MULTIPLE SCLEROSIS

NMOSD - Neuromyelitis optica spektrum disorders

ADEM - Acute disseminated encephalomyelitis

J.Szilasiová

Department of Neurology

LF UPJŠ Košice

11.3.2020

Multiple Sclerosis (MS)• Definition: chronic autoimmune

inflammatory disease of the CNS

• Damage of myeline and axons

• Inflammatory infiltrates

/lesions: disseminated in the

white and gray matter:

• Periventriculary, in the corpus

callosum, brain stem,

cerebellum and spinal cord

Epidemiology

• Occurance: young adults

• Onset: 20- 40 year

• F: M – 2 : 1

• Prevalency, Slovakia: 127 / 100 000 inhabitants

• Disease of the middle climate regions

• Geografic gradient of prevalence, higher in North America andEurope, decreases with geographic lattitude

• Highest prevalency: Scandinavia, British Islands (250 /100 000 inhab.), Orkney Islands

Etiopathogenesis• MS etiology is polyfactorial: genetic + external enviromental factors

• Enviromental: viral and bacterial infections, smoking, obesity, vitamin D deficiency, salt, low sun exposition

• „Susceptibility“ to MS - 200 genes

• Familial occurance of MS and increase risk for relatives – 10-30 %

Pathogenesis

Trigger factor of MS onset:

- Abnormal interaction betweenviral infection (EBV, CMV, Herpetic virus - antigen similarity, molecular mimicry) and neuronal system leads to an autoimmune attack to theCNS myelin antigens

Pathogenesisactivated TH1 cells admitt to the CNS = > cytokines (TNFa, IL-2, INFgama)

activation of Ma, B-Ly, antibodiesproduction

= > myeline destruction

=> demyelinative lesion -

plaque ("Sclerose en plaque") -progressive lost of axons -

brain and spinal cord atrophy

Ma- macrophage, TNF- tumor necrosis factor, IL- interleukin, INF- interferon,

Ly- lymphycytes

Pathogenesis

Inflammation and loss of myelin slows down nerve impulse conduction = > exposed axons are disrupted = axon damage = >progredient degeneration and neuronal pathways atrophy = > neurodegeneration

Disease progression (non treated MS patient)

time

Dis

ab

ility

pro

gre

ssio

n

Lesion accumulation- MRI

New gadolinium enhancing lesions

Cognitive dysfunction

Subclinical

Mono-symptomatic

First attackRelaps-remitting phase

Secondary-progressive phase

Relapses

Symptoms of MS

neurol. symptoms are caused by conductive block, or slowing of nerve impulses in demyelinative fibers

+ axonal loss - irreversible symptoms

depends on localization of the lesion, the pathway in which the lesion is located

summation of residual symptoms after relapses

Disease course, MS clinical phenotypes /forms

• Relapsing-remitting form / RRMS• 55-85%, a half of them go on to SPMS form after

approx. 10 years of disease course

• Primary progressive form / PPMS 15%

• Secondary – progressive form / SPMS

Attack, relapse

• Symptoms subjected to the patient, or objective finding

typical of an acute inflammatory demyelinating event of the

CNS, present or past

• New symptoms, or significant worsening of existing

symptoms

• Symptoms of an attack last at least 24 hours

• Absence of fever or infection

• The paroxysmal symptoms must last for at least 24 hours

• The attack is followed by a period of variable improvement

(full or partial)

• Pseudorelapse - fluctuation of symptoms during the day,

dependence on stress, body temperature and physical

exertion, menstrual cycle, co-morbidities

Clinical symptoms • Sensitivity and motor activity disturbances -limbs, trunk

and face

• Visual problems - blurred vision, scotoma, diplopia

• Balance problems - ataxia (vestibular, spinal, cerebellar)

• Fatigue, cognitive deficit, depression, neuropathic pain

• Sfincter problems

The manifestation of MS symptoms is given by the conduction block (or slowing) in the demyelinative lesion and axonal disruption (irreversible status)

They depend on the site of the lesion, the pathway that is damaged

CIS (Clinically Isolated Syndrome)

• The first, initial symptom/syndrom

• Episode of new demyelinative lesion

• Episode of the brain or spinal cord lesion

• The first MS attack

• Acute, or subacute episode related to the demyelination location

CIS - typical , monofocal symptoms- 2/3 of patients

- atypical- multifocal symptoms

MS onset, the first episode = Clinicaly isolated syndrome/CIS – monofocal or multifocal syndrome

