chronic fatigue syndrom (cfs) a challenge for medicine and ... · evidences of international inus...

Chronic fatigue syndrom (CFS)

myalgic encephalomyelitis (ME)

a challenge for medicine and social systems in the 21st century

Evidences of international INUS Study for Aspects of epidemiology,

inflammation, immunology,, infectiology, genetics and (environmental)-toxicology,

The use of INUSpheresis® as part of tertiare prevention.

Dr. med. Richard Straube

Medical Head of

INUS Medical Center AG / Cham-Germany

in cooperation with

Prof. Dr. med. Stefan R. Bornstein, internal medicine

Medical University Carl Gustav Carus

of technical University Dresden

Co authors:

Dr. med. Til Steinmeier - Biologicum Hamburg,

Dr. med. Althunjan Gor - INUS Medical Center AG

A Future Without ME/CFSLondon, 15th February 2020

74%

10%

7%

9%

Origin of patients with CFS/MEGermany EU non EU USA


Features of Parameters of ME/CFS Patients :

General database (top on 1.1.2020): 1400 patients registered

Subgroup CFS/ME: 928 patients registered

Age female: 50, 6years; age male: 50,8 years

Body-mass-index: female 23,1kg / m2; male: 24,6kg / m2

Cerebropheresis® treatment frequency/patient: 4

Treatment period: 214 days

Blood pressure/puls before Cerebropheresis® : 141/70; 72/min

Blood pressure/puls after Cerebropheresis® : 138/70; 70/min

Inoculations registered: 19/patient


0 Decade 1 Decade 2 Decade 3 Decade 4 Decade 5 Decade 6 Decade 7 Decade 8 Decade

ME/CFS 12 36 76 112 163 108 41 6

0

20

40

60

80

100

120

140

160

180

num

ber

of fe

male

patient

distribution of teh decades of life in female patients suffering ME/CFS

22,4% up 3.decade


0 Decade 1 Decade 2 Decade 3 Decade 4 Decade 5 Decade 6 Decade 7 Decade 8 Decade

ME/CFS 9 25 47 87 110 62 28 7

0

20

40

60

80

100

120

num

ber

of patients

distribution of decades of life in men suffering ME/CFS

21,6% up the 3.decade


early retirement23%

self-employment16%

health system12%

pedagogigs6%

home6%

employee6%

students5%

management5%

engineers3%

artists3%

state service3%

manufacturers2%

technical-chemical2%

aeronautics2% farming

2%

scientists1%

service1%

military service0% spiritual

0%

distribution of life situation and professions in patients suffering ME/CFS


doctors, 0.95

clinical treatment, 0.61

naturopaths, 0.57

naturopathy, 0.75

orthomolecular medicine, 0.74

homeopathy, 0.72

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

doctors

clinical treatment

naturopaths

naturopathy

orthomolecular medicine

homeopathy

Relative frequency

Pathways of suffering and treatment of CFS /MEpatients in the health systems


USA, 14.97Germany, 14.4

EU, 13.29

nonEU, 11.3

0

2

4

6

8

10

12

14

16

USA Germany EU nonEU

ye

ars

Time of suffering of CFS/ME patients in relation to their origin


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1im

mu

no

…

MC

S/T

ILT

ne

uro

pa

…

lea

ky …

bo

rre

lio

sis

mito

ch

o…

fib

rom

y…

ne

ph

rop

…

de

rmo

p…

hyp

ert

e…

oth

er …

de

pre

ssi…

mu

scle

d…

ren

al …

ca

rdio

m…

tin

nitu

s

mig

rain

e

AL

S

ha

sh

imo

to

ne

uro

de

…

MS

ae

roto

xi…

rhe

um

at…

pso

ria

sis

CID

P

he

pa

top

…

pa

rkin

so

n

va

scu

litis

Va

scu

litis

art

ial …

ep

ile

psia

RE

LA

TIV

E F

RE

QU

EN

CY

Distribution of relative frequencies in CFSME for comorbidities


Inflammation features in CFS/ME


0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Grad0 Grad 1 Grad 2 Grad 3 Grad 4

per

cen

tage

distribution of genetic inflammation degree in patients with CFS/ME

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Grad 0+1 Grad 2+3+4

perc

enta

gel

comprehension low inflammtion degrees versus high

inflammation degrees


sCRP cut off

CFS/ME 5.3 2

0

1

2

3

4

5

6

7

8

mg/d

l

sCRP in patients suffering CFS/ME

TNFalpha cut off

CFS/ME 10.2 8.1

0

2

4

6

8

10

12

pg/m

l

TNFalpha in patients suffering CFS/ME


ECP cut off

CFS/ME 17.4 13.3

0

5

10

15

20

25

ug/l

Eosinophilic cationic protein (ECP) in patients suffering CFS/ME

RANTES(CCL5)

