Theme: Epilepsy and no convulsive paroxysmal syndromes.

Infection diseases of nervous system.

Demyelination diseases

 

 

Epilepsy and convulsion syndromes

 

 

 

Epilepsy is a chronic disorder, which is characterized by the presence of:

·        Epileptic focus

·        Recurrent attacks with various clinical signs

·        Personality disorders between attacks

·        Some specific paraclinical signs

 

Epidemiology

      The prevalence of epilepsy is 0.8 – 1.2%. About 40 million people are affected worldwide. Among them 6 million people live in Europe. In men the incidence of epilepsy is 1.5 times higher than in women. The disease begins at the age under 10 – in 31 %; 20 – in 29 %; 30 – in 30 %; 40 – in 14 %; elder – in 6  %. About 200 billions of Euro are spent for the treatment of epilepsy in Europe.

 

Epilepsy as a disease should be differentiated from:

·        Epileptic reaction

·        Epileptic syndrome

 

Epileptic reaction – is the response of the brain to the strong external and internal damaging factors (such as electro – shock, insulin shock, brain hypoxia, severe alcohol intoxication and so on). The main clinical features of epileptic reaction are abortive seizures or general tonic – clonic seizures.

 

Epileptic syndrome – is characterized by recurrent epileptic attacks on the background of pathologic focus in brain. The attacks are variable and depend on the localization of focus. Focal symptoms are obligatory in this case.

 

Risk factors

1.   Inheritance

2.   Organic brain diseases

·        Prenatal (infections – cytomegalovirus, rubella, toxoplasmosis, toxicosis of pregnancy, diet disturbances)

·        Perinatal (physical trauma, child birth anoxia, metabolic disorders, neonatal infection)

·        Postnatal (infections, trauma, dehydration, toxins)

3.   Disorders of brain function. Sleep disorders.

4.   Paroxysmal states in childhood

·        Newborns seizures

·        Febrile seizures

·        Affective – respiratory seizures

 

Pathology

There are such changes:

·        The results of organic diseases

·        The results of epileptic process

Each epileptic attack causes hypoxic changes in brain and leads to the development of encephalopathy.

 

Pathologic physiology

1.   There is a group of neurons with pathologic activity, which is called epileptic focus

2.   There is the ability to enforce and spread the activity

3.   Weakness of anti – epileptic protection. (It is provided by caudal parts of the brain)

 

Neurochemistry of epilepsy

1.   Disorders of balance between glutamate (exciting neurotransmitter), GABA (inhibitory neurotransmitter

 

Immunology of epilepsy

     There is increasing content of anti–brain antibodies. The primary attack causes disturbances of HEB. Immune system butts into strange to it nervous system. The result is production of antibodies and CIC that are fixed in brain tissue and favour its damage iew places.

 

Classification of epileptic attacks

I.   Partial epileptic

1.   Simple

a.   Simple motor

·        Focal motor without march

·        Focal motor with march

·        Adversive

·        Postural

·        Phonatory simple

b.   Simple sensory

·        Somatosensory (with and without march)

·        Visual, acoustical, gustatory, smell)

c.   Simple autonomic – visceral

d.   Simple with psychiatric disorders

·        Aphatic

·        Dysmnestic

·        With thinking disturbances (ideatory)

·        Emotional – affective

·        Hallucinatory

2.   Complex

a.   Temporal pseudoabsance

b.   Automatisms

3.   Simple with generalization (secondary general)

II.           General attacks

1.   Absance

·        Typical

·        Atypical

2.   Myoclonic

3.   Tonic – clonic

4.   Tonic

5.   Clonic

6.   General atonic

III.          Non classified

IV.         Epileptic status

 

Clinical features

I.             A. General seizures.

Epileptic general tonic – clonic attack (grandmal) usually begins with short initial stage that lasts several seconds. The last can manifest as:

·        Bilateral general muscle jerks

·        Loss of consciousness

·        Autonomic changes

·        Enlargement of pupils

Karlov called this stage initial one.

 

The tonic stage lasts about 10 – 20 seconds. During this stage seizures involve all the muscles. Usually seizures dominate in the extensors but at the beginning flexors are even more involved. The eyes are opened and are looking upwards. Mouth is opened too. Seizures start from axial muscles and then involve extremities. Shoulders are lifted and adducted. Muscles of lower extremities are seldom involved. Opistotonus and “obstetrician arm” are often observed. Extension of great toe is a common symptom in this case. Because of the diaphragm muscles contraction epileptic shouting is often associated with the attack.

