This is an Accepted Article that has been peer-reviewed and approved for publication in

the Journal of Internal Medicine, but has yet to undergo copy-editing and proof
correction. Please cite this article as an Accepted Article; doi: 10.1111/j.1365-
2796.2011.02428.x

Accepted Date : 15-Jul-2011
Article type : Review


!"#$%&'()*'+,-#$./"+$&0&12((3*0+4*#0&.*#$(5.*1+*161(54&0+4&#(
8ruce M Carruthers, Mu, CM, l8C(C) (coedlLor), lndependenL, vancouver, 8.C., Canada
Mar[or|e I van de Sande, 8Ld, Cradulp Ld (coedlLor), lndependenL, Calgary, A8, Canada
kenny L De Me|r|e|r, Mu, hu, ueparLmenL of hyslology and Medlclne, vrl[e unlverslLy of 8russels,
PlmmunlLas loundaLlon, 8russels, 8elglum.
Nancy G k||mas, Mu, ueparLmenL of Medlclne ,unlverslLy of Mlaml Mlller School of Medlclne and Mlaml
veLerans Affalrs Medlcal CenLer, Mlaml, lL, uSA
Gordon 8roder|ck, hu, ueparLmenL of Medlclne, unlverslLy of AlberLa, LdmonLon, A8, Canada
1erry M|tche||, MA, Mu, l8CaLh, Ponorary ConsulLanL for nPS aL eLerborough/Cambrldge, LowesLofL,
Suffolk, unlLed klngdom.
Don Sta|nes, M88S, MP, lAlPM, lAlCLM, Cold CoasL ubllc PealLh unlL, SouLhporL, Cueensland,
PealLh Sclences and Medlclne, 8ond unlverslLy, 8oblna, Cueensland, AusLralla
AC eter ow|es, M8AC, l8AC, l8C(C), A8SM, laculLy of PealLh Sclences, McMasLer unlverslLy and
SL. !oseph's PealLhcare PamllLon, PamllLon, Cn, Canada.
N|ge| Spe|ght, MA, M8, 8Chlr, l8C, l8CCP, uCP, lndependenL, uurham, unlLed klngdom
kosamund Va|||ngs, MnZM, M8, 8S, M8CS, L8C, Powlck PealLh and Medlcal CenLre, Powlck, new
Zealand.
Luc|nda 8ateman, MS, Mu, laLlgue ConsulLaLlon Cllnlc, SalL Lake 8eglonal Medlcal CenLer: ad[uncL
faculLy - lnLernal Medlclne, lamlly racLlce, unlverslLy of uLah, SalL Lake ClLy, u1, uSA.
8arbara 8aumgarten-Austrhe|m, Mu, ML/ClS CenLer, Cslo unlverslLy PosplLal Pl, norway.
Dav|d S 8e||, Mu, lAA, ueparLmenL of aedlaLrlcs, SLaLe unlverslLy of new ?ork, 8uffalo, n?.
N|co|etta Car|o-Ste||a, Mu, hu, lndependenL, avla, lLaly
Iohn Ch|a, Mu, Parbor-uCLA Medlcal CenLer, unlverslLy of Callfornla, Los Angeles, Lv Med 8esearch,
LomlLa, CA, uSA
Aust|n Darragh, MA, Mu, llSLM. (8Cl, 8CSl), l8SPll 8lol l (Pon), Un|vers|ty of L|mer|ck, L|mer|ck,
Ire|and
Daehyun Io, Mu, hu, aln Cllnlc, konyang unlverslLy PosplLal, uae[eon, korea
Don Lew|s, Mu, uonvale SpeclallsL Medlcal CenLre, uonvale, vlcLorla, AusLralla
A|an k L|ght, hu, uepLs or AnesLheslology, neuroblology and AnaLomy,unlverslLy of uLah, SalL Lake
ClLy, uLah, uSA.
Sonya Marsha||-Grad|sb|k, hu, PealLh Sclences and Medlclne, 8ond unlverslLy, 8oblna, Cueensland,
AusLralla.
Ismae| Mena, Mu, ueparL. Medlclna nuclear, Cllnlca Las Condes, SanLlago, Chlle
Iudy A M|kov|ts, hu, WhlLLemore eLerson lnsLlLuLe, unlverslLy of nevada, 8eno, nv uSA
kun|h|sa M|wa, Mu, hu, Mlwa nalka Cllnlc, 1oyama, !apan
Modra Murovska, Mu, hu, A. klrchensLeln lnsLlLuLe of Mlcroblology and vlrology, 8lga SLradlns
unlverslLy, 8lga, LaLvla,
Mart|n L a||, hu, ueparLmenL of 8lochemlsLry & 8aslc Medlcal Sclences, WashlngLon SLaLe unlverslLy,
orLland, C8, uSA
Stac| Stevens, MA, ueparLmenL of SporLs Sclences, unlverslLy of Lhe aclflc, SLockLon, CA uSA.



kunn|ng 1|t|e: ML: lnLl. Consensus CrlLerla


Abstract
1he label chronlc faLlgue syndrome" (ClS) has perslsLed for many years because of lack of
knowledge of Lhe eLlologlcal agenLs and of Lhe dlsease process. ln vlew of more recenL
research and cllnlcal experlence LhaL sLrongly polnL Lo wldespread lnflammaLlon and
mulLlsysLemlc neuropaLhology, lL ls more approprlaLe and correcL Lo use Lhe Lerm myalglc
encephalomyellLls"(ML)

because lL lndlcaLes an underlylng paLhophyslology. lL ls also
conslsLenL wlLh Lhe neurologlcal classlflcaLlon of ML ln Lhe World PealLh CrganlzaLlon's
lnLernaLlonal ClasslflcaLlon of ulseases (lCu C93.3). ConsequenLly, an lnLernaLlonal Consensus
anel conslsLlng of cllnlclans, researchers, Leachlng faculLy and an lndependenL paLlenL
advocaLe was formed wlLh Lhe purpose of developlng crlLerla based on currenL knowledge.
1hlrLeen counLrles and a wlde range of speclalLles were represenLed. CollecLlvely, members
have approxlmaLely 400 years of boLh cllnlcal and Leachlng experlence, auLhored hundreds of
peer revlewed publlcaLlons, dlagnosed or LreaLed approxlmaLely 30,000 ML paLlenLs, and
several members coauLhored prevlous crlLerla. 1he experLlse and experlence of Lhe panel
members as well as ubMed and oLher medlcal sources were uLlllzed ln a progresslon of
suggesLlons/drafLs/revlews/revlslons. 1he auLhors, free of any sponsorlng organlzaLlon,
achleved 100 consensus Lhrough a uelphl Lype process.
1he scope of Lhls paper ls llmlLed Lo crlLerla of ML and Lhelr appllcaLlon. Accordlngly, Lhe
crlLerla reflecL Lhe complex sympLomaLology. CperaLlonal noLes enhance clarlLy and speclflclLy
by provldlng guldance ln Lhe expresslon and lnLerpreLaLlon of sympLoms. Cllnlcal and research


appllcaLlon guldellnes promoLe opLlmal recognlLlon of ML by prlmary physlclans and oLher
healLh care provlders, lmprove conslsLency of dlagnoses ln adulL and paedlaLrlc paLlenLs
lnLernaLlonally, and faclllLaLe clearer ldenLlflcaLlon of paLlenLs for research sLudles.

Introduct|on
Myalglc encephalomyellLls (ML), also referred Lo ln Lhe llLeraLure as chronlc faLlgue
syndrome (ClS), ls a complex dlsease lnvolvlng profound dysregulaLlon of Lhe cenLral nervous
sysLem (CnS) [1-3] and lmmune sysLem [4-8],

dysfuncLlon of cellular energy meLabollsm and lon
LransporL [9-11], and cardlovascular abnormallLles [12-14].

