Chronic Postconcussive Headaches in 

OEF/OIF/OND Service Members and Veterans: 

A Novel Treatment Approach

Elaine R. Peskind, MD

Co-Director, VA Northwest Network VISN 20

Mental Illness Research, Education and Clinical Center

Friends of Alzheimer's Research Professor of Psychiatry

University of Washington School of Medicine

Staff Psychiatrist

Madigan Army Medical Center
2.4 million Service Members have been deployed to 

Iraq and Afghanistan

Helmand Province, 

Afghanistan. July 13, 

2009. (MSNBC)

The Nature of an Emerging and Unprecedented Problem
Chronic Postconcussive Headache in 

OEF/OIF/OND Veterans

 Estimated 19% of OEF/OIF/OND 

Veterans have sustained deploymentrelated mTBI

 Majority of mTBIs are result of blast 

concussion

 Prevalence of post-traumatic headaches 

(PTHAs) is approximately 40% 
Chronic Postconcussive Headache

 International Classification of Headache 

Disorders defines PTHA:

 Secondary HA precipitated by head trauma

 In practice, new onset HAs within months of 

trauma

 Postconcussive headaches that persist for 3 

months or more are considered chronic
Chronic Postconcussive 

Headache

 Tendency for PTHAs to become 

chronic is increased by:

PTSD 

Depression

Sleep deprivation

Female gender
Chronic Postconcussive Headache 

 In a recent cross sectional study of 978 

soldiers with deployment-related 

concussion, 20% met criteria for chronic 

daily headaches (15 days or more/month)

 4-5-fold higher than in general population

 66% had headaches with migraine 

features

Theeler et al, Headache 52(5):732-738, 2012.
Characteristics of 

Chronic Postconcussive Headache

 Considered to be one of most disabling and 

difficult to treat headache syndromes

 Injudicious use of opioids or other analgesics 

can provoke superimposed rebound 

(“medication over-use”) headaches, particularly 

in those with frequent headaches at baseline

 “Medication over-use” headaches occur in 19-

42% of patients with PTHA
Chronic Postconcussive Headache in 

Iraq/Afghanistan Veterans

 In civilian TBI population, PTHA tends to be 

tension-type, migraine or mixed

 In military combat population, headaches with 

migraine features predominate

 Migraine results in significantly more functional 

impairment and more sick call days than other 

types of headaches

 77% of migraine attacks interfered with duty 

performance on a mean of 2.4 days per month
Treatment Outcomes of Chronic Post-Traumatic Headaches After 

Mild Head Trauma in US Soldiers: An Observational Study

LTC Jay Erickson, MD, et al

(Headache 2011;51:932-944) 

 Retrospective cohort study of 100 soldiers 

treated with migraine prophylaxis for chronic 

PTHA at Madigan Army Medical Center 

Neurology Clinic

 77 had blast PTHA

 23 had non-blast (impact) PTHA

 Multiple concussions significantly more 

common in those with blast PTHA (51% vs. 

23%)

Erickson et al, Headache 51(6):932-944, 2011.
Treatment of Blast Concussion 

Migraine is Challenging

 Blast concussion migraine was usually responsive to 

acute abortive therapy with a triptan

 77% reported reliable headache relief within 2 hours

 Triptans equally effective in blast and non-blast PTHA

 However, compared to impact postconcussive migraine, 

blast postconcussive migraine was poorly responsive to 

standard migraine prophylaxis (TCAs, propranolol, 

valproate, topiramate) 

Erickson et al, Headache 51(6):932-944, 2011.
Change at 3 Months in Headache Frequency in 

Response to Migraine Prophylaxis in Blast vs. 

Impact PTHA 

Headache 

(Days/Months)

Baseline 

Mean (SD) 

Follow-Up 

Mean (SD) 

Change 

Mean (%) P Value Responders* 

Blast PTHA

(n=77) 

17.3 (9.2) 15.8 (10.4) -1.5 (-9.1%) 0.21 22/77 (29%) 

Impact 

PTHA 

(n=23) 

16.5 (9.2) 9.8 (8.7) -6.7 (-41%) 0.003 13/23 (57%) 

*Defined as ≥ 50% decline in headache frequency at follow-up 

compared to baseline.

