- Email: [email protected]
The pathogenesis of multiple sclerosis: a commentary
Clinical Neurology and Neurosurgery 102 (2000) 191 – 194 www.elsevier.com/locate/clineuro
The pathogenesis of multiple sclerosis: a commentary Charles M. Poser * Har6ard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline A6enue, Boston, MA 02215, USA Accepted 25 July 2000
Abstract A series of recently published articles by a group of Austrian, German and American neuropathologists have proposed the existence of several different pathogenetic pathways in multiple sclerosis (MS). These studies were based on both biopsy and autopsy material. A review of the available published clinical, imaging and cerebrospinal fluid data suggest that some the cases used in those studies were more probably instances of disseminated encephalomyelitis rather than MS. This has serious implications regarding the specificity and significance of the findings in regard to MS pathogenesis. The specific myelinoclastic sequence and the variable clinical course of MS are determined by the individual’s genetic endowment and immunologic history. Regardless of pathogenetic pathway and clinical course, the final pathologic picture of MS is always the same. The MS brain is genetically programmed to produce a unique, pathognomonic change, the plaque with sharply demarcated borders. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Pathogenesis; Multiple sclerosis; Myelinoclastic sequence
During the past several years a series of articles written by a group of Austrian, German and American neuropathologists have provided new insights in the pathogenesis of multiple sclerosis (MS). These new ideas are highly significant in that they may lead to innovative therapeutic guidelines for MS. By the same token, differentiating MS from other inflammatory demyelinating diseases, both clinically and in terms of pathogenesis, assumes great importance. It has become clear that a T-cell mediated immune response is the commonest driving force in the formation of MS lesions, but it alone is not sufficient to explain the widespread and selective destruction of myelin. Antibodies directed against surface components of myelin sheaths are at least one factor involved in the demyelinating process, along with other serum-derived immune mediators such as complement. It is also likely that the inflammatory reactions in MS may be induced or propagated by simultaneous immune reactions against a variety of different autoantigens [1,2]. Indeed, antibodies may be targeted for specific sites: myelin is not a homogeneous substance. There are immunologi* Tel.: +1-617-6672063; fax: + 1-617-6675216. E-mail address: [email protected] (C.M. Poser).
cal, and probably chemical, differences between the myelin of different species, and between peripheral and central myelin [3]. Within the CNS itself, similar subtle differences may well exist between various regions, a possible explanation for the frequency with which certain parts of the CNS such as the optic nerves, the cerebellum and the spinal cord are affected. What is the origin of these antibodies? How and where do the antibody-producing B-cells come in contact with myelin components such as MBP, MOG, MAG, PLP and others? One possibility is that injury to the blood-brain barrier (BBB) from a cryptic viral infection, an insignificant reaction to a routine vaccination, or even mild CNS trauma during childhood results in injury to myelin. Myelin abbau products then enter the systemic circulation inducing a response from lymphocytes, an event that has been shown to occur from damage to cranial and peripheral nerves [4]. Several recent studies have proposed that different pathogenetic mechanisms may exist in MS. This idea came from the examination of the numbers of oligodendrocytes (ODC) in areas of demyelination, the degree of expression of antibodies to MOG and PLP on ODC, and the extent of remyelination. The results of these examinations were combined in a first overview article
0303-8467/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 0 0 ) 0 0 1 0 1 - 3
192
C.M. Poser / Clinical Neurology and Neurosurgery 102 (2000) 191–194
