Learning from Civilians about Medically Unexplained Syndromes

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Learning from Civilians about Medically
Unexplained Syndromes

• Benjamin H. Natelson, MD
• Director, Pain Fatigue Study Center, Department
  of Pain Medicine,
• Beth Israel Medical Center and
• Professor of Neurology, Albert Einstein Medical
  Center, New York

2
The Problem

• Across many conflicts, some veterans return home
  with physical symptoms that have no apparent
  medical cause
• Shell shock, Battle Fatigue , Neuroasthenia
• Ranging from 5 to 10 of all combat vets
• While this occurred with Vietnam-era vets also,
  major focus was on their mental symptoms
• PTSD
• With Gulf vets, concern moved to physical
  symptoms
• Concern about exposures as cause

3
The Problem

• Gulf Veterans reported high rates of severe
  fatigue, musculoskeletal pain, and cognitive
  problems
• Suggested the diagnoses of chronic fatigue
  syndrome, its milder version idiopathic chronic
  fatigue and/or fibromyalgia
• My colleagues and I applied for DVA funding to
  identify a cohort of GVs with CFS or ICS for
  physiological studies
• Our NJ site was awarded one of three Centers for
  Environmental Hazards Research
• Established to evaluate role of chemical exposure

4
Case Definition of CFS

• New onset of fatigue producing substantial
  decrease in activity and lasting 6 months
• Accompanied by rheumatologic, infectious or
  neuropsychiatric symptoms
• Only diagnosed when medical and psychiatric
  causes of fatigue are ruled out
• Obesity hypothyroidism Lyme lupus, etc.
• Bipolar Eating disorders substance abuse
  schizophrenia
• Prevalence 0.5 women 0.25 men

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CFS Is The Tip of the Iceberg!

• Idiopathic chronic fatigue subsyndromal
• Primarily severe fatigue without other symptoms
• Most pain syndromes associated with fatigue
• FM IBS CRPS TMJD
• Associated with medical illness
• The obvious such as heart failure
• The less than obvious
• Post Infectious
• Breast cancer survivors
• Neurologic disease Parkinsons, MS, stroke

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Risk Factors for Unexplained Fatigue

• Female gender
• Being on the shady side of the fatigue spectrum
• Early history of anxiety or depression
• Many exceptions to these

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CFS

• Cause remains a question for active research
• Unclear data regarding infection/immune
  upregulation
• Disrupted sleep may be a cause ? Rx ??
• HPA and ANS abnormalities may be 2 to
  deconditioning
• Our group has data pointing to CNS for some CFS
• Patients with no comorbid major depressive
  disorder
• Have more marked reduction in Cerebral Blood Flow
• Have greater problems on neuropsychological
  testing
• Have more abnormalities on brain MR imaging
• More often have abnormal spinal fluid protein or
  cell count
• Have higher levels of cerebroventricular lactate
• We strongly believe that stratifying into cleaner
  patient subgroups is the tactic to take for
  progress

9
Fibromyalgia

• 3 mo. of wide-spread pain
• Pain on both sides of the body
• Pain above and below the waist
• Axial skeleton pain
• Tenderness or pain with 9 lb pressure, in 11 or
  more of 18 areas depicted
• A measure of diffuse tenderness that often
  extends into face and jaw Temporo-mandibular
  joint dysfunction

Wolfe et al. Arth Rheum.33160, 1990 Plesh et
al.. J. Rheumatol, 231948, 1996
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Epidemiology of FM

• Problem in womens health (WM 2-31)
• Widespread pain in the absence of rheumatological
  disease 15 of population with more even gender
  split1
• With multiple tender points requirement, rates
  fall to 2-42 Primary FM
• Rates are the same in population of Amish women
  with limited secondary gain3
• Not hypochondriasis or classical somatizing
• In the presence of rheumatological disease, FM
  rates increase five-fold (secondary FM)2

1) Gran, Best Pract Res Clin Rheumatol, 2003 2)
Wolfe, Arthitis Rhem. 1995 3) White, J.
Rheumatol. 2003
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Gender Age by Decade for FM
Wolfe et al. Arthritis Rheum 3819-28, 1995
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Prevalence of Comorbidities Among FM and Non-FM
Patients
US Health Insurance Database(N33,176)
Non-fibromyalgia patients
22.8
22
Fibromyalgia patients
plt0.001
patients
12.3
12.1
5.9
5.7
3.9
2.8
2.8
1
Painfulneuropathies
Circulatory disorders
Depression
Diabetes
Sleep disorders
GERD (5.4 vs 1.5), anxiety (5.4 vs 1.3), and
IBS (1.5 vs 0.2) were also more prevalent
(plt.001) in fibromyalgia patients
Berger et al. Int J Clin Pract 2007611498-508
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? Rate of Autoimmunity in FM