1he underlylng paLhophyslology
produces measurable abnormallLles ln physlcal and cognlLlve funcLlon and provldes a basls for
undersLandlng Lhe sympLomology. 1hus, Lhe developmenL of lnLernaLlonal Consensus CrlLerla
LhaL lncorporaLe currenL knowledge should advance Lhe undersLandlng of ML by healLh
pracLlLloners, and beneflL boLh Lhe physlclan and paLlenL ln Lhe cllnlcal seLLlng as well as cllnlcal
researchers.
1he prob|em w|th broad|y |nc|us|ve cr|ter|a [13, 16] ls LhaL Lhey do noL selecL homogeneous
seLs of paLlenLs. 1he CenLers for ulsease ConLrol prevalence esLlmaLes lncreased Lenfold from
0.24 uslng Lhe lukuda crlLerla [17] Lo 2.34 uslng Lhe 8eeves emplrlcal crlLerla [16]. !ason eL
al. [18] suggesL Lhere are flaws ln 8eeves' meLhodology because lL ls posslble Lo meeL Lhe
emplrlcal crlLerla for ML wlLhouL havlng any physlcal sympLoms and lL does noL dlscrlmlnaLe
ML/ClS paLlenLs from Lhose wlLh Ma[or uepresslve ulsorder. aLlenL seLs LhaL lnclude people
who do noL have Lhe dlsease lead Lo blased research flndlngs, lnapproprlaLe LreaLmenLs, and
wasLe scarce research funds [19].



Some sympLoms of Lhe lukuda crlLerla overlap wlLh depresslon whereas Lhe Canadlan
Consensus CrlLerla [20] dlfferenLlaLe ML paLlenLs from Lhose who are depressed and ldenLlfy
paLlenLs who are more physlcally deblllLaLed and have greaLer physlcal and cognlLlve funcLlonal
lmpalrmenLs [21].

Internat|ona| Consensus Cr|ter|a
1he Canadlan Consensus CrlLerla were used as a sLarLlng polnL, buL slgnlflcanL changes were
made. 1he slx-monLh walLlng perlod before dlagnosls ls no longer requlred. no oLher dlsease
crlLerla requlre LhaL dlagnoses be wlLhheld unLll afLer Lhe paLlenL has suffered wlLh Lhe affllcLlon
for slx monLhs. noLwlLhsLandlng perlods of cllnlcal lnvesLlgaLlon wlll vary and may be
prolonged, dlagnosls should be made when Lhe cllnlclan ls saLlsfled LhaL Lhe paLlenL has ML
raLher Lhan havlng Lhe dlagnosls resLrlcLed by a speclfled Llme facLor. Larly dlagnoses may ellclL
new lnslghLs lnLo Lhe early sLages of paLhogenesls, prompL LreaLmenL may lessen Lhe severlLy
and lmpacL.
uslng faLlgue" as a name of a dlsease glves lL excluslve emphasls and has been Lhe mosL
confuslng and mlsused crlLerlon. no oLher faLlgulng dlsease has chronlc faLlgue" aLLached Lo
lLs name - e.g. cancer/chronlc faLlgue, mulLlple sclerosls/chronlc faLlgue - excepL ML/ClS.
laLlgue ln oLher condlLlons ls usually proporLlonal Lo efforL or duraLlon wlLh a qulck recovery,
and wlll recur Lo Lhe same exLenL wlLh Lhe same efforL or duraLlon LhaL same or nexL day. 1he
paLhologlcal low Lhreshold of faLlgablllLy of ML descrlbed ln Lhe followlng crlLerla ofLen occurs
wlLh mlnlmal physlcal or menLal exerLlon, and wlLh reduced ablllLy Lo underLake Lhe same
acLlvlLy wlLhln Lhe same or several days.


1he lnLernaLlonal Consensus CrlLerla (1able 1) ldenLlfy Lhe unlque and dlsLlncLlve
characLerlsLlc paLLerns of sympLom clusLers of ML. 1he broad specLrum of sympLoms alerLs
medlcal pracLlLloners Lo areas of paLhology and may ldenLlfy crlLlcal sympLoms more accuraLely
[18-20]. CperaLlonal noLes followlng each crlLerlon provlde guldance ln sympLom expresslon
and conLexLual lnLerpreLaLlon. 1hls wlll asslsL Lhe prlmary cllnlclan ln ldenLlfylng and LreaLlng
ML paLlenLs ln Lhe prlmary care seLLlng.

(Please insert Table 1 here.)

Cr|ter|a Are Supported by kesearch
CrlLerlal sympLoms are supporLed by a sLudy of more Lhan 2,300 paLlenLs LhaL deLermlned
whlch sympLoms had Lhe greaLesL efflcacy Lo ldenLlfy ML paLlenLs [22]. lnvesLlgaLlons of gene
expresslon [23-27] and sLrucLure furLher supporL Lhe crlLerla aL a molecular level lncludlng
anomalles of lncreased oxldaLlve sLress [4, 28], alLered lmmune and adrenerglc slgnalllng [29,
30], and alLered oesLrogen recepLor expresslon [31]. ln addlLlon, evldence supporLlng a geneLlc
predlsposlLlon Lo ML polnLs Lo modlflcaLlons ln seroLonln LransporLer genes [32, 33], Lhe
glucocorLlcold recepLor gene [34], as well as PLA class ll lnvolvemenL [33]. 1he poLenLlal
comblnaLorlal effecLs of Lhese modlflcaLlons have recelved llmlLed aLLenLlon [36, 37]. Some
early broad based sLudles show a lack of ob[ecLlve flndlngs such as no assoclaLlon wlLh PLA
genoLype [38]. A sLudy of paLlenLs from a Lwln reglsLry suggesLed LhaL envlronmenLal facLors
may ouLwelgh any geneLlc predlsposlLlon ln broad based paLlenL populaLlons [39].


underlylng problems of lnconslsLenL flndlngs ln research sLudles have been ldenLlfled [40,
41] and lnclude a need for sLudles Lo be based on larger sample slzes wlLh a more clearly
deflned phenoLype, ln parLlcular one LhaL recognlzes Lhe llkely exlsLence of slgnlflcanL
subgroups wlLhln Lhe paLlenL populaLlon. ln a sLudy of Lhe 8eeves emplrlcal crlLerla [16], !ason
eL al [18] reporLed LhaL LhlrLy-elghL percenL (38) of paLlenLs dlagnosed wlLh Ma[or uepresslve
ulsorder were mlsclasslfled as havlng ClS and only Len percenL (10) of paLlenLs ldenLlfled as
havlng ClS acLually had ML. Accordlngly, Lhe prlmary goal of Lhls consensus reporL ls Lo
esLabllsh a more selecLlve seL of cllnlcal crlLerla LhaL would ldenLlfy paLlenLs who have
neurolmmune exhausLlon wlLh a paLhologlcal low-Lhreshold of faLlgablllLy and sympLom flare ln
response Lo exerLlon. 1hls wlll enable llke paLlenLs Lo be dlagnosed and enrolled ln research
sLudles lnLernaLlonally under a case deflnlLlon LhaL ls accepLable Lo physlclans and researchers
around Lhe world.
A. osL-LxerLlonal neurolmmune LxhausLlon (LnL pen-e)
Malalse - a vague feellng of dlscomforL or faLlgue" [42] ls an lnaccuraLe and lnadequaLe
word for Lhe paLhologlcal low-Lhreshold faLlgablllLy and posL-exerLlonal sympLom flare. aln
and faLlgue are cruclal bloalarm slgnals LhaL lnsLrucL paLlenLs Lo modlfy whaL Lhey are dolng
ln order Lo proLecL Lhe body and prevenL furLher damage. osL-exerLlonal neurolmmune
exhausLlon ls parL of Lhe body's global proLecLlon response and ls assoclaLed wlLh
dysfuncLlon ln Lhe regulaLory balance wlLhln and beLween Lhe nervous, lmmune and
endocrlne sysLems, and cellular meLabollsm and lon LransporL [43-47]. 1he normal
acLlvlLy/resL cycle, whlch lnvolves performlng an acLlvlLy, becomlng faLlgued, and Laklng a
resL whereby energy ls resLored, becomes dysfuncLlonal.


