On this page you will learn about:
Hear what Dr. Henderson has to say about biological illnesses that can present with psychiatric symptoms.
Mild traumatic brain injury (“mTBI”) is a common cause of neurocognitive deficits. Until recently, concussions were considered minor events with no persistent damage. In recent years, researchers have recognized that structural injury and activation of pathological protein cascades that lead to functional impairment can occur in concussion. Concussion and mTBI are now considered synonymous terms.
The Centers for Disease Control and Prevention referred to mTBI as “the silent epidemic” in its 2003 Report to Congress on Mild Traumatic Brain Injury in the United States: Steps to Prevent a Serious Public Health Problem.1 It notes that about 75% of all of the then estimated 1.5 million traumatic brain injury cases reported in the U.S. each year are mTBI. Today, nearly 1.7 million Americans are seen in hospitals for some form of traumatic brain injury each year.2 It is also known that there are hundreds of thousands of unreported sports and recreation-related head injuries each year, making the actual number of TBIs as high as 3.8 million annually.3 This coupled with the estimated 320,000 service men and woman who have returned home since 2001 with a traumatic brain injury4,5, yields a staggering number of affected individuals with demonstrable neuropsychological deficits who often go unrecognized, untreated, and even misjudged.
Although most patients recover fully from mTBI, up to 33% of patients have persistent neurocognitive problems.6 As many as 15% have been reported to have disabling symptoms a year later.7 For military or civilian patients with mild or moderate TBI, approximately 25-70% will have some memory loss; impaired judgment, difficulty with concentration and with completing tasks8-12. All frontal lobe functions can be affected, leading to changes in personality, impulse control, judgment, motivation and communication13-15. Up to 40% of patients with mild or moderate TBI will have neurological symptoms, such as seizures, changes in sensations, speech impairments, headaches, dizziness, fatigue and loss of balance5,11,12.
Depression or anxiety occur much more frequently after mTBI5,11-13,16,17. Notably, the symptoms of mTBI often overlap with those of Post-Traumatic Stress Disorder (PTSD), such as headache, dizziness, irritability, memory impairment, delayed problem solving, slowed reaction time, fatigue, visual disturbances, sleep disturbances, sensitivity to light and noise, impulsivity, judgment problems, emotional outbursts, depression, and anxiety5,9,12,15,18-20. An estimated 8-19% of returning Warfighters meet criteria for PTSD,5,21,22 while approximately 20% of returning Warfighters have screened positive for a probable mTBI. It is not surprising that the RAND study estimated that roughly one third of those screening positive for mTBI also had overlapping PTSD or depression4. The differentiation of mTBI and PTSD in returning Warfighters is a critical diagnostic and programmatic need for the DoD11,23. These two overlapping populations have potentially different treatment requirements and different prognoses24. Neuropsychological testing has been unsuccessful in clearly differentiating these two disorders and facilities are struggling to adequately treat the many affected Warfighters without the benefit of adjunctive and adequate diagnostic tests11,12,25. For civilians with mTBI there are even fewer resources (see Links).
Sports is a common cause of mTBI (concussions), be it skiing, football, soccer, or wrestling. In one study, 6.3% of college football players had experienced a concussion over the course of a single season26,27. A significant proportion of those who had a concussion experienced repeated concussion and the research showed a progressive increased risk for re-injury. With one concussion the odds ratio of a repeat concussion was 1.5; with 2 concussions the odds ratio of repeat concussion increased to 2.8; and at 3 concussions, the odds ratio increased to 3.4. With each successive concussion, recovery time became more and more prolonged26,27. Research indicates that younger athletes are at higher risk of injury – a serious concern for parents of children playing football in high school, middle school, and even elementary school. Patients in my private practice who have received concussions (from football, soccer, cheerleading, or motor vehicle accidents) have experienced marked cognitive impairment – often being unable to compute simple math problems – for several weeks. Sideline assessments are inadequate to demonstrate the presence or absence of mTBI. The recent introduction of computerized assessments has resulted in a tendency to delay return-to-play until a player can be evaluated by a physician28. However, computerized assessments are not reliably predictive of long-term outcome. Computerized assessments have a positive predictive value (a positive test is predictive of protracted recovery with associated high vulnerability to repeat concussion) of about 73% and a negative predictive value (a negative test is predictive of no long-term neuropsychological symptoms) of 74%29. In contrast, a SPECT scan (see below) has a positive predictive value of 90-100% and a negative predictive value of 100% in mTBI following motor vehicle accidents30,31.
Treating Mild Traumatic Brain Injury
A wide variety of symptoms and difficulties can occur following mTBI. Each symptom or symptom cluster requires a different treatment strategy. Medications often can be helpful to stabilize neurocircuitry or systems that have become impaired as a result of injury. The frontal lobes are often damaged in mTBI and improving frontal lobe function is a critical step in treatment. Research is being vigorously pursued to find effective treatments for TBI. As yet, there is no promising treatment that repairs brain injury.
Identifying Mild Traumatic Brain Injury
Traditional brain imaging modalities such as MRI and CT have provided little assistance in identifying mTBI, let alone differentiating it from PTSD. CT and MRI certainly have their applications in helping to diagnose traumatic brain injuries (especially severe injuries). Typically, CT remains a vital first step in the assessment of any traumatic brain injury due to its superior capacity to visualize hemorrhage and skull fracture. However, SPECT has been repeatedly demonstrated to be superior to CT in localizing functional cerebral damage in traumatic brain injury.30-42 In fact, in a large series of patients with post-concussive syndrome, SPECT demonstrated a 10-fold superiority to CT in predicting clinical symptoms.36 SPECT has also been repeatedly demonstrated to be superior to MRI in localizing functional cerebral damage in traumatic brain injury.30-35,37 Indeed, new MRI applications such as diffusion-weighted MRI 43-46 and flow MRI 47,48 have utilized SPECT as the “gold standard” against which to measure results.
