Multiple sclerosis diagnosis

Current standard for diagnosing MS is based in the 2018 revision of McDonald criteria. They rely in MRI detection (or clinical demonstration) of demyelinating lesions in the CNS, which are distributed in space (DIS) and in time (DIT). It is also a requirement that any possible known disease that produces demyelinating lesions is ruled out before applying McDonald's criteria.

This last requirement makes MS an ill-defined entity, whose borders change every time that a new disease is set apart. Some previous cases considered MS are now considered apart, like Neuromyelitis optica or antiMOG associated encephalomyelitis. Besides, because of the requirement of distributed lesions, a single lesion (RIS) is not considered MS. For the same reason, the prodromal stage of MS (the unknown condition that causes the lesions) would not be considered as MS if it could be found.

Sometimes the diagnosis must be retrospective, relying on gradual worsening of neurological signs/symptoms, due to the lack of understanding of the pathogenicity driving disease progression.[1] However, the only definite diagnosis of MS is post-mortem autopsy, where lesions typical of MS can be detected through histopathological techniques.[2][3]

Schumacher criteria

To get a diagnosis of CDMS a patient must show the following:[4]

  1. Clinical signs of a problem in the CNS
  2. Evidence of two or more areas of CNS involvement
  3. Evidence of white matter involvement
  4. One of these: Two or more relapses (each lasting ≥ 24 hr and separated by at least 1 month) or progression (slow or stepwise)
  5. Patient should be between 10 and 50 yr old at time of examination
  6. No better explanation for patient's symptoms and signs

The last condition, no better explanation for symptoms, has been heavily criticised, but it has been preserved and it is currently included in the new McDonalds criteria in the form that "no better explanation should exist for MRI observations"

Poser criteria

Poser criteria can be summarized in this table:

Any of the five conclusions have subpossibilities. Here a table is shown with each one of them:

Clinical Presentation Additional Data Needed
CDMS * Two or more attacks (relapses) Two clinical evidence
One clinical and one paraclinical evidence
LSDMS * At least one attack and oligoclonal bands Two attacks and one evidence (clinical or paraclinical)
One attack and two clinical evidences
One attack, one clinical and one paraclinical evidences
CPMS * At least one attack Two attacks and one clinical evidence
One attack and two clinical evidences
One attack, one clinical and one paraclinical evidences
LSPMS * Two attacks No more evidence is required

If none of these requirements is accomplished, the diagnosis is "No MS", meaning that there is not enough clinical evidence to support a clinical diagnosis of MS.

Barkhof-Tintoré criteria

Barkhof criteria,[5] later modified by Tintoré[6] were an early attempt to use MRI to diagnose MS.

Their observations were taken into account when McDonald criteria were published, and therefore they can be considered deprecated by the latter.

McDonald criteria

The 2017 McDonald criteria can be summarize in this table:

Clinical Presentation Additional Data Needed
* 2 or more attacks (relapses)
* 2 or more objective clinical lesions
None; clinical evidence will suffice (additional evidence desirable but must be consistent with MS)
* 2 or more attacks
* 1 objective clinical lesion (as well as clear-cut historical evidence of a previous attack involving a lesion in a distinct anatomical location)
None.
* 2 or more attacks
* 1 objective clinical lesion
Dissemination in space, demonstrated by an additional clinical attack implication a different CNS site or by MRI.
* 1 attack
* 2 or more objective clinical lesions
Dissemination in time, demonstrated by an additional clinicak attack or bz MRI

OR

Demonstration of CSF-specific oligoclonal bands

* 1 attack
* 1 objective clinical lesion
(monosymptomatic presentation)
Dissemination in space demonstrated by an additional clinical attack implicating a different CNS site or by MRI.
AND
Dissemination in time demonstrated by an additional clinical attack or by MRI, OR

Demonstration of CSF-specific oligoclonal bands

Insidious neurological progression
suggestive of MS
(primary progressive MS)
One year of disease progression (retrospectively or prospectively determined) and

Two of the following:

  • One or more T2-hyperintense lesions characteristic of multiple sclerosis in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
  • Two or more T2-hyperintense lesions in the spinal cord
  • Presence of CSF-specific oligoclonal bands

Okuda Criteria

Published by D.T.Okuda mainly for research in MS, these criteria define what should be considered a Radiologically Isolated Syndrome (RIS).[7] Some reports point to the possibility of predicting RIS to CIS conversion based on oligoclonal bands and neurofilament light chain.[8]

Research into diagnostic techniques

Multiple sclerosis diagnosis can only be made when there is proof of lesions disseminated in time and in space. Therefore, when damage in the CNS is big enough to be seen. It would be desirable to make it faster.

The ideal diagnosis schema would be able to determine for any given subject, if he will develop MS, at any point in his life, and when. Nevertheless, not enough is currently known about the MS underlying conditions to achieve that.

In order to get as close as possible to the ideal diagnosis status, a lot of research into multiple sclerosis biomarkers is taking place currently.