by Lucchinetti et al. [5] reporting on the immunohistological study of 395 lesion areas obtained from 113 MS patients, in 84 by biopsy and in 29 at autopsy. Except for the mean ages, sex distribution and type of clinical course, no clinical, CSF or radiological details were given. Some of these data, however, were available from previous publications [6 – 9]. The proposal that different pathogenetic mechanisms may exist in MS is not only exciting, but also logical and readily acceptable. None the less, this new concept must be examined with great caution because much of the tissue was obtained from biopsies. Even the most experienced neuropathologist may have considerable difficulty differentiating between MS and disseminated encephalomyelitis (DEM) looking at the tissue fragments yielded by a needle biopsy. It is very rare that lesion edges are obtained and that one can determine that the plaque has the pathognomonic sharply demarcated border of MS. The accuracy of the MS diagnosis of a number of the biopsied cases is questionable. The fact that a biopsy was done suggests that the case was unusual. More importantly, the clinical history, the CSF findings and the MRI of some of the cases are also atypical and strongly suggest the diagnosis of DEM. Dependence on the interpretation of changes of the MRI in suspected MS by radiologists who are rarely provided with adequate clinical information has led to an alarming increase in the rate of misdiagnoses involving, in my personal experience, well over one-third of the cases [10]. Many of these errors are in actuality cases of DEM, a mostly monophasic, but rarely recurrent (RDEM) or multiphasic (MDEM) condition [11]. The first suspicion of the accuracy of the MS diagnosis of some of the cases arose with the 1991 report by Nesbit et al. [12] of the histopathologic and MR or CT correlation of 37 biopsied and three autopsied cases of MS. Complete clinical records were available for 24 of these cases, but previous episodes of neurologic symptoms were noted in only seven. The illustrations of the MRI of several of these cases (figures 2d, 3e, 4d of [12]) are strongly reminiscent of DEM [11,13 – 15]. In 1992, Sigrid Poser et al. [6] provided clinical and MRI details of five patients who had brain biopsies (Table 1), all of which were then republished by Bru¨ck et al. in 1994 [8] with the addition of one new case (case 6 in the Table 1) and once again by Bru¨ck et al. in 1997 [9], with a different sixth case (case 7 in the Table 1). In 1993, Rodriguez et al. [7] published clinical and MRI data on 11 biopsied cases. It is assumed that some if not all the cases mentioned in these four articles were included in Lucchinetti et al’s paper [5]. In their two articles Bru¨ck et al. [8,9] provided some follow-up information: cases 2 and 3 had no further bouts, case 1 had ‘several bouts with visual and psychomotor disturbances,’ case 4 had ‘one possible bout’, and
case 6 had one further bout that is not described after the initial presentation, which consisted only of convulsions. Rapid progression and new MRI lesions were described in cases 5 and 7. Cases 8–16 in the table were reported by Rodriguez et al. They noted that the diagnosis in cases 9 and 10 was either the initial bout of MS, or an acute DEM. The nine cases in the Table 1 have been selected because of their atypical features: the very late age of onset (cases 8, 11 and 15), and the elevated CSF protein level (cases 8, 10, 14 and 15). Nausea, vomiting, stupor, confusion, fever, convulsions, and aphasia are uncommon clinical features in MS. Simultaneous bilateral optic nerve involvement is rare in MS but not in DEM. Illustrations of the MRIs are available in ten cases: all of them are atypical for MS and more consistent with DEM (Fig. 1), as are the descriptions of some of those not reproduced [11,13– 15]. The sketchily described recurrences and the MRIs suggest that some of these cases may be instances of RDEM or MDEM. One intriguing aspect of these studies is that the loss of ODCs is only marginally related to the stage of demyelinating activity within the lesion, suggesting that demyelination is independent of ODC destruction. Lucchinetti et al. [16] have now published a new report which rather curiously, mentions neither their 1999 paper [5], nor the Poser, Rodriguez and Bru¨ck articles [6–9], yet is clearly based on some of the same material. One important difference is that, without explanation, the number of biopsied cases dropped from 84 to 49, and three new autopsies were added. In this new report, no clinical data are given except for a sketchy case history of one of the pattern III patients, who clearly had a relapsing-remitting course after the biopsy, but whose MRI was very similar to those seen in DEM [11,13–15]. Follow-up T-2 MRIs showed al-
Fig. 1. T-2 weighted magnetic resonance images of five cases of ‘multiple sclerosis’. c: case 1 (the case numbers refer to the Table 1, not those of the original article): biopsy at 11 days. b: same case 1, biopsy at 7.5 months; f: case 5; i: case 3; d: case 4; h: case 2. the triangle indicates the site of the biopsy. Reproduced with permission from Bru¨ck et al. [9].
