- Email: [email protected]
The diagnosis of primary progressive multiple sclerosis
Journal of the Neurological Sciences 206 (2003) 145 – 152 www.elsevier.com/locate/jns
The diagnosis of primary progressive multiple sclerosis Jerry S. Wolinsky *, the PROMiSe Study Group1 Department of Neurology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Abstract Primary progressive multiple sclerosis (PPMS) is a rather unique form of the more common relapsing inflammatory demyelinative disease. The absence of attacks that typify relapsing forms of MS imposes special challenges for diagnosis, but also provides an opportunity to study the pathogenesis of the more progressive aspects of the disease process in isolation of confounding transient clinical events. In this review, recent advances in diagnostic approaches are considered in relationship to baseline data from a large multinational study designed to better characterize and treat this clinical phenotype. PPMS subjects with cerebral spinal fluid (CSF) findings consistent with intrathecal immunoglobulin production may have a more tissue destructive disease process than those whose CSF lacks evidence of a B-cell immunopathogenic disease component. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Magnetic resonance imaging (MRI); Cerebral spinal fluid (CSF)
1. Introduction Nearly 150 years ago, Charcot [1] recognized that some forms of multiple sclerosis (MS) could be progressive from onset, failing to exhibit any of the acute episodes of neurologic deterioration that typify the more common clinical presentations of the disease. Subsequent students of the disease distinguished such cases from those whose initial relapsing clinical course had passed into a phase of nearly unrelenting accumulation of clinical neurologic disability with or without continued superimposed attacks that we now categorize as secondary progressive MS [2]. Primary progressive multiple sclerosis (PPMS) is the least common clinical disease phenotype exhibited by MS patients. Current consensus definitions of the various disease phenotypes demand that patients with PPMS have a progressive disease from onset and a clinical course without discernible attacks [3]. Some minor amount of improvement or worsening is allowed, but episodes that fit most modern clinical trial definitions of acute relapses eliminate patients from this subtype and consign them to either secondary progressive or progressive relapsing MS categories, depending upon
* Corresponding author. Tel.: +1-713-500-7048; fax: +1-713-5007041. 1 The participating centers and principal investigators of the PROMiSe trial are listed in the acknowledgement.
whether the clinical attack occurred prior to or following the onset of their progressive neurologic dysfunction. Approximately 15% of MS patients have a progressive disease onset, but nearly one-third of these will eventually experience one or more clinical attacks. Thus, only about 10% of all MS patients have a lifetime clinical course that fits a strict definition of the PPMS phenotype. As a consequence, any descriptive cross-sectional or longitudinal analysis of PPMS must, by definition, be contaminated to some extent by patients who will have future attacks that will segregate them into the progressive relapsing clinical phenotype. Moreover, it is quite likely that some patients who present with an ingravescent accumulation of neurologic disability simply fail to recall remote episodes of neurologic dysfunction. Such events may or may not have been attended by physicians or resulted in a formal diagnosis of relapsing MS or clinically isolated demyelinative syndrome of the type commonly seen in MS [4,5]. Such cases of ‘‘cryptic’’ secondary progressive or ‘‘transitional’’ MS [6] will contaminate to some extent any cohort of rigorously defined PPMS patients. Further complicating our understanding of this clinical phenotype is the common use of the now disparaged ‘‘chronic progressive MS’’ to describe patient cohorts that indiscriminately include subjects with secondary progressive, progressive relapsing and primary progressive MS. Until recently, few investigators attempted to specifically isolate patients with PPMS for the purpose of clinical trials
0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 3 4 6 - 5
146
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
of therapeutic agents. Nor had generally accepted criteria for the clinical diagnosis of MS addressed the special issues raised by this clinical phenotype [7]. However, apparent differences in the clinical trial outcomes of various preparations of interferon beta in patients with relapsing and secondary progressive disease have now highlighted the difficulties in separating the effects of therapeutic agents on disease progression from their benefits on attacks and the more inflammatory aspects of the underlying pathology as monitored by magnetic resonance imaging (MRI) [8,9]. Patients with PPMS provide the ideal study population with which to investigate the effects of a therapeutic agent on clinical disease progression in the absence of the confounding influence of clinical attacks. Contemporary neuropathology studies have attempted to classify MS based on characteristic immunohistochemical features of lesions [10]. While some PPMS cases exhibit an oligodendrogliopathy that may be unique to this clinical phenotype, all cases reported thus far show some inflammatory change [10,11], and the majority of the PPMS cases share pathologic features common to those with relapsing forms of the disease [10]. Should the pathogenesis of lesion formation or evolution differ as the MS patient transitions from a purely relapsing into a progressive phase of their disease, then detailed comparative study of patients with relapsing disease and those with purely progressive disease might aid to clarify the pathophysiological differences that underlie the later phases of the relapsing MS phenotype. Unfortunately, studies of the pure PPMS phenotype introduce complexities of design not encountered with relapsing MS patient populations. This paper will concentrate on the diagnosis of PPMS. It will also review the clinical, laboratory and neuroimaging features of PPMS, drawing heavily on the
cross-sectional findings of a large cohort of subjects at entry into a multinational, multicenter, double-blind, placebo-controlled study—the PROMiSe Trial [12].
2. Diagnosis Older consensus criteria for the diagnosis of MS concentrated on relapses as an absolute requirement for fulfillment of the cardinal feature of a disease process disseminated in both time and in space [7]. As such, individuals presenting with progressive neurologic dysfunction were by inference required to develop clinical or paraclinical evidence of a new lesion consistent with dissemination of the process in time and in space, or to evidence intrathecal synthesis of immunoglobulin (IgG) to enable a laboratorysupported diagnosis of definite MS. Still earlier consensus criteria had emphasized the steady or stepwise accumulation of signs and symptoms of neurologic dysfunction over at least 6 months and the exclusion of competing diagnoses as the basis for diagnosing the more progressive disease forms [13]. Given increasing recognition of the inadequacy of the Washington Panel criteria as specifically applied to PPMS [14,15], a heightened interest in determining if PPMS is simply part of a broad spectrum MS or a distinct disease, and an eagerness to learn if PPMS can be beneficially influenced by drugs of known efficacy in relapsing forms of MS, European investigators formulated a diagnostic algorithm exclusively for PPMS [16]. This diagnostic schema is shown in Fig. 1. Central elements of the suggested PPMS diagnostic tree are the necessity of at least 1 year of observed progression of neurologic symptoms before conferring the diagnosis,
Fig. 1. A diagnostic approach to primary progressive multiple sclerosis. The diagnostic algorithm is adapted from that suggested by Thompson et al. [16]. Central to the approach is sound differential diagnosis to exclude competing conditions. The major split in the flow diagram is a demonstration of intrathecal immunoglobulin synthesis as either the presence of cerebral spinal fluid (CSF)-specific oligoclonal bands or elevated IgG index. Lesion requirements for definite neuroimaging findings (MRI+) and supportive but not fully conclusive neuroimaging findings (MRI+/ ) are detailed in the text. Only convincing findings on visual-evoked responses (VER) contribute to this flow scheme. The presence or absence of these findings lead through the flow diagram to varying levels of diagnostic certainty including definite (PPMS), probable (prob PPMS), possible (pos PPMS) and not primary progressive MS (PPMS).
