Neuropathies des

vasculites (systémiques)

thierry.kuntzer@chuv.ch

Le diagnostic et les traitements des neuropathies

vasculitiques sont pluridisciplinaires

• Contexte clinique

• Résultats biologiques et recherche de

biomarqueurs

• Electrophysiologie

• Chirurgie et pathologie

• Importance du suivi

Contexte clinique • Atteinte aigue, sub-aigue, chronique, par paliers?

• Différents systèmes potentiellement ciblés?

• Raisonnement phénotypique: propédeutique mais utile:

6 TTR - FAP

1 = P03 LL - leprosis

# Age

at

EXA

Sex,

male

=1

Age

at

onset

Dur CTS TTR

gene

Drug Skin BMI NSS OH NIS_LL aN

SNAP

H

echo

TTR

FAP

stag

PND TTR-

FAP

Class

Total Mot Sen aut Total W R S

P01 37 0 27 10 1 Val30Met

1 1 28.5 4 0 2 2 1 6 0 0 6 1 0 1 1 2

P02 50 0 45 10 1 Val30Met

1 0 31.2 2 0 2 0 0 2 0 0 2 0 0 1 1 1

P03 53 1 39 5 1 Leprosis

0 0 28.7 10 3 5 2 1 27 8 3 16 1 0 3

P04 51 0 35 14 0 Val30Met

1 0 29.8 5 2 2 1 1 12 2 4 6 1 1 1 2 3

P06 55 0 46 9 1 Glu89Lys

1 0 28.3 4 0 2 2 1 6 0 2 4 1 1 1 1 2

P09 37 0 23 14 0 Val30Met

1 0 29 2 0 2 0 0 0 0 0 0 0 0 1 0 1

P10 58 0 45 15 1 Val30Met

1 1 31.9 4 0 4 0 0 12 0 8 4 0 0 1 2 2

- clinical staging of TTR-FAP - polyneuropathy disability score - portuguese classification

neurological symptom score

neurological impairment score

Patient 2

Résultats de

la

conduction

nerveuse

Patient 1

Asymétrie = >50% différence des réponses, en amplitude ou surface

Vasculitis in nerve & muscle Vital C et al. JPNS 2006

• Necrotizing vasculitis – microscopic polyangiitis (MPA)

– Or the classic panarteritis nodosa (PAN), according to Chapel Hill CCNV (Jennette et al.1994).

• Microvasculitis that involves smaller vessels with few smooth-muscle fibers and whose walls are infiltrated by inflammatory cells without any necrosis (Vincent et al., 1985; Dyck et al. 1999; 2000) , sometimes reported as lymphocytic vasculitis (Said, 1995; Lacomis et al., 1997; King, 1999).

• Inflammatory perivascular infiltrates – no specificity (can be observed in any other inflammatory process).

– However, IPI are in favor of probable vasculitis if they are associated with at least one of the following features: regenerating small vessels, endoneurial purpura, asymmetric nerve fiber loss, or asymmetric acute axonal degeneration

• Combined biopsy of nerve and muscle > nerve only, by 27% (Vital et al. JPNS 2006)

PNS Classification of vasculitic neuropathies Gwathmey et al. Lancet Neurol 2014

• Primary systemic vasculitides (mostly nerve large arteriole)

• Secondary systemic vasculitides (mostly nerve large arteriole)

• Non-systemic or localised vasculitides (mostly nerve microvasculitides)

≠ CHCCNV, Jennette et al. Arthritis Rheum 2013 all vessels in peripheral nerves, including the largest arteries, are

categorised as small vessels

division of small vessel vasculitis into 2 categories

• with vessel wall immunoglobulin deposition, and without (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis).

• Microscopic polyangiitis, Wegener’s granulomatosis (recently renamed granulomatosis with polyangiitis), and Churg- Strauss syndrome (recently renamed eosinophilic granulomatosis with polyangiitis) fall under the category of ANCA-associated vasculitis.

*ANCA-associated vasculitides

Prévalence relative des affections

comportant une neuropathie par

vasculite (=505)

Panartérite noueuse 31%

PAN restreint au SNP 38%

Polyarthrite rhumatoïde 16%

Syndrome de Churg &

Strauss

7%

Connectivite mixte 7%

Syndrome de Sjögren 3%

Lupus systémique 3%

VIH 1%

Cryoglobulinémie essentielle 1%

Wegener 1%

Divers (cancer, sclérodermie) 2%

Selon Kissel KT, Syllabus AAN 2009

2005-15: 50 dossiers

15 hommes; âge moyen de 64 (34-87)

Type de vasculite: 24/50 avec une vasculite non-systémique

• 19 vasculite nécrosante: – 5 I systémique: 5 PAN

– 5 II systémique: 1 HIV, 1 HCV, 2 PR, 1 SS

– 9 non systémique

• 13 microvasculite: – 5 I systémique: 5 PAN, 2 cryo, 1 Wegener

– 4 II systémique: 3 SS, 1 Crest

– 4 non systémique

• 18 infiltrat inflammatoire périvasculaire : – 5 I systémique: 3 PAN,1 cryo, 1 Wegener