numerous papers documenL abnormal blologlcal responses Lo exerLlon, such as loss of Lhe
lnvlgoraLlng effecLs of exerclse [20], decreased paln Lhreshold [48-30], decreased cerebral
oxygen and blood volume/flow [31-34], decreased maxlmum hearL raLe [33],

lmpalred
oxygen dellvery Lo muscles [36], elevaLed levels of nlLrlc oxlde meLabollLes [37], and
worsenlng of oLher sympLoms [38]. aLlenLs reach Lhe anaeroblc Lhreshold and maxlmal
exerclse aL a much lower oxygen consumpLlon level [39]. 8eporLed prolonged effecLs of
exerLlon lnclude elevaLed sensory slgnalllng Lo Lhe braln [60] LhaL ls lnLerpreLed as paln and
faLlgue [61], elevaLed cyLoklne acLlvlLy [62], delay ln sympLom acLlvaLlon [63]

and a recovery
perlod of aL leasL 48 hours [38].

When an exerclse LesL was glven on Lwo consecuLlve days,
some paLlenLs experlenced up Lo a 30 drop ln Lhelr ablllLy Lo produce energy on Lhe second
evaluaLlon [64]. 8oLh submaxlmal and self-paced physlologlcally llmlLed exerclse resulLed ln
posL-exerLlonal malalse [49].

8. Neuro|og|ca| Impa|rments


Some vlruses and bacLerla can lnfecL lmmune and neural cells and cause chronlc
lnflammaLlon. SLrucLural and funcLlonal paLhologlcal abnormallLles [3] wlLhln Lhe braln and
splnal cord suggesL dysregulaLlon of Lhe CnS conLrol sysLem and communlcaLlon neLwork
[64], whlch play cruclal roles ln cognlLlve lmpalrmenL and neurologlcal sympLoms [20].
neurolnflammaLlon of Lhe dorsal rooL ganglla, gaLekeepers of perlpheral sensory
lnformaLlon Lravellng Lo Lhe braln, has been observed ln splnal auLopsles. (Chaudhurl A.
8oyal SocleLy of Medlclne MeeLlng 2009) ldenLlfled cerebrosplnal fluld proLeomes
dlsLlngulsh paLlenLs from healLhy conLrols and posL-LreaLmenL Lyme dlsease [63].


neurolmaglng sLudles reporL lrreverslble puncLuaLe leslons [66], an approxlmaLe 10
reducLlon ln gray maLLer volume [67, 68],

hypoperfuslon [69-74] and braln sLem
hypomeLabollsm [1]. LlevaLed levels of laLeral venLrlcular lacLaLe are conslsLenL wlLh
decreased corLlcal blood flow, mlLochondrlal dysfuncLlon and oxldaLlve sLress [73].

8esearch
suggesLs LhaL dysregulaLlon of Lhe CnS and auLonomlc nervous sysLem alLers processlng of
paln and sensory lnpuL [48, 61, 76, 77]. aLlenLs' percepLlon LhaL slmple menLal Lasks
requlre subsLanLlal efforL ls supporLed by braln scan sLudles LhaL lndlcaLe greaLer source
acLlvlLy and more reglons of Lhe braln are uLlllzed when processlng audlLory

and spaLlal
cognlLlve lnformaLlon [78-80].

oor aLLenLlonal capaclLy and worklng memory are promlnenL
dlsabllng sympLoms [20, 78, 81].

C. Immune Impa|rments
MosL paLlenLs have an acuLe lnfecLlous onseL wlLh flu-llke and/or resplraLory sympLoms.!!
A wlde range of lnfecLlous agenLs have been reporLed ln subseLs of paLlenLs lncludlng
xenoLroplc murlne leukemla vlrus-relaLed vlrus (xM8v) [82] and oLher murlne leukemla vlrus
(MLv)-relaLed vlruses [83], enLerovlrus [84-86], LpsLeln 8arr vlrus [87], human herpes vlrus 6
and 7 [88-90], Chlamydla [91],

cyLomegalovlrus [92], parvovlrus 819 [93] and Coxlella
burneLLl [87]. Chronlc enLerovlrus lnfecLlon of Lhe sLomach and alLered levels of u LacLlc acld
produclng bacLerla ln Lhe gasLrolnLesLlnal LracL have been lnvesLlgaLed [83, 94].

osslbly Lhe
lnlLlal lnfecLlon damages parL of Lhe CnS and lmmune sysLem causlng profound deregulaLlon
and abnormal responses Lo lnfecLlons [4].

ubllcaLlons descrlbe decreased naLural klller cell
slgnalllng and funcLlon, abnormal growLh facLor proflles, decreased neuLrophll resplraLory


bursLs and 1h1, wlLh a shlfL Lowards a 1h2 proflle [4-8, 93, 96]. Chronlc lmmune acLlvaLlon
[27], lncreases ln lnflammaLory cyLoklnes, pro-lnflammaLory alleles [4-8, 97-99], chemoklnes
and 1 lymphocyLes, and dysregulaLlon of Lhe anLlvlral rlboneuclease L (8nase L) paLhway [64,
100-103] may play a role ln causlng flu-llke sympLoms, whlch aberranLly flare ln response Lo
exerLlon [3, 93].

D. Lnergy roduct|on]1ransport Impa|rments
1he conslsLenL cllnlcal plcLure of profound energy lmpalrmenL suggesLs dysregulaLlon of
Lhe mlLochondrla and cellular energy meLabollsm and lon LransporL, and channelopaLhy [9-
11, 103, 104].

A blochemlcal poslLlve feedback cycle called Lhe 'nC/CnCC- cycle' may play a
role ln malnLalnlng Lhe chronlc naLure of ML, Lhe presence of oxldaLlve sLress [103-107],

lnflammaLory cyLoklne elevaLlon [97-99] and mlLochondrlal dysfuncLlon [108-111], and resulL
ln reduced blood flow and vasculopaLhy [109, 110].


llndlngs of small hearL" wlLh small lefL venLrlcular chamber and poor cardlac
performance ln paLlenL subseLs [112, 113] supporL prevlous reporLs of cardlac and lefL
venLrlcular dysfuncLlon [114-116],

whlch predlspose Lo orLhosLaLlc lnLolerance [14, 117].
Low blood pressure and exaggeraLed dlurnal varlaLlon may be due Lo abnormal blood
pressure regulaLlon [118]. AlLered conLrol and reduced corLlsol producLlon durlng and
followlng exerclse may be lnvolved.

CrLhosLaLlc lnLolerance ls assoclaLed wlLh funcLlonal
lmpalrmenL and sympLom severlLy [119]. Measurable vascular abnormallLles suggesL LhaL
Lhe braln ls noL recelvlng sufflclenL clrculaLlng blood volume ln an uprlghL poslLlon [12, 117],
whlch ls lnLenslfled when sLandlng ln one place such as a grocery sLore check-ouL llne.


