SUU, Alm.del - 2024-25 - Bilag 187: Henvendelse af 2/3-25 fra ME Foreningen om igangværende vidensafdækning af ME/CFS

Sundhedsudvalget 2024-25
SUU Alm.del Bilag 187
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Sundhedsudvalget

Til

Indenrigs- og sundhedsminister

Sophie Løhde

Kære Jørgen Nielsen, Louise Brown, Peder Hvelplund, Rasmus Lund-Nielsen &

Mathilde Powers.

og sundhedsminister Sophie Løhde

Kære Indenrigs-

24.2.2025

Vedr. ME/CFS vidensafdækningen: Principielle fejl og mangler

ME Foreningen ønsker hermed at udtrykke vores bekymring over den snart afsluttede vidensafdækning

af ME/CFS, som sundhedsministeren igangsatte i 2024. Vi anerkender ministerens intention om at sikre

en grundig og evidensbaseret afdækning, men vi må desværre konstatere, at processen hidtil ikke lever

op til de forventninger, der med rette kan stilles til en så vigtig indsats.

Vores kommentarer beror på de to eksterne leverandørers (Defactum og Implement) præsentationer af

deres foreløbige resultater hhv. d. 22.11.24 og 04.02.25 (vores skriftlige feedback til disse

præsentationer ses i bilag 1 og 2). Rapporterne forventes offentliggjort af Sundhedsstyrelsen i

begyndelsen af marts 2025.

1. Manglende inddragelse af ME-patienter og ME-eksperter

På samrådsmødet den 28. november 2023 understregede ministeren nødvendigheden af at inddrage

ME Foreningen og ME-patienterne. Alligevel blev kun to ME-patienter interviewet af Implement (+ en

repræsentant for ME foreningen). Kun én af de to af ME Foreningen foreslåede ME-eksperter blev

interviewet, og vedkommende har siden sendt en kritisk vurdering af leverandørens foreløbige

resultater, mens Defactum kun indledningsvist inddrog en repræsentant ifm. udarbejdelse af

projektbeskrivelse. Desuden er væsentlig international viden ikke integreret i arbejdet til trods for, at

ME Foreningen løbende har stået til rådighed med litteratur.

2. Ensidigt fokus og mangelfuld litteraturudvælgelse

Vidensafdækningen blev oprindeligt placeret i den afdeling i Sundhedsstyrelsen, der har ansvaret for

funktionelle lidelser

–

en beslutning, vi fandt påfaldende, da vidensafdækningen ikke skulle omhandle

funktionelle lidelser. Senere blev opgaven dog overdraget til afdelingen for evidensbaseret medicin,

men det reviderede udbudsmateriale udelod det grundlæggende spørgsmål om, hvorvidt ME er en

somatisk eller funktionel lidelse. Denne udeladelse har medført, at op mod 80 % af den biomedicinske

litteratur om ME, som er afgørende for korrekt diagnostik og behandling, er ekskluderet i

vidensafdækningen. De to eksterne leverandører har derfor formentlig ikke anvendt den specifikke,

internationalt anerkendte diagnose ME/CFS, (G93.3), men har i stedet fokuseret på ”fatigue”, dvs.

kronisk træthed eller udmattelse, som herhjemme kategoriseres som en funktionel lidelse under

betegnelsen ”almen træthed” med en anden diagnosekode

(DR688A9).

3. Metodiske mangler og brug af forældede studier

Det ser ikke ud til, at de eksterne leverandørers to rapporter vil belyse ME/CFS biomedicinske natur,

herunder mulige årsager og risikofaktorer, da afklaringen af dette er udeladt i vidensafdækningen. Også

sygdommens epidemiologi (forekomst) afhængig af diagnostiske kriterier og alvorsgrad er udeladt.

Dermed bliver det heller ikke muligt at sammenligne diagnosticeringen og behandlingsindsatsen for

ME/CFS i Danmark med vores nabolande, da sygdommen i disse lande kategoriseres med WHOs

diagnosekode G93.3 og ikke som en funktionel lidelse.

SUU, Alm.del - 2024-25 - Bilag 187: Henvendelse af 2/3-25 fra ME Foreningen om igangværende vidensafdækning af ME/CFS

Defactums resultater bygger i høj grad på systematiske reviews, der primært omfatter studier foretaget

før 2011. Disse studier anvender forældede diagnosekriterier, der bl.a. ikke inkluderer PEM

–

nøglesymptom for ME/CFS. Dette svækker resultaternes validitet. Derudover er der inddraget svage,

ikke-blindede studier med subjektive endemål, hvilket yderligere underminerer evidensgrundlaget.

4. Begrænset internationalt perspektiv

Implement formåede ikke at inkludere Storbritannien i deres undersøgelse

–

det land, hvor

afdækningen af ME-vidensgrundlaget via NICE-rapporten 2021 i dag sætter standarden for ME i andre

lande. Desuden er vigtige internationale konsensusudtalelser og guidelines fra blandt andet USA,

Belgien, Tyskland, Østrig og Schweiz ikke tilstrækkeligt inddraget. Denne manglende inddragelse

forringer muligheden for, at Danmark kan sammenligne sin praksis med internationale standarder.

5. Mangel på gennemsigtighed

ME Foreningen har gentagne gange anmodet om mulighed for at gennemlæse og kommentere de

endelige rapporter fra Defactum og Implement inden offentliggørelse. Disse anmodninger er blevet

afvist, hvilket rejser væsentlige spørgsmål om processens transparens.

6. Konsekvenser for danske patienter

Med den nuværende tilgang risikerer danske ME/CFS-patienter at blive diagnosticeret og behandlet på

et niveau, der ikke er i overensstemmelse med internationale standarder. Det kan betyde, at patienter i

Danmark afskæres fra at få adgang til de nyeste behandlingsmuligheder. Vi kan på baggrund af de to

eksterne leverandørers vidensafdækning konstatere, at den internationale WHO-diagnose (G93.3) for

sygdommen, som resten af verden bruger, i praksis ikke anvendes i Danmark, mens Defactums

fremlæggelse lige så klart viste, at de behandlinger, som anbefales til ME/CFS i Danmark (Cognitive

behavioral therapy og Graded exercise therapy) ikke har nogle positive langtidseffekter, og da heller

ikke anbefales internationalt som helbredende behandling for ME/CFS.

Afsluttende bemærkninger

På baggrund af ovenstående vurderer ME Foreningen, at vidensafdækningen ikke giver et retvisende

billede af den nuværende viden om ME/CFS. Vi finder det særlig problematisk, at vidensafdækningen

ikke udfordrer den danske tilgang til ME som en funktionel lidelse. Dette står i kontrast til internationale

standarder og risikerer at fastholde danske patienter i en uholdbar og effektløs behandlingssituation.

Det er vores håb, at denne tilbagemelding vil blive taget i betragtning i det fremtidige arbejde på

området, der bør omfatte etablering af en arbejdsgruppe med deltagelse af internationale ME-

eksperter således at danske ME/CFS-patienter kan få adgang til diagnose og behandling på linje med

patienter i andre lande. Til slut vil vi gerne henvise til vedhæftede diagnose- og behandlingsvejledning

udarbejdet af ME-ekspert Jesper Mehlsen (se bilag 3, obs. ikke offentliggjort endnu).

ME Foreningen står naturligvis fortsat til rådighed for dialog og vidensdeling, der kan bidrage til en

forbedret praksis fremover.

Med venlig hilsen

ME Foreningen samt medlemmer i ME foreningens Advisory Board (Bernard Jeune, Lektor emeritus,

Epidemiologi, Biostatistik og biodemografi (EBB), Jesper Mehlsen, Klinisk fysiolog

Peter la Cour, prof. Sundhedspsykolog og Vibeke Vind, senior scientist, biokemiker).

SUU, Alm.del - 2024-25 - Bilag 187: Henvendelse af 2/3-25 fra ME Foreningen om igangværende vidensafdækning af ME/CFS

Bilag 1

Opfølgning på ’Præsentation af foreløbige resultater fra vidensafdækningen

af ME/CFS’ afholdt i Sundhedsstyrelsen d. 22.11.24

På baggrund af mødet sender vi her en række bekymringspunkter, som også blev fremhævet ved

mødet. Vi håber meget, at I vil tage disse med i det videre arbejde med vidensafdækningerne, så

kvalitet og relevans sikres.

Vi er i særdeleshed bekymrede for de resultater, der blev præsenteret fra Implements afdækning af

erfaringer i relevante lande med organisering af behandlingstilbud samt diagnosticering og behandling

af ME/CFS. Afdækningen besvarer i sin nuværende form på ingen måde det grundspørgsmål, der blev

stillet, ligesom den heller ikke forholder sig kritisk til metode eller inkluderer den viden, der er

tilgængelig. Vi vil understrege, at den oprindelige opgave, der blev stillet af ministeren, var en

afdækning af ME – ikke af Funktionelle lidelser (FL):

”Der er afsat 1,5 millioner kroner i 2024 til en afdækning af evidensgrundlaget for diagnosticering og

behandling af lidelsen ME/CFS (Myalgisk Encephalomyelitis/Chronic Fatigue Syndrome).

Vidensafdækningen bør inddrage international forskning samt erfaringer i relevante lande. I

vidensafdækningen bør inddrages relevante aktører med faglig viden om ME/CFS.”

Dette understreges af ministerens udtalelse på samråd d. 28.11.23 fra Sophie Løhde (Minuttal: 39.40):

Samråd d. 28.11.23

”Funktionelle lidelser er ikke en del af den afdækning, som vi sætter i gang nu. Vi har afsat 1,5 mio. kr.

til vidensafdækning med henblik på at få afdækket evidensgrundlaget for diagnosticering og

behandling af ME og sørger dermed også for at få inddraget international forskning og erfaring fra andre

lande – og at der også inddrages relevante aktører i forbindelse med vidensafdækningen. Dette vil ske

under indkøb af en ekstern leverandør. Vidensafdækningen kommer til at være offentlig tilgængelig.”

Selvom I i Implement søger neutrale beskrivelser, så bør I som vidensorganisation ikke fravælge

hverken en kritisk beskrivelse og tilgang eller at gøre rede for mulige fremtidstendenser og

fremtidsscenarier. Det skal dertil siges, at vi fra ME-foreningen løbende har understøttet med relevant

litteratur og nyeste viden, fx fra de lande, der indgår i afdækningen. Vi fremsender gerne litteraturen

igen. Hvis dette ikke nuanceres, kan vi som forening kun tage afstand fra rapportens metode og

resultater – også offentligt.

Nedenfor følger en række yderligere punkter til hhv. Implements og Defactums præsentationer

samt opsummerende bemærkninger til Sundhedsstyrelsen.

Til Implements afdækning:

•

Afdækningen beskriver behandlingsforløb for en gruppe patienter, som givetvis ikke har ME, men

FL, da man ikke har forholdt sig til konsensuskriterierne for ME. Hvis der faktisk findes patienter

med ME i FL-gruppen, må de tilhøre den absolut lettest ramte del af ME-spektret, idet de ellers ikke

vil kunne klare de krævende gruppeforløb og transporten til og fra. Der mangler generelt klarhed

over, hvor mange ME-patienter der har en FL-diagnose eller er blevet diagnosticeret på FL-centre.

SUU, Alm.del - 2024-25 - Bilag 187: Henvendelse af 2/3-25 fra ME Foreningen om igangværende vidensafdækning af ME/CFS

•

Afdækningen må holde sig til beskrivelsen af forekomsten af WHO-diagnosekoden for ME og ikke

for FL. Når det drejer sig om beskrivelsen af FL, som selvfølgelig må inddrages, da ME pt. ligger

under disse, må det være for at afklare, hvilke af disse patienter der har ME. Hvis det ikke kan

afklares, må det beskrives, hvorfor det ikke kan opregnes. Landspatientregistrets registrering af

WHO-koden for ME må gennemgås (og gerne på hvilke afdelinger denne er registreret). Det bør

undersøges, hvor mange af de 15.000-20.000 ME-patienter i Danmark (ifølge prævalens) der har

ME-diagnosen, hvor de er i systemet, hvilke behandlinger de får, hvor mange der er syge og

sengeliggende, og hvor mange der er børn under 16 år. Ligesom Implement bør beskrive Mehlsen-

klinikkens ME-patientmateriale. Her findes oplysninger på ca. 1.200 patienter, der er

diagnosticeret regelret efter konsensuskriterierne.

Problematikken ift. de anvendte diagnosekoder kan yderligere udfoldes: Ifølge

diagnosevejledningen for FL kan danske læger stille diagnosen DG933A, men på FL-centrene er

ME diagnosen kun stillet fire gange, hvilket ligger meget langt fra prævalensen for ME (0,2-0,4%).

Det er 100% udtrykkeligt angivet af WHO at de danske FL-diagnoser ikke kan bruges til samkodning

med ME-diagnosen under multiple parenting

. I opgørelsen kan der derfor ikke pludselig

argumenteres for, at to FL-diagnoser i virkeligheden er ME DG933A. Ingen ved hvad de dækker over.

Kort sagt: Danske patienter fra FL-centre ved ikke, om de har ME, fordi FL-centrene ikke anvender

opdaterede diagnosekriterier med PEM for DG933A – og der kan derfor ikke interviewes mere end

fire patienter (i perioden frem til 10.05.2021) om ME i dette regi. Relevante patienter m.v. bør derfor

findes i andet regi.

Afdækningen bør inkludere og beskrive de sværest syge, herunder de permanent sengeliggende,

bl.a. ved at søge oplysninger om ME-patienter, som har fået førtidspension, evt. også ved at

inddrage avisartikler i BT, Se og Hør, lokale aviser m.fl. Disse er blandt andet også beskrevet her:

https://www.tandfonline.com/doi/full/10.1080/27707571.2024.2359958.

Afdækningen mangler (ud fra det vi fik præsenteret) status på curriculum om ME på medicin og

speciallægeuddannelsen; status på medicinsk behandling af generelle symptomer og af ME

specialiserede symptomer, og status på hvorvidt kurser i FL omfatter viden om ME med PEM.

