Multiple sclerosis

Multiple sclerosis

Demyelinating diseases of the central nervous system

• Epidemiology

Multiple sclerosis is one of the most common neurologic disorders, affecting approximately 300,000 patients in the United States, and its highest incidence is in young adults.
Initial symptoms generally commence before the age of 55 years, with a peak incidence between ages 20 and 40 years; women are affected nearly twice as often as men.
Epidemiologic studies show that the prevalence of the disease rises with increasing distance from the equator.

• Etiology

The cause of MS is unknown; however, it is believed to occur as a result of some combination of genetic and environmental factors.

environmental factors

Genetic factors

Vitamin D level may also play a role as may exposure to Epstein-Barr virus.

MS is not considered a hereditary disease; however, In identical twins are affected in 30% of the time, while around 5% for non-identical twins and 2.5% of siblings are affected.


• Pathophysiology
• MS has 4 distinct pathological stages:
inflammation, demyelination, and axonal transection and as the disease progress there will neurodegenerative phase of the disease.

• The cause of multiple sclerosis is unknown, but tissue damage and neurologic symptoms are thought to be triggered by an immune mechanism directed against myelin antigens.
• Viral infection or other inciting factors may promote the entry of T cells and antibodies into the central nervous system by disrupting the blood–brain barrier. This leads to increased expression of cell-adhesion molecules, matrix metalloproteinases, and proinflammatory cytokines. These molecules work in concert to attract additional immune cells, break down the extracellular matrix to aid their migration, and activate autoimmune responses against several antigens (eg, myelin basic protein, myelinassociated glycoprotein, myelin oligodendrocyte glycoprotein, Binding of these target antigens by antigen presenting cells triggers an autoimmune response that attack myelin which slows nerve conduction. Together with loss of axons and nerve cell bodies, this leads to progressive neurologic symptoms.

Clinical Findings

Initial or presenting symptoms
Multiple sclerosis can cause a wide variety of symptoms mirroring involvement of any part of the CNS. The spinal cord, optic nerves and brainstem are commonly involved sites.

Brain and spinal cord

Focal paresthesia, numbness and weakness

Optic nerve

Optic neuritis (sudden unilateral painful loss or blurring of vision in one eye).
Diplopia, vertigo and cranial nerve palsy.
Ataxia and unsteadiness.
Urinary urgency or hesitancy and incontinence.
Brainstem
cerebellum
Bladder dysfunction


The first demyelinating attack which is called clinically isolated syndrome is often transient, disappearing after a few days or weeks, even though some residual deficit may be found on neurologic examination.
Subsequent course
Months or years may elapse after the initial episode before further symptoms appear.
Then, either new symptoms develop or the original ones recur and progress this is called relapse.
Relapses may be triggered by infection and, perperium likely in the 3 months or so after childbirth (but are reduced during the pregnancy itself). Fever can cause transient deterioration in patients with a fixed and stable deficit.
With time and after a number of relapses and usually incomplete remissions the patient may become increasingly disabled by weakness, stiffness, sensory disturbances, unsteadiness of the limbs, impaired vision, and urinary incontinence.

MS has 4 clinical patterns:

• relapsing-remitting form (85% of cases), in which progression does not occur between attacks.
• secondary progressive form (80% of cases after 25 years) characterized by a gradually progressive course after an initial relapsing-remitting pattern;
• primary progressive form (10% of cases) with gradual progression of disability from clinical onset.
• progressive-relapsing form occurs rarely, with acute relapses being superimposed on a primary progressive course.

The course of MS

The diagnosis of MS requires the demonstration of otherwise unexplained CNS lesions separated in time and space.
traditionally, this meant two or more clinical relapses affecting different parts of the nervous system, and the first ever episode was labelled ‘clinically isolated syndrome’ (CIS). Recent changes to diagnostic criteria mean that MS may be diagnosed after an isolated episode (i.e. at the CIS stage), provided that certain criteria are met

Diagnosis

Diagnostic criteria for primary progressive MS:
1 year of progression plus 2 of the following:
• Evidence for dissemination in space with ≥ 1 T2 lesions in MS-typical brain regions
• Evidence for dissemination in space based on ≥ 2 lesions in the spinal cord
• Positive cerebrospinal fluid (evidence of oligoclonal band and/or elevated immunoglobulin G index)
CSF oligoclonal band


There is no single diagnostic test that is definitive for MS and the results of investigation need to be combined with the clinical picture in order to make a diagnosis.
MRI is the most important investigation as it is the most sensitive technique for imaging lesions in brain and spinal cord and for excluding other causes that have provoked the neurological deficit and exclude other disorders but do not themselves justify a definitive diagnosis of multiple sclerosis.

