An accurate description of the clinical features (phenotypes) of multiple sclerosis (MS) is important for mutual communication, prognostic assessment, clinical study design and inclusion, and treatment strategy development. standardized descriptions published in 1996 were based on clinical phenotypes provided by international MS experts and based on information only, and were agreed upon at the time; however imaging and biological correlates were missing.
The increasing understanding of MS and its pathology, coupled with the general consensus that the original descriptions may not adequately reflect the most recently identified clinical features of MS, prompted the International Advisory Committee on MS Clinical Research to reevaluate the MS disease phenotype.
Because imaging and biological markers that provide an objective basis for the different clinical phenotypes are still missing, the authors suggest that the revised description should take into account disease activity (based on clinical relapse rates and imaging findings) and disease progression. Strategies for how to conduct future studies to better describe the disease phenotype are also outlined in this article.
This article was authored by Professor Lublin of the Icahn School of Medicine at Mount Sinai and was published in a recent issue of Neurology.
In 1996, the Advisory Committee on Clinical Trials in Multiple Sclerosis of the National Multiple Sclerosis Society (NMSS) defined clinical subtypes of MS. These typing definitions provide a consistent terminological expression for describing the different clinical features of MS and highlight parts where there is a lack of agreement or ambiguity in meaning.
The basic idea behind the above typologies was to satisfy the requirement for clarity and consistency in defining subgroups of patients through natural history and demographic studies, to enhance the homogeneity of clinical studies, and to provide clarity in communication between clinicians and patients with MS.
The committee standardized definitions for 4 MS clinical features: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). Soon after, it was recommended to discard the term relapsing-progressive MS because of its ambiguous meaning and overlap with other subtypes.
It was also proposed to replace the term chronic progressive with the more specific terms SP and PP, and to define benign and malignant MS. At that time, these phenotypic descriptors were considered to cover a broad spectrum of MS clinical subtypes, but it was recognized that these descriptors should be revised over time.
The 1996 classification was rapidly applied in clinical practice and became an inclusion criterion in almost all subsequent clinical studies in MS; it was also used to some extent to guide the regulatory review and licensing of new therapies. The descriptor is sometimes conflated simply as relapsing (including RR, SP, and PR) and progressive (including PP, SP, and PR), distinguishing primarily whether patients are predominantly relapsing or progressive, although the above distinction has never been clearly delineated.
Once the 1996 classification was proposed, it was recognized that it was based on the subjective opinion of MS experts and lacked objective biological evidence to support it. the absence of MRI, biology, and other relevant markers left a lack of knowledge clearly related to the clinical features of MS.
The authors of the 1996 classification noted that the above factors may have an impact on future revisions and additions to the method as imaging and biomarker studies evolve, changing the definition from one that relies purely on clinical features; and suggested that the clinical features of MS typing should be redefined accordingly.
In 2011, the committee and other experts (The MS Phenotype Group) reevaluated the MS phenotype, exploring clinical, imaging, and biomarker advances. in October 2012, the authors met to review the 1996 classification and resolved that sufficient progress had been made to recommend updating the original classification. The specific objectives of the meeting were as follows.
1. the 1996 classification was reevaluated to clarify whether a better classification could be developed that incorporates improved clinical description terminology, MRI and other imaging techniques, analysis of body fluid biomarkers, and other methods of analysis including neurophysiology.
2, A summary of the discussion was made, presenting what is known to the author, what the author recommends, and what remains to be addressed.
3. Recommendations for future research strategies are made for areas where information or consensus is lacking.
Key Consensus
1. The essential elements of the 1996 taxonomy are retained and clarified.
The 1996 taxonomy has become part of standard MS clinical practice and clinical research. the MS phenotyping group recommends that the essential features of the original descriptive method should be retained but revised and clarified, as detailed below.
The authors note that the diagnosis of MS should be made on the basis of imaging and other necessary clinical test data. The assessment of the clinical phenotype should be based on the patient’s current and previous data, guided by the idea that this assessment is a dynamic process and that the subtype opinion derived from the initial assessment may change over time. For example, the RR subtype may change to the SP subtype.
2. New disease regression processes.
(1) Clinically isolated syndromes (CIS): CIS was not included in the original MS classification. CIS is now considered to be the first clinical manifestation of a disease that exhibits inflammatory demyelinating features suspected of MS, but has not yet developed sporadic lesions that fully meet the diagnostic criteria for MS. Studies of the natural history of the disease and clinical studies of improved therapies for MS have shown that CIS combined with brain MRI lesions are highly likely to meet the diagnostic criteria for MS.
