Chronic Traumatic Encephalopathy: A Critical Review

Chronic Traumatic Encephalopathy: A Critical Review

Abstract

For many decades, there has been knowledge of progressive neurological deterioration that is linked to boxing and other contact sports. It was initially termed as the “dementia pugilistic,” more recently the Chronic Traumatic Encephalopathy.  Neuropathological chronic traumatic encephalopathy is often coupled by atrophy of the brain’s cerebral hemisphere, medial temporal part, thalamus, and the mammillary bodies. Potential signs of chronic traumatic encephalopathy are problems that are usually associated with issues of memory, personality changes and the changes in individual behaviour such as aggression and depression. People with the disease, according to this survey, may not at all the time experience the possible signs of chronic traumatic encephalopathy until years after the damage. The research also finds the clinical implication of the disease is so severe, mainly aiming at elderly persons. The condition has been found to affect those in contact sports over a more extended period. Through the various cases analyzed, it has been established to have affected professional athletes and military veterans almost at the same level. The report details some of the facts concerning this brain disease.

Keywords: Brain trauma, Traumatic Brain Injury, Brain Injury, Chronic traumatic encephalopathy

Chronic Traumatic encephalopathy

                                                      Introduction

Chronic Traumatic encephalopathy CTE is an advanced illness of the brains that is usually common among sportspersons, army veterans, and another individual with repetitive trauma of the mind. CTE is caused by a protein that is referred to as the Tau, which procedures clumps that gradually after some time move to the in the whole brain resulting in the death of the cells of the brain. CTE has been witnessed in persons as 17 years old. However, signs of the diseases do not commonly start appearing till years afterwards, the onset of the skull impacts[1].  For individuals with these diseases of the brain, the critical symptom frequently appears when the patient is in its early 20s and 30s[2].   A conclusive judgment of CTE can solitary be complete after the death of the patients during the autopsy since the diagnose is based on the revelation on whether there is a known change in the brain of the diseased which could have been as a result of CTE. It usually affects the patient’s mood and general behaviour[3].  Some of the frequent changes that can also be witnessed included problems of control, aggression, episode of depression, and in other cases, paranoia[4]

1. Method

The methodology of the study involved the analysis of the different sources which have been on CTE diseases[5] It involved the review of secondary sources on the information concerning the Chronic Traumatic encephalopathy. The data from the different articles and healthcare journals will be coordinated to develop a proper understanding of these diseases, including the signs and symptoms, the clinical implication, pathophysiology, biochemistry, genetics, and the scientific analysis of the CTE diseases. However, the gap which exists in the study will be identified[6]

2. Results

From the analysis and reviews of the various sources did indicate the Chronic Traumatic encephalopathy has a relatively higher prevalence among the contact sports personalities and military veterans[7]. The results suggest that an athlete who begins live interaction athletic at a younger age is at a considerably advanced age of CTE. Several published studies on the same reveal that experience to head impacts earlier than 12 years are linked with inferior consequences than beginning at an age above 12. Also, an athlete with lengthier vocations lives interaction sports are at higher risk than those with shorter career durations[8]. CTE has been found in people whose main exposer to headbang effects was through tackle football with over 100 cases confirmed, military with over 39 instances established, hockey 20 cases confirmed, boxing 15 instances, and soccer over  10 cases have been confirmed

    Pathophysiology of  Chronic Traumatic Encephalopathy

The ever best indication that tells about CTE is the aspect of progressive hits to the head that is constant over the years. Most individuals who got diagnosed by CTE suffered numerous impacts of the head over the years in the line of play, especially for the constant sports.   The most significant accessible indication of CTE makes points in the direction of the sub-concussive consequences, on in other cases head hits that do not cause a full-blown kind of concussion as the most significant factor for the diseases.  The first clinical cases were designated in fighters in the early 1990s and defined as the “Punch Drunk.” It has since then evolved to become a known condition, and several people, especially sportsmen and women, have been diagnosed by the disease[9]

 Biochemistry of Chronic Traumatic Encephalopathy

Every single individual who has been detected or diagnosed with CTE has only thing in common an account of injury to the head. CTE is usually shared amongst people in contact with sports athletes. In armed veterans, this is possible since these are some of the careers where people do expose an individual to purposeful repetitive injury on the head[10]. In other but few examples, intimate spouse fierceness and persons with growing illnesses who have over time been engaged in head banging characters to have been diagnosed with CTE.  It is, however, good noting that not everyone who  has suffered some head impact will develop CTE[11]