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
rigorous exclusion of competing conditions, incorporation of findings on MRI with specific guidelines, retention of graded levels of diagnostic certainty (definite, probable and possible PPMS), and delineation of a central role for the presence of evidence of intrathecal IgG synthesis for a definite diagnosis. The extension of the duration of clinical progression from 6 to 12 months and the reliance on the presence of CSF abnormalities was empiric, designed to increase the level of diagnostic certainty. In large part, this diagnostic algorithm was incorporated into the new international panel criteria for the diagnosis of all forms of MS [17]. There are nonetheless a few notable exceptions. The new international panel criteria eliminated several former formal levels of diagnostic certainty, restricting diagnostic certainty for all forms of MS as either MS or not MS. Those subjects still undergoing evaluation or with features suggestive of MS but not fulfilling all diagnostic criteria are considered as ‘‘possible’’ MS. The international panel criteria also require the presence of intrathecal synthesis of IgG to achieve the diagnosis of PPMS. As a consequence, patients lacking cerebral spinal fluid (CSF) abnormalities who would have been categorized as probable PPMS [16] must be considered possible PPMS, regardless of findings on MRI or visual-evoked responses seen at presentation or noted to evolve over time [17]. This conservative stance fully recognizes the difficulty in distinguishing PPMS from other diagnostic considerations. The international panel criteria represent an advance in the diagnosis of relapsing forms of MS based on a wealth of additional information gleaned from the introduction of MRI into organized natural history studies and clinical trials of patients with clinically isolated syndromes of the type typically seen in demyelinating disease and in relapsing forms of clinically definite MS. One might similarly anticipate future evidence-based revision of these criteria as additional information is acquired from the organized study of patients with ‘‘possible’’ and ‘‘probable’’ PPMS. The usefulness of any diagnostic scheme may fluctuate considerably dependent upon when one encounters a particular patient and how biologic markers of the disease evolve over time. Similarly, the time elapsed before neurologic symptoms dictate when a subject seeks the attention of a physician varies with the mode of presentation, access to care and personal perceptions of disease. Correspondingly, the correct interpretation of the patient’s symptoms varies with the experience of the diagnostician. As a consequence, rigid diagnostic criteria provide high specificity but low sensitivity for diagnosis early in the disease course. Conversely, less rigorous criteria increase the opportunity for diagnostic error. The unfortunate current state of effective disease management for PPMS imposes none of the pressures for early diagnosis envisioned for relapsing forms of the disease. Nor should symptomatic management require a firm diagnosis of PPMS. However, early exclusion of other conditions with presenting symptoms that might suggest PPMS is mandatory.
147
In general, symptom evolution in PPMS is regionally specific at onset. The vast majority of PPMS patients present with symptoms and signs of progressive myelopathy, most often those of a spastic paraparesis [18 –20]. Less frequent presentations seen in a contemporary series of PPMS patients included progressive cerebellar dysfunction (8%), progressive hemiplegia (6%), progressive visual loss (1%), progressive brain stem disturbances (1%) or progressive cognitive deficits (1%) [6]. Patients with PPMS are more likely to be older than those presenting with relapsing forms of the disease, and there are less strong gender differences found among PPMS cohorts than for relapsing forms of MS. The age of presentation, duration of symptoms and, particularly, the regionally specific presentation may serve to guide the diagnostic evaluation. MRI has become the cornerstone of diagnosis, both to exclude other conditions and to fulfill current diagnostic criteria as discussed below. Similarly, findings on CSF analysis are useful in directing alternative diagnoses, and to establish a diagnosis of PPMS according to international panel criteria. Wellperformed visual- and, in selected cases, somatosensoryevoked response results can provide neurophysiologic evidence of central demyelination and sometimes provide evidence for disease dissemination.
3. MRI MRI criteria for the diagnosis of PPMS have been adapted from an extensive experience with MRI findings in patients with relapsing forms of the disease [16,21]. Based on findings in a single neuroimaging session, demonstration of dissemination of disease in the PPMS subject currently rests on the presence of at least nine hyperintense white matter lesions on a T2-weighted cerebral MRI, each having a diameter of at least 3 mm, or at least two intrinsic spinal cord lesions. The presence of spinal cord lesions on MRI is given disproportionate weight as these lesions are more specific to MS and their meaning is less likely confounded by the patient’s age [22]. As the majority of patients with PPMS present with a progressive spastic myelopathy, most require imaging of the cervical and thoracic cord to exclude extramedullary compressive or vascular abnormalities, or intrinsic cord neoplasia. When a single spinal cord lesion is found, demonstration of at least four cerebral white matter lesions suffices to fulfill criteria for dissemination in PPMS; three cerebral white matter lesions are adequate if visual-evoked responses show a clear conduction delay in the presence of well-preserved waveforms. In addition, it is expected that disease dissemination over time is confirmed by a follow-up MRI demonstrating new lesion formation, or that the patient shows continued evidence of disease progression over an additional year [17]. While useful in the diagnosis of relapsing disease, the use of gadolinium to define new lesions in PPMS is less rewarding. As suggested by studies of several cohorts
148
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
[12,23,24], patients with PPMS are less likely to have gadolinium enhancement as implied by their very low mean enhanced tissue volumes compared to either patients with relapsing or secondary progressive disease. Based on entry data from a clinical trial, only between 12% and 16% of PPMS patients should be expected to show any tissue enhancement on a ‘‘random’’ cerebral MRI. This is consistent with the suggestion from pathologic studies that PPMS is less inflammatory than relapsing disease [11]. The important implication is that serial gadolinium-enhanced MRI is less likely to provide evidence of disease dissemination in PPMS than in relapsing disease, or to provide an inference of lesion formation at different times on initial imaging by enhancement of some but not all lesions. The MRI criteria for PPMS are stringent, and may eventually prove to be excessive. The older age at median presentation and diagnosis of PPMS increases the potential for finding nonspecific hyperintense signal abnormalities in the cerebral white matter, leading in large part to this conservative approach. When applied to an established cohort of 145 patients with PPMS [6], 7% failed to meet MRI criteria for diagnosis [16]. Moreover, PPMS patients have substantially reduced lesion burdens as measured on T2-weighted images when compared to relapsing patient cohorts of similar clinical disability [6,12]. This suggests that smaller numbers of lesions might be present in PPMS at all stages of disease evolution, particularly at the earliest symptomatic presentation. Currently there is no data dealing with MRI findings for ‘‘inception’’ PPMS cohorts [25,26]. In contrast, the hypointense lesion load seen on T1weighted images of an established PPMS cohort approximates that observed in a comparative cohort of clinically comparably impaired patients with secondary progressive disease, and is substantially larger than that seen in patients with relapsing disease and similar clinical disability. Among comparably imaged and analyzed groups, those with the PPMS clinical phenotype had a higher T1 hypointense lesion load as a proportion of their T2-defined disease burden than did those with relapsing or secondary progressive clinical disease phenotypes [12]. These finding suggest that while gadolinium-enhanced inflammatory lesions are less common among PPMS patients, they may result in proportionately greater tissue destruction over time than when encountered in patients with relapsing forms of the disease. The presence or character of hypointense lesions, or features found on advanced imaging methods such as magnetization transfer ratio imaging, diffusion imaging and magnetic resonance spectroscopic imaging have yet to be factored into clinical diagnostic criteria.
