multiple sclerosis allied demyelinating diseases neuroimmunology & glycobiology 蔡清標...

Multiple Sclerosis Allied Demyelinating DiseasesNeuroimmunology & Glycobiology

蔡清標副教授 Msci MD

國立陽明大學台北榮民總醫院

Figure 2

BI 2004Essential Animal Cell Biology

Cell membranes 1The lipid bilayer

Dr Gordon McEwanDepartment of Biomedical Sciences

Lipid bilayer

Lipidmolecule

Proteinmolecule

Lipidbilayer(5 nm)

Adapted from ECB Fig 11-4

Myelin antigen : proteins and lipids

PROTEINS proteolipid protein myelin basic protein wolfgram fraction myelin associated glycoprotein MAG

Myelin antigen : proteins and lipids

LIPIDS Glycolipid galactocerebroside sulfatide gangliosides. GM1 GM4 etc

glycosphingolipids in peripheral neuroapthies

glycosphingolipids --cell surface molecules– hydrophilic sugar moiety– hydrophobic ceramide– as autoantigens development of certain autoimmune d

iseases– antigen reaction side at sugar moiety

Glycolipid terminology and structure

long chain aliphatic amine sphingosine (acylated ceramide)

attached to one or more sugars ceramide immersed in the lipid bilayer carbonhydrate structure exposed extracellularly

Metabolic Defect

Glycolipid structures

cerebroside -- monohexosyl ceramide galactocerebroside -- galactosyl ceramide sulfatide -- galactocerebroside sulfated

in the carbon-3 position main antigen in sensory predominantly neuropathies

Glycolipid structures

gangliosides complex glycosphingolipids sialic acid residues M mono D di T tri

GM1 G ganglioside M mono sialic acid

1 sequence of migration by TLC

Gangliosides in the brain

four major gangliosides in the brain

GM1 GD1a GD1b GT1b

Metabolic Defect Fabry’s Disease

Vascular Endothelium

SevereendothelialGL-3 accumulation

Multisystemic Manifestations

Progressive accumulation of GL-3 causes increasing involvement of multiple organ systems.

Neurologic Dermatologic Ocular Gastrointestinal

Renal Cardiac Cerebrovascular

Signs and Symptoms

Early ischemic stroke

Left ventricular hypertrophy

Angiokeratomas

Acroparesthesia

Acroparesthesia

Progressive renal insufficiency

Hypohidrosis

Demyelination and Dysmyelination

Adrenoleukodystrophy X-linked recessive 1/20,000 Impairment in peroxismal oxidation of very long

chain fatty acids Accumulation in the brain and adrenal gland

Adrenoleukodystrophy 4 y/o bronzing skin 7 y/o dysarthria, dysphonia, quadriparesis 8 Y/o seizure Decerebrate posture bed ridden before death

glycolipids

autoantigens for the development of autoimmune diseases

demyelinating polyneuropathy motor neuron disease multiple motor neuropathy with

conduction block AIDP CIDP

Reaction site of glycolipid antibody

react with epitopes on the carbonhydrate region

shared reactivity for bacterial lipopolysaccharides

react with SGPG and MAG

Anti-glycolipid antibodies are pathogenic

improved disease progression and clinical S/S accompanying a decreased antibody titer

therapeutic reduction of these antibodiesby plasmapheresis immunos

uppressents

Ganglioside antibodies in patients with neuropathy

Acute inflammatory demyelinating polyneuroapthy AIDP 30% with GM1 Ab

Chronic inflammatory demyelinating polyneuropayhy CIDP

multiple motor neuropathy with conduction block MMN

Lower motor neuron syndrome LMNS GQ1b in Miller Fisher Syndrome 90% GBS 2.7%

Figure 1


MAG Myelin associated glycoprotein and SGGL

– MGUS monoclonal gammopathy Sulfatide antibody

– Sensory neuronopathy GQ1b ganlioside

– Miller-fisher syndrome

Antibodies to sulfatides

Pestronk et al 1991 sulfatide antibodies Sensory neuropathy esp in sensory axonopathy primary Sjogren syndrome