28 15 43 74 31 61 67 22 25 54
67 F 18 F
5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16.
M M F M F M F F F F
Hemiparesis, aphasia focal convulsion Bilateral amaurosis, limb ataxia, nausea, vomiting Tetraparesis, dysarthria, dysphagia, hemianesthesia, stupor Tetraplegia, ataxia, dysarthria, dysphagia, bilateral amaurosis, confusion Hemiparesis, hypesthesia trigeminal nerve Convulsion Visual loss, hemiparesis, ataxia, bladder dysfunction Gait ataxia, previous RBN Aphasia, R arm dyspraxia Gait ataxia, diplopia, nystagmus, R VI, VII cn Diplopia, dysarthria, bilateral Babinskis, R III, V cn Loss fine motor control R hand for 2 weeks Aphasia, hemiparesis, focal seizures, previous leg numbness Fatigue, hemiparesis, confusion, memory loss, previous weakness and paresthesiae R side Gait ataxia, loss of memory, hemianesthesia, urinary frequency Personality change, fever, previous bilateral ON, myelopathy
Clinical signs/symptoms
78/+ N/0
N/+ 106/0
69/0
N/+ N N/+ 108/0
+/+ N N/+ N/+
CSF tp/ob
@ @ @
@ @ @ @
@ @ @ @
MRI
5/MS
1/SC 2/SC 3/TS 4/MA
3/MS 6/MS
1/MS 4/MS 5/MS 2/MS
Poser 1992 c /dx Bru¨ck 1994 a c /dx a
6/LS
3/LS
1/CD 4/LS 5/LS 2/CP
Bru¨ck 1997 c /dx a
9/CD 11/CD
1/MS 2/?MS 3/?MS 5/C 6/CD 7/CD 8/CD
Rodriguez 1993 c /dx a
b
References: [6–9]. Abbreviations: tp, total protein; ob: oligoclonal bands; @, picture of MRI; SC, Schilder’s disease; TS, transitional sclerosis; MA, Marburg’s disease; CD, clinically definite MS; LS, laboratory-supported definite MS; CP, clinically probable MS; cn, cranial nerve; ON, optic neuritis; RBN: retrobulbar neuritis.
a
21 20 21 25
1. 2. 3. 4.
F F M M
Age Sex
Nr
Table 1 Cases included in the oligodendrocyte studiesa,b
C.M. Poser / Clinical Neurology and Neurosurgery 102 (2000) 191–194 193
194
C.M. Poser / Clinical Neurology and Neurosurgery 102 (2000) 191–194
most complete resolution of the very large areas of increased signal intensity (AISIs) but no mention is made of appearance of new ‘lesions’. The pathological lesions in pattern III patients, half of whom have a monophasic course, should not be classified as MS since ‘the borders of the active lesions were ill defined, showing diffuse spread into the surrounding white matter’. This case is reminiscent of some of those cited by Kepes [17] with MRIs showing the very large AISIs of DEM, with inflammatory demyelination demonstrated by open biopsy. Twenty-eight of the 31 patients had monophasic courses. Kepes surmised that postinfectious DEM was the most likely diagnosis in his cases (personal communication). Another possible explanation for these unusual instances is the suggestion made by Lumsden [18] ‘‘while they are different diseases, in rare cases, MS may arise from acute DEM, which is merely one of the potential precipitating factors of some essentially intrinsic process in the myelin’’. Because some of the biopsied cases may be instances of DEM, are the histoimmunological findings truly specific for MS? Is there any correlation between the immunohistological patterns and the MRIs? It might be wise to select only tissue obtained at autopsy from anatomically and clinically classical cases of MS, with typical MR images, to see if specific pathogenetic patterns emerge that are different from those seen in other inflammatory demyelinating diseases. Much speculation has centered on the significance of the various clinical courses of the disease, inferring that MS is not a single disease, e.g. that primary progressive and relapsing-remitting MS are different entities. A study reporting immunogenetic heterogeneity of three DBQ1 alleles between these two types has been cited in support of this concept [19], but such a conclusion is unacceptable: immunogenetic testing defines the patients, not their disease. In summary, the specific myelinociastic sequence and the variable clinical courses of MS are determined by the person’s genetic endowment and immunologic history. Regardless of the clinical course and the pathogenetic pathway, the final pathologic picture is always the same. The MS brain is genetically programmed to produce a unique pathological change, its pathognomonic feature seen in no other demyelinating disease, the plaque with sharply demarcated borders that Ludo van Bogaert so well described as ‘de´coupe´es a` l’emportepie`ce’.
