We searched MEDLINE and Embase with the search terms “multiple sclerosis”, “neuromyelitis optica”, “acute disseminated encephalomyelitis”, “diagnosis”, “diagnostic criteria”, and “differential diagnosis” for papers published in English between Jan 1, 1995, and May 15, 2016. We sought additional articles from the reference lists of relevant articles. We gave priority to new studies published in the past 5 years. Where appropriate, we reference review articles to provide more detailed information
SeriesDiagnosis of multiple sclerosis: progress and challenges
Introduction
Multiple sclerosis is a chronic, immune-mediated, demyelinating disorder of the CNS. It can present with changes in sensation, mobility, balance, sphincter function, vision, and cognition. Although the course is highly variable, many people develop irreversible disability and multiple sclerosis remains a major cause of neurological disability in young adults. The disease is classified as either relapsing-remitting or primary progressive based on the initial disease course. Relapsing-remitting multiple sclerosis is more common, affecting 85–90% of patients with multiple sclerosis, and is characterised by relapses (episodes of neurological dysfunction lasting at least 24 h in the absence of fever or infection1) followed by periods of remission. Recovery from relapses is variable and can be incomplete.2 Relapsing-remitting multiple sclerosis typically affects young adults (mean age at onset 30 years) and women are affected three times more often than are men.3 Evidence suggests that the incidence of relapsing-remitting multiple sclerosis might be increasing, particularly in women.3 Primary progressive multiple sclerosis (10–15% of patievnts) is characterised by an insidious, slowly progressive increase in neurological disability over time, usually without relapses.2 Primary progressive multiple sclerosis typically presents at an older age than does relapsing-remitting multiple sclerosis (mean age at onset 40 years) and there is no sex bias. People with relapsing-remitting multiple sclerosis may develop a progressive course with time (secondary progressive multiple sclerosis) with a gradual increase in disability with or without relapses.2
An early and accurate diagnosis of multiple sclerosis is essential because there are now effective treatments for relapsing-remitting multiple sclerosis. Diagnosis is based on the presence of clinical symptoms and signs and findings on MRI, which is highly sensitive to detect characteristic CNS lesions.1 Advances in MRI, serological and genetic testing have improved the diagnosis of other disorders that can be mistaken for multiple sclerosis. A major discovery was the association between neuromyelitis optica spectrum disorder and serum aquaporin 4 IgG (AQP4-IgG), confirming that it is a different disease from multiple sclerosis and needs distinct treatment.4
In this, the first in a Series of papers about multiple sclerosis, we discuss the diagnosis of multiple sclerosis, including the approach to investigation of patients with suspected disease and diagnostic criteria and their application in clinical practice. We discuss key differential diagnoses with particular focus on other idiopathic inflammatory disorders, including acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorder. Finally, we consider areas of controversy and uncertainty and the potential for future changes in diagnostic criteria.
Section snippets
Presenting symptoms
The initial presentation of multiple sclerosis varies according to both the location of lesions and the type of symptom onset (relapsing or progressive). Patients can present to a broad range of doctors depending on the nature of their symptoms (eg, general practitioners or family doctors, ophthalmologists, and orthopaedic surgeons) and if multiple sclerosis is suspected, prompt referral to a neurologist is needed.
Panel 1 shows some common presenting symptoms and signs of multiple sclerosis and
Children
Up to 5% of patients with multiple sclerosis develop their first symptoms in childhood, and these are almost always those of relapsing-remitting multiple sclerosis.32 In younger children (<12 years of age) multiple sclerosis can present differently from in adolescents and adults; encephalopathy, multifocal neurological deficits (often with prominent brainstem or cerebellar involvement), and seizures are more common.32 MRI findings can include large, confluent, T2-hyperintense lesions that show
Alternative diagnoses
The differential diagnosis of multiple sclerosis is broad and many neurologists use the approach of identifying so-called red flag clinical, imaging, or other laboratory features that suggest an alternative diagnosis.42 The differential diagnosis depends on the clinical presentation, with different considerations in patients with relapsing or progressive courses. These disorders include several closely related idiopathic inflammatory CNS diseases (Table 1, Table 2), along with a range of other
Misdiagnosis of multiple sclerosis
Rates of misdiagnosis of multiple sclerosis might be as high as 10%.63 In a survey of multiple sclerosis specialist neurologists in the USA, 95% of respondents had seen one or more patients in the previous year who had been misdiagnosed with multiple sclerosis, many of whom were being treated inappropriately with disease-modifying therapies. The major disorders identified that were misdiagnosed as multiple sclerosis were small vessel cerebrovascular disease, migraine, fibromyalgia, and
Controversies and areas of uncertainty
Although there has been major progress in the diagnosis of multiple sclerosis, areas of uncertainty remain. The role of spinal cord imaging65 and CSF examination66 in diagnosis is particularly controversial. Guidelines recommend spinal cord MRI in patients with symptoms of myelopathy or when brain MRI findings are not diagnostic of multiple sclerosis.12 However, spinal cord lesions can be very helpful in making a diagnosis of multiple sclerosis (cord lesions do not occur with healthy ageing or
Conclusions and future perspectives
Current diagnostic criteria for multiple sclerosis integrate clinical and MRI findings and enable an earlier and more reliable diagnosis of multiple sclerosis than with clinical findings alone, potentially facilitating earlier treatment. The criteria are best applied in an individual patient when there are typical symptoms and signs of multiple sclerosis and when relevant differential diagnoses have been excluded. Further supportive information from CSF and evoked potentials can be obtained if
Search strategy and selection criteria
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