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 and Europe, 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 between viral infection (EBV, CMV, Herpetic virus - antigen similarity, molecular mimicry) and neuronal system leads to an autoimmune attack to the CNS myelin antigens Pathogenesis activated TH1 cells admitt to the CNS = > cytokines (TNFa, IL-2, INFgama) activation of Ma, B-Ly, antibodies production = > 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)
Mono- Secondary-progressive Subclinical symptomatic Relaps-remitting phase phase
First attack Disability progressionDisability
time Cognitive dysfunction Relapses Lesion accumulation- MRI New gadolinium enhancing lesions 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
Optic neuritis
Multifocal syndrome Myelitis Brainstem/ cerebellar syndrome CIS: Optic neuritis
• Unilateral optic nerve (n.II) infammation, and focal demyelination • Unilateral, blurred vision, retrobulbar pain, central scotoma, loss of 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, intention tremor, 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 work After 25 years - 50 % of pts disable to walk
• Total surviving is 7 years shorten than common population (immobility, decubits, infections, ...) Case report
Mono- Subclinical Mono- RelapsRelaps-remi-rtujúcaemitting forma Secondary-progressive symptomaticsymptomatic
3/2006 – LL paraparesis, partial urinary incontinence, need 1/2004- diplopia assisstance with walking, cerebellar dyzarthria and ataxia, 3/2002 6/2004- hemiparestesias cognitive deficit in atention 6/2001 Left side fatigue Optic 12/2004- sfincter neuritis problems and lost of sense perianogenitaly
7/2005- cerebellar dyzarthria and ataxia
EDSS 1,5 EDSS 2,0 EDSS 4,5 EDSS 7,0 MS diagnosis
Presence of lesions disseminated in the CNS in time (DIT) and space (DIS)
1. History, typical clinical course 2. Neuroimaging – MRI (brain, spinal cord) 3. CSF - diff. diagnosis 4. Evoked potentials - VEP
None of these investigations are specific for 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 typical localizations 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 which leads to progressive brain atrophy • Gd+ enhancing lesion (Gd - gadolinium) - new, active, inflammatory lesion (last 6-8 weeks)
•
T2 T1 Gd+T2 GD+T1 Magnetic resonance
perpendicularly stored
„Dawson´s fingers“ - typical perpendicularly located lesions on corpus callosum
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 Evoked potentials, EP Evidence of clinical asymptomatic, silent lesions
Pathol. results: - conduction slowing - complete block of impulse spreading - abnormal wave shape 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 finding of 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 other diseases (infections, systemic diseases) Differential diagnosis of demyelinating disorders
• Stroke – small vessel disease, lacunar stroke, cardioembolic stroke, 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
PML
SSPE
Neuroboreliosis Toxo-metabolic diseases
Intoxiication CO Drug-induced demyelinizáation (metotrexát, cyklosporín)
Central pontinne and extrapontine myelinolysis 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
1 A) Symptoms of NS, age (optic neuritis, myelitis, brain stem/cerebellar syndrome History B) Comorbidity, treatment
2 Neurological examination Included sense and cognition 3 A) Blood cells count, biochemistry, CRP Laboratory tests / blood, B) Autoantibodies, AQP4-IgG, MOG-IgG, tyreopathy, celiakia, rheumatic diseases, vasculitis serum/ C) infections: borreliosis, syphilis, EBV, CMV, HSV, VZV D) Metabolic disorders, : m.Fabry, vit.B12, vitamin D, folat acid E) Haematological disorders - trombophilias 4 - Biochemistry - Cells, plazmatic cells CSF evaluation - 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 duration 1. Good trasfer though HEB 2. Antiinflammatory effect 3. It acts on both cellular and humoral levels: antiedematous, decreases HEB 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 modifying treatments
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 DMT by clinical form
RRMS SPMS PPMS
Non - relapsing Moderate activity High activity Relapsing SPMS SPMS
• Fingolimod • Interferon beta • Interferon beta • Mitoxantron^ • Natalizumab • Mitoxantron • Ocrelizumab • Glatirameracetate response • Alemtuzumab • Dimetylfumarate • Ocrelizumab • Teriflunomide
• Cladribine Suoptimal • Siponimod*
Confidential and Proprietary DMT (Disease modifying treatment) SM treatment
Efficacy Risk Alemtuzumab Cladribine Ocrelizumab
Natalizumab Fingolimod Dimetylfumarát
Teriflunomid Glatirameracetate 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, thalamic electrostimulation / 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
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
Lennon VA, et al. Lancet 2004; Wingerchuk DM, et al. Neurology 1999; Sven J. and Wildemann . Neuroinflammation 2013; De Seze J, et al. J Neurol Sci 2002; Wingerchuk DM, et al. Lancet Neurol 2007; Wingerchuk et al. Neurology 2015; 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 defined NMO (optic neuritis + myelitis + AQP4 Abs) this spectrum also includes other diseases defined by a similar clinical picture or by the presence of specific antibodies
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 high concentration 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 pathogenesis
T-lymphocytes (subtype Th17) recognize the AQP4 channel – B- lymphocytes are activated and antibodies AQP4-IgG pass through 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 inflammatory lesion with perivascular demyelination, macrophage and granulocyte infiltration, astrocyte loss, axons and gray matter and white matter necrosis especially in the optic 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 bilateral 2. 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 segments 3. 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 clinical manifestations 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
NMOSD
AQP4-IgG AQP4- IgG seropositive seronegative
MOG-IgG Anti α-subunit of glycine receptor
MOG – Myeline oligodendrocyte glykoprotein MOG-IgG antibodies are present in about 4 - 11% NMOSD patients
Jarius et al. J Neuroinflammation 2012; Kitley et al. Neurology 2012; Woodhall et al. J Neurol Sci 2013 NMOSD disease course
• Relapsing-remitting – more often, 90% - Relaps - optic neuritis, myelitis or brainstem sy, area postrema 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 volume and chiazma • 22% of patients experience blindness after the first 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, exceeding more 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 postcontrast enhancement
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 NMOSD treatment and prognosis
• 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- monoclonal antibodies • Symptomatic treatment - sfincter problems, neuropathic pain, ...
• DMT drugs used in MS do not work in NMOSD, they may even worsen the course of the NMOSD! Prognosis: worse than MS, serious neurological deficit
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 ADEM Acute disseminated encephalomyelitis Definition: 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, Rikettsia rickettsii, 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, cranial nerve 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 children with ADEM and may determine its prognosis
• ADEM with MOG-IgG - MOG-IgG is positive in 33–66% of all pediatric 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 during 3 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 mild residual symptoms (hemiparesis, visual deficit, ...)
• Poor prognosis: a sudden onset, severe neurological symptoms, lack of response 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%)