SlgnlflcanL reducLlon ln hearL raLe varlablllLy durlng sleep ls assoclaLed wlLh poor sleep
quallLy and suggesLs a pervaslve sLaLe of nocLurnal sympaLheLlc hypervlgllance [120].

App||cat|on of Cr|ter|a
ulagnosLlc crlLerla serve Lwo necessary buL dlvergenL funcLlons - Lhe flrsL ls dlagnoslng
lndlvlduals ln a cllnlcal seLLlng and Lhe second ls ldenLlfylng paLlenL seLs for research sLudles.

A. C||n|ca| App||cat|on
1. Genera| Cons|derat|ons
a. "#$#%&'(#! )*#$*#%! +,&-$.&! /01+$#%! -2$$#%(+! 2%#! /.(3%1#($! wlLh Lhose expecLed
from dysfuncLlon of an underlylng causal sysLem. !
b. 4,&-$.&+! '($#%2/$! 5,(2&'/200,! wlLhln a sLable clusLer because Lhey share Lhe same
deep causal rooLs. aLlenLs' conLexLual observaLlons are essenLlal ln deLermlnlng Lhe
expresslon of lnLeracLlon of sympLom paLLerns and severlLy of Lhelr lmpacL.
c. 4,&-$.&! +#6#%'$, '&-2/$ musL resulL ln a 30 or greaLer reducLlon of a paLlenL's
premorb|d acLlvlLy level for a dlagnosls of ML. M||d: approxlmaLely 30 reducLlon ln
acLlvlLy, moderate: mosLly housebound, severe: mosLly bedbound, and very severe:
bedbound and dependenL on help for physlcal funcLlons.
d. 4,&-$.&! +#6#%'$,! *'#%2%/*, should be deLermlned perlodlcally Lo help orlenL and
monlLor LreaLmenL.
e. 7%'$#%'20!+183%.1-+9!!osL-exerLlonal neurolmmune exhausLlon ls Lhe hallmark feaLure.
lL may be helpful Lo subgroup accordlng Lo whlch of Lhe oLher dlagnosLlc crlLerlal


paLLerns besL represenL a paLlenL's clusLer of mosL severe sympLoms: neurologlcal,
lmmune, energy meLabollsm/LransporL, or eclecLlc (sympLoms wldely dlsLrlbuLed
among subgroups).
f. 4#-2%2$#!-%'&2%,!+,&-$.&+!:%.&!+#/.(52%,!+,&-$.&+!2(5!233%262$.%+;!ulsLlngulsh
prlmary sympLom complexes formed by a dlsease process from secondary effecLs of
coplng wlLh Lhe dlsease, such as anxleLy abouL flnances. ueLermlne Lhe effecLs and
burden of aggravaLors and sLress enhancers such as fasL paced envlronmenLs and
exposure Lo Loxlns.
g. "#$#%&'(#!$.$20!'00(#++!81%5#(!8,!2++#++'(3!+,&-$.&!+#6#%'$,<!'($#%2/$'.(!2(5!.6#%200!
'&-2/$;!!Conslder all aspecLs of Lhe paLlenL's llfe - physlcal, occupaLlonal, educaLlonal,
soclal and personal acLlvlLles of dally llvlng. aLlenLs who prlorlLlze Lhelr acLlvlLles may
be able Lo do one lmporLanL acLlvlLy by ellmlnaLlng or severely reduclng acLlvlLles ln
oLher aspecLs of Lhelr llfe.
h. =*#! >($#%(2$'.(20! 4,&-$.&! 4/20# should noL be parL of Lhe lnlLlal cllnlcal lnLervlew
because lL may dlsLurb Lhe welghLlng and slgnlflcance of resulLs obLalned for an
lndlvldual paLlenL. When used perlodlcally, lL can help poslLlon Lhe paLlenL wlLhln Lhe
group, orlenL Lhe LreaLmenL program and monlLor lLs effecLlveness.

2. aed|atr|c Cons|derat|ons
a. lf posslble, lnLervlew a young person wlLh boLh parenLs because each may remember
dlfferenL sympLoms or lnLeracLlve evenLs LhaL may help deLermlne onseL and when
Lhe lllness began Lo lnLerfere wlLh dally funcLlon.


b. Chlldren cannoL be expecLed Lo [udge pre-lllness funcLlon wlLh currenL funcLlon.
Assess lmpacL by comparlng hobbles, educaLlonal, soclal and sporL acLlvlLles Lhe chlld
parLlclpaLed ln before lllness wlLh presenL acLlvlLy level.
c. Chlldren may appear lrrlLable when Lhey are asked Lo do someLhlng when Lhey feel
exhausLed. Cn Lhe oLher hand, Lhey are ofLen able Lo accommodaLe faLlgue by
resLlng, whlch may be lnapproprlaLely lnLerpreLed as belng lazy.
d. 4/*..0! ?*.8'29 ?oung paLlenLs spend mosL of Lhelr ouL-of-school hours resLlng
whereas chlldren wlLh school phobla wlll be soclallzlng and parLlclpaLlng ln acLlvlLles.
Powever, lL ls posslble LhaL school phobla may become a secondary sympLom
because of bullylng or academlc dlfflculLles due Lo havlng ML.
e. @2$1%20! 7.1%+#9 Chlldren can be very severely affllcLed buL Lhose whose sympLoms
are of mlld Lo moderaLe severlLy generally are more llkely Lo have Lhem go lnLo
remlsslon Lhan adulLs. rognosls cannoL be predlcLed wlLh cerLalnLy.

8. kesearch App||cat|on
A cllnlcal dlagnosls musL be conflrmed before a paLlenL can provlde useful general
knowledge abouL Lhe dlsease. 1he daLa obLalned from paLlenLs allows conLrolled and
meanlngful observaLlons and suggesLs hypoLheses Lo be LesLed and conflrmed or refuLed.



1. Genera| Cons|derat|ons
a. ?2$'#($+!+*.105!&##$!$*#!:100!/%'$#%'2!for epldemlologlcal sLudles. lf speclflc subgroups
or aLyplcal ML are lncluded ln a research sLudy, LhaL should be clearly lndlcaLed.
b. 4-#/':'/'$,9 8ecause crlLlcal sympLoms are compulsory, lL ensures proper selecLlon of
paLlenLs. key operaLlonal guldellnes enhance clarlLy and speclflclLy. 8anklng Lhe
hlerarchy of Lhe mosL Lroublesome sympLoms may be helpful ln some sLudles.
c. A#0'28'0'$,9 SympLoms musL noL be vlewed as a nomlnal checkllsL. 1he lnLernaLlonal
Consensus CrlLerla focus on sympLom paLLerns, whlch lncrease rellablllLy. 1he
Internat|ona| Symptom Sca|e ensures conslsLency ln Lhe way quesLlons are asked and
furLher lncreases rellablllLy of daLa collecLed ln dlfferenL locaLlons. aLlenLs should
compleLe Lhe lnLernaLlonal SympLom Scale pr|or to enter|ng a research study.

2. Cpt|ona| Cons|derat|ons
Classlfylng paLlenLs by subgroups Lo!enable comparlson of paLlenLs wlLhln Lhe dlagnosls of
ML may be helpful ln some sLudles.
a. B(+#$9!acuLe lnfecLlous or gradual
b. B(+#$!+#6#%'$,!may be a good predlcLor of severlLy ln Lhe chronlc phase.!
c. 4,&-$.&!+#6#%'$,9!mlld, moderaLe, severe, very severe !!
d. 7%'$#%'20!+183%.1-+9!neurologlcal, lmmune, energy meLabollsm/LransporL, or eclecLlc !
(5ee cllolcol oppllcotloo fot symptom sevetlty ooJ ctltetlol sobqtoops.)



