Accuracy in Space and Time: Diagnosing Multiple Sclerosis 2012 Genzyme Corporation, a Sanofi company. Brought All rights to reserved. you by www.msatrium.com, MS.US.PO876.1012 your gateway to MS knowledge. Brought to you by www.msatrium.com, Powered by your gateway to MS knowledge. 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 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 Powered by 3
Clinical disease starts with a clinically isolated syndrome 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. Powered by 5
What s the first step to effective treatment? Powered by 6
Diagnostic principles 1. Dissemination in space (DIS) 2. Dissemination in time (DIT) 3. Rule out mimics Powered by 7
Differential diagnosis 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) Powered by 9
MRI mimics: Which is which? Powered by 10
MRI alone is NOT specific for MS Powered by 11
Evolution of diagnostic criteria: Early history 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. Powered by 13
1982 Poser criteria Note: Paraclinical evidence defined as evoked potentials, CT or MRI; at least two oligoclonal bands, none in serum. 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. 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 Powered by 16
2010 McDonald MRI criteria: Demonstration of DIS Powered by 17
2010 McDonald MRI criteria: Demonstration of DIT Powered by 18
2010 McDonald criteria: PPMS 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 Powered by 20
Review of McDonald updates from 2001 to 2011 MRI DIT 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 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 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) Powered by 24
Future directions MRI techniques 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 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. 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. Powered by 28