.
References [1] Brosnan C, Raine C. Mechanisms of immune injury in multiple sclerosis. Brain Pathol 1996;6:243 – 57. [2] Storch M, Lassmann H. Pathology and pathogenesis of demyelinating disease. Curr Opin Neurol 1997;10:186 – 92. [3] Kadlubowski M, Hughes R. The neuritogenicity and encephalitogenicity of P2 in the rat, guinea pig and rabbit. J Neurol Sci 1980;48:171 – 8. [4] Olsson T, Sun J, Solders G, et al. Autoreactivity of T and B cell responses to myelin antigens after diagnostic sural nerve biopsy. J Neurol Sci 1993;117:130 – 9. [5] Lucchinetti C, Bru¨ck W, Parisi J, et al. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. Brain 1999;122:2279– 95. [6] Poser S, Luer W, Bruhn H, et al. Acute demyelinating disease. classification and non-invasive diagnosis. Acta Neurol Scand 1992;86:579 – 85. [7] Rodriguez M, Scheitauer B, Forbes G, et al. Oligodendrocyte injury is an early event in lesions of multiple sclerosis. Mayo Clin Proc 1993;68:627 – 36. [8] Bru¨ck W, Schmied M, Suchanek G, et al. Oligodendrocytes in the early course of multiple sclerosis. Ann Neurol 1994;35:65– 73. [9] Bru¨ck W, Bitsch A, Kolenda H, et al. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 1997;42:783 – 93. [10] Poser C. Misdiagnosis of multiple sclerosis and b-interferon. Lancet 1997;349:1915. [11] Poser C. The epidemiology of multiple sclerosis: a general overview. Ann Neurol 1994;36(S2):S180– 93. [12] Nesbit G, Forbes G, Scheithauer B, et al. Multiple sclerosis: histopathologic and MR and/or CT correlation in 37 cases at biopsy and three cases at autopsy. Radiology 1991;180:467–74. [13] Kesselring J, Miller D, Robb S, et al. Acute disseminated encephalomyelitis. MRI findings and the distinction from multiple sclerosis. Brain 1990;113:291 – 302. [14] Triulzi F, Scotti G. Differential diagnosis of multiple sclerosis: contribution of magnetic resonance imaging. J Neurol Neurosurg Psychiatry 1998;64(suppl 1):S6 – S14. [15] Singh S, Alexander M, Korah I. Acute disseminated encephalomyelitis: MR imaging features. Am J Roentgenol 1999;173:1101– 7. [16] Lucchinetti C, Bru¨ck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implication for the pathogenesis of demyelination. Ann Neurol 2000;47:707 – 17. [17] Kepes J. Large focal tumor-like demyelinating lesions of the brain: intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients. Ann Neurol 1993;33:18 – 27. [18] Lumsden C. Related demyelinating processes and the experimental pathology of multiple sclerosis. In: McAlpine D, Compston N, Lumsden C, editors. Multiple Sclerosis. Edinburgh: Livingstone, 1955:240 – 74. [19] Olerup O, Hillert J, Fredrikson S, et al. Primarily chronic progressive and re lapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Nat Acad Sci USA 1989;86:7113 – 7.
