The Gulf War and its Diseases

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

22 Years of Subjective Symptomatologyvs.

A Toxicological Approach for Objective Markers

James N. Baraniuk, MDGeorgetown University

Washington, DC

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

CMI≥1 “severe” symptom in 2

or 3 categories(Fukuda 1998)

“Kansas” GWIdefinition

3 moderate or severe

FM 2010 FM 1990

CFSFatigue plus 4 of 8 others

(Fukuda 1994)

PotentialMechanistic Outcomes

□ fatigue □ fatigue / sleep □ fatigue   □ fatigue □ fatigue

□ mood / cognition

□ sleep□ cognitive□ anxiety□ depressive□ moody

□ cognitive / neurological / mood

□ waking unrefreshed□ cognitive symptoms

 

□ sleep disturbance□ memory or concentration

□ working memory□ attention networks□ sleep□ affect□ anxiety

□ myalgia / arthralgia

□ arthralgia□ stiffness□ myalgia

□ pain

□ widespread pain index (WPI)

□ wide spread pain

□ myalgia□ arthralgia

□ nociceptive,interoceptive & somatosensorycentral sensitization□ migraine

 □ GI□ airways□ skin

□ somatic symptoms

 □ sore throat□ lymph node□ headache

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

 □ manual tenderness

 □ systemic hyperalgesia

 □ exertional exhaustion exercise-induced dysfunction

Nociceptive, Interoceptive and FaTiguing Illnesses (NIFTI)

I disagree: Use a “Toxicological Approach”

Prevalence

Deployed

NotDeployed

Cohort

CMI

CMIViet Nam

(AgentOrange?)

CMI

CMI1980

to1989

CMI

CMI1990

to1991

CMI

CMI1992

to2001

CMI

CMI2002

to2012

CMI

CMIProspective

2013

CMI

CMIFuture

Exposures

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 syndromes5. These patterns identify risk factors and allow risk reduction to future “exposures”

No CMI

No CMI

Unique Aspects of CMI 1990-19911979 Iran hostage crisis1980-1988 Iraq-Iran War1990-1991 Airborne exposure to acetylcholinesterase inhibitors and glycine-toxicants, SCUDs, Khamisiyah March 1991 “Acute” GWI med-evac1991-1994 Official denial, confusionFeb. 1994 Riegle Report: Dual Use Exports. Senate Committee on Banking. May 25, 19941997 CIA report: Which way was the wind blowing?1998 CMI, Fukuda 19982000 Steele, “Kansas”, NOT deployed excluded2013 Acute, Subacute, Chronic

Delayed progressive symptomsObjective criteria

Khamisiyah “Toxicological Exposure”: Which way was the wind blowing?

Persian Gulf War Illnesses Task ForceIntroductory Note From the Acting Director of Central Intelligence John Tenet, 9 April 1997 

https://www.cia.gov/library/reports/general-reports-1/gulfwar/555/425055597.html

LandSat 11 Mar, 1991

LandSat

CIA

Exposed?

1997 CIA Model for Exposure ()

Which way was the wind blowing?No records (e.g. 82nd, 101st, USAF?)1,200 exposed (CIA)? Or 190,000?

Nobody knows.

CIA

OBJECTIVE CRITERIA: testable hypotheses

Screen(baseline status)

fMRI with cognitive test

Day 1 Exercise Day 2 Exercise ╚═ Exercise-induced fatigue ═╝

fMRI with cognitive test

Follow-up of fatigue & activity ╚═Exercise-induced cognitive and autonomic dysfunction═╝

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 QuestionnaireFatigue vs. Sum of 8 Ancillary Criteria

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

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

0 10 20 30 400123456789

McGill total score

Do

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R2=0.46 P=0.000003

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Ordinal Fatigue

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R2=0.40 P=0.000003

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Ordinal Fatigue

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R2=0.46 P=0.000003

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Dol

orim

etry

(kg

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0.0 0.2 0.4 0.6 0.8 1.00.0

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tivity

0.0 0.2 0.4 0.6 0.8 1.00.0

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1-Specificity**

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CB

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

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)

0 1 2 3 4 5 6 7 8 91.1

1.2

1.3

1.4

Dolorimetry (kg)0 1 2 3 4

1.1

1.2

1.3

1.4

Ordinal fatigue

AD

0 10 20 30 401.1

1.2

1.3

1.4

McGill total score

R IFOF1.1

1.2

1.3

1.4

AD

0.0 0.2 0.4 0.6 0.8 1.00.0

0.2

0.4

0.6

0.8

1.0

1-Specificity

Se

ns

itiv

ity

*

A

C

B

D

X= 38 Y= -13 Z= -8

DIMENSION 1:Increased AD in right Inferior Frontal Occipital Fasciculus

A. Map of increased AD in rIFOFB. Significantly higher AD in GWI (red) than controls (yellow)C. Correlations of AD with ordinal fatigue, dolorimetry (systemic

hyperalgesia) and McGill Total Pain ScoreD. 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 InsulaPerceptions of nociception, interoception and link to sympathetic nervous system

Right Posterior fusiform, cuneus, lateral cortices of the occipital lobePosterior component of Ventral Attention Network (VAN)