      Then tonic stage is converted in clonic one. That means that on the background of tonic muscles straining there is trembling of the muscles. Then between the muscles straining relax pause appear. This stage is often associated with tongue biting, clonic vocalization. This phase lasts 30–40 seconds. During the tonic–clonic attack there are severe autonomic disorders – apnoe, cyanosis, small skin hemorrhages, pulsation of carotic arteries. Pulsation is frequent, AP is increased. There is also midriasis with pupils areflexia, hypersalivation that usually manifest as bloody foam. After attack the next stage can be divided into early and late ones.

 

Early stage lasts 1 – 5 min and is characterized by: after the last clonic attack a new phase of tonic contraction appears. The last is very similar to the one at the beginning. But the seizure dominates in the face, especially in chewing muscles and causes trismus. Usually the extremities aren’t involved. The eyes are looking upwards. There is midriasis. This stage is finished by muscles atonia that leads to involuntary urination. Corneal reflexes are absent. Deep reflexes are increased. There is loss of consciousness. And that means that the patient is in coma.

        Late after attack (recovery) stage is characterized by decreasing of midriasis, normal superficial reflexes, decreased deep reflexes and Babinski sign. The behavior of the patient is often automatic. When the patients are conscious they can complain on headache, muscles pain and complete amnesia. This period lasts 5 – 15 min.

        There can be different types of general tonic – clonic attack because of the age of the patient. In children tonic stage can last longer than clonic one. Iewborn babies there is often difference between right and left hemisphere seizures. Sometimes in children general tonic – clonic attacks are associated with vomiting and feces incontinence.

        Tonic attacks are seldom in grown – ups. In children tonic attacks are often associated with atypical absentia epileptica.

There are three types of epileptic tonic attacks:

1. Axial – body and facial muscles are involved in attack. There is spasm of respiratory muscles and breathing stop at expiration.

2. The same signs plus less involvement of extremities muscles.

3. Global means involvement of body and extremities muscles in the same way.

These attacks are associated with loss of consciousness. There is midriasis, tachycardia, increased AB and so on.

     General tonic – clonic attacks are very dangerous for the patient. They can cause trauma, aggression and sudden death as a result of autonomic disorders and respiratory disturbances, acute suprarenal insufficiency.

 

Clonic epileptic attacks

General typical clonic attacks are often observed iewborn babies. There is loss of consciousness, autonomic disorders, rhythmic clonic seizures. Between the attacks of clonic muscles jerks there is muscle hypotonia.

       If the attacks last 1–2 min the consciousness recovers quickly. But these attacks can last 4–5 min and even more. Then after the attack coma can be developed.

 

B. Without seizure attacks

      Absentia epileptica are characterized by sudden and short – lasting (2–30 sec) loss of consciousness and EEG – peculiarities. They are associated with absent gaze, interruption of patient’s activity, autonomic disorders (paleness or hyperemia of face, midriasis). The attack is finished suddenly. The patient doesn’t remember anything about it. This picture is typical for simple attack, when motor activity, seizures or loss of muscles tonus are absent.

       If absentia is associated with any motor component it is called complex absentia.

Complex absentia can be divided into myoclonic, atonic, tonic and with automatisms.

      Myoclonic absentia is characterized by loss of consciousness, rhythmic bilateral myoclonus in face and upper extremities. There are jerks of eyelids, periorbital muscles, mouth edges, eye bulbs. The patient can loose some objects he is holding in his arms.

      Atonic absentia is characterized by decreasing of postural tonus, hanging head and sudden drops.

      Tonic absentia is associated with looking of eyes upwards. There is domination of either extensor or flexor component, symmetric or asymmetric.

      Absentia with automatism can be the sign of focal attack and absentia. The main condition for automatism is incomplete loss of consciousness. Differential diagnosis in this case is very complicated. That’s why EEG should be made for such patients.

       Typical absentia are associated with bilateral symmetric complexes “top – waves” with frequency 3 per sec in frontal – central lobe.

        Typical absentia are much more common in children and can be caused by hyperventilation or light. They are very refractory to the antiepileptic drugs.

