Chronic Traumatic Encephalopathy

What is chronic traumatic encephalopathy

Chronic Traumatic Encephalopathy is a progressive disorder due to Repetitive mild TBI (mTBI), such as can occur in professional sports.

It can be associated with the progressive development of cognitive decline, behavioral changes (aggression, impulsivity), changes in mood (depression, fatigue, apathy, suicidality), and motor/parkinsonian symptoms.

The combination of a mood disorder and impulsivity has led to several suicides.

The definitive diagnosis of CTE can only be established after death upon postmortem examination of the brain, which demonstrates hyperphosphorylated tau protein deposits in the depths of sulci.

Chronic traumatic encephalopathy (CTE) is a pathologically defined neurogenerative disorder often found in athletes and veterans that is associated with repetitive concussive or subconcussive head injury. CTE presents with cognitive, psychiatric, and sometimes motor symptoms.

Synonyms

CTE
Traumatic encephalopathy syndrome (clinical diagnosis)
Dementia pugilistica (older term)
Punch drunk syndrome (older term)

Epidemiology & Demographics

Peak Incidence & Prevalence

The incidence and prevalence of CTE are currently unknown. In the largest CTE case series to date, of 202 deceased individuals who had a significant history of repetitive head trauma related to either contact sports or military service, Mez and colleagues reported that CTE was diagnosed in 177 former professional football players (or 87% of the cases) and, more specifically, in 110 out of 111 (99%) of the former National Football League (NFL) players. The authors noted that the study was limited by ascertainment bias since individuals with symptoms consistent with possible CTE were much more likely to participate in the brain donation program, and, therefore, the true frequency of CTE pathology is unknown.

•Among participants with severe CTE pathology, 89% had behavior, mood symptoms, or both, 95% had cognitive symptoms, and 85% had signs of dementia. 1Mez J et al: Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football, JAMA 318(4):360-370, 2017.

Predominant Sex and Age

CTE may present early (20s-30s) or later (50s-60s) in adulthood. The relationship with gender is unknown.

Who are at risk of Chronic Traumatic Encephalopathy?

Repetitive head injuries leading to concussions or subconcussive injuries are the strongest risk factor for the development of CTE.

Athletes, veterans, and victims of repetitive head trauma are at highest risk.

Although repetitive head trauma is required for CTE to develop, head trauma alone is insufficient. The search for genetic and environmental risk factors are underway.

Genetics

Currently there are no known genetic risk factors that predispose to the development of CTE, although some studies raise the possibility of a relationship to the APOE4 allele and others do not confirm this association.

Physical Findings & Clinical Presentation

CTE causes progressive cognitive, behavior, and mood changes and may even lead to motor deficits.

CTE is a delayed presentation of repetitive concussive or subconcussive injuries and should not be confused with acute or postacute sequelae of traumatic brain injury. The most common cognitive domains affected are memory and executive function. The most common presenting symptoms in patients with autopsy confirmed CTE are found in the below table.

Because CTE is a pathological diagnosis currently made only postmortem, a search for in vivo biomarkers is underway. Patients with a clinical syndrome thought to be the consequence of repetitive blows to the head are considered for research purposes to have traumatic encephalopathy syndrome (TES). Some TES patients are found postmortem to have CTE, whereas others may have other forms of neurodegeneration or even psychiatric conditions lacking specific neurodegenerative pathology. Like CTE, TES does not refer to either the acute or postacute sequelae of TBI such as concussion, postconcussive syndrome, or moderate to severe TBI. TES can take one of four clinical types: (1) behavioral/mood variant, occurring in younger patients; (2) cognitive variant, occurring later in life; (3) a mixed variant; and (4) a dementia variant.

Clinical Features at Initial Presentation of Patients with Autopsy-Confirmed Chronic Traumatic Encephalopathy

Reprinted with permission from Budson AE, Solomon PR. Memory loss, Alzheimer’s disease, and dementia: a practical guide for clinicians, ed 2. Edinburgh, UK, 2016, Elsevier Health Sciences, using data from Stern RA et al. Clinical presentation of chronic traumatic encephalopathy, Neurology 81(13):1122-1129, 2013. doi:10.1212/ WNL.0b013e3182a55f7f.

•Memory impairment (85%)
•Executive dysfunction (79%)
•Attention and concentration difficulties (73%)
•Sadness/depression (64%)
•Hopelessness (64%)
•Explosivity (58%)
•Language impairment (58%)
•Visuospatial difficulties (55%)
•“Out of control” (52%)•Physically violent (52%)
•Verbally violent (49%)
•Impulse and control problems (46%)
•Suicidal ideation/attempts (30%)
•Motor symptoms (30%)

The behavioral/mood variant first presents early in life (later 20s-30s), with primarily psychiatric and behavioral manifestations such as depression, anxiety, paranoia, impulsivity, explosivity, and aggression. Cognitive problems are more common as the disease progresses. The cognitive and dementia forms present later in life (50s-60s), with impairment in episodic memory, attention, and executive function. Currently it is thought that CTE progresses in four stages with increasing severity along each stage. Symptoms progress from headaches, attention problems, and depression to explosivity, aggression, dementia, and suicidality as the disease progresses.

