Demyelination diseases

 

Multiple sclerosis

Multiple sclerosis (MS) – is a chronic disease that begins most commonly in young adults and is characterized pathologically by multiple areas of central nervous system (CNS) white matter inflammation, demyelination, and glial scarring (sclerosis). The lesions are therefore multiple in spaces.

The clinical course varies from a benign, largely symptom – free disease to one that is rapidly progressive and disabling. Most patients begin with relapsing and remitting symptoms. At first recovery from relapses is almost complete, but theeurological disabilities accrue gradually. The lesions are therefore multiple in time and space.

The cause is elusive, although autoimmune mechanisms, possibly triggered by environmental factors in genetically susceptible individuals, are thought to be important.

 

Epidemiology

       Age of onset is between 20 – 40 years. Usually it is 21 – 25 years, in women – 2 – 3 years earlier. In women the incidence of MS is 1.5 – 2 times higher than in men. Nowadays there are about 2 mln people with MS all over the world. The geographic distribution is uneven. Most of northern USA, southern Canada, northern Europe, southern Australia and New Zealand are areas of high prevalence.

      In Ukraine the incidence of MS is 15 per 100 000 people. But it is much more higher in western regions (25 per 100 000 people) than in eastern and southern ones (6 – 8 per 100 000 people).

The main cause of the increased growth of the disease

1.      Better diagnosis

2.      Unitary diagnostic scales

3.      Increasing possibilities of treatment that leads to the growth of percentage of the patients with long lasting course of the disease

4.      True growth of MS incidence

 

Etiology

The cause of MS is unknown. There are 2 groups of possible reasons of the disease:

I.      Genetic susceptibility

II.     Environmental factors

1.      Infections (the virus can influence oervous system directly or through the autoimmune mechanisms).

2.      Geographical (ground, water properties, the number of light days in a year)

3.      Toxic

4.      Social conditions

5.      Diet (domination of meat in the diet)

6.      Other factors (trauma)

 

I.      Compelling data indicate that susceptibility to MS is inherited. The major histocompatibility complex (MHC) on chromosome 6 has been identified as one genetic determinant for MS. The MHC encodes the genes for the histocompatibility antigens (the human leucocyte antigen [HLA] system) involved in antigen presentation to T cells. The class II haplotype DR15, DQ6, Dw2 is associated with increased risk of MS.

II.     1.  In MS demyelination could be precipitated by a viral infection. Measles, rubella, mumps, coronavirus, parainfluenza, herpes simplex, Epstein – Barr and human T – cell lymphotropic virus type I viruses all have been reported to be present in patients with MS. Perhaps no single virus is the trigger for demyelination in all patients with MS. Instead, several different viruses may be involved.

2.        The geographic distribution of MS is uneven. In general, the disease increases in frequency with latitude in both the northern and southern hemispheres, although the rates tend to decreases above 65 degrees north or south. Most of northern Europe, northern United States, southern Canada, southern Australia and New Zealand are areas of high prevalence. Southern Europe, southern United States, Asia Minor, the Middle east, India, parts of northern Africa and South Africa have medium prevalence rates. Low prevalence areas are Japan, China, Latin and South America.

3.        Toxins can cause changes of biochemical and antigen properties of myelin. Also they suppress remyelination and activate immune modulation.  Such substances as Cu, Zn, Mn, Co and vitamin D and B12 deficiency can also cause demyelination.

4.        Emotional stress and other social conditions play important role in pathogenesis of this disease.

5.        Meat diet is considered to be one of the factors that can provoke MS.

 

Pathogenesis

      Different etiologic agents provoke autoimmune mechanisms. The result of this process is myelin destruction. At the beginning of the process auto-allergic processes prevail over the other ones. Then immunodeficiency is developed. The typical features of MS pathogenesis are:

·        Clinical and immune signs are closely connected with each other in MS patients. Usually immune signs are the first ones

·        There is disturbance of activating and suppressing cytokines balance

·        The immunity is changed in the course of the disease

·        There are signs of immune suppression and immune modulation according to the stage of the disease – exacerbation or remission

 

Pathology 

       There are multiple areas of Central Nervous System white matter inflammation, demyelination and glial scarring (sclerosis). The lesions are multiple in spaces. They are located mainly in spinal cord, cerebellum, n.Opticus, brain white substance.