4. Cerebral spinal fluid Analysis of CSF allows determination of the presence or absence of intrathecal IgG synthesis, whether reflected by
the presence of oligoclonal bands unique to this compartment, an elevated IgG index or increased IgG synthetic rate. No other current approach provides similar insight into the extent of compartmentalized immunoregulatory abnormalities characteristic of most MS patients. While determination of serum and CSF IgG and albumin (required for calculation of the IgG index and synthetic rate) are well standardized and readily available through most diagnostic laboratories, the methods used for demonstrating oligoclonal bands are less well standardized, and the various techniques used differ in sensitivity. Isoelectric focusing of paired serum and CSF samples, with or without immunofixation, is the presently preferred approach for the demonstration of distinct CSF oligoclonal bands [27]. The sensitivity and specificity of the approach used in a particular reference laboratory should be considered in interpreting the meaning of negative results. The supportive diagnostic importance of CSF analysis has been de-emphasized for relapsing forms of the disease in part by patient preference but largely by the emergent role of MRI. Recognizing the difficulties in differential diagnosis peculiar to PPMS, a recent international panel concluded that positive findings on CSF analysis remain central for a definite diagnosis of this disease phenotype [17]. Undoubtedly, the level of comfort with the clinical diagnosis of PPMS is greatly enhanced by finding CSF abnormalities typical of MS. Whether this cardinal role of CSF in the diagnosis of PPMS should yield as it has in relapsing forms of MS may require future reassessment. Nonetheless, in progressive neurologic disease, great caution should be exercised in making the diagnosis of PPMS in the absence of supportive information of intrathecal IgG synthesis. The CSF status is known for nearly all of 943 patients formally considered for entry and randomized into the PROMiSe Trial, a study focused exclusively on patients with PPMS. Enrollment into this study began before the newer criteria for the diagnosis of PPMS were published. An advisory committee set study entry requirements based on consensus (members listed in the acknowledgement). Eligibility required patients to be between 30 and 65 years of age, with progressive neurologic symptoms including evidence of myelopathy for at least 6 months prior to screening, no history of prior attacks of neurologic disease, objective evidence of pyramidal damage on neurologic examination including a functional system score for the pyramidal system of at least 2 with an entry expanded disability status scale (EDSS) score of 3.0– 6.5 inclusive, and multilevel (disseminated) central nervous system disease based on objective evidence on neurologic examination alone or as supplemented by findings on the MRI, or visual- or auditory-evoked responses. All subjects were to be fully evaluated, as deemed appropriate by the participating site investigator to rule out any other known significant systemic medical disease that might confound the evaluation of PPMS or neurological conditions that
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
complicate its diagnosis. For all subjects, cervical spondylitic myelopathy was actively excluded by evidence of previous cervical imaging. Also actively excluded were thyroid dysfunction, alterations of vitamin B12 metabolism, neurosyphilis, HTLV-I seropositivity and Lyme disease. Patients who failed to meet all eligibility criteria, but were believed by the site investigator to be otherwise eligible trial candidates, had narrative and/or source documentation information supporting PPMS reviewed centrally for a binding decision whether the patient could be included in the trial. A reasonable estimate is that 0.5– 1.0% of all eligible patients within the catchment regions of the 58 contributing trial centers were entered into this study, providing a PPMS cohort reasonably representative of all patients with this disease across the range of age and disability specified by the entry criteria of the trial. As a group, these patients had clinical demographics similar to those described for smaller cohorts of patients with PPMS [14,18 –20,28,29], with a higher proportion of males, more advanced ages and a later age of onset and diagnosis than relapsing cohorts (Table 1). An important component of the PROMiSe Trial eligibility criteria was the documentation of the presence of CSF oligoclonal bands, an elevated IgG index or an elevated IgG synthetic rate. While not an absolute requirement for study entry, the clinical data on all patients lacking evidence of intrathecal synthesis of IgG were critically reviewed by a patient eligibility committee for consistency with a diagnosis of PPMS. Study candidates that had a negative CSF evaluation more than 1 year prior to trial entry or no prior
Table 1 Clinical and MRI demographics at entry into the PROMiSe trial All subjects (N = 943) Males Caucasians Age Time from first symptom Time from diagnosis Pyramidal FS scorea Cerebellar FS score Brainstem FS score Sensory FS score Bowel/bladder FS score Visual FS score Mental FS score EDSS Ambulation index 25-ft timed walk 9-hole peg test PASATb CSF positivec a
48.7% 89.8% 50.4 F 8.3 years 10.9 F 7.5 years 5.0 F 5.1 years 3.0 F 0.6 2.4 F 2.0 0.9 F 1.0 1.8 F 1.1 1.6 F 1.0 1.1 F 1.1 0.7 F 1.0 4.9 F 1.2 3.1 F 1.5 12.2 F 13.2 s 30.2 F 17.2 s 48.4 F 11.9 79.0%
FS = functional system as defined in the Extended Disability Status Scale (EDSS) [32]. b PASAT 3 = 3-min paced auditory serial addition test. c Based on the presence of oligoclonal bands, increased IgG index or elevated IgG synthetic rate.
149
Table 2 MRI findings at entry into the PROMiSe trial MRI metric
All subjects
CSF +
CSF
pa
N Gdb+ (%) Gd number Gd volumec
938 14.1 0.45 0.035
741 15.0 0.52 0.040
189 10.6 0.15 0.016
NS 0.1 0.1
N Lesions BOD1d BOD2e BODTf CSF BFg
935 134 7.24 1.13 8.36 201.5 0.86
739 137 7.60 1.18 8.78 202 0.86
188 121 5.21 0.85 6.06 199 0.86
< 0.001 < 0.0001 < 0.05 < 0.001 NS NS
a p = p value determined by Pearson chi-square for presence of enhancements, Kruskal – Wallis test for enhancements and BOD metrics that are not normally distributed, and T-test for the normally distributed CSF-derived metrics; NS = not significant. b Gd = gadolinium. c Volume = in milliliters enhanced tissue. d BOD1 = mean volume of lesions in milliliters as determined by automated segmentation analysis from the short echo and long echo fluid attenuation by inversion recovery (FLAIR) magnetization transfer contrast (MTC) images of the AFFIRMATIVE sequence [12]. e BOD2 = mean volume of lesions in milliliters as determined by automated segmentation analysis from the short echo FLAIR MTC and T2weighted images generated by the AFFIRMATIVE sequence; this corresponds to the hypointense lesion volume determined from T1-weighted images. f BODT = total lesion volume in milliliters (BOD1 + BOD2). g BF = intracranial tissue (parenchyma) as a fraction of the total segmented intracranial tissue content including CSF.
documentation of CSF findings underwent diagnostic lumbar puncture prior to trial enrollment. In this PPMS cohort, 20.2% of all subjects lacked supportive CSF findings despite having clinical MRI and/or evoked response findings compatible with PPMS. Thus, the CSF negative cohort fulfilled criteria of possible [17] to probable PPMS [16]. Others report similar proportions of patients with negative CSF findings among their PPMS cohort [18]. It is also well recognized that even in relapsing forms of MS, CSF evaluation may be normal, particularly in early phases of the disease [30]. Of considerable interest, those PROMiSe Trial patients with positive CSF findings evidenced strong trends to more enhancements and greater enhanced tissue volumes, and exhibited significantly more lesions, larger lesion volumes and evidenced greater tissue destruction within their lesions on their entry cerebral MRI than did those without these abnormalities in their CSF. In contrast, both cohorts were very similar by MRI measures of global atrophy (Table 2). Positive CSF findings imply a significant intrathecal production of IgG, presumably related to infiltration of the central nervous system with B-cells. This suggests the possibility that CSF-positive patients with PPMS have a more tissue destructive disease process than those whose CSF lacks evidence of a B-cell immunopathogenic component to their disease.
150
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
5. Evoked responses Evoked response testing in patients suspected of having MS can be useful to support the conclusion of demyelination in a central conductive pathway as a cause for clinical symptoms and signs, and to demonstrate dissemination of lesions in clinically asymptomatic sensory pathways [31]. As the majority of PPMS cases present with a component of progressive myelopathy, even when carefully performed, somatosensory-evoked responses provide limited diagnostic help, but can demonstrate central conduction delays of the type seen in MS. Visual-evoked response testing in PPMS is more informative, particularly in the patient without visual symptoms. It is essential to recognize that slowing of visualevoked responses or their absence is not supportive of MS and slowing of conduction can only be considered indicative of demyelinative lesion when the waveforms are well preserved. Brain stem auditory-evoked responses appear to add little diagnostic information in either relapsing or PPMS.
6. Summary and conclusion The introduction of MRI for the diagnosis and study of MS, and recent therapeutic successes with relapsing forms of the disease have greatly accelerated our interest and understanding of many aspects of the disease process. It is possible that relapsing and purely progressive forms of the disease differ only qualitatively and that these differences in clinical disease expression are determined in large part by the age of presentation of the patient rather than by a fundamental difference in the underlying pathologic processes. Nonetheless, the study of PPMS patients will likely improve our understanding of the different contributions of inflammatory lesion formation and non-inflammatory lesion deterioration to the distinctive clinical phases of the enigmatic disease process. Early and specific diagnosis is essential to provide cohorts of PPMS patients that are not contaminated by other disease for such important studies. The diagnostic algorithms reviewed provide a secure basis for evaluating patients and understanding diagnostic certainty in PPMS, but they will likely need revision to be useful for the sensitive and secure identification of inception cases.