Clinical studies of medications used to treat MS have shown that only a small proportion of patients with CIS experience secondary worsening (the defining event of “clinically confirmed MS”) and reduced MRI activity after treatment. The marketing approval of drugs for CIS to delay the diagnosis of MS further clarifies the status of CIS as a member of the MS phenotype spectrum.
The 2010 revision of the McDonald MS diagnostic criteria allows patients with only 1 clinical episode to be diagnosed with MS based on objective clinical evidence of 1 lesion (meeting the criteria of temporal and spatial multiplicity), reducing the number of patients who can be classified as having CIS.
(2) Radiologically isolated syndromes (RIS): RIS is a more complex condition in which patients have only imaging data showing inflammatory demyelination, but no clinical signs or symptoms. According to current MS diagnostic criteria, RIS cannot be considered a subtype of MS by itself in the absence of clinical evidence of demyelinating disease; because positive MRI findings may be nonspecific.
However, depending on the morphology and location of the lesion found on MRI, RIS may increase the propensity for the diagnosis of MS. If brain imaging changes are highly suggestive of demyelinating lesions, they can increase the risk of future clinical symptoms of MS to the greatest extent possible. Asymptomatic spinal cord lesions, lesions visible with gadolinium enhancement, or positive CSF findings increase the likelihood of a definitive diagnosis of MS.
Patients with RIS should be followed prospectively if there are no obvious clinical signs or symptoms that can be linked to MS. Unless more useful information is obtained from prospective follow-up, RIS should not be considered as a definitive MS phenotype.
3. Define secondary progressive MS (SPMS).
In most clinical practices, SPMS is a retrospective diagnosis of an initially recurrent disease process followed by a history of progressive deterioration with or without acute worsening of the disease during the progression.
To date, there are no clear clinical, imaging, immunologic, or pathologic criteria to determine the specific time point at which relapsing-remitting MS (RRMS) transforms into SPMS; the transformation is often progressive. This limits our ability to distinguish this disease type by imaging features or biomarkers.
The authors hope that existing clinical research models and natural history datasets may provide solutions to these problems.
4. primary progressive MS (PPMS).
Although some evidence suggests that PPMS represents a distinct, non-inflammatory (or at least less inflammatory) class of MS types, there is also substantial clinical, imaging, and genetic evidence that PPMS is a member of the progressive MS disease spectrum and that any differences with other MS are more relative than absolute.
Analysis of natural history cohorts of SPMS and PPMS disease demonstrated similar rates of poor prognosis for both. Although the prevalence of no acute deterioration over clinical progression makes PPMS should remain as a separate clinical process, it is likely that PPMS does not possess pathophysiologically unique features compared to SPMS.
5. Revision of the basic MS phenotype: combined disease activity and disease progression phase.
Although MS phenotypes can be classified as relapsing or progressive based on available disease and medical history, this classification does not provide information on the timing of the ongoing disease course. the MS phenotyping group believes that for relapsing or progressive MS, clear disease activity by clinical relapse or imaging (gadolinium enhancement, or new/enlarged T2 lesions) can be as meaningful an additional disease staging factors.
Available evidence of disease activity and clinical progression reflecting a persistent inflammatory or neurodegenerative course may influence prognosis, clinical treatment decisions, and the design of clinical trials and outcome settings.
(1) Assessment of disease activity: The MS Phenotyping Group recommends that disease activity be assessed by clinical criteria and brain imaging criteria at least once a year for relapsing MS. Annual clinical assessment is also recommended for progressive MS, but there is no consensus on the optimal frequency of imaging.
Because of the high correlation between brain and spinal cord MRI activity and the rare occurrence of positive spinal cord imaging without positive brain imaging, regular spinal cord imaging is not recommended (unless a spinal cord lesion is present).
The author chose to review the evaluation at least annually because this interval has been used in clinical evaluation, but shorter or longer intervals may also be appropriate in certain circumstances. The periodicity of clinical and imaging evaluation in any given case should be individualized.
For example, a patient with RRMS who has a new lesion on gadolinium-enhanced MRI should be considered to have active RR. Conversely, “inactive” as a phenotype modification could be applied in the same manner, indicating that a patient with a relapsing course has no relapses, no lesions on gadolinium enhancement, or no new/active lesions on gadolinium enhancement during this evaluation cycle. active, or no new/enlarged T2 lesions were seen during this evaluation period.