Atypical absentia are associated with such EEG changes:

1. Bilateral symmetric complex of “top – wave” which are rhythmically repeated with frequency 2 per sec.

2. Epileptic rhythm of gathering with frequency 10 per sec.

3.  Epileptic rhythm of gathering with frequency 20 per sec.

4. Complex of multiple spikes – waves with frequency 4 – 6 per sec.

Atypical absentia are resistant to hyperventilation and paroxysmal light.

II.           Focal attacks

       Focal attacks are those that clinically and on EEG manifest as the beginning of activation of neuron system of certain part of brain hemisphere.

There are three groups of focal attacks:

1.   Simple focal

2.   Complex focal

3.   Focal attacks with secondary generalization.

     The main differential feature of complex focal attacks from simple ones is loss of consciousness.

      Focal attacks are characterized by different symptoms – motor, sensory, autonomic or psychiatric that depends on focus localization and the peculiarities of morpho–functional organization of epileptic system. Motor attacks are caused by discharges in certain part of motor cortex. Somato–motor or motor Jackson attacks are seizures in certain muscle group according to the focus localization. They can be local or involve other group of muscles according to the topical localization in the brain cortex.

     In case of epileptic discharges in motor speech center speech disorders or involuntary vocalization – involuntary repetition of words are observed.

     Sensory attacks manifest as simple or complex  sensory disorders, such as somatosensory, visual, acoustical, olphactory, taste attacks and epileptic attacks of dizziness.

     Somatosensory Jackson attacks are associated with numbness, tingling in some part of the body. They can be localized or involve other parts of the body. They are caused by epileptic discharges in Post – Rollandic region. Very often the attack begins as somatosensory and then converts into somatomotor.

      As for visual, acoustical, olphactory, taste attacks and epileptic attacks of dizziness they can manifest as simple disorders or complex illusion or hallucinations.

 

Treatment

The main principals of epilepsy treatment should be – emergency, accordance to stages, following.

On the way to hospital:

1.   To release breathing air ways

2.   Digitalis drugs

3.   Sibazonum 0.01g

In ambulance:

a)   Tracheobronchial tree drain

1. Sibazonum 30 ml in 150 ml of physiological solution, in 10 min we add the medication up to 100 – 120 mg

2. Magnesiii sulfas 25% 10.0 in glucose 40 %

3. Anesthesia with nitrous oxide

4. Dosed anesthesia

5. Aminazinum 25% 1-2 ml

6. Atropinum 0.1% 1.0 s/c

7. Cardiac, antihistamine, diuretics

8. Natrii tiopentali 1g in 10 ml of physiological solution

 

Epileptic status

·        To provide permeability of respiratory airways

·        To evaluate the function of heart – vascular and respiratory systems

·        To provide free way to veins

·        Lorazepam 4mg i/v or Diazepam 10 mg

 

In the hospital

·        To take blood for analysis

·        % of urea, electrolytes

·        liver function

·        % of glucose

·        % of blood gas

·        etiology of attack – hypoglycemia – 50% solution of glucose 50 mg

–         at alcohol abuse – Tiaminum

 

Next half an hour:

§  to introduce the medication through the naso – gastral probe

§  Fenitoin 18 mg per kg or Phenobarbitalum 15 mg per kg i/v by drop 100 mg per kg

 

In 30 minutes:

§  General anesthesia

§  EEG

 

Surgical methods of treatment:

1.   Resections

§  Anterior temporal lobectomy

§  Selective amygdalohypocampoectomia

§  Calosotomia

§  Hemisphereectomia

2.   Stereotaxic

§  Destruction of deep temporal structures. This procedure on lateral part normally decreases seizures, on medial ones – aggression.

3.   Radio – surgical with γ – knife. γ – waves from 201 sources are focused on certain aims. The effectiveness of this procedure is 70 – 80 %.

4.   Electrostimulative – stimulation of certain structures:

§  Nucleus dentatus, the caput of nucleus caudatus (the price is 3.5 – 3 000 $)

§  Stimulation of n. vagus – this method is one of the newest one. It is indicated at partial seizures with secondary generalization.

Students’ practical Study Program.