– first case report in Taiwan bind to DRG neuron sensory axon acidic glycolipid SGGL MAG


glycosphingolipids are constituents of nerve cells antibodies to glycosphingolipids found in certain auto

immune disorders GM1 in

– GBS Guillain-Barre syndrome

– MMN multiple motor neuropathy

– MND motor neuron disease

– LMN lower motor neuron syndrome

Serum anti-GM1 antibodies in patients with motor neuron disease

A Pestronk USA 1988 Neurol High GM1 Ab in ALS ALS 42/74 57%

normal control 2/23 9% Lower ALS 21/29 72%

Upper ALS 1/15 7% Upper and Lower ALS 20/30 67%


Salazar-Grueso USA 1990 Ann Neurol MND 9/48 19%

OND -- Other neurological disease 4/40 10%

As frequent as other neurological disease Markedly elevated titer -- more significant

Clinical correlations of anti-GM1 antibodies in ALS and Neuropathy

Nancy L LAMB USA 1991 Muscle & Nerve positive titer

ALS 7/16 44% 57 ALS and gammopathy 6/6 100% 246 Motor CIDP 10/13 77% 562 Motor neuropathy 7/9 78% 556


C.Voumvourakis Athens Greece 1992 E.Neurol 100 individuals 20 with MND 25 with PN and 4

0 controls significant P<0.05 IgM GM1 Ab in MND


W-J HSU Hsu-Chuan China 1992 Lower ALS 4/6 67%

Upper ALS 4/6 67%Upper and Lower 9/14 64.2

Control 2/18 11.1% P<0.001

Population based case control study

Willison HJ UK 1993 J. Neurological Sciences 82 cases of MND and matched for age sex and ge

ographical area GM1 antibodies in

26% MND and 18% Controlsno significant autoimmune basis in sp

oradic ALS


C-P TSAI TAIWAN 1994 CMJ MND 32/52 62% PN

10/38 26% Upper and Lower ALS 7/22 32%

Lower ALS 25/30 83%All ALS 32/52 62%

Diagnostic value of GM1 antibodies in motor neuron disorders

Van Schaik IN The Netherlands 1995 Neurology The frequency of GM1 antibodies ranged from

MMN 0-100%GBS 0-33%ALS 0-65%

LMN 0-81%CIDP 0-77%

Diagnostic value of GM1 antibodies in motor neuron disorders

RK YU Richmond USA anti-GM1 antibody titer in most cases of ALS are

considerably lower than those in LMN and motor neuropathy

Pathogenesis of GM1 antibodies

antibodies to GM1 at the nodes of Ranvier in human and experimental autoimmune neuropathy Microscopy Research and Technique 1996

anti-GM1 M-protein damage human spinal cord neurons co-cultured with muscles Journal of the Neurological Sciences 1993

Conclusion

GM1 antibodies elevated in many cases with neurological disease

ALS -- elervated but low titer Lower motor neuron syndrome -- high titer MMN with conduction block -- high titer Treatment not effective in cases without conducti

on block

Guillain-Barre syndromeclinical spectrum

AIDP AMSAN C. J

ejuni cross reaction GM1 axonal loss axolemma at nodes of Ranvier

Miller-Fisher some C. Jejuni strain GQ1b nodal region of 3 rd nerve and cerebellar neuron

Figure 1

Figure 1 GQ1b and LPS core OS structures. The entire structure for GQ1b is shown. Other gangliosides and core LPSs are highlighted. NeuAc = N-acetyl neuraminic acid; Gal = galactose; GaINAc = N-acetyl galactosamine; X = Glc (1->1) ceramide (gangliosides) or the remaining core OS/lipid A (LPSs). From: Goodyear: J Clin Invest, Volume 104(6).September 1999.697-708