Afdækningen bør inddrage den danske del af den europæiske interviewundersøgelser af over 500

danske patienter

https://www.europeanmealliance.org/documents/emeaeusurvey/EMEAMEsurveyreport2024.pdf

https://me-foreningen.dk/wp-content/uploads/2024/11/Paneuropaeisk-danske-tal.pdf

ligesom

der også er værdifuld viden i ME-Foreningens medlemsundersøgelser fra 2008, 2014 og 2019 (vi

stiller gerne data til rådighed,

https://me-foreningen.dk/wp-

content/uploads/2016/10/Sp%C3%B8rgeskemaunders%C3%B8gelse-2012-2.0-kopi.pdf,

https://me-foreningen.dk/wp-content/uploads/2020/06/Medlemssurvey-2019-561-patienter.pdf

Der findes også tilsvarende i de omkringliggende lande, ikke mindst den selvstændige norske

rapport af over 5000 norske ME-patienter.

Afdækningen af Tysklands tilgang bør inddrage den konsensusvejledning om diagnostik og

behandling af ME, som Tyskland har lavet i samarbejde med Østrig og Schweiz i maj 2024. Dette D-

A-CH Konsensus statement er grundlaget for det videre arbejde med ME i Tyskland.

https://link.springer.com/article/10.1007/s00508-024-02372-y

Som tidligere rejst, så er det meget beklageligt, at Implement ikke har kunnet få fat i relevante

kilder i UK. I den forbindelse blev en rapport fra 2023 om implementeringen af NICE2021 i UK

tilsendt, som der som minimum bør refereres til, da den giver svar på det meste om ME i UK efter

NICE2021.

SUU, Alm.del - 2024-25 - Bilag 187: Henvendelse af 2/3-25 fra ME Foreningen om igangværende vidensafdækning af ME/CFS

•

Endelig bør der også henvises til den nyligt publicerede embedslægerapport fra England om

forebyggelse af dødsfald ved ME

https://www.judiciary.uk/prevention-of-future-death-

reports/maeve-boothby-oneill-prevention-of-future-deaths-report/.

Det blev nævnt på mødet, at

der i Danmark er oprettet to højt specialiserede funktioner til de sygeste patienter, men det er

vigtigt at præcisere, at det er til patienter med funktionel lidelse uden specialiseret ME-behandling.

Ligesom I England har Danmark ikke en eneste sengeplads eller anden sundhedsydelse til

patienter med svær ME.

Til Defactums afdækning:

•

For at være sikker på, at den inkluderede målgruppe er korrekt, bør søgningen begrænses til

undersøgelser, der inddrager PEM.

•

Det er i orden at fokusere på systematiske reviews og klinisk kontrollerede forsøg, men

afdækningen må kritisk tage stilling til, hvad der ikke kan/bliver afklaret i disse typer studier. Fx de

mange epidemiologiske undersøgelser, som har sammenlignet hyppigheden på samme stikprøver

afhængigt af, hvilke diagnostiske kriterier man anvender. Dette bør inkluderes i en diskussion af

metoden, som er meget væsentlig.

Til Sundhedsstyrelsen:

•

Som det også blev fremhævet til mødet, vil vi meget gerne deltage i et opfølgende møde, hvor vi får

mulighed for at se Defactums resultater. Hvis dette ikke er muligt, vil vi meget gerne have

rapporten til kommentering. Det samme gælder for den færdige udgave af Implements rapport.

•

Vi håber (set i lyset af de mange kommentarer til afdækningerne og generel god skik), at I vil sende

begge rapporter i eksternt review blandt internationale ME-eksperter. Hvis det ikke er muligt at

oversætte rapporterne, bør de som minimum sendes til nordiske eksperter. Vi vil meget gerne

bidrage med forslag til specifikke personer.

•

Desuden vil vi meget gerne høre mere om processen efter rapporterne er afleveret til jer.

Nedsættes der fx en arbejdsgruppe med SST og eksterne ME-eksperter, der kan trække

konklusioner og evt. anbefalinger til Sundhedsministeren fra de to rapporter? Eller hvad vil

processen være? Dette stod ikke helt klart på mødet.

•

Endelig vil vi gerne høre, hvad processen er for de to leverandører: Vil de udgive rapporterne?

”Multiple parenting” er en paralelldiagnosticering som WHO kun anbefaler til 2 diagnoser som

supplerer hinanden. ME G93.3 og FL-diagnosen ”almen træthed” udelukker gensidigt hinanden og derfor er

”multiple parenting” ikke et begreb der kan anvendes her. Ifølge WHO må der ikke anvendes 2 koder for samme

sygdom/symptomer: Fx udelukker ME G93.3 – ifølge WHO - diagnoser som MG22 træthed og Neurasteni F48.

SUU, Alm.del - 2024-25 - Bilag 187: Henvendelse af 2/3-25 fra ME Foreningen om igangværende vidensafdækning af ME/CFS

Bilag 2

Opfølgning på mødet: Præsentation af foreløbige resultater fra

vidensafdækningen af ME/CFS gennemført af Defactum d. 04.02.24

Tak for at holde et opfølgende møde, hvor vi fik præsenteret de foreløbige resultater og fik mulighed for

at komme med vores input. Nedenfor følger en skriftlig tilbagemelding med en uddybning af de

punkter, der blev fremhævet på mødet, som vi håber, I vil inkludere i det videre arbejde. Som tidligere

fremført vil vi meget gerne gennemlæse rapporten og komme med skriftlige kommentarer hertil.

Basal viden om sygdommens karakter:

•

Der er en gennemgående og afgørende mangel på basal viden om sygdommen.

Hvis man

ønsker en hurtig og umiddelbar introduktion, kan man fx spørge OpenAI, som opsummerer det

meget fint. Se bilag 1 til dette dokument.

OpenAI’s rapport giver et solidt biokemisk og patofysiologisk grundlag for forståelsen af ME og

PEM. Det kunne være relevant for Sundhedsstyrelsen at læse denne opsummering

Som immunologen Derya Unutmaz fra Jackson Laboratory udtrykker det: OpenAI’s dybdegående

forskningsrapporter er “ekstremt imponerende, troværdige og på niveau med eller bedre end

publicerede review-artikler.”

Opgavens formål og resultater vedr. diagnose:

•

Opgaven gik ud på at belyse:”Hvilke

kliniske undersøgelser, parakliniske og diagnostiske test og

kriterier bør indgå ved mistanke om ME”.

Det blev bekræftet, at der ikke findes en simpel biomarkør til diagnosticering, hvilket også gør sig

gældende for mange andre sygdomme, hvor diagnosen stilles på baggrund af kliniske symptomer,

fx migræne.

•

Manglende inklusion/fokus på diagnosekriterier:

Det fremgik på mødet, at der i rapporten vil

foreligge en række forskellige diagnosekriterier, der bør indgå ved mistanke om ME, men det

fremgik ikke, hvad der vil blive oplyst om dem.

Diagnosekriterierne for ME/CFS har udviklet sig meget de sidste 25 år, idet de er gået fra at være

meget brede kriterier, der medtager træthed af mange typer og af mange årsager og har bevæget

sig frem til langt mere specifikke og dermed snævre kriterier. De internationale konsensuskriterier

(Carruthers et al 2011

) er formentlig det afgørende vendepunkt mellem de gamle og de nye

forståelser. Det er her, at PEM bliver et nødvendigt, men ikke tilstrækkeligt hovedsymptom for

https://www.nature.com/articles/d41586-025-00377-9;

https://x.com/DeryaTR_/status/1886487553387430396

Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus

criteria. J Intern Med. 2011;270(4): 327-38. PMID: 21777306.

SUU, Alm.del - 2024-25 - Bilag 187: Henvendelse af 2/3-25 fra ME Foreningen om igangværende vidensafdækning af ME/CFS

ME/CFS. Mayo-klinikkens diagnostiske procedurer for ME/CFS omtaler PEM som patognomonisk

symptom, dvs. både nødvendigt og tilstrækkelig

Der er meget store forskelle på de prævalenser, men kommer frem til ved anvendelse af brede og

specifikke kriterier. De anvendte diagnosekriterier er også af afgørende vigtighed for, hvilken gruppe

patienter man undersøger i forhold til behandlinger.

Ved alle andre sygdomme uden biomarkør findes der også en række kliniske kriterier for

sygdommen, fx for demens. Disse kriterier udvikler sig historisk og bliver i reglen mere og mere

specifikke for sygdommen og adskiller den fra andre. Der opstår i tiden konsensus om, hvilke

kriterier, der bør anvendes i forskningen om ME/CFS på nuværende tidspunkt, og kriterierne må

angives specifikt, idet forskning med et sæt kriterier ikke kan sammenlignes direkte med forskning

med andre kriterier.

Som det blev anført på mødet, viser de såkaldte ”cykeltests”, at der kan påvises klare biologiske

forskelle i energiforvaltningen hos patienter defineret nutidsvarende med ME/CFS og immobile

patienter, der lider af andre former for træthed, der kan indfanges af bredere definitioner. De

anvendte kriterier er derfor af yderste vigtighed omkring en nutidig beskrivelse af ME/CFS.

Rapporten bør indeholde en redegørelse for og overblik over udviklingen af (og diskussion om)

diagnosekriterierne for ME/CFS, hvilket er god videnskabelig praksis omkring kliniske

symptomdiagnoser.

•

Internationale diagnosekriterier:

Der findes forskellige international anerkendte diagnostiske

kriterier, som har udviklet sig over tid, hvor de nyeste alle indeholder symptomet PEM sammen

med en gruppe af andre symptomer. Vores nabolande, der diagnosticerer G93.3 anvender ofte

Canada-kriterierne. Da det er målbart, at patienter med PEM adskiller sig fra kontroller er det en

vigtig parameter. Hvis man anvender kriterier uden PEM fx Oxford eller de danske kriterier for

funktionelle lidelser, som ikke anvendes internationalt, risikerer man at diagnosticere en patient

med ME uden patienten har den sygdom. Det bør fremgå af rapporten

Opgavens formål og resultater vedr. behandling:

•

Opgaven gik ud på at belyse:

”Hvilken behandling farmakologisk og non-farmakologisk (herunder

pacing), der bør anvendes til voksne med ME”.

Graded exercise therapy (GET):

Dette afsnit hviler meget på Cochranes review, som i 2019 blev

vurderet til at være forældet

. Der står således i reviewet: “All studies were conducted with

outpatients diagnosed with 1994 criteria of the Centers for Disease Control and Prevention or the

Oxford criteria, or both. Patients diagnosed using other criteria may experience different effects”.

Reviewet er derfor ikke gældende i sin nuværende form for ME defineret med nyere diagnose-

•

Consensus recommendations (2021): Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of

Diagnosis and Management - Mayo Clinic Proceedings

Consice review for clinicians (2023):Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue

Syndrome

Publication of Cochrane Review: ‘Exercise therapy for chronic fatigue syndrome’ | Cochrane

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kriterier. Ydermere er reviewet kun gældende for ambulante patienter (outpatients) (mild ME), og

ikke for moderat, severe og very severe ME, der udgør mere end halvdelen af patientgruppen.

Det fremgik af Defactums præsentation at ”alvorlige bivirkninger er sjældne og ligeligt fordelt

mellem grupperne”, men der står i reviewet, at de er dårligt belyst ”the evidence regarding adverse

effects is uncertain”. Da dem, der får det dårligt af træning, er dem, som har PEM, kan man ikke

konkludere, at bivirkninger er sjældne. Dette bør tydeligt fremgå af rapporten.

•

Cognitive behavioral therapy (CBT):

I dette afsnit er der inkluderet et systematisk review, hvor der

står: “Most studies (k = 10) used the international definition criteria (Centers for Disease Control

and Prevention, [1]) for inclusion of CFS patients, while the other studies either used the Oxford

criteria ([22], k = 3), or cut-off values (k = 2)”. Sætningen fra Cochranes review om GET, må derfor

også gælde her:” Patients diagnosed using other criteria may experience different effects”.

Ydermere er nogle af studierne kun gældende for mild/moderat ME. Dette bør tydeligt fremgå af

rapporten.

Metodediskussion:

•

Manglende basal viden om sygdommens karakter – og betydning for udvælgelse af studier:

fik fra præsentationen det indtryk, at det basale overblik over, hvilken sygdom man har med at

gøre, ikke har været retningsgivende i udvælgelsen af hvilke artikler, man udvalgte at gå videre med

i opgavens anden del.

Manglende viden om, hvilke kriterier, der var givet for inklusion i de udvalgte undersøgelser:

Det fremgik af en slide i præsentationen, at der er gennemgået 8 studier, og at de 7 af disse studier

er foretaget før 2011, hvor konsensuskriterierne udkom – og det senere studie fra 2017 angiver, at

anvende helt brede, nu ud-daterede kriterier for CFS (ME er overhovedet ikke nævnt i studiet). Der

er altså anvendt kriterier, hvor PEM ikke er medtaget. Resultaterne fra disse studier kan derfor ikke

overføres til ME/CFS patienter. Det vil være en metodefejl at overføre resultater fra en

patientgruppe til en anden patientgruppe – og der må som minimum gøres ganske udtrykkeligt

opmærksom på dette forhold, hvilket vi også forventer, at det gøres i den endelige rapport. Andet

vil være videnskabeligt forkert.

Inklusion af svage studier:

Alle de enkelt-studier for GET og GBT, der indgår i de systematiske

reviews er meget svage (tæt på ikke-valide), da det er ikke-blindet studier med subjektive endemål.

PACE-studiet indgår i begge reviews, selvom det er fejlbehæftet. Det bør være den korrigerede

genberegning, der anvendes

. Dette bør også tydeligt fremgå af rapporten.

Manglende inklusion af europæiske) guidelines/HTA-rapporter:

I inklusionskriterier for begge

review står der, at (europæiske) guidelines/HTA rapporter fra større anerkendte institutioner

ønskes inddraget. Ud fra præsentationen så det ikke ud til, at disse er blevet inddraget. Der findes

•

Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent

major trial of graded exercise and CBT | BMC Psychology | Full Text

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for eksempel en europæisk NICE-guideline

og en amerikansk IOM-rapport

, der beskriver hvordan

ME diagnosticeres og tilgås med hensyn til behandling og pleje. Her fremgår det meget tydeligt, at

pacing ikke er en behandlingsform – det kan derfor ikke undersøges i RCT’er – men en måde at

undgå at udløse PEM og få forværring. Det fremgår også, at simpel symptomlindring er vigtig for at

bedre patienternes meget ringe livskvalitet. Dette tilbydes andre patientgrupper uden der skal

foreligge RCT’er, så det bør også gælde for ME-patientgruppen. Dette bør tydeligt fremgå af

rapporten.

