Chronic Fatigue in EDS (Dr. Peter Rowe)

EDNF Learning Conference July 2011

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Chronic Fatigue in EDS

Peter C. Rowe, MD

Sunshine Natural Wellbeing Foundation Professor of Chronic Fatigue and Related Disorders

Department of Pediatrics Johns Hopkins University School of Medicine

EDNF Learning Conference

July 22-23, 2011


•  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






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 co-

morbid 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 Dyspnea Syncope Chest Discomfort Diminished concentration Palpitations Headache Tremulousness Blurred vision Anxiety Fatigue Nausea Exercise intolerance Nocturia



↑ pooling, ↓ vasoconstriction ↓ intra-vascular volume

↑ sympatho-adrenal response

NMH POTS

NE/Epi NE/Epi

Orthostatic stress

Response To Upright Tilt: CFS

Abnormal Normal

Stage of tilt 1 2 3

CFS 16 3 3 1 CONTROL 0 1 3 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.



JAMA 1995;274:961-7.

Response to open treatment of orthostatic intolerance

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



White PD et al. PACE trial. Lancet 2011

12 wks 24 wks 52 wks






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

EDS/ Joint hypermobility CFS



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

0

5

10

15

20

25

30

35

0 - 1 2 - 3 4 - 5 6 - 7 8 - 9

HealthyCFS

Beighton scores

#

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.”






Anxiety

Inhalant allergies/asthma

Infection

Pelvic vein incompetence

EDS/JHS Depression

Chiari type I or c-spine

stenosis

Chronic fatigue syndrome

Migraines

Orthostatic intolerance

Food allergies

Movement restrictions



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: EDS OI (already on Florinef) Milk protein intolerance Migraines Movement restrictions Dsythymia

Plan: Milk-free diet instituted Low dose cyproheptadine

Anxiety


Infection

Pelvic vein incompetence

EDS/JHS Depression


stenosis


Migraines


Food allergies




16 year old with fatigue

Visit 2: GI symptoms resolved unless he gets inadvertent milk re-exposure; mood more of the problem

Plan: Low dose Lexapro for mood Visit 3: Mood improved, but still has some

orthostatic exacerbation of migraines; still tight on PT exam

Plan: Add midodrine for OI; begin PT

16 year old with fatigue

Visit 4: 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”

Plan: Continue PT

Visit 5: Good year, on HS soccer and tennis teams No syncope; migraines only if he does not maintain good hydration

Plan: 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






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

0123456789

10

0 10 20 30 40 50 60 0

FatigueLHCog FogVis Blur

Degrees of SLR

Severity



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, symptom-free 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






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



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 co-

morbidities in JHS and EDS improve QOL?

Opportunities for Research



Treatment of orthostatic intolerance

Webinar from September 2010 available on the CFIDS Association of America web site:

www.cfids.org

Low High

Common

Uncommon

Chronic Fatigue

Tolerance of orthostatic stress

Relationship of orthostatic intolerance to chronic fatigue



Low High

Common

Uncommon

Chronic Fatigue

Tolerance of orthostatic stress

Can we move fatigue levels from A to B by treating orthostatic intolerance?

A

B

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




Compression garments – Support hose

(waist high > thigh high > knee high) – Body shaper garments – Abdominal binders




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]


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




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

Anxiety


Infection

Menstrual pain; ovarian

varices

EDS/JHS Depression


stenosis


Migraines


Food allergies




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 β-blockers, disopyramide, SSRIs, ACE inh. •  Vasoconstriction Midodrine, dexedrine, methylphenidate, SSRIs,

SNRIs, aescin (horse chestnut seed extract) •  Misc

pyridostigmine bromide



↑ pooling, ↓ vasoconstriction ↓ intra-vascular volume

↑ sympatho-adrenal response

NMH POTS

↑ NE/Epi ↓ NE/Epi

Orthostatic stress

Vasoconstrictors Volume expanders

Reduce catecholamine release/effect

How to select initial therapy?

Algorithm vs. individualized approaches



Johnson JN, et al. Pediatr Neurology 2010; 42:77-85

Algorithm approach for POTS from Mayo Clinic investigators

Individualized approach

•  SBP < 110: fludrocortisone, midodrine

•  Increased HR at baseline or when upright: β-blocker

•  Based on other clinical clues Increased salt appetite: fludrocortisone HA: β-blocker Dysmenorrhea/worse fatigue with menses: OCP, Depo Anxiety/low mood: SSRI, SNRI Myalgias prominent: SNRI FH of ADHD: stimulant Hypermobility: stimulant, midodrine

Modified from Bloomfield, Am J Cardiol 1999;84:33Q-39Q



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)

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Chronic Fatigue in EDS (Dr. Peter Rowe)

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