                                              Genetics of the disease

Investigators have acknowledged a genetic difference that might impact chronic traumatic encephalopathy (CTE) illness harshness. TMEM106B is unique to the primary genes to be concerned with CTE. There exist some other danger factors at play that makes approximately persons susceptible to developing CTE compared to others, such includes; the age of primary contact to head impact and length of the head impacts. An athlete who begins live interaction athletic at a younger generation is at a considerably advanced age of CTE. Several published studies on the same reveal that experience to head impacts earlier than 12 years are linked with inferior consequences than beginning at an age above 12. Also, an athlete with lengthier vocations lives interaction sports are at higher risk than those with shorter career durations.  Among the individuals established to be having CTE, those with longer jobs are more probable to have unadorned pathology than that one with smaller jobs[12].

      Scientific analysis of Chronic Traumatic Encephalopathy

CTE van only is established after death through a brain material examination. Neurosurgeons do slice the tissues of the brain and use the select elements to make the Tau clumps noticeable. They then conducted a systematic exploration of extents of the mind for the Tau clumps with rare forms that are definite to CTE alone. This development is slow and is capable of take numerous months to comprehensive, and the examination not characteristically conducted as a fragment of a routine postmortem. At the moment, there are only a few specialists in the CTE and those who know its diagnosis[13]. For instance, in 2015, scientists from VA-BU-CLF brains bank headed by Dr. Anne McKee joined forces with the national institute of health in developing analytic standards for CTE. It was done to enable any neuropathologist who was familiar with brain condition to conduct an accurate diagnosis of CTE.  This crucial work has helped it to be possible for ad more doctors and neurosurgeons to be able to be on the lookout for CTE and help in e acceleration of the progress[14]

The two articles that were used were Greenwald et al. (2012) and Tator et al. (2013). These sources all address CTE diseases. Both the article does give a compressive understanding of the disorders with a greater focus on the need for a further study concerning CTE. However, Tator et al. (2013) are more detailed a give elaborate information concerning every aspect of the diseases compared to CTE.

   The clinical implication of the Chronic  Traumatic Encephalopathy

Clinically the CTE diseases have various impacts on the patient. It can be servers or mild, depending on the level of the diseases[15]. Below are some of the clinical implication of the bugs and the method of treatment associated with each;

 Memory

For those suffering from this condition, here usually experience changes in the blood, which can include depression, anxiety, and irritability. It can, however, be treated with cognitive-behavioural therapy[16]

 Headache

A variety of options for treatment for problems exist, which include craniosacral therapy, reflexology, and acupuncture and suppositories. Functioning with the psychotherapist to regulate the exact type of headache is critical in the determination of the best option for conduct. Operating under a cognitive-behavioural psychotherapist can, in utmost cases, assist the patient in developing approaches that might also help them in the management of specific disposition symptoms that are instigating the most significant difficulties[17]

Memory problems

The therapy for me memory problems can include, among other essential treatments, dependable note-taking tactics[18]. It can be of help for ongoing a patient’s deeds of day-to-day existing, despite the snowballing struggle with recollection[19]

The most reliable means of preventing the occurrence of CTE is by avoiding any instance of Head injuries[20]. Though numerous head hurts are often problems to foresee or in another case, elude, especially for the constant athletes, there are thighs that one can reduce to lower their risk of the CTE[21]. Such include

• Wearing the right or recommended protective equipment for contact sport or military individuals
• Flowing the therapist’s recommendation about returning to play of military operation after a concussion.
• Ensuring that qualified personals supervise any contact sport that one is involved in
• Obtaining the right medical advice if any symptoms of the prevision injury of the head reoccur.

Unanswered Questions

The unanswered question about the CTE is the prevalence of the diseases on the number of constant that an individual might have[22]. The conditions which are common among veteran military and contact sports personalities do affect people differently depending on the various factors which are yet to be established[23]. The primary question which remains answered is what is the number of contacts that are responsible for the disease[24]

Conclusion and Future Perspectives.

