EDITORIAL
Magnetic Resonance Imaging and Laboratory Ads in the Diagnosis of Multiple Sclerosis This editorial concerns the role of magnetic resonance imaging (MRI) and other diagnostic aids in the differential diagnosis of multiple sclerosis (MS). The diagnosis of MS is basically a clinical one. No laboratory finding is diagnostic. A number of diseases (old and newly recognized) can have features that suggest MS, and the clinician must be wary of malung the diagnosis of MS unless these disorders can be clearly excluded. The clinical diagnosis of MS has long depended on the ability of the physician to demonstrate the occurrence of white matter lesions in both time and space that cannot be explained on another basis. Schumacher and colleagues {l) gave an excellent exposition of this principle, which served for many years as the standard diagnostic guide for MS. In addition to showing dissemination of white matter lesions in time and space, one must take into consideration that the risk for MS is higher in the following groups than in the general population: 1. Young adults. 2. Women. 3. Those of northern European Caucasian descent. 4. Persons who spent their childhood years in temperate latitudes. 5. First-degree relatives of persons who are known to have MS.
Clinical judgment, then, takes into account age, sex, race, location of residence up to puberty, and family history either to raise or to lower the index of suspicion for the diagnosis. Also, it is generally recognized that the diagnosis of clinically definite MS (CDMS) has an accuracy of 90 to 95% r2). The last 15 years have brought progress in making the diagnosis of MS. A number of procedures that have been developed detect either immunological evidence for central nervous system (CNS) i n f l m a t i o n (i.e., cerebrospinal fluid {CSF) oligoclonal banding or increased CSF IgG synthesis rates) or evidence of clinically asymptomatic lesions disseminated in space (i.e., through abnormalities of visual-evoked potentials [VEP}, somatosensory-evoked potentials {SEP), brainstem auditory-evoked potentials [BAEP), central motor conduction, and computed tomography {CT) and MRI scans). The application of these procedures
was not included in the report by Schumacher and colleagues {I). However, experience has shown that findings from such studies have predictive value for the subsequent development of MS in patients who lack the necessary clinical criteria for diagnosis at initial presentation. At several meetings during 1980 and 1981, a number of investigators interested in the diagnosis of MS debated the use of these tests in diagnosis, and concluded that paraclinical findings which show asymptomatic dissemination in space or detect evidence for an immune response in the CNS were legitimate aids in making the diagnosis of MS. However, it was emphasized that abnormalities detected by these tests were no more specific for MS than individual clinical findings such as nystagmus or an extensor plantar response. A new category in the diagnosis of MS was proposed: laboratory-supported definite MS (LSDMS) { 3 ) . Initially this diagnostic category was proposed primarily for use in research protocols, but subsequently, it has proved useful in clinical practice. The key to the diagnosis of LSDMS is the presence of oligoclonal bands or an increased IgG synthesis rate in the CSF. When such CSF immunoglobulin abnormalities are present, LSDMS can be diagnosed with a history of two episodes of neurological disturbance and clinical evidence of one lesion and paraclinical evidence for a second lesion. When the CSF changes are present, LSDMS may also be diagnosed in patients with steadily progressive deficit from onset, provided the illness has been present for at least 6 months and sequential discrete involvement of the CNS white matter can be demonstrated clinically or paraclinically. The category of “probable” MS for certain patients in whom all criteria are not fulfilled was expanded to include CSF and other investigative data. The details and restrictions on diagnosis are discussed in the original publication 13). More recent experience indicates that LSDMS reliably predicts the diagnosis of CDMS in many patients, even when there is no clear-cut dissemination in time {4) at the initial assessment. Polman, Koetsier, and Wolters { 5 } examined the clinical impact of the new laboratory-supported criteria and found that the diagnosis of LSDMS could be made both earlier and more readily than the diagnosis of CDMS. Although MRI was unavailable, it is interesting that VEP and oligoclonal bands together were
Copyright 0 1991 by the American Neurological Association
3
responsible for 90% of the conversions from suspected MS to LSDMS. In contrast, BAEP, SEP, and CT scans were considerably less useful. In one study of laboratory (paraclinical) tests used in the diagnosis of MS [b], 200 patients with suspected MS were assessed. This included 52 patients with chronic progressive myelopathy, 38 with optic neuritis, and 34 who had normal findings on neurological examination at the time of the study. All patients were entered into a prospective evaluation protocol using VEP, SEP, MRI, and CSF evaluation for oligoclonal bands. MRI was the best procedure for demonstrating asymptomatic dissemination in space. The criteria for the MRI category “strongly suggestive of MS” were conservative {G} (e.g., three white matter lesions greater than 3 mm in diameter, one of them periventricular, or a total of four white matter lesions present). Lesser degrees of abnormality, especially smooth-appearing symmetrical periventricular “capping,” were not considered suggestive of MS on their own. An abnormal VEP or SEP suggesting asymptomatic dissemination in space was usually accompanied by the MRI finding: “strongly suggestive of
