MS diagnostic algorithm.
cord conditions such as Sjögren syndrome, sarcoid disease, systemic lupus erythematosus (SLE), Devic's disease, and slow-growing intrinsic cord tumour.
Diseases with Multiple Lesions and a Relapsing Course
Cerebral Vasculitis Cerebral vasculitis may present with relapsing neurologic deficits including optic neuropathy and hemiparesis and can occur in isolation or associated with systemic disease. It is usually classified according to the size of the vessels involved. Associated neurologic features atypical for MS include headache, meningism, encephalopathy, seizures, and a rapidly progressive course. In addition, systemic enquiry may highlight weight loss, rash, arthropathy, and fever. Isolated or primary CNS vasculitis poses the greater diagnostic challenge, because systemic features and serologic markers usually are absent. The brain MRI may show supra- and infratentorial white matter lesions that resemble white matter plaques. A raised CSF protein level and lymphocytosis help to distinguish it from MS, but this is not a uniform finding. Angiographic abnormalities may help exclude MS, but usually only show changes with large- and medium-sized vessel vasculitis (i.e., those conditions usually lBLE 4.1| Abbreviated Pathologically Categorized Differential Diagnosis of MS
Balo disease Schilder disease Marburg disease
Optic neuritis Transverse myelitis
Other demyelinating disease
Harding disease (Leber variant)
Acute/monophasic disseminated encephalomyelitis (ADEM)
Noninflammatory diseases such as PML, central pontine myelinolysis, and B12 deficiency (demyelinating)
Common leukodystrophies such as adrenoleukodystrophy (ALD)/metachromatic leukodystrophy (MLD) and Krabbe disease
Other inflammatory diseases
Connective tissue disease (Sjögren syndrome, SLE)
Infective disease (human T-cell lymphotropic virus 1 [HTLV1], tertiary Lyme disease) Malignancy and genetic (HSP)
Vascular disease, including antiphospholipid syndrome involving non-CNS sites as well). Additionally, the vascular changes often are not specific for vasculitis. Because primary CNS vasculitis is a small-vessel disorder, brain biopsy using meningeal sampling is the most definitive diagnostic test. This can also help exclude alternative infective, inflammatory, and neoplastic conditions. The risk of biopsy generally is believed to be less than that of inappropriate cyclophos-phamide therapy. However, the noted investigations may fail to reach a diagnosis in vivo, and a definitive diagnosis of isolated CNS vasculitis may only become established at postmortem examination.
Systemic Lupus Erythematosus (SLE) CNS lupus is histologically neither a primary demyelinating disease nor a vasculitis, but a microvasculopathy. Clinically, it may mimic MS. This is less of a problem when CNS symptoms are accompanied by systemic features such as a photosensitive or malar rash, arthralgia, ulcers, proteinuria, and serologic markers such as dsDNA or anti-SM antibodies. The American College of Rheumatology diagnostic criteria claim good specificity (greater than 95%) in patients with at least three of ten non-neurologic features and an appropriate neurologic picture for SLE. Difficulty may occur in patients with an isolated relapsing CNS disease and positive lupus serologic markers, although this presentation is unusual in SLE (<5%). Unfortunately, typical MS investigations may not be distinguishing: In SLE with CNS involvement, intrathecal oligoclonal bands are reported to occur in up to 45%, white matter lesions similar to those seen in MS also occur, and delayed VEPs are not uncommon. Features such as headache, seizures, encephalopathy, psychiatric symptoms (may be precipitated by corticos-teroids), stroke-like episodes, or presentation in a black patient (Afro Caribbean-born) are more characteristic of SLE and unusual in MS. SLE patients also rarely present with optic neuritis or myelitis. The latter is often progressive, although onset may be acute or subacute. CSF abnormalities, such as an elevated protein and lymphocyte count and sometimes a reduced glucose level, may be found, but the CSF can be normal. Transverse myelitis in SLE often demonstrates spinal cord abnormalities that are continuous over several segments (so called longitudinal myelitis) unlike those in MS, which are short (usually less than two spinal cord segments). Response to treatment is variable and usually involves a combination of steroids, cyclophosphamide, and anticoagulation.
Antiphospholipid (APL) Syndrome This typically affects young women and can coexist as an entity in itself or with SLE, human immunodeficiency virus (HIV) infection, or lymphoproliferative disorders. Patients may present with arterial and venous thromboembolic CNS events causing focal CNS lesions that may resemble those seen in MS. A history of migraine, seizures, recurrent miscarriage, livedo reticularis, and peripheral venous thrombosis together with thrombocytopenia and a raised activated partial thromboplastin time (aPTT) all point to the diagnosis, which may be confirmed by checking for antiphospholipid antibodies. Transient APL antibodies may occur following acute infection and should be confirmed by repeat testing. Anticoagulation is usually advocated as treatment for this syndrome.
Sjögren Syndrome Sjögren syndrome may present with features similar to MS, including a fluctuating spinal cord and optic nerve syndrome (Case 3). The more usual neurologic manifestations of Sjögren syndrome are a sensory neuropathy including an isolated trigeminal mononeuropathy. Dry eyes and dry mouth are not uncommon general complaints and are often attributable to medication. However, sicca syndrome or the presence of another connective tissue disease may be relevant in patients with optico-spinal MS. Further investigation for Sjögren syndrome requires speckled antinuclear, anti-Ro, anti-La antibodies, and a Schirmer test. Minor salivary gland biopsy is the most definitive test. CSF analysis, MRI, and VEP findings may not be distinct from those in MS, although CSF oligoclonal bands matched in the serum are more commonly reported, and the spinal cord lesions are usually long. The neurologic symptoms may respond to cyclophosphamide in addition to corticosteroids.
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