– 2 II systémique: 1 sclérodermie, 1 Crest

– 11 non systémique

Type de neuropathie – Mononeuropathie multiple; sensitive; SM; mononeuropathie

Gwathmey et al. Lancet Neurol 2014

2859416

2426358

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un

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C A

nto

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, A

J S

teck , M

uscle

& N

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e 2

004

Callaghan BC. Lancet Neurol 2012

Potential patterns of nerve injury in patients with diabetes: can have more than one pattern of nerve injury or have radiculopathy without a disc herniation The following patterns of nerve injury are shown in the figure: A. distal symmetrical polyneuropathy, & small-fibre predominant neuropathy B. radiculoplexopathy and radiculopathy C. mononeuropathy and mononeuritis multiplex D. autonomic neuropathy

Callaghan BC. Lancet Neurol 2012

Potential patterns of nerve injury in patients with diabetes: can have more than one pattern of nerve injury or have radiculopathy without a disc herniation The following patterns of nerve injury are shown in the figure: A. distal symmetrical polyneuropathy, & small-fibre predominant neuropathy B. radiculoplexopathy and radiculopathy C. mononeuropathy and mononeuritis multiplex D. autonomic neuropathy NOT SEEN IN PRIMARY OR SECONDARY VN

Callaghan BC. Lancet Neurol 2012

Patiente de 72 ans

• Hospitalisée pour suspicion

d'une maladie du

motoneurone:

• nov 2013: perte de force

progressive des MS, à

prédominance proximale et

gauche

• diminution de l'endurance avec

fatigabilité musculaire, mais

peut marcher environ 60

minutes et monter les escaliers

• Amyotrophie des membressupérieurs proximo-distale

• Parésie proximale avec :– D: abduction épaule M4+,

extension coude M4+, flexioncoude M5-, extension poignetM5, distalement M5

– G: abduction épaule M4,extension coude M3+, flexioncoude M4-, extension poignetM4+, extension des doigts etécartement à M3, flexion desdoigts à M4;

• Aréflexie aux membressupérieurs

bilan biologique

• CK à 219

• fonctions rénale et hépatique N

• vitamine B12, folate), sérologie (Lyme, syphilis, HIV, hépatite E), endocrinien (TSH, PTHi) et électrophorèse des protéines : normales

• Auto-anticorps : facteur rhumatoïde à 366 et ANA 1/640 mouchetés, anticytoplasme positifs

• HCV et HBV et anticorps antiphospholipides et cryoglobulines négatives; le complément C4 est par contre consommé à 0.03

NP motrice >>> sensitive avec vasculite nécrosante

Traitement Pre & Cyc 6 fois

Evolution avec rupture coiffe de rotateurs

Mme CL Mme RC

Anamnèse Perte d'endurance à la

marche avec talalgies,

gonflement des chevilles

Brulures-picotements

avec dysesthésies des

pieds, insomniantes

(G>D), ↑ par les

contraintes mécaniques

AVQ Autonome Autonome

AP Douleurs abdominales X

(2012)

OP bilatérale des

hanches, canal

carpien bilatéral,

migraine

cataméniale

Examen

Œdème douloureux de la

face postérieure des

chevilles et du pied G

Hypertrophie nerveuse

cervicale?

NP purement sensitives

Examens Mme CL Mme RC

Formule sanguine

&

chimie

Nl Hypovitaminose B12

Sérologies HCV, HIV, syphilis,

Borrélies

HCV, HIV, syphilis,

Borrélies

Auto-anticorps Douleurs abdominales X

(2012)

OP bilatérale des hanches,

canal carpien bilatéral,

migraine cataméniale

Imagerie Radiographie du thorax nl

US des tendons d'Achille:

Aspect tumoral des nerfs

tibial et sural D, confirmé

par IRM musculaire

CT-scan thoraco-

abdominal nl

Autre Frottis nasal nl Biopsie nl de glande

salivaire accessoire

CL RC

hématoxyline-éosine

CL RC

Semi-fine protéine basique de la myéline

CL RC

Immunomarquages CD68 &CD3

Synthèse Mme CL Mme RC

Phénotype MNM sensitive MNM sensitive

Facteurs de

risque

Séjours au Brésil Séjours au Brésil

ENMG Perte axonale S>M,

asymétrique

Perte axonale S>M,

asymétrique

Biologie et FS Pas informatif Pas informatif

Biopsie

nerveuse

neuropathie axonale multifocale,

avec atteinte interstitielle

(œdème, fibrose, granulomatose

tuberculoide), avec périvasculite

Lympho-monocytaire

neuropathie axonale

multifocale,

inhomogene, avec atteinte

interstitielle (fibrose peri- et

epineurale) avec vasculite

lymphocytaire de vasa

nervorum

Diagnostic

retenu

Lèpre tuberculoïde, isolée du nerf

périphérique

Micro-vasculite de type PAN,

isolée du nerf péripherique

Traitements Rifampicine 600mg/j, Dapsone

100mg/j (6 mois)

