Multiple Sclerosis (MS) is the most common non-trauma cause of nervous system related disability in young adults, with the typical age of diagnosis being between 20-40 years old.  It is a disease of the central nervous system (CNS) in which the ability of neurons to transmit neural signals breaks down. As a result, the body cannot interpret and respond to environmental stimuli as effectively. Since MS can affect various parts of the CNS, it can have a wide variety of symptoms, ranging from motor, sensory, or cognitive deficits. Usually, patients initially experience unpredictable episodes of symptoms before progressing to more persistent and permanent states of disability.

Pathophysiology of MS

The pathophysiological hallmark of MS is the formation of demyelinating lesions in the central nervous system (an area with loss of myelin and relative preservation of axons). Since the role of myelin is to increase the speed of neuronal action potentials, the breakdown of myelin in MS results in slower or potentially absent signals. Some of the most commonly affected sites are the optic nerves (esp optic chiasm and tract),  white matter serving the cortex (subcortical), areas around the ventricles of the brain (periventricular), and grey matter below the cortex (deep grey nuclei).

While the exact cause of MS is not completely understood, it is considered an immune mediated disease influenced by both genetic and environmental factors. It is thought that a breakdown of the blood brain barrier (BBB) occurs, which promotes the infiltration of reactive immune cells such as T cells, B cells, and myeloid cells into the CNS tissue. These immune cells produce antibodies that mark myelin as foreign, causing inflammation and the destruction of the myelin. This inflammatory component of MS likely may explain the on and off nature of symptoms that most patients initially experience (this type of MS is called relapsing-remitting MS).

Through the demyelination around axons, scarring and fibrosis also occurs. This is where the name of the disease comes from; sclerosis means hardening or scarring of tissue. Multiple scars are found in the white matter of the brain and spinal cord. Although new myelin may be formed in these lesions, this remyelination is often limited and variable between patients.

In addition to neuronal conduction, myelin also functions to protect and nourish axons. Thus, prolonged areas of demyelination can eventually lead axonal loss as well, causing irreversible clinical and cognitive deficits (this type of MS is called progressive MS). However, for unknown reasons, a small subset of patients experience a progressive style MS right from disease onset.

Histopathology of MS

MS lesions can be designated as active, inactive, or mixed active/inactive. This differentiation is based on the distribution of inflammatory cells around the plaque and the existence of demyelination. Histological and immunohistological stains can be used for identifying these lesions. For example, myelin can be seen with special stains (e.g. Luxol fast blue, Klüver-Barerra-Stains) while cell morphology can be seen with hematoxylin and eosin stains.  Moreover, inflammatory cells such as macrophages can be seen with immunohistochemical markers (e.g. CD68).   Thus, a combination of the prementioned stains can help illuminate the loss of myelin in neurons caused by macrophages.

Figure 12-53. Histologic staining of MS lesion showing loss of myelin staining (left) and increase in macrophage staining (right). The picture on the left shows brain tissue stained with Klüver-Barerra, which colours myelinated tissue a bright navy blue. The area of discolouration indicates demyelinated MS plaque tissue. The picture on the right shows immunohistochemical staining for CD68, in which the brown dots indicate the presence of macrophages. This image shows that there are many more macrophages within the lesion compared to the normal tissue.

https://commons.wikimedia.org/wiki/File:MS_Demyelinisation_KB_10x.jpg

https://commons.wikimedia.org/wiki/File:MS_Demyelinisation_CD68_10xv2.jpg

It should be noted that the presence of inflammatory cells within the plaques varies depending on the lesion’s stage. While active lesions tend to contain many macrophages, inactive/chronic lesions often contain few or none. Thus, stains such as CD68 may help determine lesion stage.

MS pathology with common signs and symptoms

Patients often have many complaints of problems with sensory and/or motor control long before an official diagnosis.  Because demyelination can occur in any white matter in the CNS (i.e. brain and spinal cord), signs and symptoms can be separated from each geographically and temporally.  For example, a patient may have issues with vision of right eye (sensory) and then problems with controlling the left foot (motor)  two months later.  Below is a table of some common signs and symptoms reported in MS. Please note that this is not an exhaustive list.

Table 12-5 Signs and symptoms of MS and location of demyelination

Diagnosis of MS

The diagnosis of MS is largely based on the signs and symptoms. Moreover, it is also required that there be multiple lesions that vary in time and space, and to exclude other conditions with similar symptoms. In other words, the lesions must be in various stages and various locations within the CNS. This can be determined using tests such as magnetic resonance imaging (MRI) of the brain and spinal cord,  cerebral spinal fluid (CSF) analysis, or measuring electricity flowing in nerves (evoked potentials).

MRI of CNS

Through MRI, a contrast agent called gadolinium is used to highlight lesions with active demyelination. The McDonald criteria is the most commonly used criteria to diagnose MS, combining both clinical assessment of symptoms and the additional tests mentioned. In order to diagnose MS using this criteria, a patient must have a least one symptomatic episode, as well as an MRI scan showing lesions at various stages and locations in the CNS.

Figure 12-54.  MRI showing MS lesion (red arrow) using gadolinium contrast

https://commons.wikimedia.org/wiki/File:MSMRIMark.png

CSF Analysis

Cerebral spinal fluid is collected by an invasive procedure known as  lumbar puncture. Because CSF circulates around both the brain and spinal cord, this CSF sample can show the presence of antibodies, which are abnormally present during MS.

Evoked potential tests

Evoked potential tests measure the electricity of the nervous system upon a stimulus (visual or electrical).  While being stimulated (e.g. watching a visual pattern or by electrical stimulation via electrodes), electrical impulses are applied to the affected limbs and electrodes measure the speed the electricity travels down the  nerves.

Treatment of MS

There is no cure for multiple sclerosis. Some people have mild symptoms where  no treatment is necessary and others have flare ups with periods of remission.  However, when MS affects health and activities of daily living, treatment focuses on reducing the inflammatory and circulating antibodies associated with MS.

Corticosteroids are prescribed to reduce inflammation, particularly the inflammatory process which is attacking the myelin.

Plasma exchange (plasmapheresis) occurs when MS has a bout of new, severe symptoms which don’t respond to corticosteroids.  Plasmapheresis involves separating whole blood into blood cells (E.g. red and white blood cells) and the watery plasma where antibodies are found.  After antibody removal, the plasma is mixed back with the blood cells and put back into circulation.

Monoclonal antibodies are synthetic antibodies made to directly interfere with the B cells to prevent their formation of the offending antibodies that cause demyelination.

Summary

Review questions

short questions

• – Warm readers up to this, write about the manifestations of spinal cord demyelination generally (eg sensory and motor impairments)
  • o Then present as question form – more specific symptoms like – foot drop
  • o Focus on the how part (patho -> manifestations)
  • o Tiny case studies – give the manifestation, and then explain why the lesion is where it is

References

Huang WJ, Chen WW, Zhang X. Multiple sclerosis: Pathology, diagnosis and treatments. Exp Ther Med. 2017 Jun;13(6):3163-3166. doi: 10.3892/etm.2017.4410. Epub 2017 Apr 28. PMID: 28588671; PMCID: PMC5450788.

https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/diagnosis-treatment/drc-20350274