Report of a Consensus Panel on the New International Panel Guidelines for Diagnosis of Multiple Sclerosis

Publication of the new International Panel (IP) guidelines for diagnosis of multiple sclerosis (MS) by McDonald et al. ¹ has raised some concerns in the North American neurological community. These concerns relate to the general complexity of the guidelines, their potential use as treatment rules and, in particular, the complexity of the MRI criteria for dissemination in time and space, and for the diagnosis of primary progressive MS (PPMS). Because of these concerns, the Consortium of MS Centers (CMSC) convened a consensus conference to review and discuss the guidelines and their interpretation. The consensus conference met November 30 to December 2, 2001 in Fort Worth Texas. The following consensus statements were endorsed during the conference:

• The IP guidelines represent a significant advance over previous criteria^2,3 in that they incorporate MRI criteria to allow earlier, more accurate diagnosis.
• The IP guidelines are for diagnosis only. They are not designed to make treatment decisions or to determine prognosis.
• Since they are guidelines only, diagnosis ultimately depends upon a physician (preferably a neurologist) skilled and knowledgeable in the diagnosis and management of MS patients.
• MRI should be part of the diagnostic evaluation in all cases in Canada and the US, unless a contraindication exists.
• Steps are being taken to standardize MRI acquisition, interpretation and reporting. Similar steps should be taken to standardize other paraclinical tests used in the diagnosis of MS, such as cerebrospinal fluid (CSF).
• In the next few years, new information should allow refinement of these guidelines to improve their ease of application and their sensitivity without compromise to specificity.

It is recognized that the IP guidelines need to be clarified in certain areas where evidence is lacking. Further research should establish:

• Minimal MRI criteria to diagnose PPMS
• Appropriate CSF requirements for PPMS
• The validity of defining MS on the basis of MRI characteristics alone
• The optimal protocol for follow up MRI when required for diagnosis

The conference members recognize that primary evidence exists to support disease modifying therapy in certain patients presenting with their first demyelinating event (referred to by the IP as "possible MS")^4,5. Further research is needed to identify factors in these patients that predict tissue destruction and future disability.

The following summary expands on each of the consensus statements, based on discussions during the meeting.