Biomarkers in MS

See also Multiple sclerosis biomarkers

An active field of research is looking for biomarkers for MS that could speed-up the diagnosis doing it more accurate at the same time. While most of them are still under research, there are some of them already well stablished:

  • oligoclonal bands: They present proteins that are in the CNS or in blood. Those that are in CNS but not in blood suggest a diagnosis of MS.
  • MRZ reaction: A polyspecific antiviral immune response against the viruses of measles, rubella and zoster found in 1992.[9] In some reports the MRZR showed a lower sensitivity than OCB (70% vs. 100%), but a higher specificity (69% vs. 92%) for MS.[9]
  • free light chains (FLC), specially the kappa-FLCs (kFLCs). Several authors have reported that the nephelometric and ELISA FLCs determination is comparable with OCBs as markers of IgG synthesis, and kFLCs behave even better than oligoclonal bands.[10]

Differential diagnosis

Several conditions can mimic MS. Given the unknown pathogenesis of MS, its differential diagnosis is based in exclusion of known conditions.

Very close diseases with similar symptoms are the whole "inflammatory demyelinating diseases spectrum", specially neuromyelitis optica and anti-MOG associated encephalomyelitis.

Outside this spectrum, another important mimic is neuroborreliosis. A Borrelia-specific IgG index exist, and testing for it could make the differential diagnosis[11]

History

Since the first description of multiple sclerosis (MS) by Charcot, the Neurological community has been striving to create reliable and reproducible criteria for diagnosis of MS.[12] The first attempts were made by Charcot himself, followed by Marburg and later Allison. The first criteria however were lacking in sensitivity and specificity for clinical use.[12]

The first landmark event in the history of diagnostic criteria for MS was the development of the Schumacher criteria. These were the first internationally recognized criteria for diagnosis of MS and introduced very important diagnostic concepts that are the cornerstone of MS diagnosis nowadays, such as the clinical definition of MS and the requirement of dissemination in time and space for accurate diagnosis.

Since then, other diagnostic criteria have been proposed. Among them, Poser criteria utilized several laboratory and paraclinical studies to enhance the diagnostic accuracy. McDonald criteria, which are the ones used today, successfully introduced MRI findings as surrogates for the criterion of dissemination in time and space when clinical data are lacking, thus allowing earlier diagnosis of MS.[12]

References

  1. Oki S (February 2018). "Novel mechanism and biomarker of chronic progressive multiple sclerosis". Clinical and Experimental Neurology. 9 (1): 25–34. doi:10.1111/cen3.12449.
  2. McDonald WI, Compston A, Edan G, et al. (July 2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Ann. Neurol. 50 (1): 121–7. CiteSeerX 10.1.1.466.5368. doi:10.1002/ana.1032. PMID 11456302.
  3. Polman CH, Reingold SC, Edan G, et al. (December 2005). "Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"". Ann. Neurol. 58 (6): 840–6. CiteSeerX 10.1.1.604.2677. doi:10.1002/ana.20703. PMID 16283615.
  4. Paul O'Connor, James Marriott, Multiple Sclerosis, Chapter 2, Differential Diagnosis and Diagnostic Criteria for Multiple Sclerosis: Application and Pitfalls
  5. Barkhof, F; Filippi, M; Miller, D; et al. (November 1997). "Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis". Brain. 120 (11): 2059–2069. doi:10.1093/brain/120.11.2059. PMID 9397021.
  6. Tintoré, M; Rovira, A; Martínez, MJ; et al. (April 2000). "Isolated demyelinating syndromes: Comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis". AmJ Neuroradiol. 21 (4): 702–706. PMID 10782781.
  7. Okuda, D. T.; Mowry, E. M.; Beheshtian, A.; et al. (3 March 2009). "Incidental MRI anomalies suggestive of multiple sclerosis: The radiologically isolated syndrome". Neurology. 72 (9): 800–805. doi:10.1212/01.wnl.0000335764.14513.1a. PMID 19073949.
  8. Matute-Blanch, Clara; Villar, Luisa M; Álvarez-Cermeño, José C; et al. (1 April 2018). "Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome". Brain. 141 (4): 1085–1093. doi:10.1093/brain/awy021. PMID 29452342.
  9. Hottenrott, Tilman; Dersch, Rick; Berger, Benjamin; Rauer, Sebastian; Eckenweiler, Matthias; Huzly, Daniela; Stich, Oliver (13 December 2015). "The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort". Fluids and Barriers of the CNS. 12 (1:27): 27. doi:10.1186/s12987-015-0024-8. PMC 4677451. PMID 26652013.
  10. Fabio Duranti; Massimo Pieri; Rossella Zenobi; Diego Centonze; Fabio Buttari; Sergio Bernardini; Mariarita Dessi (August 2015). "kFLC Index: a novel approach in early diagnosis of Multiple Sclerosis". International Journal of Scientific Research. 4 (8).
  11. Katarzyna Kotulska-Jóźwiak et al. LYME DISEASE or MULTIPLE SCLEROSIS? Two cases with overlapping features. Journal of the International Child Neurology Association, FEB 18, 2019
  12. Ntranos, Achilles; Lublin, Fred (2016-08-22). "Diagnostic Criteria, Classification and Treatment Goals in Multiple Sclerosis: The Chronicles of Time and Space". Current Neurology and Neuroscience Reports. 16 (10): 90. doi:10.1007/s11910-016-0688-8. ISSN 1528-4042. PMID 27549391.
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