BHC Activity Intolerance & Post-Exertional Malaise 2018

Bateman Horne Center (BHC)
Education Program
Activity Intolerance and Pacing
Fibro-Flare and
Post-Exertional Malaise of ME/CFS
Lucinda Bateman MD, 2018
Bateman Horne Center | BatemanHorneCenter.org

Important Principles of Management: FM and ME/CFS
u 1) Good differential diagnosis to identify and address
all aspects of illness and comorbid conditions
u 2) “Pace” activity to prevent symptom escalation
(preventive activity management). Avoid push/crash.
u 3) Address the major aspects of illness
u SLEEP: Achieve most restorative
u MENTAL HEALTH/COGNITION: bolster
u PAIN: control severe pain and learn to manage chronic pain
u FITNESS: Achieve best fitness based on tolerance and illness
relapse
u ORTHOSTATIC INTOLERANCE– if applicable

FM: worsening might be called “fibro-flare”
ME/CFS: worsening is called PEM or a
“crash”

Fibromyalgia
• Sleep disturbances
• Stress or duress
• Activity that is too long or
intense (4-8 hours)
• Sensory overload---sounds,
light, odors, pain (signal
amplification)
• Medications: usually helpful
• Too little activity (Exercise helps).
ME/CFS (w/wo FM)
• Sleep disturbances
• Stress or duress
• Physical, cognitive, orthostatic
stress/activity (0-4 hours)
• Sensory overload
• Medications: often poorly
tolerated
• Infections, allergies, exposures
may cause illness flare.
Certain factors worsen illness symptoms:

*Gene expression
*CardioPulmonary Exercise Testing
*Orthostatic testing
*Metabolomics
There is mounting evidence for activity-induced illness relapse in
ME/CFS
How do we know people with ME/CFS can get worse with exercise?

Gene Expression

University of Utah
Alan Light PhD and Kathy Light PhD
2009
2011
2017?
Bateman Horne Center | BatemanHorneCenter.orgCourtesy of Alan Light

Exercise on Airdyne bike at 70% of age-predicted max Heart Rate for 25 minutes.
(Example: 50 year old, HR 120 bpm, 25 min)
Blood draws pre-exercise baseline and post-exercise at 30 min, 8 hours, 24 and
48 hours to examine gene expression changes.
Used exercise as a stressor to study post-exertional blood findings
(gene expression)in patients with CFS, CFS/FM and FM-only.
Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and
Fibromyalgia Syndrome. Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC. J Intern Med. 2012
Jan;271(1):64-81. doi: 10.1111/j.1365-2796.2011.02405.x. PubMed PMID: 21615807; PubMed Central PMCID: PMC3175315.

FoldIncreasesinmRNA(+SEM)
0.8
2.8
4.8
6.8
8.8
10.8
Baseline 30 min 8 h 24 h 48 h
All CFS patients (both those with and without FMS) at times indicated after 25
minutes exercise to 70% of predicted maximal heart rate (n=19)
All controls at times indicated after 25 minutes exercise
to 70% of predicted maximal heart rate (n=15)
0.8
2.8
Multiple sclerosis patients with fatigue (n=9)
0.8
2.8
4.8
ASIC3
P2X4
P2X5
TRPV1
α2A
β1
β2
COMT
IL6
IL10
TNFα
TLR4
CD14
Sensory
Adrenergic
Immune
0.8
High-intensity exercise controls at times indicated after 25 minutes
of full-body exercise to 85% of predicted maximal heart rate
Light A, et al. Journal of Pain. 2009. Bateman Horne Center | BatemanHorneCenter.org

Patient 061016
0.8
2.8
4.8
6.8
8.8
10.8
12.8
14.8
baseline 30 min 8 hour 24 hour 48 hour
FoldincreasesinmRNA
P2X4
P2X5
AD2A
ADB1
ADB2
COMT
TLR4
CD14
All CFS patients (both those with and without FM)
0.8
2.8
4.8
6.8
8.8
10.8
FoldincreasesinmRNA
All controls at times indicated
0.8
2.8
4.8
baseline 30 min 8 hr 24 hr 48 hr
For all graphs times are after
25 minutes of moderate
Whole body exercise
KJ
Courtesy of Alan Light

0.8
2.8
4.8
6.8
Patient CB24 (Primarily Ad2A increase)
Control patients: Low intensity exercise at times indicated after
25 minutes exercise to 70% of predicted maximal heart rate (n=18)
0.8
1.8
2.8
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB1
ADB2
COMT
IL6
IL10
TNFalpha
TLR4
CD14
FoldincreasesinmRNA

Patient 091006 (Ad2A decrease) vs. Control subjects
0.01
0.1
1
10
baseline 30 min 8 hr 24 hr 48 hr baseline 30 min 8 hr 24 hr 48 hr
091006 Controls (N=35)
FoldincreasesinmRNA
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB1
ADB2
COMT
IL6
IL10
TNF beta
TLR4
CD14