1. The IP guidelines represent a significant advance over previous criteria in that they incorporate MRI criteria to allow for earlier, more accurate diagnosis.
   Although the new MRI criteria were generally regarded as difficult to apply, they do allow MRI to be used to define dissemination in space and (with a repeat MRI) dissemination in time. Their difficulty in application refers in particular to the fact that most radiologists do not report lesion distribution and most generalists are not sufficiently conversant with the details of MRI to do it themselves. Most conference members felt there was a need to simplify the MRI criteria. Since the criteria are evidence based, simplification will require additional research.
2. The IP guidelines are for diagnosis only. They are not designed to make treatment decisions or to determine prognosis.
   Conference members felt that there are individuals who clearly have MS, and who will not meet IP criteria at the time diagnosis is considered. Some of these individuals will have findings that suggest aggressive disease. In other cases, individuals who meet criteria may have very few lesions, years between attacks, no significant clinical residual and a benign MRI picture. Because of this, most panel members felt that treatment decisions should not be based on the diagnostic criteria. These concerns are also discussed below with regard to the final consensus statement.
3. Since these are guidelines only, the diagnosis depends ultimately upon a physician (preferably a neurologist) skilled and knowledgeable in the diagnosis and management of MS patients.
   Diagnostic criteria will change over time as technology and knowledge advance. There are clearly individuals who have MS and who do not meet the guidelines. At the time of the first attack, no one meets criteria for definite MS, but many clearly already have the disease. In addition, the caveat "no better explanation" requires broad neurologic knowledge including familiarity with diseases that mimic MS. Conference members recognize that there are some non-neurologists that are skilled in the diagnosis of MS, but they are few in number. In practice, a neurologist usually makes the diagnosis. In particular, it was felt that a neurologist with expertise in MS should evaluate difficult and atypical cases.
4. MRI should be part of the diagnostic evaluation for MS in all cases in Canada and the US, unless a contraindication exists.
   MS has many mimics. A number of these are most easily picked up on MRI. While it is possible to diagnose MS without MRI, the number of errors in diagnosis is reduced markedly when both clinical and MRI studies are available to the diagnosing physician. Additionally, the MRI burden of disease on T2 or FLAIR images provides useful prognostic information. For this reason the conference members considered that MRI of the brain should always be included as part of the work up and evaluation except in those situations where there are contraindications. The conference members realize that there are parts of the world in which MRI is not available. In these areas diagnosis must be made without MRI. In countries where the technology is available, the conference members considered MRI to be an essential part of evaluation and diagnosis.
5. Steps are being taken to standardize MRI acquisition, interpretation and reporting. Similar steps should be taken to standardize other paraclinical tests used in the diagnosis of MS such as CSF assays).
   The CMSC has convened a panel to standardize acquisition, interpretation and reporting of MRI results in MS. Such standardization will facilitate use of the IP MRI criteria, make them easier to apply, and therefore more useful to neurologists. Similar standardization is needed in other areas. Assessment of cerebrospinal fluid (CSF) needs further standardization. For example, isoelectric focusing is much more sensitive than agarose gel electrophoresis to detect oligoclonal bands. Some CSF specimens that are reported as negative are positive when assessed by more sensitive techniques. The IP did not accept somatosensory evoked potentials (SSEPs) in their criteria. These tests lack standardization in technique and interpretation. Many neurologists feel that SSEPs can be used to objectify sensory complaints, thus making purely sensory symptoms into an objective finding useful in diagnosis.
6. New information should refine the IP guidelines, to improve their ease of application, and their sensitivity, without compromising specificity.
   It is now more than 17 years since the Washington panel was convened and the diagnostic criteria revised. The new IP criteria represent an advance but the conference members felt that we should not wait years to revisit and revise the criteria. The revision process should be recurring with appropriate updates based on new technology and new research findings. Ultimately, a biological marker may make these criteria obsolete. Until that time, there must be periodic revisions to include the results of new research.

The conference members recognized that the criteria were designed and intended to have high specificity at the cost of sensitivity. The conference members agreed that high specificity is more important than sensitivity in these criteria.

Areas for Clarification
The following is a list of areas where the conference members felt that further research was indicated to clarify issues related to the diagnostic criteria. This list is by no means exhaustive but represents selected areas where the conference members saw a pressing need for more research.

Minimal MRI criteria for primary progressive MS (PPMS) Diagnosis of primary progressive MS remains difficult. The IP criteria are very insensitive, and it is clear that some clinically typical cases will not meet the formal MRI criteria. Additional information is likely to become available as results of current PPMS clinical trials are published. Further research is needed to help clinicians to differentiate PPMS from spinal cord degenerative disease and other mimics. This remains one of the most difficult diagnostic areas in MS, and more information is needed if we are to avoid the pitfalls of underdiagnosis and misdiagnosis. This is not a pressing issue at present since there are no approved treatments for PPMS, but it will become urgent if useful disease therapy is developed.

CSF requirements in PPMS
The IP criteria require abnormal CSF. Given the unsatisfactory state of CSF testing, this presents difficulty. Isoelectric focusing techniques to detect oligoclonal bands need to become standard to increase the diagnostic sensitivity of CSF testing for PPMS. Even using this, more sensitive technique, some patients with PPMS have normal CSF. There must be a way to diagnose PPMS in patients with normal CSF while maintaining the current level of diagnostic specificity.

Validity of defining MS on the basis of MRI characteristics at first attack.
The diagnosis of MS remains clinical. Ancillary tests including MRI assist in the diagnosis but individuals must meet criteria for dissemination in time and location to be diagnosed. There are some who believe that, if certain fairly rigid criteria are met, MS can be diagnosed on the basis of MRI in clinically isolated syndromes such as optic neuritis or transverse myelitis. If MRI can be diagnosed on the basis of MRI in this situation, either alone or with the addition of MR spectroscopy or other developing techniques, the validity of the approach must be established.