cut off

CFS/ME 46 30

0

10

20

30

40

50

60

ug/l

RANTES (CCL5) in patients suffering CFS/ME


Lp-

PLA2

cutoff

CFS/ME 303.6 151

0

50

100

150

200

250

300

350

400

um

ol/m

in/l

endothelial inflammation

represented by Lp-PLA2 in patients

suffering ME/CFSCFS/ME

Fibrinogen

cutoff

CFS/ME 305.66 250

0

50

100

150

200

250

300

350

400

mg/d

l

Fibrinogen as an inflammtion and

rheological marker in endothelila

inflammtion in patients suffering

CFS/ME

alpha2Makrogobulin

cutoff

CFS/ME 8 3

0

2

4

6

8

10

12

g/l

alpha2Makroglobulin as an inflammtion and rheological

marker in endothelial inflammtion in

patients suffering CFS/MECFS/ME

Endothelial Inflammation and Rheology in patients suffering CFS/ME


0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

rela

tive

Häu

fig

ke

it

distribution rheumatologic/vasculitic Parameters in CFS/ME Patients

Immunolgical Features in patients suffering CFS/ME

cCP: 1:53 (cut off < 1,0)

ANA (Antinucleare Antibodies): 1:323 (cut off < 1:100)

RF (Rheumafactor): 6,5 8 (cut off < 14IU/ml)

P-ANCA*: 60 U/ml (cut off < 5U/ml)

c-ANCA*: 38 U/ml (cut off < 10U/ml)

SCL70-Antibodies: 1:37 (cut off negativ)

(*ANCA = Anti-Neutrophile cytoplasmatic antibodies)


Distribution and Concentration of Circulating Immune Complexes (CICs) in Patients with CFS/ME

IgA IgG IgM C3c C1q

CFS/ME 72.8 217.2 139.1 37.68 96.19

cut off 25 147 77 35 97

0

50

100

150

200

250

300

concentr

ation u

g/m

l


0.508

0.46

0.357

0.29 0.288

0.230.22

0.167 0.160.15 0.145 0.14 0.1375

0.109 0.109 0.103 0.1020.09 0.088 0.087

Realtiv

efr

equencie

s

Distribuiton of relatives frequencies of irregulare Gangliosid-Aut-Antibbodies in CFS/ME Patienten


0

2

4

6

8

10

12

14

16

18

beta1 beta2 M3 M4

ug/l

Neurotransmitter-Aut-Antibbodies against beta1 und beta 2 adrenerge receptors, and muskaric Type 3 und Type 4

acetylcholinrezeptors


CFS/ME and chronic infection diseases an important aspect in diagnostics and

Treatment findings in the INUS Study and current new aspects

0.2240.211

0.1789

0.061

0.029 0.0243 0.016 0.012 0.008 0.008Realtiv

efr

equencie

s


ELISA IgG ELISA IgM

CFS beiBorreliose

//AU/ml60.3 12.8

Referenz//AU/ml

3 3

0

10

20

30

40

50

60

70

80

90

AU

/ml

ELISA bei CFS/ME durch Borreliose

WesternBlot IgM

WesternBlot IgG

CFS beiBorreliose/ IE

61 18.34

Referenz IE 1 1

0

10

20

30

40

50

60

70

80

90

IE

Western/Immunoblot bei CFS/ME durch Borreliose

CFS/ME and chronic infection diseases an important aspect in diagnostics and treatment

findings in the INUS Study and current new aspects

The 1.st differential diagnosis: Borreliosis


LTT B.ss B.afz. B.gar. LTT OspC

Borreliose beiCFS/SI

2.86 3.1 3.19 2.7

Referenz /SI 2 2 2 2

0

0.5

1

1.5

2

2.5

3

3.5

SI-

Ein

he

ite

n

Muster des LTT Borreliose bei CFS/ME

0

0.5

1

1.5

2

2.5

3

3.5

4

Bu

rra

sca

no

Qu

otie

nt

Burrascano Score bei CFS/ME Patienten mit später nachgewiesener chronischer Borreliose

CFS/ME and chronic infection diseases an important aspect in diagnostics and treatment

findings in the INUS Study and current new aspects:

the 1.st differential diagnosis in CFS/ME: Borreliosis (61,3% of all CFS/ME patients !!)