 

Step I. Aim: to put of the clinical diagnosis. For this purpose it is necessary:

1. To examine the patient (history, somatic-neurological state).

2. To use the results of the laboratory investigation (general and biochemical blood and urine analyses, EEG, craniography, CT –scan tomography).

3. To make the differential diagnosis using the algorithm.

4. To make the clinical diagnosis.

Step II. Aim: To prescribe adequate treatment.

The treatment of patients with convulsive seizure can be divided into four parts:

1.    Elimination of the factors of importance in the causation or precipitation of attacks

2.    General mental and physical hygiene

3.    Medical therapy directed toward elevation of the convulsive threshold and thus the prevention of the attacks

4.    Surgical therapy in carefully selected patients with focal epilepsy

Elimination of the factors of importance in the causation or precipitation of attacks – requires treatment of all underlying physiologycal or structural abnormalities which have been discovered in the examination of the patient. This includes surgical removal of operable tumors of the brain, evacuation of the brain abscess, treatment of infections or endocrine abnormalities, and the correction of the physical defects

General mental and physical hygiene – Patients must be encouraged to use all of their resources to overcome their feelings of inferiority and self-consciousness resulting from the attacks. Adults should be assisted in obtaining productive work which will occupy their time and give them remuneration. Children should be kept in school unless the frequency of attacks unduly disturbs the routine of the classroom, or unless mental deficiency requires special facilities.

Physical activity of the patient should be regulated so that there is a set time for eating and sleeping and regular exercises every day. Alcoholic beverages are to be avoided. Special activities, such as parties, dancing, moving pictures, and so on, should be encouraged. Swimming, horseback riding and otherwise dangerous sports can be permitted when there are proper safeguards.

Medical Therapy. They should be given an adequate, thorough trial in each individual patient.

Anticonvulsive drags:

1.    Barbiturats (Phenobarbital (max 240 mg), Bensonal

2.    Phenylhydantoin (Diphenin)

3.    Trimethdione (Trimetin)

4.    Ethosuximide

5.    Carbamazepine (Tegretol, Finlepsin)

6.    Depakin, Convulex

7.    Diacarb

8.    Bromides

Phenobarbital is the drag of choice in the treatment of patients with grand mal seizures because of their high therapeutic index. A combination of phenytoin with Phenobarbital is often more effective than any one these drugs when used alone. In patients with psychomotor-temporal lobe or psychic equivalent seizures, carbamasepine is the drags of choice.

For petit mal seizures, ethosuximide is the drags of choice. If the patients are subject to petit ml seizures and grand mal or psychomotor attacks, one of the «anti petit mal» drugs shhould be given in combination with phenytoin sodium, Phenobarbital.

Surgical Treatment. Whenever convulsive seizures are associated with a surgically removable lesion of the brain, such as tumor or abscess, removal of.

Step III. Aim: Preventive determination.

Prognostic examination is determined according the clinical diagnosis and effectiveness of the treatment. To make the prognosis to live, to recover, to work, make a complex of the preventive measures.

Meningitis

 

Meningitis is an acute infectious disease with involvement of the arachnoid and pia of the brain and spinal cord by pathogenic microorganisms. The most common organisms that cause meningitis are bacteria, viruses, sometimes fungus, micoplasma and rickettsia.

Classification

1.    According to the inflammatory process in the meninges and cerebrospinal fluid (CSF) changes all meningitis are divided into serous and suppurative, purulent. At serous meningitis there is increased number of lymphocytes in CSF, while at suppurative and purulent meningitis neutrophiles dominate.

2.    According to the pathogenesis there are primary and secondary meningitis. Primary meningitis are developed without previous general infection or infectious disease of any organ. Secondary ones are developed in case of general or focal infectious disease, that means that they are complications of different infectious diseases. For example tuberculous, syphilitic meningitis are considered to be secondary meningitis.

3.    According to the localization of pathologic process there are general, basal, convexital meningitis.

4.    According to the rate of development there are fulminant, acute, subacute, chronic meningitis.

5.    According to the severity there are mild, moderate and severe meningitis.

6.    According to the etiology there are bacterial, viral, fungal meningitis.

 

Pathogenesis

There are three ways of meninges infection:

1.    In case of open head or spinal trauma, fractures of scull basis associated with liquorrhea.

2.    Direct extension (sinusitis, mastoiditis, middle ear infection)

3.    Hematogenic way of infection (the source of infection is localized in intestine, stomach, nose).

      Organisms multiply rapidly in cerebrospinal fluid with inflammation of meninges. Neutrophiles react with release chemicals. Bacterial toxins and inflammatory response cause brain edema. Increased metabolic demand and reduced blood flow result as inadequate tissue perfusion. That causes raised intracranial pressure and systemic effects of infection.  