MS.” None of these laboratory abnormahies are specific for MS. For example, it has long been known that oligoclonal bands and increased I g G synthesis rates can be found in a wide range of disorders associated with subacute and chronic inflammation of the nervous system. These conditions include chronic meningitis, vasculitis, sarcoidosis, Lyme disease [7-91, human T-lymphotropic virus type 1-related myelopathy/ tropical spastic paraplegia (HAMITSP) {lo, 111, and neurosyphilis. Similarly, it is well established that delayed evoked potentials can be seen with compressive lesions, degenerative disorders, and vascular disease. Recent studies of a variety of specific disorders associated with multifocal and often sequential CNS white matter lesions (e.g., sarcoidosis, systemic lupus erythematosus, polyarteritis, Bechet’s syndrome, Sjogren’s syndrome) have shown that MRI changes indistinguishable from those found in MS {12-151 may occur. There is no doubt that MRI has contributed greatly toward the early and accurate diagnosis of MS. However, there seems to be a developing tendency toward overenthusiastic interpretation of MRI findings. Use of MRI must be put into proper perspective. The diagnosis of MS at any age cannot be based solely on MRI findings, and this rule is especially true in patients over the age of 50. An ad hoc committee on the impact of MFU on the diagnosis of MS [l6} concluded: Magnetic resonance imaging (MRI) has been shown in a number of studies to be a very sensitive method for detecting focal areas of damage in the white matter of the cerebral hemispheres. This sensitivity has been reflected in the wave
4 Annals of Neurology Vol 29 No 1 January 1991
of enthusiasm with which MRI has been used in the diagnostic evaluation of suspected multiple sclerosis (MS). MRI cannot, at this time, distinguish between various tissue characteristics such as edema, infarction, inflammation, or demyelination. The detection of a discrete white matter lesion that has a strong signal on spin echo (SE) or a weak signal on inversion recovery (IR) has no specificity for MS or demyelination, but can be used as evidence of neurological abnormality just as can nystagmus or a Babinski sign.
A diagnosis of CDMS cannot be made unless new lesions have been shown to appear over time. An additional diagnostic caution is that the lesions seen on a single MRI scan cannot be identified as being new or old. Although the use of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) [17, 181 may help to identify the age of lesions, the only reliable MRI evidence for dissemination in time comes from serial examinations. Therefore, critical judgment is as important in interpreting the significance of the results of tests (evoked potentials, MRI, CT, CSF) as in the interpretation of clinical findings. For example, when one detects a reflex asymmetry, extensor plantar response, or nystagmus, the assessment of the relevance of that finding to the diagnosis depends on experience and judgment. None of these clinical findings would be considered diagnostic of MS. Each is an indicator of neurological damage, but provides no information about etiological factors. The experienced physician sorts out the significance of the various pieces of clinical and paraclinical evidence and decides what weight should be placed on each.
D. W. Paty, M D Division o f Neurology, Department o f Medicine University of British Columbia Vancouver General Hospital Vancouver, B ritirh Cotzlmbia Canada D. E. McFarlin, M D National lnstitgte o f Neurological Disorders and Stroke Betbesda, M D
W . I . McDonald, FRCP University Department of Clinical Neurology Institute of Neurology London, United Kingdom References 1. Schumacher GA, Beebe G, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965;122:552-568 2. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol 1988;78:39-44 3. Poser CM, Paty DW, ScheinbergL, er al. New diagnostic crite-
ria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231 4. Lee KH, Hashimoto SA, Hooge J, et al. MRI in the diagnosis of MS: a prospective 3-year follow up with comparison of clinical evaluation, evoked potentials, ohgoclonal banding and CT. Can J Neurol Sci 1989;16:286 5. Polman CH, Koetsier JC, Wolters ECH. Multiple sclerosis: incorporation of results of laboratory techniques in the diagnosis. Clin Neurol Neurosurg 1985;87:187-192 6. Paty DW, Oger JJF, Kastrukoff LF, et al. MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1988;38:180-185 7. Finkel MF. Lyme disease and its neurological complications. Arch Neurol 1988;45:99-104 8. Pachner AR, Duray P, Steere AC. Central nervous system manifestation of Lyme disease. Arch Neurol 1988;46:790-795 9. Halperin JJ, Luf BJ, Anand AK, et al. Lyme neuroborreliosis: central nervous system manifestations. Neurology l987;39: 753-759 10. Osame M, Usuku K, Izumo S, et al. HTLV-1 associated myelopathy: a new clinical entity. Lancet 1986;1:1031-1032 11. Cruickshank JK, Rudge P, Dalgleish AG, et al. Tropical spastic
12.
