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Multiple sclerosis
RESEARCH PAPER
Using atypical symptoms and red flags to identify non-demyelinating disease Siobhan B Kelly,1 Elijah Chaila,1 Katie Kinsella,1 Marguerite Duggan,1 Cathal Walsh,2 Niall Tubridy,1 Michael Hutchinson1 < An additional table is
published online only. To view this file please visit the journal online (http://jnnp.bmj.com/ content/83/1.toc). 1
Department of Neurology, St. Vincent’s University Hospital, Dublin, Ireland 2 Department of Statistics, Trinity College, Dublin, Ireland Correspondence to Professor Michael Hutchinson, Consultant Neurologist, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland;
[email protected] Received 13 June 2011 Accepted 4 July 2011 Published Online First 17 August 2011
ABSTRACT Background Red flags and atypical symptoms have been described as being useful in suggesting alternative diagnoses to multiple sclerosis (MS) and clinically isolated syndrome (CIS); however, their diagnostic utility has not been assessed. The aim of this study was to establish the predictive value of red flags and the typicality/atypicality of symptoms at presentation in relation to the final diagnosis of patients referred with suspected MS. Methods All patients referred with suspected MS over a 3-year period were assessed by the typicality of the clinical presentation and the occurrence of red flags in relation to the eventual diagnosis. The extent of agreement of trainee and consultant neurologists as to typicality of clinical presentations was determined. Results Of 244 patients referred, 119 (49%) had MS/CIS and 125 (51%) did not. 41 patients were referred because of an abnormal MRI. Of 203 with clinical symptoms, 96 patients had atypical symptoms of whom, 81 (84%) did not have MS and 15 (16%) had MS/CIS. Typical symptoms occurred in 107 patients; 10% did not have MS/CIS. Atypical symptoms had a sensitivity of 84%, specificity of 90% and positive likelihood ratio (PLR) of 8.4, whereas red flags had a sensitivity of 47%, specificity of 88% and PLR of 3.9 for the exclusion of MS/CIS. Mean percentage agreement between consultants and trainees was 73% with a range of 32e96%. Conclusions Atypical features at presentation are more sensitive, specific and have a higher PLR than red flags to refute a diagnosis of MS/CIS.
INTRODUCTION The diagnosis of multiple sclerosis (MS) requires demonstration of dissemination of demyelinating lesions in both time and space using strict clinical, paraclinical and imaging criteria.1 However, many other diseases exhibit dissemination both in time and space; thus, the McDonald criteria emphasise that even if the clinical evidence and paraclinical studies are strongly indicative of MS, there must be “no better explanation for the findings than MS for a secure diagnosis”.1 2 The term ‘red flag’ is used to indicate that something in the history, examination or clinical investigation is not suggestive of MS. The utility of MRI in delineating the distinctive imaging features of diseases considered in the differential diagnosis of MS has been described by the European MAGNIMS (Magnetic Resonance Network in Multiple Sclerosis) group.3 In contrast to imaging criteria, specific guidance for appropriate clinical and laboratory assessment to satisfy the 44
requirement for ‘no better explanation’ has not been available. A number of clinical and MRI red flags were provided by a group of experts and rated as being of major, intermediate or minor significance in suggesting an alternative diagnosis to MS.4 Major red flags (eg, bone lesions or the presence of diabetes insipidus) provide strong evidence of a different diagnosis to MS. Intermediate red flags, such as a prominent family history or seizures as a presenting feature, might suggest an alternative diagnosis; however, it may be entirely consistent with MS. The expert group also described minor red flags, such as the absence of gadolinium enhancement, which also occur with a relatively high frequency within the population of newly diagnosed patients with MS. Red flags may be useful in identifying patients who have another neurological disorder than MS; however, their predictive value has not been formally assessed. In addition to this, they do not address patients who have no determined medical cause for their symptomsdmedically unexplained symptoms (MUS). The typicality or atypicality of symptom presentation has been proposed as a discriminator between patients who are or are not eventually diagnosed as having MS.5 Atypical symptoms indicate an alternative diagnosis to MS and include symptoms suggestive of either other neurological disease (OND) or MUS. Atypical symptoms suggesting OND include numbness in a glove and stocking distribution consistent with peripheral sensory neuropathy; those indicating MUS include non-dermatomal facial numbness and quivering, pulsing and or flitting sensations. The aim of this study was to establish the predictive value of the absence or presence of red flags and the typicality/atypicality of presentation in relation to the final diagnosis in patients referred with suspected MS.
