Chronic Fatigue in EDS
EDNF Learning Conference
July 22-23, 2011
Peter C. Rowe, MD
Sunshine Natural Wellbeing Foundation Professor of Chronic Fatigue
and Related Disorders
Department of Pediatrics Johns Hopkins University School of
Medicine
Chronic Fatigue in EDS
•
•
•
•
Chronic fatigue and CFS definitions
Lessons from CFS
CF and CFS in EDS
Insights of treating chronic fatigue
–
–
–
–
Treating orthostatic intolerance
Non IgE-mediated food protein allergies
The paradox of movement restrictions in EDS
Ovarian vein varices/pelvic congestion
Fatigue
An overwhelming sustained sense of
exhaustion and decreased capacity for
physical and mental work.
Piper BF. 1989
Fatigue Definitions
• Prolonged fatigue: fatigue lasting 1 – 6 mo.
• Chronic fatigue: fatigue lasting > 6 mo.
• Chronic fatigue syndrome: new onset fatigue,
lasting > 6 mo., unrelieved by rest and 4/8 somatic
symptoms
From MJA 2002; 176:S17-S55
Symptom Criteria For CFS
4 of 8 needed for diagnosis
Fukuda et al. Ann Int Med 1994;121:953-9
• unrefreshing sleep
• postexertional malaise lasting > 24 hours
• self reported impairment in short-term memory
or concentration
• sore throat
• tender cervical or axillary glands
• muscle pain
• multijoint pain without swelling
• headaches of a new type, pattern, severity
CFS Clinical Evaluation
Fukuda et al. Ann Int Med 1994;121:953-9
• History, physical, mental status exam
• Screening labs:
– CBC, ESR/CRP, Chemistries, TSH
– Urinalysis
– Iron studies, vitamin B12, celiac screening, and,
in endemic areas, labs for Lyme and tick-borne
infections
• Other labs as clinically indicated
Chronic Fatigue in EDS
•
•
•
•
Chronic fatigue and CFS definitions
Lessons from CFS
CF and CFS in EDS
Insights of treating chronic fatigue
–
–
–
–
Treating orthostatic intolerance
Non IgE-mediated food protein allergies
The paradox of movement restrictions in EDS
Ovarian vein varices/pelvic congestion
CFS Epidemiology
General
Affects previously active individuals
Heterogeneous precipitating &
perpetuating factors
Shift in perception of CFS:
No longer considered a single disease
More likely a convergence of comorbid pathophysiologic influences
CFS Epidemiology
Prevalence 4/1,000 adults; 1/1,000 adolescents
Age
Uncommon under 10 years
Peak prevalence 40-49 years
Gender
2-4 F : 1 M
SES
Affects all groups
Genetics Twice as common in MZ as DZ twins
Associated with EDS
Associated with joint hypermobility
Research Findings
• Acute illness appears to precipitate symptoms in
up to 2/3, but evidence of active infection not
detected in chronic state
(enteroviral infection, Lyme may be exceptions)
• Severity of acute infection, not psychological
factors, is key determinant of who develops CFS
after acute illness
• XMRV not an etiologic agent
• Immune abnormalities inconsistent & mild
• Post-exercise increases in cytokines and genes
involved with adrenergic function and pain
Light AR et al.
J Pain 2009;10:1099
Research Findings
• Orthostatic stress and exercise consistently
provoke CFS symptoms
• All pediatric and most adult studies confirm
higher prevalence of orthostatic intolerance
• Open treatment of OI leads to improvement in
function
• CBT and graded exercise provide modest
improvement in function but not cure
• Low rates of spontaneous improvement for those
with > 3 yrs of symptoms
Orthostatic Intolerance
The term “orthostatic intolerance” refers to
a group of clinical conditions in which
symptoms worsen with quiet upright
posture and are ameliorated (although not
necessarily abolished) by recumbency.
Modified from: Low PA, Sandroni P, Joyner M, Shen WK. Postural
tachycardia syndrome (POTS). J Cardiovasc Electrophysiol
2009;20:352-8.
