Neuroscience Clerkship

MULTIPLE SCLEROSIS

Multiple Sclerosis (MS) is a common neurologic disorder and one of the leading causes of disability in young adults. It is characterized by multiple demyelinating lesions in the central nervous system (CNS) separated by time and space. As MS can affect different areas of the brain, brainstem, cerebellum and spinal cord, a variety of different neurologic symptoms and signs may be seen. The most common temporal course in MS is a relapsing / remitting pattern. These patients experience intermittent neurologic attacks that last days to weeks. Often, patients recover back to their baseline, but others may have some residual deficit following an attack. A minority of patients have a primary progressive course. Many patients with a relapsing / remitting course will evolve into a secondary progressive course years into their disease.  

Like many presumed autoimmune disorders, MS is more common in women than men. Although any age can be affected, it is much more common to present in younger adults. The mean age of onset is 30. For unclear reasons, it is more common in temperate climates compared with tropical ones.

Pathogenesis

MS is a disorder affecting myelin in the CNS with relative preservation of axons. The etiology remains unknown but many observations point to a likely autoimmune disorder. Plaques usually develop in a perivenular distribution and are characteristically seen in the periventricular white matter, brainstem, and spinal cord. The active lesions contain T lymphocytes and macrophages.

Common Signs and Symptoms

As noted above, patients with MS can develop a variety of neurologic symptoms and signs. These can include cognitive, visual, cranial nerve, corticospinal, sensory, cerebellar and/or bladder/sexual impairments. Although not completely specific for MS, certain clinical patterns are highly suggestive of MS, especially in the appropriate age group. These include:

• Optic neuritis

Optic neuritis presents as an acute unilateral loss of vision (mainly central vision), often accompanied by pain in the eye, that worsens with eye movement. On examination, a relative afferent pupillary defect is usually present.

• Uhthoff's phenomenon

This refers to an increase of neurologic symptoms with an increase of body temperature (e.g., following exercise, a hot bath, or fever). This phenomenon occurs as the transmission through demyelinated segments of nerve fails with higher temperatures.

• Internuclear Ophthalmoplegia

Horizontal gaze of the eyes is mediated by neural circuits (see figure below) in the pons and midbrain in which the medial longitudinal fasciculus (MLF) plays a central role. For a patient to gaze to one side, the control center of horizontal eye movements is located in the ipsilateral paramedian pontine reticular formation (PPRF). The PPRF must signal the ipsilateral CN VI nucleus to turn the ipsilateral eye outwards (lateral rectus muscle). At the same time, the signals must reach the subnucleus of the contralateral 3rd nerve nucleus CN III nucleus to simultaneously turn the contralateral eye inwards (medial rectus muscle). The MLF is the pathway that connects to the contralateral third nerve nucleus. A lesion of the MLF does not allow the neural impulse to reach the contralateral third nerve nucleus. This results in an eye movement abnormality known as an internuclear ophthalmoplegia (INO). In an INO, the abducting eye moves correctly, but the adducting eye does not. Often, the abducting eye movement is accompanied by nystagmus.

Above: Circuitry of horizontal eye movements and the central role the MLF plays in mediating neural signals to the contralateral medial rectus muscle.

To differentiate an INO from a partial 3rd nerve palsy, one must test convergence as convergence is not mediated through the MLF. Thus, patients will be able to converge normally, confirming that the medial rectus (and 3rd nerve) are functioning normally. Unilateral and bilateral INOs are most commonly seen in patients with MS. In a younger patient, an INO is almost always due to MS. In older individuals, an INO can be see in brainstem stroke as well (typically basilar ischemia).

Above:  Unilateral Internuclearophthalmoplegia (INO) (Lesion A in the circuitry figure above) [place the cursor over the box and the video will play]

Above:  Bilateral Internuclearophthalmoplegia (INO) (Lesion B in the circuitry figure above) [place the cursor over the box and the video will play]
 

• Lhermitte's Phenomenon

Lhermitte's phenomenon is a transient "electric shock" or "buzzing" sensation that runs down the spine or into the limbs when the neck in flexed (note: this sign can sometimes be seen in structural diseases compressing the spinal cord, e.g., spondylosis, tumor, etc.).

Diagnostic Evaluation of Suspected MS

Until the recent era, MS was often very difficult to diagnose with certainty. Brain CT is usually normal in MS, unable to visualize the demyelinating plaques. The diagnosis was based on a clinical course of a relapsing and remitting disease (two or more deficits separated in time and space) in the appropriate age group, and in the absence of another explanation. The diagnosis was often supported by:

• CSF Abnormalities

Often the protein is elevated with some lymphocytic pleocytosis. In addition, signs of myelin breakdown and an ongoing immune response may be seen, especially during an attack (e.g., elevated myelin basic protein, oligoclonal bands, elevated IgG synthesis rate).

• Demonstration of "Silent" Lesions

Evoked potentials (EPs) were often used to confirm the presence of additional subclinical lesions. In these tests, a pathway was stimulated (visual, auditory or sensory) and their resultant potentials were recorded over the brain using scalp electrodes similar to those used during EEG. Visual evoked potentials were useful in detecting subclinical lesions in the optic nerves and visual pathways; auditory evoked potentials were able to detect lesions in the brainstem (thus, they were also known as brainstem evoked potentials); and somatosensory evoked potentials could assess the posterior columns and rostral sensory pathways.

Although CSF studies and EPs were often used in suspected MS, many cases were negative or equivocal. In addition, these studies are not completely specific for MS; thus, false positives can occur.

• Magnetic Resonance Imaging

MRI has markedly improved the ability to diagnose MS correctly. Not only is MRI able to exclude conditions that may mimic MS, it is able to see the characteristic demyelinating plaques in over 90% of patients.  These plaques are typically located in the deep white matter, especially in a periventricular pattern. There are also seen in the brainstem, cerebellum and spinal cord. Several examples follow:

Above: Note several plaques in the deep white matter. Looking closely at the image on the left, note the small plaque in the right posterior medulla.

Above: Late case of MS. Note the numerous periventricular white matter plaques.

Above: Note the plaque in the spinal cord adjacent to the C3 level.

Treatment

Management and treatment of MS is complex, involving both symptomatic and disease modifying therapy. Symptomatic therapy is available for spasticity, tremor, fatigue, bladder dysfunction and depression.

Intravenous methylprednisolone (solumedrol) is used for acute attacks to promote a quicker recovery. It is most commonly used in optic neuritis. It is also used for any attack where the symptoms are serious enough to interfere with daily functioning. However, this treatment likely does not change the natural history of the disease.

Several disease-modifying drugs are now approved by FDA in patients with relapsing and remitting MS. These include:

Interferon ß-1b (Betaseron)

Interferon ß-1a (Avonex and Rebif)

Glatiramer acetate/copolymer 1 (Copaxone)

All have been shown to significantly reduce the relapse rate as well as reduce the burden of lesions on MRI. All are given as an injection, either by subcutaneous or intramuscular route. They vary in how often they are given, from once a week for Avonex, three times a week for Rebif, and daily for Betaseron and Copaxone.

As a general rule, all patients with relapsing forms of MS should receive one of these agents indefinitely.

Treatment of the progressive phase of MS is much more difficult. A variety of immunosuppressive regiments have been tried, including total lymphoid radiation, methotrexate, cyclophosphamide, mitoxantrone, and azathioprine. All of these drugs are nonspecific immunosuppressive agents. They may halt a rapidly progressive course, but are problematic to use indefinitely, as they are associated with significant toxicity and risks.

The table below details the various disease modifying agents and when they should be used. Please note: students are NOT expected to know or memorize this table.