In evaluating mTBI, Bonne and colleagues call for a multimodal integration of clinical evaluation, neuropsychological assessment, and cerebral perfusion studies.49 SPECT brain imaging has proven to be highly sensitive for detecting regional cerebral blood flow disturbances in patients with mTBI30-42,49-60, despite a critique published over 14 years ago by the American Academy of Neurology which was based on a very small number of early studies.61 SPECT has been found to have high predictive value at 3, 6 and 12 months post injury of 90%, 100% and 100%, respectively.30,31 It is clear that patients with persistent clinical symptoms continue to have abnormal follow-up SPECT findings. As with any abnormality, the ability to determine progress over time is crucial in choosing the best treatment option. SPECT has been utilized to track neurological changes during a course of treatment, providing clear evidence of neurophysiological changes52,56-60. SPECT at 1 and 50 weeks was more predictive of functional impairment and yielded more prognostic information compared with MRI at 1 and 50 weeks in a study of traumatic brain injury.56 Laatsch and colleagues demonstrated that SPECT and neuropsychological assessment were strongly correlated.57 Neurology as a field tends to dismiss SPECT as a tool for evaluating mTBI, repeatedly citing a critique of early studies – referred to as the TTASAN report61. Neurology seems to be unaware of the wealth of research literature I have presented here and also disregard the opinions of thought leaders in Nuclear Medicine54 and Radiology53. More recent reviews62 critical of SPECT have scrupulously ignored the key powerful studies demonstrating the effectiveness of SPECT30,31,36. Oddly, Neurology also seems to miss the point that SPECT imaging can demonstrate functional changes that occur in response to treatment, making it a potent tool for assessing treatments52,57-60,63-69.
On March 19, 2014, an international team led by Dr. Theodore Henderson published a comprehensive review of the utility of SPECT neuroimaging in the evaluation and treatment of traumatic brain injury (TBI). This review published in PLos ONE, summarized data derived from research studies conducted over 30 years and involving 2,634 patients. This quantitative analysis and review found that the frontal lobe was the most common area of injury occurring in 94% of patients with TBI. The temporal lobe was the second most common area injured (77%). In studies comparing SPECT to more conventional neuroimaging techniques such as computed tomography (CT scan) or magnetic resonance imaging (MRI), SPECT proved far superior in detecting TBI in both the acute and chronic condition. Particularly in the case of mild TBI, also known as concussion, anatomical findings that can be picked up by CT or MRI are rarely present. We will have to watch to see if Neurology finally gets the message.
1. National Center for Injury Prevention and Control. Report to Congress on Mild Traumatic Brain Injury in the United States: Steps to Prevent a Serious Public Health Problem. Atlanta, GA: Centers for Disease Control and Prevention; 2003.
2. Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010.
3. Langlois JA, Rutland-Brown W, Wald M. (2006) The epidemiology and impact of traumatic brain injury: a brief overview. Journal of Head Trauma Rehabilitation; 21(5):375-8.
4. Tanielian T, Jaycox LH. (2008). Invisible wounds of war: Psychological and cognitive injuries, their consequences, and services to assist recovery. Santa Monica (CA): RAND Corp.
5. Lew HL, Vanderploeg RD, Moore DF, Schwab K, Friedman L, Yesavage J, Keane TM, Warden DL, Sigford BJ. (2008). Overlap of mild TBI and mental health conditions in returning OIF/OEF service members and veterans. J Rehabil Res Dev.;45(3):xi-xvi.
6. Rimel, R.W., Giorani B., Barth, J.T., Boll, T.J. & Jane, J.A. (1981). Disability caused by minor head injury. Neurosurgery. 9, 221-228.
7. Alexander, M.P. (1995). Mild traumatic brain injury: Pathophysiology, natural history, and clinical management. Neurology 45, 1253-1260.
8. Rao V, Lyketsos CG. (2000). Neuropsychiatric sequelae of traumatic brain injury, Psychosomatics 41: 95-103.
9. Lew HL. (2005). Rehabilitation needs of an increasing population of patients: Traumatic brain injury, polytrauma, and blast-related injuries. J. Rehabil. Res. Dev. 42, xiii-xvi.
10. Taber KH, Warden DL, Hurley RA. (2006). Blast-related traumatic brain injury: What is known? J. Neuropsychiatry Clin. Neurosci. 18, 141-145.
11. Brenner LA, Vanderploeg RD, Terrio H. (2009). Assessment and diagnosis of mild traumatic brain injury, posttraumatic stress disorder and other polytrauma conditions: Burden of adversity hyposthesis. Rehabil psychology 54:239-246.
12. Vaishanavi S, Rao V, Fann JR. (2009). Neuropsychiatric problems after traumatic brain injury: unraveling the silent epidemic. Psychosomatics 50(3):198-205.
13. Hibbard MR, Bogdany J, Uysal S, Kepler K, et al. (2000). Axis II psychopathology in individuals with traumatic brain injury. Brain Inj 14:45-61.