Conc|us|ons
1he lnLernaLlonal Consensus CrlLerla provlde a framework for Lhe dlagnosls of ML LhaL ls
conslsLenL wlLh Lhe paLLerns of paLhophyslologlcal dysfuncLlon emerglng from publlshed
research flndlngs and cllnlcal experlence. SympLom paLLerns lnLeracL dynamlcally because Lhey
are causally connecLed. 1hls has been formally addressed by some lnvesLlgaLors who have used
well-esLabllshed mulLlvarlaLe sLaLlsLlcal Lechnlques, such as common facLor or prlnclpal
componenL analyses Lo ldenLlfy sympLom consLrucLs [121, 122]. CLhers have exLended Lhe use
of such meLhods Lo gulde Lhe analysls of gene expresslon proflles [28] and Lo dellneaLe paLlenL
sub-groups [123]. ConslsLenL wlLh Lhls approach, Lhe panel ls developlng an lnLernaLlonal
Consensus SympLom Scale (lCSS) LhaL wlll bulld on Lhese underlylng lnLeracLlons. Powever a
necessary flrsL sLep ln esLabllshlng a quanLlLaLlve score for any dlagnosLlc lnsLrumenL ls Lhe
speclflcaLlon of measurable facLors LhaL are mosL relevanL Lo Lhe lllness. LsLabllshlng such
crlLerla was Lhe prlmary ob[ecLlve of Lhls work and we belleve Lhe lnLernaLlonal Consensus
CrlLerla wlll help clarlfy Lhe unlque slgnaLure of ML.
lL ls lmporLanL Lo noLe LhaL Lhe currenL emphasls musL prlmarlly remaln a cllnlcal assessmenL,
wlLh selecLlon of research sub[ecLs comlng laLer. lor Lhls reason Lhe panel ls developlng
hyslclans' Culdellnes, whlch wlll lnclude dlagnosLlc proLocol based on Lhe lnLernaLlonal
Consensus CrlLerla and LreaLmenL guldellnes LhaL reflecL currenL knowledge. lndlvlduals
meeLlng Lhe lnLernaLlonal Consensus CrlLerla have myalglc encephalomyellLls and should be
removed from Lhe 8eeves emplrlcal crlLerla and Lhe naLlonal lnsLlLuLe for Cllnlcal Lxcellence
(nlCL) crlLerla for chronlc faLlgue syndrome. 1hese guldellnes are deslgned speclflcally for use
by Lhe prlmary care physlclan ln Lhe hope of lmprovlng rapld dlagnosls and LreaLmenL by flrsL-


llne medlcal care provlders. 1hls may resulL ln Lhe developmenL of an addlLlonal shorL form
verslon LhaL would bulld on Lhe relaLlonshlps llnklng sympLoms Lo formulaLe an abbrevlaLed
screenlng proLocol. lor Lhe flrsL Llme cllnlcal, paedlaLrlc and research appllcaLlons are provlded,
whlch wlll advance Lhe undersLandlng of myalglc encephalomyellLls and enhance conslsLency of
dlagnoses lnLernaLlonally. 1he compulsory crlLlcal crlLerla allow comparable daLa Lo be
collecLed ln varlous locaLlons and may asslsL ln developlng conslsLenL blomarkers and furLher
lnslghLs lnLo Lhe mechanlsm and eLlology of myalglc encephalomyellLls.

kL WCkDS: myalglc encephalomyellLls, chronlc faLlgue syndrome, crlLerla, deflnlLlon, dlagnosls.
Iund|ng
1hls Consensus paper ls free of sponsorshlp. All auLhors conLrlbuLed Lhelr Llme and experLlse
on a volunLeer basls and no one recelved any paymenLs or honorarlums.
Conf||ct of Interest Statement.
All auLhors have dlsclosed poLenLlal confllcLs of lnLeresL and all members declare LhaL Lhey have
no compeLlng lnLeresLs.
Acknow|edgements
1he panel would llke Lo graLefully acknowledge Lhe parLlclpaLlon and supporL of Lhe paLlenLs
and Lhelr famllles ln Lhe research descrlbed hereln and upon whlch Lhese guldellnes are based.



Author Contr|but|ons
Coed|tors - concept|on, draft|ng of paper and rev|s|ons: 8.M. CarruLhers, M.l. van de Sande.

In|t|a| suggest|ons and subsequent cr|t|ca| rev|ews: k.L. ue Melrlelr, n.C. kllmas, C. 8roderlck,
1. MlLchell, u. SLalnes, A.C.. owles, n. SpelghL, 8. valllngs, L. 8aLeman, 8. 8aumgarLen-
AusLrhelm, u.S. 8ell, n. Carlo-SLella, !. Chla, A. uarragh, u. !o, u. Lewls, A.8. LlghL, S. Marshall-
Cradlsblk, l. Mena, !.A. MlkovlLs, k. Mlwa, M. Murovska, M.L. all, S. SLevens.

I|na| approva| and consensus: 1here was 100 consensus by Lhe auLhors on Lhe flnal
consensus paper. 8. M. CarruLhers, M. l. van de Sande, k.L. ue Melrlelr, n.C. kllmas, C.
8roderlck, 1. MlLchell, u. SLalnes , A.C.. owles, n. SpelghL, 8. valllngs, L. 8aLeman, 8.
8aumgarLen-AusLrhelm, u.S. 8ell, n. Carlo-SLella, !. Chla, A. uarragh, u. !o, u. Lewls, A.8. LlghL,
S. Marshall-Cradlsblk, l. Mena, !.A. MlkovlLs, k. Mlwa, M. Murovska, M.L. all, S. SLevens.

Consensus Coord|nator: M. van de Sande



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Correspondence address.

Correspond|ng author: ur. 8ruce CarruLhers, 4607 8lenhelm SL., vancouver, 8rlLlsh Columbla
v6L 3A3, Canada. bcarruLh[Lelus.neL

Correspond|ng author for subm|ss|on of document: ur. Cordon 8roderlck, ulvlslon of
ulmonary Medlclne, ueparLmenL of Medlclne, unlverslLy of AlberLa, WMC 2L4.41 WC
Mackenzle PealLh Sclences 8ldg, 8440 - 112 SLreeL, LdmonLon A8 16C 287, Canada.
gordon.broderlck[ualberLa.ca

kequests for S|ng|e kepr|nts: Ms. Mar[ van de Sande, 131 Arbour 8ldge Clrcle nW, Calgary,
AlberLa 13C 3v9, Canada. mvandes[shaw.ca




