The Gulf War and its Diseases

IOM Subjective GWI Case Designation Criteria IX, X, or XI

22 Years of Subjective Symptomatology vs. A Toxicological Approach for Objective Markers

James N. Baraniuk, MD Georgetown University Washington, DC

Table 1. Overlap of SUBJECTIVE case designations & potential mechanistic outcomes

CMI 1 severe symptom in 2 or 3 categories (Fukuda 1998) fatigue Kansas GWI definition 3 moderate or severe fatigue / sleep CFS Fatigue plus 4 of 8 others (Fukuda 1994) fatigue sleep disturbance memory or concentration

FM 2010

FM 1990

Potential Mechanistic Outcomes

fatigue working memory attention networks sleep affect anxiety nociceptive, interoceptive & somatosensory central sensitization migraine

fatigue waking unrefreshed cognitive symptoms widespread pain index (WPI) somatic symptoms manual tenderness

mood / cognition

sleep cognitive cognitive / anxiety neurological / depressive mood moody

arthralgia myalgia stiffness / arthralgia myalgia

pain
GI airways skin

wide spread pain

myalgia arthralgia sore throat lymph node headache

Extensive exclusion criteria including pregnancy, depression, HIV, chronic viral, autoimmune, neoplastic or medical disease.

systemic hyperalgesia exertional exhaustion exercise-induced dysfunction

Nociceptive, Interoceptive and FaTiguing Illnesses (NIFTI)

I disagree: Use a Toxicological Approach

Prevalence Deployed Not Deployed CMI Viet Nam (Agent Orange?) CMI 1980 to 1989 CMI 1990 to 1991 CMI 1992 to 2001 CMI 2002 to 2012 CMI

CMI

CMI

CMI

CMI

CMI

CMI

No CMI No CMI

Cohort

CMI CMI Prospective Future Exposures 2013

HYPOTHESIS: CMI in 1990-1991 cohort (GWI) is a unique syndrome. Null Hypothesis: CMI is an occupational consequence of military service. 1. Military service is a risk factor for CMI [1998] with increased odds ratio vs. civilians. a. ORs for CMI are equivalent for deployed vs. nondeployed from each era. b. Patterns of claims data reveal consistent comorbid conditions and mortality. 2. 1990-1991 cohort had a toxicological exposure. a. Odds ratio for CMI is significantly higher in GWI than other cohorts. b. OR for nondeployed GWI from 1990-1991 is significant higher than other cohorts. 3. Viet Nam era deployment exposure cohort provides a model of natural history IF CMI is related to military service alone (LaCoste Syndrome model) 4. GWI provides a predictive model for 2002-2012 exposures and syndromes 5. These patterns identify risk factors and allow risk reduction to future exposures

Unique Aspects of CMI 1990-1991

1979 Iran hostage crisis 1980-1988 Iraq-Iran War 1990-1991 Airborne exposure to acetylcholinesterase inhibitors and glycine-toxicants, SCUDs, Khamisiyah March 1991 Acute GWI med-evac 1991-1994 Official denial, confusion Feb. 1994 Riegle Report: Dual Use Exports. Senate Committee on Banking. May 25, 1994 1997 CIA report: Which way was the wind blowing? 1998 CMI, Fukuda 1998 2000 Steele, Kansas, NOT deployed excluded 2013 Acute, Subacute, Chronic Delayed progressive symptoms Objective criteria

Khamisiyah Toxicological Exposure:

Which way was the wind blowing?
Persian Gulf War Illnesses Task Force Introductory Note From the Acting Director of Central Intelligence John Tenet, 9 April 1997 LandSat 11 Mar, 1991

1997 CIA Model for Exposure ()

CIA
LandSat Exposed? CIA

Which way was the wind blowing? No records (e.g. 82nd, 101st, USAF?) 1,200 exposed (CIA)? Or 190,000? Nobody knows.
https://www.cia.gov/library/reports/general-reports-1/gulfwar/555/425055597.html

OBJECTIVE CRITERIA: testable hypotheses

Screen fMRI with Day 1 Exercise Day 2 Exercise fMRI with (baseline cognitive test Exercise-induced fatigue cognitive test status) Exercise-induced cognitive and autonomic dysfunction Follow-up of fatigue & activity

