Understanding and Managing
Chronic Fatigue Syndrome
慢性疲労症候群(CFS/ME)の理解と症状の管理Charles W. Lapp, MD
Charlotte, North Carolina, USA
drlapp.com

1Brain Abnormalities
脳の異常
MRI Scan shows high intensity
spots in 80% of cases

SPECT Scan shows decreased
blood flow in specific areas

2

Neuro-psychiatric testing confirms problems
with attention, memory, processing speed…

Autonomic Nervous System
自律神経系
Abnormalities of thesympathetic andparasympathetic nervous
system are common, including:• Tachycardia• Orthostatic intolerance(syncope) in up to 100% ofsubjects• Low plasma volume and red
blood cell mass

3

Tilt Table testing for syncope

Sleep Disruption
睡眠障害
Sleep is markedly disturbed
in up to 62.5% of patients:• Sleep apnea• Parasomnias(sleep walking)• Narcolepsy• Upper Airway Resistance4Hypothalamic-Pituitary-Adrenal Axis
視床下部-下垂体-副腎系
The HPA Axis issuppressed leading tolower levels of:

••
•
••
•

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Thyroid hormone
Cortisol
Estrogen
Testosterone
Growth hormone
Prolactin

Sleep

Fatigue

Serotonin

GrowthHormone

HYPOTHALAMCRH

PITUITARY

MuscleFitness

THYROID
Thyroxine,T3AVPEndorphins

Pain
Threshold

ADRENAL

Cortisol,
DHEA
Fludro,EpiGONADS

Estr,Testo.

Immune System免疫系• Elevated levels of CD8+/38+“cytotoxic” T-cells Poorly
functioning natural killer cells• Upregulation of the 2-5A system
and RNaseL• Increased production of proinflammatory cytokines• Reduced levels of gammaglobulin
and IgG subclasses

6Genetics
遺伝• Significantly increased prevalence of DR4,DR5, DQ3 and DQ1• Twin study shows hereditability estimate of51%• Significant risk for developing CFS among
1st (OR=2.7), 2nd (OR=2.34), or 3rd degree
relatives (OR=2.03)• Neuroendocrine gene variants (TPH2,COMT, NR3C1) associated with CFS

7

Oxidative Stress / Energy Metabolism
酸化ストレス/エネルギー代謝

8• LDL is increased, HDLdecreased• Isoprostanes increased• Cellular ATP is decreased• Mitochondrial oxidative
phosphorylation reduced• Impaired cardiovascularresponse to exercise• Abnormal mRNA
response to exercise

40
30
20
10038.230.8
oxLDL
500
400
300
200
100040 31
6 8

isoprostanes

CFSControl

ASIC3

P2X44P2X5TRPV1

Fold increase in mRNA from baseline(+SEM)

Controls n=48

AD2A
ADB1ADB2COMTIL61IL10TNFβ.7baseline

30 min

8 hr

24 hr

48 hr

TLR4CD14n.s. for all AUC compared to baseline

CFS and CFS co-morbid with FMS n=34
10(without Ad2A decrease patients)

ASIC3
P2X4 ****

P2X5 *
TRPV1 **
AD2A ****

4ADB1 **
ADB2 ****
COMT ****
IL6IL10 ***TNFβTLR4CD1419baseline

30 min

8 hr

24 hr

48 hr

(* P<.05, ** P<.01, *** P<.001, **** P<.0005 compared to controls for AUC)

Post-Infectious CFS/ME
感染後CFS/ME
Dubbo Study• 11% developed CFS/ME after infection with EBV, Q-Fever, or Ross
River Virus• CFS not more likely in patients with particular premorbid psychiatricand demographic factors
Post-Mononucleosis Study (Miami)
Adolescents with mono met CFS/ME
criteria at:• 6 months (13%)• 12 months (7%)• 24 months (4%)

12

MYTH:
CFS/ME is due to depression
作り話: CFS/ME はうつ病に起因する

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Depression versus CFS/ME
うつ病と CFS/ME

14Depression

CFS/ME

Onset
発症Insidious
知らぬ間に進行

Abrupt in 85%
突然Epidemiology

IndividualClusters

Medical therapy

Improves

No response

Exercise

Improves

Worsens

Symptoms

Some overlap(No headache,fever)

Severe symptoms
including headacheand feverAttributions

Hopeless, helplessand withdrawn

Proactive, seek
medical care,politically activeDepression versus CFS/ME
うつ病と CFS/ME

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Depression

CFS/ME

Onset

Insidious

Abrupt in 85%

Epidemiology
疫学

Individuals
個人

Clusters
集団

Medical therapy

Improves

No response

Exercise

Improves

Worsens

Symptoms

Some overlap(No headache,fever)

Severe symptoms
including headacheand feverAttributions

Hopeless, helplessand withdrawn

Proactive, seek
medical care,politically activeDepression versus CFS/ME
うつ病と CFS/ME