14. Rao V. Lyketsos CG. (2002). Psychiatric aspects of traumatic brain injury. Psychiatr Clin North Am; 25: 43-69.
15. Warden DL, Gordon B, McAllister TW, Silver JM, et al (2006).Guidelines for the Pharmacologic Treatment of Neurobehavioral Sequelae of Traumatic Brain Injury. J Neurotrauma 23:1468-1501.
16. Fann, J.R., Burington, B, Leonetti, A., Jaffe, K., Katon, W.J., Thompson, R.S. (2004). Psychiatric illness following traumatic brain injury in an adult health maintenance organization population. Arch Gen Psychiatry, Jan;61(1):53-61.
17. Jorge, R.E., Robinson, R.G., Moser, D., Tateno, A., Crespo-Facorro, B., Arndt, S. (2004). Major depression following traumatic brain injury. Arch Gen Psychiatry, Jan;61(1):42-50.
18. Okie S. (2005). Traumatic brain injury in the war zone. N. Engl. J. Med. 352, 2043-2047.
19. Kennedy JE, Jaffee MS, Leskin GA. Stokes JW, et al. (2007). Posttraumatic stress disorder and posttraumatic stress disorder-like symptoms and mild traumatic brain injury. J. Rehabil. Res. Dev. 44, 895-920.
20. Anderson R.J. Shell shock an old injury with new weapons. (2008). Molecular interventions. 8: 204-218.
21. Milliken CS, Auchterlonie JL, Hoge CW. (2007). Longitudinal assessment of mental health problems among active and reserve component soldiers returning from Iraq war. JAMA 298: 2142-2148.
22. Smith TC, Ryan MA, Wingard DL, Slymen DJ, et al. (2008). New onset and persistent symptoms of post-traumatic stress disorders self reported after deployment and combat exposures: Prospective population based US military cohort study. BMJ. 336:366-71.
23. Hill JJ III, Mobo BHP Jr., Cullen MR. (2009). Separating deployment-related traumatic brain injury and posttraumatic stress disorder in veterans: Preliminary findings from the Veterans Affairs traumatic brain injury screening program. Am J Phys Med Rehabil 88: 605-614.
24. Bremner JD. (2002). Neuroimaging studies in post-traumatic stress disorder. Current Psychiatry Reports 4: 254-263.
25. Terrio H, Brenner LA, Ivins BJ, Cho JM, et al. (2009). Traumatic brain injury screening: preliminary findings in a US Army brigade combat team. J Head Trauma Rehabil 24:14-23.
26. McCrea M, Guskiewicz KM, Marshall SW, Barr W, Randolph C, Cantu RC, Onate JA, Yang J, Kelly JP. (2003). Acute effects and recovery time following concussion in collegiate football players: the NCAA Concussion Study. JAMA. 19;290(19):2556-63.
27. Guskiewicz KM, McCrea M, Marshall SW, Cantu RC, Randolph C, Barr W, Onate JA, Kelly JP. Cumulative effects associated with recurrent concussion in collegiate football players: the NCAA Concussion Study. (2003). JAMA. 290(19):2549-55.
28. Meehan WP 3rd, d’Hemecourt P, Collins CL, Taylor AM, Comstock RD. Computerized neurocognitive testing for the management of sport-related concussions. (2012). Pediatrics. 2012 129(1):38-44.
29. Lau BC, Collins MW, Lovell MR. Sensitivity and specificity of subacute computerized neurocognitive testing and symptom evaluation in predicting outcomes after sports-related concussion. (2011). Am J Sports Med. 2011 39(6):1209-16.
30. Jacobs, A., Put, E., et al. (1994). Prospective Evaluation of Technetium-99m-HMPAO SPECT in Mild and Moderate Traumatic Brain Injury. J Nucl Med. 35(6);947-8.
31. Jacobs, A., Put, E., Ingels, M. & Bossuyt, A. (1996). One-year follow-up of Technitium-99m-HMPAO SPECT in mild head injury. The Journal of Nuclear Medicine, 37, 1605-1609.
32. Abdel-Dayem, H.M., Abu-Judeh, H., Kumar, M., Atay, S., Naddaf, S., El-Zeftawy, H., et al. (1998). SPECT brain perfusion abnormalities in mild and moderate traumatic brain injury. Clincial Nuclear Medicine, 23, 309-317.
33. Bavetta, S., Nimmon, C., et al. (1994). A prospective study comparing SPET with MRI and CT as prognostic indicators following severe closed head injury. Nucl Med Commun, Dec;15(12), 961-8.
34. Ichise, M., Chung, D.G., Wang, P., Wortzman, G., Gray, B.G., & Franks, W. (1994). Technetium-99m-HMPAO SPECT, CT and MRI in the evaluation of patients with chronic traumatic brain injury: A correlation with neuropsychological performance. Journal of Nuclear Medicine, 34, 217-226.
35. Cihiangiroglu, M., Ramsey, R.G., & Dohrmann, G.J. (2002). Brain injury: Analysis of imaging modalities. Neurological Research, 24, 7-18.
36. Newberg, A.B., Alavi, A. (2003). Neuroimaging in patients with head injury. Seminars in Nuclear Medicine, 33, 136-147.
37. Prayer, L., Wimberger, D., Oder, W., Kramer, J., Schidler, E., Podreka, I., et al. (1993). Cranial MR imaging and cerebral 99m Tc HM-PAO-SPECT in patients with subacute or chronic severe closed head injury and normal CT examinations. Acta Radiologica, 34, 593-599.