Table 1. Study protocol HYPOTHESIS: Day 1 exercise stressor will lead to deterioration of Day 2 exercise performance, cognitive performance, and MRI correlates SUBJECTS: CMI (1998) = GWI [all met CFS (1994)] versus sedentary controls

MODEL SYSTEM: Exertional exhaustion was the model complaint since this unusual symptom infers that stressors alter perceptions and function. GWI/CFS and sedentary control subjects had bicycle exercise stress tests on 2 consecutive days with functional magnetic resonance imaging (fMRI) studies before and after the exercise. Outcomes: 3 subjective and 3 objective

CFS Severity Questionnaire Fatigue vs. Sum of 8 Ancillary Criteria

Figure removed to decrease file size. Please see figure in manuscript.

Baraniuk et al. A Chronic Fatigue Syndrome (CFS) Severity Score based on case designation criteria. Am J Transl Res 2013;5(1):53-68 www.ajtr.org /ISSN:1943-8141/AJTR1211008

Correlation of Pain, Fatigue and Dolorimetry (tenderness) in GWI

A
4
Ordinal Fatigue

B
9 8 7 6 5 4 3 2 1 0 0 10 20
R2=0.46 P=0.000003

C
Ordinal Fatigue Sensitivity

1.0 0.8 0.6 0.4 0.2 0.0

2 1 0
Controls CMI

Dolorimetry (kg)

30

40

0.0

0.2

0.4

0.6

0.8

1.0

McGill total score 1.0

1-Specificity**

30 McGill total score

McGill total score

25 20 15 10 5 0 Controls

McGill total score Sensitivity

45 40 35 30 25 20 15 10 5 0 0

R2=0.46 P=0.000003

0.8 0.6 0.4 0.2 0.0

2
Ordinal Fatigue

4
1.0 Dolorimetry (kg) Sensitivity 0.8 0.6

0.0

0.2

0.4

0.6

0.8

1.0

CMI

1-Specificity**

9 8 7 6 5 4 3 2 1 0

9 8 7 6 5 4 3 2 1 0
0

Dolorimetry (kg)

Dolorimetry (kg)

R2=0.40 P=0.000003

0.4 0.2
0.0

trols

CMI

2 3 Ordinal Fatigue

0.0

0.2

0.4

0.6

0.8

1.0

1-Specificity**

MRI DIMENSION 1: Diffusion Tensor Imaging (DTI)

Measures orientation of protons on water molecules in magnetic field with radio frequency modulation

-Liquid water -Random orientation of diffusion Random walk Brownian motion -Spherical distribution -Vector lengths (eigenvectors) are equal in each of the 3 dimensions, and cancel out

-Neuronal axon tubes constrain diffusion

-Ellipsoid distribution (blue & green) -Vector lengths (eigenvectors) in each of the 3 dimensions are different -Longest eigenvector = Axial diffusivity (AD) (cyan vector) -2 perpendicular eigenvectors = Radial diffusivity (RD) (white and yellow vectors)

DIMENSION 1: Increased AD in right Inferior Frontal Occipital Fasciculus

A

X= 38

Y= -13

Z= -8

B
1.4

1.3

AD
1.2 1.1

C
1.4 1.4 1.4

R IFOF

D 1.0
0.8
Sensitivity

1.3

1.3
1.2 1.1 0 1 2 3 4 0 1 2 3 4 5 6 7 8 9
Dolorimetry (kg) Ordinal fatigue

1.3
1.2 1.1 0 10 20 30 40
McGill total score

AD

0.6 0.4 0.2

1.2 1.1

0.0 0.0 0.5

1-Specificity

1.0

A. Map of increased AD in rIFOF B. Significantly higher AD in GWI (red) than controls (yellow) C. Correlations of AD with ordinal fatigue, dolorimetry (systemic hyperalgesia) and McGill Total Pain Score D. ROC of AD in rIFOF to distinguish GWI from controls

DIMENSION 1: Increased AD in rIFOF of GWI

Ventromedial prefrontal cortex (vmPFC) Orbitofrontal cortex (OFC) rMFG = Ventral Attention Network (VAN) Orbitalfrontal cortex = Valuation of experiences Right Anterior Insula Perceptions of nociception, interoception and link to sympathetic nervous system Right Posterior fusiform, cuneus, lateral cortices of the occipital lobe Posterior component of Ventral Attention Network (VAN)