Guillain-Barre syndrome

Diagnosis criteria1.Required

progressive weakness and areflexia

2.supportingprogressive days to weeks

realtively symmetry mild sensor cranial nerve autonomic

dysfunction and CSF protein


Epidemiology1.3-1.9/100,000 Taiwan 400/year

occur in all ages peak in adult another peak in the elderly

8.6/100,000 over 70Y/O


preceding events antecedent infection 2/3

patients had URI or GI disturbance eg. diarrhea onset to peak plateau 11days virus: CMV 10-20% EB 10% Campylobacter Jejuni 20-40%

HS-19 AMSAN 60% GM1 AMSAN GQ1b MFS


vaccine and GBS rabies antigen 1890 Swine-flue influenza 1976 sligh

tly elevated risk of GBS Recent studies at N Eng J Med no r

elationship


AMSAN and AMAN 10-20% of GBS primary immune reaction attack directed on nerve ax

ons EMG showed CMAPs more severe form ventilation in 2-4 days poor recovery biospy: axonal degeneration


AMAN and AMSAN Campylobacter Jejuni in North China 60-70% seropositive to C.Jejunipathology showed IgG to the axolemm

a at node of Ranvier


MFS Miller-Fisher Syndrome another serotype of C.Jejuni GQ1b antibody 96% GQ1b in nodal region of oculomotor nerve, do

rsal root ganglion and cerebellum ophthalmoplegia, ataxia and areflexia

GQ1b in Miller-Fisher Syndrome

lipopolysaccharides in Campylobaccter jujuni surface epitope C jujuni GalNacB1-4GalB1-4GlcB1

– Neu5Aca2 – GQ1b 3GalNacB1-4GalB1-1– Neu5Aca2-8neu5Aca2

GQ1b in Miller Fisher syndrome Yuki et al 1993

GQ1b in MFS related to ataxia ophthalmoplegia

immnnostaining at paranodal region of human oculomotor trochlear and abducences with GQ1b monoclonal antibodies

GQ1b binding to cerebeller molecular layer 1996 Kornberg St louis

anti cerebellar antibody 1995 Japan

post-infectious neuritis

facial palsy isolated 3rd 4th 6th nerve palsy vestibular neuritis (Yu RK 1997 63.6% SGLPG

rich in inner ear and cochlear nerve) hypoglossal neuritis cranial polyneuropathy (1997 Matsuchiba et al)

Why post infectious?

Campylobacter jejunilipopolysaccharides share the same epitope

of ganglioside

3 group 1. motor GBS and CJ infection GM1 2. sensory GBS and EBV 3. motor and cranial n. CJ

and GQ1b

why different virus induce same AIDP ?

virus and interferon alpha beta and gamma interferon gamma interferon induced expression of class II myelin cell act as Antigen presenting cell APCs ongoing autoimmune demyelination occurred

why different nerve?

Sulfatide, SGGL rich in dorsal root ganglion GQ1b rich in oculomotor nerve 1993 Chiba et al 11.6- 13.2 % in oculomotor and 5.2-8.4% in other

nerve

Pathophysiology of GBS

humoral or cellular mechanism activation of complement and deposition of mem

branolytic attack complex on myelin circulating antiganglioside antibody cytokines interferon autoimmune disordertriggered by antecedent

bacteria or viral infection

Figure 1

Figure 1 GQ1b and LPS core OS structures. The entire structure for GQ1b is shown. Other gangliosides and core LPSs are highlighted. NeuAc = N-acetyl neuraminic acid; Gal = galactose; GaINAc = N-acetyl galactosamine; X = Glc (1->1) ceramide (gangliosides) or the remaining core OS/lipid A (LPSs). From: Goodyear: J Clin Invest, Volume 104(6).September 1999.697-708