CTE is neurodegeneration cynically linked with conflicts of the brain memory, behavioral and personality changes[25]. Clinically, CTE is coupled by cerebral and medial temporal lobes atrophy and in other extreme cases, can be associated with the spinal cord[26]. There exist overwhelming indications that this illness is as a result of repeated sub-lethal trauma of the brain that usually happens well before the growth of the other clinical manifestation[27]. Repetitive head injury does occur in an extensive diversity of interactive sport as well as resulting from accidents or in seeing the military services[28]. In most cases, CTE pathologically shares some of the similarities with AD[29]. Numerous researches have indicated that head injuries are a danger issue for AD and exist numerous cases intelligence that suggests that one head injury is a risk of AD but in most cases, not a risk factor for CTE[30].

Name: Dennis Adjepong, MD, MBA ( Neurosurgery Residency candidate, Author)

Email Address: Dennisadjepong@gmail.com

Efax: 1-804-409-1695

Name: Dr. Bilal Haider Malik ( Mentor)

References

1. McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013 Jan 1;136(1):43-64.
2. Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, Fritts NG, Stamm JM, Robbins CA, McHale L, Simkin I. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013 Sep 24;81(13):1122-9.
3. Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML, Solomon TM, Nowinski CJ, McHale L, Cormier KA. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. Jama. 2017 Jul 25;318(4):360-70.
4. McKee AC, Stein TD, Kiernan PT, Alvarez VE. The neuropathology of chronic traumatic encephalopathy. Brain pathology. 2015 May;25(3):350-64.
5. McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta neuropathologica. 2016 Jan 1;131(1):75-86.
6. Montenigro PH, Baugh CM, Daneshvar DH, Mez J, Budson AE, Au R, Katz DI, Cantu RC, Stern RA. Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimer’s research & therapy. 2014 Oct;6(5):68.
7. Stein TD, Montenigro PH, Alvarez VE, Xia W, Crary JF, Tripodis Y, Daneshvar DH, Mez J, Solomon T, Meng G, Kubilus CA. Beta-amyloid deposition in chronic traumatic encephalopathy. Acta neuropathologica. 2015 Jul 1;130(1):21-34.
8. Faden AI, Loane DJ. Chronic neurodegeneration after traumatic brain injury: Alzheimer’s disease, chronic traumatic encephalopathy, or persistent neuroinflammation?. Neurotherapeutics. 2015 Jan 1;12(1):143-50.
9. Iverson GL, Gardner AJ, McCrory P, Zafonte R, Castellani RJ. A critical review of chronic traumatic encephalopathy. Neuroscience & Biobehavioral Reviews. 2015 Sep 1;56:276-93.
10. Baugh CM, Robbins CA, Stern RA, McKee AC. Current understanding of chronic traumatic encephalopathy. Current treatment options in neurology. 2014 Sep 1;16(9):306.
11. Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V. Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PloS one. 2015 Feb 11;10(2):e0117338.
12. Petraglia AL, Plog BA, Dayawansa S, Chen M, Dashnaw ML, Czerniecka K, Walker CT, Viterise T, Hyrien O, Iliff JJ, Deane R. The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy. Journal of neurotrauma. 2014 Jul 1;31(13):1211-24.
13. Stein TD, Alvarez VE, McKee AC. Concussion in chronic traumatic encephalopathy. Current pain and headache reports. 2015 Oct 1;19(10):47.
14. Omalu B. Chronic traumatic encephalopathy. InConcussion 2014 (Vol. 28, pp. 38-49). Karger Publishers.
15. Hazrati LN, Tartaglia MC, Diamandis P, Davis K, Green RE, Wennberg R, Wong JC, Ezerins L, Tator CH. Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Frontiers in human neuroscience. 2013 May 24;7:222.
16. Barrio JR, Small GW, Wong KP, Huang SC, Liu J, Merrill DA, Giza CC, Fitzsimmons RP, Omalu B, Bailes J, Kepe V. In vivo characterization of chronic traumatic encephalopathy using [F-18] FDDNP PET brain imaging. Proceedings of the National Academy of Sciences. 2015 Apr 21;112(16):E2039-47.
17. Hazrati LN, Tartaglia MC, Diamandis P, Davis K, Green RE, Wennberg R, Wong JC, Ezerins L, Tator CH. Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Frontiers in human neuroscience. 2013 May 24;7:222.
18. Daneshvar DH, Goldstein LE, Kiernan PT, Stein TD, McKee AC. Post-traumatic neurodegeneration and chronic traumatic encephalopathy. Molecular and Cellular Neuroscience. 2015 May 1;66:81-90.
19. Bieniek KF, Ross OA, Cormier KA, Walton RL, Soto-Ortolaza A, Johnston AE, DeSaro P, Boylan KB, Graff-Radford NR, Wszolek ZK, Rademakers R. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta neuropathologica. 2015 Dec 1;130(6):877-89.
20. Iverson GL. Chronic traumatic encephalopathy and the risk of suicide in former athletes. Br J Sports Med. 2014 Jan 1;48(2):162-4.
21. Mez J, Stern RA, McKee AC. Chronic traumatic encephalopathy: where are we and where are we going?. Current neurology and neuroscience reports. 2013 Dec 1;13(12):407.
22. Hay J, Johnson VE, Smith DH, Stewart W. Chronic traumatic encephalopathy: the neuropathological legacy of traumatic brain injury. Annual Review of Pathology: Mechanisms of Disease. 2016 May 23;11:21-45.
23. Cherry JD, Tripodis Y, Alvarez VE, Huber B, Kiernan PT, Daneshvar DH, Mez J, Montenigro PH, Solomon TM, Alosco ML, Stern RA. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta neuropathologica communications. 2016 Dec;4(1):112.
24. Petraglia AL, Plog BA, Dayawansa S, Dashnaw ML, Czerniecka K, Walker CT, Chen M, Hyrien O, Iliff JJ, Deane R, Huang JH. The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surgical neurology international. 2014;5.
25. Yi J, Padalino DJ, Chin LS, Montenegro P, Cantu RC. Chronic traumatic encephalopathy. Current sports medicine reports. 2013 Jan 1;12(1):28-32.
26. Randolph C. Is chronic traumatic encephalopathy a real disease?. Current sports medicine reports. 2014 Jan 1;13(1):33-7.
27. Lucke-Wold BP, Turner RC, Logsdon AF, Bailes JE, Huber JD, Rosen CL. Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development. Journal of neurotrauma. 2014 Jul 1;31(13):1129-38.
28. Meehan W, Mannix R, Zafonte R, Pascual-Leone A. Chronic traumatic encephalopathy and athletes. Neurology. 2015 Oct 27;85(17):1504-11.
29. Montenigro PH, Stein TD, Cantu RC, Stern RA. Chronic traumatic encephalopathy: Historical origins and current perspective. Annual review of clinical psychology. 2015 Mar 30;11.
30. Goldstein LE, McKee AC, Stanton PK. Considerations for animal models of blast-related traumatic brain injury and chronic traumatic encephalopathy. Alzheimer’s research & therapy. 2014 Dec 1;6(5-8):64.