Acknowledgements This work was supported in part by a grant from Teva Neuroscience. The PROMiSe Trial Study Group principal investigators, centers and cities are as follows: Canada—Lorne Kastrukoff, University of British Columbia, Vancouver; Pierre Duquette, Hopital Notre
Dame, Montreal; Mark Freedman, University of Ottawa Medical Associates, Ottawa; Paul O’Connor, St. Michael’s Hospital, Toronto. France—Marc Debouverie, Hopital Central, Nancy; Catherine Lubetski, Hopital la Pitie-Salpetriere, Paris; Gilles Edan, Hopital Pontchaillou, Rennes; Etienne Roullet, Hopital Tenon, Paris; Christian Confavreux, Hopital Neurologique, Lyon. United Kingdom—Alan Thompson, Institute of Neurology, London; Lance Blumhardt, Queens Medical Centre, Nottingham; Stanley Hawkins, Royal Victoria Hospital, Belfast. United States—Thomas Scott, Allegheny General Hospital, Pittsburgh; Daniel Wynn, Consultants in Neurology, Chicago; Joanna Cooper, East Bay Neurology, Berkeley; Stephen Thurston, Henrico Doctor’s Hospital, Richmond; Stanton Elias, Henry Ford Hospital, Detroit; Clyde Markowitz, Hospital of the University of Pennsylvania, Philadelphia; David Mattson, Indiana University School of Medicine, Indianapolis; Aaron Miller, Maimonides Medical Center, Brooklyn; John Noseworthy, Mayo Clinic, Rochester; Elizabeth Shuster, Mayo Clinic of Jacksonville, Jacksonville; Jonathan Carter, Mayo Clinic Scottsdale, Scottsdale; Fred Lublin, Medical College of Pennsylvania-Hahneman School of Medicine, Philadelphia; William Stuart, MS Center at Shepherd Center, Atlanta; Michael Kaufman, MS Center of the Carolinas, Charlotte; Gary Birnbaum, MS Treatment and Research Center, Golden Valley; Kottil Rammohan, Ohio State University School of Medicine, Columbus; Ruth Whitham, Oregon Health Science University, Portland; Cornelia Mihai, Research Foundation of the State University of New York, Syracuse; Steven Greenberg, Roswell Park Cancer Center, Buffalo; Craig Smith, Swedish Medical Center, Seattle; Mark Agius, University of California Davis Medical Center, Davis; Stan van den Noort, University of California Irvine, Irvine; Lawrence Myers, University of California Los Angeles MS Research, Los Angeles; James Nelson, University of California San Diego, La Jolla; Douglas Goodin, University of California San Francisco, San Francisco; Barry Arnason, University of Chicago, Chicago; Khurram Bashir, University Hospital, Birmingham; Sharon Lynch, University of Kansas Medical Center, Kansas City; Kenneth Johnson, University of Maryland Hospital, Baltimore; Patricia Coyle, University Medical Center at State University of New York, Stony Brook; Stephen Kamin, University Medical and Dental New Jersey Medical School, Newark; William Sheremata, University of Miami School of Medicine, Miami; Corey Ford, University of New Mexico, Albuquerque; Galen Mitchell, University of Pittsburgh MS Center, Pittsburgh; Andrew Goodman, University of Rochester Medical Center, Rochester; Norman Kachuck, University of Southern
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
California, Los Angeles; Peter Dunne, University of South Florida, Tampa; J. William Lindsey, University of Texas Health Science Center, Houston; Elliot Frohman, University of Texas Southwestern Medical Center, Dallas; James Bowen, University of Washington School of Medicine, Seattle; Benjamin Brooks, University of Wisconsin, Madison; John Rose, University of Utah, Salt Lake; Harold Moses, Vanderbilt Stallwort Rehabilitation Center, Nashville; Douglas Jeffrey, Wake Forest University Baptist Medical Center, Winston-Salem; Anne Cross, Washington University, St. Louis; Robert Lisak, Wayne State University School of Medicine, Detroit; Tim Vollmer, Yale University School of Medicine, New Haven. Advisory Committee—Lance Blumhardt, Christian Confavreux, Kenneth Johnson, Fred D. Lublin, (now at Mt. Siani Hospital, New York), John Noseworthy, Paul O’Connor, Alan Thompson, John Whitaker (deceased), Jerry Wolinsky. Data Safety Monitoring Board—Henry McFarland, chair, Jack Antel, Gary Cutter, Luanne Metz, Stephen Reingold. Teva Neuroscience and Teva Pharmaceuticals, Ltd.— Lillian Pardo, Rob Elfont, Rivka Kreitman, Shaul Kadosh, Galia Shifroni, Irit Pinchasi, Yafit Stark, David Ladkani. MRI-Analysis Center, Jerry Wolinsky, Ponnada Narayana, Irina Vainrub, Lucie Lambert, Rimma Boykin, Saria Momin, Fengwei Zhong.
References [1] Charcot J-M. Histologie de la sclerose en plaques, vol. 41. Paris: Gazette Hopital; 1868. p. 554 – 8. [2] McAlpine D. Multiple sclerosis: a review. Br Med J 1973;2:292 – 5. [3] Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46:907 – 11. [4] Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898 – 904. [5] Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:1576 – 82. [6] Stevenson VL, Miller DH, Rovaris M, et al. Primary and transitional progressive MS: a clinical and MRI cross-sectional study. Neurology 1999;52:839 – 45. [7] Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227 – 31. [8] Kappos L, for the European Study Group on interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352:1491 – 7. [9] Francis G, Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001;56:1496 – 504.
151
[10] Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2001;47:707 – 17. [11] Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 1994;117:759 – 65. [12] Wolinsky JS, Narayana PA, He R. Overview of treatment trials: early baseline clinical and MRI data of the PROMiSe trial. In: Filippi M, Comi G, editors. Primary progressive multiple sclerosis. Milano: Springer-Verlag Italia; 2002. p. 47 – 61. [13] Schumacher GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F. 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 Med 1965;122: 552 – 68. [14] Thompson AJ, Polman CH, Miller DH, et al. Primary progressive multiple sclerosis. Brain 1997;120:1085 – 96. [15] McDonnell GV, Hawkins SA. Application of the Poser criteria in primary progressive multiple sclerosis. Ann Neurol 1997;42:982 – 3. [16] Thompson AJ, Montalban X, Barkhof F, et al. Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Ann Neurol 2000;47:831 – 5. [17] McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121 – 7. [18] McDonnell GV, Hawkins SA. Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK. J Neurol Neurosurg Psychiatry 1998;64:451 – 4. [19] Cottrell DA, Kremenchutzky M, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study: 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain 1999;122:625 – 39. [20] Bashir K, Whitaker JN. Clinical and laboratory features of primary progressive and secondary progressive MS. Neurology 1999;53: 765 – 71. [21] Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120:2059 – 69. [22] Thorpe JW, Kidd D, Moseley IF, et al. Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI. Brain 1996;119: 709 – 14. [23] Filippi M, Campi A, Martinelli V, et al. Comparison of triple dose versus standard dose gadolinium – DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 1995;59:540 – 4. [24] Filippi M, Rovaris M, Gasperini C, et al. A preliminary study comparing the sensitivity of serial monthly enhanced MRI after standard and triple dose gadolinium – DTPA for monitoring disease activity in primary progressive multiple sclerosis. J Neuroimaging 1998;8: 88 – 93. [25] Rovaris M, Comi G, Filippi M. Magnetization transfer and diffusion tensor magnetic resonance imaging. In: Filippi M, Comi G, editors. Primary progressive multiple sclerosis. Milano: Springer-Verlag Italia; 2002. p. 77 – 88. [26] Caramanos Z, Santos AC, Francis SJ, Narayanan S, Pelletier D, Arnold DL. Proton magnetic resonance spectroscopy. In: Filippi M, Comi G, editors. Primary progressive multiple sclerosis. Milano: Springer-Verlag Italia; 2002. p. 89 – 112. [27] Andersson M, Alvarez-Cermeno J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 1994;57:897 – 902. [28] Andersson PB, Waubant E, Gee L, Goodkin DE. Multiple sclerosis that is progressive from the time of onset: clinical characteristics and progression of disability. Arch Neurol 1999;56:1138 – 42. [29] Cottrell DA, Kremenchutzky M, Rice GP, Hader W, Baskerville J, Ebers GC. The natural history of multiple sclerosis: a geographically based study: 6. Applications to planning and interpretation of clinical
152
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
therapeutic trials in primary progressive multiple sclerosis. Brain 1999;122:641 – 7. [30] Pirttila T, Nurmikko T. CSF oligoclonal bands, MRI, and the diagnosis of multiple sclerosis. Acta Neurol Scand 1995;92:468 – 71. [31] Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients
with suspected multiple sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1720 – 5. [32] Kurtzke JF. Clinical definition for multiple sclerosis treatment trials. Ann Neurol 1994;36:S73 – 9.