1
10Log10mRNArelativetoTF2B(+SEM)
baseline 30 min 8 hr 48 hr24 hr baseline 30 min 8 hr 48 hr24 hr
The study showed two CFS groups—decreased or increased Ad2A—w/wo FM
CFS-only patients
Ad2A Low (n=6) Ad2A High (n=10)
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB1
ADB2
COMT
IL6
IL10
TNFalpha
TLR4
CD14
Courtesy of Alan Light. Bateman Horne Center | BatemanHorneCenter.org

The study showed two CFS groups—reduced Ad2A or increased Ad2A---w/wo FM
CFS/FM patients
1
10 Ad2A Low (n=12) Ad2A High (n=20)
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB1
ADB2
COMT
IL6
IL10
TNFalpha
TLR4
CD14
Log10mRNArelativetoTF2B(+SEM)
baseline 30 min 8 hr 48 hr24 hr baseline 30 min 8 hr 48 hr24 hr
Courtesy of Alan Light.
Gene associated
With PAIN

Patient 090602CFIDS1 vs Control subjects
0.01
0.1
1
10
090602CFIDS1 Controls
FoldincreasesinmRNA
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB1
ADB2
COMT
IL6
IL10
TNF beta
TLR4
CD14
20 yr male (teenage onset) rockhound with CFS/FM and orthostatic intolerance

Patient 090624CFIDS1 vs Control subjects
0.01
0.1
1
10
090624CFIDS1 Controls
FoldincreasesinmRNA
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB1
ADB2
COMT
IL6
IL10
TNF beta
TLR4
CD14
22 yo woman, teenage onset, severely ill. Pursuing life. Married.
Recently gave birth to second child. Full time assistance with childcare.

Patients with FM-only had the
same post-exercise gene
expression as controls

A: Healthy sedentary control patients
B: CFS and CFS/FM
Ad2A
C: CFS and CFS/FM
Ad2A
D: FM-only (no CFS)

0
.05
.1
.15
.2
.25
FM con
P2X4
P<.001
0
.004
.008
.012
.016
TRPV1
FM con
P<.005
0
.002
.004
.006
IL10
FM con
P<.031
AmountmRNArelativetoTF2B(+SEM)
Baseline mRNA amounts in FM-only patients compared to controls (N=18)
1
2
FMS-only n=18
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB1
ADB2
COMT
IL6
IL10
TNFβ
TLR4
CD14n.s. for all AUC compared to controls
FoldincreaseinmRNA
frombaseline(+SEM)
Patients with FM-only on the left
and healthy controls on the right
Courtesy of Alan Light.
Although gene expression after
exercise was normal, the FM patients
had abnormal baseline expression of
certain genes compared to controls

Control Subjects --vs-- CFS/FM Subject
0.1
1
10
ASIC3
P2X4
P2X5
TRPV1
AD2A
ADB2
COMT
IL6
IL10
TNF beta
TLR4
CD14
FoldincreaseinmRNA
Controls 090429
Symptom Scoresà

MENTAL FATIGUE before during and after exercise
For patient 090429 vs. 49 other Chronic Fatigue Syndrome patients,
18 Fibromyalgia patients, and 50 healthy control subjects
0
10
20
30
40
50
60
70
MF base MF mid MF imm MF 30 MF 8 MF 24 MF 48
VisualAnalogScale
100=theworstmentalfatigue
youcanimagine
Mental Fatigue CFS/FM
Mental Fatigue CFS
Mental Fatigue FM
Mental Fatigue Controls
090429 mental fatigue

PHYSICAL FATIGUE before during and after exercise
0
10
20
30
40
50
60
70
80
PF base PF mid PF imm PF 30 PF 8 PF 24 PF 48
Peripheral Fatigue CFS/FM
Peripheral Fatigue CFS
Peripheral Fatigue FM
Peripheral Fatigue Controls
090429 physical fatigue
VisualAnalogScale
100=theworstphysicalfatigue
youcanimagine

PAIN before during and after exercise
0
10
20
30
40
50
60
70
80
90
Pain base Pain mid Pain imm Pain 30 Pain 8 Pain 24 Pain 48
Pain CFS/FM
Pain CFS
Pain FM
Pain Controls
090420 pain
VisualAnalogScale
100=theworstpain
youcanimagine