Current Author Addresses
Dr. Carruthers: 4607 8lenhelm SL., vancouver, 8C, v6L 3A3, Canada. bcarruLh[Lelus.neL
Ms. van de Sande: 131 Arbour 8ldge Clrcle nW, Calgary, A8 13C 3v9, Canada.
mvandes[shaw.ca
Dr. De Me|r|e|r: ueparLmenL of hyslology, vrl[e unlverslLy of 8russels, PlmmunlLas

loundaLlon, 8russels, 1120, 8elglum. DE.MEIRLEIR@telenet.be

Dr. k||mas: ueparLmenL of Medlclne, unlverslLy of Mlaml, 1201 nW 16 SL., Mlaml, lL 33123,
uSA. nkdoc123[aol.com
Dr. 8roder|ck: ulvlslon of ulmonary Medlclne, ueparLmenL of Medlclne, unlverslLy of AlberLa,
WMC 2L4.41 WC Mackenzle PealLh Sclences 8ldg, 8440 - 112 SLreeL, LdmonLon, AlberLa, 16C
287, Canada. gordon.broderlck[ualberLa.ca
Dr. M|tche||: LowesLofL, Suffolk, n832 3Pu, unlLed klngdom. Lerry[gerken.org.uk
Dr. Sta|nes: ubllc PealLh Medlclne and neurolmmunology, Cueensland PealLh, Cold CoasL
ubllc PealLh unlL, SouLhporL, Cueensland 4213, laculLy of PealLh Sclences and Medlclne, 8ond
unlverslLy, 8oblna, Cueensland 4229, AusLralla. uon_SLalnes[healLh.qld.gov.au
Dr. ow|es: laculLy of PealLh Sclences, McMasLer unlverslLy and SL. !oseph's PealLhcare
PamllLon, 30 CharlLon Ave L., PamllLon, CnLarlo L08 1P2, Canada. ppowles[sL[osham.on.ca
Dr. Spe|ght: SouLhlands CllesgaLe, uurham, uP1 1Cn, unlLed klngdom. spelghL[docLors.org.uk
Dr. Va|||ngs: Powlck PealLh and Medlcal CenLre, 108 8ldge 8oad, Powlck, new Zealand.
valllngs[xLra.co.nz
Dr. 8ateman: laLlgue ConsulLaLlon Cllnlc , 1002 LasL SouLh 1emple, SulLe 408, SalL Lake ClLy,
uLah 84102, uSA. fccllnlc[xmlsslon.com


Dr. 8aumgarten-Austrhe|m: ML/ClS CenLer, Cslo unlverslLy PosplLal Pl, b 4936 nydalen, n-
0424 Cslo, norway. uxbaba[ous-hf.no

Dr. 8e||: 77 SouLh Maln SLreeL, Lydonvllle n? 14098, n?, uSA. dsbellmd[yahoo.com

Dr. Car|o-Ste||a: Menocchlo 10, l-27100, avla, lLaly. nlcklcs[llbero.lL
Dr. Ch|a: Parbor-uCLA Medlcal CenLer, unlverslLy of Callfornla, Los Angeles, CA 90024, Lv Med
8esearch, 23332 narbonne Ave. #170, LomlLa, CA 90717, uSA. evmed[sbcglobal.neL
Dr. Darragh: '1arabeag', Plll of 1ara, 1ara, Co MeaLh, lreland , Chemlcal & LnvlronmenLal
Sclence ueparLmenL, unlverslLy of Llmerlck, Llmerlck, lreland. daraLara[elrcom.neL
Dr. Io: aln Cllnlc, konyang unlverslLy PosplLal, uae[eon, korea. pand[o[paran.com
Dr. Lew|s: ClS ulscovery, uonvale SpeclallsL Medlcal CenLre, SulLe 8, 90 MlLcham 8oad,
uonvale, vlcLorla 3111, AusLralla. dplewls[cfsdlscovery.oc.au
Dr. L|ght: uepLs. of AnesLheslology, neuroblology and AnaLomy, 3C 444 SCM, unlverslLy of
uLah, 30n 1900L, SalL Lake ClLy, uLah 84132, uSA. alan.llghL[hsc.uLah.edu
Dr. Marsha||-Grad|sn|k: laculLy of PealLh Sclences and Medlclne, 8ond unlverslLy, 8oblna,

Cueensland 4229, AusLralla. smarshal[bond.edu.au

Dr. Mena: ueparL. Medlclna nuclear, Cllnlca Las Condes, SanLlago, Chlle. lmenamd[gmall.com
Dr. M|kov|ts: WhlLLemore eLerson lnsLlLuLe for neuro-lmmune ulsease, Applled 8esearch
laclllLy, 8m. 401/MS199, 1664 norLh vlrglnla SL., unlverslLy of nevada, 8eno, nA 89337, uSA.
[udym[wplnsLlLuLe.org
Dr. M|wa: Mlwa nalka Cllnlc, ShlnLomlcho 1-4-3, 1oyama 930-0002, !apan.
k-3wa[pm.cLL.ne.[p

Dr. Murovska: A. klrchensLeln lnsLlLuLe of Mlcroblology and vlrology, 8lga SLradlns unlverslLy,
8aLsuplLes SL. 3, 8lga, LaLvla, Lv-1067. modra[laLneL.lv


Dr. a||: uepL. of 8lochemlsLry and 8aslc Medlcal Sclences, WashlngLon SLaLe unlverslLy, 638 nL
41
sL
Ave., orLland, C8 97232 uSA. marLln_pall[wsu.edu
Ms. Stevens: aclflc laLlgue LaboraLory, ueparLmenL of SporL Sclences, unlverslLy of Lhe
aclflc, 3601 aclflc Avenue, SLockLon, CA 93211, uSA. ssLevens[paclflc.edu


=280#!C MALGIC LNCLnALCMLLI1IS: IN1LkNA1ICNAL CCNSLNSUS CkI1LkIA
Adu|t and ed|atr|c C||n|ca| and kesearch
D,203'/! #(/#-*20.&,#0'$'+! '+! 2(! 2/E1'%#5! (#1%.0.3'/20! 5'+#2+#! )'$*! /.&-0#F! 30.820! 5,+:1(/$'.(+;!!
?2$*.0.3'/20! 5,+%#3102$'.(! .:! $*#! (#%6.1+<! '&&1(#! 2(5! #(5./%'(#! +,+$#&+<! )'$*! '&-2'%#5! /#00102%!
#(#%3,! &#$28.0'+&! 2(5! '.(! $%2(+-.%$! 2%#! -%.&'(#($! :#2$1%#+;! ! G0$*.13*! +'3(+! 2(5! +,&-$.&+! 2%#!
5,(2&'/200,! '($#%2/$'6#! 2(5! /21+200,! /.((#/$#5<! $*#! /%'$#%'2! 2%#! 3%.1-#5! 8,! %#3'.(+! .:!
-2$*.-*,+'.0.3,!$.!-%.6'5#!3#(#%20!:./1+;!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
A pat|ent w||| meet the cr|ter|a for post-exert|ona| neuro|mmune exhaust|on (A), at |east one
symptom from three neuro|og|ca| |mpa|rment categor|es (8), at |east one symptom from three
|mmune]gastro-|ntest|na|]gen|tour|nary |mpa|rment categor|es (C), and at |east one symptom from
energy metabo||sm]transport |mpa|rments (D).
A. ost-Lxert|ona| Neuro|mmune Lxhaust|on (LNL pen-e) Compu|sory
1h|s card|na| feature |s a patho|og|ca| |nab|||ty to produce suff|c|ent energy on demand w|th
prom|nent symptoms pr|mar||y |n the neuro|mmune reg|ons. Character|st|cs are:
1. Marked, rap|d phys|ca| and]or cogn|t|ve fat|gab|||ty |n response to exert|on, wh|ch may be
m|n|ma| such as act|v|t|es of da||y ||v|ng or s|mp|e menta| tasks, can be deb|||tat|ng and cause a
re|apse.
2. ost-exert|ona| symptom exacerbat|on: #;3;! 2/1$#! :01H0'I#! +,&-$.&+<! -2'(! 2(5! ).%+#('(3! .:!
.$*#%!+,&-$.&+!
3. ost-exert|ona| exhaust|on may occur |mmed|ate|y after act|v|ty or be de|ayed by hours or days.
4. kecovery per|od |s pro|onged, usua||y tak|ng 24 hours or |onger. A re|apse can |ast days, weeks
or |onger.
S. Low thresho|d of phys|ca| and menta| fat|gab|||ty (|ack of stam|na) resu|ts |n a substant|a|
reduct|on |n pre-|||ness act|v|ty |eve|.
B-#%2$'.(20!@.$#+9!!J.%!2!5'23(.+'+!.:!DK<!+,&-$.&!+#6#%'$,!&1+$!%#+10$!'(!2!+'3(':'/2($!%#51/$'.(!.:!2!
-2$'#($L+! -%#&.%8'5! 2/$'6'$,! 0#6#0;! ! D'05! M2(! 2--%.F'&2$#! NOP! %#51/$'.(! '(! -%#H'00(#++! 2/$'6'$,! 0#6#0Q<!
&.5#%2$#!M&.+$0,!*.1+#8.1(5Q<!+#6#%#!M&.+$0,!8#5%'55#(Q<!.%!6#%,!+#6#%#!M$.$200,!8#5%'55#(!2(5!(##5!
*#0-!)'$*!82+'/!:1(/$'.(+Q;!!=*#%#!&2,!8#!&2%I#5!:01/$12$'.(!.:!+,&-$.&!+#6#%'$,!2(5!*'#%2%/*,!:%.&!
52,! $.! 52,! .%! *.1%! $.! *.1%;! 7.(+'5#%! 2/$'6'$,<! /.($#F$! 2(5! '($#%2/$'6#! #::#/$+;! A#/.6#%,! $'&#9! #;3;!