GQ1b in Miller Fisher Syndrome

Ching-Piao TSAI Msci MD

Neurological Institute

Veterans General Hospital TAIPEI

Miller-Fisher Syndrome

49 GBS and 11 MFS in the past 10 years age 12-78 mean age of onset 44 8 males and 3 females 4/5 had positive GQ1b antibodies


Primary care 33% cases need ventialtion autonomic and hemodynamic changes arrhythmia airway protect bowel care and nutrition pain management mortality 5-8%

Treatment of Guillain-Barre syndrome

steroid : methylprednisolone immunosuppressive : fucidin interferon CSF pheresis plasmapheresis IVIG PP and IVIG IVIG and methylprednisolone


plasmapheresis North American trial of 245 cases within 2 weeks of the disease 122 PP 50ml/kg 5 changes 123 convential treatment


Results wean ventilator ambulation

PP 24 days 53 days control 53 days 85 days 1 year later PP 71% control 52%

full motor strength less ICU days no effect after 2 weeks


secondary worsening persistent active phase or antibody rebound

impreoved by additional changes

recommendation

2 changes for mild and 4-5 for severe start as soon as possible


IVIG 1992 Netherland 150 GBS 0.4gm/kg for 5 days vs PP equal efficiency not equally matched of the 2 group


1997 Hughes383 cases 38 centers in 11 countries 121 PP 50ml/kg 5 changes 130 IVIG 0.4gm/kg /day for 5 days

128 PP and IVIG PP and IVIG had similar effect combination of PP and IVIG

no additional effect


IVIG plus methylprednisolone IVIG 0.4gm/kg and MP 500mg/day

1994 Ann Neurol Dutch GBS group 19/25 (76%) improved one score in IVIG plus

MP infusion after 4 weeks 39/74 (53%) IVIG alone remove humoral factor and B cell function


Appropriate number of PP? mild walk more than 5m can not run

2 courses of PP moderate unable to stand unaided

4 pp severe ventilator needed

6 PP


Lancet 1997 London RAC Hughes IVIG PP PP + IVIG seven point disability grade score 0. health 1. minor S/S able to run 2.able to wa

lk 5m without aid 3. able to walk 5m with aid 4. unable to walk bed bound 5. require ventialtion 6. dead

Guillain-Barre syndrome 4 weeks later PE 0.9 point IVIG 0.8 PE and IVIG 1.1 secondary outcome measure : time to recovery of una

ided walking, DC ventilation, recovery from disability

PE and IVIG of equal effect combination of PP and IVIG do not confer better

IVIG and PP for GBS in VGH

IVIG 8 cases 3 with ventilator weaning 7-28 days

PP 10 cases 4 with ventilator weaning 9-32 days

PP and IVIG ventialtor 21 days ventialtor


steroid : no effect methylprednisolone ? Lancet 1993 double-blind trial IVMP 500mg/day for 5 days 0.06 grade improve in the IVMP vs control conclusion: IVMP is ineffective in GBS


CSF filtration CSFF Germany Wollinsky KH

compared with PP 32 GBS 15 with CSFF daily filtration 200-300 ml 1

7 with PP PP 23D and CSFF 23.5 one score improvement PP 51 CSFF 43 walking unaid PP and CSFF equal effective

Treatment of GBS with interferon 47 Y/O male diarrhea and flue like syndrome 1 week later severe paresis of 4 limbs C jejuni 1:128 GM1 1:400 abscence responses to PP EMG/NCV peroneal and tibial <0.1MV slow NCV 38-35m/sec normal sensory molecular mimicy cross reaction with ganglioside surface GBS--AIDP 85% Sc cell, demyelination GBS--Axonal form 15% axonal GM1

Treatment of GBS with interferon

cytokine : inetrferon in EAN MHC expression MS Beta interferon decreases the severity of M

S relapse modulates the course of experimental allergic

neuritis EAN

Treatment of GBS with interferon

4 courses of plasma phresis 50ml/kg QOD day 12 B-interferon 6 MIU/QOD day 28 treatment interrupted patient can walk 10m without aid 1 year later able to walk for 1 km


immunosuppressant sodium fusiadte (fucidin) 1.5gm/week rapid decline in the cytokine concentration interleukin-2 , gamma-interferon ,TNF