38. Gray, B.G., Ichise, M., Chung, D., Kirsh, J.C. & Franks, W. (1992). Technetium-99m-HMPAO SPECT in the evaluation of patients with a remote history of traumatic brain injury: A comparison with x-ray computed tomography. The Journal of Nuclear Medicine. 33,52-58.
39. Varney, N.R., Bushnell, D.L, Nathan, M. Kahn, D., Roberts, R., Rezai, K., et al. (1995). NeuroSPECT correlates of disabling mild head injury: Preliminary findings. Journal of Head Trauma, 10,18-28.
40. Nedd, K., Sfakianakis, G., Ganz, W., Uricchio, B., Vernberg, D., Villanueva, P., et.al. (1993). 99mTc-HMPAO SPECT of the brain in mild to moderate traumatic brain injury patients: Compared with CT-A prospective study. Brain Injury, 7, 460-479.
41. Abdel-Dayem, H.M., Sadek, S.A., Kouris, K., Bahar, R.H., Higazi, I., Erickson, S., et al. (1987). Changes in cerebral perfusion after acute head injury: Comparison of CT with Tc-99m-HM-PAO SPECT. Radiology; 165, 221-226.
42. Masdeau JC, VanHeertman RL, et al. (1994). Early single-photon emission computed tomography in mild head trauma. Am. Soc. Neuroimaging.; 4:177.
43. Ezura M; Takahashi A; Shimizu H; Yoshimoto T. (2000). Diffusion-weighted MRI and selection of patients for fibrinolytic therapy of acute cerebral ischaemia; Neuroradiology; 42(5); 379-83.
44. Sagiuchi T; Ishii K; Asano Y; Woodhams R; Yanaihara H; Kan S; Hayakawa K. (2001). Transient seizure activity demonstrated by Tc-99m HMPAO SPECT and diffusion-weighted MR imaging; Ann Nucl Med; 15(3); 267-70.
45. Chu K; Jung KH; Kim HJ; Jeong SW; Kang DW; Roh JK. (2004). Diffusion-weighted MRI and 99m Tc-HMPAO SPECT in delayed relapsing type of carbon monoxide poisoning: evidence of delayed cytotoxic edema; Eur Neurol; 51(2); 98-103.
46. Karonen Jari O; Vanninen Rivata L; Liu Yawu; Ostergaard Leif; Kuikka Jyrki; et al. (1999). Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke; Stroke; 30; 1583-1590.
47. Wirestam R; Ryding E; Lindgren A; Geijer B; Holtas S; Stahlberg F. (2000). Absolute cerebral blood flow measured by dynamic susceptibility contrast MRI: a direct comparison with Xe-133 SPECT; MAGMA;11(3); 96-103.
48. Ernst T; Chang L; Oropilla G; Gustavson A; Speck O. (2000). Cerebral perfusion abnormalities in abstinent cocaine abusers: a perfusion MRI and SPECT study; Psychiatry Res; 99(2);63-74.
49. Bonne O, Gilboa A, Louzonn Y, Kempf-Sherf O, Katz M, Fishman Y, et al. (2003). Cerebral blood flow in chronic symptomatic mild traumatic brain injury. Psychiatry Res.; 30;124(3):141-52.
50. Davalos, D.B., Bennett, T.L. (2002). A Review of the Use of Single-Photon Emission Computerized Tomography as a Diagnostic Tool in Mild Traumatic Brain Injury. Applied Neuropsychology, 9(2), 92-105.
51. Abu-Judeh, H.H., Parker, R., Singh, M., el-Zeftway, H., Atay, S., Kumar, M., Naddaf, S., Aleksic, S., & Abdel-Dayem, H.M. (1999). SPET brain perfusion imaging in mild traumatic brain injury without loss of consciousness and normal computed tomography. Nucl Med Commun, 20(6),
52. Maxfield, 55th Annual Meeting of Southwestern Chapter of Society of Nuclear Medicine, 2010.
53. Graham MM. (2007). ACR Practice Guideline for the Performance of Single Photon Emission Computed Tomography (SPECT) Brain Perfusion Imaging. 823-828.
54. Tatsch, K., Asenbaum, S., Bartenstein, P., Catafau, A., Halldin, C., Pilowsky, L.S., Pupi, A. (2002). European Association of Nuclear Medicine Procedure Guidelines for brain perfusion SPECT using 99mTc-labelled radiopharmaceuticals. European Journal of Nuclear Medicine, 29,BP36-BP42.
55. Kant, R, Smith-Seemiller, L., Isaac, G., & Duffy, J. (1997). Tc-HMPAO-SPECT in persistent post-concussion syndrome after mild head injury: comparison with MRI/CT. Brain Inj, 11(2), 115-24.
56. Stamatakis EA; Wilson JT; Hadley DM; Wyper DJ. (2002). SPECT imaging in head injury interpreted with statistical parametric mapping; J Nucl Med; 43(4); 476-83.
57. Laatsch L; Pavel D; Jobe T; Lin Q; Quintana JC. (1999). Incorporation of SPECT imaging in a longitudinal cognitive rehabilitation therapy programme; Brain Inj. 13(8); 555-70.
58. Laatsch L, Jobe T, Sychra J, Lin Q, Blend M. (1997). Impact of cognitive rehabilitation therapy on neuropsychological impairments as measured by brain perfusion SPECT: a longitudinal study. Brain Inj.; 11(12):851-63.
59. Hattori N, Swan M, Stobbe GA, Uomoto JM, Minoshima S, Djang D, Krishnananthan R, Lewis DH. (2009). Differential SPECT activation patterns associated with PASAT performance may indicate frontocerebellar functional dissociation in chronic mild traumatic brain injury. J Nucl Med. 50(7):1054-61.
