Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized with demyelinating plaques scattered throughout the white matter of the brain and the spinal cord. In the areas of demyelination, gliosis develops which causes ‘multiplication’ of the brain matter which inspired the name of the disease.
The incidence of MS varies in the different parts of the world. It increases with distance from the equator in both hemispheres. The Caucasians are more susceptible to developing the disease. A high-risk area with morbidity rate of >30/100,000 people covers North Europe, North America, South Canada and New Zealand. The rest of Europe and Australia with a morbidity rate of 5-29/100,000 fall within the medium-risk area. The low-risk area includes Asia, large part of Africa, Latin America and the Middle East.
In Bulgaria, the morbidity rate is estimated to over 40/100,000 people.
Susceptibility to MS is determined by gender; it is more common in women. MS is the disease of young people as it most frequently affects individuals at the ages between 20 and 40 years, with a peak of the disease at about 30 years. Recently, there is a tendency of the disease to increasingly occur among young people of 15-16 years of age. MS is rare after the age of 59 years.
The etiological cause of MS is still not known. Various infectious agents (viruses, bacteria, spirochetes) are identified as its main factors. Most important of them are the viruses of Herpes simplex, rabies, measles, cytomegalovirus, influenza.
It is believed that these agents activate human T-lymphocytes using the so called ‘molecular mimicry’. This means that the disease agents produce proteins similar to the proteins of unaffected cells. Therefore, the immune system destructs its own structural units by attacking the pathogenic cause. This is followed by a complex cascade of autoimmune processes resulting in the release of inflammatory factors. They cause changes to the blood-brain barrier and ultimately lead to the destruction of myelin and oligodendrocytes. Myelin is the sheath surrounding nerve cell axon. The nerve current flows through Na channels located in the so called ‘voltage-clamped nodes of Ranvier’. Then the integrity of myelin is damaged, then the nerve current is slowed down and the symptoms of MS occur.
Demyelinating plaques are formed as a result of the process of demyelination. They have a typical positioning, mainly surrounding the small vessels where the inflammatory foci are formed. Plaques are usually localized around the lateral ventricles, corpus callosum, cerebellum, brainstem, optic nerves, and cervical segment of the myelon. Plaques can be fresh (active) with marked manifestations of inflammation (edema, perivascular infiltrates of lymphocytes and macrophages). The myelin is destroyed leading to axon exposure. Development of gliosis can be observed in the chronic inactive plaques.
The symptoms of MS are diverse and significantly vary among different patients and in the different moments of disease progression in a single patient. Some patients with multiple sclerosis may not develop symptoms for different periods of time. Others experience 2-3 seizures per year. Symptoms can be divided in several groups:
1) Sensory disorders: These are one of the most common complaints. They may include numbness, tingling or impaired sensitivity of one or more limbs. Typical symptom is the electric shock-like sensation that occurs when abruptly bending the head forward (Lhermitte's sign). Patients often experience chronic pain in the limbs.
2) Visual disorders: The optic neuritis (retrobulbar neuritis) is the first sign of the disease in approximately 25% of the patients. It is characterized by partial or complete loss of vision of one eye which develops for hours to days. At a later stage, most of the patients develop the other MS symptoms. Some patients experience relapsing retrobulbar neurites.
3) Stem disorders: Double vision, disturbed eye movement, internuclear ophthalmoparesis. They are the results of affected eye movement nerves and brain structures (fasciculus longitudinalis medialis).
4) Motor disorders and muscle weakness: Loss of muscle strength due to pyramidal lesions of deep tendon reflexes and occurrence of pathological reflexes of the Babinski and Rossolimo group, typical loss of abdominal reflexes. Development of mono-, hemi-, para-, or quadriparesis and plegias.
5) Changes in muscle tone: Developing spasticity with difficulty in walking.
6) Coordination disorders: Developing paleocerebellar and neocerebellar syndrome (dysmetria, dysdiadochokinesia, ataxia, slurred speech, intentional tremor). The cerebellar symptoms are one of the most disabling.
7) Pelvic floor dysfunction: Miction disorders with the occurrence of imperative urges to urinate, incontinence (involuntary leakage of urine) or retention (inability to empty the bladder and pass urine).
8) Fatigue syndrome: This is one of the most typical symptoms with multiple sclerosis. It is characterized with the lack of energy and motivations. It is the result of immune dysfunction.
9) Cognitive disorders and mental changes: Depression or euphoria, problems with memory, attention or concentration.
10) Seizures and paroxysmal symptoms: Observed in about 5% of the patients, they can be manifested in partial motor and sensory seizures or generalized tonic-clonic seizures. Paroxysmal tonic spasms or paroxysmal dysarthria can also be observed.
There are four clinical forms of disease progression:
1) Relapsing-remitting form (RRMS): The most common form of all where patients experience exacerbations followed by total or partial remission of symptoms.
2) Primary progressive form (PPMS): It is defined by slow and gradual progression from the very onset of the disease and frequent lack of clear exacerbations.
3) Secondary progressive form (SPMS): With the progression of disease, patients with relapsing-remitting MS convert into secondary progression. It may run with or without further attacks, with progression between cycles.
4) Progressive relapsing form (PRMS): Progression begins from the very onset of the disease. Clear attacks with or without total remission, and constant progression in between-attack periods are observed.
Different clinical, laboratory, neuroimaging and electrophysiological methods are used to diagnose patients with MS. A mild to moderate pleocytosis and increased gamma globulins are observed during the CSF test, or oligoclonality during electrophoresis.
Magnetic resonance tomography is the most sensitive method for evidencing MS. There are diagnostic X-ray criteria for dissemination of lesions in time and space. Evidence of dissemination of lesions in space is demonstrated by >1 Т2 lesions present in two of four of the following areas of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord. Dissemination of lesions in time is demonstrated by either a new T2 or contract-enhanced lesion on follow-up MRI. The most typical of all are the lesions located next to the lateral ventricles, corpus callosum or spinal cord. Testing of visual and auditory evoked potentials is also used.
Differential diagnosis is used with different diseases that can cause multifocal CNS disorders, such as systemic lupus erythematosus, Sjögren's syndrome and other vasculites, neuroborreliosis, spinocerebellar degeneration, strokes, vitamin B12 deficiency, Wegener’s granulomatosis (WG), etc.
The treatment of MS is administered during exacerbations, in between-attack periods, and symptomatically.
MS during exacerbations is treated with corticosteroids (CS). CS have an anti-inflammatory, immunomodulating and brain-blood-barrier stabilizing action. Often the therapy is pulsed at high CS doses (500÷1000 mg i.v.) The treatment regime varies from three to seven days based on the severity of the attack, followed by a CS therapy with dose tapering.
MS in between-attack periods is treated with beta interferons, glatiramer acetate, immunoglobulins, immunomodulators, immunosuppressants. Beta interferons and glatiramer acetate are medications of first choice which modify the course of the disease. The aim is to extend the attack-free period and reduce the number of exacerbations.
The symptomatic treatment is aimed at influencing the spasticity, chronic fatigue, tremor, pelvic floor dysfunction, pain. Physiotherapy and rehabilitation have an important role in MS therapy.