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Depression

CFS/ME

Onset

Insidious

Abrupt in 85%

Epidemiology

IndividualClusters

Medical therapy
薬物療法

Improves
有効No response
無効

Exercise

Improves

Worsens

Symptoms

Some overlap(No headache,fever)

Severe symptoms
including headacheand feverAttributions

Hopeless, helplessand withdrawn

Proactive, seek
medical care,politically activeDepression versus CFS/ME
うつ病と CFS/ME

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Depression

CFS/ME

Onset

Insidious

Abrupt in 85%

Epidemiology

IndividualClusters

Medical therapy

Improves

No response

Exercise
運動

Improves
有効Worsens
悪化

Symptoms

Some overlap(No headache,fever)

Severe symptoms
including headacheand feverAttributions

Hopeless, helplessand withdrawn

Proactive, seek
medical care,politically activeDepression versus CFS/ME
うつ病と CFS/ME

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Depression

CFS/ME

Onset

Insidious

Abrupt in 85%

Epidemiology

IndividualClusters

Medical therapy

Improves

No response

Exercise

Improves

Worsens

Symptoms
症状

Some overlap(No headache,fever)
一部は重複(頭痛、微熱なし)

Severe symptoms
including headacheand fever
頭痛や微熱などの重度の症状Attributions

Hopeless, helplessand withdrawn

Proactive, seek
medical care,politically activeDepression versus CFS/ME
うつ病と CFS/ME

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Depression

CFS/ME

Onset

Insidious

Abrupt in 85%

Epidemiology

IndividualClusters

Medical therapy

Improves

No response

Exercise

Improves

Worsens

Symptoms

Some overlap(No headache,fever)

Severe symptoms
including headacheand fever

Outlook
前途Hopeless, helplessand withdrawn
絶望的、無力感、
内向的Proactive, seek
medical care,politically active
率先して行動、医療を探求、政治的活動に積極的

BIOLOGICAL EVIDENCE AGAINST DEPRESSION
うつ病とは反する生物学的な証拠

DEPRCortisol ↑
CRH

↑

CFS
HYPOTHAL↓↓GrowthHormoneCA
R PITUITARY VHP

Endorphins

ACTH
GONADS

THYROID.
ADRENAL20

Demitrack MA, et al., ,” J Clin Endocrinol
Metab. 1991 Dec; 73(6): 1224-34

Four Cardinal Symptoms of CFS/ME
CFS/ME の 4 つの中核症状• Pain (痛み)• Cognitive difficulties (認知機能障害)• Fatigue (疲労)• Sleep disruption (non-restorativesleep) (非回復性睡眠)21Overlap Syndromes (or Comorbidities)
併存疾患
Irritable bowel or bladder, migraine, sicca (Sjögren’s),orthostatic intolerance…

Epidemiology
疫学– No known cause, but triggers have been identified– A majority of persons improve over time (months to years)– Neither CFS nor FM are degenerative illnesses

22CFS/ME Triangle (CFS/ME トライアングル)
Sleep
睡眠

23

Pain

Fatigue

痛み疲労Managing Sleep Problems
睡眠障害の症状管理• Sleep habits• OTC Medications:– melatonin, diphenhydramine, doxylamine,proprietaries• Non-hypnotics: Eszopiclone (Lunesta), zaleplon(Sonata), ramelteon (Rozerem)• Hypnotics: Zolpidem (Ambien) > benzodiazepines

24Managing Pain
痛みの管理• Non-pharmacological therapies
Rest, cold/heat, balneotherapy, liniments
massage, PT, chiropractic, acupuncture
TENS, EMS
• Pharmacologic therapy
Tylenol (acetaminophen), ASA, NSAIDs, coxibs
Anti-epileptic drugs: pregabalin, gabapentin, others
NSRIs: duloxetine, milnacipran, others
Tramadol or Low Dose Naltrexone
Narcotics
Short acting (hydrocodone, oxycodone)Long acting (oxycodone, morphine, fentanyl)25

4 CFS Characteristics
CFSの4つの 特徴• Exertional (労作による)• Positional (姿勢による)• Hypersensitivities (過敏性)• Stress intolerance (ストレスに対する不耐性)26

Pacing
ペースの調整• Rest periods
10-30 minutes
Supine or semi-recumbent
Clear your mind
• Limit setting
Most push and crash
Energy conservation

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The Fallacy of Push ‘n’ Crash
無理してクラッシュするのは誤り
Pushing hard on twodays requires two daysof recuperation

Moderation allows you tofeel better, do more overthe same 4 days!

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Activity
活 動
Worst case: couch or bed boundEvidence: you can and must be active
Objective limits– Aerobic interval activity– Heart rate limited• MPHR=230-Age, AT occurs at 0.6 x MPHR

– Pedometer (1000-5000 steps)29

Anaerobic Interval Activity
間隔を空けた無酸素運動• Persons with CFS cannot
tolerate anaerobic activity• Anaerobic means notenough oxygen gets tomuscles.
• Most PWCs can only exert
3-5 minutes before
reaching the AnaerobicThreshold.
• Then rest for 5 minutes.