 

Pathomorphology

 The main changes at suppurative and purulent meningitis are:

a)    Infection and inflammatory response are generally confined to the subarachnoid space and the arachnoid and pia.

b)    Brain and meninges edema.

c)    Blood repletion of cortical veins

d)    Internal hydrocephalus

e)    Perivascular infiltration of cortical cells

      At serous meningitis meninges and brain edema, dilatation of liquor spaces is usually observed.

      At tuberculous meningitis basal exudation occurs. As a result of commissural process hydrocephalus and subarachnoid space obstruction can occur.

 

Clinical features

In spite of the etiology there are three common syndromes for all meningitis:

1.    General – infectious

2.    Meningeal

3.    CSF changes

 

1.  General – infectious syndrome means headache, shiver, inflammatory changes of blood, rash, tachycardia, tachypnoe with rhythm disorders.

 

2.  Meningeal   syndrome manifests as neck stiffness, Kernig sign, Brudzinski signs (upper, middle and lower ones), Lessage symptom (in children), Bechterev’s cheek bone phenomena. Increased intracranial pressure causes bulging of an unclosed anterior fontanelle in children.

 

Kernig sign

 

 

Upon meningeal symptoms general cerebral signs are developed. They are headache (as a result of increased intracranial pressure), vomiting, nausea, general hyperesthesia, changes of consciousness, psychomotor agitation, and seizures.

 

 

1.    CSF changes manifest as cellular – protein dissociation, colour changes, cerebrospinal fluid is cloudy (purulent), the sugar content is decreased; clot formation on standing is observed at tuberculous meningitis.

 

The results of CSF examination have an important meaning for differential diagnosis and prescription of etiotropic treatment. In order to put a diagnosis we should make bacteriologic and serologic examinations. Usually we use immunologic express – methods of investigation. They are:

·         Countercurrent immunoelectrophoresis (CIE)

·         Latex agglutination

These methods are used in order to reveal specific antigens (protein components of organisms). It is necessary to find out sensation of organisms to antibiotics in order to prescribe a proper therapy.

 

Epidemic cerebrospinal meningitis

 

Etiology

      It is usually caused by Meningococcus Weichselbaum. The source of infection is ill person or carrier. Meningococcal infection can manifests as suppurative meningitis, asymptomatic bacterio – carriage, nasopharyngitis, arthritis, meningococcemia.

 The entrance is mucose membrane of pharynx and nose. Meningococcal infection can be transmitted by air drops or contact. In most instances the spread of meningococcus is haematogenous. Usually this disease is observed in winter and spring. Meningococcus is instable at high temperature, humidity and day light.

 

Pathogenesis

      Meningococcus in upper respiratory ways usually causes primary nasopharygitis .The last in typical cases is rapidly cured. In those persons who are less resistant to infections meningococcus is getting into the blood and then it is spread in the human body. In severe cases meningococcemia develops, which is usually associated with typical hemorrhagic rash. Endotoxin can even cause endotoxic shock.

 

Clinical features and diagnosis  

       Incubation period of meningococcal infection lasts from 2 to 10 days (usually about 3 – 7 days).The onset of meningococcal meningitis is acute (about several hours). The temperature is elevated at 39 – 40°.

The main peculiarities of clinical picture are:

1.    General cerebral syndrome is well – expressed and increases rapidly. Meningeal syndrome increases during 2 – 3 days.

2.    Focal neurologic symptoms manifest as lesion of III-rd and IV- th CN’s – diplopia, ptosis, cross – eye, anizokoria.

3.    Herpes labialis is often observed on the 2 – nd or 5 –th day. Sometimes hemorrhagic rash occurs, that is the sign of meningococcemia.

4.    Sometimes brain tissue is involved. Then there is clinical picture of meningoencephalitis.  That means occurrence of hyperkinesis, ataxia, nystagmus, paralysis, seizures, sometimes epistatus.

