Scleroza Multipla

CURSDE NEUROLOGIEUNIVERSITATEA DE MEDICINA SI FARMACIECAROL DAVILABUCURESTI

Conf. Dr. Ioan Buraga - Curs Neurologie

BOLILE DEMIELINIZANTE

Clasificare

- scleroza multipla - scleroza cerebrala difuza (boala Schilder) - encefalomielita acuta diseminata (secundar vaccinrii / viroze) - leucoencefalit hemoragica necrotizanta acutacomun au o componenta autoimuna ce distruge teaca de mielina


Scleroza Multiplamaduva si a unei simptomatologii variate O afectiune cronica a SNC caracterizata prin inflamatie, demielinizare si neurodegenerare

Prima data descrisa de Charcot si Vulpian in 1866

Caracterizata prin prezenta de placi sclerotice diseminate la nivelul substantei albe din emisferele cerebrale, cerebel,


Scleroza multiplaforma recurent remisivaforma primara progresivaSM acutaneuromielita optica= scleroza diseminata / in placi-boala a adulilor tineri, in special femei


CLINIC episoade de deficit focal prin leziuni la nivelul nervilor optici, creierului, mduvei spinrii - evoluia remisiv recurenta - latenta mare (1-10 ani) intre primul simptom si dezvoltarea celor ulterioare - in evolutie la un moment dat, semnele nu se mai remit => forma secundara progresiva> principiu vechi, dar corect: diseminare in timp (apare un simptom, dispare, apoi altul) si spaiu (locuri diferite in SNC)SIMPTOMATOLOGIE

- deficit motor - parestezii- tulburri de acuitate vizuala- diplopie- nistagmus- tremor intenional- ataxie- tulburri de sensibilitate- incontinenta urinara - alterarea rspunsului emoional


PATOGENIE boala inflamatorie autoimuna mpotriva mielinei, oligodendrocitelor, axonilor - pierdere celularamarca histopatologica = placa demielinizatademielinizareremielinizare redusa (shadow plaques) modificri distrofice axonale - glioza (cicatrice)

SCENARIU PATOGENIC1. lovitura iniiala un focar inflamator minor la nivelul venei postcapilarfactori adiionali:

- subclone celulare citotoxice CD8- mecanisme de aprare deficitare - capacitate sczuta de a stinge inflamaia => defecte de apoptoza limfocitara- afectarea capacitatii de regenerare a creierului2. declanarea procesului autoimun- infecii sau vaccinri - celule T autoreactive, expansiune clonala CD8 si atac axonal


Factori cheie in procesul patologic al SM

MielinaCelule inflamatorii

Celule prezentatoare de antigen (APCs)Celule Th1Sistem imun: in principal macrofageCelulele sistemului nervos

Celule gliale: OligodendrociteAstrocite (participa in procesul activarii neuronale)Microglia (macrofagele din SNC)Neuroni


Demielinizarea si degenerarea axonalaDizabilitate clinicaPrag clinicVolum cerebralInflamatiePierdere axonalaWaxman SG, NEJM. 1998;338:323.

Conf. Dr. Ioan Buraga - Curs NeurologieInflammation and Axonal Loss in MSThe above figure illustrates the course of MS.1-5 During the relapsing-remitting phase, the disease is characterized by frequent inflammation, demyelination, axonal transection, and remyelination. Relapses are more frequent and complete recovery from disability generally occurs.2-5 During the secondary-progressive phase of the disease, inflammation and relapses occur infrequently, axonal loss is increased and disability progresses. MRI-defined plaque burden and clinical impairment accumulate over time.

1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-1231. Erratum in: Lancet. 2002;360:648.2. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911. 3. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A. 1989;86:7113-7117. 4. Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ. 1990;300:631-634. 5. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994;117:759-765.