•

General diskussion af metode:

Defactum bør som vidensorganisation ikke fravælge hverken en

kritisk stillingtagen til formål, metode og resultater – ej heller ikke selvom resultaterne bygger på et

systematisk review. Det er ikke tydeligt for os, hvordan det vil fremgå i rapporten.

Konsensusarbejde fra andre lande:

•

Opmærksomhed på den internationale konsensus på området:

Andre landes

sundhedsmyndigheder har, uafhængig af hinanden, konkluderet at ME er en kronisk,

multisystemisk sygdom: USA (2014), USA (2015), USA (2016), Nederlandene (2018), Belgien

(2020), Storbritannien (2021), USA (2023) og Tyskland (2023). Tyskland/Østrig/Schweitz (2024)

Dette bør som minimum indgå i baggrund eller diskussion.

Evidence reviews - October 2021 | Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome:

diagnosis and management | Guidance | NICE

Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness - PubMed

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Myalgic Encephalomyelitis (ME/CFS)

Pathobiology, diagnosis, and treatment

Jesper Mehlsen, MD

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

About the Author

Jesper Mehlsen is medical doctor graduated from the University of Copenhagen in

1979 and a specialist in Clinical Physiology. As such his primary clinical work and

research has been focused on complex medical conditions – in particular those that

involves dysfunction of the autonomic nervous system.

Jesper Mehlsen has worked clinically with patients suffering from myalgic

encephalomyelitis for more than 10 years and has diagnosed and treated more than

2,000 patients with this disease. Jesper Mehlsen is the current chairman of the

European ME Clinician’s Council.

Jesper Mehlsen has mor than 300 publications - 175 in peer reviewed medical and

technical journals. Jesper Mehlsen is co-chairing the European ME Research Group

and is co-chairing the ME/CFS Clinical Trial Working Group under the National

Institute of Health, USA.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Preface

The myalgic encephalomyelitis (ME) stems from Latin: myalgia i.e., pain in a muscle or groups of

muscles and

inflammation of the brain (encephalon) and the spinal cord (myelon). The diagnosis

was first use to describe a multiorgan disease epidemic at the Royal Free Hospital in London in an

editorial in the Lancet in 1956. An outbreak of a similar condition occurred in Nevada 1984 and

was given the more generalized term Chronic Fatigue Syndrome (CFS) by the Centre for Disease

Control in 1984 and hence the short form ME/CFS. The diagnosis of ME has been recognized by

WHO since 1969 and is - in the current disease classification - listed under the group of Postviral

and related fatigue syndromes with the specific code of G93.32.

ME/CFS is a disabling chronic inflammatory condition causing generalized symptoms affecting

multiple organ systems and leading to invalidity ranging from partial incapacitation in daily

activities to a severe condition in which the patient is bedridden, dependent on care 24/7 and

sometimes needing tube feeding. In the severe stage, the patient is hypersensitive to light and

sound, often unable to communicate in a normal fashion and has a very low stress level. Even

though ME/CFS is a life-long condition it is possible with the right care and treatment to achieve a

lower severity level over months to years.

Like in many diseases and illnesses, such as the common cold, migraine headaches, generalized

pain and others, ME/CFS lacks a single and accurate biomarker. Many countries have developed

guidelines for diagnosis, treatment, and care based on scientific evidence and achieved consensus.

In 2011 an international group of clinicians and researchers working with ME/CFS published a

consensus on a medical case definition for the diagnosis of ME/CFS. Quantitative support for the

diagnosis and for grading of severity can be obtained through validated questionnaires as well as

by testing physical and cognitive functions, and through laboratory analyses.

The contents of this expert report are based on clinical experience from more than 2,000 ME/CFS

patients combined with intensive studies of the vast literature on pathobiology and suggested

treatments in this group of patients.

Part 1 of the report is focused on diagnosis, probable causes, and background.

Part 2 of the report describes possible treatment options for mitochondrial dysfunction,

neuroinflammation, and autonomic dysfunction.

Frederiksberg February 2025

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Contents

Section 1: Diagnosis, Probable Causes & Background

1.1.

Diagnosis

1.1.1. Screening diagnosis for ME/CFS – Institute of Medicine Criteria

1.1.1.1. Diagnostic algorithm for ME/CFS

1.1.2. Final diagnosis for ME/CFS - International Consensus Criteria (ICC)

1.1.2.1. Checklist for diagnosing ME/CFS according to ICC.

p. 5

p. 6

p. 7

p.11

1.2.

Probable causes

1.2.1.

1.2.2.

Vira reactivation/infection

Neuroinflammation

p. 12

p. 14

1.3.

Fatigue

1.3.1.

1.3.2.

Mitochondrial dysfunction

Exercise intolerance and post exertional malaise

p. 16

p. 18

p. 20

1.4.

Quantifying disease impact

1.4.1.

Symptom-based questionnaires

p. 22

p. 23

p. 26

p. 27

p. 29

1.4.1.1. General health - SF 36

1.4.1.2. General health – EQ-5D-5L/3L

1.4.1.3. Functional capacity – FunCap

1.4.1.4. Fatigue questionnaires

1.4.1.5. Autonomic dysfunction – COMPASS31

1.4.2. Muscle strength and endurance - Hand-grip testing.

1.4.2.1. Autonomic function

1.4.2.2. Tilt-testing and Valsalva manoeuvre

1.4.2.3. Heart rate variability

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Section 2: Treatment

2.1. Mitochondrial dysfunction

2.1.1 Co-enzyme supplementation

2.1.2 Antioxidants

p. 30

p. 32

2. Neuroinflammation

2.1. Dietary supplements for neuroinflammation.

2.1.1. Palmitoylethanolamide

2.1.2. Pycnogenol

2.2. Treatment of neuroinflammation, medical treatment

2.2.1. Low dose Naltrexone (LDN)

P. 34

p. 34

p. 36

p. 38

3. Antiviral treatment

3.1. Valacyclovir

p. 40

4. Autonomic dysfunction

4.1. Postural tachycardia syndrome (POTS)

p.42

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Section 1

1. 1. Screening diagnosis – Institute of Medicine Criteria for ME/CFS

The Institute of Medicine (IOM) has proposed simplified criteria for the diagnosis of ME/CFS.

According to these criteria differential diagnoses should be excluded and the patients must have

the following three symptoms and at least one of two other manifestations.

A. A substantial reduction or impairment in the ability to engage in pre-illness levels of

activity (occupational, educational, social, or personal life) that:

a. lasts for more than 6 months,

b. is accompanied by fatigue that is:

i. often profound

ii. of new onset (not life-long)

iii. not the result of ongoing or unusual excessive exertion

iv. not substantially alleviated by rest

B. Post-exertional malaise (PEM) - worsening of symptoms after physical, mental, or

emotional exertion that would not have caused a problem before the illness. PEM often

puts the patient in a relapse that may last days, weeks, or even longer. For some patients,

sensory overload (light and sound) can induce PEM. The symptoms typically get worse 12

to 48 hours after the activity or exposure and can last for days or even weeks.

C. Unrefreshing sleep—patients with ME/CFS may not feel better or less tired even after a full

night of sleep despite the absence of specific objective sleep alterations.

At least one of the following

two additional manifestations

must also be present:

1. Cognitive impairment—patients have problems with thinking, memory, executive function,

and information processing, as well as attention deficit and impaired psychomotor

functions. All can be exacerbated by exertion, effort, prolonged upright posture, stress, or

time pressure, and may have serious consequences on a patient’s ability

to maintain a job

or attend school full time.

2. Orthostatic intolerance—patients develop a worsening of symptoms upon assuming and

maintaining upright posture as measured by objective heart rate and blood pressure

abnormalities during standing, bedside orthostatic vital signs, or head-up tilt testing.

Orthostatic symptoms including lightheadedness, fainting, increased fatigue, cognitive

worsening, headaches, or nausea are worsened with quiet upright posture (either standing

or sitting) during day-to-day life and are improved (though not necessarily fully resolved)

with lying down. Orthostatic intolerance is often the most bothersome manifestation of

ME/CFS among adolescents.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.1.1. Diagnostic algorithm for ME/CFS according to Institute of Medicine, USA

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.1.2 Final diagnosis for ME/CFS - International Consensus Criteria (ICC)

Differential diagnoses must have been excluded. Patients must – to receive the diagnosis of myalgic

encephalomyelitis - meet the criteria for post exertional malaise, and have:

A. at least one symptom from three neurological dysfunctions

B. at least one symptom from three immunologic/gastrointestinal/genitourinary change categories

C. at least one symptom from energy metabolism/mobility impairments.

Post-exertional Malaise (PEM): Mandatory

A pathological inability to produce sufficient energy as needed with prominent symptoms in the

neuroimmune areas.

Characteristics are as follows:

•

Pronounced, rapid physical and/or cognitive fatigue in response to exertion, which may be

minimal such as activities of daily living or simple mental tasks, may be disabling and cause

relapse.

•

Worsening of symptoms after exertion: e.g., acute flu-like symptoms, pain and worsening of other

symptoms.

•

Post-exertional fatigue can occur immediately after activity or be delayed by hours or days.

•

The refund period is extended and usually takes 24 hours or longer. A relapse can last days, weeks

or longer.

•

Low threshold for physical and mental fatigue (lack of endurance) results in a significant reduction

in activity level before illness.

Notes: To be diagnosed with ME, symptom severity must result in a significant reduction in a patient's

premorbid activity level.

• Mild (approx. 50% reduction in activity level before illness),

• Moderate (mostly at home),

• Severe (mostly bedridden) or

• Very severe (completely bedridden and needs help with basic functions).

There can be marked fluctuations in symptom severity and hierarchy from day to day or hour to hour.

Consider activity, context, and interactive effects.

Regardless of a patient's recovery time after reading for �½ hour, it will take much longer to recover

from grocery shopping for �½ hour and even longer if repeated the next day – if possible.

Those who rest before an activity or have adjusted their activity level to their limited energy may have

shorter recovery periods than those who do not pace their activities sufficiently.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Neurological disorders

At least one symptom from three of the following four symptom categories:

Cognitive dysfunction

•

Difficulty processing information: slowed thinking, reduced concentration, e.g., confusion,

disorientation, cognitive overload, difficulty making decisions, slowed speech, acquired or

effortful dyslexia.

•

Short-term memory loss: e.g., difficulty remembering what you wanted to say, what you said,

retrieving words, recalling information, poor working memory.

Pain

•

Headache: e.g., chronic, generalized headache often involves tenderness in the eyes, behind the

eyes, or in the back of the head that may be associated with cervical muscle tension; migraine;

tension headache.

Significant pain can be experienced in muscles, muscle-tendon connections, joints, abdomen, or

chest. It is non-inflammatory in nature and often migrates e.g., generalized hyperalgesia,

widespread pain (may meet fibromyalgia criteria), myofascial or radiating pain.

Disturbed sleep patterns: e.g., insomnia, prolonged sleep including naps, sleeping most of the

day and being awake most of the night, frequent awakenings, waking much earlier than before

onset of illness, vivid dreams/nightmares.

Unrefreshing sleep: e.g., waking up feeling exhausted regardless of the duration of sleep,

daytime sleepiness.

Neurosensory, perceptual, and motor disturbances

Neurosensory and perceptual: e.g., inability to focus vision, sensitivity to light, noise, vibration,

smell, taste, and touch; reduced depth perception.

Engine: e.g., muscle weakness, twitching, poor coordination, unsteadiness on the feet, ataxia.

Notes: Cognitive dysfunction - reported or observed - becomes more pronounced with fatigue.

Overload phenomena can be evident when two tasks are performed simultaneously. Abnormal

pupillary accommodative reactions are common.

Sleep disorders are typically manifested by prolonged sleep, sometimes extreme, in the acute

phase and often develop into significant sleep changes in the chronic phase.

Motor disturbances may not be evident in mild or moderate cases, but abnormal gait and

positive Romberg test may be observed in severe cases.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Immunological, gastrointestinal, and genitourinary changes

At least one symptom from three of the following five symptom categories

•

Flu-like symptoms may be recurrent or chronic and are typically activated or worsened by

exertion e.g., sore throat, sinusitis,

•

Cervical and/or axillary lymph nodes may be enlarged or tender with accompanying

palpitations.

•

Susceptibility to viral infections with extended recovery periods

•

Gastrointestinal tract: e.g., nausea, abdominal pain, bloating, irritable bowel syndrome

•

Genitourinary: e.g., frequent urge to urinate, incontinence or bladder emptying problem

•

Hypersensitivity to food, medicine, odors, or chemicals

Notes: Sore throat, tender lymph nodes, and flu-like symptoms are obviously not specific

to ME, but their activation in response to exertion is abnormal. The throat may feel sore,

dry and scratchy. Color changes can be seen in the tonsils, as an indication of immune

activation.

Energy production/mobility disorders

At least one symptom of the following:

•

Cardiovascular

Orthostatic intolerance,

neurally mediated hypotension,

Postural orthostatic tachycardia syndrome,

Palpitations with or without cardiac arrhythmias,

Dizziness

•

Respiratory:

air hunger,

labored breathing,

fatigue of the chest wall muscles.

•

Loss of thermostatic stability: e.g.

subnormal body temperature

significant daily fluctuations

Sweating episodes

Recurrent feeling of fever with or without low fever

Cold extremities.

Intolerance to extreme temperatures

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.1.2.1 Checklist for diagnosing ME/CFS according to ICC

At least 3 positive answers to questions 2-5, at least 3 positive answers to questions 6-10, at least 1

positive answer to questions 11-14

Symptom

1. PEM

2. Cognitive dysfunction

3. Pain

4. Sleep disturbances

5. Sensory/motor disturbances

6. Flu-like symptoms

7. Susceptibility to infections

8. Gastrointestinal problems

9. Bladder problems

10. Sensitivity

11. Cardiovascular disorders

12. Difficulty breathing

13. Temperature sensitivity

14. Difficulties in keeping warm

Yes

Uncertain

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.2.

Probable causes

1.2.1.

Viral activation/infection

The concept of ME/CFS as being caused by viral infections is strongly supported by a large

number of cases reported in outbreaks of probable viral origin, the most publicized being

outbreaks in Los Angeles

, Akureyri in Northern Iceland

, the Royal Free Hospital in

London

, Incline Village in Nevada

, and in Tapanui, New Zealand

Chronic symptoms following other acute infections are experienced by some patients.