R

Representative transverse slice of brain

DIMENSION 1: Increased AD in rIFOFA. Ventral Attention Network

-Right middle frontal gyrus connected to right parietal–temporal 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 symptomsC. 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

0

20

40

60

80

1002-

Bac

k A

ccu

racy

(%

)

DAY 1 DAY 2 DAY 1 DAY 2 Controls GWI+CFS

HC/HVetGWI onlyGWI+CFS IncreasersGWI+CFS Decreasers

p<10-6

p=0.009

“Ceiling”

“Increasers”

“Decreasers”

2-BackAccuracy

2-Back Test Accuracy

DIMENSION 2:Exercise – Induced Differences in Cerebral Lactate

Between Increasers and Decreasers

A

High lactate

Low lactate

INCREASERsincrease scores

and lactate

DECREASERsExercise had no

net effect on accuracy or the

high basal lactate

DIMENSION 3a: Independent START vs. STOPP Phenotypes

defined by responses to exercise and atrophy

Δ HeartRate

(Standingminus

Recumbent)

Δ DiastolicBlood

Pressure

STARTStress Test AssociatedReversible Tachycardia

ControlSTOPPStress Test OriginatedPhantom Pain

STARTStress Test AssociatedReversible TachycardiaControlSTOPPStress Test OriginatedPhantom Pain

DIMENSION 3b: Voxel Based Morphometry (VBM) Potential Diagnostic Test for START vs. STOPP Phenotypes

B. Loss in R pons & R medulla (P< 0.02; red)

START vs. ControlsA. Lower gray matter volume L lingual gyrus to L cuneus (P< 0.025; yellow)

STOPP vs. ControlsC. Trend for less gray matter in R superior parietal lobule to R precuneus (P< 0.07; red)

E. Reduced left cerebellartonsil and left pyramis(P< 0.012)

START vs. STOPP

D. Reduced white matterin left pons (P< 0.004

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

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

DIMENSION 3c: Independent START vs. STOPP PhenotypesDay 1 Pre-Exercise BOLD 2>0-back condition

Sedentary ControlsDorsal 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 conditionSedentary ControlsAutomaticityMore efficient cognition

STOPPLoss of basal ganglia BOLD compensationGeneral ↑ DLPFC and Inferior Parietal cognitivereserves

STARTLoss of BOLD in Vermis Loss of compensationNo 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

DIMENSION 2:Exercise-induced changes:i. 2-back accuracyii. brain lactate

INCREASER DECREASER

DIMENSION 3:a. Post-exercise tachycardiab. VBM: brain stem atrophyc. BOLD in 2-back: Vermis vs. Basal

Ganglia compensationd. Loss of compensation; No BOLD

signal in START for 2>0 condition

START

STOPP

INCR START DECR START

INCR STOPP DECR STOPP

Two mutually exclusive dimensions

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

Baraniuk JN, Casado B, Maibach H, Clauw DJ, Pannell LK, Hess S. A chronic fatigue syndrome related proteome in cerebrospinal fluid. BMC Neurology 5:22, 2005. http://www.biomedcentral.com/1471-2377/5/22

Ravindran MK, Zheng Y, Timbol C, Merck SJ, Baraniuk JN. Migraine headaches in Chronic Fatigue Syndrome (CFS). BMC Neurology 11:30, 2011

Ravindran MK, Adewuyi O, Zheng Y, Rayhan RU, Le U, Timbol CR, Merck S, Esteitie R, Cooney M, Read C, Baraniuk JN. Dyspnea in Chronic Fatigue Syndrome (CFS): Comparison of two prospective cross-sectional studies. Global Journal of Health Science 5:94-110, 2013 doi:10.5539/gjhs.v5n2p94

Baraniuk JN, Adewuyi O, Merck SJ, Ali M, Ravindran MK, Timbol CR, Rayhan R, Zheng Y, Le U, Esteitie R, Petrie KN. 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

Baraniuk JN, El-Amin S, Corey R, Rayhan RU, Timbol CR. Carnosine treatment for Gulf War Illness: A randomized controlled trial. Glob J Health Sci. 2013; 5(3):69-81.

Rayhan RU, Stevens B, Adewuyi O, Timbol C, VanMeter JW, Walitt B, Baraniuk JN. Increased brain white matter axial diffusivity is associated with pain, fatigue and hyperalgesia in Gulf War Illness. PLOS ONE. 2013; 8 (3): e58493 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0058493

Rayhan RU, Raksit MP, Timbol CR, Adewuyi O, VanMeter JW, Baraniuk JN. Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness. Am J Transl Res 01/2013 5(2):212-223.

Rayhan RU, Stevens BW, Raksit M, Adewuyi O, Ripple JA, Timbol CR, VanMeter JW, Baraniuk JN. Exercise challenge in Gulf War Illness reveals two subgroups with altered brain structure and function. PLOS ONE. 2013; 8 (4): e63903.

Rayhan RU, Baraniuk JN. Prevalence of migraine headaches in Gulf War Illness and Chronic Fatigue Syndrome. Frontier Physiol, in press

Rayhan RU, Zheng Y, Uddin E, Timbol CR, Adewuyi O, Baraniuk JN. Administer and collect medical questionnaires with Google documents: a simple, safe, and free system. Trials. 2013, in press

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