R
Representative transverse slice of brain

DIMENSION 1: Increased AD in rIFOF

A. Ventral Attention Network -Right middle frontal gyrus connected to right parietaltemporal junction -Surveys environment for novel, task related cues -Disrupts ongoing activities of Dorsal Attention Network (DAN) and Working Memory (Inferior Parietal regions) B. Orbitofrontal Prefrontal communications provide valuation of pain, fatigue, and other symptoms C. Anterior Insula for perception of nociceptive / interoceptive information and connections to sympathetic nervous system (right insula) and parasympathetic nervous system (left insula)

D. Differential Diagnosis of Increased Axial Diffusivity: 1. Recovery from traumatic brain injury (TBI) 2. Early transient phase of Mild Cognitive Impairment (MCI) 3. Amyotrophic lateral sclerosis (internal capsule corticospinal tract) 4. Heart failure chronic or recurrent ischemia E. Increased axial diffusivity distinguished CMI / CFS from sedentary controls: - DTI as a Diagnostic Test ?

DIMENSION 2: 2-Back Working Memory Accuracy Before vs. After 2 Bicycle Exercise Tests and Brain Lactate
100

2-Back Test Accuracy

Increasers

Ceiling

2-Back Accuracy (%)

80
p<10-6

2-Back Accuracy

60

40

p=0.009

Decreasers

20

HC/HVet GWI only GWI+CFS Increasers GWI+CFS Decreasers

DAY 1 DAY 2 Controls

DAY 1 DAY 2 GWI+CFS

DIMENSION 2: Exercise Induced Differences in Cerebral Lactate Between Increasers and Decreasers
A

High lactate

DECREASERs Exercise had no net effect on accuracy or the high basal lactate
INCREASERs increase scores and lactate

Low lactate

DIMENSION 3a: Independent START vs. STOPP Phenotypes defined by responses to exercise and atrophy
Heart Rate START Stress Test Associated Reversible Tachycardia Control STOPP Stress Test Originated Phantom Pain (Standing minus Recumbent) START Stress Test Associated Reversible Tachycardia Control STOPP Stress Test Originated Phantom Pain

Diastolic Blood Pressure

DIMENSION 3b: Voxel Based Morphometry (VBM)

Potential Diagnostic Test for START vs. STOPP Phenotypes
START vs. Controls A. Lower gray matter volume B. Loss in R pons & L lingual gyrus to L cuneus R medulla (P< 0.02; (P< 0.025; yellow) red) STOPP vs. Controls C. Trend for less gray matter in R superior parietal lobule to R precuneus (P< 0.07; red)

START vs. STOPP

D. Reduced white matter in left pons (P< 0.004

E. Reduced left cerebellar tonsil and left pyramis (P< 0.012)

F. Reduced gray matter in R culmen to R fastigial & L dentate nuclei of cerebellum (P< 0.035).

All P values were corrected for age, gender and multiple comparisons using non-stationary cluster correction.

DIMENSION 3c: Independent START vs. STOPP Phenotypes Day 1 Pre-Exercise BOLD 2>0-back condition
Sedentary Controls Dorsal Activation Network (DAN; DLPFC) Working memory (inferior parietal)

STOPP Basal ganglia BOLD cognitive compensation Anterior insula BOLD Phantom Perception

START BOLD in Vermis of cerebellum for cognitive compensation

DIMENSION 3d: Independent START vs. STOPP Phenotypes Day 2 POST-Exercise BOLD 2>0-back condition
Sedentary Controls Automaticity More efficient cognition

STOPP Loss of basal ganglia BOLD compensation General DLPFC and Inferior Parietal cognitive reserves START Loss of BOLD in Vermis Loss of compensation No BOLD signal in 2>0-back condition. (Max. BOLD in 0-back)

Algorithm for Objective Diagnosis

Populations: CMI+CFS / GWI & Controls Define ranges of normal & thresholds

DIMENSION 1: Increased AD by DTI in CMI&CFS vs. Controls

Two mutually exclusive dimensions DIMENSION 2: Exercise-induced changes: i. 2-back accuracy ii. brain lactate DIMENSION 3: a. Post-exercise tachycardia b. VBM: brain stem atrophy c. BOLD in 2-back: Vermis vs. Basal Ganglia compensation INCREASER DECREASER d. Loss of compensation; No BOLD signal in START for 2>0 condition

