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New Disease Concepts
Although genetic vulnerability is probably a prerequisite for development of MS, it is not sufficient in the absence of other contributing factors. With recognized low-, medium-, and high-risk geographic disease zones, environmental factors clearly play a role. Exposures to common viruses and bacteria relatively early in life, in a way that is not yet understood, set the stage for MS. Infections probably act as disease triggers, although continued active neural or extraneural infection has not been ruled out as a disease factor in selected patients. Molecular mimicry (shared epitope sequences between ubiquitous infectious agents and autoantigens, including CNS antigens) is well documented. It is commonly believed, although not proven, that infection-triggered cross-reactivity to a myelin component initiates MS in genetically vulnerable individuals. Epitope spread occurs when CNS damage releases multiple sequestered antigens to the systemic immune system. Two types of epitope spreading may be involved: intermolecular epitope spread is when the immune response moves from 1 myelin antigen to another (ie, started against myelin basic protein (MBP), but with attack of myelin, other antigens such as myelin oligodendrocyte glycoprotein (MOG) are released and the immune response then spreads to MOG); and intramolecular epitope spreading, which occurs when the immune response is directed against a specific peptide of a specific protein (eg, MBP amino acid sequence 82-99) then with the destruction of myelin, it exposes other hidden or "cryptic" epitopes of MBP and the immune response shifts to these new epitopes (eg, MBP 102-118).[1] This expands the immune attack and acts to enhance and perpetuate organ-specific autoimmune disease. Epitope spread occurs in animal models of MS, and preliminary data indicate it is also a factor in MS.[2]

Therapeutic Implications of Epitope Spread
The concept of epitope spread carries important therapeutic implications. It argues for starting effective MS treatment at the earliest possible time point (ideally, at the first attack of definite MS), in order to minimize expansion and reinforcement of the damage process. The concept even provides a rationale for considering initial induction therapy (with broad-spectrum immunosuppression), followed by maintenance therapy. Supporting evidence that the early disease process is critical comes from natural history studies of first-attack, clinically isolated syndrome (CIS) patients. The number and volume of T2 brain lesions on the presenting MRI are the strongest correlates of disability at 14 years, followed by MRI lesion development during the first 5 years.[3]

New Insights Into Pathophysiology: Axons
MS is now believed to involve a biphasic disease process. Early on, inflammation is prominent, corresponding to the relapsing and potentially reversible phase of MS. Later, there is transition to a primarily neurodegenerative phase, corresponding to progressive MS with irreversible deficits. Although inflammation and neurodegeneration are detected at all time points, 1 process appears to dominate. This concept is consistent with natural history studies of MS, since most patients begin with relapsing disease but ultimately transition to secondary progressive disease. The presence of distinct MS phases argues for therapy that is tailored to the nature of the disease process.

The classic view of MS is that it is a disease that involves CNS inflammation and demyelination. It is now clear from direct pathologic data and indirect neuroimaging data that it also involves damage to axons and neurons.[4,5]Both axon density and volume are reduced in MS, not just within the plaque but also in normal-appearing CNS tissue.[6,7]Analysis of n-acetyl aspartate (NAA), an axon/neuron marker measured by MR spectroscopy, indicates that whole brain NAA is reduced even in early MS.[8]Loss or shrinkage of axons is a major contributor to brain and spinal cord volume loss (atrophy). In patients with MS, prominent CNS atrophy is present very early, even at the time of the first clinical attack.[9,10] On a yearly basis, brain volume loss in MS is accelerated 3- to 10-fold over that of matched controls.

The importance of axon damage in MS cannot be overstated; it is believed to be the neuroanatomic substrate of permanent disability and disease progression. Injury to axons undoubtedly reflects multiple factors (Table 3). At least some of the immune and inflammatory elements that injure axons are distinct from those that damage myelin. Axons or axon components (such as ion channels and neurofilaments) could be the target of a direct primary or secondary immune attack. Antibodies to neurofilament components, gangliosides, and myelin oligodendrocyte glycoprotein have been linked to progressive MS.[11-13]Alternatively, damage could reflect secondary bystander effects from inflammatory or toxic factors released into the microenvironment by intrinsic (microglia, astrocyte) or extrinsic (lymphocyte, macrophage) cells. Acute axon injury, measured by amyloid precursor protein expression, correlates with macrophage and CD8+ T-cell infiltration. In addition, ongoing myelin loss harms axons. It disrupts axon transport, with increased metabolic stress on neurons and axons.[14] The symbiotic relationship between myelin and axon means that demyelination itself is an axon damage mechanism. Loss of myelin also affects ion channel expression on the denuded axon surface.[15] These changes can restore nerve conduction, or produce axon destruction.

Table 3. Potential Contributors to Axon Damage in MS
Damage Mechanisms
Direct immune attack
- primary

- secondary

Indirect (bystander) immune damage
- from intrinsic CNS components

- from extrinsic components

Loss of myelin
- disrupted axonal transport

- damaging ion channel remodeling

- metabolic stress

Loss of neurons

Damage Factors
CD8+ T cells


Macrophages


Antibodies


- myelin oligodendrocyte glycoprotein

- neurofilament components

- gangliosides

Neurotoxic factors



Therapeutic Implications of Axonal Damage
Because insertion of new sodium channels allows conduction, enhanced or more rapid expression of such channels is a desirable therapeutic goal. By contrast, calcium channels (alpha 1-beta), normally expressed only at the presynaptic axon terminal, may also be inserted into demyelinated membrane. Because the insertion of these channels leads to axon damage (mediated by calcium-dependent proteases called calpains), one would want to prevent their expression. Ion-channel manipulation is likely to be a future therapeutic focus in MS.

New Insights Into Pathophysiology: Neurons
Axons are also lost when neurons die. A recent study of brain autopsy material examined the thalamus, a gray matter region rich in neurons. MS brains showed 30% to 35% fewer neurons than control brain tissue.[4] NAA measurements indicate diffuse gray matter disturbances even in patients with early MS. Loss of neurons likely reflects primary damage, from direct and indirect inflammatory injury, as well as secondary neurodegeneration, from a variety of toxic factors (Table 4).

Table 4. Potential Neurotoxic Factors in MS
Proinflammatory cytokines


Excitotoxins


Free radicals


Oxidative and metabolic stress factors


Disturbed extracellular ionic milieu


Immune system cells/immunoglobulins



The full significance of neuron involvement in MS is unclear, but it could well play a role in cognitive disturbances. The fact that axons and neurons are damaged, with proven correlates to clinical disability and MS disease progression and possible correlates to cognitive loss, highlights their importance as a therapeutic target. Neuroprotective strategies, neurotrophic growth factors, immunomodulatory therapies, cell transplantation, and even gene transfer are future approaches to make neurons and axons less vulnerable to injury; to promote remyelination and axon repair; and to replace lost oligodendrocytes and neurons.

