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    • MULTIPLE SCLEROSIS: A DOMAIN FOR THE APPLICATION OF ADVANCED AI TECHNIQUES Mauro Gaspari*; Lino P. Marchello†; Cinzia Scandellari†; Sergio Stecchi† * Dipartimento di Scienze Dell'Informazione, Università di Bologna, Italy †Centro Sclerosi Multipla, Villa Mazzacorati, A.U.S.L.Bologna, Italy gaspari@cs.unibo.it; centrosm@iol.it Abstract Multiple Sclerosis is still an unsolved disease and although several advances have been achieved in the last few years some problems such as the ethiology and the prognostic criteria are unknown or still have not a satisfying solution. In this paper we give a brief introduction to this disease and we underlying the complexity of its domain and the knowledge involved. Finally we present a study on a phase of this disease that could be approached ex- ploiting Artificial Intelligence techniques. 1 Introduction formation retrieval from computerised patients records in Multiple Sclerosis, for instance ontologies (Falas- Multiple sclerosis (MS) is an inflammatory disease coni and Stefanelli, 1994), data warehousing (Barquin characterised by demyelinization of the central nervous and. Edelstein, 1996), and data mining (Agrawal, system (CNS) (Storch and Lassmann, 1997). It is an 1994). immunological disease, and even if its pathogenetic mechanism is well known, some problems such as the In this paper we give a brief introduction to Multiple ethiology and the prognostic criteria are unknown or Sclerosis and we underline the complexity of its do- still have not a satisfying solution (Cook, 1996). main and the knowledge involved. Finally we present Although several advances have been achieved in the a study on a phase of this disease that could be ap- last few years, predicting with accuracy how and when proached exploiting Artificial Intelligence techniques. the problem of multiple sclerosis will eventually be solved is not easy (Compston, 1994). The efforts of contemporary research are oriented to 2 Multiple Sclerosis develop complex strategies based on ideas originating from immunology, neurobiology, brain imaging, and Histopathology of MS is defined by a chronic inflam- animal modelling. The advent of these increasingly mation and demyelination. Ongoing disease activity is complex strategies makes clinical trials difficult to con- due to an active inflammatory process, mainly mediat- trol, in fact, numerical powerful studies on uncertain ed by T lymphocytes and macrophages, and is associat- markers are needed involving multicenter collaboration ed with blood-barrier damage. B lymphocytes and for reaching a critical mass of patients. plasma cells are present especially in the lesions that occur during the late chronic stage of the disease. The MS research community has recognised these Although all plaques are characterized by demyelina- problems developing databases to store computerised tion, the patterns of oligodendroglia destruction and of patient records stored in a standard form: EDMUS damage to other tissue elements, such as axons and as- (Confavreux, 1994) and MS-COSTAR (Paty et al., trocytes, are variable in different cases. Oligodendro- 1994). Unfortunately, the uncertainty, the incomplete- cytes are less affected by plaques that develop during ness, and the temporal nature of some of the observed the first bouts of the disease than by those plaques aris- data make ordinary database query techniques and ing after several years of disease duration. tools not completely adequate to support an automatic interpretation of future clinical trials. In our opinion more complex techniques are needed to manage in- 2.1 Diagnosis
    • For MS the best set of diagnostic criteria is still that of perivenular demyelination illness without evi- the Schumacher Panel (Schumacher et al., 1968). This dence of infection of the CNS. essentially spells out MS as a white matter disease with - In human immunodeficiency virus-en- evidence of continued or repeated clinical activity over cephalopathy and myelopathy virus is present time. These criteria have been amended by the Poser in macrophages and microglia and the myelin committee (1983) to include laboratory evidence, the abnormalities apparently are caused by solu- paraclinical evoked responses, and the cerebrospinal ble factors such as viral proteins, cytokines, or fluid (CSF). neurotoxins. However the MS diagnosis is essentially a clinical pro- These findings may have implications on how, when cess based on spatial and temporal dissemination of and were to seek viruses in MS. symptoms and lesions. 2.4 Classification of MS Forms 2.2 Genetics McAlpine and associates (1998) have depicted the vari- There is evidence to support the view that MS is a ation in the natural history of MS in his textbook. Six- complex trait determined by both genetic and environ- ty percent of MS patients have attacks, particularly at mental factors. The genetic component is reflected in the beginning of their illness, with quite good recovery the higher rate of concordance in monozygotic (MZ) vs and minimal deficit. Ultimately MS culminates in a dizygotic (DZ) twins and in familial recurrence risk progressive course with relatively fewer exacerbations, data. yet gradually worsening disability. There is no evidence that any genetic marker, acting Fifteen percent of MS patients have progressive MS alone or in combination, protect individual from devel- from onset, with no or relatively few attacks, but devel- opment of the disease. But with the more recent com- op gradually worsening disability. Finally, there is an- pletion of full genome screens, new regions of potential other group that constitutes 15 or 20% of all MS pa- genetic interest with respect to multiple sclerosis sus- tients, who have benign MS, having relatively few at- ceptibility have emerged. tacks early on, without developing any or very little Nevertheless, there remains a substantial amount of in- permanent disability. formation gathered from a variety of epidemiological In summary, the course of the disease can be character- and genetic sources which provides evidence for the ised the following forms (Lublin and Reingold, 1996): contribution of genetic factors in determining suscepti- - benign forms, with few attacks and no disabil- bility to multiple sclerosis; what remains uncertain is ity; the number of genes involved and their location within the genome, the relative importance of genes and