 

Macroscopy

•  Some degree of cerebral and spinal cord atrophy is usually seen at postmortem.

• The characteristic lesion consists of a demarcated periventricular plaque of demyelination.

• Although the plaques predominantly occupy the white matter, cortical lesions are encountered.

• The plaques tend to be perivenular.

• The optic nerve, brainstem and spinal cord are all usually affected by the time of death

 

Clinical features

The beginning of the disease usually is slow. The first symptom is one of the next ones:

1.      Paresthesia. It is the feeling of numbness or tingling in one of the extremity. It can be spread during the next 3 – 4 days and lasts for about 1 – 2 weeks, then gradually disappear.

2.      Motor disorders – weakness in lower extremities. This symptom is much more common at the age of 25 – 40 years.

3.      Retrobulbar neuritis is a progressive loss of vision, colour vision disturbances. It lasts for about several weeks.

4.      N. Oculomotorius disorders (diplopia and cross eye).

5.      Pelvis disorders (retention of urine, micturition)

6.      Acute vestibular syndrome

7.      Cerebellar disorders – ataxia, disorders of coordination.

 

The typical clinical features of MS:

1.      Motor disorders – 89 – 97%

2.      Ataxia – cerebellar, sensitive and vestibular – 62 – 74%

3.      Sensory disorders – pains and sensitive ataxia  – 72 – 74%

4.      Brain stem symptoms – vestibular syndrome, dysarthria, CN’s lesion – 47 – 58%

5.      Visual and eye movements disorders – 42 – 52%

6.      Autonomic disturbances – pelvic and sexual disorders – 46 – 60%

7.      Nonspecific symptoms – cognitive, memory disturbances, loss of attention – 62%

8.      Paroxysmal symptoms

 

1.      Motor disorders

Hemiparesis, lower paraparesis and monoparesis are common symptoms of MS. Upper extremities are injured very seldom. The typical signs of these symptoms are low muscle strength, the presence of pathological reflexes and low abdominal reflexes. There are also changes of muscle tonus – spastic hypertonus, hypotonus or dystonus. Hypotonus can be the sign of cerebellum and spinal cord posterior columns lesion.

2.      Ataxia

There are dynamic and static ataxia, dysmetry, hypermetry, intention, asynergy.

3.      Sensory disorders

Subjective sensory disturbances are early signs of MS. Then conductive sensory disorders are joined to them. Muscle – joint sense usually suffers at the fifth year of the disease and later. The loss of vibration sense points on posterior columns lesion.

4.      Brain stem disturbances

There is vestibular symptom with dizziness, nystagmus and vestibular ataxia. Sometimes trigeminal pains are observed.

5.      Visual and eye movements disorders

The typical features of MS are retrobulbar neuritis, subatrophy of optic nerve disc, decoloration of disc’s temporal part. Eye movement disorders mean that there are syndromes of ophthalmoplegia.

6.      Autonomic (pelvic) disorders

A.     Syndrome of m. Detrussor hyperreflexion. That means urine bladder inability to accumulate urine. The main symptoms are micturition, increased frequency of urination, incontinence of urine, retention of urine.

B.     Incomplete urine bladder emptiness. Dyssynergy of m. Detrussor and Sphincter.

 

7.      Nonspecific symptoms

There are general weakness, cognitive disorders, memory, attention disturbances, behavioral disorders, depression, euphoria and fatigue syndrome.  

8.      Paroxysmal symptoms

They unite short lasting sensory and motor disorders. They can be observed 200 – 300 times per day. They are:

a.      Tonic muscles spasm (painful and short lasting)

b.       Dysarthria and ataxia attacks

c.      Lermitt symtom – it is a short lasting feeling of electrical current along the spinal cord

d.      Paroxysmal trigeminal pains

e.      Atypical pains in extremities

f.        Paroxysmal itching

g.      Paroxysmal choreoatetosis

h.      Paroxysmal nystagmus

i.        Paroxysmal facial hemispasm

j.         Epileptic attacks (focal and general)

Pains are very often observed at MS. They can be paroxysmal or chronic ones.

In some patients Uthoff’s symptoms can be observed – it is the worsening of patients state after the hot bathroom or hot meal.