Multifocal

syndromeMyelitis

Optic neuritis

Brainstem/

cerebellar

syndrome

CIS: Optic neuritis

• Unilateral optic nerve (n.II) infammation, and focaldemyelination

• Unilateral, blurred vision, retrobulbar pain, central scotoma, lossof color vision

• MRI shows hypersignal T2 lesion in the optic nerve

• Good prognosis, partial or complete recovery

CIS: Myelitis• Focal spinal cord inflammation and demyelination

• Cervical segments - most often affected

• Partial transverse lesion

• Sense difficulties

• Motor difficulties

• Lhermitte sign

• Sfincter problems

• Sense of „belt“

• Chest numbness

• Acute dystonia

CIS: Brainstem- cerebellar syndrome

• Oculomotor palsy (Internuclear ophthalmoplegia) - diplopia, strabism

• Nystagmus

• Sensitive syndromes

• Vertigo, ataxia

• Hemiparesis

• Trigeminal neuralgia

• Hemifacial spasm

• Cerebellar ataxia, dyzartria

• Rubral tremor

MS clinical symptoms

There is no symptom specific only for MS !

Vision - blurred vision, scotoma, loss of color vision, blindness, pain of eye bulb with movements

Eye bulb movement disorder – diplopia, ophthalmoplegia, nystagmus

V, VII, VIII, IX nn. lesion - trigeminal neuralgia, loss of sense of the face, paresthesia, vertigo, ataxia, dysarthria

Sensitivity disease - tactile, vibratory, paresthesias, dysesthesias, hypesthesia, anesthesia, ...

Movement disorders - spastic paresis or plegia, monoparesis, hemiparesis, quadriparesis, triparesis

Cerebellar symptoms - ataxia, dysarthria, intentiontremor, titubations

Sfincter dysfunction - imperative urgent micturition, urine retention, stool and uronary incontinence

Cognitive dysfunction - deficit of attention, memory, information processing speed

Fatigue

Autonomic dysfunction - arrythmia, hyperhidrosis, orthostatic hypotension, cold and cyanosis of limbs,...

EDSS - Expanded Disability Status Scale

Scale used in MS for scoring of the total disability

Functional systems:

1. Vision

2. Brain stem

3. Motor/pyramidal system

4. Sense

5. Cerebellum

6. Sfincters

7. Mental and mood problems - fatigue, cognitive function,

depression, anxiety

8. Ambulation (walking with or without aid)

EDSS scale

EDSS- 0 (min.) - 10 (max.) - impairment, disability

Prognosis of MS

• Depends on• frequency of relapses in the first 2 years

• period between 1. a 2. relapses

After 10 years - 50 % of pts disable to workAfter 25 years - 50 % of pts disable to walk

• Total surviving is 7 years shorten than common population (immobility, decubits, infections, ...)

Subclinical Mono-symptomatic

Relaps-remitting Secondary-progressiveMono-symptomatic

Relaps-remitujúca forma

6/2001

fatigue

EDSS 1,5

1/2004- diplopia

6/2004- hemiparestesias

12/2004- sfincter

problems and lost of

sense perianogenitaly

7/2005- cerebellar

dyzarthria and ataxia

EDSS 4,5

3/2002

Left side

Optic

neuritis

EDSS 2,0

3/2006 – LL paraparesis, partial

urinary incontinence, need

assisstance with walking,

cerebellar dyzarthria and ataxia,

cognitive deficit in atention

EDSS 7,0

Case report

MS diagnosis

Presence of lesions disseminated in the CNS in time (DIT) and space (DIS)

1. History, typical clinical course2. Neuroimaging – MRI (brain, spinal cord)3. CSF - diff. diagnosis4. Evoked potentials - VEP

None of these investigations are specificfor MS !!!