The pathogenesis of multiple sclerosis: a commentary Charles M. Poser * Har6ard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline A6enue, Boston, MA 02215, USA Accepted 25 July 2000
Abstract A series of recently published articles by a group of Austrian, German and American neuropathologists have proposed the existence of several different pathogenetic pathways in multiple sclerosis (MS). These studies were based on both biopsy and autopsy material. A review of the available published clinical, imaging and cerebrospinal fluid data suggest that some the cases used in those studies were more probably instances of disseminated encephalomyelitis rather than MS. This has serious implications regarding the specificity and significance of the findings in regard to MS pathogenesis. The specific myelinoclastic sequence and the variable clinical course of MS are determined by the individual’s genetic endowment and immunologic history. Regardless of pathogenetic pathway and clinical course, the final pathologic picture of MS is always the same. The MS brain is genetically programmed to produce a unique, pathognomonic change, the plaque with sharply demarcated borders. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Pathogenesis; Multiple sclerosis; Myelinoclastic sequence
During the past several years a series of articles written by a group of Austrian, German and American neuropathologists have provided new insights in the pathogenesis of multiple sclerosis (MS). These new ideas are highly significant in that they may lead to innovative therapeutic guidelines for MS. By the same token, differentiating MS from other inflammatory demyelinating diseases, both clinically and in terms of pathogenesis, assumes great importance. It has become clear that a T-cell mediated immune response is the commonest driving force in the formation of MS lesions, but it alone is not sufficient to explain the widespread and selective destruction of myelin. Antibodies directed against surface components of myelin sheaths are at least one factor involved in the demyelinating process, along with other serum-derived immune mediators such as complement. It is also likely that the inflammatory reactions in MS may be induced or propagated by simultaneous immune reactions against a variety of different autoantigens [1,2]. Indeed, antibodies may be targeted for specific sites: myelin is not a homogeneous substance. There are immunologi* Tel.: +1-617-6672063; fax: + 1-617-6675216. E-mail address: [email protected] (C.M. Poser).
cal, and probably chemical, differences between the myelin of different species, and between peripheral and central myelin [3]. Within the CNS itself, similar subtle differences may well exist between various regions, a possible explanation for the frequency with which certain parts of the CNS such as the optic nerves, the cerebellum and the spinal cord are affected. What is the origin of these antibodies? How and where do the antibody-producing B-cells come in contact with myelin components such as MBP, MOG, MAG, PLP and others? One possibility is that injury to the blood-brain barrier (BBB) from a cryptic viral infection, an insignificant reaction to a routine vaccination, or even mild CNS trauma during childhood results in injury to myelin. Myelin abbau products then enter the systemic circulation inducing a response from lymphocytes, an event that has been shown to occur from damage to cranial and peripheral nerves [4]. Several recent studies have proposed that different pathogenetic mechanisms may exist in MS. This idea came from the examination of the numbers of oligodendrocytes (ODC) in areas of demyelination, the degree of expression of antibodies to MOG and PLP on ODC, and the extent of remyelination. The results of these examinations were combined in a first overview article
0303-8467/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 0 0 ) 0 0 1 0 1 - 3
192
C.M. Poser / Clinical Neurology and Neurosurgery 102 (2000) 191–194