• Of 35 patients with primary Sjögrens Disease,
  20 had FM1
• Of 35 patients with Hashimotos thyroiditis, 33
  had FM 2
• These rates parallel the high rates seen in
  rheumatolgoical disease and suggest autoimmunity
  as cause of some cases of FM

1) Priori et al. Clin. Exp Rheumaol. 28S82,
2010 2 ) Bazzichi et al. Rheumatol Int, Nov 18
,2010
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Sleep and Fatigue/Pain
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Obstructive Sleep Apnea (120 sec window)
EEG EEG EOG EOG Chin Therm Rib Abd NC Flow O2 Sat
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Disturbed Sleep Leads to Pain Fatigue

• Disrupted sleep in HCs ? ? pain thresholds
• OSA ? excessive daytime sleepiness/fatigue
• 124 OSA patients evaluated for CFS and/or FM
• 36 with mild 50 women 88 with severe 25
  women
• 3 had FM same as in population 14 had CFS
• CFS but not FM seen in OSA
• With Hx suggestive of OSA and fatigue ? do PSG
• Polysomnography was not a required test in case
  definition for CFS
• Insomnia difficulty sleeping or in falling or
  staying asleep ? CFS report it unrefreshing
• 28 insomniacs 61 women
• 33 had FM 14 had CFS
• Complaint of unrefreshing sleep indicates
  insomnia

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Hereditability in CFS and FM

• Concordance for CFS Dx in twins1
• Monozygotic 57 Dizygotic 19
• Family Study in FM compared to RA2
• First degree relatives of CFS have more FM.,
  more anxiety disorders OCD and PTSD, and
  somewhat more depression than relatives of RA
• Both studies point to hereditary factors playing
  a role in pathogenesis
• 1 Buchwald et al, 2001 2 Aaron et al., 2004

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COMT haplotype is a risk factor for TMJ joint
disease onset

• 3-year prospective study on initially TMJD-free
  females (ages 18-34)
• Assessed pain phenotype
• Thermal
• Ischemic
• Pressure
• Examined predictors
• of developing TMJD
• Pain sensitivity
• Genetic polymorphisms

Low pain sensitivity
High pain sensitivity
Diatchenko L, et al. Hum Mol Genet.
200514135-43.
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TMJD Incidence Rates x Haplotypes x Pain Grp
APS average pain sensitivity HPS high pain
sensitivity LPS low pain sensitivity.
Diatchenko L, et al. Hum Mol Genet.
200514135-43.
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Pain Perception and Sensitivity
(n16)
(n16)
(n16)
Gracely, Arthritis Rheum 2002
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Sensory Processing in Fibromyalgia A problem
with pain volume control

• Patients display a normal detection threshold
  to sensory stimuli, but a decreased noxious
  threshold
• This is not just to pressure, but also other
  stimuli, e.g. heat, noise, electrical
  stimulation.
• The general increase in sensory sensitivity could
  theoretically be due to
• psychological (e.g. expectancy or
  hypervigilance) or
• neurobiological changes in nociceptive
  processing (e.g., sensitization or reduced
  descending pain inhibition).

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Mechanism Peripheral?

• Results have been UNREMARKABLE
• Muscle MR spectroscopy findings have failed to
  identify differences in either energy metabolism
  or susceptibility to activity induced muscle
  damage
• No evidence of histochemical or molecular
  abnormalities in nociceptive biochemicals (i.e.
  substance P 5HT)

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Or Central?

• More sensitive to experimental pain such as heat,
  noise, pressure and electrical stimuli
• Cook et al., 2004 Kosek et al., 1996
  Lautenbacher et al., 1994
• Lack of normal inhibition of painful stimuli
• Cook et al., 2010 Kosek, Hansson, 1997
  Lautenbacher, Rollman, 1997 Staud et al., 2003b
• Enhanced CNS sensitivity to repeated painful
  stimuli
• Price et al., 2002 Staud et al., 2001
• Exaggerated brain responses to sensory stimuli
• Cook et al., 2004 Gracely et al., 2002

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FM is a disease of brain, not muscle
FM fail to show increased pain thresholds
Diffuse Noxious Inhibitory Control
Kosek Hansson, 1997
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Risk Factors for Unexplained WSP

• Female gender
• Overweight
• Low Socio-economic Status
• Prior history of depression and somatic
  complaints
• Many exceptions to these