13.
14.
15.
16.
17.
18.
paraparesis and human T cell lymphotropic virus type 1 in the United Kingdom. Brain 1989;112:1057-1090 Miller DH, Kendall BC, Barter S, et al. Magnetic resonance imaging of the central nervous system sarcoidosis. Neurology 1988;38:378-383 Miller DH, Ormerod IEC, Gibson A, et al. MR brain scanning in patients with vascdtis: differentiation from multiple sclerosis. Neuroradiology 1987;29:2 26-2 3 1 Alexander EL, Beall SS, Gordon B, et al. Magneric resonance imaging of cerebral lesions in pariena with Sjogren’s syndrome. Ann Intern Med 1988;108:815-823 Kesselring J, Ormerod IEC, Miller DH, et al. Magnetic resonance imaging in multiple sclerosis. An atlas of diagnosis and differential diagnosis. Stuttgart: Thieme, 1989 Paty DW, Asbury AK, Herndon RM, et al. Use of magnetic resonance imaging in the diagnosis of multiple sclerosis: policy statement. Neurology 1986;36: 1575 Miller DH, Rudge P, Johnson G, et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 1988,111:927-939 Grossman RI, Braffman BH, BrorsonJR, et al. Multiple sclerosis: serial study of gadolinium-enhanced MR imaging. Radiology 1988;169:117-122
Editorial: Paty e t al: MRI and Laboratory Aids for MS
5
Magnetic Resonance Imaging and Laboratory Ads in the Diagnosis of Multiple Sclerosis This editorial concerns the role of magnetic resonance imaging (MRI) and other diagnostic aids in the differential diagnosis of multiple sclerosis (MS). The diagnosis of MS is basically a clinical one. No laboratory finding is diagnostic. A number of diseases (old and newly recognized) can have features that suggest MS, and the clinician must be wary of malung the diagnosis of MS unless these disorders can be clearly excluded. The clinical diagnosis of MS has long depended on the ability of the physician to demonstrate the occurrence of white matter lesions in both time and space that cannot be explained on another basis. Schumacher and colleagues {l) gave an excellent exposition of this principle, which served for many years as the standard diagnostic guide for MS. In addition to showing dissemination of white matter lesions in time and space, one must take into consideration that the risk for MS is higher in the following groups than in the general population: 1. Young adults. 2. Women. 3. Those of northern European Caucasian descent. 4. Persons who spent their childhood years in temperate latitudes. 5. First-degree relatives of persons who are known to have MS.