Investigative Studies

Multiple high-signal lesions (arrows) seen particularly in the periventricular region on T2 image.
In T1 image with gadolinium enhancement, recent lesions (A arrows) show enhancement, suggesting active inflammation (enhancement persists for 4 weeks); older lesions (B arrows) show no enhancement but low signal, suggesting gliosis.

Characteristic Dawson fingers reflecting periventricular demyelinating lesion that appear perpendicular to corpus callosun on sagittal MRI
Demyelinating lesion in cervical spinal cord, high-signal T2 images (arrows).

The cerebrospinal fluid (CSF) is commonly abnormal, with mild lymphocytosis or a slightly increased protein concentration, especially if examined soon after an acute relapse. CSF protein electrophoresis shows the presence of (oligoclonal bands) in 90% of patients.
If clinical evidence of a lesion exists at only one site in the central nervous system, a diagnosis of multiple sclerosis cannot properly be made unless other regions are affected subclinically. Such subclinical involvement may be detected by the electrocerebral responses evoked by monocular visual stimulation (visual evoked potentials), monaural stimulation with repetitive clicks (brainstem auditory evoked potentials), or electrical stimulation of a peripheral nerve (somatosensory evoked potentials).

The management of MS involves three different strands:

• treatment of the acute episode.
• prevention of future relapses.
• treatment of complications and patient’s disability.
The acute episode
Corticosteroids may hasten recovery from acute relapses, but the extent of the recovery itself is unchanged.
the regimen most commonly used is intravenous methylprednisolone (1 g daily) for 5 days, followed by an oral prednisone taper (1 mg/kg/d for 1 week, with rapid reduction over the ensuing 1-2 weeks).
Long-term corticosteroid administration does not prevent relapses and should not be used because of unacceptable side effects.
Management


DISEASE-MODIFYING THERAPIES “first generation”
the first disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) was approved by US FDA is Interferon beta-1b (Betaseron) in 1993 then glatiramer acetate (Copaxone) in 1996, IM interferon beta-1a (Avonex) in 1997, and subcutaneous (SC) interferon beta-1a (Rebif) in 2002.
all four agents reduce the number of relapses by approximately 30%.
For patients on interferon therapy, hematologic abnormalities, including leukopenia, thrombocytopenia, and liver function test abnormalities.
glatiramer acetate side effect include Lipodystrophy, Idiosyncratic chest pain, palpitations, anxiety, dyspnea, urticaria, flushing and throat constriction that is not cardiopulmonary in nature, and usually develops within 15 minutes of the injection and usually occurs after several months of treatment.

Prevention of further relapses

The exact mechanisms of action of interferon and glatiramer acetate are not known. In general, the injectable DMTs have an anti-inflammatory effect on the immune system, shifting from a proinflammatory state (helper T cell type 1 [TH1]) to a more anti-inflammatory (helper T cell type 2 [TH2]) cytokine profile.
SECOND-GENERATION DISEASE-MODIFYING THERAPIES
Natalizumab
represents the first second generation DMT for MS.
Mechanism of action Prevents activated T cells from crossing the blood-brain barrier by blocking the binding of antigen-4 which is expressed on all white blood cells except neutrophils to vascular cell adhesion molecule 1 which is expressed on the surface of vascular endothelium.
Effect it decreases the relapse rate by 67%
Side effects progressive multifocal leukoencephalopathy (PML) 1:1000

Primary or secondary progressive multiple sclerosis

Optimal treatment in these forms of the disease is less clear. There is no established treatment for primary progressive multiple sclerosis.
Mitoxantrone may help to arrest the course of secondary progressive disease
Treatment of complications and patient’s disability
Exercise and physical therapy are important, but excessive exertion must be avoided, particularly during periods of acute relapse.
Fatigue is a serious problem for many patients and sometimes responds to amantadine, modafinil or one of the selective serotonin reuptake inhibitor.
Treatment for spasticity with baclofen, tizanidine or local botulinum toxin injection is often needed.
Treatment for other aspects of advanced multiple sclerosis such as cognitive deficits, pain, tremor, and ataxia is generally less successful.


At least partial recovery from an acute episode can be anticipated, but it is impossible to predict when the next relapse will occur.
Features that tend to imply a more favorable prognosis include

Although some degree of disability is likely to result eventually, approximately one-half of patients are only mildly or moderately disabled 10 years after the onset of symptoms.

prognosis

• female sex,
• onset before 40 years of age,
• presentation with visual or somatosensory, rather than pyramidal or cerebellar dysfunction.

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