CFS/ME and the mitochondrial metabolic disorders

CFS Referenz

ATP 1.97 2.5

0

0.5

1

1.5

2

2.5

3

um

ol

ATP bei CFS/ME Patienten

CFSReferenz

Ubichinon(Q10)

1.04 2.5

0

0.5

1

1.5

2

2.5

3

3.5

mg/d

l

Ubichinon (Q10) bei CFS/ME Patienten


CFS/ME and the mitochondrial metabolic disorders

0

200

400

600

800

1000

1200

1400

1600

CFS Referenz

ug/l

Nitrotyrosin in patients suffering in CFS/ME

ROSXH2O2

Cut off

CFS/ME 63.67 8.1

0

10

20

30

40

50

60

70

80

90

100

mg/d

l

intracellular oxidative Stress marked as H202 in patients

suffering CFS/ME


CFS/ME and the gut dysfunction

Calprotectin

alpha1Antitryp

sin

CFS 174.76 185.75

Referenz 20 66

0

50

100

150

200

250

ut/m

l

Calprotectin und alpha1Antitrypsin bei CFS/ME Patienten

0

200

400

600

800

1000

1200

1400

1600

CFS Referenz

mg/l

sekretorisches IgA bei CFS/ME Patienten

CFSReferenz

Quecksilber ug/g

15.57 10

0

2

4

6

8

10

12

14

16

18

20

ug/g

Stu

hl

Quecksilber im Stuhl bei CFS/ME Patienten


CFS/ME and the gut dysfunction

Aceton Methlethylketon Methanol Äthanol Propanol

CFS 6.2 0.39 1.64 15.9 2

0

2

4

6

8

10

12

14

16

18

20

mg/l

Gut toxins in patients suffering CFS/ME: the endogenous brewerysyndrome


betaHCH gammaHCHPentachlorani

linPCP p-p-DDE p-p-DDT HCB

CFS 0.258 0.0703 0.432 1.45 2.095 0.1935 0.2839

Referenz 0.01 0.01 0.01 0.01 0.01 0.01 0.01

0

0.5

1

1.5

2

2.5

3

ug/l

Loading with pesticides in patients suffering CFS/ME


Ethylbenzol Xylol Toluol Trimethylbenzol Benzol

CFS 27.164 22.298 13.737 3.53 0.9867

Referenz 2 1.4 5 1 0.5

0

5

10

15

20

25

30

35

ug/l

Loading with benzene and benzene homologous in patients suffering ME/CFS


0

10

20

30

40

50

60

Pe

rcen

tage

of d

istr

ibu

tio

n

Distribution of heavy metals in INUSpheresis®-eluate in patients sufferingME/CFS


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

SOD2 n SOD2 red

Rela

tive f

requency

Distribution of activity of superoxiddsimutase in

patients suffering ME/CFS

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

CYP1A2 n CYP1A2 h NAT2 <50%NAT2 >50%

Rela

tive f

requency

Comprehension of the activities of CYP1A2 and NAT2 in patients

suffering ME/CFS

Features of genetic disturbances in cellular detoxification for (environmental)-toxins

Superoxid-dismutase (SOD2), Cytochrome P450 Typ 1A2 , N-Acetyltransferase


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

PON L55n

PONL55red

PONQ192n

PONQ192 red

rela

tive H

äufigkeit

Distribution of polymoprhismactivity of PON L55 and PON

Q192 in patients sufferingCFS/ME

0

0.1

0.2

0.3

0.4

0.5

0.6

realiv

e H

äufigkeit

Distribuiton of polymorphismactivity of mEH3 und mEH4 of

patients suffering CFS/ME

Features of genetic disturbances in cellular detoxification for (environmental)-toxins:

Paraoxonase (PON) and microsomal epoxide-hydroxilase (mEH)


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

COMT n COMT red COMT h

rela

tive H

äufigkeit

Distribution of COMT Polymorphism in patients suffering ME/CFS

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

TPH1 n TPH1 red TPH2 n TPH2 red

rela

tive H

äufigkeit

Distribution of polymorphism in TPH1 and TPH2 in patients suffering ME/CFS

Features of genetic disturbances in brain metabolism:

Catechol-oxygen-methyl-transferase(COMT) and tryptophan hydroxilase Type 1/2 (TPH1/2


y = -0,6442x4 + 13,342x3 - 88,641x2 + 215,85x - 126,78R² = 1

0

5

10

15

20

25

30

35

40

45

50

75-100% 50-75% 25-50% 10-25% 0-10%

Verb

esseru

ngm

in %

Improvement of clinical status “after Cerebropheresis” in relation to status “before Cerebropheresis® “

Cerebropheresis® as a innovative holistic procedere as option for treatment for

Myalgic encephalomyelitis syn. chronic fatigue syndrom


13.45

7.7

9.6

7.43

5.4

4.12

5.72

3.93

0

2

4

6

8

10

12

14

16

ug/l

Reduction of neurotransmitterantibodies against beta1 and beta 2

adrenerge rezeptors, and muskarinerge Type3 und Type4

acetylcholinrezeptors byCerebropheresis®

CICIgA

CICIgG

CICIgM

CICC3c

CICC1q

vor 80.6 230 150.6 40.7 97.25

nach 44.8 142 103 27.4 61.2

Referenz 25 147 77 35 97

0

50

100

150

200

250

300

ug/m

l

Effects of cerebropheresis® on circulating immuncomplexes in patients

suffering CFS/ME




beforeCerebropheresi

s

aftercerebropheresi

s

cut off

ATP 1.97 3.4 2.5

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

um

ol/l

Improvement of ATP-levels by cerebropheresis® in

patients suffering ME/CFS

0

0.05

0.1

0.15

0.2

0.25

0.3

rela

tive H

äufigkeit

Relative frequency of ATP levels in home care patients at care level




Cholesterin Triglyceride LDL HDL Lp(a) Homocystein

vor Apherese 244.4 310 146.55 53.9 46.2 16.3

nach Apherese 101.5 168.6 71 31.6 24 14.1

Referenz 180 200 80 40 30 10

0

50

100

150

200

250

300

350

400

mg/d

l buw

um

ol

Effect of lipoproteinsystems in patients suffering CFS/ME


beforeCerebropheresis

afterCerebropheresis

cut off

ROSX H2O2 62.976 6.88 20

0

10

20

30

40

50

60

70

80

90

mg/d

l H

2O

2

Reduction of H2O2 by cerebropheresis®

representing mitochondrial oxidative stress in patients

suffering ME/CFS

beforecerebroph

eresis

aftercerebroph

eresiscut off

Nitrotyrosin 986.9 444 650

0

200

400

600

800

1000

1200

1400

nm

ol/l

Reduction of nitrosative mitochondrial stress marked as Nitrotyrosin in patients suffering

ME/CFS




beforecerebroph

eresis

aftercerebroph

eresiscut off

sCRP 5.28 2.49 2

0

1

2

3

4

5

6

7

mg/d

l

Reduction of sCRP by cerebropheresis® in patients

suffering ME/CFS

beforecerebropheresis

aftercerebropheresis

cut off

RANTES (CCL5) 45.96 24.37 30

0

10

20

30

40

50

60

ug/l

Reduction of RANTES (CCL5) by cerebropheresis® in patients

suffering ME/CFS


Myalgic encephalomyelitis syn. chronic fatigue syndrom.


Conclusions

• Myalgic encephalomyelitis is the pathophysiologic/pathobiochemical base for

• the clinical picture of chronic fatigue syndrom (ICD 10 G93.3)

The background of myalgic encephalomeylitis are:

• Neurotransmitter receptor autantibodies against beta1/2 und M3/4 receptors in the brain

• Pathologic circulating inflammatoric immuncomplexes, atypical gangliosid autantibbodies

These irregulare autantibodies are based on:

• Multilevel inflammation as sCRP/RANTES/ECP/TNFalpha/fibrinogen/alpha2Makroglobulin

• Mitochondrial stress caused by inflammation causing an oxidative and nitrosative stress

• Leading to depression of ATP by breaking down the Krebs-Cyclus and loss of ubichinone

• This induces: dyslioproteinemia

For these in the background are responsible:

• Chronic infectious diesease as in 1st line: Borreliosis and Chlamydiosis but also parasites

• Additional: loading with toxins (heavy metals, solvents, pesticides)

• Additional: Leaky gut syndrom producing an „enterogene brewery syndrom“

• At least disturbances in the genetic intracellular detoxification capacity for environmental toxins

For socialand health systems now and in future:

engagement for patients in ME/CFS as not psychiatric but evidenced based diagnostic for backgrounds and

providing holistic effective therapy as Cerebropheresis® to save costs in the systems .


chronic fatigue syndrom (cfs) a challenge for medicine and ... · evidences of international inus...

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