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THE RADIOLOGICALLY ISOLATED SYNDROME OF DEMYELINATION Is it Early Multiple Sclerosis (MS)? What to do W hen Confronted by a Patient with Radiologically Isolated Syndrome (RIS)? To Treat a nd/or to Wait?.

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  1. THE RADIOLOGICALLY ISOLATED SYNDROME OF DEMYELINATIONIs it Early Multiple Sclerosis(MS)? What to do When Confronted by a Patient with Radiologically Isolated Syndrome(RIS)? To Treat and/or to Wait? Bartko D.1 2 5 , Rohalova J.2 5, Fabcin J.3 5, Kubovicova K.2 5, Ščerbíkova M.4 5, Bielikova E.4 5, Latta V.6 Institute of Medical Sciences, Neurosciences and Military Health1, Dept. of Neurology2, MRI Center3, Dept. of Ophtalmology4, Central Military University Hosptital5, Ružomberok, Dept. of MRI6, Presov, Slovak Republic Suported by EU/gov. grants ITMS2202200099,ITMS 2202200153, INTERREG IIIA 14140200032, APVV0586-06

  2. IntroductionDefinition Radiologically isolated syndrome of demyelination (RIS Ocuda et al.2009, they introduced the term) has been defined as the unanticipated • MRI findings of white matter (WM) lesions suggestive of demyelinating disease • in subjects with a normal neurologic findings and • no medical history consistent with multiple sclerosis (MS).

  3. Although WM lesions may be detected in asymptomatic subjects (De Stefano et al.2011), it is still unclear whether RIS should be considered • a subclinical MS or • an independent entity or • it is MRI finding without any association with MS

  4. There are only few studies, demonstrating the occurrence of a clinical deterioration in subjects with RIS correlated to the presence of inflammatory markers (Comi 2009, Trojano et al 2009, Lebrun et al.2008) They found approximately one-third of subjects with RIS associated later with a clinically isolated syndrome (CIS) particularly those with asymptomatic cervical spinal lesions(Okuda et al.2011)

  5. Aim • to present a case report and to discuss questions: • is the RIS realy MS presenting with RIS? and/or 3. it is not MS,it is ONLY RIS ofdemyelination? 4. If it is RIS, should we treat the patient according to MS guide-line despite no clinical neurologic symptoms exist? or 5. Should we wait? 6. What shoud we tell the patient?

  6. Case ReportHistory In 2003 18 yrs old girl, uncertain, very mild sighting problems, occasionally. Ophtalmologist´s (University Professor) diagnosis: • uveitis • Neurologic examination normal

  7. * Brain MRI T1weighted, T2 weighted, Flair, performed at local Faculty Hospital showed 5 small white matter abnormalities in supraventricular and periventricular region interpreted by radiologist (after Gd) as demyelinating MS. Spinal cord MRI not performed. CONCLUSION : MRI brain lasions are typical for MS Patient was unsatisfied with this conclusion

  8. In 2003 she was admitted to another Univesity Dept. of Neurology. Neurological findings: • normal, CSF, no oligoclonal bounds. • VEPs, SEPs, ABEPs normal findings, • Boreliosis in CSF negat. • MRI (from 2003): interpreted as no typical for MS   Diagnosis: Neurasthenia, MS not confirmed.

  9. In 2011 During period of 8 yrs patient • without clinical symtoms, • no relapses, • no remissions, • no treated.

  10. Neurological status normal, • CSF: oligoclonal bounds: positive. • VEPs, SEPs, ABEPs normal findings, • Boreliosis in CSF negat. • inflammation markers: norm

  11. new MRI: 16  brain lesions interpreted again as demyelinating. Patient is unsatisfied again, a little anxious (of course, with such unclear diagnosis). She was admitted at Central Military University Hospital

  12. Brain MRI Brain MRIT2 weigted and Flair. 16 brain MRI lesions interpreted as demyelinating. After Gd no symptoms of inflammation

  13. MRI of Cervical Spinal Cord MRI: one lesion (hyperintensity signal) in C2/C3 of spinal cord,23×5 mm, without expansion,without perifocal edem,without activity after Gd. It was interpreted as demyelinating lesion

  14. Final Diagnosis in Central Military University Hospital: Multiple Sclerosis with recommendation of DMT therapy despite the patient showed • no clinical symtoms of MS, • no relapses, • no remissions, • no oligoclonal bands • normal VEPs,SEPs,ABEPs DMT therapy was not realized

  15. March 2012 Patient want to be again examined by neurologist THEREFORE readmission of patient to hospital (RK) 1. Neurological findings: • 9 years no pathological neurologic findings, • no history of attacks, • no history of remissions, • mild problem with visus • no oligoclonal bands in CSF • normal VEPs, SEPs, ABEPs • subjectivelly she is filling healthy • she is working for full day-time • At present: normal neurological status