Poor prognosis 1. age greater than 60Y/O 2. rapid progression to quadriplegia in 7 days

3. need ventialtion 4.CMAPs less than 20% 5. preceding events with diarrhea

IVIG Immunomodulatory actions

inhibition of complement deposition neutralization of cytokines modulation of Fc-receptor mediated phagocytosis down regulation of autoantibody regulation

Effect of IVIG in Neurological Disease

Guillain-Barre syndrome multifocal motor neuropathy MMN CIDP dermatomyositis myasthenia gravis myasthenia syndrome

Effect of IVIG in Neurological Disease

inclusion body myositis paraneoplastic IgM demyelinating polyneuropath

y intractable childhood epilepsy multiple sclerosis optic neuritis

Safety of IVIG

3000-10000 donors each batch HIV hepatitis A B C inactivated by fractionantion process low pH detergents and enzyme CJD

Adverse reaction of IVIG

aseptic meningitis skin reaction thromboembolic events renal tubular necrosis

Cost of treatment

0.4gm/kg 25gm/day 12.5gm/10 bot/5days USA 6440-11200 USD/month Taiwan 600 USD/bot 6000 USD/per course 180,000 - 200,000 NT/per course

IVIG in CIDP

steroid first choice 1994 Dyck PJ 20 cases

controlled randomized cross overequally effective in muscle strengthand CMAPs amplitudes

1995 Hahn AF IVIG double-blind placebo-controlled cross over

IVIG in lower motor neuron syndrome

lower motor neuron syndrome with elevated GM1 antibody

poor responses to cyclophosphamide Kimura J reported 2 cases no conventional conduction block block may be

at the proximal part

IVIG in MMN with conduction block

poor responses to steroid and PP 1993 Chaudhry V Ann Neurol 1993 Nobile-Orazio Neurology

good responses to IVIG GM1 antibody not changed but IVIG can inhibit t

he binding of GM1 antibody to target antigen

IVIG in polyneuropathy with monoclonal gammapathy

1995 Dalakas MC Ann neurol 3/11 cases improved after medication

MAG and anti-glycolipid antibodynot changed after IVIG

IVIG in monoclonal gammapathywith polyneuropathy

over 50Y/O 1/100 and 70Y/O 3/100 had paraproteinemia

63% MGUS 12% MM 9% Amyloid 8% CLL lymphoma


10% of MGUS monoclonal gammapathy of unknown significance had polyneuroapthy

idiopathic polyneuropathy 6-10% had paraproteinemia

MGUS IgG A M IgG A mainly motor IgM mainly sensory


IgM MGUS aged people sensory predominant progressive mild MAG (+) demyelination CIDP all ages sensory motor recurrent

IVIG in myasthenia gravis

1991 Cosi V Acta Neuro Scand 1994 Gajdos P Clin exp Immunol

60% improvement similar efficacy to PP many variable in MG well designed controlled study needed

IVIG in miscellaneous

Seizure Rasmussen syndrome with antibody to glutamate recepto

r intractable seizure such as Lennox-Gastaut syndrome assumption that the seizure is caused by post-viral encep

halitis syndeham chorea viral encephalitis

IVIG in miscellaneous

Jaan S 1992 J NNP 70% polymyositis had mild to moderate improvement after IVIG

Multiple SclerosisLancet 1997 Australian MS group148 cases relapsing-remitting MS

monthly infusion of IVIG for 2 yrs improve the course and reduce the relapsing freq

uency

Suggestion for IVIG

MMN and Myositis unresponsive to standard regimen

GBS CIDP

as effective as PP considered Ist choice MG myasthenia crisis in the elderly

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multiple sclerosis allied demyelinating diseases neuroimmunology & glycobiology 蔡清標...

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