Accuracy in Space and Time: Diagnosing Multiple Sclerosis © 2012 Genzyme Corporation, a Sanofi company. your gateway to MS knowledge. All rightstoreserved. MS.US.PO876.1012 your gateway to MS knowledge.Brought to you by www.msatrium.com, Brought you by www.msatrium.com, Powered by 1 Epidemiology Multiple Sclerosis • Multiple sclerosis is a chronic, unpredictable disease of the central nervous system (the brain, optic nerves, and spinal cord) • Affects more than 400,000 in the US and 2.1 million worldwide • More than twice as common in women as in men • Most people are diagnosed between the ages of 20 and 50, although individuals as young as 2 and as old as 75 have developed it Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 2 Typical symptoms • Symptoms of MS are unpredictable and can vary from person to person, and from time to time in the same person • Symptoms may include partial or complete paralysis; difficulties with vision, cognition, speech and elimination; fatigue; sensory changes; difficulty walking; slurred speech; tremors; stiffness; bladder dysfunction • Sometimes major symptoms disappear completely and a patient may regain lost function • In severe MS, people have symptoms on a permanent basis Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 3 Clinical disease starts with a clinically isolated syndrome Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 4 Making the diagnosis of MS can be challenging Difficult diagnostic groups • Monosymptomatic presentation • Insidious neurologic progression (primary progressive MS) • Explosive onset • Vague symptoms Delays in accurate diagnosis could mean loss of crucial time in a disease with a limited treatment window. Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 5 What’s the first step to effective treatment? Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 6 Diagnostic principles 1. Dissemination in space (DIS) 2. Dissemination in time (DIT) 3. Rule out mimics Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 7 Differential diagnosis Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 8 Red flags for the misdiagnosis of MS History and physical • Normal neurologic examination • Abnormality in a single location (no DIS) • Progressive from onset (no DIT) • Onset in childhood or over age 50 • Systemic disease present • Prominent family history (consider genetic disease) • Gray matter symptoms: dementia, seizures, aphasia • Peripheral symptoms: neuropathy, fasciculations • Acute hemiparesis • Lack of typical symptoms (no optic neuritis, bladder problems, Lhermitte sign, etc) • Prolonged benign course (eg, diagnosis made years ago with few findings now) Tests • Normal or atypical MRI • Normal cerebrospinal fluid (CSF) • Abnormal blood tests (though many are false positives) Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 9 MRI mimics: Which is which? Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 10 MRI alone is NOT specific for MS… Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 11 Evolution of diagnostic criteria: Early history Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 12 1965—Schumacher criteria Clinically definite multiple sclerosis 1. Objective signs of dysfunction of the central nervous system; symptoms not acceptable 2. Evidence of damage to 2 or more sites 3. Predominantly damage to the white matter 4a. Two or more episodes of at least 24 hours separated by at least 6 months 4b. Slow or stepwise progression over 6 months 5. Age of onset 10-50 years 6. Diagnosis by a neurologist; signs and symptoms cannot be explained by other disease No pathognomonic laboratory test for MS useful in selecting cases has been discovered. Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 13 1982—Poser criteria Note: Paraclinical evidence defined as evoked potentials, CT or MRI; at least two oligoclonal bands, none in serum. Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 14 McDonald criteria *May include findings on neurological examination, visual evoked response in patients reporting prior visual disturbance, or MRI consistent with demyelination in the implicated area of the CNS. †Can include historical events with symptoms and evolution characteristics of a prior inflammatory demyelinating event. Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 15 2010 McDonald MRI criteria: Definition of attack • A patient-reported or objectively observed event, current or historical, with duration of at least 24 hours in the absence of fever or infection • It should be supported by findings on neurological examination • Reports of paroxysmal symptoms (historical or current) should consist of multiple episodes occurring over not less than 24 hours • Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by – Findings on neurological examination – Visual evoked potential response in patients reporting prior visual disturbance – MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurological symptoms Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 16 2010 McDonald MRI criteria: Demonstration of DIS Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 17 2010 McDonald MRI criteria: Demonstration of DIT Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 18 2010 McDonald criteria: PPMS Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 19 CSF no longer part of McDonald criteria for MS • According to the 2001 and 2005 McDonald criteria: – A positive CSF finding could be used to reduce the MRI requirements for reaching DIS criteria (requiring only 2 or more MRI-detected lesions consistent with MS if the CSF was positive) • In 2010: – Because imaging criteria for DIS and DIT were simplified, the panel believed further liberalizing MRI requirements in CSF-positive patients was not appropriate, and CSF was removed from the criteria for MS – The panel reaffirmed that positive CSF findings can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict CDMS Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 20 MRI DIT Review of McDonald updates from 2001 to 2011 Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 21 McDonald criteria: Accuracy for predicting future CDMS 1 year after patients presented with CIS, McDonald criteria (2001) were applied: • Sensitivity: 83% • Specificity: 83% • Positive predictive value: 75% • Negative predictive value: 89% Many more patients were identified by McDonald (2001) vs Poser • Percentage of patients diagnosed with MS 1 year after initially presenting with CIS was 48% using McDonald criteria vs 20% using Poser criteria Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 22 Prognosis remains a major challenge The most reliable prognostic factors are: • Frequency and characteristics of relapses early in disease • Occurrence of a progressive phase Characteristics of disease onset associated with better prognosis • Monosymptomatic • Optic neuritis • Complete recovery • Long time interval between first and second relapse • Lower number of relapses in initial years Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 23 Risk factors associated with future disability • Age at onset (≤40 vs >40 years) • Symptoms at onset (isolated sensory/cranial nerve vs motor or motor + sensory) • MRI status (Negative vs suspicious vs suggestive) • Interval between 1st and 2nd attack (≥2.5 years vs <2.5 years) • Attack frequency in 1st 2 years of study (≤2 vs >2) • Completeness of recovery from initial attacks (Good vs poor) Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 24 Future directions—MRI techniques Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 25 Future directions—Potential biomarkers • Genomics – Human leukocyte antigen (HLA) • Immune mediators – Cytokines – Chemokines – Activation markers – Adhesion molecules • Pathogens – Epstein-Barr – Human herpesvirus 6 – MS-associated retrovirus Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 26 References Dalton CM, Brex PA, Miszkiel KA, et al. Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis. Ann Neurol. 2002;52:47-53. De Stefano N, Battaglini M, Stromillo ML, et al. Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis. Brain. 2006;129:2008-2016. Filippi M, Agosta F. Imaging biomarkers in multiple sclerosis. J Mag Res Imag. 2010;31:770-778. Leary SM, Porter B, Thompson AJ. Multiple sclerosis: diagnosis and the management of acute relapses. Postgrad Med J. 2005;81:302-308. 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;50:121-127. National Multiple Sclerosis Society. Just the facts. NMMS Web site. http://www.nationalmssociety.org/about-multiplesclerosis/index.aspx. Accessed June 5, 2011. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Ann Neurol. 2011;69:292-302. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol. 2005;58:840-846. Poser CM, Brinar VV. Diagnostic criteria for multiple sclerosis: an historical review. Clin Neurol Neurosurg. 2004;106:147-158. Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 27 References Rolak LA, Fleming JO. The differential diagnosis of multiple sclerosis. The Neurologist. 2007;13:57-72. Scott TF, Schramke CJ, Novero J, Chieffe C. Short-term prognosis in early relapsing-remitting multiple sclerosis. Neurology. 2000;55:689-693. Shaw C, Chapman C, Butzkueven H. How to diagnose multiple sclerosis and what are the pitfalls. Intern Med J. 2009;39:792-799. Srinivasan R, Sailasuta N, Hurd R, et al. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain. 2005;128:1016-1025. Traboulsee A, Li DKB. Conventional MR imaging. Neuroimag Clin N Am. 2008;18:651-673. Trapp BD, Ransohoff RM, Fisher E, Rudick RA. Neurodegeneration in multiple sclerosis: relationship to neurological disability. Neuroscientist. 1999;5:48-57. Villoslada P. Biomarkers for multiple sclerosis. Drug News Perspect. 2010;23:585-595. Vukusic S, Confavreux C. Natural history of multiple sclerosis: risk factors and prognostic indicators. Curr Opin Neurol. 2007;20:269-274. Brought to you by www.msatrium.com, your gateway to MS knowledge. Powered by 28