Research Changes Understanding of Posttraumatic Headache

NAPLES, FL—A growing literature on posttraumatic headache suggests that many of the accepted principles of onset, course, and treatment should be re-examined. Data suggest that pathogenesis is multidimensional, and neurologists still lack evidence-based treatments, according to a lecture delivered at the 45th Annual Meeting of the Southern Clinical Neurological Society.

When Does Onset Occur?

To begin with, research is calling the current definition of posttraumatic headache into question. Data culled from head injuries in the military, professional sports, and everyday trauma show that headache onset more than seven days after the trauma is not the exception it once was believed to be.

“Regarding soldiers in particular, only 37% report posttraumatic headache onset within seven days of their injury,” reported Bert B. Vargas, MD, Director of the Sports Neurology and Concussion Program at the University of Texas Southwestern Medical Center in Dallas. “The rest of them presented up to several weeks later.”

Bert B. Vargas, MD

Of these others, 20% developed headache from one week to one month after the head trauma, and the remaining patients, more than 40% of the total, noted onset of headache more than a month later. “This is compelling evidence that seven days is perhaps not really the right timeframe” when considering a diagnosis of posttraumatic headache and suggests a need to revisit existing diagnostic criteria, said Dr. Vargas.

A New Understanding of Phenotype

The accepted phenotypes of posttraumatic headache have also shifted over the past several years, according to Dr. Vargas. Although tension-like headache was considered characteristic of most posttraumatic headache in years past, researchers familiar with International Classification of Headache Disorders (ICHD) criteria for migraine and other headache disorders found that the tension-type phenotype represented only about 20% of posttraumatic headache. Migraine (∼40%) and probable migraine (∼25%) are the most representative phenotypes, Dr. Vargas said. About 10% of patients have a cervicogenic phenotype, while other phenotypes, like cluster headache, are less common.

Prognosis has also been revisited. More rigorous follow-up shows that a one-to-two-week recovery period is not as typical as once was believed, said Dr. Vargas. An examination of military and athletic injuries suggests that half or more patients continue to have recurring headaches at three months, and as much as one-third have them at the end of one year. In one study, 24% of patients still had recurring headaches at four years. A more recent study reported that at five years after injury, as much as 36% of patients may experience headache several times per week or daily.

Research Clarifies Pathophysiology

The close association between posttraumatic headache and migraine is consistent with the underlying pathophysiology derived from experimental models. In these models, the depolarization caused by concussive force produces a shift in ions that can disrupt neuronal metabolic function, Dr. Vargas said. Similar metabolic changes are associated with migraine aura. These changes include potassium efflux and sodium influx. The increased energy demand produced by activation of ion pumps can be complicated by diminished cerebral blood flow, thus impairing the cell’s drive to maintain homeostasis.

In this cascade of events, which includes cortical spreading depression, headache pain for posttraumatic headache and migraine is believed to be generated by activation of glial cells and release of factors such as calcitonin gene-related peptide (CGRP) that are implicated in pain signaling. “If the accepted pathophysiologies are correct, then what is happening on an intracellular level after concussion is similar to what is seen in migraine aura,” said Dr. Vargas.

Potential Changes in Treatment

Regarding medications commonly used for prophylaxis of posttraumatic headache, “we see a great deal of overlap with medications that are commonly used to treat migraine,” Dr. Vargas said. The evidence supporting the benefit of these agents is generally derived from small, retrospective, open-label studies, however. In one retrospective study in soldiers, topiramate outperformed tricyclic antidepressants, propranolol, and valproate with regard to decrease in headache frequency and Migraine Disability Assessment score in patients with posttraumatic headache. In this study, triptans outperformed nontriptans for acute treatment at two hours. The response rate was better, however, for posttraumatic headache associated with blunt trauma, relative to blast trauma (86% vs 66%).

This difference is potentially important, because experimental studies of blunt and blast concussions suggest that they may be different. “In rodent models, blunt force injury has been shown to result in mast cell degranulation and decrease in the actual density of the mast cells on the ipsilateral and contralateral side of the injury within 72 hours,” said Dr. Vargas. Blast injuries in rodents, in contrast, produce “a delayed and bilateral mast cell degranulation at day seven.” Although further degranulation occurs after this point, the persistence in mast cell density suggests that “the cascades of events that ensue after blunt trauma and blast injuries may be different and may have a meaningful influence on treatment and our expectations for recovery timelines,” said Dr. Vargas.

Even if the best treatments for blast and blunt posttraumatic headache differ, however, there is a lack of well-conducted clinical trials for either condition. Based on available evidence and his own experience, Dr. Vargas concluded that all or most of the therapies used for acute treatment and prophylaxis of migraine are effective in at least some patients with posttraumatic headache. As a precaution, “despite excellent evidence that it is an effective migraine prophylactic medication, I find myself avoiding topiramate as a first-line treatment,” due to concern that this agent may exacerbate the cognitive dysfunction frequently associated with concussion, said Dr. Vargas. Despite some headache specialists’ belief that extended-release topiramate has less effect on cognitive function, Dr. Vargas is not aware of any head-to-head study confirming that the drug reduces this risk.

Despite the evidence that migraine medications offer relief in posttraumatic headache, they are not the first choice for many clinicians, said Dr. Vargas. In one study, between 2% and 5% of patients with posttraumatic headache received triptans. In an ongoing concussion registry in Texas that has now enrolled more than 2,000 patients, “we have observed frequent use of either nonsteroidal anti-inflammatory drugs or acetaminophen,” but initial treatment with migraine-specific medications, such as triptans, is not common, said Dr. Vargas. The data from this registry suggest that many patients, particularly those with a migraine phenotype, appear to report suboptimal pain control.

“Our registry data support other studies showing that migraine-specific medications may be underutilized in posttraumatic headache—including those with migrainous features,” said Dr. Vargas, who helped develop the concussion registry. “An important question that we must address is whether more aggressive treatment directed toward headache phenotype leads to better short- and long-term outcomes.

“Additionally, although current expert opinion suggests that treatment of posttraumatic headache should be based on treatment algorithms based on headache phenotype, well-designed prospective studies are needed to address this question.”

More rigorously defined treatment algorithms have become an urgent need in the context of growing evidence that posttraumatic headache can result in significant morbidity. Dr. Vargas cited one study in which 18.7% of soldiers with persistent posttraumatic headache returned to combat. Also, concern about the long-term consequences of posttraumatic headache from sports-related concussion is growing. In the context of the frequency of posttraumatic headache, Dr. Vargas believes there is an urgent need for objective studies to improve care.

Dr. Vargas reported financial relationships with Amgen, Alder, Avanir, Lilly, Pernix, and Upsher-Smith.