The Subclinical Nature of MS
By definition, relapsing MS patients are clinically stable between disease attacks. Previously, scientists and clinicians believed that MS went into remission and that active disease was confined to periods of clinical relapse. Another common belief was that the MS disease process burned out over time. We now know that virtually all patients with MS experience ongoing subclinical disease activity and CNS damage, even when no obvious worsening or changes in the patient's neurologic examination have occurred.

Frequent MRI studies indicate that 80% to 90% of new brain lesions are not associated with clinical relapse or detectable examination changes.[16] In untreated MS populations, brain lesion burden increases by 5% to 10% each year.[16] Accelerated brain atrophy is present even in early, mild, relapse-free patients with stable Kurtzke Expanded Disability Status Scale (EDSS) scores.[17] Clearly, then, clinical criteria underestimate disease activity.

With the exception of benign relapsing MS, natural history studies indicate that all untreated patients develop disability. Furthermore, benign MS has never been formally defined and probably involves no more than 5% to 10% of patients.[18] This is a retrospective diagnosis, looking back after several decades of mild disease. In 1 recent study, half of patients diagnosed with benign MS at 10 years had significant disability at 20 years.[19] When MS is viewed as an active, ongoing disease process with accumulating permanent damage to the CNS, the importance of treatment at the earliest recognizable time point becomes even more apparent.

Neuroimaging and MS: Present and Future
Not only does clinical observation underestimate the true MS damage process, but so too does the best current clinical MRI analysis. Conventional MRI techniques detect T2 hyperintense lesions (which have little to no pathologic specificity), T1 hypointense lesions (which, when chronic, indicate greater tissue damage and axon loss), and gadolinium contrast-enhancing lesions (indicating a focal major breach of the blood brain barrier and current disease activity). However, unconventional techniques can detect microscopic and physiologic changes in normal-appearing CNS tissue (Table 5).

Table 5. Neuroimaging Techniques That Detect Abnormalities in Normal-appearing CNS Tissue of MS Patients
Magnetic resonance spectroscopy


Magnetic transfer imaging


Diffusion-weighted and diffusion-tensor imaging


Functional MRI


High magnet (>/= 3 Tesla) MRI


Positron emission tomography (PET) scanning





In brain MRIs of patients with MS, up to 70% of normal-appearing white matter may actually be abnormal. Indeed, tracking changes in normal-appearing tissue may be a sensitive marker for disease severity and response to therapy. In a recent analysis, yearly whole brain NAA changes differentiated early relapsing patients into 3 groups. Approximately 20% of patients had stable NAA levels, 55% showed a modest reduction, and 25% showed a marked reduction in these levels.[8] Presumably those patients with marked reductions in NAA levels, consistent with greater axon damage, have more severe disease, a worse prognosis, and will ultimately develop more rapidly progressing disability.

Magnetic transfer imaging measures signal changes in fluid and fixed phase molecules within regions of interest. This generates a magnetic transfer ratio (MTR). MTR allows lesion severity to be measured; the lower the MTR, the greater the tissue damage. Such nonconventional neuroimaging techniques are being used in research protocols, but ultimately some will come to routine clinical use.

Heterogeneity of the Disease
One final new concept about MS is that it is probably heterogeneous. The disease demonstrates clear clinical variability, based on distinct clinical subtypes and disease severity (Table 6).

Table 6. MS Clinical Heterogeneity
Subclinical (asymptomatic) MS
Based on autopsy studies


May account for up to 20% of MS



Clinical (symptomatic) MS
Relapsing subtype
- 85% of MS at onset

- 55% of MS overall

- characterized by disease attacks, clinical stability in between

Primary progressive subtype
- 10% of MS

- Slow worsening from onset

- Distinctive disease onset features (older age onset, progressive myelopathy, equal gender ratio, no relapses)

Progressive relapsing subtype
- 5% of MS

- Indistinguishable from primary progressive except for later superimposed relapses

Secondary progressive subtype
- 30% of all MS

- ultimately 90% of untreated relapsing MS

- prior relapsing patient who transitions to slow worsening



There is also genetic heterogeneity, with distinct disease-associated genes based on race. MS also shows heterogeneity based on ability to remyelinate; only 70% of patients experience remyelination of MS plaques. The factors that prevent remyelination in 30% of patients are not known, although studies suggest that the presence of oligodendrocyte precursors, axon integrity, and axon surface molecule expression are important contributors.[20-24] Finally, recent studies suggest immunopathologic heterogeneity. A multinational consortium of neurologists and neuropathologists has studied acute plaque pathology in MS brain tissue samples obtained at biopsy or autopsy.[25] Results of this study reveal 4 distinct immunopathologies (Table 7). These observations await confirmation but, if true, suggest 4 distinct categories of MS based on primary damage mechanisms, and would have profound therapeutic implications.

Table 7. Heterogeneous MS Brain Plaque Immunopathology
Pattern Frequency Damage Mechanism Animal
Model Oligodendrocyte Numbers Remyelination Clinical Correlations
I 19% Macrophage
mediated + (myelin-
induced EAE) Preserved + Seen in all MS subtypes
II 53% Antibody,
complement
mediated + (MOG-
induced EAE) Preserved + Neuromyelitis optica, + plasma exchange response
III 26% Distal dying back oligodendrogliopathy with apoptosis (ischemic, toxic, virus induced) --- --- Balo's concentric sclerosis
IV 2% Oligodendrocyte degeneration (metabolic defect) --- --- Atypical primary progressive MS


EAE = experimental allergic/autoimmune encephalomyelitis; MOG = myelin-associated glycoprotein

Therapy of MS
The DMTs are expensive, and when trying to optimize cost-effective management of MS, several controversial issues must be confronted (Table 8). The remainder of this clinical update will address these topics and review the rationale for specific recommended approaches.

Table 8. Current Controversial Topics in the Management of MS
Should DMT be recommended for all patients with MS?


How early should DMT be started?


How do you select which DMT to use?


How do you determine suboptimal response/treatment failure?


How do you deal with suboptimal response/treatment failure?


What future treatment approaches look promising?


What is the role of steroids for patients with MS?