Clinical forms

1.      Cerebral foms:

a)     cortical (epileptic attacks, psychiatric disorders)

b)     visual

c)      brain stem

d)     cerebellar

2.      Spinal foms:

a)     Cervical

b)     Thoracic

c)      lumbar – sacral

d)     pseudotabes

3.      Cerebrospinal

 

The course of the disease:

1.   Acute

2.   Subacute

3.   Chronic – remittent, remittent – progressive, progressive – remittent, progressive

The most common is remittent course of the disease, when exacerbation follows remission.

 

The periods of the disease:

1.      Exacerbation

2.      Remission (complete, incomplete)

3.      Stable period

 

MS degree:

• I – patient has difficulty to walk only after physical training

• II – patient has difficulty to walk and weakness on 2-3 km

• III – patient has spastic-paretic gait, difficulty to walk and weakness on 200-300 m.

• IV – patient can’t to walk without help

• V – patient can’t to walk or has blindness

 

Diagnosis

In order to put a right diagnosis we use clinical and paraclinical data. There are such types of diagnosis:

·        Veridical MS

·        Credible MS

·        Possible MS

To put veridical MS we have to reveal in patient at least 2 focuses of lesion and 2 exacerbations, or 2 exacerbations of 1 clinical focus and 1 paraclinical supposed focus.

For MS diagnosis we use:

1.      Immune examinations of blood and CSF. Usually there are increased Ig G, M, A contents

2.      Insignificant increasing of protein content and moderate pleocytosis in CSF

3.      Lymphocytosis, eosynophilia – in exacerbation stage; leukopenia, lymphopenia – in the period of remission

4.      Increased thrombocytes aggregation and fibrinogen content

5.      Increased Ig content in serum and decreased T – lymphocytes quantity

 

II. The most accurate method is MRI. According to the accepted criteria there should be at least 3 focuses (2 of them should be located paraventricularly, 1 – subtentorialy (that means in brain stem or cerebellum). The diameter of focuses should be at least 6 mm, or there should be 4 focuses, 1 of them periventricularly.

III. The method of evoked potentials. This is a method that reveals bioelectrical brain activity in response to the stimulation. This method is not a specific one for MS diagnosis.

Treatment

1.      Pathogenetical treatment

2.      Symptomatic treatment

 

1.   Pathogenetical treatment

a.      Corticosteroids and ACTH

b.      Cytostatics and immune modulators, non specific immune suppressors

c.      Cytokines, interferones

d.      Antigen – specific immune therapy

 

a.      Corticosteroids and ACTH

      These medicines have immune suppressive action and can shorten the period of exacerbation. The main representatives are – Prednisone, Methylprednisolone, Dexamethasone.

Prednisone is used orally 1 – 1.5 mg/kg/day twice a day during 10 – 14 days. Then during the next 2 months we decrease the dose gradually.

One of the most popular schema for Methylprednisolone usage is 500 – 1000 mg per day i/v in 500 ml of physiological solution during 3 – 5 days. Then Prednisone is used in dose 0.5 – 1 mg/kg during 3 – 7 days with gradually decreasing of dose during the next 2 – 3 weeks. This way of usage has much more expressed and quick effectiveness and insignificant outside effects.

Dexamethasone is used i/v or i/m according to the schema – 8 mg per day during 7 days, 4 mg – 4 days, 2 mg – 3 days. It is used at retrobulbar neuritis.

The peculiarities of Corticosteroids usage:

·        Long lasting and frequent usage is undesirable

·        Usually H-2 blockers are used together with Corticosteroids

·        ACTH has immune suppressive activity, inhibits cellular and humoral immunity.  It is used in dose 40 – 100 U i/m during 10 – 14 days

·        Plasmapheresis is used in case of exacerbation

 

b.     Cytostatics and immune modulators, non specific immune suppressors

 These are the medicines of choice and are used at chronic progressive forms when there are no effects from the Corticosteroids. To them belong Asatioprine, Cyclophosfamidum, Cyclosporinum A. But all of these medicines have a lot of outside effects.

The representatives of immune modulators are – T – activinum, Timalinum, Myelopid, Levamisolum. They are prescribed at progressive forms of MS.

T – activinum is used in dose 100 mcg s/c every evening during 5 days, then 1 – 3 injections every 10 days.

Timalinum is used in dose 10 mg i/m twice a day during 5 days, then every 10 days 2 injections are used.

c.      Interferones

  They are used mainly for exacerbations’ prevention and selective immune correction. There are 3 types of Interferonum – α, β, γ.