Patients who fail to review as scheduled are considered to have “unspecified active (MS)”. Care should be taken in the technical and interpretation of imaging studies according to the diagnostic criteria for MS, especially when evaluating for new/enlarged T2 lesions.
The connotation of “active” as a modified version of the basic clinical course phenotype makes the PRMS classification no longer valid. Patients with PPMS with acute exacerbation events (meeting the previous criteria for PRMS) can be considered as “active PP” (PPCactive). On the other hand, patients with PPMS without acute seizure events and MRI changes can be considered as “inactive PP” (PPCnot active).
(2) Assessment of disease progressivity: Another emerging modification of the clinical course refers to the presence or absence of clinical evidence of disease progression in patients with progressive MS (PPMS or SPMS) over a given period of time, independent of relapse. Progressive MS does not always evolve in a consistent manner, and it is possible that the disease may remain stable over a period of time.
The authors recommend that disease progression should be assessed annually based on changes in medical history or objective information. Therefore, patients with PPMS who have not progressed in the past year may be classified as non-progressive PPMS (PPMSCnot progressing); patients with SPMS who have progressive deterioration and foci visible on gadolinium-enhanced MRI should be classified as “active and progressing SPMS” ( SPMSCactive and progressing).
The author recognizes that both relapsing and progressive disease courses can be classified according to the following factors: severity of signs and symptoms, frequency of relapses, degree of deterioration, sequelae of dysfunction, and functional impairment.
It should be noted, however, that further classification of active disease using this approach is not yet supported by clear information. Although, in essence, the degree of recovery from an acute relapse event cannot yet be considered useful in determining or modifying MS staging, the degree of recovery may serve as a proxy for the degree of disease deterioration over time. The above-mentioned areas may provide a rich source of standing for future research.
6. Persistent or definite deterioration: clarification of the meaning of the term
Many studies use the term “sustained worsening” to describe an outcome event in a clinical trial, representing a patient’s Expanded Disability Status Scale (EDSS) score over a specific period of time (usually 3 or 6 months). This is often interpreted as a progressive worsening of functional status over a specific period of time (usually 3 or 6 months). This is often interpreted as a measure of deterioration in functional impairment.
In the author’s opinion, the term “continuous” means “throughout the course of the disease”, which is sometimes not characteristic of MS disease changes and potentially misleading. In addition, it is possible that EDSS deterioration in different functional systems may occur within a specified time window, which is consistent with the definition of “persistent”; however, it is also possible that EDSS improvement in one or more functional systems may be accompanied by EDSS deterioration in other functional systems (which should not be described by “persistent” as it is now). (this should not be described as “persistent”).
The author suggests that a term with a clearer meaning than “persistent” should be used to guide the measurement of worsening dysfunction. Thus, the accumulation of clear dysfunction should be defined as “deterioration of EDSS for X months”, as is already used in some cases, independent of the functional system. A stricter definition should specify the deterioration in the same functional system.
In this context, there is an urgent need to further clarify the meaning of terms that have been used to describe the progression of disease or dysfunction (from multiple seizure events, or poor recovery from a severe seizure event, or worsening seizures that occur during disease progression).
The author suggests that the term “progressive worsening” should be used instead of “progressing” for relapsing patients and reserved for patients in the progressive phase of MS. The term “progression” is reserved for patients in the progressive stage of MS, regardless of whether they have an active relapse. As mentioned above, this may also apply to the classification of definite changes in EDSS.
7. Exploring activity and progression: much remains to be discovered
Some clinical manifestations may be too subtle and vague to be detected regardless of the frequency of assessment. Close follow-up of patients’ cognitive abilities, vision, and other clinical changes may help find clinical evidence of the degree of disease activity.
There is still a lack of agreement on how to apply patient-reported outcomes (PROs) and their usefulness in indicating disease status. Remote assessment tools for out-of-hospital patient performance may help to better understand PROs, and more relevant studies in this area may also be useful.
Although there are some initial steps in the application of MRI to measure inflammation and tissue loss, which are used to classify patients into clinical subgroups, and lesions identified by T2 imaging and gadolinium enhancement imaging now serve as measures of disease activity, there is still a lack of agreement on other means that can be included in phenotypic descriptions to measure tissue damage.