Should DMT Be Recommended for All Patients With MS?
The National MS Society has recently updated its consensus guidelines for use of MS DMT (Table 9).[26] It endorses the use of immunomodulators for all relapsing forms of MS and for consideration of treatment for selected first-attack/high-risk patients. Thus, unless a specific contraindication exists, therapy is appropriate in all relapsing patients, secondary progressive patients with superimposed relapses, progressive relapsing patients, and many first-attack patients. The single exception is benign relapsing MS, which does not need to be treated. However, because benign MS is a strictly retrospective diagnosis, most patients and physicians will choose not to gamble on a benign course and risk missing the benefits of treatment. This approach is predicated on the fact that the immunomodulator DMTs are safe and well tolerated. Contraindications to therapy include pregnancy, attempts to become pregnant, breastfeeding, inability to tolerate DMT, allergy to the drugs or their carriers, and severe comorbidity (such as significant psychiatric disease that makes compliance impossible or risky).

Table 9. NMSS Disease Management Consensus Statement (NMSS, 2002)[26]
Initiate immunomodulator treatment as soon as possible following diagnosis of MS with a relapsing course; consider for selected first-attack/high-risk patients.


Access to therapy should not be limited by relapse frequency, age, level of disability, or most medical conditions.


There should be access to/coverage for all FDA-approved agents; it is permissible to change drugs.


Immunosuppressant (mitoxantrone) therapy may be considered for selected worsening and/or relapsing patients.


None of the DMTs are approved for use in women who are pregnant, nursing, or trying to become pregnant.


Treatment should not be stopped while insurers evaluate for continuing coverage.


Therapy continues indefinitely except in the event of


- clear lack of benefit;

- intolerable side effects;

- new data; or

- better therapy.



Treatment of Secondary Progressive MS Without Relapse
Data to support treatment of patients with secondary progressive MS without relapses are mixed. The European study of IFN beta-1b found treatment to be quite effective in patients with secondary progressive MS, with or without relapses.[27] No other study has been as convincingly positive. The International MS Secondary Progressive Avonex Controlled Trial (IMPACT), using double-dose IM IFN beta-1a, documented a treatment effect on progression as measured by the MS functional composite (MSFC) (25-foot timed walk, 9-hole peg test, Paced Auditory Serial Addition Test [PASAT]), but not on the EDSS.[28] However, the only significant effect on the MSFC was in the 9-hole peg test component. Neither the North American IFN beta-1b study nor the SC IFN beta-1a Secondary Progressive Efficacy Clinical Trial of Recombinant IFN beta-1a in MS (SPECTRIMS) trial showed an effect on progression based on EDSS.[29,30]

Despite the discrepancies in the effect of treatment on EDSS progression, all the trials of treatments for secondary progressive MS have shown benefits in suppressing superimposed relapses, and on MRI (T2 lesion burden, Gd+ lesions) parameters. The only DMT approved for secondary progressive MS in the United States is the immunosuppressor mitoxantrone. Because of concerns about cardiotoxicity, this drug can only be used up to a lifetime maximum of 140 mg/m2 (about 11 doses). The pivotal mitoxantrone in MS (MIMS) trial entered 194 patients who had relapsing and secondary progressive MS with or without relapses, but participants were randomized to 1 of 3 treatment arms,[31] and thus, no statement about statistical significance of treatment is possible with regard to the group of patients with secondary progressive MS without relapses.

Treatment of Primary Progressive MS
There is no proven treatment for primary progressive MS. The recent phase 3 trial of glatiramer acetate (GA), the PROMISE trial, did not find a treatment benefit on progression. Although the drug was well tolerated, neither placebo- nor GA-treated patients deteriorated at the rate predicted from natural history studies. Two phase 2 trials of IFN beta in primary progressive MS have proved disappointing; 1 suggested modest benefits on secondary outcomes, the other was almost uniformly negative.[32,33] An ongoing phase 2 trial of mitoxantrone has not yet reported any results.

Thus, based on available evidence, use of DMT cannot be endorsed for patients with either secondary progressive MS without relapses or those with primary progressive MS, who together may account for 25% of all patients with MS. At the same time, a case can be made for treatment benefit in patients who have secondary progressive MS with Gd+ activity on MRI, who have worsened by greater than 1 EDSS point in the previous 2 years, or who are temporally close to their relapsing phase. In addition, a benefit of DMT, especially over the long term, has not been disproven for primary progressive MS.

How Early Should DMT Be Started?
The National MS Society consensus statement endorses consideration of therapy in selected first-attack/high-risk patients. This is based on 2 phase 3 trials, the Controlled High-risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) and Early Treatment Of MS (ETOMS). In both studies, patients randomized to DMT were significantly less likely to experience a second attack or to develop new brain MRI lesions during the study period than if they received placebo treatment.

CHAMPS enrolled patients between the ages of 18 and 50 years who had a clinically isolated syndrome (unilateral optic neuritis, incomplete transverse myelitis, isolated brainstem/cerebellar syndrome), abnormal brain MRI, and no better diagnosis for their neurologic attack.[34] Brain MRI had to show at least 2 unrelated T2 lesions >/= 3mm in size, at least 1 of which had to be ovoid in shape or periventricular in location (both these lesion features are suggestive of MS). Patients were randomized to receive IFN beta-1a 30 mcg IM weekly or placebo for 18 months. In a recent analysis of the placebo arm of the CHAMPS trial, 2 or more Gd+ lesions at presentation predicted that 52% of patients would experience a second clinical attack within 18 months, 92% would have an attack or demonstrate 2 or more new or enlarging T2 brain lesions, and 96% would have a clinical attack or at least 1 new or enlarging MRI lesion.[35] The presence of >/= 2 Gd+ lesions was the best predictive marker for development of clinically definite MS.

The ETOMS study entered 308 first-attack patients, ages 18 to 40 years, with unifocal or multifocal (39%) CNS presentations and abnormal brain MRI.[36] The MRI was required to show 4 T2 white matter lesions, or 3 T2 white matter lesions if 1 was enhancing or infratentorial. Patients were assigned to receive IFN beta-1a 22 mcg SC weekly or placebo, and were followed for 2 years. In both the CHAMPS and ETOMS studies, conversion to clinically definite MS (a second relapse) within the next 18 to 24 months occurred significantly less frequently in the IFN beta-treated groups.

The number of new/enlarging MRI lesions and lesion burden were also significantly less with treatment. In the ETOMS study, which used a very low dose of IFN beta-1a, 84% of treated patients had either a clinical relapse or new MRI lesions, as did 94% of those who received placebo. Patients with a multifocal presentation experienced an approximately 2-fold higher conversion to clinically definite MS. ETOMS suggests that MS is easier to treat early, since the dose of SC IFN beta-1a used in that trial failed to treat established relapsing MS in the Once Weekly Interferon for MS (OWIMS) trial.[37] In view of these data, which support therapy as soon as possible in the disease process, it would seem prudent to treat first-attack patients who fall into a high-risk group for MS. CHAMPS had the least stringent MRI entry requirements, yet was quite successful in identifying first-attack MS patients. Suggested criteria for offering DMT to first-attack patients are outlined in Table 10.