McDonald diagnostic criteria of MS – 2017 revision

• The key principle of MS diagnosis is the evidence of lesions dissemination in space(DIS) and in the time (DIT) in the CNS

A) DIS- dissemination in space – 2 and more lesions in any of 4 typical localisations

B) DIT - dissemination in time – damage was repeated several times

• MRI protocol of brain and spinal cord evaluation in suspected MS:• T2V0 + FLAIR + T1V0 native scan and postcontrast scan (gadolinium is used as a contrast in MRI)

• Hypersignal lesions in T2 weighted scan - typical shape and localization in MS

– DIS - the presence at least one T2 lesion in at least 2 different localisations (there are 4 typicallocalizations for MS lesions: periventricular, juxtacortical, infratentorial, spinal cord)

– DIT - if gadolinium enhancing lesion (Gd +) is present with gadolinium inactive (Gd-) lesions, or a new T2 lesion

and / or 1 Gd + lesion at any time since MR examination is present

– or CSF positive for MS

https://www.news-medical.net/news/20171222/

Magnetic resonance imaging in MS

• T2-weighted imaging – hyperintensive/hypersignal lesions in the white matter, most often periventriculary

• T1-weighted imaging – hypointensive lesions, black holes = axonal loss whichleads to progressive brain atrophy

• Gd+ enhancing lesion (Gd - gadolinium) - new, active, inflammatory lesion (last6-8 weeks)

•

T2 T1 Gd+T2 GD+T1

Magnetic resonance

„Dawson´s fingers“ - typical

perpendicularly located

lesions on corpus callosum

perpendicularly stored

MS diagnostic McDonald criteria

2010 and 2017 - DIT and DIS

• Patient with MS must meet the criteria:

• DIS - 2 or more T2 lesions in typical location

• DIT - new T2 lesion or Gd+ enhancing lesion, or

positive OCB (ologoclonal bands) in CFS

Brain atrophy in MS

is accelerated in MS (0,6 - 1,35 % of brain volume/year) in contrast with heathy controls (0,1 - 0,4 % of brain volume /year)

Brain atrophy can

be measured using

different methods of

MRI

MRI Volumetry (whole brain volume,

white matter, gray matter

volume, ...)

Evoked potentials, EP•VEP: visual EP •SEP: somato - sensory EP•BAEP: auditory brainstem EP•MEP: motor EP

Evidence of clinical asymptomatic, silent lesions

Pathol. results:

- conduction slowing

- complete block

of impulse spreading

- abnormal wave shape

Evoked potentials, EP

VEP, visual EP

•prolonged latency of P100 wave – positivity in 90%

persons after optic neuritis and 50 % patients without

ON history

CSF evaluation in MS

It help us in differential diagnosis

Total proteins : normal (up to 400 mg/l)Spectrum and number of cells: normal

Presence of plasmatic cells(plasmocytes- B-Lymphocytes)

CSF in MS

We find non-specific abnormalities showing immunological abnormalities:

1. Oligoclonal bands (OCB) >2 bands of IgG - means presence of abnormal antibodies, positive in 95% of MS, also positive findingof kappa and lambda light chains

2. Pathological increase of albumine quotient (Q Alb = Alb CSF/Alb S)

3. Abnormal increase of intrathecal IgG synthesis, higher IgG index

• Important in differentiation of otherdiseases (infections, systemic diseases)

Differential diagnosis of demyelinating disorders

• Stroke – small vessel disease, lacunar stroke, cardioembolicstroke, arterial hypertension

• Migraine

• Tumor – glioma, lymfoma (dif dg: PET, CSF, biopsy)

• Intervertebral disc lesion- spinal cord compression

• AV vascular malformation - AG, DSA

• Neuroborreliosis - Lyme disease, CSF Ab detection

• CNS vasculitis, SLE

• Leucodystrophy

• Mitochondrial diseases

• Celiakia

• Thyreopathy

Differential diagnosis

Stroke, lacunar infarcts SLE - Systemic lupus

erythematosus

Differential diagnosis

Adrenoleucodystrophy Borreliosis

Differential diagnosis

Arterial hypertension Hashimoto thyroiditis

Infectious inflammatory diseases

Neuroboreliosis

PML

SSPE

Toxo-metabolic diseases

Central pontinne and extrapontine

myelinolysis

Intoxiication CO Drug-induced

demyelinizáation

(metotrexát, cyklosporín)

Hypoxic-ischemic diseases

• Arterial hypertension, diabetes mellitus, dyslipidemia

Arterial hypertension Diabetes mellitus

Hereditary thrombophilias

- F V Leiden

- MTHFR mutation

- Hyperhomocysteinemia

- protein C and protein S deficit

Examination procedure in suspected MS

1History A) Symptoms of NS, age (optic neuritis, myelitis, brain stem/cerebellar syndrome