The diagnosis of primary progressive multiple sclerosis Jerry S. Wolinsky *, the PROMiSe Study Group1 Department of Neurology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Abstract Primary progressive multiple sclerosis (PPMS) is a rather unique form of the more common relapsing inflammatory demyelinative disease. The absence of attacks that typify relapsing forms of MS imposes special challenges for diagnosis, but also provides an opportunity to study the pathogenesis of the more progressive aspects of the disease process in isolation of confounding transient clinical events. In this review, recent advances in diagnostic approaches are considered in relationship to baseline data from a large multinational study designed to better characterize and treat this clinical phenotype. PPMS subjects with cerebral spinal fluid (CSF) findings consistent with intrathecal immunoglobulin production may have a more tissue destructive disease process than those whose CSF lacks evidence of a B-cell immunopathogenic disease component. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Magnetic resonance imaging (MRI); Cerebral spinal fluid (CSF)
1. Introduction Nearly 150 years ago, Charcot [1] recognized that some forms of multiple sclerosis (MS) could be progressive from onset, failing to exhibit any of the acute episodes of neurologic deterioration that typify the more common clinical presentations of the disease. Subsequent students of the disease distinguished such cases from those whose initial relapsing clinical course had passed into a phase of nearly unrelenting accumulation of clinical neurologic disability with or without continued superimposed attacks that we now categorize as secondary progressive MS [2]. Primary progressive multiple sclerosis (PPMS) is the least common clinical disease phenotype exhibited by MS patients. Current consensus definitions of the various disease phenotypes demand that patients with PPMS have a progressive disease from onset and a clinical course without discernible attacks [3]. Some minor amount of improvement or worsening is allowed, but episodes that fit most modern clinical trial definitions of acute relapses eliminate patients from this subtype and consign them to either secondary progressive or progressive relapsing MS categories, depending upon
* Corresponding author. Tel.: +1-713-500-7048; fax: +1-713-5007041. 1 The participating centers and principal investigators of the PROMiSe trial are listed in the acknowledgement.
whether the clinical attack occurred prior to or following the onset of their progressive neurologic dysfunction. Approximately 15% of MS patients have a progressive disease onset, but nearly one-third of these will eventually experience one or more clinical attacks. Thus, only about 10% of all MS patients have a lifetime clinical course that fits a strict definition of the PPMS phenotype. As a consequence, any descriptive cross-sectional or longitudinal analysis of PPMS must, by definition, be contaminated to some extent by patients who will have future attacks that will segregate them into the progressive relapsing clinical phenotype. Moreover, it is quite likely that some patients who present with an ingravescent accumulation of neurologic disability simply fail to recall remote episodes of neurologic dysfunction. Such events may or may not have been attended by physicians or resulted in a formal diagnosis of relapsing MS or clinically isolated demyelinative syndrome of the type commonly seen in MS [4,5]. Such cases of ‘‘cryptic’’ secondary progressive or ‘‘transitional’’ MS [6] will contaminate to some extent any cohort of rigorously defined PPMS patients. Further complicating our understanding of this clinical phenotype is the common use of the now disparaged ‘‘chronic progressive MS’’ to describe patient cohorts that indiscriminately include subjects with secondary progressive, progressive relapsing and primary progressive MS. Until recently, few investigators attempted to specifically isolate patients with PPMS for the purpose of clinical trials
0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 3 4 6 - 5
146
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
of therapeutic agents. Nor had generally accepted criteria for the clinical diagnosis of MS addressed the special issues raised by this clinical phenotype [7]. However, apparent differences in the clinical trial outcomes of various preparations of interferon beta in patients with relapsing and secondary progressive disease have now highlighted the difficulties in separating the effects of therapeutic agents on disease progression from their benefits on attacks and the more inflammatory aspects of the underlying pathology as monitored by magnetic resonance imaging (MRI) [8,9]. Patients with PPMS provide the ideal study population with which to investigate the effects of a therapeutic agent on clinical disease progression in the absence of the confounding influence of clinical attacks. Contemporary neuropathology studies have attempted to classify MS based on characteristic immunohistochemical features of lesions [10]. While some PPMS cases exhibit an oligodendrogliopathy that may be unique to this clinical phenotype, all cases reported thus far show some inflammatory change [10,11], and the majority of the PPMS cases share pathologic features common to those with relapsing forms of the disease [10]. Should the pathogenesis of lesion formation or evolution differ as the MS patient transitions from a purely relapsing into a progressive phase of their disease, then detailed comparative study of patients with relapsing disease and those with purely progressive disease might aid to clarify the pathophysiological differences that underlie the later phases of the relapsing MS phenotype. Unfortunately, studies of the pure PPMS phenotype introduce complexities of design not encountered with relapsing MS patient populations. This paper will concentrate on the diagnosis of PPMS. It will also review the clinical, laboratory and neuroimaging features of PPMS, drawing heavily on the
cross-sectional findings of a large cohort of subjects at entry into a multinational, multicenter, double-blind, placebo-controlled study—the PROMiSe Trial [12].
2. Diagnosis Older consensus criteria for the diagnosis of MS concentrated on relapses as an absolute requirement for fulfillment of the cardinal feature of a disease process disseminated in both time and in space [7]. As such, individuals presenting with progressive neurologic dysfunction were by inference required to develop clinical or paraclinical evidence of a new lesion consistent with dissemination of the process in time and in space, or to evidence intrathecal synthesis of immunoglobulin (IgG) to enable a laboratorysupported diagnosis of definite MS. Still earlier consensus criteria had emphasized the steady or stepwise accumulation of signs and symptoms of neurologic dysfunction over at least 6 months and the exclusion of competing diagnoses as the basis for diagnosing the more progressive disease forms [13]. Given increasing recognition of the inadequacy of the Washington Panel criteria as specifically applied to PPMS [14,15], a heightened interest in determining if PPMS is simply part of a broad spectrum MS or a distinct disease, and an eagerness to learn if PPMS can be beneficially influenced by drugs of known efficacy in relapsing forms of MS, European investigators formulated a diagnostic algorithm exclusively for PPMS [16]. This diagnostic schema is shown in Fig. 1. Central elements of the suggested PPMS diagnostic tree are the necessity of at least 1 year of observed progression of neurologic symptoms before conferring the diagnosis,
Fig. 1. A diagnostic approach to primary progressive multiple sclerosis. The diagnostic algorithm is adapted from that suggested by Thompson et al. [16]. Central to the approach is sound differential diagnosis to exclude competing conditions. The major split in the flow diagram is a demonstration of intrathecal immunoglobulin synthesis as either the presence of cerebral spinal fluid (CSF)-specific oligoclonal bands or elevated IgG index. Lesion requirements for definite neuroimaging findings (MRI+) and supportive but not fully conclusive neuroimaging findings (MRI+/ ) are detailed in the text. Only convincing findings on visual-evoked responses (VER) contribute to this flow scheme. The presence or absence of these findings lead through the flow diagram to varying levels of diagnostic certainty including definite (PPMS), probable (prob PPMS), possible (pos PPMS) and not primary progressive MS (PPMS).