Table 10. Proposed Criteria for Treatment of First-attack/High-risk Patients
Appropriate age


- 10 to 50 years

Suggestive clinical syndrome


- Unilateral optic neuritis with pain and without macular abnormality

- Incomplete transverse myelitis

- Isolated brainstem/cerebellar syndrome (eg, internuclear ophthalmoplegia, trigeminal neuralgia)

- Paroxysmal attacks

- Lhermitte sign

- Multifocal white matter syndrome (not suggestive of acute disseminated encephalomyelitis)

Abnormal brain MRI*


- Lesions unrelated to clinical attack

- Lesions >/= 3 mm

- >/= 2 contrast lesions, or >/= 2 T2 lesions (1 periventricular or ovoid)

Other diagnoses ruled out





*Minimal MRI criteria are adapted from the CHAMPS study.

T2 MRI has a very high sensitivity for detecting tissue changes, and many disorders can produce brain MRI lesions. However, there are recognized lesion features that have high predictive value for MS (Table 11; Figure). These can be used to increase confidence of the MS diagnosis.


Figure 1. MRI changes in multiple sclerosis. This composite shows some of the changes captured by serial MRI that are characteristic of the dynamic nature of the underlying pathologic disease activity in multiple sclerosis. The patient was evaluated serially by high-resolution MRI, and the images were quantified automatically. The patient had no clinically defined change in his neurologic symptoms or findings during this 7-month interval despite the significant activity demonstrated by MRI. Source: Lindsey JW, Wolinsky, JS. Section IX: Demyelinating Diseases. Chapter 11: Neurology. In: Dale DC, Federman DD, eds.WebMD Scientific American® Medicine Online. New York, NY: WebMD Corp; 2001. Reproduced with permission of publisher.



Table 11. Brain MRI Features That Increase Likelihood of Further Disease Activity
High number of T2 lesions


High volume of T2 lesions


Gd+ lesions


Juxtacortical, infratentorial, corpus callosum lesions


Large T2 lesions



In summary, immunomodulator DMT should be initiated as soon as there is a confident diagnosis of a relapsing form of MS. It can also be offered to first-attack/high-risk patients who meet criteria that indicate high likelihood of MS (Table 10).

How Do You Select the Appropriate Disease-modifying Therapy?
It is not appropriate to let patients choose their DMT in isolation. Multiple factors must be considered, and the treating neurologist should provide an informed perspective and guide the optimal choice (Table 12).

Table 12. Factors in Choosing an Immunomodulator DMT
MS Factors


- Clinical subtype

- Disease duration

- Prognostic profile

- Clinical disease severity (relapse rate, type of relapse, extent of
recovery, disability)

- MRI disease severity

Patient Factors


- Comorbidity

- Lifestyle preferences

- History of drug tolerance

- Ability to inject

- Compliance

Drug Factors


- Efficacy

- Side-effect profile

- Convenience

- Expense

- Route of delivery



Disease/Patient Factors
Disease considerations involved in the choice of treatment include clinical subtype, duration of MS, prognostic profile, and a variety of disease severity measures. Although the formal trials in first-attack patients were carried out with IFN beta-1a, it is reasonable to conclude that any immunomodulator that works for patients with relapsing MS will work for first-attack patients.

Clinical disease severity is measured by relapse criteria, including number, severity (motor, cerebellar, and sphincter involvement indicate a more severe attack), and degree of recovery, and by development of disability/progression. More severe clinical disease clearly warrants more effective DMT. When seen early in relapsing MS, certain factors suggest a more rapid onset of progressive disease and disability (Table 13). The patient's prognostic profile is also an important factor when choosing therapy. Patient-specific factors include comorbidity (psychiatric disorders, hepatic disease, psoriasis), which may influence choice of drug, as well as practical issues such as ability to self-inject or availability of a partner to do so (Table 13).

Table 13. Factors Indicating Worse Prognosis in Relapsing MS
Early high relapse rate


- > 2 in yr 1

Late in relapse rate


Poor relapse recovery


- EDSS >/= 3 by yr 3

- moderate pyramidal involvement

IgG index (> 1.0) at diagnosis


Late age at onset


EDSS > 3.5


Polyregional onset


- especially sphincter, motor involvement

Sphincter, motor relapses



Drug Factors
Among drug factors, efficacy and side-effect profile are probably the 2 most important considerations. Good data now exist to show that the 3 IFN beta DMTs are not equally effective. Two randomized, prospective, multicenter phase 3 trials have compared the different IFN betas head-to-head. The Independent Comparison of Interferon (INCOMIN) study was funded by the Italian government and the Italian MS Society.[38] The 2-year study enrolled 188 patients with mild (EDSS 1.0-3.5) active relapsing disease. Patients were randomized to receive IFN beta-1a 30 mcg IM once weekly or IFN beta-1b 8 MIU SC every other day. At the end of 2 years, the group receiving IFN beta-1b included a higher proportion of relapse-free patients (51% vs 36%, P = .035), fewer patients with sustained EDSS worsening (14% vs 30%, P = .04), and a greater proportion of patients with no new T2 lesion activity on brain MRI (55% vs 26%, P = .0003) compared with the IFN beta-1a group. Although treating physicians and patients were not blinded, MRIs were read blinded at a central site.

The European-North American Comparative Efficacy (EVIDENCE) study was funded by Serono, the makers of the SC formulation of IFN beta-1a.[39]This 48-week study entered 677 patients with active relapsing MS. Patients were randomized to receive IFN beta-1a 30 mcg IM weekly or IFN beta-1a 44 mcg SC 3 times weekly. Participants underwent monthly MRI scans for 24 weeks, then a final scan at 48 weeks. The critical primary and secondary outcomes, judged at 24 weeks, were proportion of relapse-free patients and combined unique MRI lesions (Gd+ plus T2 lesions, not double counted). Although patients and treating physicians were aware of their therapy, evaluating physicians (who judged relapses) were blinded, and MRIs were read blinded at a central site.