Erickson et al, Headache 51(6):932-944, 2011.
Does the PTSD Drug Prazosin Reduce Blast 

PTHA in OEF/OIF Veterans?

 OEF/OIF Veterans with blast concussion PTHA have a high prevalence of 

comorbid PTSD trauma nightmares and sleep disturbance

 Robert Ruff, MD, VA Director of Neurology, used open label prazosin to 

treat comorbid PTSD in OEF/OIF Veterans with blast mTBI manifested by 

PTHA and other postconcussive symptoms1 

 Prazosin is a CNS-active alpha-1 adrenoreceptor antagonist 

demonstrated effective for combat PTSD trauma nightmares, sleep 

disruption, and global clinical status2,3,4

1Ruff et al, J Rehabil Res Dev 46:1071-1084, 2009.

2Raskind et al, J Clin Psychiatry 63:565-568, 2002.

3Raskind et al, Biol Psychiatry 61:928-934, 2007.

4Raskind et al, Am J Psychiatry (in press).
An Open Label Prazosin and Sleep Hygiene Trial for 

OIF/OEF Blast mTBI with Comorbid PTSD

Baseline Week 9 p value

Headaches per month 12.4 ± 8.1 4.8 ± 2.9 < 0.001

Headache intensity 7.1 ± 1.4 4.1 ± 1.6 < 0.001

Daytime sleepiness 

(Epworth)

16.1 ± 2.4 7.3 ± 2.9 < 0.001

% subjects with “restful and 

restorative” sleep

7.0% 87.8% < 0.001

Montreal Cognitive 

Assessment

24.1 ± 2.0 28.1 ± 2.2 < 0.001

Ruff et al, J Rehabil Res Dev 46:1071-1084, 2009.
 Data from our recent positive RCT of prazosin 

for PTSD in active duty combat soldiers is 

consistent with beneficial effects of prazosin on 

PTHA
Active Duty OEF/OIF 

Prazosin RCT

 Parallel group RCT (1:1) at Joint Base Lewis 

McChord, WA

 Active duty OIF/OEF soldiers with combat 

operations PTSD (CAPS > 50) and distressing 

trauma nightmares (at least two nights/week)

 Majority of participants had comorbid mTBI

Raskind et al, Am J Psychiatry ( in press).
Design Methodology

 6-week dose titration to maximum 20 mg qhs and 5 mg 

midmorning

 Study duration 15 weeks

 Outcome measures:

 Total Clinician Administered PTSD Scale (CAPS) 

 CAPS “recurrent distressing dreams” item

 Pittsburgh Sleep Quality Index

 Clinical Global Impression of Change

 Adverse Events (including headache)

Raskind et al, Am J Psychiatry ( in press).
Effects on PTSD Outcome Parameters in Combat Soldiers 

Randomized to Prazosin (n=32) or Placebo (n=35)

Raskind et al, Am J Psychiatry ( in press).
Emergent and Clinically Worsening 

Adverse Events

Prazosin (n=32) Placebo (n=35)

Syncope 2 0 

Dizziness 6 6 

Drowsiness 1 2 

Depressed mood 0 2 

Headache* 1 7 

Nasal congestion 5 2 

Nausea 2 5 

Palpitations 4 1 

*more frequent in placebo condition, p < 0.05

Raskind et al, Am J Psychiatry ( in press).
Participants with Chronic 

Headaches at Baseline

• Of participants who had headaches prior 

to randomization:

• 20% in placebo group had improvement 

or resolution of headache

• 50% in prazosin group had 

improvement or resolution of 

headaches

Raskind et al, Am J Psychiatry ( in press).
Conclusion

 Results of these studies provide 

rationale for a placebo-controlled 

trial of prazosin for blast concussion 

PTHA
TBI: Screening and Evaluation of 

Headaches and Endocrine Disorders 



Part II: Endocrine Disorders

Charles W. Wilkinson, PhD 

 