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
rigorous exclusion of competing conditions, incorporation of findings on MRI with specific guidelines, retention of graded levels of diagnostic certainty (definite, probable and possible PPMS), and delineation of a central role for the presence of evidence of intrathecal IgG synthesis for a definite diagnosis. The extension of the duration of clinical progression from 6 to 12 months and the reliance on the presence of CSF abnormalities was empiric, designed to increase the level of diagnostic certainty. In large part, this diagnostic algorithm was incorporated into the new international panel criteria for the diagnosis of all forms of MS [17]. There are nonetheless a few notable exceptions. The new international panel criteria eliminated several former formal levels of diagnostic certainty, restricting diagnostic certainty for all forms of MS as either MS or not MS. Those subjects still undergoing evaluation or with features suggestive of MS but not fulfilling all diagnostic criteria are considered as ‘‘possible’’ MS. The international panel criteria also require the presence of intrathecal synthesis of IgG to achieve the diagnosis of PPMS. As a consequence, patients lacking cerebral spinal fluid (CSF) abnormalities who would have been categorized as probable PPMS [16] must be considered possible PPMS, regardless of findings on MRI or visual-evoked responses seen at presentation or noted to evolve over time [17]. This conservative stance fully recognizes the difficulty in distinguishing PPMS from other diagnostic considerations. The international panel criteria represent an advance in the diagnosis of relapsing forms of MS based on a wealth of additional information gleaned from the introduction of MRI into organized natural history studies and clinical trials of patients with clinically isolated syndromes of the type typically seen in demyelinating disease and in relapsing forms of clinically definite MS. One might similarly anticipate future evidence-based revision of these criteria as additional information is acquired from the organized study of patients with ‘‘possible’’ and ‘‘probable’’ PPMS. The usefulness of any diagnostic scheme may fluctuate considerably dependent upon when one encounters a particular patient and how biologic markers of the disease evolve over time. Similarly, the time elapsed before neurologic symptoms dictate when a subject seeks the attention of a physician varies with the mode of presentation, access to care and personal perceptions of disease. Correspondingly, the correct interpretation of the patient’s symptoms varies with the experience of the diagnostician. As a consequence, rigid diagnostic criteria provide high specificity but low sensitivity for diagnosis early in the disease course. Conversely, less rigorous criteria increase the opportunity for diagnostic error. The unfortunate current state of effective disease management for PPMS imposes none of the pressures for early diagnosis envisioned for relapsing forms of the disease. Nor should symptomatic management require a firm diagnosis of PPMS. However, early exclusion of other conditions with presenting symptoms that might suggest PPMS is mandatory.
147
In general, symptom evolution in PPMS is regionally specific at onset. The vast majority of PPMS patients present with symptoms and signs of progressive myelopathy, most often those of a spastic paraparesis [18 –20]. Less frequent presentations seen in a contemporary series of PPMS patients included progressive cerebellar dysfunction (8%), progressive hemiplegia (6%), progressive visual loss (1%), progressive brain stem disturbances (1%) or progressive cognitive deficits (1%) [6]. Patients with PPMS are more likely to be older than those presenting with relapsing forms of the disease, and there are less strong gender differences found among PPMS cohorts than for relapsing forms of MS. The age of presentation, duration of symptoms and, particularly, the regionally specific presentation may serve to guide the diagnostic evaluation. MRI has become the cornerstone of diagnosis, both to exclude other conditions and to fulfill current diagnostic criteria as discussed below. Similarly, findings on CSF analysis are useful in directing alternative diagnoses, and to establish a diagnosis of PPMS according to international panel criteria. Wellperformed visual- and, in selected cases, somatosensoryevoked response results can provide neurophysiologic evidence of central demyelination and sometimes provide evidence for disease dissemination.
3. MRI MRI criteria for the diagnosis of PPMS have been adapted from an extensive experience with MRI findings in patients with relapsing forms of the disease [16,21]. Based on findings in a single neuroimaging session, demonstration of dissemination of disease in the PPMS subject currently rests on the presence of at least nine hyperintense white matter lesions on a T2-weighted cerebral MRI, each having a diameter of at least 3 mm, or at least two intrinsic spinal cord lesions. The presence of spinal cord lesions on MRI is given disproportionate weight as these lesions are more specific to MS and their meaning is less likely confounded by the patient’s age [22]. As the majority of patients with PPMS present with a progressive spastic myelopathy, most require imaging of the cervical and thoracic cord to exclude extramedullary compressive or vascular abnormalities, or intrinsic cord neoplasia. When a single spinal cord lesion is found, demonstration of at least four cerebral white matter lesions suffices to fulfill criteria for dissemination in PPMS; three cerebral white matter lesions are adequate if visual-evoked responses show a clear conduction delay in the presence of well-preserved waveforms. In addition, it is expected that disease dissemination over time is confirmed by a follow-up MRI demonstrating new lesion formation, or that the patient shows continued evidence of disease progression over an additional year [17]. While useful in the diagnosis of relapsing disease, the use of gadolinium to define new lesions in PPMS is less rewarding. As suggested by studies of several cohorts
148
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
[12,23,24], patients with PPMS are less likely to have gadolinium enhancement as implied by their very low mean enhanced tissue volumes compared to either patients with relapsing or secondary progressive disease. Based on entry data from a clinical trial, only between 12% and 16% of PPMS patients should be expected to show any tissue enhancement on a ‘‘random’’ cerebral MRI. This is consistent with the suggestion from pathologic studies that PPMS is less inflammatory than relapsing disease [11]. The important implication is that serial gadolinium-enhanced MRI is less likely to provide evidence of disease dissemination in PPMS than in relapsing disease, or to provide an inference of lesion formation at different times on initial imaging by enhancement of some but not all lesions. The MRI criteria for PPMS are stringent, and may eventually prove to be excessive. The older age at median presentation and diagnosis of PPMS increases the potential for finding nonspecific hyperintense signal abnormalities in the cerebral white matter, leading in large part to this conservative approach. When applied to an established cohort of 145 patients with PPMS [6], 7% failed to meet MRI criteria for diagnosis [16]. Moreover, PPMS patients have substantially reduced lesion burdens as measured on T2-weighted images when compared to relapsing patient cohorts of similar clinical disability [6,12]. This suggests that smaller numbers of lesions might be present in PPMS at all stages of disease evolution, particularly at the earliest symptomatic presentation. Currently there is no data dealing with MRI findings for ‘‘inception’’ PPMS cohorts [25,26]. In contrast, the hypointense lesion load seen on T1weighted images of an established PPMS cohort approximates that observed in a comparative cohort of clinically comparably impaired patients with secondary progressive disease, and is substantially larger than that seen in patients with relapsing disease and similar clinical disability. Among comparably imaged and analyzed groups, those with the PPMS clinical phenotype had a higher T1 hypointense lesion load as a proportion of their T2-defined disease burden than did those with relapsing or secondary progressive clinical disease phenotypes [12]. These finding suggest that while gadolinium-enhanced inflammatory lesions are less common among PPMS patients, they may result in proportionately greater tissue destruction over time than when encountered in patients with relapsing forms of the disease. The presence or character of hypointense lesions, or features found on advanced imaging methods such as magnetization transfer ratio imaging, diffusion imaging and magnetic resonance spectroscopic imaging have yet to be factored into clinical diagnostic criteria.