Low PA
Rowell LB
Human Cardiovascular
Control, 1993
Symptoms Of Orthostatic Intolerance
Lightheadedness
Syncope
Diminished concentration
Headache
Blurred vision
Fatigue
Exercise intolerance
Dyspnea
Chest Discomfort
Palpitations
Tremulousness
Anxiety
Nausea
Nocturia
↑ pooling,
↓ vasoconstriction
Orthostatic
stress
↓ intra-vascular volume
↑ sympatho-adrenal
response
NE/Epi
NMH
NE/Epi
POTS
Response To Upright Tilt: CFS
Abnormal
Normal
Stage of tilt
1
2
3
CFS
CONTROL
16
0
3
1
3
3
1
10
OR for abnormal tilt in those with CFS: 55 (95% CI, 5.4 - 557)
Bou-Holaigah, Rowe, Kan, Calkins. JAMA 1995;274:961-7.
Response to
open treatment
of orthostatic
intolerance
JAMA 1995;274:961-7.
CFS And Psychiatry
• Many CFS patients have anxiety or depression,
but prevalence estimates vary widely
depending on the case definition used
• Severity usually mild, anhedonia uncommon
• Post-exertional malaise more common in CFS
• Treating depression and anxiety can improve
these symptoms, but usually does not cure CFS
12 wks
24 wks
52 wks
White PD et al. PACE trial. Lancet 2011
Chronic Fatigue in EDS
•
•
•
•
Chronic fatigue and CFS definitions
Lessons from CFS
CF and CFS in EDS
Insights of treating chronic fatigue
–
–
–
–
Treating orthostatic intolerance
Non IgE-mediated food protein allergies
The paradox of movement restrictions in EDS
Ovarian vein varices/pelvic congestion
Classical type EDS:
“Fatigue is a frequent complaint.”
Beighton P, De Paepe A, Steinmann B, Tsipouras P,
Wenstrup R. Ehlers Danlos Syndromes: Revised nosology,
Villefranche, 1997
Orthostatic
Intolerance
CFS
EDS/
Joint hypermobility
Orthostatic Intolerance And Chronic
Fatigue Syndrome Associated With EDS
Among approximately 100 adolescents seen
in the CFS clinic at JHH over a 1 year
period, we identified 12 subjects with EDS
6 classical-type, 6 hypermobile-type EDS
11 female; median age 15 yrs (9-21)
NMH in 9/12, POTS in 10/12
Rowe PC, Barron DF, Calkins H, Maumanee IH, Tong PY, Geraghty
MT. J Pediatr 1999;135:494-9
Joint Hypermobility In Children With CFS
Study question: do children with CFS have a higher
prevalence of joint hypermobility?
Beighton scores obtained in 58 new & 58 established
CFS patients, and in 58 controls
Median Beighton scores higher in CFS (4 vs. 1)
Beighton score > 4 higher in CFS (60% vs. 24%)
Barron DF, Cohen BA, Geraghty MT, Violand R, Rowe PC. J Pediatr 2002;141:421-5
Beighton Joint Hypermobility Scores in 58
Adolescents With CFS And 58 Healthy Controls
35
30
25
20
#
Healthy
CFS
15
10
5
0
0-1
2-3
4-5
6-7
Beighton scores
8-9
Barron, Geraghty, Cohen,
Violand, Rowe. J Pediatr
2002;141:421-5
How might joint hypermobility be
associated with OI and CFS?
Working hypothesis:
Connective tissue laxity in blood vessels
allows increased vascular compliance,
promotes excessive pooling during upright
posture, leading to diminished blood return
to the heart, and thus to OI symptoms
Rowe PC, et al. J Pediatr 1999;135:494-9
Fatigue is a frequent and clinically relevant
problem in EDS
(Voermans NC, et al. Semin Arth Rheum 2010; 40:267-74)
• 273 patients with EDS
• 77% severe fatigue
• 57% reported fatigue as 1 of their 3 most important
symptoms
• Severe fatigue was more common in hypermobile
than classical EDS (84% vs. 69%; P=.032)
• Fatigue had a greater impact on daily function than
did pain
Fatigue is a frequent and clinically relevant
problem in EDS
(Voermans NC, et al. Semin Arth Rheum 2010; 40:267-74)
On the basis of their results, the authors speculate
about a potential treatment:
“A cognitive behavioral intervention focusing on
pain, sleep disturbances, the reaction of others to the
symptoms, and self-efficacy concerning fatigue could
help reduce fatigue and fatigue-related disabilities.”