Geriatric Research, Education and Clinical 

Center

VA Puget Sound Health Care System

Seattle, Washington
Poll

• How knowledgeable are you about 

endocrinology? 

a) World expert

b) Well versed

c) Basic understanding

d) Endo what?
Human Pituitary: Miniature Master 

Gland 
Pituitary Vulnerability to TBI
Posttraumatic Hypopituitarism 

(PTHP): Acute and Chronic Stages 

 Multiple transient endocrine abnormalities in 

the initial (~ 3-month) period following TBI 

 Some problems resolve in the following months

 Smaller proportion of new dysfunctions emerge 

during the same period

 After 6-12 months, PTHP is generally 

considered permanent 
Growing Awareness of PTHP

 Hypopituitarism: deficient production of one or 

more pituitary hormones 

 Chronic post-traumatic hypopituitarism (PTHP) 

from TBI was first reported in 1918

 Until 12 years ago, only scattered reports 

existed and the condition was considered rare

 A significant burst of studies has appeared since 

2000

 Those studies have found the prevalence of 

chronic TBI-related hypopituitarism to be 25-50%
Chronic Hypopituitarism After 

TBI from All Causes

1st Author Year #Pts %HP 1st Author Year #Pts %HP

Kelly 2000 22 37 Tanriverdi 2008 30 30

Lieberman 2001 70 69 Wachter 2009 55 25

Bondanelli 2004 50 54 Srinivasan 2009 18 56

Agha 2004 102 28 Berg 2010 246 21

Popovic 2004 67 34 Englander 2010 119 65

Aimaretti 2005 70 23 High 2010 83 51

Leal-Cerro 2005 99 25 Krahulik 2010 89 21

Schneider 2006 70 36 Park 2010 45 31

Tanriverdi 2006 52 51 Pavlovic 2010 61 33

Herrmann 2006 76 24 Kokshoorn 2011 112 5 

Bushnik 2007 64 90 Reimunde 2011 19 58

Klose 2007 104 15 Schneider 2011 825 37

Bavisetty 2008 70 43

 
Consequences of PTHP for 

Psychological Health

 Pituitary abnormalities have been associated 

with behavioral and cognitive deficits, reductions 

in quality of life (QoL), and increased mortality

 The symptoms are similar in many respects to 

those of postconcussive syndrome and PTSD

 PTHP is generally responsive to treatment with 

replacement hormones

 Failure to screen for PTHP may result in 

inappropriate and ineffective treatment of these 

symptoms
Poll

• Would you consider consulting an 

endocrinologist about chronic postconcussive symptoms?

a) Yes

b) Maybe; it would depend on the symptoms

c) No 
Study Rationale & Questions

 High PTHP prevalence after TBI from other causes

 Absence of studies of the effects of blast mTBI on 

pituitary function

 Lack of routine hormonal screening after TBI

 Considerable overlap in symptoms between PTHP 

and PTSD

 Question 1: Does blast mTBI result in rates of 

PTHP comparable to those after TBI from other 

causes? 

 Question 2: What pituitary hormone axes are most 

frequently affected?
Experimental Design 

 Acquisition of blood samples from two groups of Veterans of 

deployment to Iraq/Afghanistan

 Veterans diagnosed with blast mTBI – T group (N = 26)

 Deployed Veterans not blast exposed – DC group (N = 

7)

 Establishment of normal hormone reference ranges using 

samples from age-matched community controls

 Measurement of basal levels of 12 pituitary and targetorgan hormones in serum or plasma

 Determination of prevalence of abnormalities in each 

pituitary hormone axis in each group
Anterior Pituitary & Target Organ 

Hormones 

Growth 

Hormone (GH)

 Insulin-like Growth Factor I 

(IGF-I) 

Luteinizing Hormone (LH)

Follicle-stimulating Hormone 

(FSH)

