. New Daily Persistent Headache was first recognized in medical literature in 1986. Just over thirty years ago. Why isn’t there reference to this headache in the literature in the hundreds of years before that? If genetics are involved then it is unlikely that only hereditary mutations are involved. There would be many more cases of NDPH for many centuries. If somatic mutations are involved (mutations occuring during a person's lifetime caused by an outside disruption, which don’t get inherited) then what are these outside disruptions that came to haunt us some thirty to thirty five years ago? Perhaps the smart money is on a combination of both, Inherited mutations coupled with somatic mutations coupled with a perfect storm of stressors and pathogens. We won’t know unless we research it. Please support research.
Coming Soon: Genetic Variants found in those with Chronic Lyme Disease
New Daily Persistent Headache
New daily persistent headache (NDPH) is a primary headache syndrome which can mimic chronic migraine and chronic tension-type headache. The headache is daily and unremitting from very soon after onset (within 3 days at most), usually in a person who does not have a history of a primary headache disorder. The pain can be intermittent, but lasts more than 3 months. Headache onset is abrupt and people often remember the date, circumstance and, occasionally, the time of headache onset. One retrospective study stated that over 80% of patients could state the exact date their headache began.
The cause of NDPH is unknown, and it may have more than one etiology. NDPH onset is commonly associated with an infection or flu-like illness, stressful life event, minor head trauma, and extra cranial surgery. Infection or flu-like illness and stressful life event are most often cited. The pathophysiology of NDPH is poorly understood.
The syndrome is difficult to treat and may persist for years. The age of onset ranges from 6 to greater than 70 years old, with a mean of 35 years. It is found to be more common in females in both the adult and pediatric populations. NDPH is rare. The Akershus study of chronic headache, a population based cross sectional study of 30,000 persons aged 30–44 years in Norway, found a one-year prevalence of 0.03 percent in the population.
In 1986, Vanast was the first author to describe the new daily-persistent headache (NDPH) as a benign form of chronic daily headache (CDH). The criteria for the diagnosis of NDPH were proposed in 1994 (the Silberstein–Lipton criteria) but not included in the International Classification of Headache Disorders (ICHD) until 2004. (Wikipedia)
New Daily Persistent Headache being poorly understood, we hope to bring interest and possibly demonstrate involved pathways of mechanism for future study. We are interested in funding trials of combinations of off label readily available medications that have a history of anecdotal limited efficacy in treating the symptoms of New Daily Persistent headache and or other related symptoms. For example: neurontin, flunarizine, propranolol, topiramate, famciclovir, LDN have some history of efficacy for NDPH. We are interested in multiple combinations of these drugs which have in other trials shown greater efficacy with a synergistic effect towards a variety of conditions. 66% of chronic migrainers also present with fibromyalgia. We are interested in trialing off label readily available medications that have some efficacy in treating chronic migraine and fibromyalgia. We believe that some patients with Chronic Migraine, NDPH, Fibromyalgia, PTSD, ME/CFS, Lyme Disease, CRPS & GWI have more in common with each other than with episodic migrainers. We are open to the idea that NDPH is not a subset of migraine at all and that perhaps it should be studied along with neuroinflammatory conditions triggered by some metabolic dysfunction.
Jeff Fowler, Director
NDPH Research Foundation
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