the - primary-progressive (PP) with an highly dis- environment, the mechanisms of their interactions and ability degree; the issue of heterogeneity. - relapsing-remitting (RR) which is character- ised by exacerbations which normally remits and sometimes evolves in secondary pro- 2.3 Virology of demyelinating disease gressive forms. - secondary progressive (SP) having a progres- Infectious agents have been postulated as causes of sive course with relatively fewer exacerba- multiple sclerosis for over a century. tions, yet gradually worsening disability. The possible role of a virus or viruses is supported by data that a childhood exsposure is involved and “viral” infections may precipitate exacerbations of disease, ex- perimental infections in animals and natural infections 3 The Data in humans can cause diseases with long incubation pe- riods, remitting and relapsing courses, and demyelina- The principal descriptors of the natural history of MS tion and patients with MS have abnormal immune re- are attacks (frequency, severity and recovery), remis- sponses to viruses. sions (frequency and duration), temporal course (re- The pathogenesis of three human demyelinating dis- lapsing and remitting vs progressive) and disability sta- eases of known viral etiology is discussed: tus. - In progressive multifocal leukoencephalopa- - An attack (or relapse) require the appearance thy, a papovavirus selectively infects oligo- of a new symptom or worsering of an old dendrocytes and causes focal areas of de- symptom over at least 24 h that could be at- myelination. tributed to MS activity and is preceded by sta- - In postmeasles encephalomyelitis, the virus is bility or improvement for at least 30 days (Shumacher et al., 1968). lymphotrophic and disrupts immune regula- tion than can result in an autoimmune
    • - A remissions is a regression of most of the Evoked potentials are electrical waveforms elicited by symptoms of the associated attack. A remis- and temporally related to a stimulus, most commonly sion can be complete, mostly in the early stage an electrical or magnetic stimulus delivered to a sens- of the disease, or incomplete with permanent ory receptor or nerve (Chiappa, 1990). These tech- deficits. niques allow the specialist to verify the assessment of - The temporal course depends on the form of the entire length of the sensory or motor pathways. SM (PP, RR, SP). Evoked potentials are distinguishable in: - The disability status is the global deficit - visual evoked potential; caused by the disease. - brain stem auditory evoked potential; The instrumental tools for the diagnosis and the follow - somatosensory evoked potential; up of the MS are: Magnetic Resonance Imaging (MRI), - motor evoked potential. evoked potentials, liquor examination. For each of these evoked potential there are two signi- ficant parameters: latency and amplitude of the re- sponse. Latency is misured in milliseconds and amp- 3.1 Disability Status Scale litude in microV; it can be represented by a floating point number. One measure of neurologic status is the Disability Sta- Abnormal evoked potentials may have a role in predict- tus Scale (DSS) (Kurtzke, 1955), which grades clinical ing both the diagnosis of MS and clinical deterioration. impairment due to MS on a 0 (normal) to 10 (death due to MS) basis. The expanded DSS (EDSS) (Kurtzke, 3.4 Liquor examination 1983) subdivides each step 1 through 9 into two. Type and severity of neurological impairment is defined by Cerebrospinal fluid analysis in MS checks for the pres- graded involvement in the following eight functional ence of particular proteins in the fluid. The most spe- systems (FS): pyramidal, cerebellar, brainstem, senso- cific abnormality is the oligoclonal banding i.e. the ry, bowel and bladder, visual, cerebral and other. presence of two or more distinct IgG bands in the gamma region of the electrophoresis (McApline 1998). 3.2 Magnetic Resonance Imaging This pattern usually remain the same over time and if it is positive in 85%-95% of clinical defined MS and pos- Magnetic Resonance Imaging (MRI) is increasingly itive in 40%-50% of suspected MS. The number of being used as a measure of pathological disease activi- bands can be represented as an integer. ty in monitoring the efficacy of potential new treat- ments for MS. A major advantage of MRI over clinical 3.5 Additional Problems monitoring is that it detects a large amount of sub-clini- cal disease activity. There several problems which do not depend from The two main approaches to MRI are detecting active computer science or artificial intelligence aspects that lesions and measuring total lesion load. In RR and SP make the availability of these data more difficult. MS gadolinium enhancement increases the number of detectable active lesions and also probably correlates 3.5.1 Old Patient Records with pathological activity. An important limitation of MRI monitoring is that con- Since patient records are the result of several exams ventional brain MRI abnormalities often show little or starting from the time of the diagnosis until now, it no relationship with clinical disability. may happen that they do not contain all the significant One explanation of this fact may be the pathological data. Typically new medical analysis and criteria heterogeneity of lesions that all look the same on a which often are more significant could not be included conventional image. Other MR techniques are needed in old patient records. that specifically identify the pathological features most likely to result in disability, namely demyelination and 3.5.2 Geographical Distribution of Patient Records axonal loss. Magnetization transfer imaging and proton MR spec- To realise more significant experiments and trails it is troscopy are two techniques that show promise in this necessary to consider data which belongs from differ- regard. ent laboratories in the same country, and also data from Significant data are the number of lesions, and the fact different countries. that these lesions are active or not. It is difficult to Thus a distributed solution is necessary which allows evaluate the influence of the place where the lesions the specialist to integrate data which belong from sev- appear. eral laboratories. This implies that issues such has dis- tribution, interoperability and integration of multi-lin- 3.3 Evoked Potentials gual records must also be addressed to obtain more in- teresting results.