PAIN before during and after exercise
0
10
20
30
40
50
60
70
Pain base Pain mid Pain imm Pain 30 Pain 8 Pain 24 Pain 48
Visualanalogscale(+SEM)
CFS-α-2A increase
CFS-α-2A decrease
CFS-only
FM-only
controls
* only points not signficantly different from baseline in patient groups.
All other patient group points signficantly different from baseline and from controls P<.05
# only point in control group signficantly different from baseline P<.05
MENTAL FATIGUE before during and after exercise
0
10
20
30
40
50
60
70
MF base MF mid MF imm MF 30 MF 8 MF 24 MF 48
CFS-α-2A increase
CFS-α-2A decrease
CFS-only
FM-only
controls
* *
PHYSICAL FATIGUE before during and after exercise
0
10
20
30
40
50
60
70
PF base PF mid PF imm PF 30 PF 8 PF 24 PF 48
CFS-α-2A increase
CFS-only
CFS-α-2A decrease
FM-only
controls
#
A
B
C
Figures
From JIM
paper
Courtesy of Alan Light Bateman Horne Center | BatemanHorneCenter.org

Cardiopulmonary Exercise
Testing (CPET)

Cardiopulmonary Exercise Testing (CPET)
• Patients with ME/CFS are unable to replicate the test
parameters if tested 2 days in a row.

15
20
25
30
35
Test 1 Test 2
PeakVO2(ml/kg/min)
CFS
Control
Peak Oxygen Consumption (VO2) in CFS
compared to Controls
Using serial cardiopulmonary exercise tests to support a diagnosis of
Chronic Fatigue Syndrome. VanNess, JM, et al. Med. Sci. Sports. Exerc. 38(5), 2006.

Inability of ME/CFS patients to reproduce VO2 peak
indicates functional impairment. Keller, et al.
Journal of Translational Medicine 2014, 12:104.

Orthostatic Intolerance

Orthostatic Intolerance:
• Uncertain contribution to PEM…but…
• Periods of reduced blood flow to the brain when standing or upright
may result in “payback” symptoms

• Tilt Table Testing [or equivalent]
• Cardiovascular measurements (heart rate, blood
pressure, respiratory volume and rate, end tidal
CO2)
• Blood vessel responsiveness using laser doppler
flow.
• Brain blood flow using transcranial doppler (US)
Methods of studying orthostatic changes:
The work of Marvin Medow, PhD, Julian Stewart, MD, Benjamin Natelson, MD

0 10 0 20 0 30 0 40 0 50 0 60 0 70 0 80 0
T ime (s ec )
0
50
10 0
15 0
20 0
HeartRate(bpm)
0 10 0 20 0 30 0 40 0 50 0 60 0 70 0 80 0
T ime ( s ec )
-2 0
-1 2
-4
4
12
20
RelativeRespVolume
0 10 0 20 0 30 0 40 0 50 0 60 0 70 0 80 0
T ime ( s ec )
20
30
40
50
ETCO2
(mmHg)
H eart Ra te R espi rat ion s ET CO2
0 10 0 20 0 30 0 40 0 50 0 60 0 70 0 80 0 90 0
T ime ( s ec )
0
50
10 0
15 0
20 0
HeartRate(bpm)
0 10 0 20 0 30 0 40 0 50 0 60 0 70 0
T ime ( s ec )
-2 0
-1 2
-4
4
12
20
RelativeRespVolume
0 10 0 20 0 30 0 40 0 50 0 60 0 70 0
T ime ( s ec )
20
30
40
50
ETCO2
(mmHg)
Control
POTS
control
CFS/POTS
Thorax Splanchnic Pelvic Leg
-50
-30
-10
10
30
50
PercentChangeinSegmentalBloodVolume
Control CFS/POTS
*
*
Courtesy Marvin Medow.
Presented via webinar
Previously available at
www.cfids.org

Courtesy Marvin Medow and
CFIDS Association of America
www.cfids.org
Mean Arterial Pressure
and
Cerebral Blood Flow
are reduced during Tilt

Metabolomics

People with ME/CFS appear to have a very
low metabolic capacity at a cellular level,
similar to mitochondrial deficiency. The
details of this phenomenon are under
study.

Metabolomic diagnosis of CFS.
Naviaux et al.
(A,C) Males. (B,D) Females
ME/CFS n=45 Controls N=39
• The products of several
metabolic pathways
distinguish ME/CFS from
controls.
• Male and Female
ME/CFS share common
pathways, but also have
sex-specific pathways
• Sphingolipids stand out
Metabolic features of chronic fatigue syndrome.
Robert K. Naviaux et al. PNAS
PNAS September 13, 2016 vol. 113 no. 37 E5472-E5480