INCR START DECR START

START
STOPP

INCR STOPP DECR STOPP

Hypotheses Derived from Objective Data

4 independently defined phenotypes indicate distinct but overlapping pathophysiological mechanisms.
White matter axonopathy to separate CMI+CFS from controls (DTI) Working memory and attention network dysfunction Vermis vs. Basal Ganglia compensation (START vs. STOPP) Exercise stressor reveals cognitive decompensation Neuron astrocyte lactate shuttle dysfunction and defective energy utilization (INCR vs. DECR) Dysfunctional GABA-ergic and other inhibitory interneurons Smoking (nicotine) and ethanol increase mGlu2 R (metabolotropic glutamate receptor 2) and modulate inhibitory neural responses Smoking (nicotine) alters sensitivity to cholinergic activation
e.g. ACh toxicity with ACh-esterase agents?

GABA A receptors are 5-subunit ion channels. Clonazepam and beta-alanine (carnosine) are agonists of subunit polymorphisms. Ethanol interacts with GABAAR. Beta2 subunit, and alpha7 homopentamers may be targets on distinct interneuron populations.

Hypotheses Derived from Objective Data

Cohort analysis of a 1990-1991 toxicological exposure compared to pre-1990 and post-1992 cohorts may determine if morbidity and mortality were increased only in 1990-91 cohort. Deployed and nondeployed and illness vs. well cohorts can be compared from each epoch. Actuarial epidemiology, mortality and morbidity incidence and prevalence data for onset of CMI and allied syndromes are not available from VA or DoD. VA claims data may show differences in diagnostic codes, use of services, and types of services and treatments made in each cohort. Proxy differences? Is there a set of VA diagnosis codes that may identify the majority of CMI+CFS/GWI subjects vs. other VA patients? Can their health and care be followed retrospectively? Statistical and cluster analysis for CMI subsets.

Hypotheses Derived from Objective Data

Dysfunctional GABA, glycine, somatostatin, VIP and other inhibitory interneuron receptor activity Strychine rodent poison destroys inhibitory glycine feedback loops that regulate spinal cord motor neuron activity.
Attention tremor. Progressive toxicity and Parkinsonian motor degeneration?

RDBPC 3 month dose escalation study of carnosine:

(beta-alanine histidine dipeptide)

Beta-alanine from carnosine is a GABA - alpha subunit agonist. Carnosine improved cognition and diarrhea.

Hypotheses Derived from Objective Data

Distinct mechanisms imply discrete targets for new diagnostics and therapeutics Attention and working memory. No drugs. Amygdala GABA-glutamate fear circuit generalization leads to generalized anxiety. Responds clinically to clonazepam (GABA alpha subunit agonist). Migraine mechanisms. 80% prevalence. Under diagnosed and undertreated. Responsive to triptans and topiramate. Irritable bowel mechanisms: increased neural-mediated peristalsis and water influx into bowel. Beneficial effect of carnosine / beta-alanine on intestinal neural networks? Periaqueductal grey matter loss of volume (atrophy) may be related to sleep irregularities, pain, and dysautonomia

Conclusions
Subjective criteria are numerous, overlapping, and after 15 years have not resolved the debate over GWI. Objective MRI and biomarkers indicate phenotypes of CMI&CFS veterans. Use a toxicological exposure approach with comparisons of multiple cohorts to:
determine if there are excess symptoms in deployed Gulf War I veterans define the natural history of GW exposure disease(s)

These objective criteria must replace subjective responses. Potential mechanisms open up opportunities for new therapeutics. Need confirmation studies.
HYPOTHESIS: I want to be the one to prove myself wrong.

Recommendations
Eliminate VA conflict of interest between reducing costs of care vs. high research costs for objective tests and new treatments Transfer grant programs and funding to independently managed CDMRP GWIRP program GWI RAC should report directly to Congress on global progress on GWI Examine CMI incidence, prevalence, causes, and associated risk factors in Iraq and Afghanistan veterans Examine military lifestyle changes:
PTSD was more likely than not related to extreme frustration with constantly changing VA standards ratings and disability problems PTSD was frequently related to blue on blue military rape Nicotine as co-factor for increasing sensitivity to harmful effects of cholinergic toxicity and anticholinergic Repetitive head trauma from rifle / artillery discharge, vehicles Motor vehicle accidents helmets, seat belts, head restraints

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