Chronic Fatigue in EDS
•
•
•
•
Chronic fatigue and CFS definitions
Lessons from CFS
CF and CFS in EDS
Insights of treating chronic fatigue
–
–
–
–
Treating orthostatic intolerance
Non IgE-mediated food protein allergies
The paradox of movement restrictions in EDS
Ovarian vein varices/pelvic congestion
Inhalant
allergies/asthma
Infection
Movement
restrictions
Migraines
Food
allergies
Anxiety
Orthostatic
intolerance
Chiari type I
or c-spine
stenosis
EDS/JHS
Depression
Pelvic vein
incompetence
Chronic fatigue syndrome
Treating chronic fatigue
1. Careful history and physical exam,
supplemented by questionnaires, to develop
working hypotheses about the dominant
influences on fatigue
2. Begin working on graded increases in
activity, physical therapy if needed
3. Begin treating the dominant influences on
symptoms
4. Reassess and repeat steps 1-3
16 year old with fatigue: visit 1
Gastroesophageal reflux and colic in 1st year of life
Onset of fatigue and daily lightheadedness at age 13
Develops syncope X 3; Migraines
GI: early satiety, reflux, abdo pain, aphthous ulcers
O/E: Beighton score 7/9, blue sclerae, easy eyelid
eversion, pes planus, papyraceous scar of L knee.
Limitations on physical therapy ROM despite joint
hypermobility
Beck Depression Inventory: dysthymia
Visit 1 hypothesis formulation
Imp:
Plan:
EDS
OI (already on Florinef)
Milk protein intolerance
Migraines
Movement restrictions
Dsythymia
Milk-free diet instituted
Low dose cyproheptadine
Inhalant
allergies/asthma
Infection
Movement
restrictions
Migraines
Food
allergies
Anxiety
Orthostatic
intolerance
Chiari type I
or c-spine
stenosis
EDS/JHS
Depression
Pelvic vein
incompetence
Chronic fatigue syndrome
16 year old with fatigue
Visit 2:
Plan:
Visit 3:
Plan:
GI symptoms resolved unless he gets
inadvertent milk re-exposure; mood more
of the problem
Low dose Lexapro for mood
Mood improved, but still has some
orthostatic exacerbation of migraines; still
tight on PT exam
Add midodrine for OI; begin PT
16 year old with fatigue
Visit 4:
Plan:
Visit 5:
Plan:
Migraine resolved; better ROM
Trial off Lexapro: mood & HA worse, but
able to drop to 2.5 mg daily
“The more I do, the more I can do”
Continue PT
Good year, on HS soccer and tennis teams
No syncope; migraines only if he does not
maintain good hydration
No changes.
Non-IgE mediated food allergy :
3 cardinal features
1. Recurrent vomiting or GER
2. Recurrent epigastric or abdominal pain
3. Food refusal, picky eating, early satiety
Other: aphthous ulcers, unexplained
fevers, diarrhea or constipation, headache,
myalgias, fatigue, asthma
Kelly KJ et al. Gastroenterology 1995;109:1503-12
Non-IgE mediated food allergy
•
•
•
•
Reaction to suspected food usually delayed 2-6 hrs
IgE level, prick skin tests, RAST tests often neg.
Eosinophilic esophagitis only the tip of the iceberg
Treated with strict avoidance of offending food
proteins (milk > soy > egg > wheat); amino acid
formulas occasionally needed in infants
• Diagnosis supported by clinical response to diet,
recurrence of symptoms 2-6 hours after inadvertent
dietary challenge, confirmed by DBPCOFC
Improvements in esophageal eosinophils after
amino acid formula diet
Kelly KJ et al. Gastroenterology 1995;109:1503-12
Chronic Fatigue in EDS
•
•
•
•
Chronic fatigue and CFS definitions
Lessons from CFS
CF and CFS in EDS
Insights of treating chronic fatigue
–
–
–
–
Treating orthostatic intolerance
Non IgE-mediated food protein allergies
The paradox of movement restrictions in EDS
Ovarian vein varices/pelvic congestion
Paradox of movement restrictions in EDS
• Increased prevalence of postural abnormalities and
movement restrictions among those with CFS
• CFS symptoms can be reproduced by selectively
placing tension on the neural tissues
• Focal movement restrictions are common even in
those with generalized joint hypermobility/EDS
• Improvement in ROM, orthostatic tolerance, and
exercise tolerance can follow manual therapy
Abnormal
postures
Restricted Straight Leg Raise
Healthy
CFS
Symptom Changes with SLR over 12 minutes in
Adolescent with CFS
Severity
10
9
8
7
6
5
4
3
2
1
0
Fatigue
LH
Cog Fog
Vis Blur
0
10
20
30
40
Degrees of SLR
50
60
0
How Might Movement Restrictions Be
Associated With CFS?