At 24 weeks, the proportion of relapse-free patients was higher in the SC IFN beta-1a compared with the IM regimen arm (75% vs 63%, P = .0005), and combined unique MRI lesions were fewer compared with the IM arm (0.8 vs 1.2, P < .0001). In addition, the group receiving the higher, more frequent IFN beta-1a dose experienced a lower relapse rate (P = .022), fewer treated relapses (P = .004), longer time to relapse (P = .001), lower rate of active MRI scans (P < .0001), and included more patients without any MRI activity (P < .0001).

The 48-week data continued to show a statistically significant difference in favor of the higher, more frequent dose regimen of IFN beta-1a. The proportion of relapse-free patients was 62% vs 52% (P = .009) in the SC vs IM dose regimen, and the number of mean T2 active lesions was lower (0.9 vs 1.4, P < .001), as were proportions of active scans per patient (27% vs 43%, P < .001). The higher, more frequent regimen group was also more likely to have shown no MRI activity (63% vs 45%, P < .001).

In summary, these randomized, prospective comparison trials indicate that, for a broad spectrum of patients with MS, IFN beta has greater efficacy when it is given several times a week (vs once a week) and at higher doses. This is consistent with data showing that a sustained level of IFN beta (with a greater area under the curve drug concentration) is better than brief periods of IFN beta exposure. Dosing frequency may be more important than dosing amount, since a recent study of IM IFN beta-1a given at 30 vs 60 mcg once a week showed similar clinical and MRI effects for both dosing schedules.[40]

Side effects are another important factor in drug selection. Among the DMTs, GA has the best side-effect profile. Since this DMT also has good long-term efficacy data, it is an attractive choice when overall tolerability is a major issue.

How Do You Determine Suboptimal Response/Treatment Failure?

Response to DMT spans a wide spectrum. Patients may be super responders, partial responders, or even biologic nonresponders. Response may also change over time. Criteria used to judge poor treatment outcome include clinical and MRI criteria (Table 14).

Table 14. Criteria to Determine Suboptimal Response/Treatment Failure
Clinical Criteria


- Intolerable side effects

- Relapse rate

failure to show relapse rate


of < 33%


> 1 mild relapse/yr


- Transition from relapsing to SP MS

- Progression rate on therapy is unchanged or accelerated

MRI Criteria


- Gd+ lesion activity continues unchanged, only mildly , or (high-dose IFN beta suppresses by 70% to 90%, low-dose IFN beta by 50%, GA by 35%)

- T2, T1 burden of disease

- Marked in CNS atrophy



In general, patients doing well on DMT should show little disease activity, as measured by relapses or disease progression. Patients should be receiving drug for a finite period of time (generally 6 months) before judging therapeutic response. The most valuable laboratory assessment for evaluating suboptimal response is contrast brain MRI. Although the value of a single MRI scan has been questioned, a recent expert consensus group of neurologists and neuroradiologists endorsed performing MRI on patients with MS who were receiving treatment but in whom there was a concern about response to therapy.[41]

The role of neutralizing antibodies (NAbs) to IFNbeta and judging treatment response is unclear. To date, there is no agreed upon assay, cutoff value, or recommended time frame to evaluate NAbs. Although persistently high levels probably interfere with the drug's efficacy in most patients, this is not an absolute. The recent National MS Society Consensus Guidelines did not endorse changing therapy for patients with elevated levels of NAb who were otherwise doing well.[26]

How Do You Approach Suboptimal Response/Treatment Failure?
There are several options when a patient on DMT is not responding appropriately (Table 15).

Table 15. Treatment Options When Faced With a DMT Poor Responder
Increase IFN beta dose, frequency


Change class of DMT


Administer intensive induction therapy, with temporary discontinuation of DMT


Administer combination therapy


Discontinue therapy





The comparison IFN beta trials support the concept that suboptimal responders on once-weekly IFN beta can be switched to greater efficacy IFN beta regimens, either IFN beta-1a 44 mcg SC thrice weekly or IFN beta-1b 8 MIU SC every other day.

With any drug treatment, there are patients who are biologic nonresponders. In this situation, it is reasonable to consider a switch in the class of immunomodulator, for example, from IFN beta to GA, or vice versa. Characteristically, a biologic nonresponder experiences no period of therapeutic response, as opposed to responding for a period of time and then showing breakthrough disease activity.

Induction Therapy
Induction therapy is appealing in the presence of rapid deterioration despite reasonable immunomodulator therapy. There is precedent for a short course of immunosuppression to restore the patient's response to the primary DMT. For patients with rapid deterioration despite therapy with an effective DMT, it may be reasonable to temporarily discontinue the drug and treat with several months of IV mitoxantrone or cyclophosphamide. After a period of time (6 months or more), as soon as the disease process is controlled, the immunomodulator can be resumed.

The abnormal immunologic cascade in MS involves multiple levels, with multiple potential damage factors. Small-scale studies suggest that patients who are failing monotherapy may respond to combination therapy. There are a number of proposed combination treatments for MS (Table 16), all of which await large-scale clinical trials to compare their efficacy and safety against the existing single-drug regimens.

Table 16. Proposed Combination Therapies for MS
IFN beta + GA


DMT + immunosuppressive


- oral (azathioprine, methotrexate)

- IV (cyclophosphamide, mitoxantrone)

DMT + pulse therapy


- glucocorticoids

- intravenous immune globulin

- anti-adhesion molecule monoclonal antibody

DMT + adjuvant/neuroprotective agent

What Is the Role of Steroids in MS?

Glucocorticoids, most commonly methylprednisolone or prednisone, are typically used for symptomatic treatment of MS relapses. They are said to potentially shorten the time to recovery, but not ultimately change the degree of recovery. Glucocorticoids are not considered DMTs. Rather, they produce a number of beneficial anti-edema and anti-inflammatory effects, including temporarily decreasing blood brain barrier permeability and shutting off production of pro-inflammatory cytokines and other inflammatory and potentially damaging substances.

Recent studies suggest that glucocorticoids may have an impact on the MS disease process. In a single-center phase 2 trial, patients with relapsing MS were randomized to either receive regular pulses of intravenous steroids or only be treated at the time of relapse. At 5 years, the pulse steroid-treated patients showed less disability, brain atrophy, and T1 brain lesion load compared with those in the control group, who received steroids only for acute relapses.[49] Another small study evaluated brain lesions detected on monthly MRI scans of 4 patients with relapsing MS. Lesions showed the least permanent tissue damage (as measured by magnetic transfer ratio) when patients were treated with steroids.[50] The greatest tissue damage was noted in untreated lesions, while moderate damage was noted in lesions that occurred in IFN beta-treated patients. However, because complications involved with long-term steroid use may be significant, the role of steroids in management of MS needs further study, in terms of both safety and efficacy.

