Multiple Sclerosis (MS)
This 48 year old patient was referred with a possible diagnosis of motor neuron disease, based upon his rapidly progressive downhill clinical course with dysarthria, weakness, spasticity, gait abnormalities, and generalized hyper-reflexia. However, the diagnosis of ALS was made less likely by the presence of sensory symptoms and signs and absence of evidence of lower motor neuron disease, such as atrophy and fasciculations. Because of the referring physician's concerns, an EMG and muscle biopsy were carried out and were normal.
The evidence for bilateral pyramidal tract involvement, along with sensory signs, suggested multifocal or diffuse subcortical lesions, and prompted detailed MRI studies of the brain. The MRI studies were quite dramatic, but unfortunately not diagnostic. They showed multiple white-matter enhancing lesions with edema, often in a periventricular localization. Some of the lesions had a cystic character, and one or two lesions actually appeared to have cortical localization. The CSF findings indicated a high IgG synthesis rate within the CNS and the presence of 4-5 oligoclonal bands. The visual evoked responses were normal. Abnormal somatosensory evoked responses localized the involvement within or above the medulla, and was in accord with a subcortical localization.
The differential diagnosis with these clinical findings includes diseases of the myelin, neoplasms, infections, and inflammatory disorders.
Thus, the pathological process responsible for the subcortical lesions was not clear, and since the potential therapy of these disorders is dramatically different, a decision was reached to perform a stereotactic brain biopsy. If immunotherapy had been undertaken without a definitive diagnosis, an infectious process could have been worsened. The brain biopsy clarified the diagnosis demonstrating an inflammatory response characteristic of multiple sclerosis with no evidence of vasculitis, infections, or neoplasia.
As therapy, the patient was treated with high dose steroids and a one day course of IV cytoxan. He tolerated the treatment well and within a week he had marked improvement in his speech, gait, motor strength, and cognitive dysfunctions. He was discharged home on a rapidly tapering dose of oral steroids.
The clinical syndrome of multiple sclerosis (MS) is classically described as a relapsing-remitting disorder that affects multiple white-matter tracts within the CNS, with usual onset in young adults. The disorder, however, exhibits marked clinical heterogeneity.
Primary progressive is the term applied to those patients whose illness is progressive from the onset of disease and without attacks, plateaus, or remissions. Another group of patients have periods of relapses superimposed on a progressive course, or initially have relapses and then evolve to a progressive phase. This clinical pattern is termed relapsing and progressive or secondary progressive. Progressive-relapsing is the term used to describe those patients having progressive disease from onset with clear acute relapses (with or without full recovery), and periods between relapses marked by continuing progression.[12]
Data from a clinic-based study of 1,100 patients representing the population of the region, found that 66% of patients at onset are relapsing and remitting, 15% relapsing/progressive, and 19% progressive.[2] The course of MS with onset after the age of 40 is progressive in over 60% of patients.[11]
The Schumacher committee for MS elaborated six items needed to diagnose "clinically definite" multiple sclerosis:
Poser, et al. (1983) modified the criteria, expanding the age of onset to 59 and using data from lab studies, including CSF analysis, evoked potentials, and neuroimaging.
Cognitive impairment: Frank dementia is an uncommon feature, occurring in less than 5% of patients. Neuropsychological test results have shown that 35-65% of patients have cognitive impairment.[3] Total lesion load, based on MRI, has been found to correlate with neuropsychological testing impairment.[5]
Visual pathways: Visual disturbances due to optic neuritis are the most common presentation, usually unilaterally in an acute or a sub-acute form. Other common abnormalities include nystagmus, oscillopsia, and internuclear ophthalmoplegia. In various studies, the visual pathways have been found to be affected in 17-36% of patients at onset.
Sensory pathways: About 22-45% of patients have sensory symptoms at onset. These reflect spinothalamic, posterior column, or dorsal root entry zone lesions.
Motor pathways: About 20-43% of patients have motor symptoms at onset, due to corticospinal tract dysfunction. Pyramidal tract dysfunction is often mixed with impairment of the cerebellar pathways, as well as involvement of bladder, bowel, and sexual functions.
This is quite limited in the setting of a young adult with two or more clinically distinct episodes. Problems arise with progressive illness, monophasic episodes, and atypical presentations. Differential diagnosis includes:
Sex: MS appears to follow a more benign course in women.
Age at onset: The average age at onset is 29 years. Onset at a later age carries a less favorable prognosis, and the progressive form is more common in the older age group.
Initial disease course: The relapsing form of MS favors a better prognosis than the progressive form.
Initial complaints: Impairment of sensory pathways or cranial nerve dysfunction, particularly optic neuritis, are found in several studies to be favorable features; while pyramidal, brainstem, and cerebellar symptoms, carry a poorer prognosis.
MRI: MRI is now the modality of choice as an aid to the diagnosis. Clinical definite MS patients will have white-matter lesions typical of MS in over 90% of cases. Other entities such as ischemia, vasculitides, etc. make MRI criteria much less reliable for the diagnosis of MS in patients over the age of 50. Typical lesions include ovoid plaques in the periventricular region, corpus callosum, and centrum semiovale which appear hyperintense on proton density and T2 weighted images and hypodense on T1 weighted images.
CSF: CSF findings alone cannot make or exclude the diagnosis, but they are useful adjuncts. IgG synthesis is elevated in 70-90%; IgG/albumin ratio is abnormal in 60-73%; and oligoclonal bands are found in 85-95% of patients.
Evoked Potentials: Visual evoked potentials are abnormal in 80-85%; brainstem evoked potentials in 50-65%; and somatosensory evoked potentials in 65-80% of patients with MS.
The pathological hallmark of MS are plaques, which are discrete regions of demyelination with relative preservation of axons. Active plaques have perivascular infiltration of lymphocytes (predominantly T cells), macrophages, and occasional plasma cells. Myelin debris is found in clumps or within lipid laden macrophages. Most of the T cells express the alpha/beta T cell receptor (TcR). Both CD4+ and CD8+ T cells are present. Chronic, inactive plaques have sharp demarcations, are hypocellular, and exhibit astrocytic proliferation.
Corticosteroids: Corticosteroids are the most commonly used agents for treating relapses or progressive illness. Two large controlled trials have shown marginal efficacy of steroids in MS. There are several therapeutic regimens published using intravenous methylprednisolone for 3-5 days, at dosages of 500-1000 mg per day, with or without subsequent oral prednisone.
Cyclophosphamide: Cyclophosphamide is an alkalating agent with cytotoxic effects on lymphocytes. Data from European centers and the USA indicated that cyclophosphamide arrested disease progression in a proportion of treated patients, with some suggestion that booster therapy was important, and that young women benefited most. The US study did not include placebo patients and the clinical behavior of their treated group mimicked that of placebo patients in other studies. A Canadian collaborative study did not show any benefit, but no booster therapy was employed.
Methotrexate: Low dose oral methotrexate has been tested in progressive MS, and although the expanded disability status score was unaffected, upper-limb dysfunction developed more slowly in treated than placebo patients.
Other Treatments: Different modalities (plasma exchange, cyclosporine, Copolymer 1, azathioprine, interferons, etc.) have been tried with variable success, particularly in the relapsing form. None have, as yet, convincingly shown to produce benefit in the progressive form of MS.
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