• Pathophysiology of symptoms with neural
elongation strain awaits clarification, but we
hypothesize that it contributes to central sensitivity
• Informally, improvement in symptoms, ROM,
orthostatic tolerance, and exercise tolerance
appears to follow manual therapy designed to
reduce adverse neural tension and improve
movement restrictions
Manual Therapy Principles
• Use of the hands to restore full, symptomfree mobility within the neuromuscular and
articular systems
• Goal of treatment is the same as that of
exercise-based PT, but manual practitioners
treat movement restrictions first before
advancing the patient to strenuous activity
Manual Techniques
• Slow non-thrust manipulations
– Sustained stretching
– Passive oscillatory movements (neural mobs)
– Muscle energy techniques
• Gentle indirect techniques
– Myofascial release
– Strain and counter-strain
– Cranio-sacral therapy
Chronic Fatigue in EDS
•
•
•
•
Chronic fatigue and CFS definitions
Lessons from CFS
CF and CFS in EDS
Insights of treating chronic fatigue
–
–
–
–
Treating orthostatic intolerance
Non IgE-mediated food protein allergies
The paradox of movement restrictions in EDS
Ovarian vein varices/pelvic congestion
16 yr old with EDS, CFS, OI, and 2 yr history of
disabling lower back and pelvic pain
• Pain worse as the day goes on
• Pelvic pain present with urination, when back pain
present, with menses
• Unable to tolerate sitting in school
• Lower abdominal distention as the day goes on
• X-rays, scans, MRI of lumbar spine negative
• Unresponsive to OCPs, NSAIDs, TENS unit,
neurontin, TCA, lumbar support garments, PT,
inpatient evaluation
Left ovarian vein venogram
Catheter in distal L
ovarian vein plexus;
arrows denote reflux
of contrast into
internal iliac veins
Pre
Post
Pelvic Congestion Syndrome
Venbrux AC, Lambert DL. Curr Opin Ob Gyn 1999; 11:395
• Pelvic heaviness or pain with long
periods of standing
• Worse at end of the day, during menses
• Associated symptoms: fatigue,
dyspareunia, bladder urgency
• Strong association with varicose ovarian
veins
• 89% have > 80% relief after
embolization of ovarian vein varicosities
CFS and ovarian varices: JHH experience
• 24 consecutive females with chronic pelvic pain
unresponsive to NSAIDs, OCPs, & no other cause
identified on Hx, PE, imaging
• median age 19, range 16-54
• 16 were < 21 yrs; all but 4 nulliparous
• Median duration of pelvic pain 4 yrs (1-15)
• All had orthostatic intolerance
• 14/24 with EDS
Kaushik S, et al. JHH 2003
16 yr old with EDS, CFS, OI, and 2 yr history of
disabling lower back and pelvic pain
Outcome
• Improved symptoms following ovarian and
internal iliac embolization
• Able to attend school daily
• Able to wean midodrine for OI
• No further syncope
• Wellness score > 90/100
Opportunities for Research
1. What are the risk factors for fatigue in JHS/EDS?
2. What is the prevalence of OI in EDS patients?
3. What is the prevalence of CFS or fibromyalgia
symptoms in JHS/EDS?
4. Do therapies directed at OI & related comorbidities in JHS and EDS improve QOL?
Treatment of orthostatic intolerance
Webinar from September 2010 available on the
CFIDS Association of America web site:
www.cfids.org
Relationship of orthostatic intolerance to chronic
fatigue
Common
Chronic
Fatigue
Uncommon
Low
High
Tolerance of orthostatic stress
Can we move fatigue levels from A to B by
treating orthostatic intolerance?