[1] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013 Jan 1;136(1):43-64.

[2] Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, Fritts NG, Stamm JM, Robbins CA, McHale L, Simkin I. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013 Sep 24;81(13):1122-9.

[3] Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, Alosco ML, Solomon TM, Nowinski CJ, McHale L, Cormier KA. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. Jama. 2017 Jul 25;318(4):360-70.

[4] McKee AC, Stein TD, Kiernan PT, Alvarez VE. The neuropathology of chronic traumatic encephalopathy. Brain pathology. 2015 May;25(3):350-64.

[5]. McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta neuropathologica. 2016 Jan 1;131(1):75-86.

[6] Montenigro PH, Baugh CM, Daneshvar DH, Mez J, Budson AE, Au R, Katz DI, Cantu RC, Stern RA. Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimer’s research & therapy. 2014 Oct;6(5):68.

[7] Stein TD, Montenigro PH, Alvarez VE, Xia W, Crary JF, Tripodis Y, Daneshvar DH, Mez J, Solomon T, Meng G, Kubilus CA. Beta-amyloid deposition in chronic traumatic encephalopathy. Acta neuropathologica. 2015 Jul 1;130(1):21-34.

[8] Faden AI, Loane DJ. Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?. Neurotherapeutics. 2015 Jan 1;12(1):143-50.

[9]  Iverson GL, Gardner AJ, McCrory P, Zafonte R, Castellani RJ. A critical review of chronic traumatic encephalopathy. Neuroscience & Biobehavioral Reviews. 2015 Sep 1;56:276-93.

[10] Baugh CM, Robbins CA, Stern RA, McKee AC. Current understanding of chronic traumatic encephalopathy. Current treatment options in neurology. 2014 Sep 1;16(9):306.

[11] Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V. Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PloS one. 2015 Feb 11;10(2):e0117338.