B) Comorbidity, treatment

2 Neurological examination Included sense and cognition

3 Laboratory tests / blood, serum/

A) Blood cells count, biochemistry, CRPB) Autoantibodies, AQP4-IgG, MOG-IgG, tyreopathy, celiakia, rheumatic diseases, vasculitisC) infections: borreliosis, syphilis, EBV, CMV, HSV, VZVD) Metabolic disorders, : m.Fabry, vit.B12, vitamin D, folat acidE) Haematological disorders - trombophilias

4 CSF evaluation - Biochemistry - Cells, plazmatic cells- Albumín , Albumín quotient - OCG, IgG (IgA, IgM) - Kappa and lambda light chains- Borrelia and neurotrophic viruses

5 MRI - brain and spinal cord T2V0 + FLAIR + T1V0 native and postcontrast scans (T1V0/T1+ Gd)

6 Evoked potentials VEP , SSEP, BAEP

7 Ophthalmologic evaluation And OCT (optic coherent tomography)

MS treatment

• we are able to influence only active, inflammatory phase of disease - not later neurodegenerative disease course

• we cannot stop the disease at all, only to slow and subdue severity of neurological symptoms

MS treatment

1. Treatment of attack

2. Long-term treatment of active MS with antiinflammatory drugs- Disease modifying treatment (DMT), inhibits inflammation in CNS

Effect:

– Slowdown disability progression

– Reduction of number and severity of attacks

– Decrease development of new lesions

– Slowdown brain atrophy

3. Symptoms treatment: pharmacological

fyziotherapy

cognitive therapy

psychotherapy

Treatment of attack / relapse

CORTICOSTEROIDS

- Methylprednisolone i.v.

- Infusion, dose 3-5 g ( 1 g/day)

- then Prednison p.o. - 30-80mg tbl/day, with slow dose decrease

Alternative treatments - in non-responders:

- Plasmapheresis - plasma exchange

- Cytostatics : Cyclophosfamide, Mitoxantrone

Corticosteroids: mechanism of action

in MS

All effects are only short duration1. Good trasfer though HEB

2. Antiinflammatory effect

3. It acts on both cellular and humoral levels: antiedematous, decreasesHEB permeability, stabilizes ion channels, inhibits antibody and cytokine production, reduces activity of Ly and IL-2, TNF-alfa, INF-gama

4. It reduces production of inflammation mediators - PG E , leukotrien B

5. It increases the apoptosis of inflammatory cells

• HEB - hematoencefalic barrier,/BBB IL- Interleukín, INF- interferon, PG E- prostaglandin E, Ly - lymphocytes, TNF-tumor necrosis factor

Corticoid therapy side effects

• Stomach ulcer

• Hyperglycemia

• Ischemic heart disease, arterial hypertension, arhytmia

• Osteoporosis

• Hypokaliemia

• Depression

• Trombophilia

• Children- dosage according to the weight of the child

• Acne

• Obesity

Long-term treatment, DMT: disease modifyingtreatments

It is used in patients with disease activity:Immunomodulators and immunosupressives

1st. line therapy:

- Interefons beta

- Glatirameracetate

- Teriflunomide

- Dimethylfumarate

2nd. line therapy:

- Natalizumab - monoclonal Ab anti VLA4 adhesive molecule,eff. 75%

- Fingolimod - selective immunosupressant, ARR reduction 55%

- Alemtuzumab - monoclonal Ab anti-CD52 Ly

- Ocrelizumab - monoclonal Ab anti-CD20Ly

- Cladribine

Confidential and Proprietary

DMT by clinical form

Moderate activity High activity Relapsing SPMSNon - relapsing

SPMS

• Interferon beta• Mitoxantron • Mitoxantron^ • Ocrelizumab

• Siponimod*

• Interferon beta• Glatirameracetate• Dimetylfumarate• Teriflunomide

• Fingolimod• Natalizumab• Alemtuzumab• Ocrelizumab• Cladribine

Suo

pti

ma

lres

po

nse

RRMS SPMS PPMS

Efficacy Risk

DMT (Disease modifying treatment) SM treatment

Alemtuzumab

Cladribine

Ocrelizumab

NatalizumabFingolimod

Dimetylfumarát

TeriflunomidGlatirameracetate

Interferon-beta

PML - Progressive multifocal leukoencephalopathy

• Patients receiving immunosupressive therapy - monoclonal antibodies, may get reactivation and mutation of JCV (John Cunningham virus). This virus infect brain tissue. An opportunistic infection- PML with a severe course