The lack of standardized norms for the assessment and interpretation of brain volume loss and cavity evolution limits its practical application outside the research field and may not allow for appropriate differentiation of individual patient classification by clinical phenotype.
Newer imaging modalities, such as diffusion tensor imaging and magnetization transfer imaging, may not yet be available for clinical use. Optical coherence tomography (OCT) may show a correlation between retinal nerve fiber layer thickness and visual acuity, but there is still insufficient evidence that OCT can be used as an indirect measure of whole brain tissue deficit.
Further information (assessment) is needed on the above imaging assessment tools, and the value of these tools as potential markers for disease classification or course should be a high priority direction for future research.
8. In vivo biomarkers and electrophysiology
Although it was hoped that the original phenotypic description of MS would be supported by biomarkers and better defined, no blood or cerebrospinal fluid (CSF) biomarkers have so far been able to reliably and reproducibly distinguish between MS phenotypes. A detailed search for potential biomarkers to support (and in the future sublimate) MS phenotypic descriptors is urgently needed, applying the vast amount of data from a patient pool correctly classified by clinical and imaging data.
The author recognizes the potential value of electrophysiological studies in defining MS disease subtypes. However, the author notes that there is considerable variability in the measures across laboratories. Standardization of procedures and assessment is imperative if evoked potentials become a new metric for phenotypic typing of MS in the future.
9. Benign and malignant MS
The terms “benign” and “malignant” are not MS phenotypic descriptors per se, but more of an indication of the future severity of the disease, a “convention”. Both terms could theoretically be used for either MS phenotype, depending on the degree of disease activity during the time period, or damage or dysfunction at any given point in time. Both (especially “benign”) are supposed to be retrospective diagnoses, but are often misunderstood and misapplied.
In a prolonged course of disease such as MS, the severity and activity of the disease can change significantly and unpredictably. The authors suggest that these two terms should be used with caution.
10. Further sublimation of the MS phenotype: the need for more research
The 1996 version of the MS taxonomy introduced the need for objective imaging and humoral biomarkers. Progress since then (in these areas) has been limited, and a great deal of future research is needed to clarify whether biomarkers can be used to improve our understanding of MS disease subtypes.
The available data do not yet allow for significant imaging differentiation between the 1996 version of the MS classification, nor between the core disease subtypes of relapsing MS and progressive MS. Some of the original data supporting imaging differences between PPMS and SPMS have been limited by more recent data suggesting that the visible, contrast-enhancing differences in imaging lesions between the two disease subtypes are not as great as originally thought.
Patients with PPMS diagnosed on the basis of clinical data often show enhancing contrast brain lesions at an earlier age, thus making the pathologic distinction between PPMS and SPMS less clear.
Future follow-up should be prioritized in cohorts of patients who have undergone a clear clinical classification by serial clinical and imaging assessments, laboratory markers, and other tools (e.g., OCT). Such studies will be necessary to clarify whether objective indicators of the biological status of the aforementioned patients can improve the understanding of MS disease subtypes, and in particular to better understand and predict the interconversion between different disease subtypes.
Discussion
The MS Phenotyping Group experts have carefully studied previous MS descriptors and have made the following recommendations.
1. relapsing and progressive MS should be retained as core elements of the MS phenotypic descriptors with some modifications.
An important amendment to the core phenotype is the assessment of clinical activity, defined either by clinical assessment of the occurrence of relapsing events or by examination of lesion activity on CNS imaging data.
A second important amendment to the above phenotype is that it is no longer required that the progression of dysfunction occurs within a given period of time.
4. Patients classified as PRMS by the original criteria should now be classified as PP with different disease activity.
5. PPMS is part of progressive MS and differs from other subtypes in that it is relative, not absolute.
6. CIS should be included in the MS phenotype. Prospective follow-up of most patients with CIS will clarify their subsequent disease phenotype.
7. RIS should not be considered as a separate MS phenotype because patients with RIS lack the appropriate clinical signs and symptoms. Prospective follow-up is recommended.
8. The term “progressive worsening” is better and less confusing for patients in the relapse phase due to recurrent relapses and/or incomplete recovery from the attack.
In clinical trials or natural history assessments of progressive worsening MS using the EDSS or other scales, the term “confirmed” should be used instead of “confirmed” when either the functional system of progressive worsening is (more rigorously) taken into account or not. The term “confirmed” rather than “sustained” should be used to define temporality.