5.    At severe meningoencephalitis inflammation of ventricles occurs. The last manifests as hormetonia, edema of optic nerves’ disk, disturbances of breathing and cardiac activity.

6.    Cerebrospinal fluid is cloudy (purulent), the cell count in the fluid is usually between hundreds and thousands/mm³. The protein content is increased to 10 – 15 g/l. The sugar content is decreased. Meningococcus can be found out in CSF.

      According to the clinical picture there are three main forms of meningitis. They are mild, moderate and severe one. Fulminant hypertoxic form is very rare.

 

Complications of meningoccocal meningitis Severe forms can be associated with pneumonia, myocarditis, pericarditis. The most dangerous complications are acute brain edema and bacterial endotoxic shock.

The course of meningococcal meningitis   There are fulminant, acute, abortive and recidivous course of the disease. The most common are the first and the second forms.

Diagnosis It is usually based on clinical features (acute onset, general infectious, general cerebral symptoms and meningeal syndrome, hemorrhagic rash), CSF examination and revealing of meningococcus.

 

Differential diagnosis We should differentiate this disease with:

·         other forms of meningitis

·         meningism at general infections (that means the absence of CSF changes in case of meningeal syndrome)

·         subarachnoid hemorrhage (usually general – infectious syndrome is absent, there is no blood in CSF).

 

Prognosis The disease lasts from 2 to 6 weeks. In case of adequate and in time treatment it is usually cured.

       Only functional changes of CNS such as asthenic syndrome, mild disorders of mental development may be observed after meningococcal meningitis. Focal symptoms such as paresis of extremities, CN’s, hydrocephalus, seizures, decreased vision, hearing loss, and arachnoiditis are very rare.

 

Secondary purulent meningitis

Etiology, pathogenesis

      Secondary purulent meningitis are observed in case of pyogenic source in the body. The disease is developed after direct extension from pyogenic source (for example pyogenic middle ear infection) or by means of metastasis from faraway pyogenic focuses (abscess, ulcerous endocarditis).

    Usually secondary purulent meningitis is caused by different coccus (pneumococcus, staphylococcus), Hemophilus influenzae.

 

Clinical features

      The onset of the disease is accompanied by chills and fever to 40º. Then meningeal syndrome, seizures, consciousness disorders, focal neurologic symptoms, autonomic disorders occur. Sometimes the clinical picture is very similar to sepsis.

      In CSF the cell count is very high. The protein content is significantly increased. Bacteria   (staphylo –, streptococcus) are usually found.

 

Treatment

      The measures of treatment of primary suppurative and secondary purulent meningitis are the same. But the secondary purulent meningitis needs liquidation of the source of infection. If necessary we can use surgical methods of treatment.

 

Treatment of suppurative, purulent meningitis

     The patient should be hospitalized in horizontal position and isolated before the revealing of the type of meningitis.

We use:

1.     Etiotropic treatment

2.     Pathogenic treatment

3.     Symptomatic treatment

 

1.     Etiotropic treatment

        Antibiotics

     Just after the putting diagnosis we should prescribe antibiotics. It’s a pity but sometimes it is difficult to reveal the organism that causes the disease. And we loose time. That’s why very often we start with antibiotic that has wide spectrum of action – Penicillinum.

    We use it in dose 300 000 U per kg (that means about 24 – 32 mlns of U per day 6 – 8 times i/m). At severe cases the dose is increased to 48 mlns. When the treatment is started later or the patient is in coma the dose is 60 mlns of U per day. And the first 4 – 12 mlns are used i/v.  Simultaneously we prescribe 3 mlns of U of Nystatinum. The treatment lasts from 7 to 10 days. The main sign which indicates us it’s time to put off the medication is CSF sanitation (that means cell counting less than 100/mcl, lymphocytes not less than 75 %)

·         For purulent meningitis treatment we can prescribe half- synthetic Penicillinum

·         (ampicillinum) in dose 300 – 400 mg per kg per day   i/v  or i/m.

·         Cephalosporines are also used for the treatment. For example such as Cephazolinum, Cephalomycinum, Ceftriakson, Cefotaxim. They are used 1 g 4 times per day I/m or I/v.