• JCV prevalencie in common population is 55%

• JCV replicates in oligodendrocytes and astrocytes that die

Diagnosis of PML:

1. Manifestation: severe visual deficit, paresis- plegia, cerebellar ataxia, severe cognitive deficit, epileptic seizures

2. CSF: presence of JCV copies (PCS)

3. MRI brain: Gd+ enhancing large lesions of demyelination and necrosis

Therapy: does not exist, plasma exchange, antivirotics (cidofovir), mirtazapin

Fatal complications in about 21-23% of PML

Symptomatic treatment

1. SPASTICITY: stiffness, spasms

Central myorelaxances - Baclofen, Tizanidine

2. SFINCTER DYSFUNCTION:

• Retention: intermitent autocathetrisation

• Incontinence: anticholinergics, ADH / night

3. TREMOR: clonazepam, beta-blockers, thalamicelectrostimulation / VLnc.

Symptomatic treatment

4. Tonic spasms and trigeminal neuralgia:carbamazepine, pregabalin, gabapentin

4. Fatigue: fyziotherapy

5. Rehabilitation, fyziotherapy, psychotherapy, vitamins: D, B, E

NMO- NEUROMYELITIS

OPTICA

NMOSD - NEUROMYELITIS

OPTICA SPECTRUM

DISORDERS

NMOSD, Neuromyelitis Optica Spectrum Disorders

Lennon VA, et al. Lancet 2004; Wingerchuk DM, et al. Neurology 1999; Sven J. and Wildemann . Neuroinflammation 2013; De Seze J, et al. J NeurolSci 2002; Wingerchuk DM, et al. Lancet Neurol 2007; Wingerchuk et al. Neurology 2015;

History

1894 Neuromyelitis optica acuta - NMO (M.Devic, Devic disease) Eugène Devic and Fernand Gault - first describe case of woman with LL paraplegia,

blindness and death

2004 Discovery of aquaporin 4 (AQP4-IgG) antibodies in NMO patients

2006 Wingerchuk et al. : Diagnostic criteria for NMO - revision

2007 A number of atypical „limited forms“ of NMO named as NMOSD

2015 Revision of NMOSD diagnostic criteria

NMOSD – NMO spectrum disorders

• NMOSD is group of diseases, that includes NMO and others, especially limited forms with involvement of other parts of the CNS (brainstem, diencephalon, hypothalamus)

• In addition to classical, clinically and laboratory definedNMO (optic neuritis + myelitis + AQP4 Abs) thisspectrum also includes other diseases defined by a similar clinical picture or by the presence of specificantibodies

Gault, et al., 2014; Kim et al., 2015

NMOSD pathogenesis

• Autoimmunity, astrocytopathy

• Primarily activated humoral immunity - it is antibody-induced disease

• AQP4 is the main water channel in the CNS on astrocytes, it has a highconcentration in the optic nerve and gray matter of spinal cord, on the HEB astrocytes

• Astrocytes damage by antibody binding leads to demyelination and axonal loss

Lennon et al. Lancet 2004; Sven J. and Wildemann B. J.Neuroinflammation2013; Papadopoulos et Verkman 2012; Wingerchuk et al., 2007; Bennett et al., 2009

NMOSD pathogenesisT-lymphocytes (subtype Th17) recognizethe AQP4 channel – B- lymphocytes are activated and antibodies AQP4-IgG passthrough HEB and bind to AQP4 astrocytes-AQP4 count decreases as well as GFAP expression

Inflammation + complement activation + increased HEB permeability + leukocyte infiltration (Eosiniphils, Neutrophils) = astrocyte edema - acute inflammatorylesion with perivascular demyelination, macrophage and granulocyte infiltration, astrocyte loss, axons and gray matter and white matter necrosis especially in theoptic nerves and spinal cord

GFAP- Glial fibrilar acidic protein

Lennon et al. Lancet 2004; Sven J. and Wildemann B. J.Neuroinflammation 2013; Papadopoulos et Verkman 2012; Wingerchuk et al., 2007; Bennett et al., 2009

NMOSD epidemiology

• It occurs all over the world, affecting all races

• Prevalency: 1 - 4,4 /100 000 inhab.