Clinical judgment, then, takes into account age, sex, race, location of residence up to puberty, and family history either to raise or to lower the index of suspicion for the diagnosis. Also, it is generally recognized that the diagnosis of clinically definite MS (CDMS) has an accuracy of 90 to 95% r2). The last 15 years have brought progress in making the diagnosis of MS. A number of procedures that have been developed detect either immunological evidence for central nervous system (CNS) i n f l m a t i o n (i.e., cerebrospinal fluid {CSF) oligoclonal banding or increased CSF IgG synthesis rates) or evidence of clinically asymptomatic lesions disseminated in space (i.e., through abnormalities of visual-evoked potentials [VEP}, somatosensory-evoked potentials {SEP), brainstem auditory-evoked potentials [BAEP), central motor conduction, and computed tomography {CT) and MRI scans). The application of these procedures
was not included in the report by Schumacher and colleagues {I). However, experience has shown that findings from such studies have predictive value for the subsequent development of MS in patients who lack the necessary clinical criteria for diagnosis at initial presentation. At several meetings during 1980 and 1981, a number of investigators interested in the diagnosis of MS debated the use of these tests in diagnosis, and concluded that paraclinical findings which show asymptomatic dissemination in space or detect evidence for an immune response in the CNS were legitimate aids in making the diagnosis of MS. However, it was emphasized that abnormalities detected by these tests were no more specific for MS than individual clinical findings such as nystagmus or an extensor plantar response. A new category in the diagnosis of MS was proposed: laboratory-supported definite MS (LSDMS) { 3 ) . Initially this diagnostic category was proposed primarily for use in research protocols, but subsequently, it has proved useful in clinical practice. The key to the diagnosis of LSDMS is the presence of oligoclonal bands or an increased IgG synthesis rate in the CSF. When such CSF immunoglobulin abnormalities are present, LSDMS can be diagnosed with a history of two episodes of neurological disturbance and clinical evidence of one lesion and paraclinical evidence for a second lesion. When the CSF changes are present, LSDMS may also be diagnosed in patients with steadily progressive deficit from onset, provided the illness has been present for at least 6 months and sequential discrete involvement of the CNS white matter can be demonstrated clinically or paraclinically. The category of “probable” MS for certain patients in whom all criteria are not fulfilled was expanded to include CSF and other investigative data. The details and restrictions on diagnosis are discussed in the original publication 13). More recent experience indicates that LSDMS reliably predicts the diagnosis of CDMS in many patients, even when there is no clear-cut dissemination in time {4) at the initial assessment. Polman, Koetsier, and Wolters { 5 } examined the clinical impact of the new laboratory-supported criteria and found that the diagnosis of LSDMS could be made both earlier and more readily than the diagnosis of CDMS. Although MRI was unavailable, it is interesting that VEP and oligoclonal bands together were
Copyright 0 1991 by the American Neurological Association
3
responsible for 90% of the conversions from suspected MS to LSDMS. In contrast, BAEP, SEP, and CT scans were considerably less useful. In one study of laboratory (paraclinical) tests used in the diagnosis of MS [b], 200 patients with suspected MS were assessed. This included 52 patients with chronic progressive myelopathy, 38 with optic neuritis, and 34 who had normal findings on neurological examination at the time of the study. All patients were entered into a prospective evaluation protocol using VEP, SEP, MRI, and CSF evaluation for oligoclonal bands. MRI was the best procedure for demonstrating asymptomatic dissemination in space. The criteria for the MRI category “strongly suggestive of MS” were conservative {G} (e.g., three white matter lesions greater than 3 mm in diameter, one of them periventricular, or a total of four white matter lesions present). Lesser degrees of abnormality, especially smooth-appearing symmetrical periventricular “capping,” were not considered suggestive of MS on their own. An abnormal VEP or SEP suggesting asymptomatic dissemination in space was usually accompanied by the MRI finding: “strongly suggestive of
MS.” None of these laboratory abnormahies are specific for MS. For example, it has long been known that oligoclonal bands and increased I g G synthesis rates can be found in a wide range of disorders associated with subacute and chronic inflammation of the nervous system. These conditions include chronic meningitis, vasculitis, sarcoidosis, Lyme disease [7-91, human T-lymphotropic virus type 1-related myelopathy/ tropical spastic paraplegia (HAMITSP) {lo, 111, and neurosyphilis. Similarly, it is well established that delayed evoked potentials can be seen with compressive lesions, degenerative disorders, and vascular disease. Recent studies of a variety of specific disorders associated with multifocal and often sequential CNS white matter lesions (e.g., sarcoidosis, systemic lupus erythematosus, polyarteritis, Bechet’s syndrome, Sjogren’s syndrome) have shown that MRI changes indistinguishable from those found in MS {12-151 may occur. There is no doubt that MRI has contributed greatly toward the early and accurate diagnosis of MS. However, there seems to be a developing tendency toward overenthusiastic interpretation of MRI findings. Use of MRI must be put into proper perspective. The diagnosis of MS at any age cannot be based solely on MRI findings, and this rule is especially true in patients over the age of 50. An ad hoc committee on the impact of MFU on the diagnosis of MS [l6} concluded: Magnetic resonance imaging (MRI) has been shown in a number of studies to be a very sensitive method for detecting focal areas of damage in the white matter of the cerebral hemispheres. This sensitivity has been reflected in the wave
4 Annals of Neurology Vol 29 No 1 January 1991
of enthusiasm with which MRI has been used in the diagnostic evaluation of suspected multiple sclerosis (MS). MRI cannot, at this time, distinguish between various tissue characteristics such as edema, infarction, inflammation, or demyelination. The detection of a discrete white matter lesion that has a strong signal on spin echo (SE) or a weak signal on inversion recovery (IR) has no specificity for MS or demyelination, but can be used as evidence of neurological abnormality just as can nystagmus or a Babinski sign.