Pregabaline 150 mg 4x/j,

paracetamol 3g/j

Prednisone 20mg/j (total de 20 j)

Rituximab 2x1g

Pregabaline 150 mg/j,

Paracetamol 3g/j

0

0 0

0

Clinical presentation

• sudden development of proximal deep aching pain in the limb followed by burning cutaneous pain and focal weakness in the territory of a single nerve; and within days to weeks, other nerves become involved, resulting in the MMN

• many overlapping mononeuropathies may combine to yield a symmetrical or asymmetrical distally accentuated polyneuropathy

• 30% of patients present with a slowly progressive onset, non-stepwise course

• Infarction of nerve usually occurs proximally, for example, in the mid-sciatic nerve and other distal nerves in the upper and lower extremities are less commonly damaged

• In a few patients, cranial nerves are affected (Wegener’s granulomatosis most commonly constitutional symptoms

Classic NSVN (mostly nerve

microvasculitis)

• similar in many respects to that of SVN

• average age at onset around 60 years

• women seem to be preferentially affected

• confined to the nerves and muscles

• progressing more slowly, with less frequent attacks

• not being fatal if untreated

• not causing severe constitutional symptoms or markedly abnormal laboratory

• Combined data from all reported series and cases with sufficiently detailed clinical information suggest a different breakdown of nerve pattern involvement: 45% multiple mononeuropathy, 30% asymmetrical polyneuropathy, and 25% distal symmetrical polyneuropathy

• Classic NSVN, like SVN, tends to attack both sensory and motor nerves, but 15% have predominantly sensory findings.

• Pain is a frequent symptom, occurring in up to 96% in some series.

• Around 10% of cases initially diagnosed as classic NSVN later evolve into systemic vasculitis, and patients must be followed up for this possibility.

• NSVN is part of the continuum of systemic vasculitis:

– In support, microscopic polyangiitis and NSVN share many clinicopathological features.

– Against this proposition, NSVN also has several unique features, including much better prognosis (rarely fatal), generally milder severity, relapses confined to the PNS, infrequent spread to other organs during prolonged follow-up, and rare incidence of ANCAs.

Consensus recommendations for laboratory

investigation of suspected vasculitic neuropathy Gwathmey et al. Lancet Neurol 2014

Routinely indicated studies:

• Complete blood count, eosinophil count

• chemistry panel (electrolytes, renal function, and liver function)

• urinalysis, glycated haemoglobin,

• erythrocyte sedimentation rate, C-reactive protein,

• antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies,

• serum protein immunofixation electrophoresis, complement (C3, C4, total), cryoglobulins, hepatitis B surface antigen, hepatitis C antibodies, and chest x-ray.

Occasionally indicated studies:

• SSA or SSB antibodies, other antibodies against extractable nuclear antigens, double-stranded DNA antibodies, cyclic citrullinated peptide antibodies, angiotensin converting enzyme, lysozyme, vascular endothelial growth factor, β2-microglobulin, HIV antibodies, Lyme antibodies, hepatitis C RNA, cytomegalovirus antigen or DNA, paraneoplastic autoantibodies, lactate dehydrogenase, HDL cholesterol, porphyria screen,

• DNA for PMP22 deletion associated with hereditary neuropathy with liability to pressure palsies, DNA for transthyretin gene, chest CT, gallium-67 scan, visceral angiography, salivary gland biopsy, lumbar puncture, and other body imaging for malignancy.

Wiik A, Cur Opin Rheumat, 2008

Traitements Vrancken AFJE. Cochrane Database Syst Rev 2007

– Prednisone 1mg/kg/j 3 mois, puis 25, 20, 10 jusqu’à 6

mois

– Cyclophosphamide en bolus i.v., 0.6g/m2 toutes les 2

sem 3x, puis 0.7g/m2 toutes les 3 sem, 3-6 doses (de Groot K et al. Ann Intern Med. 2009)

– Autres (RAVE-ITN Research Group : Stone JH et al N Engl J

Med. 2010: 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis, Rituximab versus

cyclophosphamide)

Mais aussi fonction du contexte associé!

Conclusions

Recommandations

-- PNS Gwathmey et al. Lancet Neurol 2014

-- CHCCNV Jennette et al. Arthritis Rheum 2013 Plateau technique

+autres pôles médicaux

NLG

+

IAL

+

Vasculite non-systémique du NP

Vasculite systémique

Limitations :

Absence de données nouvelles concernant la dysrégulation immune; quelles voies

d’activation de l’autoimmunité et du maintien inflammatoire?

Analogie possible?

-- Myosites: mTOR is expressed in Polymyositis but not in sporadic IBM. Clinical

Neuropathology 2015

-- Neuropathies inflammatoires: Gene expression changes in chronic inflammatory

demyelinating polyneuropathy skin biopsies. J Neuroimmunology 2014