For a patient with multifocal neurological symptoms and signs, what diagnoses need consideration and what investigations are requried?

Multiple Sclerosis
No single clinical sign or test is diagnostic of MS. The diagnosis is readily made in a young adult with relapsing and remitting symptoms involving different areas of CNS white matter. The possibility of an alternative diagnosis should always be considered, particularly when (1) symptoms are localized exclusively to the posterior fossa, craniocervical junction, or spinal cord; (2) the patient is 60 years of age; (3) the clinical course is progressive from onset; (4) the patient has never experienced visual, sensory, or bladder symptoms; or (5) laboratory findings (e.g., MRI, CSF, or EPs) are atypical. Similarly, uncommon or rare symptoms in MS (e.g., aphasia, parkinsonism, chorea, isolated dementia, severe muscular atrophy, peripheral neuropathy, episodic loss of consciousness, fever, headache, seizures, or coma) should increase concern about an alternative diagnosis. Diagnosis is also difficult in patients with a rapid or explosive (strokelike) onset or with mild symptoms and a normal neurologic examination. Rarely, intense inflammation and swelling may produce a mass lesion that mimics a primary or metastatic tumor. The specific tests required to exclude alternative diagnoses will vary with each clinical situation; however, an erythrocyte sedimentation rate, serum B12 level, ANA, and treponemal antibody should probably be obtained in all patients with suspected MS.

Magnetic Resonance Imaging
MRI has revolutionized the diagnosis and management of MS (Fig. 375-3); characteristic abnormalities are found in >95% of patients. An increase in vascular permeability from a breakdown of the BBB is detected by leakage of intravenous gadolinium (Gd) into the parenchyma. Such leakage occurs early in the development of an MS lesion and serves as a useful marker of inflammation. Gd enhancement persists for approximately 1 month, and the residual MS plaque remains visible indefinitely as a focal area of hyperintensity (a lesion) on spin-echo (T2-weighted) and proton-density images. Lesions are frequently oriented perpendicular to the ventricular surface, corresponding to the pathologic pattern of perivenous demyelination (Dawson's fingers). Lesions are multifocal within the brain, brainstem, and spinal cord. Lesions larger than 6 mm located in the corpus callosum, periventricular white matter, brainstem, cerebellum, or spinal cord are particularly helpful diagnostically. Different criteria for the use of MRI in the diagnosis of MS have been proposed.

The total volume of T2-weighted signal abnormality (the "burden of disease") shows a significant (albeit weak) correlation with clinical disability, as do measures of brain atrophy. Approximately one-third of T2-weighted lesions appear as hypointense lesions (black holes) on T1-weighted imaging. Black holes may be a marker of irreversible demyelination and axonal loss, although even this measure depends on the timing of the image acquisition (e.g., most acute Gd-enhancing T2 lesions are T1 dark).

Newer MRI measures such as magnetization transfer ratio (MTR) imaging and proton magnetic resonance spectroscopic imaging (MRSI) may ultimately serve as surrogate markers of clinical disability. For example, MRSI can quantitate molecules such as N-acetyl aspartate, which is a marker of axonal integrity, and MTR may be able to distinguish demyelination from oedema.

Evoked Potentials
EP testing assesses function in afferent (visual, auditory, and somatosensory) or efferent (motor) CNS pathways. EPs use computer averaging to measure CNS electric potentials evoked by repetitive stimulation of selected peripheral nerves or of the brain. These tests provide the most information when the pathways studied are clinically uninvolved. For example, in a patient with a remitting and relapsing spinal cord syndrome with sensory deficits in the legs, an abnormal somatosensory EP following posterior tibial nerve stimulation provides little new information. By contrast, an abnormal visual EP in this circumstance would permit a diagnosis of clinically definite MS. Abnormalities on one or more EP modalities occur in 80–90% of MS patients. EP abnormalities are not specific to MS, although a marked delay in the latency of a specific EP component (as opposed to a reduced amplitude or distorted wave-shape) is suggestive of demyelination.

Cerebrospinal Fluid
CSF abnormalities found in MS include a mononuclear cell pleocytosis and an increased level of intrathecally synthesized IgG. The total CSF protein is usually normal or slightly elevated. Various formulas distinguish intrathecally synthesized IgG from IgG that may have entered the CNS passively from the serum. One formula, the CSF IgG index, expresses the ratio of IgG to albumin in the CSF divided by the same ratio in the serum. The IgG synthesis rate uses serum and CSF IgG and albumin measurements to calculate the rate of CNS IgG synthesis. The measurement of oligoclonal banding (OCB) in the CSF also assesses intrathecal production of IgG. OCBs are detected by agarose gel electrophoresis. Two or more OCBs are found in 75–90% of patients with MS. OCBs may be absent at the onset of MS, and in individual patients the number of bands may increase with time. It is important that paired serum samples be studied to exclude a peripheral (i.e., non-CNS) origin of any OCBs detected in the CSF.

A mild CSF pleocytosis (>5 cells/L) is present in ~25% of cases, usually in young patients with RRMS. A pleocytosis of >75 cells/L, the presence of polymorphonuclear leukocytes, or a protein concentration of >1.0 g/L (>100 mg/dL) in CSF should raise concern that the patient may not have MS.