These chronic symptoms resemble ME/CFS, and because of this, ME/CFS is probably a

chronic illness following an infection

. A prospective cohort study tracking 253 patients

from the time of acute infection with Epstein-Barr virus, Coxiella burnetii, or Ross River

virus found that 28 of the 253 participants met the diagnostic criteria for chronic fatigue

syndrome at six months

. The phenotype was stereotyped and occurred at a similar

incidence after each infection. The syndrome was predicted largely by the severity of the

acute illness rather than demographic, psychological, or microbiological factors

In a prospectively recruited cohort of 4,501 college students, 238 developed infectious

mononucleosis (IM) and were followed up at six months to determine whether they

recovered or met the criteria for ME/CFS

. Those who developed ME/CFS did not have any

significant baseline differences in stress, coping, anxiety, or depression, but before IM, they

had several cytokine markers that were significantly different from those who did not

develop ME/CFS

ME/CFS following IM is a severely debilitating disease in adolescents, and although the

prognosis seems better than in adults, their condition can fluctuate and significantly impact

their health-related quality of life

In a cohort of 280 adults with COVID-19, it was observed that fatigue and neurocognitive

dysfunction at a median of four months following initial diagnosis were independently

associated with serological evidence suggesting recent EBV reactivation

. The study

concluded that their findings suggest differential effects of chronic viral coinfections on the

likelihood of developing long COVID

Even though EBV is the primary suspect in ME/CFS, others have pointed to the enterovirus

family as being the main cause of ME/CFS

. During the polio epidemic from 1934 to 1935

60 times as many hospital employees working with polio patients developed a condition

with a cluster of symptoms including pain, fever, headache, nausea, sensory disturbances,

constipation or diarrhoea, vertigo, photophobia, and double vision. Patients also

experienced fatigue when walking short distances, loss of concentration, lapses of memory,

and sleep disturbances, very similar to symptoms reported by patients with ME/CFS; 55%

of the staff were still off duty six months after the peak of the epidemic

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

References for viral activation.

Gilliam AG. Epidemiological study of an epidemic, diagnosed as poliomyelitis, occurring

among the personnel of the Los Angeles County General Hospital during the summer of

1934.

Public Health Bull.

1938, 130:231–40.

2. Sigurdsson B. Clinical findings six years after outbreak of Akureyri disease.

Lancet.

(1956)

270:766–7. doi: 10.1016/S0140-6736(56)91236-3

3. Staff M. An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in

1955.

Br Med J.

(1957) 2:895–904. doi: 10.1136/bmj.2.5050.895

4. Levine PH, Jacobson S, Pocinki AG, Cheney P, Peterson D, Connelly RR, et al. Clinical,

epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome.

Arch

Intern Med.

(1992) 152:1611–6

5. Levine PH, Snow PG, Ranum BA, Paul C, Holmes MJ. Epidemic neuromyasthenia and chronic

fatigue syndrome in west Otago, New Zealand. A 10-year follow-up.

Arch Intern Med.

(1997)

157:750–4.

6. https://www.cdc.gov/me-cfs/causes/index.html#:~:text=injury%2C%20and%20genetics.-

,Infections,an%20illness%20like%20ME%2FCFS.

7. Hickie I, Davenport T, Wakefield D, et al. Dubbo Infection Outcomes Study Group. Post-

infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens:

prospective cohort study. BMJ. 2006, 333: 575.

8. Jason LA, Cotler J, Islam MF, et al. Risks for developing ME/CFS in college students following

Infectious Mononucleosis: A prospective cohort study. Clin Infect Dis 2021; 73(11): e3740–

e3746.

9. Pricoco R, Meidel P, Hofberger T, et al. One-year follow-up of young people with ME/CFS

following infectious mononucleosis by Epstein-Barr virus. Frontiers in Pediatrics 2024, 11,

DOI=10.3389/fped.2023.1266738

10.

Peluso MJ, Deveau T-M, Munter SE, et al. Chronic viral coinfections differentially affect the

likelihood of developing long COVID.

J Clin Invest. 2023,

133:

e163669.

11. Hanson MR. The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome. PLoS

Pathog. 2023 Aug 17;19(8):e1011523.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.2.2 Neuroinflammation

Neuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome

(ME/CFS) affecting 85-90% of all patients yet the underlying mechanism(s) responsible for the

initiation and/or promotion of this process is largely unknown. It has been hypothesised to be the

central cause of ME/CFS due to failure of the normal function of neuroglia

. An animal study has

suggested that a protein secreted by herpes virus 4 (Epstein-Barr virus) can change the blood brain

barrier and thus initiate the neuroinflammatory reaction

Following the initial stressor event i.e., a

viral infection, the inflammatory response moves to the brain through neurovascular pathways or

the dysfunctional blood-brain barrier in the central regions of the brain (paraventricular nuclei and

hypothalamus. This elicits a chronic neuroinflammation leading to a sustained illness with chronic

relapse/recovery cycles

. This could help explain the widespread pathophysiology of ME/CFS, the

involvement of the hypothalamic/pituitary/adrenal axis

, the autonomic nervous system, and the

sensitivity normal life stressors of physical, cognitive, psychological, emotional, and environmental

origin. The hypothalamus connects the nervous system to the endocrine system, regulating both

the HPA axis and homeostatic control of body temperature, fatigue, sleep, and circadian rhythms-

all disturbed in ME/CFS.

The CNS is supported by glia cells (“glue” in Greek) that make up

half the volume of neural tissue

and includes

microglia astrocytes, oligodendrocytes,

and

ependymal cells. Under physiological

conditions, microglia play a role in development and maturation of the CNS and subsequently

serve in immune surveillance as the resting phenotype. The

microglia

can release pro-

inflammatory cytokines, reactive oxygen, and nitrogen species as well as other chemokines in

response to pathogens and/or damage associate debris as they change to

a proinflammatory

phenotype. If overactivated microglia may lead to a neuroinflammatory cascade and may interfere

with nerve repair

5,6

Activated microglia will activate astrocytes and cause these cells to secrete proinflammatory

chemokines associated with a loss in neuronal survival and function. Astrocytes also signal the

endothelial cells of the brain vasculature resulting in further disruption of the blood-brain barrier,

increasing perfusion and facilitating immigration of blood immune cells

Over time, the phenotype of microglia and astrocytes changes to an anti-inflammatory form - M2

and A2 respectively

. By virtue of the immune and glial cells’ ability to influence the activity of

other neuroglial cells, effects thereof can be conveyed to distant parts of the brain

. On the

functional level, CNS inflammation has been associated with cytokine-mediated sickness

behaviour

, excitotoxicity (Dong

et al., 2009)

and dysfunctional connectivity within the brain

(notably due to synaptic loss and demyelination) (Rao

et al., 2012)

that leads to CNS dysfunction

affecting sleep.

Magnetic resonance spectroscopi has shown metabolic abnormality in different brain areas in

MECFS (see reference 11 for full information). Newer diagnostic imaging modalities have been able

to demonstrate changes compatible with neuro-inflammation in ME/CFS. Nakatomi compared PET

scanning of the brain in nine patients with ME/CFS and 10 healthy controls

. They used a

C-

labelled translocator protein analogue and found

widespread accumulation in brain areas in

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

ME/CFS patients, and the level of the inflammatory marker was associated with the severity of

neuropsychologic symptoms

. Mueller et al used magnetic resonance spectroscopy to show that

ME/CFS patients had increased temperature in several brain regions, which was not attributable to

increased body temperature or differences in cerebral perfusion

. They found correlation between

the brain temperature and metabolic signs of inflammation

References for Neuroinflammation

Renz-Polster H, Tremblay ME, Bienzle D, Fischer JE. The Pathobiology of Myalgic

Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. Front Cell Neurosci.

2022, 16: 888232.

Williams MV, Cox B, Lafuse WP, Ariza ME. Epstein-Barr Virus dUTPase Induces Neuroinflammatory

Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clin Ther. 2019, 41:

848-63.

3. Tate W, Walker M, Sweetman E, et al. Molecular Mechanisms of Neuroinflammation in ME/CFS and

Long COVID to Sustain Disease and Promote Relapses. Front Neurol. 2022, 13: 877772.

Stanculescu D, Bergquist J. Perspective: Drawing on Findings From Critical Illness to Explain Myalgic

Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne). 2022, 9:818728

5. Wanga J, Heb W, Zhanga J. A richer and more diverse future for microglia phenotypes. 2023 Heliyon 9,

e14713.

Liddelow, S., Guttenplan, K., Clarke, L., et al. Neurotoxic reactive astrocytes are induced by activated

microglia. Nature 2017, 541: 481–87.

Olofsson PS, Rosas-Ballina M, Levine YA, Tracey KJ. Rethinking inflammation: neural circuits in the

regulation of immunity. Immunol Rev. 2012, 248: 188-204.

Norden DM, Trojanowski PJ, Villanueva E, et al. Sequential activation of microglia and astrocyte

cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune

challenge. Glia. 2016, 64: 300-16.

Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am. 2009, 29:

247-64.

10. Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in Patients with Chronic Fatigue

Syndrome/Myalgic Encephalomyelitis: An

C-(R)-PK11195 PET Study. J Nuclear Med 2014, 55:

945-

950.

11.

Mueller C, Lin JC, Sheriff S, et al. Evidence of widespread metabolite abnormalities in Myalgic

encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance

spectroscopy. Brain Imaging Behav. 2020, 14: 562-72

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1.3 Fatigue

Intractable or chronic fatigue lasting more than 6 months, unrelieved by sleep, is the most

common complaint in patients seeking medical attention

1-4

. It occurs naturally during aging and is

also an important secondary condition in many clinical diagnoses. The phenomenon of fatigue

(fatigue) has been defined as a multidimensional sensation, and attempts have been made to

determine possible causes of fatigue

5-10

. Most patients understand fatigue as a loss of energy and

the inability to perform even simple tasks without effort. Many medical conditions are associated

with fatigue, including lung, cardiovascular, musculoskeletal, and gastrointestinal diseases as well

as infections and cancer

5-10

Fatigue is related to reduction in the efficiency of cellular energy systems found primarily in

mitochondria. Damage to mitochondrial components, mainly by oxidation, can impair their ability

to produce high-energy molecules such as ATP and NADH. This occurs naturally with aging

9-10

and

during chronic diseases, where the production of reactive oxygen species (ROS) can cause oxidative

stress and cellular damage, resulting in oxidation of lipids, proteins, and DNA

7-12

. Upon oxidation,

these molecules change structurally and sometimes functionally. Important targets for ROS

damage are the phospholipid-containing membranes of mitochondria as well as mitochondrial

DNA

In patients with chronic fatigue syndrome, there is evidence of oxidative damage to DNA and

lipids

10,11

as well as the presence of oxidized blood markers, such as methemoglobin, indicating

excess oxidative stress

. In addition, oxidative damage to DNA and membrane lipids has been

found in muscle biopsy samples from patients with chronic fatigue syndrome

. These authors also

found increases in antioxidant enzymes, such as glutathione peroxidase, suggesting that this was

an attempt to compensate for excess oxidative stress

. Chronic fatigue syndrome patients have

persistently elevated levels of peroxynitrite due to excess nitric oxide, and this has been suggested

to result in lipid peroxidation and loss of mitochondrial function, as well as changes in cytokine

levels that exert a positive feedback on nitric oxide production In addition to mitochondrial

membranes, mitochondrial enzymes are also inactivated by peroxynitrite, and this may contribute

to loss of mitochondrial function

15,16

. Finally, although there are cellular molecules that counteract

the excess oxidative capacity of ROS, such as glutathione and cysteine, these are found at lower

levels in patients with ME/CFS

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

References for Fatigue

10.

11.

12.

Kroenke K, Wood DR, Mangelsdorff AD, et al: Chronic fatigue in primary care. Prevalence,

patient characteristics, and outcome. JAMA 260: 929-934, 1988.

Morrison JD: Fatigue as a presenting complaint in family practice. J Family Pract 10: 795-801,

1980.

McDonald E, David AS, Pelosi AJ, Mann AH: Chronic fatigue in primary care attendees. Psychol

Med 23:987-998, 1993.

Nicolson GL: Lipid replacement as an adjunct to therapy for chronic fatigue, anti-aging and

restoration of mitochondrial function. J Am Nutraceut Assoc 6: 22-28, 2003.

Huang H, Manton KG: The role of oxidative damage in aging: a review. Front Biosci 9: 1100-

1117, 2004.

Richter C, Par JW, Ames B: Normal oxidative damage to mitochondrial and nuclear DNA is

extensive. Proc Natl Acad Sci USA 85: 6465-6467, 1998.

Wei YH, Lee HC: Oxidative stress, mitochondrial DNA mutation and impairment of antioxidant

enzymes in aging. Exp Biol Med 227: 671-682, 2002.

Harman D: Aging: A theory based on free radical and radiationchemistry. J Gerontol 2: 298-

300, 1956.

Halliwell B: Role of free radicals in the neurodegenerative diseases: therapeutic implications

for antioxidant treatment. Drugs Aging 18: 685-716, 2001.

Logan AC, Wong C: Chronic fatigue syndrome: oxidative stress and dietary modifications.

Altern Med Rev 6: 450-459, 2001.

Manuel y Keenoy B, Moorkens G, Vertommen J, et al: Antioxidant status and lipoprotein

peroxidation in chronic fatigue syndrome. Life Sci 68: 2037-2049, 2001.

Richards RS, Roberts TK, McGregor NR, et al: Blood parameters indicative of oxidative stress

are associated with symptom expression in chronic fatigue syndrome. Redox Rep 5: 35-41,

2000.

Felle S, Mecocci P, Fano G, et al: Specific oxidative alterations in vastus lateralis muscle of

patients with the diagnosis of chronic fatigue syndrome. Free Radical Biol Med 29: 1252- 1259,

2000.

Pall ML: Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med

Hypotheses 54: 115-125, 2000

Castro L, Rodriguez M, Radi R: Aconitase is readily inactivated by peroxynitrite, but not by its

precursor, nitric oxide. J Biol Chem 269: 29409-29415, 1994.

Radi R, Rodriguez M, Castro L, Telleri R: Inhibition of mitochondrial electronic transport by

peroxynitrite. Arch Biochem Biophys 308: 89-95, 1994.

Manuel y Keenoy B, Moorkens G, Vertommen J, et al: Magnesium status and parameters of the

oxidant-antioxidant balance in patients with chronic fatigue: effects of supple- mentation with

magnesium. J Am Coll Nutr 19: 374-382, 2000.