Summary
Fundamental changes in our understanding of MS are refining treatment approaches. Current emphasis involves early use of DMT and use of logical combination strategies when the response to monotherapy is suboptimal. Future emphasis will involve axon/neuron strategies, novel therapies, and effective repair mechanisms.

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Редактирано от lvo lll на 03.06.03 01:24.

някой
има ли възможност и желание
да преведе тази статия ?

Ха, не съм убедена че ще е рабираема за всеки, но както и да е.
Преведох една част и просто нямам сили повече за днес - ще преведа останалото по-нататъка. Подчертавам с червено думи които не знам как се превеждат на български.


Въведение
Множествената склероза (МС) е най-често срещаното придобито неврологично заболяване при младите хора. Прототипа на пациента с МС е млада жена във възраста за раждане, въпреки че 25-30% от случаите с МС са мъже.МС засяга Централната нервна система( ЦНС) довеждайки до широк спектър от симптоми свързани с главния и гръбначния мозък обикновено с 2 клинични профила. Обикновено пациентът започва да изпитва периоди на неврологични аномалии (МС с релапс и ремисия) – остра атака на болестта, чиито симптоми може да изчезнат спонтанно. В повечето случаи този тип МС преминава във вторична прогресивна МС със или без атаки и без значително подобряване. В 10% до15% от случаите болестта започна направо с прогресивна фаза (Първична прогресивна МС,) като само малко част от тези пациенти изпитват от време на време някакоя атака ( релапс), която се появява по-късно в развитието на болестта. Не е известно какво причинява МС, но се предполага че е комбинациа от 3 фактора – вродена предразположеност ( наследявайки много предразполагащи гени и малко протектиращи), излагане на някакъв вид външен фактор и развитие на патологична иммунна реакция, която е насочена срещу ЦНС.
До преди 10 години нямаше никакво лечение за МС. От 1993г. 5 лекарства които повлияват на протичането на заболяването бяха одобрени от FDA* (*американската агенция отговорна за одобряването на лекарства, които се употребяват в САЩ)
(таблица 1).
Четири от тях са имуномодулатори, а едно е имуносупресант. Всяко от тях
oказва благоприятно въздействие върху имунната система . За да бъдат разбрани текущите терапии, важно e да се оценят новите познания за естеството и степента на процеса на заболяването, които бяха придобите в последните няколко години(таблица 2). Тези идеи тласкат новите терапевтични подходи.

Таблица 1 – Съвременни лекарства които повлияват на протичането на МС

Имуномодулатори:
IFNbeta-1a (Avonex) - anti-inflammatory cytokine- 30 микрограма на седмица- мускулна инжекция; Множество системни ефекти върху имунната система.
- регулиране на клетките към и от имунната система
- пропускливостта на кръвно-мозъчната бариера
- активиране на Т клетките
- реакции на мястото на инжекцията
- депресия
- аномалии в чернодробните изследвания и ПКК
-спазми

IFN beta-1a (Rebif) 44 микрограма подкожно 3 пъти в седмицата ( Rebif всъщност е същото лекарство като Avonex, само че се дава подкожно и по-често)
ефект- виж по-горе

IFN beta-1b (Betaseron) - 250 mcg (8 MIU) подкожно, през ден - - ефект- виж горе


Glatiramer acetate (Copaxone)- неопределен полимер от 4 аминокиселини; универсален антиген на клетките; 20mg подкожно, всеки ден.
- активира TH2 suppressor клетки;
- ....
- вероятна невропротективна/ ремиелинираща функция
- реакции на мястото на инжекцията
- системни ( веднага след инжекцията) реакции
- реакции, които се дължат на хиперчувствителност към лекарството

Имуносупресанти:

Mitoxantrone (Novantrone) Anthracenedione (химиотерапия) 12 mg/m2 венозно всеки 3 месеца (максимум 140 mg/m2)
-ширoка имуносупресивна функция (T клетки, B клетки, macrophages ,
- кардиотоксичен
- намалява броя на белите кръвни клетки
- менструални отклонения
- гадене
- предазположение към инфекции
- левкимия ( рядко)

Таблица 2
- Нови представи за МС
- Ранната фаза от развитието на МС е критичен период – роля на
разпространението на epitope
- Основното естество на процеса на унищожаване може да се промени с времето
- Характерно за МС е че аксониете и невроните са включени в процеса на болестта
-по-голямата част от развитието на болестта протича без симптоми
- има много микроскопични аномалии в мозъчна тъкан коятоизглежда нормална
- МС е хетерогенна


Нови представи за МС
Въпреки че генетичната предразположеност е задължителна за развитието на МС, тя не е достатъчна в отсъствието на други съдействащи фактори. Околкната среда със сигурност играе роля, тъй като има определени ниско- средно- и високорискови географски зони.
Излагане на често срещани вируси в ранна възраст (по все още неясен начин), подготвя сцената за МС по-късно. Инфекциите вероятно играят роля при започване на болестта, въпреки че продължителна активна нервна инфекция не е изключена като фактор за MC при определни пациенти.
Молякулярна мимикрия* ( * означава имитиране - определени външни молекули може да имат форма, която е много близка до тази на клетките от нервната система и затова организма, след като веднъж е изградил имунна рекация към чуждите клетки, започва бърка собствените си клетки с чужди ) e доста добре документирана. Общоприето е да се вярва, въпреки че не е доказано, че в предразположени индивиди реактивност към миелина която започва от инфекция е в основата на МС. Разпространението на epitope става след като повредата в ЦНС причинява изпускане на множество sequestered antigens в имунната система. Най-вероятно има 2 вида epitope разпространение. Интермолекулярна – когато имунната рекация се придвижва от един на друг антиген на миелина( започнала е срещу myelin basic protein (MBP) , но понеже е атакуван миелина други антигени като например myelin oligodendrocyte glycoprotein (MOG) се произвеждат и имунната реакция се разпространява и срещу МОG. Интрамолекулярна – когато имунната реакция е насочена срещу определен пептид на определен протеин( например MBP аминокиселина 82-99) и след унищожението на миелина разкрива други скрити epitopes от myelin basic protein и имунната рекация се прехвърля върху тези нови epitopes. Това разширява имунната атака, така че тя се превръща в специфицна към определен орган автоимунна болест.