by Lucchinetti et al. [5] reporting on the immunohistological study of 395 lesion areas obtained from 113 MS patients, in 84 by biopsy and in 29 at autopsy. Except for the mean ages, sex distribution and type of clinical course, no clinical, CSF or radiological details were given. Some of these data, however, were available from previous publications [6 – 9]. The proposal that different pathogenetic mechanisms may exist in MS is not only exciting, but also logical and readily acceptable. None the less, this new concept must be examined with great caution because much of the tissue was obtained from biopsies. Even the most experienced neuropathologist may have considerable difficulty differentiating between MS and disseminated encephalomyelitis (DEM) looking at the tissue fragments yielded by a needle biopsy. It is very rare that lesion edges are obtained and that one can determine that the plaque has the pathognomonic sharply demarcated border of MS. The accuracy of the MS diagnosis of a number of the biopsied cases is questionable. The fact that a biopsy was done suggests that the case was unusual. More importantly, the clinical history, the CSF findings and the MRI of some of the cases are also atypical and strongly suggest the diagnosis of DEM. Dependence on the interpretation of changes of the MRI in suspected MS by radiologists who are rarely provided with adequate clinical information has led to an alarming increase in the rate of misdiagnoses involving, in my personal experience, well over one-third of the cases [10]. Many of these errors are in actuality cases of DEM, a mostly monophasic, but rarely recurrent (RDEM) or multiphasic (MDEM) condition [11]. The first suspicion of the accuracy of the MS diagnosis of some of the cases arose with the 1991 report by Nesbit et al. [12] of the histopathologic and MR or CT correlation of 37 biopsied and three autopsied cases of MS. Complete clinical records were available for 24 of these cases, but previous episodes of neurologic symptoms were noted in only seven. The illustrations of the MRI of several of these cases (figures 2d, 3e, 4d of [12]) are strongly reminiscent of DEM [11,13 – 15]. In 1992, Sigrid Poser et al. [6] provided clinical and MRI details of five patients who had brain biopsies (Table 1), all of which were then republished by Bru¨ck et al. in 1994 [8] with the addition of one new case (case 6 in the Table 1) and once again by Bru¨ck et al. in 1997 [9], with a different sixth case (case 7 in the Table 1). In 1993, Rodriguez et al. [7] published clinical and MRI data on 11 biopsied cases. It is assumed that some if not all the cases mentioned in these four articles were included in Lucchinetti et al’s paper [5]. In their two articles Bru¨ck et al. [8,9] provided some follow-up information: cases 2 and 3 had no further bouts, case 1 had ‘several bouts with visual and psychomotor disturbances,’ case 4 had ‘one possible bout’, and
case 6 had one further bout that is not described after the initial presentation, which consisted only of convulsions. Rapid progression and new MRI lesions were described in cases 5 and 7. Cases 8–16 in the table were reported by Rodriguez et al. They noted that the diagnosis in cases 9 and 10 was either the initial bout of MS, or an acute DEM. The nine cases in the Table 1 have been selected because of their atypical features: the very late age of onset (cases 8, 11 and 15), and the elevated CSF protein level (cases 8, 10, 14 and 15). Nausea, vomiting, stupor, confusion, fever, convulsions, and aphasia are uncommon clinical features in MS. Simultaneous bilateral optic nerve involvement is rare in MS but not in DEM. Illustrations of the MRIs are available in ten cases: all of them are atypical for MS and more consistent with DEM (Fig. 1), as are the descriptions of some of those not reproduced [11,13– 15]. The sketchily described recurrences and the MRIs suggest that some of these cases may be instances of RDEM or MDEM. One intriguing aspect of these studies is that the loss of ODCs is only marginally related to the stage of demyelinating activity within the lesion, suggesting that demyelination is independent of ODC destruction. Lucchinetti et al. [16] have now published a new report which rather curiously, mentions neither their 1999 paper [5], nor the Poser, Rodriguez and Bru¨ck articles [6–9], yet is clearly based on some of the same material. One important difference is that, without explanation, the number of biopsied cases dropped from 84 to 49, and three new autopsies were added. In this new report, no clinical data are given except for a sketchy case history of one of the pattern III patients, who clearly had a relapsing-remitting course after the biopsy, but whose MRI was very similar to those seen in DEM [11,13–15]. Follow-up T-2 MRIs showed al-
Fig. 1. T-2 weighted magnetic resonance images of five cases of ‘multiple sclerosis’. c: case 1 (the case numbers refer to the Table 1, not those of the original article): biopsy at 11 days. b: same case 1, biopsy at 7.5 months; f: case 5; i: case 3; d: case 4; h: case 2. the triangle indicates the site of the biopsy. Reproduced with permission from Bru¨ck et al. [9].