[12] Petraglia AL, Plog BA, Dayawansa S, Chen M, Dashnaw ML, Czerniecka K, Walker CT, Viterise T, Hyrien O, Iliff JJ, Deane R. The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy. Journal of neurotrauma. 2014 Jul 1;31(13):1211-24.

[13] Stein TD, Alvarez VE, McKee AC. Concussion in chronic traumatic encephalopathy. Current pain and headache reports. 2015 Oct 1;19(10):47.

[14] Omalu B. Chronic traumatic encephalopathy. InConcussion 2014 (Vol. 28, pp. 38-49). Karger Publishers.

[15] Hazrati LN, Tartaglia MC, Diamandis P, Davis K, Green RE, Wennberg R, Wong JC, Ezerins L, Tator CH. Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Frontiers in human neuroscience. 2013 May 24;7:222.

[16] Barrio JR, Small GW, Wong KP, Huang SC, Liu J, Merrill DA, Giza CC, Fitzsimmons RP, Omalu B, Bailes J, Kepe V. In vivo characterization of chronic traumatic encephalopathy using [F-18] FDDNP PET brain imaging. Proceedings of the National Academy of Sciences. 2015 Apr 21;112(16):E2039-47.

[17] Ling H, Morris HR, Neal JW, Lees AJ, Hardy J, Holton JL, Revesz T, Williams DD. Mixed pathologies, including chronic traumatic encephalopathy, account for dementia in retired association football (soccer) players. Acta neuropathologica. 2017 Mar 1;133(3):337-52.

[18] Daneshvar DH, Goldstein LE, Kiernan PT, Stein TD, McKee AC. Post-traumatic neurodegeneration and chronic traumatic encephalopathy. Molecular and Cellular Neuroscience. 2015 May 1;66:81-90.

[19] Bieniek KF, Ross OA, Cormier KA, Walton RL, Soto-Ortolaza A, Johnston AE, DeSaro P, Boylan KB, Graff-Radford NR, Wszolek ZK, Rademakers R. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta neuropathologica. 2015 Dec 1;130(6):877-89.

[20] Iverson GL. Chronic traumatic encephalopathy and risk of suicide in former athletes. Br J Sports Med. 2014 Jan 1;48(2):162-4.

[21] Mez J, Stern RA, McKee AC. Chronic traumatic encephalopathy: where are we and where are we going?. Current neurology and neuroscience reports. 2013 Dec 1;13(12):407.

[22] Cherry JD, Tripodis Y, Alvarez VE, Huber B, Kiernan PT, Daneshvar DH, Mez J, Montenigro PH, Solomon TM, Alosco ML, Stern RA. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta neuropathologica communications. 2016 Dec;4(1):112.

[23] Cherry JD, Tripodis Y, Alvarez VE, Huber B, Kiernan PT, Daneshvar DH, Mez J, Montenigro PH, Solomon TM, Alosco ML, Stern RA. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta neuropathologica communications. 2016 Dec;4(1):112.

[24] Petraglia AL, Plog BA, Dayawansa S, Dashnaw ML, Czerniecka K, Walker CT, Chen M, Hyrien O, Iliff JJ, Deane R, Huang JH. The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surgical neurology international. 2014;5.

[25] Yi J, Padalino DJ, Chin LS, Montenegro P, Cantu RC. Chronic traumatic encephalopathy. Current sports medicine reports. 2013 Jan 1;12(1):28-32.

[26] Randolph C. Is chronic traumatic encephalopathy a real disease?. Current sports medicine reports. 2014 Jan 1;13(1):33-7.

[27] Lucke-Wold BP, Turner RC, Logsdon AF, Bailes JE, Huber JD, Rosen CL. Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential

[28] Meehan W, Mannix R, Zafonte R, Pascual-Leone A. Chronic traumatic encephalopathy and athletes. Neurology. 2015 Oct 27;85(17):1504-11.

[29] Montenigro PH, Stein TD, Cantu RC, Stern RA. Chronic traumatic encephalopathy: historical origins and current perspective. Annual review of clinical psychology. 2015 Mar 30;11.

[30] Goldstein LE, McKee AC, Stanton PK. Considerations for animal models of blast-related traumatic brain injury and chronic traumatic encephalopathy. Alzheimer’s research & therapy. 2014 Dec 1;6(5-8):64.