Common
A
Chronic
Fatigue
B
Uncommon
Low
High
Tolerance of orthostatic stress
Step 1: Non-pharmacologic measures
Where possible, avoid factors that
precipitate symptoms
Precipitating Factors For OI
• Increased pooling/decreased volume
Prolonged sitting or standing
Warm environment
Sodium depletion
Prolonged bed rest
Varicose veins
High carbohydrate meals
Diuretics, vasodilators, alpha-blockers
Alcohol
Precipitating Factors For OI
• Increased catecholamines
Stress
Exercise
Pain
Hypoglycemia
Albuterol
Epinephrine
Step 1: Non-pharmacologic measures
Compression garments
– Support hose
(waist high > thigh high > knee high)
– Body shaper garments
– Abdominal binders
Step 1: Non-pharmacologic measures
Use postural counter-measures
• standing with legs crossed
• squatting
• knee-chest sitting
• leaning forward sitting
• elevate knees when sitting (foot rest)
• clench fists when standing up
[Use the muscles as a pump]
Step 1: Non-pharmacologic measures
Fluids:
Minimally 2 L per day
Drink at least every 2 hours
Need access to fluids at school
Avoid sleeping > 12 hrs/day
Salt:
Increase according to taste
Supplement with salt tablets
Step 1: Non-pharmacologic measures
Exercise
Avoid excessive bed rest/sleeping
For most impaired, start exercise slowly,
increase gradually
Recumbent exercise may help at outset
Manual forms of PT may be a bridge to
better tolerance of exercise
“Inactivity is the enemy”
[Similar to principles of CBT regarding graded increases in activity]
Treatment Of Orthostatic Intolerance
• Step 1: non pharmacologic measures
• Step 2: treating contributory conditions
• Step 3: medications
– Monotherapy
– Rational polytherapy
Inhalant
allergies/asthma
Infection
Movement
restrictions
Migraines
Food
allergies
Anxiety
Orthostatic
intolerance
Chiari type I
or c-spine
stenosis
EDS/JHS
Depression
Menstrual
pain; ovarian
varices
Chronic fatigue syndrome
Treatment Of Orthostatic Intolerance
• Step 1: non pharmacologic measures
• Step 2: treating contributory conditions
• Step 3: medications
– Monotherapy
– Rational polytherapy
Therapy For Orthostatic Intolerance
•  blood volume
Sodium (PO & occasionally IV),
fludrocortisone, clonidine, OCPs
•  catecholamine release or effect
-blockers, disopyramide, SSRIs, ACE inh.
• Vasoconstriction
Midodrine, dexedrine, methylphenidate, SSRIs,
SNRIs, aescin (horse chestnut seed extract)
• Misc
pyridostigmine bromide
↑ pooling,
↓ vasoconstriction
Vasoconstrictors
↓ intra-vascular volume
Volume expanders
↑ sympatho-adrenal
response
Orthostatic
stress
↓ NE/Epi
NMH
Reduce
catecholamine
release/effect
↑ NE/Epi
POTS
How to select initial therapy?
Algorithm vs. individualized approaches
Algorithm approach for POTS from Mayo Clinic investigators
Johnson JN, et al. Pediatr Neurology 2010; 42:77-85
Individualized approach
• SBP < 110: fludrocortisone, midodrine
• Increased HR at baseline or when upright: -blocker
Modified from Bloomfield, Am J Cardiol 1999;84:33Q-39Q
• Based on other clinical clues
Increased salt appetite: fludrocortisone
HA: -blocker
Dysmenorrhea/worse fatigue with menses: OCP, Depo
Anxiety/low mood: SSRI, SNRI
Myalgias prominent: SNRI
FH of ADHD: stimulant
Hypermobility: stimulant, midodrine
Management of orthostatic intolerance
• requires careful attention by the patient and the
practitioner to the factors that provoke symptoms
• requires a willingness to try several medications
before a good fit is achieved
• requires a realization that meds often can treat
symptoms but do not necessarily cure OI
• management of OI is one part of a comprehensive
program of care for patients with other disorders (GI
dysautonomia, CFS)