Nicolson GL, Ellithorpe R: Lipid replacement and antioxidant nutritional therapy for restoring

mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing

illnesses. J Chronic Fatigue Syndr,

2016 Feb 18;4(1):e54.

Nicolson GL. Lipid Replacement/Antioxidant Therapy as an Adjunct Supplement to Reduce the

Adverse Effects of Cancer Therapy and Restore Mitochondrial Function. Pathology oncology

research 2005 11: 139-44

13.

14.

15.

16.

17.

18.

19.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.3.1 Mitochondrial dysfunction

Metabolic studies indicate differences between ME/CFS patients and healthy controls, with the

most consistent findings being in cellular energy generation and oxidative and nitrosative stress

Increased mitochondrial damage, reductions in ATP production and impaired oxidative

phosphorylation all point to ME/CFS potentially being a mitochondrial disease. According to

Naviaux et al

, many of the pathways and metabolites that have been found abnormal in ME/CFS

are like those of “dauer” (German for

persistence),

a well-studied, hypometabolic state comparable

to hibernation that permits survival and persistence under conditions of environmental stress but

at the cost of severely curtailed function and quality of life.

The main abnormality in mitochondrial function in ME/CFS seems to be a shift in fuel utilization by

reduction in carbohydrate oxidation and a reliance on fat combustion. Like in hibernating animals

this seems primarily mediated by an upregulation of several pyruvate dehydrogenase kinases with

an impairment of the pyruvate dehydrogenase complex

. Others have pointed to impairments in

glycolysis in addition to mitochondrial function with lower rates of ATP production across the

board

. Based on measurements of ATP production by peripheral blood mononuclear cells

(PBMCs) in the presence of different concentrations of glucose, it has been speculated that

ME/CFS may reduce cellular competency in adapting to changing energetic demands, which would

be consistent with an inability to ramp up ATP production upon exertion. A potential molecular

explanation for this deficiency was provided by Missailidis et al. who identified potential defects in

mitochondrial complex V (ATP synthase) from an analysis of mitochondrial function in

immortalized lymphoblasts generated from 51 ME/CFS patients

PDK4 (pyruvate dehydrogenase kinase isoform 4) is expressed ubiquitously in the mitochondrion

matrix of tissues with highest expression seen in liver, heart and skeletal muscles. PDK4 is regulated by

glucocorticoids, retinoic acid and insulin, and is found elevated with diabetes, fasting and other

conditions where fatty acids act as energy source. PDK4 inhibits the mitochondrial pyruvate

dehydrogenase complex (PDC) thus contributing to glucose metabolism regulation. Insulin resistance is

associated with PDC dysregulation in skeletal muscles and excessive insulin on the other hand

downregulates PDK4 expression. PDK4 exerts conservation of glucose as well as three-carbon

compounds such as lactate, alanine, pyruvate etc. which serve as substrates for gluconeogenesis and

this conservation helps maintain euglycemia during starvation, however, exacerbates hyperglycemia in

diabetes.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

References - Mitochondrial dysfunction

1. Morris G, Maes M. Mitochondrial dysfunctions in Myalgic Encephalomyelitis/chronic fatigue

syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways.

Metab. Brain Dis., 29 (2014), pp. 19-36.

2. Naviaux RK, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S

A, 113 (2016), pp. E5472-5480

3. Fluge O, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic

encephalopathy/chronic fatigue syndrome. JCI Insight, 1 (2016), p. e89376

4. C. Tomas JL, et al. The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

severity on cellular bioenergetic function. PLoS One, 15 (2020), Article

5. D. Missailidis SJ et al. An isolated complex V inefficiency and dysregulated mitochondrial function in

immortalized lymphocytes from ME/CFS-patients. Int. J. Mol. Sci., 21 (2020).

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.3.2 Exercise intolerance and post exertional malaise.

Exercise intolerance

It is often claimed that exertional intolerance in ME/CFS mainly results from deconditioning. In line

with that, some clinicians think that graded exercise can help exercise intolerance in ME/CFS.

However, aerobic capacity is lower in ME/CFS patients than in sedentary control subjects

and it

has been demonstrated that ME/CFS patients present clinically significant decrease in peak

maximal oxygen uptake only on day 2 of exercise testing

. Lien et al

showed that lactate

production per workload was significantly higher in ME/CFS and that the difference was greater on

day 2 of the exercise test

. The response to a two-day exercise testing differs significantly between

patients with idiopathic chronic fatigue and those with ME/CFS with the first group improving and

latter group deteriorating on the second day of testing

. Deconditioning in otherwise healthy

subjects is characterized by low cardiac output at peak exercise4 but the study by Joseph P et al

found increased cardiac output in ME/CFS patients. They also noted low cardiac filling pressures in

ME/CFS rather than the higher pressures seen in detrained individuals. A recent, deep phenotyping

study

found previously undescribed dysfunction of brain regions that drive the motor cortex

abnormality apparently impeding the voluntary muscle performance.

Even though deconditioning cannot explain exertional intolerance in ME/CFS, it is important to

prevent secondary deconditioning by encouraging fitness with a careful, individualised exercise

program to help compensate for disease-associated cardiovascular limitations.

Post exertional malaise.

Exertion-induced aggravation of symptoms generally called post-exertional malaise (PEM) is the

hallmark of ME/CFS and often described by the patients as a “crash”. PEM is a delayed worsening

of any or all ME/CFS symptoms irrespective of whether the exertion is physical, social, mental, or a

combination. Focussing on PEM in the clinical situation has significant importance for the outcome

in ME/CFS patients. Cross-sectional surveys covering specialist healthcare services for ME/CFS

patients in Norway found that PEM was infrequently addressed and that failure to address PEM

roughly doubled the risk of health deterioration, following rehabilitation

A study on lactate levels in ME/CFS and healthy controls

indicates that previous exercise increases

lactate accumulation in ME/CFS as opposed to the reduction seen in healthy controls

. This could

be one of the mechanisms responsible for PEM and if repeated could cause inflammation and

myopathy. It has been found that elevated blood lactate in the resting condition correlates with

PEM in ME/CFS

A study in Long-COVID-patients fulfilling the main ME/CFS criterion of PEM has

shown that local and systemic metabolic disturbances, severe exercise-induced myopathy,

infiltration of amyloid-containing deposits, and immune cells in skeletal muscles were key

characteristics PEM which further underlines the importance of limited exercise programs to avoid

such pathological and perhaps long-term deterioration of physical function in both ME/CFS and

Long-COVID

Characterizing the nature of post-exertional symptom exacerbation is important for developing

and evaluating rehabilitation strategies, including the potential benefits or harms of exercise for

persons living with ME/CFS. A study by Davenport TE et al

indicate clinicians only need to focus

on the presence and duration of just a few symptom categories and prolonged duration to identify

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

its existence. According to that study, inquiring about post-exertional cognitive dysfunction,

decline in function, and lack of positive feelings/mood may help identify PEM quickly and

accurately. A newly developed questionnaire addresses the consequences of exertion in ME/CFS

the premise being that ME/CFS patients can cope with various forms of exertion but at the cost of

deterioration in their health for days to months and perhaps even permanently.

References for Exercise intolerance and post-exertional malaise

10.

11.

12.

Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome

patients to reproduce VO

peak indicates functional impairment. J Transl Med. 2014; 12:104.

Lien K, Johansen B, Veierød MB, et al. Abnormal blood lactate accumulation during repeated

exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2019

Jun;7(11):e14138.

van Campen CLMC, Visser FC. Comparing Idiopathic Chronic Fatigue and Myalgic

Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day

Cardiopulmonary Exercise Testing Protocol. Healthcare (Basel). 2021 9(6):683.

Saltin B, Blomqvist G, Mitchell JH, Johnson RL Jr, Wildenthal K, Chapman CB. Response to exercise

after bed rest and after training. Circulation. 1968;38(5 Suppl):VII1-VII78.

Joseph P, Arevalo C, Oliveira RKF, Faria-Urbina M, Felsenstein D, Oaklander AL, Systrom DM. Insights

From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic

Fatigue Syndrome. Chest. 2021; 160: 642-651.

Walitt, B., Singh, K., LaMunion, S.R. et al. Deep phenotyping of post-infectious myalgic

encephalomyelitis/chronic fatigue syndrome. Nat Commun 2024, 15: 907.

Wormgoor MEA and Rodenburg SC (2023) Focus on post-exertional malaise when approaching

ME/CFS in specialist healthcare improves satisfaction and reduces deterioration. Front. Neurol.

14:1247698

Lien K, Johansen B, Veierød MB, et al. Abnormal blood lactate accumulation during repeated exercise

testing in myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2019 Jun;7(11):e14138.

Ghali A, Lacout C, Ghali M, et al. Elevated blood lactate in resting conditions correlate with post-

exertional malaise severity in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Sci

Rep. 2019 Dec 11;9(1):18817.

Appelman B, Charlton RT, Goulding RP, et al. Muscle abnormalities worsen after post-exertional

malaise in long COVID. Nature Communications 2024 15: 17

Davenport TE, Chu L, Stevens SR, et al. Two symptoms can accurately identify post-exertional malaise

in myalgic encephalomyelitis/chronic fatigue syndrome. Work. 2023;74(4):1199-1213.)

Sommerfelt, K.; Schei, T.; Seton, K.A.; Carding, S.R. Assessing Functional Capacity in ME/CFS: A

Patient Informed Questionnaire. Preprints 2023, 2023092091.

https://doi.org/10.20944/preprints202309.2091.v1

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

1.4

Quantifying disease impact

1.4.1. Symptom-based questionnaires

1.4.1.1. General health - SF 36

Short Form 36-Item Health Survey or SF-36 is a patient-reported health measure that

assesses health-related quality of life in 8 areas: 1) limitations in physical activities

because of health problems; 2) limitations in social activities because of physical or

emotional problems; 3) limitations in usual role activities because of physical health

problems; 4) bodily pain; 5) general mental health; 6) limitations in usual role activities

because of emotional problems; 7) vitality (energy and fatigue); and 8) general health

perceptions. A score of zero represents completely disability, and a score of 100 no

disability. It is available in many languages including Danish with Danish normative

data.

A study including 289 ME/CFS patients diagnose with ME/CFS using the International

Consensus Criteria (ICC) and quantified disease impact by SF36, mean number of steps

per day, and estimated maximal oxygen consumption. They concluded that using these

methods of quantification made the disease impact more comprehensible for the

patient and his/her caretakers, treating physicians and authorities

1.4.1.2. General Health - EQ-5D-5L/3L

EQ-5D-5L or 3L is a standardised measure of health-related quality of life developed by

the EuroQol Group

and assesses health status in terms of five: 1) mobility; 2) self-care;

3) usual activities; 4) pain/discomfort; and 5) anxiety/-depression dimensions. The

questionnaire is available in Danish and was used in study of ME/CFS-patients in

Denmark

. Results from the questionnaire was compared to a large Danish study

(177,639 included) of health- related quality of life in the general population i.e. both

healthy subjects and people with various diseases

. The study concluded that the

health-related quality of life in patients with ME/CFS is significantly lower than the

population mean and the lowest of all the compared other diseases

. The adjusted

analysis confirms that poor quality of life is distinctly different from and not a proxy of

the other included conditions.

A multinational study to assess the impact on the quality of life (QoL) of people with

ME/CFS 2022

. The study included 1,418 people with ME/CFS and their 1,418 family

members/partner from 30 countries.

Impact on quality of life was significantly correlated between those with ME/CFS and

their family member. Family members were most impacted emotionally by worry,

frustration and sadness and personally by family activities, holidays, sex life and

finances

Almost all ME/CFS participants (1,397) had problems performing their usual activities

and more than half were unable to perform usual activities at all. Almost 94%

experienced pain and discomfort and in one-third, pain and discomfort was classified

as extreme. Mobility was affected in 89%, with participants experiencing some

problems (1,063) with walking or were confined to bed (193). In terms of self- care,

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

67% had some problems or were unable to wash or dress themselves. Anxiety and

depression were the least affected dimension, 576 participants were not anxious or

depressed at all, while 678 were either moderately and 164 were extremely anxious or

depressed

. The authors concluded that despite the limitations of selection bias in

open participation surveys, this research has revealed the significant worldwide burden

of ME/CFS on the quality of life of people with ME/CFS and on their family members

1.4.1.3 Functional capacity - FUNCAP

FUNCAP (FC), is a questionnaire primarily developed to accurately assess FC in ME/CFS

patients

. The questionnaire consists of eight domains divided by activity types: A)

personal hygiene/basic functions, B) walking/movement, C) being upright, D. activities

in the home, E) communication, F) activities outside the home, G) reactions to light and

sound, and H) concentration. A Danish translation is in progress.

Initial testing in 1263 Norwegian and 1387 English-speaking patients showed FUNCAP

to be a reliable and valid tool for assessing functional capacity in ME/CFS patients.