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Heart Rate Limits
心拍数の限界• The AT (AnaerobicThreshold) always occurs at
the same heart rate
• Keep the heart rate belowthat limit• Predicted max HR= 230-age
in years– 230 - 50 years = 180 MPHR

• Maximum HR= MPHR x 0.6

31– 180 x 0.6 = 108 beats/minutePedometer (Steps Per Day)
歩数計 （ 1 日あたりの歩数）
We know from experiencethat:• 1000 steps per day is
too little• 5000 steps per day is
too much for most32

Severely Affected Patients
重症患者• Home visits from the doctor or specialist• Occupational therapy to improve the homeenvironment• Home physical therapy (range of motion orresistance against gravity, supine)• Home Health Aid or caregiver• Balanced nutrition and healthy organic or whole
foods• Pleasant activities• Socialization

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Severely Ill Patients
重症患者• Minimize medications and supplements• Prescribe medications in very low doses and titrate
slowly• Stress management and grief/loss counseling• Encouragement• Lowered expectations for themselves and from others

Above all the severely ill need “peace of mind and afeeling that they and their family were taken care of, sothat they could use all their energy on getting better.”(Irma Pinxterhuis, PhD, Oslo University Hospital, Norway )34

Pediatric CFS/ME
Epidemiology
小児のCFS/ME
疫学• Prevalence– USA: 100-300 per 100,000• 5-12 years old: none
• 13-17 years old: 181 per 100,000– Japan: about the same• Gender– M:F :: 1:2 to 1:535

Comparison of Symptoms
in Adolescents and Adults
青年と成人における症状の比較

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SYMPTOM

CHILD

ADULT

Fatigue

100%

100%

Neurologic

97

92

Abdominal Pain*

97

84

Headache

97

92

Sore Throat*97

90

Eye Pain / Photophobia*

97

88

Lymphodynia*

91

78

Myalgia91

96

Arthralgia

88

88

Rash*

88

56

Fever / Chills

7284Differences Between Adolescent and Adult
Definitions
青年と成人の診断基準の相違• De-emphasizes fatigue and highlights symptoms(dizziness, decreased endurance, pain, & flu-like)• Symptoms endured for only three months• Abdominal symptoms have been added to list
• Autonomic symptoms added(orthostatic intolerance, palpitations, dizziness,shortness of breath)• Symptoms rated according to severity
1 = not present
4 = moderate
7 = severe• Symptoms must be either moderate to severe to37 meet criteria

Pediatric CFS/ME Management
小児のCFS/MEの病状の管理• Similar to adult management
Sleep, pain > orthostatic intolerance, GI• Must address– Education– Social development– Psychological issues such as school phobia

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Prognosis in Adolescents(15 Year Follow-Up )青年期における予後（15年にわたる追跡調査）

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Completely resolved

13 (37%)

Well, but not resolved

15 (42.9%)

Remaining ill

4 (11.4%)

Very Ill

3 (8.6%)
Bell DS, April 1998 CFSCC ReportSummary of Pediatric CFS/ME
小児のCFS/MEのまとめ• CFS has a high prevalence in adults, but a lower
prevalence in adolescents (100-300/100,000)• Symptoms are similar to adults, but more
abdominal pain, orthostatic intolerance, sorethroat, photophobia and rash
• Diagnosis is made by “case definition”• Management is supportive and symptomatic,must address education and social development• Prognosis is favorable in adolescents40

Supplements
サプリメント• Multivitamin• B12• Vitamin D3• Magnesium• Calcium• DHEA41• Acetyl carnitine• NADH / CoQ10• Lysine• d-Ribose• Methyl-folate• Folinic Acid
• Phosphatidyl Serine

Advanced Therapies
高度な治療法• Orthostatic Intolerance– Water, salt, fludrocortisone, beta-blockade• Modified Elimination Diet
– Avoid gluten, dairy• Viral or Immunological Symptoms– Valtrex, Isoprinosine, Nexavir , Valcyte• Low dose cortisol– 10-15 mg hydrocortisone• Human Growth Hormone– Recombinant hGH > secretagogue• Ampligen• Rituxan / rituximab

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Summary
まとめ• Biological evidence for CFS is abundant• CFS is not due to depression• Begin management by addressing pain andsleep disorders first• It is important to stay physically active, but not
too active to trigger a flare43Summary (continued)
まとめ• Use interval activity, heart rate monitoring, orsteps-per-day to prevent over-exertion• The severely ill require additional care andresources, but can be rehabilitated• Advanced therapy may benefit specificsubsets of patients
Don’t ever give up!
決してあきらめないで ！

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HUNTER-HOPKINS CENTER
7421 Carmel Executive Park
Charlotte, North Carolina
704 543 9692
Web: www.drlapp.com

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