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Determine if primary or secondary FM

• Blood Tests
• Sedimentation rate C reactive protein
• Rheumatoid factor anti-nuclear antibodies
• Sjögrens antibodies
• Usually negative but consider biopsy if dry
  eyes/mouth
• Thyroid studies
• Vitamin D and B12
• Others
• L-S X-Ray or CT to R/O ankylosing spondylitis
• Sleep study if history and risk factors warrant

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Suggested Change in Case Definition for FM

• Group of rheumatologists suggested dropping
  tender points and adding questions about fatigue,
  cognitive function, sleep and symptoms
• Would greatly increase rate of FM
• No empiric data to support change
• FM and CFS have some important differences
• FM responds to SNRIs CFS does not
• FM has elevated spinal Substance P CFS does not
• CFS has cognitive impairment CFSFM do not

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Prolactin Response to IV Tryptophan Infusion
Weaver Natelson, J. Women.s Health, 2010
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Suggested Change in Case Definition for FM

• Group of rheumatologists suggested dropping
  tender points and adding questions about fatigue,
  cognitive function, sleep and symptoms
• Would greatly increase rate of FM
• No empiric data to support change
• FM and CFS have some important differences
• FM responds to SNRIs CFS does not
• FM has elevated spinal Substance P CFS does not
• CFS has cognitive impairment CFSFM do not
• I think this will confuse rather than help our
  understanding of these syndromes ? stick with
  separate diagnoses pending new evidence

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Medically Unexplained Sx in GVs

• CFS is more common in GVs than controls
• 2.2 in GVs vs 0.3 in community controls1
• 1.6 in GVs vs 0.1 in era vets2
• Disabled GVs have higher rates of CFS than
  disabled era vets or disabled Bosnian vets3
• While widespread pain is acknowledged to be
  higher in GVs than era, rates of FM less clear
• FM in 2 of GVs vs 1.2 era vets gtgt significant2
  but these rates approach those seen in the
  community
• We compared 30 GVs to 84 non-vets all Caucasian
  males and all fulfilling the 1994 case definition
  for CFS4
• 1McCauley et al., 2002 2Eisen et al, 2005
  3Ismail et al., 2008 4Ciccone Natelson, 2010

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Multiple Chemical Sensitivity MCS

• Exposure to more than one odor or chemical
  produces symptoms in more than one organ system
• Detergent and perfume ? HAs, gastric distress
• Can be sudden in onset related to some exposure
• Patients avoids exposure to odorants
• Since GVs were exposed to multiple chemicals
  including diesel, burning garbage, AChEs,
  hypothesis is GVs with CFS should have more MCS
  than civilians with CFS

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Gulf Vets Vs Civilians with CFS
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Stress Reactivity in GVs with CFS/ICF

• Lower BP response to cognitive stress but same
  to cold pressor
• Due to failure to constrict peripheral vessels
• Not explained by psych Dx
• Change in TPR correl-ated with energy for sick
  but not healthy vets
• Defective stress reactivity may play a role in
  symptom of fatigue

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GVs w/ WSP are more sensitive to heat pain than
healthy GVs and this increases following acute
exercise
GroupTrialsTime F6,205.9, plt0.01
GroupTrialsTime F6,202.7, plt0.05
Cook et al, J Pain, 2010
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Relation of PTSD and CFS to Stressor Intensity
Kang Natelson, Am J Epidemiol, 2003
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PTSD Physical Disease

• We are taught to think that stress produces
  mental and emotional problems only BUT
• Vietnam vets with PTSD had a two-fold increase in
  risk of dying from CV disease1
• Effect remained after controlling for diabetes
  and depression
• Risk increased as PTSD symptom severity increased
• PTSD severity predicts RA in Vietnam vets2
• 1Boscarino, 2008 2Boscarino, 2010

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This Holds for OEF-OIF Vets Too

• OEF/OIF vets with PTSD have more physical disease
  diagnoses than those without PTSD
• Andersen et al, 2010

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Diagnoses in OEF/OIF Vets with PTSD
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What About OEF-OIF Vets?
Current thinking is focused on mild traumatic
brain injury but how about other possibilities?
Of 675 OEF/OIF vets who came to the New Jersey
WRIISC with health concerns, 17.6 fulfilled
criteria for CFS!!
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This Result Leads to an Inference
Although this study is based on health care
seeking vets and is not a random sample, the high
rate of CFS in OEF/OIF strongly suggests that the
epidemic of CFS seen after the Gulf conflict
was not a function of exposure to burning diesel
fumes or AChEs including Sarin
41
PCS scores of OEF/OIF with norms of various
disease states and 9/11 first responders Dashed
vertical line is U.S. population norm
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Treatment