  16. 2. Diagnostic programme a) New Brain MRI and new cervical spinal cord MRI b) Optical Coherence Tomography (OCT) c) Neurpsychological Assessment and d) ADL and QoL Scales Some studies confirmed that • evaluation of changes in morphology and function of optical nerve by mean of highly sophisticated methods ( RNFLT, OCT and others) over time was likely one of the best approach to monitor early disease onset and progression in MS

  17. 2. New Brain MRI ( March 26. 2012) FLAIR tra Rbk FLAIR Rbk Brain MRIT2 weigted and Flair. 16 brain MRI lesions interpreted as demyelinating. After Gd no symptoms of activity, no expansion, no perifocal edema. Conclusions, the same findings comparing to MRI( 2011), After Gd: no symptoms of infammation, no cortical atrophy

  18. 3. New Cervical Spinal Cord MRI MRI of Cervical part of spinal cord. MRI :one lesion (hyperintense signal) in C2/C3, 23 × 5 mm, without expansion, without perifocal edema and without activity after Gd Conclusions: the same findings comparing to 2011

  19. Do we know Diagnostic Criteria for RIS ? Comparison of these Criteria with the results of our patient

  20. Diagnostic criteria for the RIS • MRI criteria: • Ovoid, well-circumscribed. and homogeneous foci with or without involvement of the corpus callosum • T2 hyperintensities measuring >3 mm and fulfilling Barkhoft criteria (at least 3 out of 4) for dissemination in space and time 3.CNS white matter anomalies not consistent with a vascular pattern

  21. No history of remitting clinical symptoms consistent with neurologic dysfunction • The MRI anomalies do not correlate • with impairments in social, • in occupational, or • generalized areas of functioning

  22. The MRI anomalies are not due to • the direct physiologic effects of substances (recreational drug abuse, toxic exposure) • or a medical conditions • Exclusion of individuals • with MRI phenotypes suggestive of leukoaraiosis • or extensive white matter pathology lacking involvement of the corpus callosum Our patient fulfils all these criteria BUT

  23. BUT There exist another possibility for explaining our main question: • Optical Coherence Tomography • Neurpsychological Assessment and • ADL and QoL Scales

  24. 4. Optical Coherence Tomography OCT (healthy subject OCT MS patient

  25. 5. Neuropsychological Assessment • London Handicap Scale: 6 points MS has no infuence on social life of patient • Fatigue Severity Scale 28/63 points (mild signs of fatigue) • Montreal Cognitive Assesment (MCCA) 28/30 points (normal findings, without cognitive impairment) • Intrelect Potential Test (IPT) 20/29 points (normal findings, time perception takes as a stress) • Wechsler Memory Scale MQ=101, mild deficit in logical memory

  26. Rey Complex Figure • Disjunctive Reaction Time (DRT) 56/60 pointsperfect working tempo • Hospital Anxiety and Depression Scale Anxiety Scale ´10 points, Depression Scale = 2 points • Beck Depression Inventory 5/63 points, normal • Eisenck Personality Inventory Extravesion Scale=10/24, Neurotiscism Scale =19/24,

  27. Sensefulness Life Scale 76/90 point • MSQOL-54 Škala kvality života 79/100 • Physical Health Composit Score 82 • Mental health Composite Score 76 • ADL for MS 6 points (independant during activity of daily living Summarising: all neuropsychological parameters showed normal findings

  28. COMMENT- DISCUSSION In 2009, Okuda and colleagues" introduced the term “radiologically isolated syndrome” (RIS) to describe patients who have • brain MRI abnormalities • suggestive of MS but c) who have no signs or symptoms of the disease. d) without clinical evidence of MS that ful- filled at least 3 of 4 Barkhof criteria.

  29. Table. 1. Barkhof–Tintore criteria for anatomic dissemination by brain MRI (greatest accuracy in predicting clinically definite MS achieved with ≥3positive parameters) --------------------------------------------------------------------------------------------- • At leastone or more Gdenhancing lesionsor nine T2 hyperintense lesionsif there is no Gd enhancing lesion • At leastthree or moreperiventricular lesions • At leastone or moreinfratentorial lesions • At leastone or morejuxtacortical lesions • one ormore spinal cord lesions(revisited July 2011)

  30. Two years later (2011) the same authors described a retrospective study of 71 subjects with RIS who had cervical MRI scans performed. • 35%of the subjects with RIS had T2 hyperintensitiesin the cervical cord, and • 84%of these subsequently developed a CIS.

