Signs and Symptoms of MS
The presentation of multiple sclerosis is characterized by a variety of symptoms that reflect involvement of the central nervous system, classically known as “separated in time and space.” Episodes may occur months or years apart, and typically present at different anatomic locations, which may reflect, for example, visual disturbances during one period of time, followed by paresthesia or weakness in an extremity. Symptoms should last longer than 24 hours during a clinical exacerbation.
Because the presentation of multiple sclerosis differs among patients, it may be difficult to diagnose. Additionally, one must remember that physical or cognitive disability may progress in the absence of an exacerbation.
Other symptoms may include, rarely, aphasia or dysphasia. Approximately 5 percent of patients with MS will experience a seizure. There are other paroxysmal symptoms that include ataxia, akinesia, paresthesias, or pruritis. Paroxysmal symptoms occur in bouts, often the result of triggering by movement or sensory stimuli. In patients with multiple sclerosis, there may be significant motor symptoms that occur in the absence of either sensory deficits or dysautonomia.
On physical examination, a thorough neurologic examination should be performed to determine the presence of deficits. Bulbar involvement usually refers to dysfunction of the lower cranial nerves, and may manifest as dysphagia. This is not typical of early multiple sclerosis, so it may be attributed to a different disorder. Ophthalmologic examination may not reveal any signs to the examining physician in the instance of a patient with optic neuritis, as the condition is retrobulbar in most MS patients. Visual field changes, loss of visual acuity, or a relative afferent pupillary defect may be present.
Other possible findings upon physical examination include hyperreactive reflexes, increased tone or stiffness in the extremities, poor coordination, or wide-based gait. Secondary findings can include urinary problems, musculoskeletal complaints, infection, or skin breakdown.
Clinical Rating Scales
Clinical rating scales may be used to rate disability, and they include the 10-point Kurtzke Expanded Disability Status Scale (EDSS).1
Criteria used to diagnose MS are largely based upon clinical findings, which include frequency of clinical relapses, time to progression of the disease, and development of the lesion on MRI. MRI studies have shown that, although MS was long thought to have been silent in the intervals between relapse, inflammatory events continue to occur in the brain at as high as 10 to 20 times the predicted rate that is indicated by the mean relapse rate.
Diagnosis of MS
The diagnosis of multiple sclerosis is made based upon the clinical findings and evidence from ancillary diagnostic tests, which include MRI of the brain and spinal cord and examination of the cerebrospinal fluid. The duration of the deficit is usually days to weeks, and the attack is expected to be compatible with the neurologic deficits.
In the past, physicians required the appearance of lesions that were separated “in time and space,” which meant that the diagnosis could not be made at the time of the first episode. The disease was expected to “declare” itself with another attack. In 2010, the McDonald criteria were validated, allowing the diagnosis of MS with the first exacerbation.
Because there is evidence that early intervention with interferon treatment will decrease disability and will lower secondary relapse rates, it is important to make the diagnosis of MS as early as possible. Axonal loss may be present in patients who are symptomatic at an early point in the progress of the disease. The McDonald criteria were developed in 2001 by a panel of international experts. Revisions were made in 2005 and 2010, and imaging is an essential part of the criteria.2
Magnetic resonance imaging cannot diagnose MS, but it is the imaging procedure of choice for confirmation and to monitor the progression of the disease in both brain and spinal cord. MRI is the most sensitive imaging modality for diagnosing MS in the spinal cord, evaluating the extent of disease, and following response to treatment. It is more sensitive for identification of active plaques than clinical examination or CT scanning. However, is it not specific for MS. Use of MRI has significantly changed the diagnosis and monitoring of MS.
A limitation of MRI in identification of lesions of MS is that there is sometimes a discordance between the location of the lesion and the clinical presentation, and depending upon the findings, their number, and their location, MS may vary in sensitivity and specificity. When used in the evaluation of patients with only one episode of neurologic symptoms, who do not meet the criteria for MS, researchers have found that the overall risk of development of multiple sclerosis after an episode of neurologic impairment is as low as 12 percent.
It is critical that the images be described in detail and referenced to a set of diagnostic criteria, which may include the Paty or Barkhof criteria. The diagnosis requires that the lesions found on imaging are consistent with the clinical findings and neurologic history. The Paty or Barkhof criteria require three or four lesions, including a periventricular lesion, and have been found to have a sensitivity of 86 percent with a low specificity of 54 percent. However, the modified Barkhof criteria have been found to have a moderate predictive value for conversion to clinically defined multiple sclerosis (CDMS) over a period of three years, although all patients received interferon beta-1b therapy for a period of at least a year. The overall conversion rate was 42 percent.3,4
MRI in the Diagnosis of MS
Magnetic resonance imaging can reveal changes in the white matter in the cerebral hemispheres, infratentorium, and spinal cord. The use of MRI is normally the sole imaging modality required for diagnosis of patients with MS, due to its superior positive predictive value for the disease.
MRI reveals abnormalities of the brain in 90 to 95 percent of patients with MS, and in those with spinal cord lesions, they are evident in up to 75 percent of patients. T2-weighted images are more sensitive for chronic lesions or cerebral edema, and T1-weighted lesions are more sensitive for identification of cerebral atrophy and of the “black holes” that represent regions of axonal death. Other than allowing appreciation of cerebral atrophy that may occur in cases of advanced chronic MS, T1-weighted imaging is less sensitive than other MRI modalities and does not represent acute lesions at all.