ME/CFS Metabolomics: (Hansen et al)
• 17 patients and 15 matched controls
• 74 differentially accumulating metabolites,
out of 361 (P < 0.05), and 35 significantly
altered after statistical correction (Q < 0.15)
Pathway analysis points to a few pathways
with high impact:
• taurine and glycerophospholipid
metabolism,
• bile acid metabolism
• glyoxylate and dicarboxylate metabolism
• Purines, including ADP and ATP, pyrimidines
and several amino acid metabolic pathways
significantly disturbed.
• Glucose and oxaloacetate were two main
metabolites affected that have a major
effect on sugar and energy levels.
Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort
reveals disturbances in fatty acid and lipid metabolism. Germain A, Ruppert D, Levine SM, Hanson MR.
Mol. BioSyst., 2017 Jan 31;13(2):371-379. doi: 10.1039/c6mb00600k

ME/CFS Metabolomics: (Fluge et al)
• Metabolic profiling suggests
impaired pyruvate
dehydrogenase function in
myalgic
encephalopathy/chronic
fatigue syndrome,
• suggesting inadequate ATP
generation by oxidative
phosphorylation and excessive
lactate generation upon
exertion.
• Analysis in 200 ME/CFS
patients and 102 healthy
individuals showed a specific
reduction of amino acids that
fuel oxidative metabolism via
the TCA cycle, mainly in female
ME/CFS patients
• Serum 3-methylhistidine, a
marker of endogenous protein
catabolism, was significantly
increased in male patients.
Metabolic profiling indicates impaired pyruvate dehydrogenase function in
myalgic encephalopathy/chronic fatigue syndrome. Øystein Fluge ... Olav Dahl,
Karl J. Tronstad. January 3, 201 JCI Insight. 2017;1(21):e89376

PACING to avoid
Fibro-Flare or
Post-Exertion Malaise:
Know the threshold of pain flare or relapse
and spend most of your time below this threshold.
Staying below the threshold while gradually improving capacity
may gradually move the threshold up.

If healthy people have $10/day in energy and you
have only $1/day, how do you spend it?

• Spend the dollar and more to go into debt? à crash and delayed recovery
• $1 in the morning?---then have nothing to spend the rest of the day?
• $0.50 in the morning and $0.50 in the afternoon?
• $0.25 at 9 am, 11 am---3 pm and 6 pm?
• $0.10 at 9 am, 10 am, 11 am----1 pm, 2 pm, 3 pm, 4 pm----6 pm, 7 pm, 8 pm?

"pacing" is….
• Limiting activity to your $1 most of the time
• Activity spread out through the day.
• Recovery behaviors between activities
• Avoidance of DEBT (PEM)
• Awareness that when debt accrues, it should be “paid
off” asap and completely.
• Being mostly in a preventive, not a rescue mode
• Earning interest (+) instead of paying interest (-
)raises the threshold of relapse and reduces
symptoms.

"Pacing" reduces the frequency and
severity of PEM and improves prognosis
• Do the amount of activity that doesn't induce PEM for more
than 12-24 hours
• The ideal goal is feeling "back to baseline" the following
morning after sleep
• If PEM is induced, rest until it resolves.
• Develop a heightened sense of awareness about the threshold
of relapse, and the consequences of pushing beyond it.
• Don’t be afraid ---be in charge

Self monitoring devices can help you:
Activity. Sleep. Heart rate.

Monitor steps per day….
PACING…
NOT PACING…

PACE and achieve better FITNESS:
Physical Conditioning—can be done carefully with success.
• Increases ability to function. Reduces falls.
• Reduces fatigue and can improve or worsen pain.
• Improves sleep.
• Improves mood and self esteem
• Helps reduce weight gain
Stretching, strengthening, light aerobic activity: Must be completely adapted to
the individual. Relapse symptoms should be avoided. Some patients, at some
times, have LIMITED ability to perform any physical activity or even cognitive
activity without relapse.
Bateman L. CFS and the Exercise Conundrum. www.iacfsme.org/CFSandExercise/tabid/103/Default.aspx

§Stretching, range of motion, balance
§Low impact strength training
§ Yoga. Pilates. Water activities. Isometrics. Light weights.
§ Core: abs and back. Arms/shoulders. Legs/calves.
§Low impact, low intensity, short duration cardio
§ Walking. Recumbent bike. Water activities.
§Weight awareness.

The more ill and limited, the more
methodical and strategic you must be
• Feldencreis ? Restorative Yoga?
• Physical therapy with an informed and skilled therapist
• Design your own exercise regimen to be done at home so you can
control the type, intensity and duration.
• Trial and error. Try an exercise. Observe. Scale up or scale down
based on PEM.
• Allow rest and recovery between exercise attempts
• Reduce muscle weakness and establish adequate strength to
engage in daily activities
• Maintain joint flexibility and overall balance

PAIN reduction
Restorative SLEEP
MENTAL
HEALTH
FITNESS
ORTHOSTATIC INTOLERANCE…
CHRONIC
UNWELLNESS
PACING and activity management

BHC Activity Intolerance & Post-Exertional Malaise 2018

BHC Activity Intolerance & Post-Exertional Malaise 2018

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