60. Lewis DH, Bluestone JP, Savina M, Zoller WH, Meshberg EB, Minoshima S. (2006). Imaging cerebral activity in recovery from chronic traumatic brain injury: a preliminary report. J Neuroimaging. 16(3):272-7.
61. Assessment of brain SPECT. Report of the Therapeutics and Technology Assessment Subcomeittee of the American Academy of Neurology. 1996. Neurology 46:278-285.
62. Wortzel HS, Filley CM, Anderson CA, Oster T, Arciniegas DB. Forensic applications of cerebral single photon emission computed tomography in mild traumatic brain injury. (2008). J Am Acad Psychiatry Law. 36(3):310-22.
63. Diler RS, Kibar M, Avci A. Pharmacotherapy and regional cerebral blood flow in children with obsessive compulsive disorder. Yonsei Med J. 2004 Feb 29;45(1):90-9.
64. Carey PD, Warwick J, Niehaus DJ, van der Linden G, van Heerden BB, Harvey BH, Seedat S, Stein DJ. Single photon emission computed tomography (SPECT) of anxiety disorders before and after treatment with citalopram. BMC Psychiatry. 2004 Oct 14;4:30.
65. Carey PD, Warwick J, Harvey BH, Stein DJ, Seedat S. Single photon emission computed tomography (SPECT) in obsessive-compulsive disorder before and after treatment with inositol. Metab Brain Dis. 2004 Jun;19(1-2):125-34.
66. Lee JS, Kim BN, Kang E, Lee DS, Kim YK, Chung JK, Lee MC, Cho SC. Regional cerebral blood flow in children with attention deficit hyperactivity disorder: comparison before and after methylphenidate treatment. Hum Brain Mapp. 2005 Mar;24(3):157-64.
67. Cho SC, Hwang JW, Kim BN, Lee HY, Kim HW, Lee JS, Shin MS, Lee DS. The relationship between regional cerebral blood flow and response to methylphenidate in children with attention-deficit hyperactivity disorder: comparison between non-responders to methylphenidate and responders. J Psychiatr Res. 2007 Sep;41(6):459-65.
68. Amen DG, Hanks C, Prunella J. Predicting positive and negative treatment responses to stimulants with brain SPECT imaging. J Psychoactive Drugs. 2008 Jun;40(2):131-8.
69. Richieri R, Boyer L, Farisse J, Colavolpe C, Mundler O, Lancon C, Guedj E. Predictive value of brain perfusion SPECT for rTMS response in pharmacoresistant depression. Eur J Nucl Med Mol Imaging. 2011 Sep;38(9):1715-22.
70. Raji CA, Tarzwell R, Pavel D, Schneider H, Uszler M, Thornton J, van Lierop M, Cohen P, Amen D, & Henderson T. (2014) Clinical Utility of SPECT Neuroimaging in the Diagnosis and Treatment of Traumatic Brain Injury: A Systematic Review. PLoS ONE 9(3): e91088. doi:10.1371/journal.pone.0091088)
“Over time, the explanation of psychiatric illnesses has shifted from afflictions by evil humors or spirits to dysfunction in neurophysiological processes. More recently, research and clinical experience has shown that infectious agents, such as viruses, can cause the neurophysiological dysfunction. Just as research proved syphilis could cause psychiatric symptoms and dementia in the 1940’s-1960’s, recent research is demonstrating that viral and certain bacterial infections can persist undetected in the brain and cause a wide array of symptoms.”
Unlike the medical diagnostic process in the rest of medicine, psychiatric diagnoses are neither objective, nor precise. For example, hypercholesterolemia is defined as a cholesterol level above certain objectively defined numerical norms. Histopathology is the primary means of diagnosing and characterizing cancer. In contrast, psychiatric diagnoses are made by following largely subjective descriptors developed by committees. Increasingly, the Diagnostic and Statistical Manual of Mental Disorders (DSM) has become a system of pigeonholes that do not provide insight into psychiatric illnesses, but instead are used by insurance companies to discriminate against patients. DSM diagnoses are not formulated based on demonstrable pathophysiological disruptions in the brain1. There are few objective findings in psychiatry to identify any single diagnosis. Moreover, diagnoses deduced by different methods often fail to agree. For example, Rettew and colleagues demonstrated that structured clinical interviews often yield a different diagnosis compared to that derived by clinical evaluation2. In addition, research has made it clear that there is more than one mechanism underlying a given psychiatric diagnosis, such as depression3,4 or ADHD5,6,7. So, it is unlikely that DSM diagnoses represent distinct neurophysiological entities. They will likely prove to represent groups of neurophysiological processes.
More importantly, growing evidence suggests that not all psychiatric symptoms, such as anxiety, fatigue, listlessness, low mood, or poor concentration, result from intrinsic flaws in the patient’s brain. Extrinsic causes, such as infections and toxins, can cause these psychiatric symptoms. The resulting cluster of symptoms might mimic anxiety, depression and other psychiatric disorders, leading to misdiagnosis and ineffective treatment. For example, lead or other heavy metal toxicity can lead to poor attention, hyperactivity, and impulsivity – mimicking ADHD8. Hypothyroidism can mimic depression in every way, but be unresponsive to antidepressant medications. Mild traumatic brain injury can lead to depression, anxiety, inattention, and loss of motivation9,10. Certain rare autoimmune disorders can lead to the formation of antibodies against specific neurotransmitter receptors11,12. Much more widespread autoimmune disorders, such as systemic lupus erythematosus, can lead to cognitive changes, anxiety, seizures, and mood disorders13,14.