A#32%50#++! .:! 2! -2$'#($L+! %#/.6#%,! $'&#! :%.&! %#25'(3! :.%! R! *.1%<! '$! )'00! $2I#! &1/*! 0.(3#%! $.! %#/.6#%!
:%.&!3%./#%,!+*.--'(3!:.%!R!*.1%!2(5!#6#(!0.(3#%!':!%#-#2$#5!$*#!(#F$!52,!S!':!280#;!!=*.+#!)*.!%#+$!
8#:.%#! 2(! 2/$'6'$,! .%! *26#! 25T1+$#5! $*#'%! 2/$'6'$,! 0#6#0! $.! $*#'%! 0'&'$#5! #(#%3,! &2,! *26#! +*.%$#%!
%#/.6#%,!-#%'.5+!$*2(!$*.+#!)*.!5.!(.$!-2/#!$*#'%!2/$'6'$'#+!25#E12$#0,;!>&-2/$9!#;3;!G(!.1$+$2(5'(3!
2$*0#$#! /.105! *26#! 2! NOP! %#51/$'.(! '(! *'+U*#%! -%#H'00(#++! 2/$'6'$,! 0#6#0! 2(5! '+! +$'00! &.%#! 2/$'6#! $*2(! 2!
+#5#($2%,!-#%+.(;!!!
8. Neuro|og|ca| Impa|rments
At |east Cne Symptom from three of the fo||ow|ng four symptom categor|es
1. Neurocogn|t|ve Impa|rments
a. D|ff|cu|ty process|ng |nformat|on: s|owed thought, |mpa|red concentrat|on #;3;! /.(:1+'.(<!
5'+.%'#($2$'.(<!/.3('$'6#!.6#%0.25<!5'::'/10$,!)'$*!&2I'(3!5#/'+'.(+, +0.)#5!+-##/*<!2/E1'%#5!
.%!#F#%$'.(20!5,+0#F'2
b. Short-term memory |oss: #;3. 5'::'/10$,!%#&#&8#%'(3!)*2$!.(#!)2($#5!$.!+2,<!)*2$!.(#!)2+!
+2,'(3<!%#$%'#6'(3!).%5+<!%#/200'(3!'(:.%&2$'.(,!-..%!).%I'(3!&#&.%,
2. a|n
a. neadaches: #;3;!/*%.('/<!3#(#%20'V#5!*#252/*#+!.:$#(!'(6.06#!2/*'(3!.:!$*#!#,#+<!8#*'(5!$*#!
#,#+! .%! 82/I! .:! $*#! *#25! $*2$! &2,! 8#! 2++./'2$#5! )'$*! /#%6'/20! &1+/0#! $#(+'.(W! &'3%2'(#W!
$#(+'.(!*#252/*#+
b. S|gn|f|cant pa|n can be exper|enced |n musc|es, musc|e-tendon [unct|ons, [o|nts, abdomen or
chest. It |s non-|nf|ammatory |n nature and often m|grates. #;3;! 3#(#%20'V#5! *,-#%203#+'2,
)'5#+-%#25!-2'(!M&2,!&##$!:'8%.&,203'2!/%'$#%'2Q<!&,.:2+/'20!.%!%25'2$'(3!-2'(!
3. S|eep D|sturbance
a. D|sturbed s|eep patterns9!#;3;!'(+.&('2<!-%.0.(3#5!+0##-!'(/015'(3!(2-+<!+0##-'(3!&.+$!.:!$*#!
52,! 2(5! 8#'(3! 2)2I#! &.+$! .:! $*#! ('3*$<! :%#E1#($! 2)2I#('(3+<! 2)2I'(3! &1/*! #2%0'#%! $*2(!
8#:.%#!'00(#++!.(+#$<!6'6'5!5%#2&+U('3*$&2%#+
b. Unrefreshed s|eep: #;3;!2)2I#(! :##0'(3! #F*21+$#5!%#32%50#++! .:! 51%2$'.(! .:!+0##-<! 52,H$'&#!
+0##-'(#++ !
4. Neurosensory, erceptua| and Motor D|sturbances
a. Neurosensory and perceptua|: #;3. '(28'0'$,! $.! :./1+! 6'+'.(<! +#(+'$'6'$,! $.! 0'3*$<! (.'+#<!
6'8%2$'.(<!.5.1%<!$2+$#!2(5!$.1/*W!'&-2'%#5!5#-$*!-#%/#-$'.(
b. Motor:!#;3;!&1+/0#!)#2I(#++<!$)'$/*'(3<!-..%!/..%5'(2$'.(<!:##0'(3!1(+$#25,!.(!:##$<!2$2F'2
@.$#+9! @#1%./.3('$'6#! '&-2'%&#($+<! %#-.%$#5! .%! .8+#%6#5<! 8#/.&#! &.%#! -%.(.1(/#5! )'$*! :2$'31#;!
B6#%0.25! -*#(.&#(2! &2,! 8#! #6'5#($! )*#(! $).! $2+I+! 2%#! -#%:.%&#5! +'&10$2(#.1+0,;! G8(.%&20!
%#2/$'.(! $.! 0'3*$! H! :01/$12$'.(! .%! %#51/#5! 2//.&&.52$'.(! %#+-.(+#+! .:! $*#! -1-'0+! )'$*! %#$#($'.(! .:!
%#2/$'.(; 40##-! 5'+$1%82(/#+! 2%#! $,-'/200,! #F-%#++#5! 8,! -%.0.(3#5! +0##-<! +.&#$'&#+! #F$%#&#<! '(! $*#!
2/1$#! -*2+#! 2(5! .:$#(! #6.06#! '($.! &2%I#5! +0##-! %#6#%+20! '(! $*#! /*%.('/! +$23#;! ! D.$.%! 5'+$1%82(/#+!
&2,! (.$! 8#! #6'5#($! '(! &'05! .%! &.5#%2$#! /2+#+! 81$! 28(.%&20! $2(5#&! 32'$! 2(5! -.+'$'6#! A.&8#%3! $#+$!
&2,!8#!.8+#%6#5!'(!+#6#%#!/2+#+;!
C. Immune, Gastro-|ntest|na| & Gen|tour|nary Impa|rments
At |east Cne Symptom from three of the fo||ow|ng f|ve symptom categor|es
1. I|u-||ke symptoms may be recurrent or chron|c and typ|ca||y act|vate or worsen w|th exert|on.