A diagnosis of CDMS cannot be made unless new lesions have been shown to appear over time. An additional diagnostic caution is that the lesions seen on a single MRI scan cannot be identified as being new or old. Although the use of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) [17, 181 may help to identify the age of lesions, the only reliable MRI evidence for dissemination in time comes from serial examinations. Therefore, critical judgment is as important in interpreting the significance of the results of tests (evoked potentials, MRI, CT, CSF) as in the interpretation of clinical findings. For example, when one detects a reflex asymmetry, extensor plantar response, or nystagmus, the assessment of the relevance of that finding to the diagnosis depends on experience and judgment. None of these clinical findings would be considered diagnostic of MS. Each is an indicator of neurological damage, but provides no information about etiological factors. The experienced physician sorts out the significance of the various pieces of clinical and paraclinical evidence and decides what weight should be placed on each.
D. W. Paty, M D Division o f Neurology, Department o f Medicine University of British Columbia Vancouver General Hospital Vancouver, B ritirh Cotzlmbia Canada D. E. McFarlin, M D National lnstitgte o f Neurological Disorders and Stroke Betbesda, M D
W . I . McDonald, FRCP University Department of Clinical Neurology Institute of Neurology London, United Kingdom References 1. Schumacher GA, Beebe G, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965;122:552-568 2. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol 1988;78:39-44 3. Poser CM, Paty DW, ScheinbergL, er al. New diagnostic crite-
ria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231 4. Lee KH, Hashimoto SA, Hooge J, et al. MRI in the diagnosis of MS: a prospective 3-year follow up with comparison of clinical evaluation, evoked potentials, ohgoclonal banding and CT. Can J Neurol Sci 1989;16:286 5. Polman CH, Koetsier JC, Wolters ECH. Multiple sclerosis: incorporation of results of laboratory techniques in the diagnosis. Clin Neurol Neurosurg 1985;87:187-192 6. Paty DW, Oger JJF, Kastrukoff LF, et al. MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1988;38:180-185 7. Finkel MF. Lyme disease and its neurological complications. Arch Neurol 1988;45:99-104 8. Pachner AR, Duray P, Steere AC. Central nervous system manifestation of Lyme disease. Arch Neurol 1988;46:790-795 9. Halperin JJ, Luf BJ, Anand AK, et al. Lyme neuroborreliosis: central nervous system manifestations. Neurology l987;39: 753-759 10. Osame M, Usuku K, Izumo S, et al. HTLV-1 associated myelopathy: a new clinical entity. Lancet 1986;1:1031-1032 11. Cruickshank JK, Rudge P, Dalgleish AG, et al. Tropical spastic
12.
13.
14.
15.
16.
17.
18.
paraparesis and human T cell lymphotropic virus type 1 in the United Kingdom. Brain 1989;112:1057-1090 Miller DH, Kendall BC, Barter S, et al. Magnetic resonance imaging of the central nervous system sarcoidosis. Neurology 1988;38:378-383 Miller DH, Ormerod IEC, Gibson A, et al. MR brain scanning in patients with vascdtis: differentiation from multiple sclerosis. Neuroradiology 1987;29:2 26-2 3 1 Alexander EL, Beall SS, Gordon B, et al. Magneric resonance imaging of cerebral lesions in pariena with Sjogren’s syndrome. Ann Intern Med 1988;108:815-823 Kesselring J, Ormerod IEC, Miller DH, et al. Magnetic resonance imaging in multiple sclerosis. An atlas of diagnosis and differential diagnosis. Stuttgart: Thieme, 1989 Paty DW, Asbury AK, Herndon RM, et al. Use of magnetic resonance imaging in the diagnosis of multiple sclerosis: policy statement. Neurology 1986;36: 1575 Miller DH, Rudge P, Johnson G, et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 1988,111:927-939 Grossman RI, Braffman BH, BrorsonJR, et al. Multiple sclerosis: serial study of gadolinium-enhanced MR imaging. Radiology 1988;169:117-122
Editorial: Paty e t al: MRI and Laboratory Aids for MS
5