1.4.1.4 Fatigue questionnaires

Fatigue Severity Scale

There has been limited research comparing the efficacy of different fatigue rating

scales for use with individuals with ME/CFS, but the Fatigue Scale and the Fatigue

Severity Scale (FASS)

have commonly been used as a measure of the severity of

specific fatigue-related symptoms, and to assess functional outcomes related to

fatigue, respectively

. A comparison between the scales in an ME/CFS-population

found FSS to be more accurate and comprehensive measure of fatigue-related severity,

symptomatology, and functional disability

and a study by the same group found that

FSS had the best ability to differentiate ME/CFS from healthy controls

. Fatigue severity

scale has been validated in Danish

Chalder Fatigue Questionnaire (CFQ)

was developed to measure severity of fatigue

illnesses and has been used in to study the effect of ME/CFS such as the disputed PACE-

trial

. In a recent study in a small group of ME/CFS-patients

, CFQ was described as

consisting of one item clearly related to physical symptoms, four items clearly related

to cognitive function, and one item relating to fatigue which could be interpreted as

cognitive and/or physical fatigue. According to participants, the remaining five

questions lacked clarity, were relating to behaviour not symptoms, or relating to

sleepiness not fatigue. The CFQ has not been accepted as a tool for research use by the

US National Institute of Neurologic Diseases and Stroke

1.4.1.5 Autonomic dysfunction – COMPASS31.

The Composite Autonomic Symptom Score (COMPASS 31) is a validated self-

assessment questionnaire quantifying the severity and distribution of autonomic

symptoms across six domains (orthostatic intolerance, vasomotor, secretomotor,

gastrointestinal, bladder and pupillomotor functions) by scoring 31 clinically selected

questions

. It was developed to detect and quantify the degree of autonomic failure, to

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

monitor disease progression and to evaluate response to treatment. The total score of

the COMPASS 31 questionnaire ranges 0-100 with higher values mirroring more severe

symptoms of autonomic dysfunction

The COMPASS 31 questionnaire has been extensively validated in different patient

categories and in healthy subjects. A study comparing COMPASS31 in ME/CFS-patients

to healthy controls showed that a cut off level in total score of 32.5 was a diagnostic

criterion for autonomic dysfunction in CFS patients15. There is some skewing in the

number of questions with few addressing orthostatic intolerance and tree times as

many focussing on gastrointestinal problems. The National Institute of Neurological

Disorders and Stroke rates COMPASS31 as” highly recommended in ME/CFS”

but the

shortcomings in orthostatic symptoms seem to require further testing. COMPASS31 has

been translated and validated in Danish

References on Symptom-based questionnaires

van Campen CLMC, Rowe PC, Visser FC. Validation of the Severity of Myalgic Encephalomyelitis/-

Chronic Fatigue Syndrome by Other Measures than History: Activity Bracelet, Cardiopulmonary

Exercise Testing and a Validated Activity Questionnaire: SF-36. Healthcare (Basel). 2020, 8:273

https://euroqol.org/

Falk Hvidberg M, Brinth LS, Olesen AV, et al. The Health-Related Quality of Life for Patients with

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/ CFS). PLoS ONE 2015, 10: e0132421

Christensen AI, Ekholm O, Glümer C, et al. The Danish National Health Survey 2010. Study design and

respondent characteristics. Scand J Public Health. 2012; 40: 391

Vyas J, Muirhead N, Singh R, et al. Impact of myalgic encephalomyelitis/ chronic fatigue syndrome

(ME/CFS) on the quality of life of people with ME/CFS and their partners and family members: an

online cross- sectional survey. BMJ Open 2022, 12: e058128. doi:10.1136/ bmjopen-2021-058128

Sommerfelt K, Schei T, Seton KA, Carding SR. Assessing Functional Capacity in Myalgic

Encephalopathy/Chronic Fatigue Syndrome: A Patient-Informed Questionnaire. J Clin Med. 2024 Jun

14;13(12):3486.

Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale: Application to patients

with multiple sclerosis and systemic lupus erythematosus. Archives of Neurology. 1989, 46:1121–23

Taylor RR, Jason LA, Torres A. Fatigue rating scales: an empirical comparison. Psychol Med. 2000

Jul;30(4):849-56.

Jason LA, Evans M, Brown M, Porter N, Brown A, Hunnell J, Anderson V, Lerch A. Fatigue Scales and

Chronic Fatigue Syndrome: Issues of Sensitivity and Specificity. Disabil Stud Q. 2011, 31: 1375.

Lorentzen K, Danielsen MA, Kay SD, Voss A. Validation of the Fatigue severity scale in Danish patients

with systemic lupus erythematosus. Dan Med J 2014;61(4):A4808

Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. Journal of

Psychosomatic Medicine. 199337:147–153.

White, P.D.; Goldsmith, K.A.; Johnson, AL, et al. Comparison of adaptive pacing therapy, cognitive

behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome

(PACE): a randomised trial. The Lancet 2011, 377: 823–836.

Gladwell, P., Harland, M., Adrissi, A., et al. (2024). Exploring the content validity of the Chalder Fatigue

Scale using cognitive interviewing in an ME/CFS population. Fatigue: Biomedicine, Health &

Behavior. 2024, 12: 217–37.

10.

11.

12.

13.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

14.

15.

Sletten DM, Suarez GA, Low PA et al. COMPASS 31: a refined and abbreviated Composite Autonomic

Symptom Score. Mayo Clin Proc. 2012, 87:1196-201.

Newton JL, Okonkwo O, Sutcliffe K,et al. Symptoms of autonomic dysfunction in chronic fatigue

syndrome,

QJM: An International Journal of Medicine,

Volume 100, Issue 8, August 2007, Pages 519–

526.

National Institute of Neurological Disorders and Stroke/NIH 2022.

https://www.commondataelements.ninds.nih.gov/report-

viewer/24150/Composite%20Autonomic%20Symptom%20Scale%20(COMPASS-31).

Brinth L, Pors K, Mehlsen J, et al. Translation and linguistic validation of the Composite Autonomic

Symptom Score COMPASS 31 in Danish. Dan Med J 2022, 69: A07210576.

16.

17.

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1.4.2 Muscle strength and endurance – Hand-grip testing

Maximal exercise performances are characterized by the peak oxygen uptake and the maximal

work force, but these procedures will cause post exertional malaise in patients with ME/CFS. A

comparative study in 66 ME/CFS-patients

concluded that handgrip strength can predict maximal

exercise performance in these patients.

Hand-grip dynamometry is recommended to perform in sitting position with the arm flexed at the

elbow and cannot be applied to patients following abdominal surgery, musculoskeletal spine or hip

injuries

. In a population of young healthy subjects, the reproducibility was nearly perfect

Normative data have been determined

and can be used for comparisons.

Hand grip strength (HGS) has been used as an objective measure of muscle strength and fatigue in

primary symptom of ME/CFS

. In a group of 272 British ME/CFS patients, HGS indicators were

associated with having ME/CFS, with magnitudes of association stronger in severely affected than

in mild/moderately affected patients. The association persisted after adjusting for age, sex and

body mass index and there were significant correlations between HGS indicators and clinical

parameters of disease severity, including fatigue analogue scales

. A study in 105 German ME/CFS

patients found that - compared to controls - the patients had a significantly lower strength and that

the decline in strength during repeat maximal HGS measurement was significantly higher. Lower

HGS parameters correlated with severity of disease, post-exertional malaise and muscle pain and

with higher blood levels of creatinine kinase and lactate after exertion.

References

1. Jammes Y, Stavris C, Charpin C, et al. Maximal handgrip strength can predict maximal physical

performance in patients with chronic fatigue. Clinical Biomechanics 2020, 73: 162-65.

Huerta Ojeda Á, Fontecilla Díaz B, Yeomans Cabrera MM, Jerez-Mayorga D. Grip power test: A new

valid and reliable method for assessing muscle power in healthy adolescents. PLoS One. 2021, 20

16: e0258720

Massy-Westropp NM, Gill TK, Taylor AW, et al. Hand Grip Strength: age and gender stratified

normative data in a population-based study. BMC Res Notes. 2011, 4: 127.

Nacul LC, Mudie K, Kingdon CC, et al. Hand Grip Strength as a Clinical Biomarker for ME/CFS and

Disease Severity. Front Neurol. 2018, 9:992

5. Jäkel B, Kedor C, Grabowski P, et al. Hand grip strength and fatigability: correlation with clinical

parameters and diagnostic suitability in ME/CFS. J Transl Med. 202119:159.

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1.4.3. Autonomic function

Measurements of autonomic function is primarily based on measurements of

cardiovascular control i.e. heart rate and blood pressure responses to different physical

challenges such as deep breathing, exhaling against an expiratory resistance (the Valsalva

manoeuvre) and changes in position from supine to upright.

Quantitative sweat test is also used in some laboratories to detect abnormalities in the

small nerve fibres of the peripheral autonomic nervous system.

1.4.3.1.

Tilt-testing and Valsalva manoeuvre

In tilt testing the subject is place in the supine position on tilt-table and heart rate and

blood pressure are recorded continuously in a non-invasive manner. After resting for

at least 10 min in the supine position the table is tilted to 60 degrees head-up

position. At this tilt angle the body is submitted to 90% of the gravity force attained in

the full upright position. Dependent on the diagnostic purpose the subject remains in

this position for 10 to 45 min. in the tilted position the force of gravity causse a

displacement of blood from the upper to the lower body compartments causing a

reduction in cardiac filling pressure. As a consequence, there is an immediate

reduction in cardiac stroke volume and hence in blood pressure which is initially

compensated by an increase in heart rate an within the first minute followed by

peripheral vasoconstriction increasing blood pressure and causing heart rate to return

to a level 10-20 beats per minute higher than in the supine. Tilt testing has been

widely covered in consensus satetments

1,2,3

In the Valsalva manoeuvre the subject is place in a sitting position with continuous

measurements of heart rate and blood pressure. After a 5 min resting period the

participant is asked to take a deep breath and then exhale through a mouth piece

connected to an aneroid manometer keeping the expiratory and hence the

intrathoracic pressure at 40 mmHg for 15 seconds and then exhale without resistance

and breath normally for 2 min. Then increased intrathoracic pressure reduces the

cardiac filling pressure causing the blood pressure to fall and the heart rate to

increase and in healthy subjects, constriction of the peripheral vasculature then

causes blood pressure to return the level prior to the manoeuvre. At release of the

expiratory pressure blood pressure falls shortly before reaching a higher level

(overshoot) as cardiac filling is normalised and the heart is pumping against an

increased vascular resistance this sequence of events allowing for calculation of the

baroreceptor sensitivity and for extraction of the activity in the parasympathetic and

sympathetic divisions of the autonomic nervous system

. The response can also be

classified in different categories relating to the degree of dysfunction in the

autonomic nervous system

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References to Tilt test and Valsalva maneuver

Sheldon R, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society Expert Consensus Statement

on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus

Tachycardia, and Vasovagal Syncope. Heart Rhythm, 2015, 12: e41.

Raj, Satish R. et al. Canadian Cardiovascular Society Position Statement on Postural Orthostatic

Tachycardia Syndrome (POTS) and Related Disorders of Chronic Orthostatic Intolerance.

Canadian Journal of Cardiology, 2020, 36: 357 – 372.

Thijs RD, Brignole M, Falup-Pecurariu C, et al. Recommendations for tilt table testing and other

provocative cardiovascular autonomic tests in conditions that may cause transient loss of

consciousness: Consensus statement of the European Federation of Autonomic Societies (EFAS)

endorsed by the American Autonomic Society (AAS) and the European Academy of Neurology

(EAN). Clin Auton Res. 2021, 31:369-384.

Randall EB, Billeschou A, Brinth LS, Mehlsen J, Olufsen MS. A model-based analysis of autonomic

nervous function in response to the Valsalva maneuver. J Appl Physiol (1985). 2019 Nov

1;127(5):1386-1402.

Novak P. Assessment of sympathetic index from the Valsalva maneuver. Nurology 2011,

76: 2010-2016.

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1.4.2.3.

Heart rate variability

Heart rate is tightly controlled to adapt to the demands of the body and therefore

show characteristic oscillation over time. There is a diurnal variation with lowest heart

rate in the middle of the sleeping period under normal circumstances. Heart rate also

varies from beat to beat – oscillations than are commonly referred to as heart rate

variability (HRV).

In testing HRV is important to differentiate between variation caused by specific

physiological manoeuvres such a deep breathing or active change in posture from

supine to standing and the spontaneous variation seen over limited time periods in the

resting supine or sitting positions. HRV can also be measured over 24-hour periods or

longer.

The strongest oscillations in heart rate are driven by breathing

and the largest

difference in heart rate in response to breathing is attained at a breathing frequency of

6 respirations per minute

. The variations in heart rate during deep breathing are

initiated primarily by the parasympathetic nervous system through the vagal nerve and

forms the basis for breathing techniques used to reduce mental stress. The other

strong oscillator causing HRV is the blood pressure control system. The activity of the

two principal oscillators can be quantified through analysis of the frequency

component embedded in HRV – practically separated into high and low frequency

component, where the high frequency component (HF) is commonly equated with

parasympathetic activity and the low frequency component (LF) represents the

sympathetic activity. The ratio between LF can then be equated to the balance

between the two components of the autonomic nervous system

. A Danish study on

normative values for HRV has been published

References for Heart Rate Variability

1. Mehlsen J, Pagh K, Nielsen JS, et al- Heart rate response to breathing: dependency

upon breathing pattern Clinical Physiology 1987 7: 115-124

2. Birdee G, Nelson K, Wallston K, et al. Slow breathing for reducing stress: The effect of

extending exhale. Complement Ther Med. 2023,73:102937.

3. Task Force of The European Society of Cardiology and The North American Society of

Pacing and Electrophysiology. Heart rate variability Standards of measurement,

physiological interpretation, and clinical use European Heart Journal 1996 17: 354-81.

4. Brinth LS, Jørgensen T, Mehlsen J, et al. Normative values of short-term heart rate

variability in a cross-sectional study of a Danish population. The DanFunD study. Scan J

Pub Health 2024, 52:48-57

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Section 2: Treatment

2.1 Mitochondrial Dysfunction

2.1.1.

Co-enzyme supplementation

Coenzyme Q

- also called Ubiquinone - is produced in the body and can be obtained

from dietary source mostly localized in the mitochondria. Q

is primarily located in the

mitochondria and together with nicotinamide adenine dinucleotide in the oxidized form

(NAD+ or the reduced form NADH), Q

is a key component of the electron transport chain

responsible for mitochondrial energy production in the form of ATP. Q

also acts as an

antioxidant

through removal of reactive oxygen species i.e. unstable molecules that may

oxidize and hence damage other molecules in the cell including the DNA. After acting as

an antioxidant, Q

must be reduced via NADH-related enzymes to be reactivated. Q

is a

product of the cholesterol synthesis in the liver, and it has been shown that statins

significantly reduce Q

levels

NAD+/NADH is critically involved in the mitochondrial ATP production together with Q

and can be synthesized from a multitude of precursors from the normal human diet – the

most prominent collectively known as B3-vitamin (niacin/nicotinamide). Normal dietary

intake of NAD+/NADH precursors is estimated to be 20-40 mg/day and stems from both

animal and plant-based diets

A recent meta-analysis of Q

supplementation in the general population

found that it

can reduce inflammatory mediators and that the optimal daily dose seemed to be 300–

400 mg.

A recent review of supplementation with NAD+/NADH

in different conditions including

CFS found that their study supported that oral administration of NADH I doses of 5 -

80mg/day can lead to an increase in quality of life and improvements in health

parameters. They also found that NADH supplementation is safe with a low incidence of

side effects.

A prospective randomized, placebo-controlled trial

of the combination of Q

/NADH in

doses of 200/20mg in 207 ME/CFS patients found reduction in cognitive fatigue

perception and overall using the Fatigue Impact Scale and an improvement in health-

related quality of life from baseline. Significant differences were also shown for sleep

duration at 4 weeks and habitual sleep efficiency at 8 weeks in follow-up visits from

baseline within the experimental group. In a previous study, the same group found

significant reductions in max HR during a cycle ergometer test combined with a decrease

in perception of fatigue in the active group compared to placebo. Both studies found that

the combination of Q

/NADH were well tolerated with no serious side-effects.