·         Aminoglycozides, such as Gentamycini, Kanamycini, Amikacini are also prescribed. Amikacinum is used 0.5 g 3 times per day. Gentamycinum is used 80 mg 2 – 3 times per day.

·         The most effective are combinations of different antibiotics. For example

1.    Penicillinum and Aminoglycozides ( Gentamycinum, Kanamycinum )

2.    Ampicillinum and Aminoglycozides

3.    Penicillinum and Cephalosporines of the second or third generation

4.    Aminoglycozides and Cephalosporines

5.    Tienamycinum

 

        Sulphanilamide

      Sulfamonomethoxine, Sulfapyridazinum, Sulfadimethoxinum are used 2 g twice a day during the first day, then 2 g once a day.

        The treatment of secondary purulent meningitis includes treatment of the source of infection (inflammation process in lungs, middle ear, and nose). Sometimes we use surgical methods of treatment in order to liquidate the source of infection.

 

2.     Pathogenetic treatment  includes:

·         Treatment of intoxication

·         Correction of heart – vascular and breathing disturbances

·         Liquidation of brain edema

·         Correction of water – electrolytes balance.

 

That’s why we use:

·         Treatment against intoxication

·         Dehydration

·         Hormones

·         Antihistamines

·         Nootrops

 

       To liquidate hypovolemia we prescribe Rheopolyglucinum 400 ml per day, 100 ml 5 % Albuminum, Plasma, Haemodesum.

       An average quantity of liquids is about 2 – 2.5 l per day. After introduction of 1 – 1.5 l we prescribe 2 – 4 ml of Lasix.

       We also use polarized compound (500 ml 5 % Glucose, 150 ml 1 % KCl, 10 U of Insulinum, 10,0 Pananginum, ATP, Cocarboxylase) and diuretics. In order to overcome metabolic acidosis we use Na hydrocarbonas 100 ml 4 %.

       Hormones are necessary in case of infectious – toxic shock treatment. We use Dexamethazonum 8 mg twice a day or Hydrocortisone 15 mg per kg. Glycosides   are also used in this case.

       Heparinum is prescribed in dose 5 000 U 4 times per day.

       Diuretics such as Manitol, Lasix, Glycocorticoids are used too.

       Antihistamine medications (CaCl2, Ca gluconas, Suprastinum, Dimedrolum, Tavegil) are used too.

       Nootrops such as Pyracetam, Nootropil, Actovegin, Instenon, and Cerebrolisyn are used.

 

3.  Symptomatic treatment

At acute kidney insufficiency we use hemodialysis.

At acute suprarenal glands insufficiency we introduce physical solution, Rheopolyglucinum plus 125 – 500 mg Hydrocortisone, 30 – 60 mg Prednisolone, 8 – 16 mg Dexamethasone, 500 – 1000 mg Ascorbin acid, Cordiamini, Strophanthinum.

At brain hypoxia we use nootropils and neuroleptics (Na oxybutiras, Relanium 0.5 % 2 ml, Sibazonum 2 – 4 ml).

At severe pain we use analgesics (Analginum, Baralginum, Tramadolum).

 

Prognosis About 20 – 25 % of all patients with suppurative, purulent meningitis die. In case of different complications and late diagnosis 60 – 80 % of all patients die. Death is much more common at secondary purulent meningitis and at pneumococal infection.

 

Serous meningitis

According to the etiology there are:

·         Bacterial serous meningitis (tuberculous, syphilitic meningitis)

·         Viral meningitis (acute lymphocytic choriomeningitis, parotid meningitis, influenza- meningitis, enteroviral, herpes – adenoviral – meningitis)

·         Fungal meningitis

 

 

Tuberculous meningitis

      Tuberculous meningitis is always secondary to tuberculosis elsewhere in the body. The primary focus of infection is usually in the lungs but may be in the lymph glands, bones, nasal sinuses or any organ of the body. This disease is observed in both – children and adults.

 

Pathomorphology 

     The process is usually most intense at the base of the brain, ependyma, III –rd and IV – th ventricules, choroids plexus. The inflammatory process may extend for a short distance into the cerebral substance. Proliferative changes are frequently seen in the inflamed vessels of the meninges, producing a panarteritis. All these changes lead to the CSF dynamics disturbances and hydrocephalus. The most typical feature of tuberculous meningitis are minute tubercles on the base of the brain.