28 15 43 74 31 61 67 22 25 54
67 F 18 F
5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16.
M M F M F M F F F F
Hemiparesis, aphasia focal convulsion Bilateral amaurosis, limb ataxia, nausea, vomiting Tetraparesis, dysarthria, dysphagia, hemianesthesia, stupor Tetraplegia, ataxia, dysarthria, dysphagia, bilateral amaurosis, confusion Hemiparesis, hypesthesia trigeminal nerve Convulsion Visual loss, hemiparesis, ataxia, bladder dysfunction Gait ataxia, previous RBN Aphasia, R arm dyspraxia Gait ataxia, diplopia, nystagmus, R VI, VII cn Diplopia, dysarthria, bilateral Babinskis, R III, V cn Loss fine motor control R hand for 2 weeks Aphasia, hemiparesis, focal seizures, previous leg numbness Fatigue, hemiparesis, confusion, memory loss, previous weakness and paresthesiae R side Gait ataxia, loss of memory, hemianesthesia, urinary frequency Personality change, fever, previous bilateral ON, myelopathy
Clinical signs/symptoms
78/+ N/0
N/+ 106/0
69/0
N/+ N N/+ 108/0
+/+ N N/+ N/+
CSF tp/ob
@ @ @
@ @ @ @
@ @ @ @
MRI
5/MS
1/SC 2/SC 3/TS 4/MA
3/MS 6/MS
1/MS 4/MS 5/MS 2/MS
Poser 1992 c /dx Bru¨ck 1994 a c /dx a
6/LS
3/LS
1/CD 4/LS 5/LS 2/CP
Bru¨ck 1997 c /dx a
9/CD 11/CD
1/MS 2/?MS 3/?MS 5/C 6/CD 7/CD 8/CD
Rodriguez 1993 c /dx a
b
References: [6–9]. Abbreviations: tp, total protein; ob: oligoclonal bands; @, picture of MRI; SC, Schilder’s disease; TS, transitional sclerosis; MA, Marburg’s disease; CD, clinically definite MS; LS, laboratory-supported definite MS; CP, clinically probable MS; cn, cranial nerve; ON, optic neuritis; RBN: retrobulbar neuritis.
a
21 20 21 25
1. 2. 3. 4.
F F M M
Age Sex
Nr
Table 1 Cases included in the oligodendrocyte studiesa,b
C.M. Poser / Clinical Neurology and Neurosurgery 102 (2000) 191–194 193
194
C.M. Poser / Clinical Neurology and Neurosurgery 102 (2000) 191–194
most complete resolution of the very large areas of increased signal intensity (AISIs) but no mention is made of appearance of new ‘lesions’. The pathological lesions in pattern III patients, half of whom have a monophasic course, should not be classified as MS since ‘the borders of the active lesions were ill defined, showing diffuse spread into the surrounding white matter’. This case is reminiscent of some of those cited by Kepes [17] with MRIs showing the very large AISIs of DEM, with inflammatory demyelination demonstrated by open biopsy. Twenty-eight of the 31 patients had monophasic courses. Kepes surmised that postinfectious DEM was the most likely diagnosis in his cases (personal communication). Another possible explanation for these unusual instances is the suggestion made by Lumsden [18] ‘‘while they are different diseases, in rare cases, MS may arise from acute DEM, which is merely one of the potential precipitating factors of some essentially intrinsic process in the myelin’’. Because some of the biopsied cases may be instances of DEM, are the histoimmunological findings truly specific for MS? Is there any correlation between the immunohistological patterns and the MRIs? It might be wise to select only tissue obtained at autopsy from anatomically and clinically classical cases of MS, with typical MR images, to see if specific pathogenetic patterns emerge that are different from those seen in other inflammatory demyelinating diseases. Much speculation has centered on the significance of the various clinical courses of the disease, inferring that MS is not a single disease, e.g. that primary progressive and relapsing-remitting MS are different entities. A study reporting immunogenetic heterogeneity of three DBQ1 alleles between these two types has been cited in support of this concept [19], but such a conclusion is unacceptable: immunogenetic testing defines the patients, not their disease. In summary, the specific myelinociastic sequence and the variable clinical courses of MS are determined by the person’s genetic endowment and immunologic history. Regardless of the clinical course and the pathogenetic pathway, the final pathologic picture is always the same. The MS brain is genetically programmed to produce a unique pathological change, its pathognomonic feature seen in no other demyelinating disease, the plaque with sharply demarcated borders that Ludo van Bogaert so well described as ‘de´coupe´es a` l’emportepie`ce’.