• Identify psychiatric co-morbidity and treat
  intensively with drugs and brief therapies
• If sleep apnea exists, treat with CPAP or dental
  prosthesis ? often symptoms remain
• Use standard of care treatments for any chronic
  Illness
• Pharmacotherapy
• Gentle physical conditioning
• CBT to overcome fears of increasing activity
• Focuses on somatic rather than psychological
  issues

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Pharmacologic Treatment of Wide Spread Pain

• Anti-epileptic drugs
• Pregabalin Alpha-2-delta (?2?) Ca channel
  blocker (approved by the FDA in 2007 for the
  management of FM) Gabapentin
• Lamotrigine, Oxcarbamazepine (sodium channel
  blockers)

This information concerns a use that has not
been approved by the US Food and Drug
Administration.
44
Pharmacologic Treatment of Wide Spread Pain

• Anti-epileptic drugs
• Pregabalin Alpha-2-delta (?2?) Ca channel
  blocker (approved by the FDA in 2007 for the
  management of FM) Gabapentin
• Lamotrigine, Oxcarbamazepine (sodium channel
  blockers)
• Serotonin/norepinephrine reuptake inhibitors
• Cyclic medications (eg, TCAs, cyclobenzaprine)

This information concerns a use that has not
been approved by the US Food and Drug
Administration.
45
Tricyclic Antidepressants CharacteristicsSecondar
y Tertiary Amines

Lipman AG. Clinics in Geriatric Medicine
199612501-15.
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Pharmacologic Treatment

• Anti-epileptic drugs
• Pregabalin Alpha-2-delta (?2?) ligand (approved
  by the FDA in 2007 for the management of
  fibromyalgia) Gabapentin
• Lamotrigine, Oxcarbamazepine (sodium channel
  blockers)
• Serotonin/norepinephrine reuptake inhibitors
• Cyclic medications (eg, TCAs, cyclobenzaprine)
• Duloxetine (approved by the FDA in 2008 for the
  management of fibromyalgia)
• 69 of effect independent of any effect on
  depression1
• Milnacipran (approved by the FDA in 2009 for the
  management of fibromyalgia)

This information concerns a use that has not
been approved by the US Food and Drug
Administration. 1Marangell et al. Pain , 15231,
2011
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Pharmacologic Treatment

• Anti-epileptic drugs
• Pregabalin Alpha-2-delta (?2?) ligand (approved
  by the FDA in 2007 for the management of
  fibromyalgia) Gabapentin
• Lamotrigine, Oxcarbamazepine (sodium channel
  blockers)
• Serotonin/norepinephrine reuptake inhibitors
• Cyclic medications (eg, TCAs, cyclobenzaprine)
• Duloxetine (approved by the FDA in 2008 for the
  management of fibromyalgia)
• Milnacipran (approved by the FDA in 2009 for the
  management of fibromyalgia)
• Sodium oxybate, tramadol, long acting opiates

This information concerns a use that has not
been approved by the US Food and Drug
Administration.
48
Summary of Exercise in the Management of
Fibromyalgia

• Aerobic training at moderate intensity likely
  improves overall well-being and physical
  function1
• Attrition rates were high (range 13?44)
  adherence poorly documented
• Small sample sizes (range 16?51)
• Strength and flexibility training may decrease
  pain, tender points, and depression, and may
  improve overall well-being1,2
• Need more high-quality studies
• Not all patients tolerate exercise

1Busch AJ et al. Cochrane Database Syst Rev.
2007. 2Rooks D et al. Arch Intern Med.
2007167(20)2192.
49
Aerobic exercise vs non-exercise controls
(combined data from 4 studies)


statistically significant

• Busch A, et. al. Cochrane Review 2003

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Cognitive Behavioral Therapy (CBT)

• A program designed to teach patients techniques
  to reduce their symptoms, to increase coping
  strategies, and to identify and eliminate
  maladaptive illness behaviors
• Shown to be effective for nearly any chronic
  medical illness1
• Not all CBT is created equal very dependent on
  content, therapist, and program
• www.knowfibro.com

1Williams DA et al. J Rheumatol.
200229(6)1280-1286.
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Improvements noted, CBT vs standard care over 12
months (n122)

OR 2.9, plt0.05
Williams DA, et al. J Rheum 2002
52
Conclusions

• New approvals offer options for the treatment of
  fibromyalgia
• CNS targets have proven to be effective
• Treatment must be individualized
• Integration of various pharmacologic and
  nonpharmacologic treatments probably useful