After Dr. W. Brck.SM: O afectiune insotita de pierdere severa a mielinei, axonilor si neuronilor

Conf. Dr. Ioan Buraga - Curs NeurologieMS: A Disease of Severe Myelin, Axonal, and Neuronal LossesNeuronal damage is now recognized as a major cause of permanent disability in people with MS. Neuronal degeneration starts early in the disease. The role of axonal demyelination has been recognized for many years as a major and prominent hallmark of MS. In recent years, however, studies have established that early axonal degeneration is also a prominent feature of the disease, and that it correlates with the persistent accumulation of permanent neurologic deficit over time. The incidence of axonal damage and degeneration is known to be highest in actively demyelinating lesions in the presence of inflammation and cytotoxic T cells, but it continues at a slow burn (~1/100th the rate in active lesions) seemingly for months or years after the active period has subsided. Curiously, the magnitude of the slow burn appears to be related to the magnitude of the preceding inflammation, as if inflammation triggers a sequence of events that leads slowly to degeneration.Evidence from animal models implicates activated T cells in initiating the pathology of MS. Subsequent injury to the CNS is mediated by T cells, B cells, and macrophages/microglia. Inflammatory components destroy myelin and oligodendrocytes. Inflammation is associated with axonal damage

Patogeneza SMAfter Prof. R. Hohlfeld.

Conf. Dr. Ioan Buraga - Curs NeurologieMS PathogenesisAutoreactive T cells in the periphery are activated by a danger signal or trigger. They migrate to, adhere at, and penetrate through the BBB, steps mediated by adhesion molecules, proteases, and chemokines.1Inside the CNS, the T cells are reactivated by APCs, predominantly microglial cells. The reactivated T cells secrete pro-inflammatory cytokines, such as IFN- or IL-2, which induce CNS inflammation by subsequent activation of macrophages such as other T cells and B cells. Macrophages and T cells attack the myelin sheath of oligodendrocytes by cytotoxic mediators, mainly TNF-, O2 radicals, and NO. B cells differentiate into plasma cells. These secrete demyelinating antibodies that can guide and activate macrophages (M) and ignite the complement cascade, which causes assembly of the membrane attack complex and pore formation in myelin membranes.Demyelination can occur by four different pathologic processes, including T-cell and macrophage attack, antibody attack, oligodendrocyte apoptosis, and primary oligodendrocyte degeneration.1

1. Neuhaus O, Archelos JJ, Hartung HP. Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection. Trends Pharmacol Sci. 2003;24:131-138.

Inflamatia si pierderea axonala in SMCompston and Coles. The Lancet. 2002;359:1221-1231).Recurent RemisivaSecundar progresivaDizabilitate clinicaPragul clinicVolum cerebralInflamatiePierdere axonalaFrecvent Inflamatie,, demielinizare, sectionarea axonilorplasticitate si remielinizareInflamatie continuademielinizare persistentaInflamatie inconstantadegenerare axonalacronica, glioza

Conf. Dr. Ioan Buraga - Curs NeurologieInflammation and Axonal Loss in MSThe above figure illustrates the course of MS.1-5 During the relapsing-remitting phase, the disease is characterized by frequent inflammation, demyelination, axonal transection, and remyelination. Relapses are more frequent and complete recovery from disability generally occurs.2-5 During the secondary-progressive phase of the disease, inflammation and relapses occur infrequently, axonal loss is increased and disability progresses. MRI-defined plaque burden and clinical impairment accumulate over time.

1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-1231. Erratum in: Lancet. 2002;360:648.2. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911. 3. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A. 1989;86:7113-7117. 4. Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ. 1990;300:631-634. 5. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994;117:759-765.

Progresia dizabilitatii Patologie vs. Evolutie clinicaTimpAparitie, evolutie si severitatePre-ClinicCISSMRRTransitionalSPMS

Conf. Dr. Ioan Buraga - Curs NeurologieProgression of DisabilityMS Courses as Redefined by MRIApproximately 85% of MS patients begin with a relapsing-remitting course, where the majority (up to 60%+) eventually develop progressive disability (SPMS). Only 10% to 15% of MS patients begin with a condition that is progressive from onset.1There is some evidence of immunogenic2 and MRI3 differences between the two types of progressive MS. For example, new lesions occur more frequently in SPMS compared to PPMS, suggesting that an inflammatory component is less important in the evolution of PPMS,4 and, hence, the importance of studying them separately.As depicted in this figure, relapses (frequency and severity) are more frequent in the relapsing-remitting stage of the disease. However, MS patients begin and continue the accumulation of MRI-defined plaque burden and clinical impairment over time, including during the primary-progressive phase of the disease.

1. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911. 2. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A. 1989;86:7113-7117. 3. Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. Br Med J. 1990;300:631-634. 4. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994;117:759-765.

Evolutia clinica a SMRRAparitie, evolutie si severitateTimpSMSPInflammatie dominantaDistrugerea matrix dominantaPrecoce RRSubclinicCISatrofiedizabilitateGdTardiv RRT2 Gauri negre cronice


FORME DISTINCTE HISTOPATOLOGICdominaia inflamaieidominaia oligodendrogliopatiei si a deficitului de remielinizare

FACTORI CE INFLUENTEAZA EVOLUIA SMfactor de cretere CNTF modelul alelic al apolipoproteinei E

MODIFICRI MALADAPTATIRE AXONALE- creste densitatea canalelor de Na, subtipuri anormale ca o reaciela demielinizare => SM = canalopatie dobndita- microglia/macrofagul se activeaz aberant distrugnd reelele nervoase- in final apoptoza neuronilorOLIGODENDROCITUL E CHEIA TRATAMENTULUI?- celula stem periventricular se divide in orice tip de celula => inclusiv oligodendrociteCELULE IMPLICATE bariera hemato-encefalica, limfocite, neuroni, oligodendrocite, astrocite, microglie


EPIDEMIOLOGIE- < 1/ 100000 la ecuator- 6-14/100000 in SUA + Europa- 30-80/100000 in Canada + N Europei- imigranii iau riscul cu ei - 15% din pacieni au o ruda afectata - gemeni monozigoti 34% risc - dizigoti 4% risc- debut ~ 30 ani (20-40 ani)- F/M = 3/1SIMPTOME fatigabilitate, scdere in greutate, mialgii, artralgie- semnele se instaleaz in cteva minute, ore, zile, saptamani/luni - deficit motor, hipoestezie, parestezie, parapareza - de afectare piramidala (! dispar reflexele cutanate abdominale) - semn Lhermitte


NEVRITA OPTICA- 25% cazuri simptom de debut - pierderea acuitatii vizuale la un ochi in ore/zile- scotom macular- edem al N optic (papilita)! Jumtate din pacienii ce se prezint cu nevrita optica vor dezvolta SM ulteriorMIELITA ACUTA TRAVERSAinflamaia e urmata de leziuni demielinizate la nivelul mduvei spinrii, care de multe ori e debut de SMparapareza, disfuncie sfincterian, nivel de sensibilitate, semn Babinsky bilateraluneori mielita recurenta trebuie difereniata de LES, sindrom Ac antifosfolipidici

ALTE SEMNE nistagmus, ataxie, vertij diplopie tipic oftalmoplegie internucleara prin leziuni la

nivelul fasciculului longitudinal medial nevralgie trigeminala depresie, mult mai rar euforie dementa subcorticala foarte rar (2-3%) crize epileptice


DIAGNOSTIC LCR - 1/3 uoara pleiocitoza - 1/3 proteinorahie crescuta - 2/3 Ig G crescute IgG index > 1,7 (Ig G in LCR/IgG in ser: Albumina in LCR / Albumina in ser) - poteniale evocate -> vizuale, auditive, somatosenzoriale alterate in 50-90 % cazuri- RMN => placi simptomatice / asimptomatice in creier, trunchi cerebral, nervi optici, mduva spinrii: - hiperintensitate in T2 si Flair predominant periventricular, asimetrica, bine demarcata - se ncarc la injectarea de substana de contrast leziunile acute, recente - monitorizarea evoluiei SMDIAGNOSTIC CRITERII MCDONALD-SM-SM posibila-Nu e -> in funcie de clinica, numrul de leziuni evideniate pe RMN, diseminarea in timp si spaiu