Optimal protocol for follow up MRI exams when required for diagnosis
The new diagnostic criteria accept the occurrence of new T2 lesions or new enhancing lesions appearing on MRI, after a minimum interval of three months, as acceptable evidence for dissemination in time. This minimum interval needs to be further validated. In addition, the optimal interval that provides maximum yield from minimum repeat MRI, and thus minimum cost, needs to be defined. Should a repeat be done every three months until a diagnosis is made? That would be unnecessarily expensive in relatively inactive cases. Perhaps MRI at 3 and 6 months then no further tests unless there is clinical evidence of disease activity would be reasonable. Unfortunately, we do not have the data to make firm recommendations at the present time. Data from serial MRI studies that have been done might provide information to make such recommendations, though selection criteria for such studies may limit their generalizability.

Finally, the conference members felt it was necessary to emphasize that the diagnostic criteria were not designed to provide prognostic information nor to determine need for treatment. There is class I evidence from both the CHAMPS and ETOMS trials regarding the utility of treating selected patients at the time of their first attack. The numbers of misdiagnosed patients in these trials was minimal and the benefits of therapy demonstrated. These patients were not required to meet the IP criteria for diagnosis. In other specialties that treat chronic diseases such as lupus erythematosus and rheumatoid arthritis, many patients are treated before the diagnosis is firm if they meet certain criteria. MS is no exception and treatment should not be withheld unnecessarily in patients with the disease who do not meet current formal diagnostic criteria. The vast majority though not necessarily all patients who meet diagnostic criteria for relapsing MS deserve access to disease modifying therapies.

References:
1. McDonald WI, Compston A, Edan G, Goodkin D et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann. Neurol. 2001;50:121-127
2. Poser CM, Paty DW, Scheinberg LC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 1983;13:227-231
3. Schumacher FA, Beeve GW, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis. Ann. N Y Acad Sci. 1965;122:552-568
4. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N. Engl. J. Med. 2000;343:898-904
5. Comi GF, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR. Effect of early interferon treatmen on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:1576-82

Organizing committee:
Robert M. Herndon, M.D. Patricia Coyle, M.D., Mark Freedman M.D., Craig Smith M.D., Richard Rudick, M.D., and Jerry S. Wolinsky

Conference Speakers:
Richard Rudick, M.D., Jerry Wolinsky, M.D., Mark Freedman, M.D., Eric Eggenberger, D.O., Revere Kinkle, M.D., Geert Lycklama, David Miller, M.D., Donald Paty, M.D. and Jack Simon, M.D.

Attendees:
Douglas Arnold, M.D., Robert W. Baumhefner, M.D., Gary Birnbaum, M.D., Donna Jo Blake, M.D., James Bowen, M.D., Jack Burks, M.D., Jonathan Carter, M.D., Stanley Cohan, M.D., PhD, Bruce Cohen, M.D., Arthur Cyrtyn, M.D., David Dawson, M.D., John Greenlee, M.D., Jeffrey Greenstein, M.D., Charles Guttman, M.D., Jodie Haselkorn, M.D., MPH, Stanley Hashimoto, M.D., FRCPC, John Huddlestone, M.D., Norman Kachuck, M.D., Michael Kaufman, M.D., Pierre Ketelaer, M.D., Mariko Kita, M.D., R. John Leigh, M.D., Thomas Leist, M.D., Robert Lisak, M.D., D. Joanne Lynn, M.D., Michele Mass, M.D., Micheline McCarthy, M.D., PhD, Luanne Metz, M.D., FRCPC, James Q. Miller, M.D., Jock Murray, OC, M.D., FRCPC, MACP, Pamela New, M.D., Hillel Panitch, M.D., Michael Racke, M.D., Anthony Reder, M.D., Loren Rolak, M.D., Jay Rosenberg, M.D., Vernon Rowe, M.D., Steven Schwid, M.D., William Sheremata, M.D., James Simsarian, M.D., Dusan Stefoski, M.D., Lael Stone, M.D., Anthony Traboulsee, M.D., FRCPC, Jay Tsurda, M.D., William Tyor, M.D., Timothy Vollmer, M.D., Bianca Weinstock-Guttman, M.D., Ernest Willoughby, M.D.