The terms “benign” and “malignant” disease are often misused and should be used with caution.
Further research is needed to better define the value of imaging data and biomarkers in assessing, clarifying, or revising the phenotypic description of MS.
For the consideration of future research studies and clinical practice applications, it is important that disease activity should be clarified by assessing clinical status and MRI findings. Currently, there are no evidence-based guidelines on how to make clinical decisions from activity assessment in clinical practice.
Clinical assessment of disease activity and progression should be performed based on the evolution of the individual disease, but should be performed at least once a year. This has been agreed upon within the MS phenotype group. Annual brain MRI scans for relapsing MS to clarify disease activity are considered useful. There is no consensus on the frequency of scans for patients with progressive MS.
However, stratification of patients with progressive MS by MRI activity may be particularly valuable for clinical and translational studies. Once a patient is found to meet modified diagnostic criteria, MRI findings should be interpreted with caution, especially when new and enlarged T2 lesions are clearly identified.
Additional markers of disease activity (worsening clinical presentation or MRI findings) and means of evaluating disease progressiveness should allow for clearer communication between physicians and patients and between physician colleagues, and should facilitate improved clinical trial design, patient recruitment, and execution. In these studies, attention should be focused on meeting the inclusion and analysis of different disease subtypes. The above-mentioned markers may also play a role in studies that clarify when treatment should be discontinued.
The author recognizes that there may be other indicators of disease activity, but evidence for their inclusion is still lacking. The author also recognizes that some may use progressivity as an indication of disease activity, but the author recommends that the two be treated as completely separate concepts so that progression can be distinguished from other, more abrupt changes. It has been suggested that there are potential pathologic differences between the clinical or MRI events described above, but the author has intentionally avoided describing the pathologic findings pending more relevant evidence.
As was the case when the original MS phenotypic descriptors were developed by a panel of experts in 1996, the author likewise hopes that these amendments will better classify MS patients and provide a theoretical framework for clinical research and ongoing clinical treatment.
Active disease clinical: relapses; new or exacerbated acute or subacute neurological deficits following full or partial functional recovery; no fever or infection. and/or imaging (MRI): T1 high signal on enhancement contrast or new/enlarged T2 high signal lesions Progressive disease clinical: steadily increasing objectively documented neurological deficits or disability without definite recovery (may have fluctuating symptoms and plateau). Imaging (MRI): There are no established or standardized imaging criteria and are not useful for tentative phenotypic definition of individual patients. Indicators currently under consideration include an increase in the number and volume of T1 high signal lesions, reduction in brain volume, and changes in magnetization transfer imaging and diffusion tensor imaging. Progressive deterioration is found as a result of relapse or progression, with increased neurological deficits/disabilities. The term “disease progression” is reserved only for the progressive phase of the disease. Definite progression or progressive deterioration is defined as a definite increase in neurological deficits within a defined time interval (e.g., March, June, or December). Because neurological deficits may still improve (especially in relapsing disease), the author recommends avoiding the term “persistent” even if progression has been established for 6 or 12 months.
Long-term longitudinal studies of clinically defined MS patients using multiple imaging assessments to better correlate imaging findings with clinical phenotypes and to explore transitions over time between disease subtypes.
2. Close clinical and imaging evaluation of patients with RIS to better explore the subtle clinical features of MS changes and to shorten the time required to diagnose MS.
3. Studies of different time windows for assessing disease activity (clinical data and imaging) to clarify whether annual assessment (as recommended) is optimal.
4. Cohort studies to understand whether grading related to clinical or imaging activity is important for changes in outcome events in the medium and long term.
5. Conduct cohort studies to understand whether recovery-related grades after acute clinical relapse events have medium- and long-term implications for outcome events and whether differences in recovery are relevant to guide the conduct of MS phenotypic classification.
6. Conduct imaging studies to better understand the value of their contribution to MS phenotypic classification through measures of tissue damage (brain atrophy, evolution of cavities, optic nerve fiber thinning, and other OCT measurements).
7, Focusing on cohort studies of large patient databases with clear clinical classification by potential humoral (blood, CSF) markers may help to better define the clinical phenotype of MS.
8. Conduct standardized electrophysiological assessments of clinically clearly classified patients to explore the possible value of this approach.
9. Explore the role of patient-reported outcomes in the assessment of clinical performance.