DIAGNOSTIC DIFERENTIAL

sifilis meningovascular- vasculite cerebrale malformaii vasculare la nivelul trunchiului cerebral /

mduvei spinrii cu sngerri repetate LES boala Behcet

EVOLUTIA

0,3 pusee/an- al doilea puseu in - primul an 30% - 1-2 ani 20% - 2-5 ani 20% - 5-9 ani 20% - 10-30 ani 10% - sarcina scade numrul de pusee, - postpartum in primele luni creste frecventa lor de doua ori


Doua aspecte ale patologiei SMDemielinizare inflamatorieCompromitereaxonalaAfectare mediata imun Reparare si protectiemediate imunDoua aspecte ale raspunsului imun in SMNeuroprotectieAntiinflamatieNecesitate unei terapii a SM cu dubla actiune


Mecanism patogenic Strategiile potentialelor terapiiDemielinizarePierdere axonalaInflamatieAnti-inflamatieProtectie axonala

SNC Intact

Conf. Dr. Ioan Buraga - Curs NeurologiePathogenic PathwaysPotential Treatment Strategies Carefully dissecting the pathogenic pathways of MS reveals inflammation and degeneration as two potential treatment targets.1 This diagram depicts the different areas where the current disease-modifying drugs, such as glatiramer acetate and interferon-, mediate their biologic effects.

1. Rieckmann P, Marer M. Anti-inflammatory strategies to prevent axonal injury in multiple sclerosis. Curr Opin Neurol. 2002;15:361-370.

Mecanism de actiune

Neuhaus O et al. Neurology 2001;56:7028Ziemssen T et al. Brain 2002;125:238191


Natura duala a inflamatiei in SMDISTRUGERE TISULARAPROTECTIE TISULARAFactori pro-inflamatori si NeurotoxiciCytokine Th1 TNF-IL-1Oxid Nitric Specii de oxigen reactivGlutamateAnticorpi si complementNeurotoxicitate mediata celular

Factori anti-inflamatori si neuroprotectiviCytokine Th2TGF-IL-1Factori neurotrofici

BDNFNGFNT-3CNTFGDNF

Conf. Dr. Ioan Buraga - Curs NeurologieThe Dual Nature of Inflammation in MSWell-established treatments such as steroids (during relapses) and glatiramer acetate or interferon- all have an anti-inflammatory action. All of them affect relapses; glatiramer acetate and some interferon- treatments also slow progression of disability.However, it is worth considering that some components of the inflammatory response are probably beneficial.Recently, an increasing body of evidence has appeared that supports the concept of neuroprotective autoimmunity in MSa dual role for the immune system in which inflammation is beneficial as well as harmful.

Target: Inflamatia Th1Th2 ShiftTerapia cu imunomodulatori reduce nivelul cytokinelor eliberate de Th1 si creste eliberare cytokinelor anti-inflamatorii eliberate de Th2Cytokine Th1

cu glatiramer acetatPro-inflamatorDistrugere tisulara

Cytokine Th2

cu glatiramer acetatAnti-inflamatorSupresie bystanderIntensifica protectia tisulara

Conf. Dr. Ioan Buraga - Curs NeurologieTargeting InflammationTh1Th2 Shift Glatiramer acetate induces a shift from a pro-inflammatory Th1 pattern of cytokine secretion to an anti-inflammatory Th2 pattern of cytokine secretion in glatiramer acetate-reactive T cells at the site of MS lesions.The Th2 cytokines suppress inflammation in the area of the lesion (bystander suppression), thereby suppressing tissue damage resulting from inflammation.

Date ImunologiceExpresia Factorilor Neurotrofici in SNC

BDNF, NT3 si NT4 sunt modulatori importanti ai functiei si supravietuirii neuronaleGA: crestere sustinuta a expresie la nivelul diferitelor regiuni cerebraleGA exercita nu numai un efect anti-inflamator, dar intensifica neuroprotectia si regenerarea elementelor neurale la nivelul regiunilor cerebrale afectate


Brain-Derived Neurotrophic Factor (BDNF) Neurotrofina potenta cu efecte profunde asupra supravieturii si reparatiei neuronale