  31. This study suggests that • pts who have RIS and • spinal cord T2 hyperintensities • may be at high risk of developing MS while • those without spinal cord abnormalitiesmay have a very low risk. • This is an important re-definition of the concept of RIS as a risk factor for developing MS and may prove to be important for decision for an early treatment of MS(Tinton 2006) However, a large prospective study is needed to delineate accurately the natural history of RIS

  32. This contribution revisited “the term RIS” BUT despite of this, the decision is not easy. How are the possibilities for right decision?

  33. There are somekey points • to findnew parameterswhich can contribute to decision • to findnew clinical or radiological findingswhich can bring new dimension for more precise diagnosis of MS • to findnew approachwhich can increase the accuracy of MS diagnosis

  34. The first key point. It is well known that the basic characteristic of all diagnostic criteria for MS require the demonstration of disease dissemination in space and time.

  35. i.e. the confirmation of two or more clinical attacks, separated in time, which involve at least two separated areas of the CNS (space). Moreover, CNS is not only brain but also spinal cord

  36. Therefore we have performed MRI of the cervical spinal cord and we have confirmed hyperintensities in cervical spinal cord. This means • this parameter can contribute to the decision BUT • it doesn´t mean that it has to confirmed the possibility of subsequent MS. • This is very important to know

  37. Why would spinal cord lesions in RIS have such a strong influence on the risk of developing symptomatic demyelinating disease?

  38. Because demyelinating brain lesion can occurin a variety of conditions • migraine, • age related changes, • asymptomatic cerebrovascular disease, • boreliosis, • others (not associated with age), THEREFORE an assumption that the brain abnormalities in RIS represent areas of demyelination associated with MS is not warranted. WHY?

  39. The Barckroft criteria were developed as a means of predicting which patients with a first clinical demyelinating event wereat high riskof developing MS and not to differentiate MS from other causes of white matter abnormalities.

  40. OUR OPINION RIS isheterogenic syndrome (not simply presymptomatic MS) consisting of pts • with MRI demyelinatig BRAIN lesions !!! • without clinical neurologic correlation • without significant influence • on functional health of subject AND/OR

  41. with MRI demyelinatig BRAIN and also SPINAL CORD lesions!!! • and therefore with possibility to development of typical MRIsymptoms of MS BUT • without clinical neurologic correlation therefore, in this group of pts it not possible touse Barkroft criteria

  42. c) All diagnostic criteria for MS, including the most recent McDonald criteria, require at least one or two clinical events consistent with MS, i.e, disseminated in TIME and SPACE

  43. The second key point is the time of the starting inflammation or demyelinating processes. We should find the marker or clinical sign of the early stage of the disease.

  44. There are two possibilities • assessment of neuropsychological profil of pts wit suspected MS. Cognitive impairment could be the first symptoms of the pathological changes in the brain associated with MS • assessment of Optical Coherence Tomography(OCT). Some studies have employed OCT to evaluate changes in optic nerv associated with multiple sclerosis (MS) • we have used both these possibilities. Why?

  45. Approximately 50 % of patients with MS have disease-related cognitive deficits. These deficits significantly interfere with everyday life activities at home and at work and erode quality of life (QoL) Amato et al (2012) in very well designed publicationreported cognitive impairment of the same profile as that of RRMS in 27.6% of subjects with RIS.

  46. On quantitative MRI they found comparable levels of lesion loads and brain atrophy • in subjects with RIS and • well-established RRMS. • in subjects with RIS, high T1 lesion volume (σ = 0.526, p = 0.025) and low cortical volume (σ = -0.481, p = 0.043) They were associated with worse cognitive performance

  47. Figure. MRI data expressed in cm3 in RIS, RRMS, and healthycontrols (HCs) NBV = normalized brain volume; NCV = normalized cortical volume; T1/LV = T1 lesion volume; T2/LV = T2 lesion volume (Amato et al. 2012)

  48. We have performed in our patient the comprehensive assessment of • psychological profil, • ADL and • QoL in our patient. • This consists of 15 scales. No significant changes in all followed parameters were found.

  49. It is well known that MS can result in a variety of ophthalmic disorders, including optic neuritis (ON). MRI is not sufficient modality for the detection of • active inflammation, • chronic post-attack neuro-degeneration and • the number and volume of clinically silent lesions, • the correlation between lesion quantification by conventional MRI and morphological and functional disabilities of optic nerve is relatively poor.

  50. There exist several new, highly sophisticated techniques(n=5) for quantitative evaluation of optic nerve: • peri-papillary retinal nerve fibre layer thickness (RNFLT), • macular volume changes with a variety of techniques, such as red-free fundus photography, • scanning laser polarimetry, • Heidelberg retinal tomography or • optical coherence tomography (OCT, Sic et al. 2010)

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