Терапевтични заключениа за Epitope Spread

Идеята за epitope spread налага важни терапевтични последствия. Това означаве, че трябва да се започне ефективна терапия за МС възможно най-рано ( идеално при първата атака ) , за да бъде намалено разширяването и подсилването на процеса на унищожение. Тази идея дори дава причина да се има предвид първоначално използване на имуносупресанти, последвано от поддържаща терапия. Допълнително доказателство, че ранния процес на заболяването е критичен, идва и от изучаването на естествената история на заболяването при пациенти с първа атака ( клинично изолиран сидром). Броя и обема на Т2 мозъчни плаки които се виждат на ЯМР( ядрено магнитен резонанс) e ясен индикатор на степента на инвалидност след 14 години, последван от плаките, които са се появили в първите 5 години.

Нови разбирания за патофизиологията на МС : Аксони
В момента се вярва, че МС е двуфазен процес. В ранния стадий възпалението е изразено и съответства на релапс и е потенциално обратима фаза на МС. По-късно ина преминаване в първична нервнодегеренативна( така ли се казва на български?) фаза, която съотвестства на прогресивна МС със необратими последици. Въпреки че възпаление и дегенерация на нервната тъкан се виждат във всяка една фаза, първото изглежда че доминира. Тази идея съвпада с историята на болестта, тъй като повечето пациенти започват с релапсивни-ремитна МС и евентyално прогресират до вторично прогресивна МС. Наличието на отделни фази е причина терапията да бъде подходяща за естеството на болестния процес.

Класическата представа за МС е, че е болест, която включва възпаление и демиелизация в ЦНС. Вече е ясно от събраната патологичната информация и индиректна информация от ЯМР, че болестта също така причинява вреди на аксоните и невроните. Плътността и обeма на аксоните при МС са намалени не само в плаките, но и в нормално изглеждаща тъкан от ЦНС. Анализи на n-acetyl aspartate (NAA)( аксоннен/ невронен маркер) дава индикации, че NAA в цялия мозък е намален дори и в ранната фаза на МС. Загуба или свиване на аксоните е основна причина за намаляване на обема на главния и гръбначния мозък. При пациенти с МС това я изразено много рано, още по време на първата атака. Всяка година намаляването на обема на мозъка се увеличава от 3 до 10 пъти повече от това на здрави хора.
Значението на увреждането на аксониете огромно. Вярва се, че именно то е в основата на перманентната инвалидност и прогресирането на болестта. Увреждането на аксоните без съмнение се изразява в множество фактори( таблица 3). Поне няколко от имунните и възпалителните елементи, които увреждат аксоните са различни от тези, които унищожават миелина. Аксони или техни компоненти ( например йонни канали или neurofilaments) може да са мишена на първична или вторична имунна атака. Намерена е връзка между наличието на антитела за компоненти на neurofilaments, gangliosides, and myelin oligodendrocyte glycoprotein и прогресивна МС. От друга стана уврежданията може да са отражение на вторични ефекти от възпалителни или токсични фактори, които биват изпускани в микросредата от вътрешни (микроглия, астоцити) или външни(лимфоцити, макрофаги) клетки. Остра фoрма на увреждане на аксоните, измерванa чрез amyloid precursor protein expression, е свързана с инфилтрация на макрофаги и CD8+ T-клетки. Tекущата загуба на миелин допълнително уврежда аксоните. Загубата на миелин пречи на аксонния трaнспорт, като увеличава метаболичния стес върху невроните и аксоните. Миелина и аксона са в симбиозна връзка и самото демиелизиране е механизъм за увреждане на аксона. Загубата на миелин също рефлектира и върху йонните канали на оголената повърхност на аксона. Тези промени може или да върнат нервната проводимост, или да унищожат аксона.

Таблица 3 Потенциални допълнителни фактори за аксонно увреждане при МС
Механизми за увреждане
Директна атака на имунната система
- първична
- вторична
Индерекнто имунно увреждане
- от върешни компоненти от ЦНС
- от външни компоненти
Загуба на миелин
- повреден аксонен транспорт
- увредено remodeling на йонните канали
- метаболичен стрес
Загуба на неврони

Фактори за увреждане
CD8+ T клетки
Макрофаги
Антитела
- myelin oligodendrocyte glycoprotein
- neurofilament компоненти
- gangliosides
Невротоксични фактори

Терапевтични заключения за аксонното увреждане
Тъй като добавянето на натриеви канали позволява кондукцията на нервни сигнали, то увеличеното или по-бързо изразяване на тези канали би било желателен терапевтичен резултат. В контраст с това, калциевите канали(alpha 1-beta), които нормално са изразени в presynaptic axon terminal, вероятно биха могли също така да бъдат вкарани в демиелинизираща мембрана. Тъй като вкарването на такива канали води до увреждане на аксона, би трябвало да се опитаваме да предотвратиме такова вкарване. Вероятно е в бъдеще фокуса на терапията за МС да бъде манипулирането на йонните канали.


Нови разбирания за патофизиологията на МС : Неврони
Загуба на аксони се получава при смърт на неврона. При неотдавнашно изследване на мозъчен материял при аутопсия, беше изследван таламуса( регион от сиво вещество/ материя богат на неврони). Мозъците на пациенти с МС показаха 30-35% по-малко неврони, от колкото тези на индивиди без МС. NAA измервания показват разпростанение на нарушения на сивата материя дори и при раннен стадий на МС.
Загубата на неврони най-вероятно показва първични щети от директно и индиректно възпалително увреждане, както и вторична дегенерация на нервната тъкан причинена от токсични фактори (таблица 4).

Tаблица 4 Потенциални невотоксични фактори при МС
Proinflammatory cytokines
Excitotoxins
Свободни радикали
Оксидиращи и метаболични стрес фактори
Disturbed extracellular ionic milieu
Клетки на имунната система/имуноглобулини

Пълното значения на товa, че невроните са замесени е неясно, но може да играе роля при умствените способности.Факта, че невроните и аксоните са увредени, със доказана връзка между това и степента на инвалидност и прогресивност на болестта и вероятна връзка между увреждането и умствените способности, показва че невроните би трябвало да бъдат основна цел на бъдещи терапии.

Стратегии за запазване на нервната тъкан , neurotrophic growth фактори, имуноизменящи терапии, клетъчни траснплантации , и дори трансфер на гени са все бъдещи подходи за да направят невроните и аксоните по-малко уязвими; да стимулират ремиелинизация и поправяне на аксона; да заменят заубените олигодендроцити и неврони.