#;3;! +.%#! $*%.2$<! +'(1+'$'+<! /#%6'/20! 2(5U.%! 2F'002%,! 0,&-*! (.5#+! &2,! #(02%3#! .%! 8#! $#(5#%! .(!
-20-'$2$'.(
2. Suscept|b|||ty to v|ra| |nfect|ons w|th pro|onged recovery per|ods
3. Gastro-|ntest|na| tract: #;3; (21+#2<!285.&'(20!-2'(<!80.2$'(3<!'%%'$280#!8.)#0!+,(5%.&#
4. Gen|tour|nary: e.g. 1%'(2%,!1%3#(/,!.%!:%#E1#(/,<!(./$1%'2
S. Sens|t|v|t|es $.!:..5<!&#5'/2$'.(+<!.5.1%+!.%!/*#&'/20+
@.$#+9! 4.%#! $*%.2$<! $#(5#%! 0,&-*! (.5#+<! 2(5! :01H0'I#! +,&-$.&+! .86'.1+0,! 2%#! (.$! +-#/':'/! $.! DK! 81$!
$*#'%!2/$'62$'.(!'(!%#2/$'.(!$.!#F#%$'.(!'+!28(.%&20; =*#!$*%.2$!&2,!:##0!+.%#<!5%,!2(5!+/%2$/*,;!!J21/'20!
'(T#/$'.(!2(5!/%'&+.(!/%#+/#($+!&2,!8#!+##(!'(!$*#!$.(+'002%!:.++2#<!)*'/*!2%#!2(!'(5'/2$'.(!.:!'&&1(#!
2/$'62$'.(; !
D. Lnergy roduct|on]1ransportat|on Impa|rments: At |east Cne Symptom
1. Card|ovascu|ar: #;3;! '(28'0'$,! $.! $.0#%2$#! 2(! 1-%'3*$! -.+'$'.(! H! .%$*.+$2$'/! '($.0#%2(/#<! (#1%200,!
&#5'2$#5!*,-.$#(+'.(<!-.+$1%20!.%$*.+$2$'/!$2/*,/2%5'2!+,(5%.&#, -20-'$2$'.(+!)'$*!.%!)'$*.1$!
/2%5'2/!2%%*,$*&'2+<!0'3*$H*#25#5(#++U5'VV'(#++
2. kesp|ratory: #;3;!2'%!*1(3#%<!028.1%#5!8%#2$*'(3<!:2$'31#!.:!/*#+$!)200!&1+/0#+
3. Loss of thermostat|c stab|||ty: #;3;! +18(.%&20! 8.5,! $#&-#%2$1%#<! &2%I#5! 5'1%(20! :01/$12$'.(+W!
+)#2$'(3! #-'+.5#+<! %#/1%%#($! :##0'(3+! .:! :#6#%'+*(#++! )'$*! .%! )'$*.1$! 0.)! 3%25#! :#6#%<! /.05!
#F$%#&'$'#+!
4. Into|erance of extremes of temperature
@.$#+9! B%$*.+$2$'/! '($.0#%2(/#! &2,! 8#! 5#02,#5! 8,! +#6#%20! &'(1$#+;! ?2$'#($+! )*.! *26#! .%$*.+$2$'/!
'($.0#%2(/#! &2,! #F*'8'$! &.$$0'(3! .:! #F$%#&'$'#+<! #F$%#&#! -200.%! .%! A2,(215L+! ?*#(.&#(.(;! ! >(! $*#!
/*%.('/!-*2+#<!&..(+!.:!:'(3#%!(2'0+!&2,!%#/#5#;!
aed|atr|c Cons|derat|ons
4,&-$.&+! &2,! -%.3%#++! &.%#! +0.)0,! '(! /*'05%#(! $*2(! '(! $##(23#%+! .%! 2510$+;! ! >(! 255'$'.(! $.! -.+$H
#F#%$'.(20! (#1%.'&&1(#! #F*21+$'.(<! $*#! &.+$! -%.&'(#($! +,&-$.&+! $#(5! $.! 8#! (#1%.0.3'/209!
*#252/*#+<!/.3('$'6#!'&-2'%&#($+<!2(5!+0##-!5'+$1%82(/#+;!
1. neadaches: Severe or chron|c headaches are often deb|||tat|ng. M|gra|ne may be accompan|ed by
a rap|d drop |n temperature, shak|ng, vom|t|ng, d|arrhoea and severe weakness.
2. Neurocogn|t|ve Impa|rments: D|ff|cu|ty focus|ng eyes and read|ng are common. Ch||dren may
become dys|ex|c, wh|ch may on|y be ev|dent when fat|gued. S|ow process|ng of |nformat|on
makes |t d|ff|cu|t to fo||ow aud|tory |nstruct|ons or take notes. A|| cogn|t|ve |mpa|rments worsen
w|th phys|ca| or menta| exert|on. oung peop|e w||| not be ab|e to ma|nta|n a fu|| schoo| program.
3. a|n may seem errat|c and m|grate qu|ck|y. Io|nt hyper-mob|||ty |s common.
@.$#+9! ! J01/$12$'.(! 2(5! +#6#%'$,! *'#%2%/*,! .:! (1&#%.1+! -%.&'(#($! +,&-$.&+! $#(5! $.! 62%,! &.%#!
%2-'50,!2(5!5%2&2$'/200,!$*2(!'(!2510$+; !
C|ass|f|cat|on
____ Mya|g|c Lncepha|omye||t|s
____ Atyp|ca| Mya|g|c Lncepha|omye||t|s: meets cr|ter|a for post-exert|ona| neuro|mmune exhaust|on
but has two or |ess than requ|red of the rema|n|ng cr|ter|a| symptoms. a|n or s|eep d|sturbance may
be absent |n rare cases.!


Lxc|us|ons: G+! '(! 200! 5'23(.+#+<! #F/01+'.(! .:! 20$#%(2$#! #F-02(2$.%,! 5'23(.+#+! '+! 2/*'#6#5! 8,! $*#!
-2$'#($L+!*'+$.%,<! -*,+'/20!#F2&'(2$'.(<!2(5! 028.%2$.%,U8'.&2%I#%! $#+$'(3! 2+!'(5'/2$#5;! ! >$! '+!-.++'80#!
$.! *26#! &.%#! $*2(! .(#! 5'+#2+#! 81$! '$! '+! '&-.%$2($! $*2$! #2/*! .(#! '+! '5#($':'#5! 2(5! $%#2$#5;! ! r|mary
psych|atr|c d|sorders, somatoform d|sorder and substance abuse are exc|uded. aed|atr|c: '-%'&2%,L
+/*..0!-*.8'2;!!!
Co-morb|d Lnt|t|es: I|bromya|g|a, Myofasc|a| a|n Syndrome, 1emporomand|bu|ar Io|nt Syndrome,
Irr|tab|e 8owe| Syndrome, Interst|t|a| Cyst|t|s, kaynaud's henomenon, ro|apsed M|tra| Va|ve,
M|gra|nes, A||erg|es, Mu|t|p|e Chem|ca| Sens|t|v|t|es, nash|moto's 1hyro|d|t|s, S|cca Syndrome,
keact|ve Depress|on. D'3%2'(#! 2(5! '%%'$280#! 8.)#0! +,(5%.&#! &2,! -%#/#5#! DK! 81$! $*#(! 8#/.&#!
2++./'2$#5!)'$*!'$;!!J'8%.&,203'2!.6#%02-+;!