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References for 2.1.1. Co-enzyme supplementation

1. Quinzii CM, Lopez LC, Gilkerson RW, et al. Reactive oxygen species, oxidative stress, and cell death

correlate with level of CoQ10 deficiency. FASEB J. 2010, 24, 3733–3743.

2. Hofer SJ, Davinelli, Bergmann M, et al. Caloric Restriction Mimetics in Nutrition and Clinical Trials.

Frontiers in Nutrition 2021, 8. DOI: 10.3389/fnut.2021.717343.

3. Hou S, Tian Z, Zhao D, et al. Efficacy and Optimal Dose of Coenzyme Q10 Supplementation on

Inflammation-Related Biomarkers: A GRADE-Assessed Systematic Review and Updated Meta-

Analysis of Randomized Controlled Trials. Mol Nutr Food Res. 2023 Jul;67(13):e2200800. doi:

10.1002/mnfr.202200800.

4. Gindri IM, Ferrari G, Pinto LPS, et al. Evaluation of safety and effectiveness of NAD in different

clinical conditions: a systematic review. Am J Physiol Endocrinol Metab. 2024, 326: E417-E427.

5. Castro-Marrero J, Segundo MJ, Lacasa M, et al. Effect of Dietary Coenzyme Q10 Plus NADH

Supplementation on Fatigue Perception and Health-Related Quality of Life in Individuals with

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Prospective, Randomized, Double-Blind,

Placebo-Controlled Trial. Nutrients. 2021,13: 2658. doi: 10.3390/nu13082658.

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2.1.2. Antioxidants

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a dual role in being

both deleterious and beneficial. ROS and RNS are normally generated by tightly regulated

enzymes and overproduction results in oxidative stress which causes damage to cell

structures, including lipids, membranes, proteins, and DNA. In contrast, ROS/RNS exerts

beneficial effects at low/moderate concentrations as - for example - defenses against

infectious agents

. The reactive oxygen species are counterbalanced by enzymatic and non-

enzymatic antioxidants. Enzymatic antioxidant defenses include - among others -

superoxide dismutase, glutathione peroxidase, and catalase. Non-enzymatic antioxidants

are represented by vitamin C, Vitamin E, glutathione (GSH), carotenoids, and flavonoids. Q

also has important antioxidant properties as has selenium and selenium is an important

component of enzymatic antioxidants

. Oxidative stress denotes a shift towards increases in

reactive oxygen species relative to antioxidant defense mechanisms and is a hallmark of

mitochondrial dysfunction in ME/CFS

3,4

. Several studies have shown aberrations in

metabolism of lipids, in the redox balance and in energy production in ME/CFS

3,4,5,6

probably caused by defects in the pyruvate dehydrogenase complex

– an essential key in

the aerobic glucose metabolism.

Vitamin C (ascorbic acid/ascorbate) is a potent antioxidant, important for the formation of

biogenic amines and contributes to immune defense. Infections significantly impact vitamin

C levels due to enhanced inflammation and metabolic requirements. Fatigue, pain,

cognitive disorders, and depression-like symptoms are known symptoms of vitamin C

deficiency

. Vitamin C concentrations are tightly controlled with oral ingestion in healthy

subjects with dose-independent plasma levels at intakes of more than 1.000 mg/day. To

achieve higher plasma concentration, intravenous administration (iv) is necessary

. A

placebo-controlled study of iv C-vitamin in healthy subjects found significantly lower

measures of oxidative stress and a positive effect on fatigue. There were no differences in

adverse events or side-effects between active and placebo treatment.

Selenium

Selenium (Se) is an essential trace element and has an important role as part of several

selenoproteins with critical roles in thyroid hormone metabolism, DNA synthesis,

reproduction, and protection from oxidative damage and infection. In foods, Se is

predominantly present as selenomethionine, which is an important source of dietary Se in

humans, and as a chemical form that is commonly used for Se supplements in clinical trials.

Daily recommended dose of Selenium in healthy subjects olde than 14 years of age is 55

microg daily. The upper tolerable limit is 400 microg in the same age group

Concern for potential deficiency diseases associated with low Se status has led to the

establishment of the recommended daily requirements for Se in many countries. Excess Se

intakes through supplementation and its potential misuse as health therapy could also pose

a risk of adverse health effects if its use is not properly regulated.

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References for antioxidants

1. Valko M, Leibfritz D, Moncola J, et al. Free radicals and antioxidants in normal physiological

functions and human disease. The Internl J Biochem Cell Bio 2007, 39: 44–84.

2. Tingii U. Selenium: its role as antioxidant in human health. Environ Health Prev Med 2008, 13:102–

108.

3. Richards RS, Roberts TK, McGregor NR, et al. Blood parameters indicative of oxidative stress are

associated with symptom expression in chronic fatigue syndrome. Redox Report 2000,

35–41.

4. Germain A, Ruppert D, Levine SM, Hanson MR. Prospective Biomarkers from Plasma Metabolomics

of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease

Symptomatology. Metabolites 2018, 8: 90.

5. Fluge O, Mella O, Bruland O, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase

function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016 1: e89376.

6. Paula BD, Lemled MD, Komaroffe AL, Snyder, SH. Redox imbalance links COVID-19 and myalgic

encephalomyelitis/chronic fatigue syndrome PNAS 2021 Vol. 118 No. 34 e2024358118.

7. Vollbracht C, Kraft K. Feasibility of Vitamin C in the Treatment of Post Viral Fatigue with Focus on

Long COVID, Based on a Systematic Review of IV Vitamin C on Fatigue. Nutrients. 2021,13:1154.

8. Levine M, Padayatty SJ, Espey MG. Vitamin C: a concentration-function approach yields

pharmacology and therapeutic discoveries. Adv Nutr. 2011, 2:78-88.

9. Kumar V, Bhushan D, Supriya S, et al. Efficacy of intravenous vitamin C in management of moderate

and severe COVID-19: A double blind randomized placebo controlled trial. J Family Med Prim Care.

2022, 11:4758-4765.

10. Suh SY, Bae WK, Ahn HY, Choi SE, Jung GC, Yeom CH. Intravenous vitamin C administration reduces

fatigue in office workers: a double-blind randomized controlled trial. Nutr J. 2012, 11:7.

11. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Vitamin C, Vitamin E,

Selenium, and Carotenoids. Washington, DC: National Academy Press; 2000.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

2.4.

Treatment of neuroinflammation: Dietary supplements.

2.1.1

Palmitoylethanolamide (PEA)

PEA is a food component first discovered in the late 1950s and shown to have anti-allergic

and anti-inflammatory activity

. PEA is an endocannabinoid, and it selectively stimulates

the cannabinoid CB2 receptor avoiding the hallucinogenic effects of stimulating the CB1

receptor. It is generally accepted that PEA has a multitargeted action and – important in the

treatment of ME/CFS and related conditions – an ability to reduce inflammation, pain,

mast-cell activation, and experimental colitis

Pharmacological properties: Because of the lipidic nature and large particle size, PEA has to

be micronized to give a better adsorption. Experimental inflammation has been shown to

be reduced by oral treatment with micronized and ultramicronized PEA whereas the

nonmicronized PEA had no effect

. The plasma elimination half-time of PEA is 12 min in the

rat

and most of the PEA is located in the extravascular compartment. PEA is found in the

brain, with a preferential retention in the hypothalamus where CB2 receptors are present

Effect on inflammation and mast-cell activation: PEA has been reported to decrease the

release of several pro-inflammatory cytokines and that PEA has a curative effect in a model

of acute inflammation

. In the brain PEA selectively binds to the cannabinoid CB2 receptor

which is abundantly present on human microglia cells which would account for the possible

beneficial effect of PEA in conditions of neuroinflammation. It has been suggested that

chronic inflammation might develop because of low endocannabinoid tissue concentration

and that a correction of this could be exploited to develop new anti-inflammatory drugs

Recently, PEA has been reported to down-modulate mast cell activation in vitro by behaving

as an agonist at the peripheral cannabinoid CB2 receptor

Tolerability of PEA: The current clinical data indicate that there are no ‘very common’ or

‘common’ serious adverse reactions but there is insufficient data to give information in the

‘uncommon’ or ‘rare’ categories

. The DTU Food Institute has assessed that no harmful

effects of PEA have been reported and that based on data from experimental studies, a safe

intake of 5 mg/kg body weight per day for PEA can be calculated

Effect on pain: A meta-analysis of double-blind, controlled, and open-label clinical trials has

shown that PEA elicits a progressive reduction of pain intensity significantly higher than

control with the effects being independent of patient age or gender, and not related to the

type of chronic pain

. A large observation study on 600+ patients from a single pain clinic

has shown that PEA significantly reduces pain when added to usual analgesic therapy

. A

meta-analysis of six randomized, placebo controlled, clinical trials point to efficacy of PEA

over placebo and when compared to NSAID the effect of PEA lasted longer than that of

NSAID

The proposed mechanism(s) of action of PEA involve – among others - the effects upon

mast cells

and CB2-like cannabinoid receptors

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Practical approach: Most of the studies have used a total daily dose micronized PEA of 800

to 1.200 mg. In clinical experience from 500+ patients this is a highly tolerable dosage, and

the onset of effect is to be expected within (several) weeks.

References for PEA

1. Esposito E, Cuzzocrea S. Palmitoylethanolamide is a new possible pharmacological treatment for the

inflammation associated with trauma. Mini Rev Med Chem. 2013 Feb;13(2):237-55. PMID: 22697514.

2. Borelli F, Romano B, Petrosino S, et al. British Journal of Pharmacology (2015)

172

142–158

3. Impellizzeri D, Bruschetta G, Cordaro M, et al. Micronized/ultramicronized palmitoylethanolamide

displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of

inflammatory pain. J Neuroinflammation. 2014 Aug 28;11: 136. doi: 10.1186/s12974-014-0136-0.

4. Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain:

pharmacokinetics, safety and efficacy. Br J Clin Pharmacol (2016) 82 932–942

5. Benito C, Tolón RM, Pazos MR, et al. Cannabinoid CB2 receptors in human brain inflammation. Br J

Pharmacol. 2008 Jan;153(2):277-85. doi: 10.1038/sj.bjp.0707505. Epub 2007 Oct 15. PMID:

17934510; PMCID: PMC2219537.

6. Costa, B., Conti, S., Giagnoni, G. and Colleoni, M. (2002), Therapeutic effect of the endogenous fatty

acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-

oxygenase systems. British Journal of Pharmacology, 137: 413-420.

7. De Filippis D, D’Amico A, Cipriano M, Petrosino S, Orlando P, Di Marzo V, et al. Levels of

endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic

granulomatous inflammation in rats. Pharmacol Res. Elsevier Ltd; 2010 Apr;61(4):321–8.

8. Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A. N-(2-hydroxyethyl)hexadecanamide is orally

active in reducing oedema formation and inflammatory hyperalgesia by down-modulating mast cell

activation. Eur J Pharmacol. 1996 Apr 11;300(3):227-36. doi: 10.1016/0014-2999(96)00015-5. PMID:

8739213.

9. DTU National Food Institute, Denmark. Request for risk assessment of palmitoylethanolamide for

food supplements, Danish Food Agency's j.nr.: 2018-29-7100-00439. 2018.

10. Paladini A, Fusco M, Cenacchi T, et al. Palmitoylethanolamide, a Special Food for Medical Purposes,

in the Treatment of Chronic Pain: A Pooled Data Meta-analysis. Pain Physician. 2016 Feb;19(2):11-

24.

11. Gatti A, Lazzari N, Gianfelice V, et al. Palmitoylethanolamide in the treatment of chronic pain caused

by different etiopathogenesis. Pain Medicine 2012; 13: 1121–1130

12. Marini I, Bartolucci ML, Bortolotti F, et al. Palmitoylethanolamide versus a nonsteroidal anti-

inflammatory drug in the treatment of temporomandibular joint inflammatory pain. J Orofac Pain.

2012 Spring;26(2):99-104.

13. Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A. N-(2-hydroxyethyl) hexadecamide is orally

active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell

activation. Eur J Pharmacol 1996; 300: 227–36

14. Rorato R, Ferreira NL, Oliveira FPet al. Prolonged Activation of Brain CB2 Signaling Modulates

Hypothalamic Microgliosis and Astrogliosis in High Fat Diet-Fed Mice. Int J Mol Sci. 2022 May

16;23(10):5527. doi: 10.3390/ijms23105527.

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2.1.2 Pycnogenol

Pycnogenol is extracted from the bark of a French pine tree (Pinus pinaster) and the main

components are procyanidins (70+/- 5%) and their monomers (catechin and epicatechin) as

well as phenolic acids

. Pycnogenol is safe for use in conventional foods, based on the

evaluation of clinical safety and preclinical toxicology data by an independent panel of

toxicology experts. Non-mutagenicity, lethal dose (LD50) > 5.0 g/kg body weight, the no

adverse event level has been determined at > 1,000 mg/kg/day [2], and this translates in a

safe dosage of > 700 mg/day. Typically, oral dosages tested in the literature are in the 30–

200 mg/day range, with some studies exploring higher dosages of 200–450 mg/day. Since it

was introduced into the market in Europe around 1970, there have been no reports of

serious adverse effects in any clinical study or from commercial use of Pycnogenol. Mild

side-effects of gastric discomfort have rarely been reported and linked to stomach-sensitive

patients. No interactions of Pycnogenol with other drugs, alcohol or food intake have been

reported

Endothelial function: Sandvik MK et al has shown that ME/CFS patients have reduced

macro- and microvascular endothelial function, indicating that vascular homeostasis may

play a role in the clinical presentation of this disease

. A study by Newton et al.

investigating flow-mediated dilation (FMD) for large vessel endothelial function and post-

occlusive reactive hyperemia (PORH) for microvascular function in ME/CFS patients,

concluded that ME/CFS patients have both large and small vessel endothelial dysfunction as

compared to age- and sex-matched controls

4,5

. Clinical studies have showed that

Pycnogenol can improve endothelial function

6,7

. The suggested mechanism of action is

activation of the endothelial nitric oxide synthase amplifying the NO generation from L-

arginine, eventually leading to an increase in vessel lumen and adequate tissue perfusion

Micro-clots and associated coagulation issues have been found present in ME/CFS and

point to a systemic vascular pathology and potential endothelial inflammation and targeted

therapies to address vascular and endothelial pathology might has been suggested

Pycnogenol lowers blood platelet aggregation as effectively as aspirin, without increasing

the bleeding time

9,10

. Pycnogenol prevents platelet hyperactivity but does not influence

bleeding time, unlike aspirin

Antioxidant activity of Pycnogenol has been investigated in several clinical studies

and has

been shown to increase the plasma antioxidant capacity and decrease the plasma oxidative

stress.