Conf. Dr. Ioan Buraga - Curs NeurologieBrain-Derived Neurotrophic Factor (BDNF)BDNF Is a Potent Neurotrophin With Profound Effects on Neuronal Survival and Repair BDNF was first cloned in 1989 and is a member of the neurotrophin (NT) family that includes NGF and NT-3, NT-4/56, and NT-7.BDNF has a well-established role in regulating the survival and differentiation of neurons and also has the ability to protect neurons against various pathologic insults. BDNF can rescue CNS neurons after axonal transection and promote remyelination and axonal regeneration.In animal models of neurodegenerative disease, BDNF has been reported to have beneficial effects.The main source of BDNF in the nervous system is neurons.1 BDNF appears to be specific for neurons: it acts through a receptor, gp145trkB, that is expressed only by neurons and astrocytes.2 The receptor is upregulated after brain insults.

1. Kerschensteiner M, Gallmeier E, Behrens L, et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med. 1999;189:865-870.2. Stadelmann C, Kerschensteiner M, Misgeld T, Brck W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain. 2002;125:75-85.

TRATAMENT

in puseu -> Metilprednison 500mg/zi IV pentru 3 - 5 zile Metilprednisolon/Prednison oral maxim 3 saptamani prevenire a recderilor

IFN (betaferon, rebif, avonex)- copolimer al MBP (copaxone)

- se mai folosesc Mitoxantrona, Ciclofosfamida, - Amantadina 100-200 mg/zi pentru fatigabil, - Baclofen pentru spasticitate


Cursul urmator:

Tromboze venoase cerebrale


Inflammation and Axonal Loss in MSThe above figure illustrates the course of MS.1-5 During the relapsing-remitting phase, the disease is characterized by frequent inflammation, demyelination, axonal transection, and remyelination. Relapses are more frequent and complete recovery from disability generally occurs.2-5 During the secondary-progressive phase of the disease, inflammation and relapses occur infrequently, axonal loss is increased and disability progresses. MRI-defined plaque burden and clinical impairment accumulate over time.

1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-1231. Erratum in: Lancet. 2002;360:648.2. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911. 3. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A. 1989;86:7113-7117. 4. Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ. 1990;300:631-634. 5. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994;117:759-765.MS: A Disease of Severe Myelin, Axonal, and Neuronal LossesNeuronal damage is now recognized as a major cause of permanent disability in people with MS. Neuronal degeneration starts early in the disease. The role of axonal demyelination has been recognized for many years as a major and prominent hallmark of MS. In recent years, however, studies have established that early axonal degeneration is also a prominent feature of the disease, and that it correlates with the persistent accumulation of permanent neurologic deficit over time. The incidence of axonal damage and degeneration is known to be highest in actively demyelinating lesions in the presence of inflammation and cytotoxic T cells, but it continues at a slow burn (~1/100th the rate in active lesions) seemingly for months or years after the active period has subsided. Curiously, the magnitude of the slow burn appears to be related to the magnitude of the preceding inflammation, as if inflammation triggers a sequence of events that leads slowly to degeneration.Evidence from animal models implicates activated T cells in initiating the pathology of MS. Subsequent injury to the CNS is mediated by T cells, B cells, and macrophages/microglia. Inflammatory components destroy myelin and oligodendrocytes. Inflammation is associated with axonal damage

MS PathogenesisAutoreactive T cells in the periphery are activated by a danger signal or trigger. They migrate to, adhere at, and penetrate through the BBB, steps mediated by adhesion molecules, proteases, and chemokines.1Inside the CNS, the T cells are reactivated by APCs, predominantly microglial cells. The reactivated T cells secrete pro-inflammatory cytokines, such as IFN- or IL-2, which induce CNS inflammation by subsequent activation of macrophages such as other T cells and B cells. Macrophages and T cells attack the myelin sheath of oligodendrocytes by cytotoxic mediators, mainly TNF-, O2 radicals, and NO. B cells differentiate into plasma cells. These secrete demyelinating antibodies that can guide and activate macrophages (M) and ignite the complement cascade, which causes assembly of the membrane attack complex and pore formation in myelin membranes.Demyelination can occur by four different pathologic processes, including T-cell and macrophage attack, antibody attack, oligodendrocyte apoptosis, and primary oligodendrocyte degeneration.1

1. Neuhaus O, Archelos JJ, Hartung HP. Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection. Trends Pharmacol Sci. 2003;24:131-138.Inflammation and Axonal Loss in MSThe above figure illustrates the course of MS.1-5 During the relapsing-remitting phase, the disease is characterized by frequent inflammation, demyelination, axonal transection, and remyelination. Relapses are more frequent and complete recovery from disability generally occurs.2-5 During the secondary-progressive phase of the disease, inflammation and relapses occur infrequently, axonal loss is increased and disability progresses. MRI-defined plaque burden and clinical impairment accumulate over time.