Субклиничната натура на МС
По принцип пациентите с релапсивно-ремисионна МС са клинично стабилни между отделните атаки. Преди се смяташе, че МС минава в ремисия и че болестта се развива само в периодите на клинични атаки. Също така че вярваше, че МС след време се “изтощава”. Сега е известно, че на практика при всички пациенти с МС болестта продължава да се развива и да уврежда ЦНС, въпреки че няма очевадно влошаване на ситуацията или промени в неврологичните показатели на пациента.
Изследвания с често правене на ЯМР показват, че 80-90% от новите мозъчни плаки не са свързани с клиничен релапс и не се установяват при неврологичен преглед. При нетретирана МС плаките се увеличават с 5-10% всяка година. Увеличено атрофиране на мозъка се вижда дори и при ранни леки случаи на МС, които са стабилни (според приетата скала за измерване на степента на инвалидност). Очевадно клиничните критерии недооценяват активността на заболяването.

С изключение на доброкачествента форма на релапсираща МС, естествената история на МС показва, че всички пациенти, които не са лекувани, придобиват някаква инвалидност. В допълнение, доброкачествена МС никога не е била официално дефинирана и вероятно вклювча не повече от 5-10% от пациентите. Това е дигноза, която се поставя ретроспективно, след като има на лице няколко десетки години лека форма на МС. В едно скорошно изследване половината от пациентите диагностицирани с доброкачествена МС след 10г. заболяване, са придобили значителна инвалидност на 20та година. Когато глeдаме на МС като на активно заболяване с натрупващи се перманентни увреждания на ЦНС, се вида оргомното значение на започването на лечение колкото се може по-рано.

Магнитен Резонанс и МС : Настояще и Бъдеще
Не само че клиничните прегледи подценяват истинското увреждане нанесена от МС, но същото става и с конвенционален ЯМР. ЯМР показва Т2 високочестотни плаки( които имат малко патологично значение) и Т1 нискочестотни плаки( които когато са хронични паказват по-голямо увреждане на тъканта и загуба на аксони) както и плаки, които се проявяват при вкарването на контраст с гадолиний (които показват значително нарушение в кръвно-мозъчната бариера и текуща активност на болестта). Въпреки тованетрадиционни методи могат да покажат микроскопични и физиологични промени във нормално изглеждаща тъкан от ЦНС( таблица 5)

Таблица 5. ( * показва различните видове скенери които се правят за откриването на плаки – не мога да я преведа).

Възможно е до 70% от нормално изглеждаща бяла материя( гледана на ЯМР) на пациентите с МС да бъде увредена. Всъщност следенето на промените в нормално изглеждащата тъкан е чуствителен показател за тежестта на заболяването и ефективността на терапията. При скорошен анализ, целогодишните промени в NAA в мозъка разделят пациентите в ранна фаза на заболяването на 3 групи. Околко 20% имаха стабилни нива на NAA, 55% имаха малко намаление на нивата и 25% със значително намаление. Вероятно тези пациенти с най-голямо намаление, което е свързано с по-голямо ужищожаване на аксони, имат по-тежка форма на заболяване, по-лоша прогноза и евентyално ще развият по-бъзо прогресираща инвалидност.
(*... следва кратко обяснение на неконвенционален метод за правене на снимки на мозъка – не мога да го преведа). За сега тази технология се използва само за научни изследвания, но евентуално ще започне да се използва и в клиничната практика.

Хетерогенност на заболяването
Едно от последните нови схаващания за МС е, че вероятно е хетерогенна. Заболяването демонстрира ясни клинични вариации основани на ясно отедлени клинични подразделения и тежест на болестта ( таблица 6) .

Таблица 6. MС Клинична Хетерогенност

Субклиничнаl (асимптоматична) МС
- Основана на изследвания при аутопсии
- Може да представлява до 20% от случаите на МС

Клинична (симптоматична) МС
Релапсен тип
- 85% от МС в началото
- 55% от МС като цяло
- характеризира се с атаки и клинична стабилност между тях

Първичнопрогресивна МС
- 10% от МС
- Бавно влошаване от началото
- Отличителни признаци в началото (по-голяма възраст при започване на болестта, прогресивна миелопатия, съотношението между мъже и жени е еднакво, без релапси)


Прогресивно-релапсираща МС
- 5% от МС
- Не се различава от Първичнопрогресивна МС, освен че по-късно се появяват и релапси

Вторично-прогресивна
- 30% от МС
- евентуално 90% от нелекувана релапсираща МС
- пациенти, които първоначално имат релапсираща МС която преминава във бавно влошаване

Също така има генетична хетерогенност със отделни гени, които са свързани с болестта на основа на расата на пациента. МС показва и хетерогенност при възможността да се ремиелинира. Само при 70% от пациентите настъпва ремиелинация на плаките. Не са известни факторите, които предотвратяват ремиелинацията при 30% от пациентите. Накрая, някои изследвания показват имунопатологична хетерогенност. Многонационален консорциум от невролози и невропатолози проведе изследване на патологията на плаките в тъкан от пациенти с МС при биопсии и аутопсии. Резултатите от това изследване показаха 4 различни имунопатологии( таблица 7). Тези наблюдения очакват потвърждение, но ако са вярни, ще се се окаже, че има 4 различни категории МС въз основа на механизмите за първично увреждане и ще има огромен ефект върху бъдещите терапии за МС.

Таблица 7. Имунопатология на хетерогенни плаки при МС ( не мога да я преведа)

Pattern Frequency Damage Mechanism Animal
Model Oligodendrocyte Numbers Remyelination Clinical Correlations

I 19% Macrophage mediated + (myelin- induced EAE) Preserved + намира се при всички видове МС

II 53% Antibody, complement mediated + (MOG- induced EAE) Preserved + Neuromyelitis optica, + plasma exchange response

III 26% Distal dying back oligodendrogliopathy with apoptosis (ischemic, toxic, virus induced) --- --- Balo's concentric sclerosis

IV 2% Oligodendrocyte degeneration (metabolic defect) --- --- Атипична първичнопрогресивна МС

EAE = experimental allergic/autoimmune encephalomyelitis; MOG = myelin-associated glycoprotein


Терапия при МС
Лекарствата изменящи курса на заболяването са скъпи и трябва да обърнем вниманиа на няколко спорни теми докато се опитваме да оптимизираме цената на лечението с ефективността му( таблица 8). Останалата част от тази публикация ще обърне внимание на тези теми и основната причина за специфичните препоръчителни подходи.

Таблица 8. Текущи спорни теми в лечението (ръководенето на терапията)на МС

- Трябва ли лекарствата изменящи курса на болестта да се препоръчват на всички пациенти с МС?
- Колко рано трябва да се започне лечението?
- Как да изберем кое лекарство да използваме?
- Как се определя неуспешно лечение?
- Как да се отнесеме с неуспешните лечения?
- Кои бъдещи подходи изглеждат обещаващи?
- Каква е ролята на стероидите за пациентите с МС?



След няколко дена ще преведа и останалaта част.

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