    • 4 Analysis of Disease Progression DEFINITION - marker A marker is a predicate P such that the following rules A promising research direction concerns the analysis of hold: the disease progression with the aim of individuate pro- ∀X. Patient(X) ∧ RRtoSP(X) → P gression markers. In particular, a transitional phase ∀X. Patient(X) ∧ RR(X) → ¬P has been observed for some of the patients affected by a RR form which gradually (in one or two years) The goal of an automatic analysis is to verify if such a evolves to a SP form (Stecchi et al., 1998). An early predicate exists, note that P is not necessarily an atomic individuation of this transitional phase is essential for predicate it can be the combination of more observa- an adequate treatment of the disease which in many tions representing parameters or examinations, and also cases can prevent the evolution of the disease into it can include a degree of uncertainty. highly disabling forms. A good progression marker al- lows the specialist to early discover the occurrence of this transitional phase and to plan for an adequate treat- 5 Related Work ment. As far as we know there are no attempts to exploit AI Although, in the last few years, this transitional phase technology in Multiple Sclerosis which have been de- has been recognised in the literature, it is still not clear scribed in the literature. Among the other approaches it if an adequate progression marker exists. Candidate is worth to remember two information systems: ED- markers are: MUS (Confavreux 1992,1994) and MS-COSTAR 1. Axonal damage. (Paty et al. 1994). These two database have been de- 2. External events, for instance a virus. signed to store clinical information concerning multiple 3. Number of relapses/year. scerosis EDMUS is the result of an European effort, 4. Progression index (EDSS/Duration while MS-COSTAR has been used mainly in USA and of the disease). Canada. See (Confavreux and Paty, 1995) for an ex- tensive comparison between EDMUS and MS-COST- In order to individuate other possible markers and to AR. Other computer based approaches only concen- verify that a given marker is significant, an analysis of trate on particular aspects of the disease, for instance clinical, instrumental and laboratory data for patients the elaboration of RMI images (Grimaud et al., 1996; affected by multiple sclerosis is necessary. Note that Molyneux et al., 1998). this data are the result of a set of observations on the patients affected by multiple sclerosis repeated over time; they represent the history of the evolution (natur- al history) of the disease for all the patients. This con- 6 Conclusion sists of a large set of heterogeneous uncertain data We strongly believe that a AI approach to multiple which must be correlated in order to confirm the can- sclerosis can be useful to medical specialist dealing didate markers. It is very difficult for the specialist to with MS in several ways. First a complete knowledge achieve this goal without the support of an automatic acquisition procedure can give an order to the medical tool, and artificial intelligence techniques seems to be knowledge on this disease which is wide, hill-struc- the more adequate to deal with this complexity. tured and characterised by a strong degree of uncer- tainty. Second several subtasks in the complex domain In the following we provide a more precise character- of this disease could benefit of a set of support mechan- isation of the concept of marker to give an idea of the isms to automatically verify some of the specialists hy- problem which must be addressed in term of AI. Note pothesis on large, possibly distributed, amount of data. that the following definitions do not intend to be com- Third, more ambitiously, discovering new results con- plete and usable, a long and complex knowledge ac- cerning the diagnosis and treatment of the disease. quisition phase is needed to reach this status. We assume the following predicates: Patient(X): X is a patient. Acknowledgements RR(X): X is affected by a relapsing-remitting form. We would like two thank Simon Colton for his valu- RRtoSP(X): X is affected by a secondary-pro- able comments on a draft of this paper. gressive form the previously was a relapsing-remitting. References Given this set of predicates a marker can be defined more formally as follows:
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