Practical approach: Treatment with Pycnogenol is recommended at a morning dose of

200mg. Besides hypersensitivity to pine bark there are no known contraindication to

Pycnogenol. Presently, documentation of the optimal duration of treatment and the long-

term effects is lacking

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

References for Pycnogenol

Weichmann F, Rohdewald P. Projected supportive effects of Pycnogenol in patients suffering from

multi-dimensional health impairments after a SARS-CoV2 infection. International Journal of

Antimicrobial Agents. 2020 56 (6): 106191

Oliff H. ABC scientific and clinical Monograph for Pycnogenol 2019 UPDATE. Am Bot Counc

Monogr. 2019:1–46

Sandvik MK, Sørland K, Leirgul E, Rekeland IG, Stavland CS, Mella O, Fluge Ø. Endothelial

dysfunction in ME/CFS patients. PLoS One. 2023 Feb 2;18(2):e0280942.

Newton DJ, Kennedy G, Chan KK, Lang CC, Belch JJ, Khan F. Large and small artery endothelial

dysfunction in chronic fatigue syndrome. Int J Cardiol. 2012; 154(3):335–6.

Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, et al. Assessment of flow-mediated

dilation in humans: a methodological and physiological guideline. American journal of physiology

Heart and circulatory physiology. 2011; 300(1):H2–12. Epub 2010/10/19

Uhlenhut K, Högger P. Facilitated cellular uptake and suppression of inducible nitric oxide synthase

by a metabolite of maritime pine bark extract (Pycnogenol). Free Radic Biol Med. 2012 Jul

15;53(2):305-13.

Nishioka K, Hidaka T, Nakamura S, Umemura T, Jitsuiki D, Soga J, et al. Pycnogenol®, French

maritime pine bark extract, augments endothelium-dependent vasodilation in humans. Hypertens

Res. 2007;30(9):775–780

Nunes JM, Kruger A, Proal A, Kell DB, Pretorius E. The Occurrence of Hyperactivated Platelets and

Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Pharmaceuticals (Basel). 2022 Jul 27;15(8):931

Pütter M, Grotemeyer KHM, Würthwein G, Araghi-Niknam M, Watson RR, Hosseini S, et al.

Inhibition of smoking-induced platelet aggregation by aspirin and pycnogenol. Thromb

Res. 1999;95(4):155–161,

10.

Araghi-Niknam M, Hosseini S, Larson D, Rohdewald P, Watson RR. Pine bark extract reduces platelet

aggregation. Integr Med. 2000;2(00):73–77.

11.

Simpson T, Kure C, Stough C. Assessing the Efficacy and Mechanisms of Pycnogenol

on Cognitive

Aging From In Vitro Animal and Human Studies. Front Pharmacol. 2019 Jul 3;10: 694

12.

Malekahmadi M, Moradi Moghaddam O, Firouzi S, Daryabeygi-Khotbehsara R, Shariful Islam SM,

Norouzy A, Soltani S. Effects of pycnogenol on cardiometabolic health: A systematic review and

meta-analysis of randomized controlled trials. Pharmacol Res. 2019 Dec;150: 104472. doi:

10.1016/j.phrs.2019.104472. Epub 2019 Oct 1. PMID: 31585179.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

2.2

Treatment of neuroinflammation, medical treatment

2.2.1 Medical treatment: Low dose Naltrexone (LDN)

Naltrexone is an opioid receptor antagonist and in low doses (0.4 to 4.5 mg) it has both analgesic

and anti-inflammatory effects

1,2,3

and is referred to as Low-dose naltrexone (LDN). LDN has been

used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn’s disease,

fibromyalgia, and other neuro-pathic/-inflammatory conditions and current evidence supports the

safety and tolerability of LDN in these illnesses

1,2,3

. Studies on quality of life and self-reported pain

demonstrate that LDN has subjective benefits over placebo

1,2,3

Naltrexone is almost completely absorbed orally but the bioavailability ranges between 5 and 40

per cent. The half-life elimination is 4 hours, and it is excreted primarily in the urine, but no dosing

adjustments are needed in mild renal impairment

Studies have indicated that LDN has a damping effect on the immune cells in the central nervous

system and counteract the proinflammatory activation that occurs in response to pain

and leads to

a reversal of neuropathy

. A retrospective review on LDN in 215 patients with multiple sclerosis

found that 77% of the participants had no side effects and no participants were hospitalized from

adverse events by LDN. The primary indication was LDN, and this was reduced in approximately 60%.

75% of the participants reported perceiving an increased or stabilized after LDN therapy.

A similar study in 218 patients with ME

reported on safety and effectiveness data of LDN in

dosages of 3.0 – 4.5 mg/day. The retrospective analysis of medical records showed positive

response in 74% experiencing improved vigilance/-alertness, improved physical and cognitive

performance. Some patients reported less pain (17%) and fever (15%), while 18% had no

response. Mild adverse effects (insomnia, nausea) were common at the onset of the treatment.

Neither severe adverse effects nor long-term adverse symptoms were reported

A randomized, double blinded study of LDN in 31 women with fibromyalgia found significant,

reduction of pain compared placebo. LDN was also associated with improved general satisfaction

with life and with improved mood. Thirty-two percent had significant reductions in pain and in

either fatigue or sleep problems contrasted with an 11% response during placebo. LDN was rated

equal to placebo in side-effects, and no serious side effects were reported.

Practical approach: Due to the unpredictable bioavailability in the individual patient it is

recommended to up-titrate the dose slowly starting with 0.5mg with stepwise increases of 0.5 mg

every third week to a maximum of 4.5mg. Should side effects appear the patient could go one step

back and try to proceed with the stepwise increments after three weeks or if there is an effect at a

lower dose the stay at that level.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

References to LDN

Patten DK, Schultz BG, Berlau DJ. The Safety and Efficacy of Low-Dose Naltrexone in the

Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn’s Disease,

and Other Chronic Pain Disorders Pharmacotherapy 2018;38(3):382–389).

Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Med Sci (Basel).

2018 6:82.

Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory

treatment for chronic pain. Clin Rheumatol. 2014 33:451-9.

4. Hutchinson MR, Zhang Y, Brown K, et al. Non-stereoselective reversal of neuropathic pain by naloxone

and natrexone: involvement of Toll-like receptor 4 (TLR4). Eur J Neruosci 2008 28:20–9.)

5. Turel AP, Oh KH, Zagon IS, McLaughlin PJ. Low dose naltrexone for treatment of multiple sclerosis: a

retrospective chart review of safety and tolerability (Letter). J Clin Psycho-pharmacol 2015 35:609–

11.

6. Polo, O., Pesonen, P., & Tuominen, E. (). Low-dose naltrexone in the treatment of myalgic

encephalomyelitis/chronic fatigue syndrome (ME/CFS). Fatigue: Biomedicine, Health &

Behavior, 2019 7, 207–217

Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome:

clinical working case definition, diagnostic and treatments protocols. J Chronic Fatigue Syndr. 2003

11:7–115.

Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia:

findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial

assessing daily pain levels. Arthritis Rheum. 2013 65:529-38.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Antiviral treatment

3.1. Valacyclovir

Acyclovir, ganciclovir, and famciclovir are nucleotide analogue inhibitors which inhibit viral

replication during DNA multiplication or RNA multiplication

. Valacyclovir is a valine derivative

of acyclovir and is well absorbed from the gastrointestinal tract where it is converted to

acyclovir

. Valganciclovir is – like valacyclovir - a valine derivative improving the absorption

from the gastrointestinal tract. Valganciclovir is commonly reserved for preventing and

treating cytomegalovirus-infections in immunosuppressed individuals. Famciclovir is readily

absorbed but does not seem to offer superiority to Valacyclovir

and - as is the case with

valganciclovir – far more expensive.

A study in 25 ME/CFS patients has evaluated the safety and efficacy study of valacyclovir given

at 1,000 to 1,500 mg every 6 hours a day for 6 months

and this dose achieved serum acyclovir

levels to have a high antiviral activity versus Herpes virus 4 (EBV). The authors concluded that

the 16 ME/CFS patients with persistent infection EBV-infection improved after 6 months of

continuous dosing with valacyclovir. Nine ME/CFS patients with Herpes virus 5 (CMV) co-

infection did not benefit from 6 months of similar treatment.

Safety monitoring data from clinical trials of valacyclovir, involving over 3,000 immuno-

competent and immunocompromised persons receiving long-term therapy for Herpes Simplex

Virus (HSV) suppression, were analysed

. Safety profiles of valacyclovir (< 1,000 mg/day),

acyclovir (< 800 mg/day), and placebo were similar. Extensive sensitivity monitoring of HSV

isolates confirmed a very low rate of acyclovir resistance among immunocompetent subjects

(< 0.5%)

References for Valaciclovir

1. De Clercq E, Neyts J. Antiviral agents acting as DNA or RNA chain terminators. Handb Exp

Pharmacol. 2009,189:53-84.

2. Weller S, Blum MR, Doucette M, et al. Pharmacokinetics of the acyclovir pro-drug valacyclovir after

escalating single and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993,

54: 595-605

3. Wald A, Selke S, Warren T, et al. Comparative efficacy of famciclovir and valacyclovir for suppression

of recurrent genital herpes and viral shedding. Sex Transm Dis. 2006 Sep;33(9):529-33

4. Lerner AM, Beqaj SH, Deeter RG, et al. A six-month trial of valacyclovir in the Epstein-Barr virus

subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc).

2002,38:549-61.

5. Tyring SK, Baker D, and Snowden W. Valacyclovir for Herpes Simplex Virus Infection: Long-Term

Safetyand Sustained Efficacy after 20 Years’ Experience with Acyclovir. The Journal of Infectious

Diseases 2002;186(Suppl 1): S40–6

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

Autonomic dysfunction

A significant minority of patients experience symptoms compatible with dysfunction of the

autonomic nervous system, including orthostatic intolerance (POTS), gastrointestinal

disturbances, bladder dysfunction, and circulation issues.

Using the Composite Autonomic Symptom Scale (COMPASS

), a study in ME/CFS found that

symptoms of autonomic dysfunction were strongly and reproducibly associated with the

presence of ME/CFS

. They also found a reverse correlation between low frequency variation

in heart rate variability and the COMPASS score Studies in ME/CFS have compared results from

the COMPASS questionnaire and data on heart rate variability HRV and have found A high

COMPASS score correlated to a significant negative correlation between LF-HRV and COMPASS

scores

In a case–controlled study of 45 female patients and 25 age- and gender-matched healthy

controls

it was found significant relationships between self-reported fatigue symptoms and

indices of heart rate variability in patients with ME/CFS

4.1. Postural tachycardia syndrome (POTS)

POTS denotes a condition where heart rate increases by more than 30 beats per minute on

assumption of the upright posture in subject older that 18 year of age and more than 40 beats

per minute in the younger age group. Heart rate increases of that magnitude i.e. postural

tachycardia can been seen in dehydrated subject and in astronauts returning after longer

periods in space where they are not submitted to gravity – the most important signal to fluid

retention in humans. POTS is diagnosed if the abnormal hemodynamic measures are

accompanied by returning symptoms of dizziness, nausea, near fainting, cognitive impairment

and other symptoms related to the upright posture

A study in ME/CFS patients with POTS showed that patients in this subgroup were significantly

younger, had a shorter length of illness, experienced greater task difficulty and were able to

stand for significantly shorter periods compared to those ME/CFS-patients without POTS.

The probable cause for POTS in ME/CFS is most likely and inability to contract the peripheral

vasculature during orthostasis and are thus dependent on increments in heart rate to keep

blood pressure at a level that ensures an adequate perfusion pressure for the cerebral

vasculature. It has also been shown that POTS patients have low frequency oscillations in heart

rate and blood pressure

. A study simulating such oscillations in healthy subjects using lower

body negative pressure demonstrated that healthy subject developed brain fog during such

oscillations

Treatment of POTS

is directed at reducing the fluid displacement during the upright posture

by increasing the intake of salt and fluid - 1 g of NaCl pr liter of fluid, reducing the tachycardia

both in the supine and upright position with adrenergic beta-blockers, muscarinic agonists like

Mestinon, and enhancing vasoconstriction with an adrenergic alpha-agonist – Midodrine. Fluid

retention can be amplified by Fludrocortisone and/or a vasopressin analogue.

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Myalgic Encephalomyelitis (ME/CFS): Pathobiology, diagnosis, and treatment

References for autonomic dysfunction and POTS

1. Sletten DM, Suarez GA, Low PA, et al. COMPASS 31: A refined and abbreviated Composite

Autonomic Symptom Score. Mayo Clinic Proceedings 2012, 87:1196–1201.

2. Newton JL, Okonkwo O, Sutcliffe K, et al. Symptoms of autonomic dysfunction in chronic

fatigue syndrome. QJM. 2007, 100: 519-26.

3. Escorihuela RM, Capdevila L, Castro JR, et al. Reduced heart rate variability predicts fatigue

severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis. J Transl

Med 2020, 18: 4.

4. Raj, Satish R. et al. Canadian Cardiovascular Society Position Statement on Postural

Orthostatic Tachycardia Syndrome (POTS) and Related Disorders of Chronic Orthostatic

Intolerance. Canadian Journal of Cardiology, 2020, 36: 357 – 372.

Reynolds GK, Lewis DP, Richardson AM, Lidbury BA. Comorbidity of postural orthostatic

tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. J Intern Med.

2014 Apr;275(4):409-17.

6. Geddes JR, Ottesen JT, Mehlsen J, Olufsen MS. Postural orthostatic tachycardia syndrome

explained using a baroreflex response model. - J Royal Society Interface, 2022, 19: 20220220

7. Stewart JM, Balakrishnan K, Visintainer P, et al. Oscillatory lower body negative pressure

impairs task related functional hyperemia in healthy volunteers. Am J Physiol Heart Circ

Physiol 2016, 310: H775–H784.