4. Cerebral spinal fluid Analysis of CSF allows determination of the presence or absence of intrathecal IgG synthesis, whether reflected by
the presence of oligoclonal bands unique to this compartment, an elevated IgG index or increased IgG synthetic rate. No other current approach provides similar insight into the extent of compartmentalized immunoregulatory abnormalities characteristic of most MS patients. While determination of serum and CSF IgG and albumin (required for calculation of the IgG index and synthetic rate) are well standardized and readily available through most diagnostic laboratories, the methods used for demonstrating oligoclonal bands are less well standardized, and the various techniques used differ in sensitivity. Isoelectric focusing of paired serum and CSF samples, with or without immunofixation, is the presently preferred approach for the demonstration of distinct CSF oligoclonal bands [27]. The sensitivity and specificity of the approach used in a particular reference laboratory should be considered in interpreting the meaning of negative results. The supportive diagnostic importance of CSF analysis has been de-emphasized for relapsing forms of the disease in part by patient preference but largely by the emergent role of MRI. Recognizing the difficulties in differential diagnosis peculiar to PPMS, a recent international panel concluded that positive findings on CSF analysis remain central for a definite diagnosis of this disease phenotype [17]. Undoubtedly, the level of comfort with the clinical diagnosis of PPMS is greatly enhanced by finding CSF abnormalities typical of MS. Whether this cardinal role of CSF in the diagnosis of PPMS should yield as it has in relapsing forms of MS may require future reassessment. Nonetheless, in progressive neurologic disease, great caution should be exercised in making the diagnosis of PPMS in the absence of supportive information of intrathecal IgG synthesis. The CSF status is known for nearly all of 943 patients formally considered for entry and randomized into the PROMiSe Trial, a study focused exclusively on patients with PPMS. Enrollment into this study began before the newer criteria for the diagnosis of PPMS were published. An advisory committee set study entry requirements based on consensus (members listed in the acknowledgement). Eligibility required patients to be between 30 and 65 years of age, with progressive neurologic symptoms including evidence of myelopathy for at least 6 months prior to screening, no history of prior attacks of neurologic disease, objective evidence of pyramidal damage on neurologic examination including a functional system score for the pyramidal system of at least 2 with an entry expanded disability status scale (EDSS) score of 3.0– 6.5 inclusive, and multilevel (disseminated) central nervous system disease based on objective evidence on neurologic examination alone or as supplemented by findings on the MRI, or visual- or auditory-evoked responses. All subjects were to be fully evaluated, as deemed appropriate by the participating site investigator to rule out any other known significant systemic medical disease that might confound the evaluation of PPMS or neurological conditions that
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
complicate its diagnosis. For all subjects, cervical spondylitic myelopathy was actively excluded by evidence of previous cervical imaging. Also actively excluded were thyroid dysfunction, alterations of vitamin B12 metabolism, neurosyphilis, HTLV-I seropositivity and Lyme disease. Patients who failed to meet all eligibility criteria, but were believed by the site investigator to be otherwise eligible trial candidates, had narrative and/or source documentation information supporting PPMS reviewed centrally for a binding decision whether the patient could be included in the trial. A reasonable estimate is that 0.5– 1.0% of all eligible patients within the catchment regions of the 58 contributing trial centers were entered into this study, providing a PPMS cohort reasonably representative of all patients with this disease across the range of age and disability specified by the entry criteria of the trial. As a group, these patients had clinical demographics similar to those described for smaller cohorts of patients with PPMS [14,18 –20,28,29], with a higher proportion of males, more advanced ages and a later age of onset and diagnosis than relapsing cohorts (Table 1). An important component of the PROMiSe Trial eligibility criteria was the documentation of the presence of CSF oligoclonal bands, an elevated IgG index or an elevated IgG synthetic rate. While not an absolute requirement for study entry, the clinical data on all patients lacking evidence of intrathecal synthesis of IgG were critically reviewed by a patient eligibility committee for consistency with a diagnosis of PPMS. Study candidates that had a negative CSF evaluation more than 1 year prior to trial entry or no prior
Table 1 Clinical and MRI demographics at entry into the PROMiSe trial All subjects (N = 943) Males Caucasians Age Time from first symptom Time from diagnosis Pyramidal FS scorea Cerebellar FS score Brainstem FS score Sensory FS score Bowel/bladder FS score Visual FS score Mental FS score EDSS Ambulation index 25-ft timed walk 9-hole peg test PASATb CSF positivec a
48.7% 89.8% 50.4 F 8.3 years 10.9 F 7.5 years 5.0 F 5.1 years 3.0 F 0.6 2.4 F 2.0 0.9 F 1.0 1.8 F 1.1 1.6 F 1.0 1.1 F 1.1 0.7 F 1.0 4.9 F 1.2 3.1 F 1.5 12.2 F 13.2 s 30.2 F 17.2 s 48.4 F 11.9 79.0%
FS = functional system as defined in the Extended Disability Status Scale (EDSS) [32]. b PASAT 3 = 3-min paced auditory serial addition test. c Based on the presence of oligoclonal bands, increased IgG index or elevated IgG synthetic rate.
149
Table 2 MRI findings at entry into the PROMiSe trial MRI metric
All subjects
CSF +
CSF
pa
N Gdb+ (%) Gd number Gd volumec
938 14.1 0.45 0.035
741 15.0 0.52 0.040
189 10.6 0.15 0.016
NS 0.1 0.1
N Lesions BOD1d BOD2e BODTf CSF BFg
935 134 7.24 1.13 8.36 201.5 0.86
739 137 7.60 1.18 8.78 202 0.86
188 121 5.21 0.85 6.06 199 0.86
< 0.001 < 0.0001 < 0.05 < 0.001 NS NS
a p = p value determined by Pearson chi-square for presence of enhancements, Kruskal – Wallis test for enhancements and BOD metrics that are not normally distributed, and T-test for the normally distributed CSF-derived metrics; NS = not significant. b Gd = gadolinium. c Volume = in milliliters enhanced tissue. d BOD1 = mean volume of lesions in milliliters as determined by automated segmentation analysis from the short echo and long echo fluid attenuation by inversion recovery (FLAIR) magnetization transfer contrast (MTC) images of the AFFIRMATIVE sequence [12]. e BOD2 = mean volume of lesions in milliliters as determined by automated segmentation analysis from the short echo FLAIR MTC and T2weighted images generated by the AFFIRMATIVE sequence; this corresponds to the hypointense lesion volume determined from T1-weighted images. f BODT = total lesion volume in milliliters (BOD1 + BOD2). g BF = intracranial tissue (parenchyma) as a fraction of the total segmented intracranial tissue content including CSF.
documentation of CSF findings underwent diagnostic lumbar puncture prior to trial enrollment. In this PPMS cohort, 20.2% of all subjects lacked supportive CSF findings despite having clinical MRI and/or evoked response findings compatible with PPMS. Thus, the CSF negative cohort fulfilled criteria of possible [17] to probable PPMS [16]. Others report similar proportions of patients with negative CSF findings among their PPMS cohort [18]. It is also well recognized that even in relapsing forms of MS, CSF evaluation may be normal, particularly in early phases of the disease [30]. Of considerable interest, those PROMiSe Trial patients with positive CSF findings evidenced strong trends to more enhancements and greater enhanced tissue volumes, and exhibited significantly more lesions, larger lesion volumes and evidenced greater tissue destruction within their lesions on their entry cerebral MRI than did those without these abnormalities in their CSF. In contrast, both cohorts were very similar by MRI measures of global atrophy (Table 2). Positive CSF findings imply a significant intrathecal production of IgG, presumably related to infiltration of the central nervous system with B-cells. This suggests the possibility that CSF-positive patients with PPMS have a more tissue destructive disease process than those whose CSF lacks evidence of a B-cell immunopathogenic component to their disease.
150
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
5. Evoked responses Evoked response testing in patients suspected of having MS can be useful to support the conclusion of demyelination in a central conductive pathway as a cause for clinical symptoms and signs, and to demonstrate dissemination of lesions in clinically asymptomatic sensory pathways [31]. As the majority of PPMS cases present with a component of progressive myelopathy, even when carefully performed, somatosensory-evoked responses provide limited diagnostic help, but can demonstrate central conduction delays of the type seen in MS. Visual-evoked response testing in PPMS is more informative, particularly in the patient without visual symptoms. It is essential to recognize that slowing of visualevoked responses or their absence is not supportive of MS and slowing of conduction can only be considered indicative of demyelinative lesion when the waveforms are well preserved. Brain stem auditory-evoked responses appear to add little diagnostic information in either relapsing or PPMS.
6. Summary and conclusion The introduction of MRI for the diagnosis and study of MS, and recent therapeutic successes with relapsing forms of the disease have greatly accelerated our interest and understanding of many aspects of the disease process. It is possible that relapsing and purely progressive forms of the disease differ only qualitatively and that these differences in clinical disease expression are determined in large part by the age of presentation of the patient rather than by a fundamental difference in the underlying pathologic processes. Nonetheless, the study of PPMS patients will likely improve our understanding of the different contributions of inflammatory lesion formation and non-inflammatory lesion deterioration to the distinctive clinical phases of the enigmatic disease process. Early and specific diagnosis is essential to provide cohorts of PPMS patients that are not contaminated by other disease for such important studies. The diagnostic algorithms reviewed provide a secure basis for evaluating patients and understanding diagnostic certainty in PPMS, but they will likely need revision to be useful for the sensitive and secure identification of inception cases.