• Incidence: 0,4 / 100 000 inhab.

• Gender ratio: F : M = 10 : 1

• Slovakia - 52 patients (jan. 2020)

• Onset: median 39 years; can occur in any age

• Initial symptom:

A) myelitis - more often over 50 years of age

B) optic neuritis - more often in younger than 50 years

Marrie RA, Gryba C. Int J MS Care 2013; Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. Lancet Neurol 2007; Etemadifar et al., 2015; Nytrova et Horakova, 2015; Mori et al., 2018; Borisow et al, Front Neurol, 2018

NMO: diagnostic criteria

• A definitive diagnosis of NMO requires that both main and at least 2 of the 3 secondary criteria be met:

• Main criteria 1. Optic neuritis unilateral or bilateral2. Acute myelitis

• Secondary criteria 1. Brain MR with normal findings or lesion non-MS type 2. Spinal MRI - LETM (longitudinal extensive transversal

myelitis) over 3 vertebral segments3. Presence of AQP4-IgG antibodies (blood serum)

Kim at al. Neurology, 2015; Wingerchuk et al. Neurology,2006;

NMOSD: diagnostic criteria and clinical syndromes

• For AQP4-IgG positive antibodies, one of the following major clinicalmanifestations is required:

1. Optic neuritis

2. Acute myelitis

3. Area postrema syndrome - singultus, nauzea, vomitus

4. Acute brainstem syndrome - hearing problems, facial nerve palsy, diplopia, trigeminal neuralgia, vertigo, respiratory insufficiency

5. Symptomatic narcolepy or acute diencephalic syndrome with NMOSD typical lesions on MRI - hypersomnia, narcolepsy, polyuria, hypothermia, obesity

6. Symptomatic cerebral syndrome with typical NMOSD brain lesions

Wingerchuk DM, et al. International Panel for NMO Diagnosis. Neurology. 2015

NMOSD: laboratory characteristics

AQP4-IgG

seropositive

AQP4- IgG

seronegative

MOG-IgG

Jarius et al. J Neuroinflammation 2012; Kitley et al. Neurology 2012; Woodhall et al. J Neurol Sci 2013

Anti α-subunit

of glycine receptor

NMOSD

MOG – Myeline oligodendrocyte glykoprotein

MOG-IgG antibodies are present in about 4 - 11% NMOSD patients

NMOSD disease course

• Relapsing-remitting – more often, 90%

- Relaps - optic neuritis, myelitis or brainstem sy, areapostrema sy, ...

- Remisision - variable (weeks- years)

• Monophasic – rare, 10%

- optic neuritis and myelitis simultaneously

Wingerchuk et al. Neurology 1999; Wingerchuk et al. Lancet Neurol 2007;

NMOSD optic neuritis• Inflammation and demyelination with loss of axons

• Clinical symptoms:

• - visual problems- severe degree

- severe visual field deficit

- loss of color vision

- often bilateral

- rapid development (hours)

- severe edema of the optic nerve and/or chiazma

MRI: affected is more then half of optic nerve volumeand chiazma

• 22% of patients experience blindness after thefirst episode of optic neuritis

Wingerchuk et al. Lancet Neurol 2007; Chan et al. Arch Neurol 2011; Samart et al. J Med Assoc Thai 2010; Viegas et al. J Neurol Neurosurg Psychiatry 2009; Zavada et al. Rheumatol Int 2013; Wingerchuk DM, Weinshenker BG. Neurology 2003; Kitley et al. Brain 2012;

NMOSD myelitis

• Myelitis occurs most often under the image of LETM

• LETM – Longitudinal extensive transversal myelitis -spinal cord inflammation at any location, exceedingmore than 3 vertebral segments

