While there is growing understanding of the pathophysiology of mTBI and acute concussion, the investigation into the pathophysiology of PCS/PCD is truly in its infancy. It is generally presumed that many of the secondary injury mechanisms involved in more severe TBIs may also contribute, in varying degrees, to the deleterious effects seen after mTBI and concussion. The magnitude, time scale, and interrelationship of these injurious cascades in mTBI are being investigated. A detailed overview of the pathophysiology is beyond the scope of this chapter and premature in its applicability to PCS/PCD. Secondary injury mechanisms recognized in TBI include [25]:

At this time it is unclear if any of these secondary injury mechanisms predominates in the development of PCS/PCD. It is also unclear if there may be a novel secondary injury mechanism of concussion not appreciated in more severe TBIs. As of today, a concussion is felt to be a functional or biochemical disturbance rather than a structural injury. However, it may be that our current imaging techniques are not advanced enough to pick up the exact structural damage occurring with concussion. It follows that PCS may be the result of persistent similar biochemical (and possibly structural) processes. Lastly, the contribution of psychogenic factors in the development of PCS engenders much debate and is currently unknown.

Accurate diagnosis of PCS is essential because these patients are severely disabled and use a disproportionate amount of healthcare. Therefore, it would be advantageous to be able to assess and identify early those patients who are likely to progress to PCS/PCD. Several methods have been explored including clinical symptoms, serum markers, and radiological studies.

The most cost-effective method of predicting PCS/PCD would be to determine which clinical signs and symptoms patients have at presentation of their initial injury that makes them high risk to progress to PCS/PCD. Lau looked at a cohort of high school football players and determined that out of many on-field signs and symptoms, only dizziness was significantly prognostic of prolonged recovery from concussion [26]. Sheedy et al. looked at a cohort of mTBI patients in the ED and at 1 month post injury. They found neurocognitive impairment, pain, and balance deficits were significantly associated with post-concussive symptoms [27]. Dischinger et al. looked at a similar cohort at 3-month follow-up and found anxiety and noise sensitivity were significantly associated with PCS [28]. Savola found skull fracture, headache, and dizziness as being significantly associated with the development of PCS [29]. Recently, Heitger et al. looked at impairment of eye movements and found that the duration of this impairment overlapped cerebral impairment in PCS/PCD [30]. Despite much effort there does not seem to be agreement in the literature about hallmark signs or symptoms that can select patients at high risk for PCS. More work is needed on the subject.

Of the many serum markers possibly linked to PCS three have received the most study: S100 protein, neuron-specific enolase, and cleaved tau protein. There are reports throughout the literature finding significance and no significance with each of these markers. However, a meta-analysis by Begaz et al. in 2006 incorporating 11 studies found that none of the above was significantly associated with development of PCS/PCD [31]. They proposed that while serum markers alone were inaccurate, perhaps a combination of serum markers and clinical signs and symptoms would be and suggested further exploration. Many imaging and monitoring techniques have been explored in an attempt to visualize structural changes in PCS patients. From electroencephalography (EEG) to positron emission tomography (PET) and most recently magnetic resonance (MR) technology, more research is being done exploring quantifiable physical changes in the parenchyma of PCS patients. Korn et al. found higher power in the delta band and lower power in the alpha band on quantitative EEG and focal reduction in perfusion and blood–brain barrier breakdown on single photon emission computed tomography (SPECT) in PCS/PCD patients versus healthy controls [32]. However, other studies found no benefit to EEG [33]. Peskind et al. looked at a cohort of 12 Iraq War Veterans with blast injuries and mTBI with fluorodeoxyglucose-PET [34]. They found hypometabolism in the cerebellar hemispheres, vermis, pons, and medial temporal lobe. They also found impairments in verbal fluency, cognitive processing speed, attention, and working memory similar to patients with non-traumatic cerebellar lesions. Though this was a small cohort, this line of research is encouraging and further investigation is warranted. Several different studies have looked at magnetic resonanace imaging (MRI) in PCS/PCD [35]. Smits et al. correlated diffusion-weighted imaging (DWI) and gradient echo images with Rivermead Postconcussion Symptoms Questionnaire. They found reduction of white matter correlated with severity of post-concussion symptoms. Though this study was limited by the small number of patients (n = 12). Messe et al. also used DWI to look at mTBI patients with PCS/PCD symptoms [36]. They found a loss of structural integrity at the subacute phase that resolved over time. Those PCS/PCD patients had larger deficits and longer duration of symptoms than controls. These studies strengthened the evidence of a structural derangement in PCS. Smits et al. looked at patients with PCS/PCD with functional MRI (fMRI) [37]. They found increased activation in the posterior parietal area, parahippocampal gyrus, and posterior cingulate gyrus. This was also proportional to severity of PCS/PCD symptoms. Though much encouraging work has been done there is a lack of consensus over imaging findings in patients with PCS. Though results are promising more work needs to be done.

As discussed above, defining, diagnosing, and predicting persistently symptomatic concussions can be a challenging endeavor. That said, treating PCS and these “difficult concussions” is often even more problematic. At this point, there are no evidence-based guidelines addressing the optimum management of persistently symptomatic concussions. This distinct clinical challenge is only recently getting the specific attention required to advance our approach to treatment. Our current treatment strategy remains largely anecdotal and incorporates many tenets from the management of acute concussions as well as more serious (and often structural) head injuries. This is obviously a suboptimal approach as these are broadly considered to be different categories of head injury. One could argue that concussion and some mTBIs fall along the same injury spectrum but it is certainly not established that these more “minor” head injuries are similar enough to severe brain injuries to justify comparable treatment paradigms. However, with our current knowledge, sharing some treatment strategies is an understandable and sensible approach while the medical community awaits more clarity on best practice strategies specifically for PCS/PCD. Lastly, severity of concussion and PCS/PCD has been notoriously hard to predict and classify. In this “new era” of concussion research most agree that there is no accurate grading scale to measure concussion severity. Most recommend against using concussion grading scales until a greater understanding of the condition is achieved. Once a grading scale can be developed that actually affords a clinician the ability to prognosticate a time frame for recovery and outcome it would be appropriate to reintroduce grading scales into the assessment of concussion. For now, it is best felt to simply gauge if a person “did” or “did not” have a concussion. The severity of a given concussion is then determined during the subsequent treatment period and stratified by the number, severity, persistence, and refractoriness of symptoms.

A treatment program for a patient with PCS/PCD should be multidisciplinary in nature and comprehensive in its scope. It is crucial to be conscious of, and treat, potential co-existing medical conditions that may be clouding the clinical picture and hampering the recovery process. During the initial evaluation of a patient with potential PCS/PCD, the fundamental tenet used in the treatment of acute concussion may still apply (depending on the symptoms and how long they have been present). This consists of physical and cognitive rest until asymptomatic with graded return to functional activity. However, continued and prolonged rest is not always a practical option, nor has it been shown to be beneficial in cases of PCS/PCD. Furthermore, prolonged rest (particularly with an ambiguous endpoint) is not feasible for many patients as socioeconomic concerns such as maintaining employment, planning for adequate short-term disability, or scheduling a substitute for a team or work environment become very genuine concerns.

As aforementioned, management of persistent (or “difficult”) concussions differs from acute concussions in that continued rest is not necessary or recommended. In contrast, the initiation of an active multidisciplinary rehabilitation and recovery program is advocated—even in the face of symptoms [38–40]. An approach to treating the persistently symptomatic concussion patient is outlined below.