Testosteron

e 

Prolactin

Adrenocorticotropin (ACTH) Cortisol

Thyroid-stimulating Hormone 

(TSH) Thyroxine 
Posterior Pituitary Hormones

 Vasopressin

 Oxytocin
Schematic of Pituitary Cell Types
Consequences of Adult GH Deficiency

 Increased incidence of depression, irritability, 

aggressiveness, social isolation, pain, physical 

mobility, sexual dysfunction, and sleep disorders

 Cognitive impairment in multiple domains

 Detrimental effects on metabolism including high 

plasma triglycerides and low HDL cholesterol

 Negative effects on body composition (reduced 

lean body mass, increased adiposity)

 Low scores on quality of life assessments

 Increased hypertension & cardiovascular 

mortality 
Insulin-like Growth Factor-I 
Luteinizing Hormone (LH) & 

Testosterone 
OT and Human Social Behavior

 Release elicited by socially relevant challenges 

resulting in attenuation of stress responses

 Released in positive social interactions and may 

mediate stress-protective effect of social support

 Linked to reduction of limbic reactivity and 

autonomic arousal to social stimuli 

 Implicated in promotion of social cognition and 

interpretation of social signals

 Altered in mental disorders characterized by 

severe social disturbances
Abnormal AVP Secretion

 Diabetes insipidus (DI): very low values with 

plasma hyperosmolity and low urine specific gravity

 Syndrome of inappropriate antidiuretic hormone 

secretion (SIADH): abnormally high values 

accompanied by hypoosmolality and hyponatremia 

 Large body of work demonstrates increased 

anxiety and depression in animal models

 High plasma and/or CSF levels are associated with 

personality disorder, depression, obsessivecompulsive disorder, schizophrenia, and PTSD 
Abnormal Hormone Levels in 

Veterans with TBI
Poll

• NOW would you consider consulting an 

endocrinologist about chronic postconcussive symptoms?

a) Yes

b) Maybe; it would depend on the symptoms

c) No 
Summary and Conclusions

 In this preliminary study, 42% of Veterans with blast 

mTBI were found to have chronic hormonal abnormalities 

 As in studies of civilian TBI, deficiencies indicative of 

GHD and hypogonadism were most frequent

 PTHP is associated with neuropsychiatric symptoms 

and reduced quality of life similar to PTSD

 Screening for hypopituitarism after blast mTBI shows 

promise for appropriately directing diagnostic and 

therapeutic alternatives that may otherwise remain 

unconsidered and for markedly facilitating recovery and 

rehabilitation.
This Work Was Made Possible by

 Co-authors/collaborators Elaine Peskind, Kathleen 

Pagulayan, Eric Petrie, Cindy Mayer, Elizabeth 

Colasurdo, Jane Shofer, Kim Hart, David Hoff, Matthew 

Tarabochia 

 Essential staff members Carl Sikkema, Natalia 

Czajkiewicz, Alka Goyal, Molly Chinn, Rebecca Walker, 

Carol Xiang, Daniel Morelli, Rebekah Rein

 Support from Department of Defense Congressionally 

Directed Medical Research Program in Psychological 

Health/Traumatic Brain Injury and the Department of 

Veterans Affairs

For More Information:

Wilkinson CW, Pagulayan KF, Petrie EC, Mayer CL, 

Colasurdo EA, Shofer JB, Hart KL, Hoff D, Tarabochia MA, 

Peskind ER: High prevalence of chronic pituitary and 

target-organ hormone abnormalities after blast-related 

mild traumatic brain injury. Front Neurol 3:11, 2012. 

http://www.frontiersin.org/Neurotrauma/10.3389/fneur.2

012.00011/abstract

Defense Centers of Excellence for Psychological Health 

and Traumatic Brain Injury (DCoE) Neuroendocrine

Dysfunction Post mTBI Clinical Recommendations, 

Reference Card, and Training Slides

http://www.dcoe.health.mil/TraumaticBrainInjury/TBI_Inf

ormation.aspx