• Clinical symptoms

– Paraparesis to quadriparesis /plegia

– Sense disfunction below lesion, radicular pain, positive Lhermitt sign

– Sfincter problems - urgency, incontinence

– Paroxysmal tonic limb spasms

Wingerchuk et al. Lancet Neurol 2007; Chan et al. Arch Neurol 2011; Samart K, Phanthumchinda K. J Med Assoc Thai 2010; Viegas et al. J Neurol Neurosurg Psychiatry 2009; Zavada et al. Rheumatol Int 2013; Wingerchuk DM, Weinshenker BG. Neurology 2003; Kitley et al. Brain 2012;

NMOSD can occur in coincidence with other disorders:

1. Systemic autoimmune disorders

- Hypotyreosis, pernicious anemia, ulcerous collitis, myasthenia gravis, idiopathic thrombocytopenic purpura

- SLE, antiphospholipid syndrome, Sjögren´s syndrome

2. Neoplasms

Hinson et al. Neurology 2007; Saadoun et al. Brain 2010; Lucchinetti et al. Brain 2002; Nytrova et al. J Neuroimmunol 2014; Jarius et al. Nat Clin Pract Neurol

2008; Roemer et al. Brain 2007; Iorio et al. Clin Gastroenterol Hepatol 2013; Mader et al. J Neuroinflammation 2011;

NMOSD - MRI

• Brain MRI : T2 hypersignal lesions in localization of high occurence of AQP4 receptors:

– Around Sylvi´s aqueduct , III. and IV. lateral ventricles

– Hypothalamus, corpus callosum

– Medulla oblongata, area postrema

– Pyramidal tract, capsula interna

– Cerebellar peduncles

• During relapse lesions show postcontrastenhancement

Kim et et al. Mult Scler 2010; Pittock et al. Arch Neurol 2006; Sinnecker et al. Neurology 2012, Kim et al., 2015;

Differential diagnosis of NMOSD

• Multiple sclerosis

• Neuroinfections

• Vasculitis

• Systemic autoimmune disorders

• Stroke

• Neoplasms (gliomas)

• PML

• ADEM

• Paraneoplastic syndromes

• LHON, noninflammatory optic neuropathy

• CADASIL

• Causal treatment does not yet exist, current treatment focusses on inflammation

• Without treatment there is a high risk of early and severe disability

• Purpose of treatment - acute treatment of relapse and subsequent prevention of further relapses with reduced risk of permanent disability

• Antiinflammatory treatment- immunosupressive and biological drugs- monoclonalantibodies

• Symptomatic treatment - sfincter problems, neuropathic pain, ...

• DMT drugs used in MS do not work in NMOSD, they may even worsen the courseof the NMOSD!

Prognosis: worse than MS, serious neurological deficit

NMOSD treatment and prognosis

Trebst et al. J Neurol 2014; Papadopoulos et al. Nat Rev Neurol 2014; Shimizu et al. Neurology 2010; Papeix et al. Mult Scler 2007; Barnett et al. Mult Scler 2012; Min et al. Mult Scler 2012; Kleiter et al., 2018

Relapse treatment

• Metylprednisolone

• High dose : 1 g/ day, 3 to 5 days

• Then Prednison p.o.

• Non-respoders:

• Plasmaexchange

• 5 – 7 PE every other day

Trebst et al. J Neurol 2014; Barnett et al. Mult Scler 2012; Min et al. Mult Scler 2012; Kleiter et al., 2018

Chronic treatment

• After treatment of the attack, it is long-term treatment in order to reduce the frequency and severity of relapses

Procedures:

• 1. line: Rituximab (anti-CD20 B-Ly), or Azatioprin, Mykofenolat mofetil, Metotrexat

in a combination with Prednison (low doses)

• 2. line: Tocilizumab (monoclonal antibody anti-IL-6) or Rituximab + Azatioprin, Mykofenolat mofetil, Metotrexat, Rituximab

• 3. line: Eculizumab (monoclonal antibody anti-C5 complement)

New perspectives: Inebilizumab (anti-CD19 B-Ly), Satralizumab (anti- IL6), Aquaporumab

Kim et al. JAMA Neurol 2013; Sellner et al. Eur J Neurol 2010; Sherman et Han, 2015; Collongues et al., 2019; Paul et al., 2018

Acute disseminated encephalomyelitis

ADEM

ADEMAcute disseminated encephalomyelitisDefinition: CNS demyelinating disease, monophasic, occuring in children and young adults