It is not a surprise that infectious agents also may trigger psychiatric symptoms. Most people have experienced fatigue and mental fogginess during an acute viral infection. But there is now evidence that a number of infectious agents can induce chronic infections leading to long-standing or progressive psychiatric symptoms of a profound nature. For example, specific DNA belonging to a bacteria that spends part of its life cycle living inside human cells (chlamydiae species) was found in higher rates in patients with schizophrenia. Chlamydiae has been found in the blood of 50% of the schizophrenic population, compared to 7% of the healthy controls, by Dr. Rudolf Wank at the Institute of Immunology, University of Munich15. The association between infectious agents and schizophrenia is a long-standing one. Studies based on populations affected by the Nazi blockade of cities in Netherlands during World War II showed that mothers who were ill or under starvation conditions during the second trimester of pregnancy were at much higher risk of having a child with schizophrenia16. In 2008, a large Swedish national cohort study of 1.2 million children born between 1973 and 1985 and followed for over 20 years showed an increased incidence of schizophrenia in people who had childhood infections of the mumps virus or cytogegalovirus (CMV)17.
Recent studies have shown that the DNA of Herpes-1 virus (the cold sore virus) is located in the pathological plaques in Alzheimer’s disease18. Cultured brain cells with the genetic material of the Herpes-1 virus inserted into their DNA accumulate amyloid abnormally19. Transgenic mice containing the Herpes-1 virus genetic material develop the mouse equivalent of Alzheimer’s disease far more rapidly20. As time goes on, research may confirm that infectious elements contribute to Alzheimer’s disease and other neuropsychiatric illnesses21,22,23, including the neurodevelopmental variation seen in the genetic disorder Down Syndrome22. We have but to look. Using in situ hybridization, a research group in Japan has found the DNA of the Herpes simplex 1 virus in the cortices of patients with AD24.
Certain bacteria may contribute to at least some cases of Alzheimer’s disease. In 2011, a meta-analysis of several different studies estimated that the bacterium Borrelia burgdorferi was found in the brains of 25.3% of patients with Alzheimer’s disease. That is 13 times more than in the brains of people not affected by Alzheimer’s Disease25.
Over the years, numerous studies have demonstrated a link between chronic viral infections and a number of conditions that alter brain function. For example, research has shown a number of chronic viral infections can be found in patients with Chronic Fatigue Syndrome (CFS). Viruses such as Epstein-Barr virus (EBV), CMV, and several herpes viruses (e.g., Herpes 1, 6, 7 – HSV-1, HHV-6, HHV-7) cause or contribute to the symptoms of a large percentage of patient with CFS. These infections are generally not acute, but represent intracellular reactivation of an old infection; hence, an elevation of IgM antibodies is typically not seen with active infections of EBV, CMV, or HHV-6. Careful studies have shown 70% of patients with CFS had active HHV-6 infection through the use of primary cell cultures and confirmation using assays of monoclonal antibodies specific for HHV-6 proteins and by PCR. Moreover, a higher proportion of CFS patients have multiple simultaneous infections26, such as HHV-6 and HHV-7.
Research also has revealed chronic occult bacterial infections in patients with CFS. This, in part, reflects a compromised immune system. Indeed Nicolson and colleagues found that 52% of CFS patients had active mycoplasma infection, 30.5% had active HHV-6 infection, and 7.5% had Chlamydia pneumonia infections vs. only 6%, 9% and 1% of controls, respectively. These authors concluded, “The results indicate that a large subset of CFS patients show evidence of bacterial and/or viral infection(s), and these infections may contribute to the severity of signs and symptoms found in these patients27.
CFS can often be confused with depression. Patients have low energy, loss of interest in activities, increased sleeping, low mood and therefore have many symptoms that would meet the diagnostic requirements for depression. As a result, patients can be diagnosed with depression and treated with antidepressants. These are often ineffective for CFS, as one might expect. A significant proportion of patients with “treatment-resistant depression” may in fact have CFS or a chronic viral infection.
A study by Lerner found that treating CFS patients with 6 months of antivirals resulted in a significant improvement in symptoms28,29. Similarly, Montoya and his colleagues at Stanford University treated CFS patients with a potent antiviral for 6 months30, if they had elevated IgG tests for HHV-6 and EBV and had at least 4 of the following symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression. Nine of the twelve treated patients (75%) “experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities.” In the nine patients with a symptomatic response to treatment, EBV IgG and HHV-6 IgG titers significantly dropped30. Others have found that antivirals are effective for the treatment of CFS, especially in patients with 1) flu-like symptoms or symptoms starting with a flu-like illness; 2) elevated IgG or EA against EBV, CMV, and/or HHV-6; 3) low natural killer cell activity; 4) high RNAse-L activity; high ACE (> 35); coagulation activation; 5) high tumor necrosis factor (TNF); and/or 6) elevated or decreased total IgA, IgM or IgG levels. A number of studies have also shown dramatic improvement in patients with interferon treatments, especially those with low natural killer cell function.