Acknowledgements This work was supported in part by a grant from Teva Neuroscience. The PROMiSe Trial Study Group principal investigators, centers and cities are as follows: Canada—Lorne Kastrukoff, University of British Columbia, Vancouver; Pierre Duquette, Hopital Notre
Dame, Montreal; Mark Freedman, University of Ottawa Medical Associates, Ottawa; Paul O’Connor, St. Michael’s Hospital, Toronto. France—Marc Debouverie, Hopital Central, Nancy; Catherine Lubetski, Hopital la Pitie-Salpetriere, Paris; Gilles Edan, Hopital Pontchaillou, Rennes; Etienne Roullet, Hopital Tenon, Paris; Christian Confavreux, Hopital Neurologique, Lyon. United Kingdom—Alan Thompson, Institute of Neurology, London; Lance Blumhardt, Queens Medical Centre, Nottingham; Stanley Hawkins, Royal Victoria Hospital, Belfast. United States—Thomas Scott, Allegheny General Hospital, Pittsburgh; Daniel Wynn, Consultants in Neurology, Chicago; Joanna Cooper, East Bay Neurology, Berkeley; Stephen Thurston, Henrico Doctor’s Hospital, Richmond; Stanton Elias, Henry Ford Hospital, Detroit; Clyde Markowitz, Hospital of the University of Pennsylvania, Philadelphia; David Mattson, Indiana University School of Medicine, Indianapolis; Aaron Miller, Maimonides Medical Center, Brooklyn; John Noseworthy, Mayo Clinic, Rochester; Elizabeth Shuster, Mayo Clinic of Jacksonville, Jacksonville; Jonathan Carter, Mayo Clinic Scottsdale, Scottsdale; Fred Lublin, Medical College of Pennsylvania-Hahneman School of Medicine, Philadelphia; William Stuart, MS Center at Shepherd Center, Atlanta; Michael Kaufman, MS Center of the Carolinas, Charlotte; Gary Birnbaum, MS Treatment and Research Center, Golden Valley; Kottil Rammohan, Ohio State University School of Medicine, Columbus; Ruth Whitham, Oregon Health Science University, Portland; Cornelia Mihai, Research Foundation of the State University of New York, Syracuse; Steven Greenberg, Roswell Park Cancer Center, Buffalo; Craig Smith, Swedish Medical Center, Seattle; Mark Agius, University of California Davis Medical Center, Davis; Stan van den Noort, University of California Irvine, Irvine; Lawrence Myers, University of California Los Angeles MS Research, Los Angeles; James Nelson, University of California San Diego, La Jolla; Douglas Goodin, University of California San Francisco, San Francisco; Barry Arnason, University of Chicago, Chicago; Khurram Bashir, University Hospital, Birmingham; Sharon Lynch, University of Kansas Medical Center, Kansas City; Kenneth Johnson, University of Maryland Hospital, Baltimore; Patricia Coyle, University Medical Center at State University of New York, Stony Brook; Stephen Kamin, University Medical and Dental New Jersey Medical School, Newark; William Sheremata, University of Miami School of Medicine, Miami; Corey Ford, University of New Mexico, Albuquerque; Galen Mitchell, University of Pittsburgh MS Center, Pittsburgh; Andrew Goodman, University of Rochester Medical Center, Rochester; Norman Kachuck, University of Southern
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
California, Los Angeles; Peter Dunne, University of South Florida, Tampa; J. William Lindsey, University of Texas Health Science Center, Houston; Elliot Frohman, University of Texas Southwestern Medical Center, Dallas; James Bowen, University of Washington School of Medicine, Seattle; Benjamin Brooks, University of Wisconsin, Madison; John Rose, University of Utah, Salt Lake; Harold Moses, Vanderbilt Stallwort Rehabilitation Center, Nashville; Douglas Jeffrey, Wake Forest University Baptist Medical Center, Winston-Salem; Anne Cross, Washington University, St. Louis; Robert Lisak, Wayne State University School of Medicine, Detroit; Tim Vollmer, Yale University School of Medicine, New Haven. Advisory Committee—Lance Blumhardt, Christian Confavreux, Kenneth Johnson, Fred D. Lublin, (now at Mt. Siani Hospital, New York), John Noseworthy, Paul O’Connor, Alan Thompson, John Whitaker (deceased), Jerry Wolinsky. Data Safety Monitoring Board—Henry McFarland, chair, Jack Antel, Gary Cutter, Luanne Metz, Stephen Reingold. Teva Neuroscience and Teva Pharmaceuticals, Ltd.— Lillian Pardo, Rob Elfont, Rivka Kreitman, Shaul Kadosh, Galia Shifroni, Irit Pinchasi, Yafit Stark, David Ladkani. MRI-Analysis Center, Jerry Wolinsky, Ponnada Narayana, Irina Vainrub, Lucie Lambert, Rimma Boykin, Saria Momin, Fengwei Zhong.
References [1] Charcot J-M. Histologie de la sclerose en plaques, vol. 41. Paris: Gazette Hopital; 1868. p. 554 – 8. [2] McAlpine D. Multiple sclerosis: a review. Br Med J 1973;2:292 – 5. [3] Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46:907 – 11. [4] Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898 – 904. [5] Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:1576 – 82. [6] Stevenson VL, Miller DH, Rovaris M, et al. Primary and transitional progressive MS: a clinical and MRI cross-sectional study. Neurology 1999;52:839 – 45. [7] Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227 – 31. [8] Kappos L, for the European Study Group on interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352:1491 – 7. [9] Francis G, Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001;56:1496 – 504.
151
[10] Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2001;47:707 – 17. [11] Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 1994;117:759 – 65. [12] Wolinsky JS, Narayana PA, He R. Overview of treatment trials: early baseline clinical and MRI data of the PROMiSe trial. In: Filippi M, Comi G, editors. Primary progressive multiple sclerosis. Milano: Springer-Verlag Italia; 2002. p. 47 – 61. [13] Schumacher GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F. 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 Med 1965;122: 552 – 68. [14] Thompson AJ, Polman CH, Miller DH, et al. Primary progressive multiple sclerosis. Brain 1997;120:1085 – 96. [15] McDonnell GV, Hawkins SA. Application of the Poser criteria in primary progressive multiple sclerosis. Ann Neurol 1997;42:982 – 3. [16] Thompson AJ, Montalban X, Barkhof F, et al. Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Ann Neurol 2000;47:831 – 5. [17] McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121 – 7. [18] McDonnell GV, Hawkins SA. Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK. J Neurol Neurosurg Psychiatry 1998;64:451 – 4. [19] Cottrell DA, Kremenchutzky M, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study: 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain 1999;122:625 – 39. [20] Bashir K, Whitaker JN. Clinical and laboratory features of primary progressive and secondary progressive MS. Neurology 1999;53: 765 – 71. [21] Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120:2059 – 69. [22] Thorpe JW, Kidd D, Moseley IF, et al. Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI. Brain 1996;119: 709 – 14. [23] Filippi M, Campi A, Martinelli V, et al. Comparison of triple dose versus standard dose gadolinium – DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 1995;59:540 – 4. [24] Filippi M, Rovaris M, Gasperini C, et al. A preliminary study comparing the sensitivity of serial monthly enhanced MRI after standard and triple dose gadolinium – DTPA for monitoring disease activity in primary progressive multiple sclerosis. J Neuroimaging 1998;8: 88 – 93. [25] Rovaris M, Comi G, Filippi M. Magnetization transfer and diffusion tensor magnetic resonance imaging. In: Filippi M, Comi G, editors. Primary progressive multiple sclerosis. Milano: Springer-Verlag Italia; 2002. p. 77 – 88. [26] Caramanos Z, Santos AC, Francis SJ, Narayanan S, Pelletier D, Arnold DL. Proton magnetic resonance spectroscopy. In: Filippi M, Comi G, editors. Primary progressive multiple sclerosis. Milano: Springer-Verlag Italia; 2002. p. 89 – 112. [27] Andersson M, Alvarez-Cermeno J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 1994;57:897 – 902. [28] Andersson PB, Waubant E, Gee L, Goodkin DE. Multiple sclerosis that is progressive from the time of onset: clinical characteristics and progression of disability. Arch Neurol 1999;56:1138 – 42. [29] Cottrell DA, Kremenchutzky M, Rice GP, Hader W, Baskerville J, Ebers GC. The natural history of multiple sclerosis: a geographically based study: 6. Applications to planning and interpretation of clinical
152
J.S. Wolinsky / Journal of the Neurological Sciences 206 (2003) 145–152
therapeutic trials in primary progressive multiple sclerosis. Brain 1999;122:641 – 7. [30] Pirttila T, Nurmikko T. CSF oligoclonal bands, MRI, and the diagnosis of multiple sclerosis. Acta Neurol Scand 1995;92:468 – 71. [31] Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients
with suspected multiple sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1720 – 5. [32] Kurtzke JF. Clinical definition for multiple sclerosis treatment trials. Ann Neurol 1994;36:S73 – 9.