.
References [1] Brosnan C, Raine C. Mechanisms of immune injury in multiple sclerosis. Brain Pathol 1996;6:243 – 57. [2] Storch M, Lassmann H. Pathology and pathogenesis of demyelinating disease. Curr Opin Neurol 1997;10:186 – 92. [3] Kadlubowski M, Hughes R. The neuritogenicity and encephalitogenicity of P2 in the rat, guinea pig and rabbit. J Neurol Sci 1980;48:171 – 8. [4] Olsson T, Sun J, Solders G, et al. Autoreactivity of T and B cell responses to myelin antigens after diagnostic sural nerve biopsy. J Neurol Sci 1993;117:130 – 9. [5] Lucchinetti C, Bru¨ck W, Parisi J, et al. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. Brain 1999;122:2279– 95. [6] Poser S, Luer W, Bruhn H, et al. Acute demyelinating disease. classification and non-invasive diagnosis. Acta Neurol Scand 1992;86:579 – 85. [7] Rodriguez M, Scheitauer B, Forbes G, et al. Oligodendrocyte injury is an early event in lesions of multiple sclerosis. Mayo Clin Proc 1993;68:627 – 36. [8] Bru¨ck W, Schmied M, Suchanek G, et al. Oligodendrocytes in the early course of multiple sclerosis. Ann Neurol 1994;35:65– 73. [9] Bru¨ck W, Bitsch A, Kolenda H, et al. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 1997;42:783 – 93. [10] Poser C. Misdiagnosis of multiple sclerosis and b-interferon. Lancet 1997;349:1915. [11] Poser C. The epidemiology of multiple sclerosis: a general overview. Ann Neurol 1994;36(S2):S180– 93. [12] Nesbit G, Forbes G, Scheithauer B, et al. Multiple sclerosis: histopathologic and MR and/or CT correlation in 37 cases at biopsy and three cases at autopsy. Radiology 1991;180:467–74. [13] Kesselring J, Miller D, Robb S, et al. Acute disseminated encephalomyelitis. MRI findings and the distinction from multiple sclerosis. Brain 1990;113:291 – 302. [14] Triulzi F, Scotti G. Differential diagnosis of multiple sclerosis: contribution of magnetic resonance imaging. J Neurol Neurosurg Psychiatry 1998;64(suppl 1):S6 – S14. [15] Singh S, Alexander M, Korah I. Acute disseminated encephalomyelitis: MR imaging features. Am J Roentgenol 1999;173:1101– 7. [16] Lucchinetti C, Bru¨ck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implication for the pathogenesis of demyelination. Ann Neurol 2000;47:707 – 17. [17] Kepes J. Large focal tumor-like demyelinating lesions of the brain: intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients. Ann Neurol 1993;33:18 – 27. [18] Lumsden C. Related demyelinating processes and the experimental pathology of multiple sclerosis. In: McAlpine D, Compston N, Lumsden C, editors. Multiple Sclerosis. Edinburgh: Livingstone, 1955:240 – 74. [19] Olerup O, Hillert J, Fredrikson S, et al. Primarily chronic progressive and re lapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Nat Acad Sci USA 1989;86:7113 – 7.