In my practice, I have found that antiviral therapy in cases of CFS or myalgic encephalomyelitis is often a chronic treatment. Remember, that herpes viruses are not killed by antivirals. They are merely prevented from replicating. The virus remains ensconced in the neurons. Only a small portion of my patients have been successful at discontinuing antivirals without relapsing symptoms. I will relate one case (an amalgam of several cases) as an example. An adolescent presented with “treatment-resistant” depression. She complained of symptoms of fatigue, “brain fog”, low motivation, and seemingly mild depression. Her history was consistent with a chronic viral encephalitis with a history of acute onset following a viral illness. She responded readily to a treatment of antiviral medication with complete resolution of all symptoms. At about 6 months into treatment, her family went to Disney World. They forgot her medication, but felt that she would do fine. After all, it had been 6 months. Within a matter of a few days, her fatigue, sleepiness, and “brain fog” had recurred. She spent her Disney World vacation in bed at the hotel. Upon return, they restarted her antiviral and within a week, her symptoms were again completely resolved. In summary, cases of CFS or myalgic encephalomyelitis are difficult and challenging. Substantial evidence supports the role of viruses in these illnesses.
Is There Such A Thing As Chronic Infections
Some may argue that there is no evidence for chronic infections in CFS and other “psychiatric” syndromes. While numerous studies have demonstrated a high incidence of chronic infections in CFS26,27, schizophrenia31, Alzheimer’s disease18,21-23, temporal lobe seizure disorders32,33, and even Autism34, medicine has dismissed these findings as circumstantial. Intracellular bacteria, such as Borrelia burgdorferi, which is responsible for Lyme’s disease, also can develop into chronic hidden infections35. Physicians, including infectious disease specialists, do not appreciate the impact created by the dysfunction of the immune system associated with these illnesses. Normally, with an acute infection, the body will start producing IgM antibodies against an infection and then start producing IgG antibodies within a few weeks. As a result, an elevation of both IgG and IgM antibodies occurs in an acute infection. However, in a chronic reactivating infection, there is no IgM response, because it is not a new infection. Often, due to immune system compromise, an elevation of IgG antibodies does not occur, so these antibody titers cannot be used as an effective means of detecting chronic infections in these patients. So, in patients with a compromised immune system, the body does not mount a IgM antibody response, nor does it maintain an IgG antibody response, despite the presence of an active infection. This has also been demonstrated to be true with AIDS patients who have a severe compromise of the immune system, as demonstrated in a study published in the New England Journal of Medicine36.
In CFS and other illnesses wherein the immune system is compromised, elevated IgG antibody titers will be interpreted by most physicians as evidence of an old infection or previous exposure. Unfortunately, in chronic infections, the immune system even if not compromised, cannot maintain an antibody response, so there is no evidence of an “active infection”. This standard way of detecting active infections therefore misses the overwhelming majority of patients with active intracellular viral infections. Polymerase chain reaction (PCR) testing has proven much more sensitive for detecting the presence of chronic viral infections. Yet, this can be challenging in the clinical setting, if the blood is allowed to sit for more than a few hours, the infectious organism’s DNA degrades and can go undetected. In addition, PCR of blood may miss the viral DNA because these infections are not concentrated in the blood, but rather in nerve cell bodies, the brain, and the white blood cells. Physicians must have a high incidence of suspicion and look for elevated IgG or early antigen (EA) antibodies along with other signs of chronic infections including low natural killer cell counts or activity, high RNAse-L activity, high ACE, high tumor necrosis factor (TNF), high interleukin-6 (IL-6), and other markers.
At the beginning of 2014, Dr. Henderson published two key papers on this topic. The first was published in Autism Open Access focuses on the plight of a single young boy who presented with treatment-resistant Bipolar Disorder, ADHD, and Autism Spectrum Disorder37. After treatment with an antiviral medication, all of the patient’s autistic features resolved and his mood disorder became much easier to treat with psychotropic medications. This case is presented in great detail to illustrate the fundamental shift in this patient’s function and quality of life after the viral infection was controlled. The second paper by Dr. Henderson38 is a case series of children and adolescents who were referred to Dr. Henderson with the diagnosis of “treatment-resistant depression”. He demonstrated that antiviral therapy reduced or reversed the symptoms of depression( insert link http://www.ncbi.nlm.nih.gov/pubmed/24445302 ), as well as reducing excessive sleep, fatigue, and low motivation. All were experiencing cognitive impairment or “brain fog”. Indeed, the majority of these adolescents had failing grades or had quit school. After treatment, all were able to return to school and perform academically. With improved energy, restful sleep, and mental clarity, the symptoms of depression and anxiety often melted away. Many of these young patients were able to stop taking psychotropic medications altogether. Dr. Henderson’s work sheds some light on possible candidate viruses responsible for the symptoms of fatigue, low motivation, academic failure, excessive sleep, emotional dysregulation, and anxiety which are often labeled as depression, but are in fact symptoms of a virally-induced Chronic Fatigue Syndrome.
1. Sorboro, J. Prognosis Negative: psychiatry and the foibles of the Diagnostic and Statistical Manual V (DSM-V). Skeptic Magazine, 2010; 15 (3): 44-49.
2. Rettew DC, Lynch AD, Achenbach TM et al. (2009). Meta-analyses of agreement between diagnoses made from clinical evaluations and standardized diagnostic interview. International Journal of Methods in Psychiatric Research 18:169-184.
3. Drevets WC, Raichle ME. Neuroanatomical circuits in depression: implications for treatment mechanisms. Psychopharmacol Bull. 1992;28(3):261-74.
4. Deckersbach T et al., Functional imaging of mood and anxiety disorders. J Neuroimaging. 2006 Jan;16(1):1-10.
5. Cherkasova M, Hechtman L. Neuroimaging in attention-deficit hyperactivity disorder: Beyond te frontostriatal circuitry. Can J Psychiatry 2009; 54:651.