• Incidence: 0,8/100 000 inhab./year

• Age of onset: 7 years, slight prevalence of boys

• In 75% ADEM is a complication after febrile illness- infection, vaccination

• Latency between the previous disease and the onset of ADEM is approx. 7 - 14 days

Krupp LB et al, International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous

system demyelinating disorders: Revisions to the 2007 definitions.Mult. Scler. 2013; Krupp L.B., Banwell B., Tenembaum S. Consensus definitions

proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007;68:S7–S12. Milargos M et al. Differential Diagnosis of Pediatric

Multiple Sclerosis 2019 Published online 2019 Jun PMCID: PMC6617098

Infections related to ADEM

• Infuenza virus, Varicella zoster -VZV, Rubeola, EBV

• Hepatitis A,B

• Coronavirus, Coxackie B, Epstein- Barr vírus

• Herpes simplex virus

• HIV

• Campylobacter, Borrelia burgdorferi, Chlamydia, Legionella, Mycoplasma pneumoniae, Rikettsiarickettsii, Streptococcus

ADEM: Disease course• more severe than MS• Initial symptoms are nonspecific, variable

• Always syndrome of encephalopahy

• Unconsciousness, epileptic seizures, severe headache, fever

• Meningeal syndrome, sleepiness, lethargy, behavioral problems, apathy

• Focal or multifocal symptoms, hemiparesis, quadruparesis, ataxia, cranialnerve lesions, cognitive problems, dyskinesias, chorea, myoklonus, etc.

• Monophasic disease !!! No relapse

ADEM: diagnosis

1. Clinical symptoms, age, previous infection or vaccination

2. MRI brain: diffuse, large lesions of demyelination in the white and gray matter, no (DIT, DIS) new lesions in follow-up

3. CSF: negative for OCB (only 12%)

1. Evoked potentials- pathological findings

Differential diagnosis

1. Infections - meningoencephalitis

2. Multiple sclerosis

3. NMOSD

4. Leukodystrophy

5. CNS vasculitis

6. CNS neoplasms

7. Neurosarcoidosis

Laboratory tests

• We don´t have one specific test of ADEM

• Autoantibodies MOG-IgG, AQP4-IgG may occur in childrenwith ADEM and may determine its prognosis

• ADEM with MOG-IgG - MOG-IgG is positive in 33–66% of allpediatric ADEMs and means non-MS demyelinating disease

• ADEM with AQP4-IgG - very rare, it means NMOSD

Krupp LB et al, International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous

system demyelinating disorders: Revisions to the 2007 definitions. Mult. Scler. 2013; Krupp L.B., Banwell B., Tenembaum S. Consensus definitions

proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007;68:S7–S12. Milargos M et al. Differential Diagnosis of Pediatric

Multiple Sclerosis 2019 Published online 2019 Jun PMCID: PMC6617098

ADEM: MRI findings

Essential for the ADEM diagnosis is typical picture of diffuse brain large

lesions affecting both white and gray matter, cortex and deep gray

matter (thalamus, basal ganglia)

Lesions tend to shrink or disappear over time

Milargos M et al. Differential Diagnosis of Pediatric Multiple Sclerosis 2019 Published online 2019 Jun PMCID: PMC6617098

Treatment• Treatment principles:

– To start as soon as possible

– Sufficient high doses of corticosteroids

• Corticoids i.v. high doses: Metylprednisolone 10 – 30 mg/kg/day during3 to 5 days or Dexamethasone

• With subsequent switch to oral corticoids, gradual decrease to withdrawal (Prednison 6 weeks)

• Alternatives to corticoid failure:

• Plasmaexchange

• Intravenous immunoglobulins (IVIG)

• Mitoxantron

• Cyklofosfamid

ADEM: prognosis

• Favorable in most cases

• Complete improvement: 50-75 % cases over a period of 3 to 6 months, or mildresidual symptoms (hemiparesis, visual deficit, ...)

• Poor prognosis: a sudden onset, severe neurological symptoms, lack ofresponse to corticoid treatment

• Mortality - 5 %

• Repeated brain MRI is needed to rule out the development of MS (20 – 30 % children with ADEM later develop MS !)

• Most ADEMs are monophasic, without recurrence for 2 -12 years of follow-up

• Multiphasic ADEM is a condition when the child develops a second ADEM event, it is rare (12%)