·        α – Interferonum has neither toxic nor treating activity

·        γ – Interferonum activates immune system and that’s why it provokes exacerbations

·        β – Interferonum inhibits production of γ – interferonum, increases activity of T – suppressors, has antiproliferative, antiviral and immune modulating properties

·        Rebif – is a modern human β – interferonum produced by “Serono” production and is used for MS treatment. It is used in dose 6 – 12 mln s/c three times per week. It is one of the most effective modern medicines in MS patients, but unfortunately it is very expensive.

 

d.     Antigen – specific immune therapy

 One of the representatives of these medications is Copaxone, made in Israel. Cost of treatment is about 7 000 $. It is used in dose 20 mg per day s/c during 6 – 24 months. It has selective immune modulating action.

Besides all of these mentioned medicines in MS patients we use also:

·        Vitamins B group

·        Desensibilizative medicines

·        Amino acids

·        Nootrops

·        ATP, Cocarboxylasa

·        Biostimulants

·        Entero and hemosorption

·        Antiplatelet

·        Antioxydants

·        Angioprotectors

·        Inhibitors of proteolytic enzymes

·        Regeneration stimulants

 

Symptomatic treatment of MS

Pelvis disorders

·        Proserinum, Halantaminum decrease m. Detrussor hyperreflexion.

·        α – Adrenoblockers decrease dysynergy of Sphincter and Detrussor.

Spasticity

·        Baclofen 5 mg 3 times per day

·        Sirdalude 4 mg 3 times per day

Tremor

·        β – Adrenoblockers are used at postural tremor

·        Clonasepam, Carbamasepam are used at intention

Hyperkinetic form

·        Adrenoblockers

·        Antidepressants

Asthenia

·        Psychostimulants

·        Dopaminergic medicines

Paroxysmal signs

·        Carbamasepinum

·        Filepsin

 

Prevention of MS To avoid catching cold, acute respiratory infections, stress, pregnancy and childbirth, isolation and heating procedures.

Working ability The patients with MS usually have one of invalidity group:

III – if they need much more comfortable working conditions

II – patients with well – expressed permanent neurological signs

I – patients that need somebody to care about them

 

Acute multiple encephalomyelitis (AMEM)

     It is an infectious – allergic disease that is characterized by acute multiple lesion of the brain and spinal cord.

The etiology of this disease is still unknown. Perhaps it is a virus.

The pathology consists of multiple perivascular demyelinating focuses and vascular inflammatory reaction. The process is localized in brain white substance, brain stem and spinal cord.

Clinical features

     The disease develops acutely in most cases. In the beginning it is very similar to acute respiratory infection. There are headache, vomiting, general weakness, fever, psychomotor excitement. Sometimes general cerebral and meningeal syndromes are well – expressed. 3 – 7 days later focal signs appear.

     Focal signs are variable. Different cerebral and spinal structures can be involved in the process.

     In some patients there are symptoms of lesion of radices and peripheral nerves associated with pain, sensory disorders, amyotrophy and low reflexes.

      Paraplegia in such patients often is associated with conductive sensory disorders, pelvis disorders and bed – sores.

      The most common cerebral disturbances in such patients are nystagmus and eye movement disorders, CN’s bulbar group lesion.

 

Clinical forms of the disease

·        Encephalomyelopoliradiculoneuritis – it is the most common form of the disease, which is characterized by the lesion of all parts of nervous system.

·        Polioencephalomyelitis – it is characterized by the lesion of CN’s nuclei and spinal cord gray substance.

·        Opticoencephalomyelitis and opticomyelitis – are characterized by optic nerve neuritis and symptoms of lesion of brain and spinal cord.

·        Disseminated myelitis – the spinal cord is damaged on different levels.

 

Treatment of the disease

     Corticoids are used in order to treat such patients. Among them are Prednisolone and Methylprednisolone. The last one is used in dose 10 – 15 mg per kg i/v by drops per day. Later we can use it in pills  – 1.5 – 2 mg/kg every other day.

 Together with this medicine we prescribe anabolics , K, Ca, vitamin C.

In acute stage we prescribe desensibilizating and dehydrating medicines. In case of severe bulbar disorders we include resuscitation measures.

Plasmapheresis and vitamin B are also used.

 In residual period we prescribe massage, dibasol, KJ, biostomulants, Lidasa, Seduxen, sanatorium treatment.