6. Bush G, Valera EM, Seidman LJ. Functional neuroimaging of attention-deficit/ hyperactivity disorder: a review and suggested future directions. Biol Psychiatry 2005; 57:1273-1284.
7. Lorberboym M, Watemberg N, Nissenkorn A, Nir B, Lerman-Sagie T. Technetium 99m ethylcysteinate dimer single-photon emission computed tomography (SPECT) during intellectual stress test in children and adolescents with pure versus comorbid attention-deficit hyperactivity disorder (ADHD). J Child Neurol. 2004 Feb;19(2):91-6.
8. Nicolescu R, et al., Environmental exposure to lead, but not other neurotoxic metals, relates to core elements of ADHD in Romanian children: performance and questionnaire data. Environ Res. 2010 Jul;110(5):476-83
9. Fann, J.R., Burington, B, Leonetti, A., Jaffe, K., Katon, W.J., Thompson, R.S. (2004). Psychiatric illness following traumatic brain injury in an adult health maintenance organization population. Arch Gen Psychiatry, Jan;61(1):53-61.
10. Jorge, R.E., Robinson, R.G., Moser, D., Tateno, A., Crespo-Facorro, B., Arndt, S. (2004). Major depression following traumatic brain injury. Arch Gen Psychiatry, Jan;61(1):42-50.
11. Kayser MS, et al., Psychiatric manifestations of paraneoplastic disorders. Am J Psychiatry. 2010 Sep;167(9):1039-50.
12. Kayser MS, Dalmau J. The emerging link between autoimmune disorders and neuropsychiatric disease. J Neuropsychiatry Clin Neurosci. 2011 Fall;23(1):90-7.
13. Brey RL, Holliday SL, Saklad AR, et al. Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology. 2002; 58:1214–1220.
14. Hanly JG, Urowitz MB, Su L, et al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2010; 69:529–535.
15. Fellerhoff B, et al., High risk of schizophrenia and other mental disorders associated with chlamydial infections: hypothesis to combine drug treatment and adoptive immunotherapy. Med Hypotheses. 2005;65(2):243-52.
16. Brown AS, Susser ES. Prenatal nutritional deficiency and risk of adult schizophrenia. Schizophr Bull. 2008 Nov;34(6):1054-63
17. Dalman C et al., Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry. 2008 Jan;165(1):59-65.
18. Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol. 2009 Jan;217(1):131-8.
19. Wozniak MA, et al. Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett. 2007 Dec 18;429(2-3):95-100.
20. Itzhaki RF, Wozniak MA. Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders. Prog Lipid Res. 2006 Jan;45(1):73-90.
21. Carter CJ. Alzheimer’s disease plaques and tangles: cemeteries of a pyrrhic victory of the immune defense network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction. Neurochem Int. 2011 Feb;58(3):301-20
22. Cheon MS, et al. Evidence for the relation of herpes simplex virus type 1 to Down syndrome and Alzheimer’s disease. Electrophoresis. 2001 Feb;22(3):445-8.
23. Miklossy J. Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med. 2011 Sep 20;13:e30
24. Isamu Mori et al., Reactivation of HSV-1 in the brain of patients with familial Alzheimer’s disease. J. Med. Virol. 73:605-611, 2004
25. Miklossy J. Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med. 2011 Sep 20;13:e30.
26. Chapenko et al., Activation of Human Herpesvirus-6 and 7 in Patients with Chronic Fatigue Syndrome, J Clin Virol, 37, S47, 2006.
27. Nicolson et al., Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of Chronic Fatigue Syndrome Patients: Association with Signs and Symptoms, Acta Pathologica, Microbiologica et Immunologica Scandinavica [APMIS] 222:557, 2003.
28. Lerner et al., A Six-Month Trial of Valacyclovir in Epstein-Barr Virus Subset of Chronic Fatigue Syndrome: Improvement in Left Ventricular Function, Drugs Today 38:549, 2002.
29. Lerner et al., Valacyclovir treatment in Epstein-Barr Virus Subset Chronic Fatigue Syndrome: Thirty-Six Months Follow-up, In Vivo, 21:707, 2007.
30. Kogelnik et al., Use of Valganciclovir in Patients With Elevated Antibody Titers Against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) Who Were Experiencing Central Nervous System Dysfunction Including Long-Standing Fatigue, J. Clin. Virol. 37:S33, 2006.
31. Prasad et al., Progressive Gray Matter Loss and Changes in Cognitive Functioning Associated with Exposure to Herpes Simplex Virus 1 in Schizophrenia: A Longitudinal Study, Am J Psychiatry, 168:822, 2011.
32. Fotheringham J, et al. Association of human herpesvirus-6B with mesial temporal lobe epilepsy. PLoS Med. 2007 May;4(5):e180.
33. Donati D, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology. 2003 Nov 25;61(10):1405-11.
34. Nicolson GL, et al., Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. J Neurosci Res. 2007 Apr;85(5):1143-8.
35. Cameron DJ. Clinical trials validate the severity of persistent Lyme disease symptoms. Med Hypotheses. 2009 Feb;72(2):153-6.
36. Dylewski et al, Absence of detectable IgM antibodies during cytomegalovirus disease in patients with AIDS , NEJM, 1983 309:493, 1983.
37. Henderson TA. Is valacyclovir a mood stabilizer? Autism Open Access, 2014 3:118.
38. Henderson, TA. Valacyclovir treatment of chronic fatigue in adolescents. Adv Mind Body Med, 2014 Winter;28:4-14.