Physical examination findings are not always present in CTE but may include symptoms of parkinsonism and motor dysfunction, such as gait disturbance, tremors, ataxia, and dysarthria. These have been found to be particularly more common in boxers.

Of note, the symptoms of CTE may present similarly to the behavioral variant of frontotemporal dementia (bvFTD), but CTE patents, in addition to their history of repetitive or subconcussive head injury, experience more memory loss than patients with bvFTD. Alzheimer disease (AD) should be in the differential diagnosis for memory loss, but in addition to the apathy or irritability that may be seen in both AD and CTE, CTE patients have explosivity and disinhibition not typically seen in AD. CTE patients with dementia may also develop parkinsonism, raising the possibility of dementia with Lewy bodies (DLB), but parkinsonism is late and rare in CTE. REM behavior disorder is typical of DLB but not a feature of CTE, and disinhibition and explosivity are features of CTE not associated with DLB.

What causes this condition?

The frequency, severity, and total exposure to head trauma and the exact pathophysiologic mechanism by which repetitive head trauma causes CTE in chronic traumatic encephalopathy are active areas of research.

•Head injury is an important but nonsufficient risk factor in the development of chronic traumatic encephalopathy; other exposure and genetic risk factors are under investigation.
•Currently, no validated clinical diagnostic criteria for chronic traumatic encephalopathy exist, although research diagnostic criteria have been developed.
•Concussion is a clinical syndrome of impaired brain function, typically impacting memory and orientation, with or without loss of consciousness that results from head injury.
•Chronic traumatic encephalopathy is defined by neuropathology: Perivascular aggregation of phosphorylated tau protein within neurons and astrocytes that begins in the depths of sulci and progresses to involve the medial temporal lobes and other parts of the brain.

CTE is believed to occur due to repetitive head injuries. Definitive diagnosis is made only through autopsy, where neurofibrillary tangles and p-tau aggregates may be found around blood vessels and in deep cortical sulci, amygdala, hippocampus, brainstem, and cerebellum depending on the stage of the disease.

Differential Diagnosis

•Alzheimer disease
•Frontotemporal dementia
•Dementia with Lewy bodies
•Bipolar disorder
•Major depressive disorder

Workup

CTE should be suspected in those with a history of repetitive head injuries with or without concussion as a result of contact sports, military service, motor vehicle accidents, domestic abuse, and battery presenting with the symptoms.

The history and progression of symptoms is of most benefit in the diagnostic process.

Neuropsychological testing may be helpful in delineating specific cognitive deficits.

Laboratory Tests

Tests including complete blood count, comprehensive metabolic panel, thyroid function tests, HIV, syphilis

Imaging Studies

MRI may aid in ruling out other causes of dementia.

CTE patients will often have imaging abnormalities such as a cavum septum pellucidum cavum vergae, or fenestrations of the lateral ventricle, evidence of increased cortical thinning consistent with neurodegeneration, cortical atrophy, and a dilated third ventricle.

•The usefulness of advanced imaging such as PET, SPECT, and DTI in CTE is still under investigation. Tau-PET is under investigation for in vivo diagnosis of CTE. The neuropathological diagnosis is based on a specific pattern of Tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer disease. An analysis of living former NFL players with cognitive and neuropsychiatric symptoms revealed higher Tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. ¹1Stern RA et al: Tau Positron-Emission Tomography in Former National Football League Players, N Engl J Med 380;1716-1725, 2019
•A negative amyloid PET would exclude AD pathology.

Treatment

Nonpharmacologic Therapy

Cognitive behavioral therapy is helpful for depression and anxiety symptoms.

Acute General Treatment

•SSRIs may be effective in treating depression symptoms. Close monitoring for suicidality is recommended in all patients with CTE.
•Acetylcholinesterase inhibitors approved for treating AD may help with memory dysfunction.
•Atypical antipsychotics may be used to control disinhibition and reduce violence, but all antipsychotics carry an FDA boxed warning about an increased mortality in patients with dementia, a risk that should be disclosed to the patient’s surrogate decision-maker and weighed on a case-by-case basis.
•Pain management to improve quality of life.

Disposition

CTE is chronic and progressive. Emphasis should be placed on improving quality of life through pain management, therapy, and symptom management.

Referral

Patients may benefit from referral to neurology, psychiatry, and psychology.

Pearls & Considerations

CTE is a slowly developing illness. Although it should be considered in patients with repetitive head injuries, it is important to conduct a thorough workup to rule out psychiatric illnesses and other forms of dementia that may present with similar symptoms.

Prevention

For athletes, wearing proper protective equipment as well as using techniques to avoid direct head impacts when playing sports is important. Furthermore, if a concussion is suspected, the player should not be allowed to resume play without further evaluation.

Patient & Family Education

Concussion foundation—CTE resources
https://concussionfoundation.org/CTE-resources
CDC—HEADS UP: For prevention of concussions
www.cdc.gov/headsup/index.html

Chronic Traumatic Encephalopathy