Common lesions of MS may be found in the periventricular white matter, cerebellum, brainstem, and spinal cord. Dawson bars or fingers are ovoid lesions that are perpendicular to the ventricles and occur along the path of the deep medullary veins. These lesions are quite common. A lesion that is fairly specific for MS is at the interface of the corpus callosum and the septum pellucidum, which on T1-weighted sagittal images reveals multiple hypointense lesions in the region. Axial T2-weighted MRI may reveal multiple white matter plaques in the callosal and pericallosal white matter distribution. The T2-weighted image reveals hyperintensity of the lesions, because of the inflammation and breakdown of the blood-brain barrier in lesions of MS. Extravascular fluid in these lesions is the cause of the hyperintensity. There is normally more than one hyperintense lesion on MRI in the patient with MS. Axial T1-weighted MRI enhanced with gadolinium may reveal multiple pericallosal white matter lesions that are intensely enhanced. This finding is consistent with active disease.
Proton Density MRI
Because the lesions of MS remain hyperintense while the CSF signal is suppressed on proton density MRI, the lesions can be easily identified, giving proton density MRI a significant advantage over standard T2 imaging. The perivascular Virchow-Robin spaces are suppressed on protein density MRI, and as these perivascular CSF spaces may penetrate to the subcortical white matter, appearing hyperintense on the standard T2-weighted MRI scan, this presents a significant advantage. Proton density–weighted MRI sequences are very sensitive for the detection of posterior fossa plaques, as well as plaques elsewhere in the brain.
Fluid Attenuated Inversion Recovery MRI
Fluid attenuated inversion recovery MRI is a T2-weighted technique, which dampens the free water signal, thus dampening the CSF signal. The highest signals on a FLAIR sequence are parenchymal abnormalities, and the CSF remains black. This differs from protein density–weighted MRI, which may result in hypointense periventricular lesions of multiple sclerosis that appear almost isointense to the adjacent CSF. The suppression of CSF on the FLAIR images when compared with protein density–weighted images enables better detection of lesions of multiple sclerosis in the cerebral hemispheres. Coronal fluid-attenuated inversion recovery MRI is highly sensitive for supratentorial lesions. Brain lesions and clinical status were correlated in one study with 1.5T and 3T MRI patients, using FLAIR sequences, finding that the MRI at 3T provided increased validity and sensitivity when compared to 1.5T images with respect to correlation to clinical status. Protein density–weighted imaging is, however, the imaging modality of choice for study of infratentorial lesions. 5
Functional MRI studies are able to detect changes in blood flow, which is correlated with energy use by brain cells. Some patients with MS may not experience significant clinical impairment despite the presence of lesions on MRI. fMRI studies have resulted in the hypothesis that limited clinical manifestation in these cases may be due to increased cognitive control recruitment in the motor system.
MR spectroscopy is a technique that detects a spectrum of chemical shifts, which is potentially capable of depicting white matter changes that are not detected with routine MR pulse sequences. These findings may be correlated with disability scores, and because of this, use of MR spectroscopy may become standard for patient monitoring after treatment and for formulation of prognosis.
One prospective study by Lebrun found that in 70 patients with an initial brain MRI, ordered for medical symptoms not consistent with MS, there was evidence of a 2.3-year mean time between the first brain MRI and clinically isolated syndrome. Clinical conversion to MS was noted in 23 of the 70 patients followed in the study.6
Proton Density MRI and Phosphorus Magnetic Resonance Spectroscopy
Because conventional MRI techniques do not distinguish demyelination, remyelination, gliosis, or axonal loss, and because it may be difficult to distinguish acute plaques from chronic plaques using conventional MRI techniques, techniques like phosphorus magnetic resonance spectroscopy (MRS) are utilized to acquire information about phospholipid metabolism. Proton MRS is used to acquire information about metabolic components such as lactic acid and creatine phosphate, or N-acetyl aspartate, which is a neuronal marker. A ratio is produced, such as the NAA/Cr ration, which reflects the reduction of NAA in chronic MS. The reduction in NAA is consistent with neuronal or axonal loss.
Diffusion-weighted and Diffusion Tensor MRI
Another current technique that is utilized in the diagnosis or evaluation of MS is diffusion-weighted and diffusion tensor MRI imaging, which permits the measurement of fractional anisotropy, reflecting the degree of diffusion of water molecules. A high degree of anisotropy reflects linear diffusion. This degree of diffusion is negatively correlated with the loss of integrity of white matter tracts, normally arranged in a linear fashion. White matter that appears normal and is adjacent to abnormal plaques may have a reduction in anisotropy, which reflects neuronal disarray not evident on a T2-weighted image.7
In addition to the predominant white matter changes seen in MS, cortical gray matter is often involved, and two- and three-dimensional fluid-attenuated inversion recover imaging, double inversion recovery imaging, phase-sensitive inversion recover T1-weighted sequences, or diffusion tensor imaging can also be utilized to better visualize gray matter lesions in MS.