PATIENTS AND METHODS All new patients referred with suspected MS to the neuroinflammation clinic at St Vincent’s University Hospital, Dublin, were recruited retrospectively from January 2007 to December 2009 and then prospectively to May 2010. The reason for referral, whether clinical symptoms or an abnormal MRI suggestive of demyelination, was documented. The initial clinical appraisal and the presumed diagnosis at the time when the patient was seen were notedd for example, MS, OND or MUS. This was correlated with the final diagnosis after investigation. The diagnostic criteria for MS were that of McDonald’s
J Neurol Neurosurg Psychiatry 2012;83:44e48. doi:10.1136/jnnp-2011-300679
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Multiple sclerosis revised criteria.1 Patients with a monophasic demyelinating disease indicating a clinically isolated syndrome (CIS) were included with the MS group as MS/CIS. There were no patients with a diagnosis of neuromyelitis optica or acute disseminated encephalomyelitis. Clinical (not MRI) referrals were assessed by two consultant neurologists on the basis of symptoms at presentation, and unaware of the ultimate diagnosis, into those with symptoms which were typical or atypical for MS/CIS. Each neurologist assessed half of the clinical referrals. In all the patients presenting with clinical symptoms, the presence of one or more of the 79 red flags reported by the MS expert consensus group was recorded (by SK).4 For patients presenting with an abnormal MRI scan, the MAGNIMS red flag criteria were used.3 The diagnostic investigations included MRI brain and spinal cord, cerebrospinal fluid (CSF) examination for cells, protein, glucose, CSF IgG index and matched CSF and serum isoelectric focusing for oligoclonal bands. Other investigations were performed according to clinical indications including C-reactive protein, routine full blood count, biochemistry screen and aquaporin 4 antibodies, among others. Patients not diagnosed with MS/CIS were classified as having either OND or MUS. The basis for the diagnosis of OND was recorded. Where the patient had a final diagnosis of MUS, the reasoning behind this diagnosis was elucidated. A sample of 20 clinical vignettes (13 of patients with OND or MUS and 7 with MS/CIS) was given to 15 consultant neurologists and 11 neurologists in training. They were asked to assign ‘typical’ or ‘atypical’ presentations for MS to each of the vignettes.
Statistical methods Sensitivity, specificity, positive and negative likelihood ratios were calculated for the postulates that (a) typical symptoms at presentation indicated a MS/CIS diagnosis, (b) atypical symptoms at presentation indicated non-MS/CIS diagnoses, (c) the absence of red flags indicated a diagnosis of MS/CIS, (d) the presence of red flags indicated a non-MS/CIS diagnosis. Where p values are quoted, this refers to the c2 test. SPSS V.16 was used for data analysis. Fleiss’s Kappa was calculated as a measure of agreement for multiple raters.6
RESULTS Total cohort There were 244 referrals for suspected MS, 119 (49%) were diagnosed as having MS/CIS and 125 (51%) as not having MS/ CIS (figure 1). Of the 119 patients diagnosed with MS/CIS, 33 had CIS, 71 had relapsing remitting MS, 2 had secondary progressive MS and 13 had primary progressive MS. Forty-one patients presented because of an abnormality found on a MRI scan; eight (20%) of the 41 were diagnosed with MS/CIS. Two hundred and three patients, referred with clinical symptoms suggesting a diagnosis of MS, were divided almost equally into those presenting with typical symptoms (107/203, 53%) and those with atypical symptoms (96/203, 47%). MS/CIS was diagnosed in 96/107 (90%) of the group presenting with typical symptoms and 15/96 (16%) of those presenting with atypical symptoms (p