1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-1231. Erratum in: Lancet. 2002;360:648.2. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911. 3. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A. 1989;86:7113-7117. 4. Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ. 1990;300:631-634. 5. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994;117:759-765.Progression of DisabilityMS Courses as Redefined by MRIApproximately 85% of MS patients begin with a relapsing-remitting course, where the majority (up to 60%+) eventually develop progressive disability (SPMS). Only 10% to 15% of MS patients begin with a condition that is progressive from onset.1There is some evidence of immunogenic2 and MRI3 differences between the two types of progressive MS. For example, new lesions occur more frequently in SPMS compared to PPMS, suggesting that an inflammatory component is less important in the evolution of PPMS,4 and, hence, the importance of studying them separately.As depicted in this figure, relapses (frequency and severity) are more frequent in the relapsing-remitting stage of the disease. However, MS patients begin and continue the accumulation of MRI-defined plaque burden and clinical impairment over time, including during the primary-progressive phase of the disease.

1. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911. 2. Olerup O, Hillert J, Fredrikson S, et al. Primary chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci U S A. 1989;86:7113-7117. 3. Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. Br Med J. 1990;300:631-634. 4. Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994;117:759-765.

Pathogenic PathwaysPotential Treatment Strategies Carefully dissecting the pathogenic pathways of MS reveals inflammation and degeneration as two potential treatment targets.1 This diagram depicts the different areas where the current disease-modifying drugs, such as glatiramer acetate and interferon-, mediate their biologic effects.

1. Rieckmann P, Marer M. Anti-inflammatory strategies to prevent axonal injury in multiple sclerosis. Curr Opin Neurol. 2002;15:361-370.The Dual Nature of Inflammation in MSWell-established treatments such as steroids (during relapses) and glatiramer acetate or interferon- all have an anti-inflammatory action. All of them affect relapses; glatiramer acetate and some interferon- treatments also slow progression of disability.However, it is worth considering that some components of the inflammatory response are probably beneficial.Recently, an increasing body of evidence has appeared that supports the concept of neuroprotective autoimmunity in MSa dual role for the immune system in which inflammation is beneficial as well as harmful.

Targeting InflammationTh1Th2 Shift Glatiramer acetate induces a shift from a pro-inflammatory Th1 pattern of cytokine secretion to an anti-inflammatory Th2 pattern of cytokine secretion in glatiramer acetate-reactive T cells at the site of MS lesions.The Th2 cytokines suppress inflammation in the area of the lesion (bystander suppression), thereby suppressing tissue damage resulting from inflammation.

Brain-Derived Neurotrophic Factor (BDNF)BDNF Is a Potent Neurotrophin With Profound Effects on Neuronal Survival and Repair BDNF was first cloned in 1989 and is a member of the neurotrophin (NT) family that includes NGF and NT-3, NT-4/56, and NT-7.BDNF has a well-established role in regulating the survival and differentiation of neurons and also has the ability to protect neurons against various pathologic insults. BDNF can rescue CNS neurons after axonal transection and promote remyelination and axonal regeneration.In animal models of neurodegenerative disease, BDNF has been reported to have beneficial effects.The main source of BDNF in the nervous system is neurons.1 BDNF appears to be specific for neurons: it acts through a receptor, gp145trkB, that is expressed only by neurons and astrocytes.2 The receptor is upregulated after brain insults.

1. Kerschensteiner M, Gallmeier E, Behrens L, et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med. 1999;189:865-870.2. Stadelmann C, Kerschensteiner M, Misgeld T, Brck W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain. 2002;125:75-85.

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