 

Clinical features and diagnosis

1.    Tuberculous meningitis develops very slowly.

2.    There are three periods of the disease :

a) prodromal stage (with loss of appetite, general weakness, headache, irritability, increased temperature and sometimes vomiting)  lasts for  2 – 3 weeks.

b) meningeal stage

c) paralytic stage

3.    Meningeal syndrome is not well – expressed.

4.    Temperature is increased up to 38º sometimes 39º.

5.    Focal neurologic signs – paresis and paralysis of Oculomotor n. (III), Abducens n. (IV), Facial n. (VII), Optic n. (II). Sometimes Vestibulocochlear n. (VIII)   is involved.

6.    Encephalitic syndrome manifests as paresis, paralysis, aphasia, hyperkinesis, cerebellar disturbances.

7.    Subacute course of the disease. Sometimes acute course is observed in children. Chronic course may be in those persons who had used antituberculosis treatment previously.

 

Diagnosis

The CSF findings are quite characteristic. These include: 

·         Increased pressure

·         Slightly cloudy

·         Increased protein content to 1 – 5 g per l

·         Moderate pleocytosis of 100 – 300 cells/mm³, 70 – 80 % of them are lymphocytes

·         Decreased sugar content with values in the range of 0.15 to 0.3 g/l

·         Formation of a clot on standing during 12 – 24 hours, where bacilli of tuberculosis are usually found out.

In blood sometimes leucocytosis and increased SR (sedimentation rate) is observed.

 

Differential diagnosis Spinal form of tuberculous meningitis should be differentiated with spinal tumor or myelopathy.

 

Treatment

Etiotropic treatment includes:

·         Isoniazid 15 mg/kg 3 times per day

·         Rifampicinum 600 mg once a day

·         Pyrazinamide 30 mg/kg (1.5 – 2.5 g per day) twice a day

     They are used during three months. Then we use only Isoniazid and Rifampicinum during 7 months.

     The most recent medications are combinative ones such as Rifogal, Rifater (Rifampicinum 120 mg, Isoniazid 50 mg, Pyrazinamide 300 mg).

Streptomycinum is used in dose 1 g once a day.

Ethambutol – 25 mg/kg per day

Usually we use all these medications about three months, as all of them have side effects such as ototoxicity, lesion of optic nerve, diarrhea, thrombocytopenia, hepatitis.

       Pathogenetic and symptomatic treatment is the same as at suppurative and purulent meningitis.

 

Prognosis Mortality is about 10 %. Residual symptomatics includes epiattacks, eye movement disorders, hemiparesis, hearing loss, neuroendocrine disturbances.

       During the first year of the disease the patients are considered to be disabled, during the next 2 or 3 years they have limited abilities.

 

Serous viral meningitis

Acute lymphocytic choriomeningitis

    The cause of the disease is Armstrong virus. Viral reservoir is domestic mice. Human being is infected by means of food infected by mice. The main way of disease transmittance is hematogenic.

 

Clinical features

1.    Incubation period lasts for 1 – 2 weeks

2.    The onset is with headache, running nose, sore throat

3.    Moderate meningeal syndrome against high temperature – 39º – 40 º

4.    On 7- th or 10- th day general – infectious and meningeal signs disappear

5.    CSF is pellucid, pleocytosis is 300 – 500 cells, most of them are lymphocytes. The content of protein and sugar is the same.

6.    There are some atypical forms of meningitis, such as

·         Flu – like

·         Encephalomyelitic

·         Poliradiculoneuritic

·         Visceral

7.    Alopecia and orhitis can occur at the 7 th week of the disease.

 

Diagnosis According to the virusologic and serologic examination we put the diagnosis. For these we use blood and CSF during the beginning of the disease.

 

Treatment

Etiotropic treatment

1.    Interferonum 500 000 U. It is prescribed in dose 1 amp. once a day during 7 days or Reaferonum  1 mln U i/m

2.    Virolex – 250 mg 3 – 4 times per day or Aciclovir 200 mg 3 times per day, or Virasolom 2 caps. 3 – 4 times per day during 7 days.

3.    Stimulators of interferonum production – Prodigiosan – 1 ml 0.005 % i/m once every three days.

4.    Acidi ascorbinici , vit. B1, B6.

5.    Antibiotics in order to prevent pneumonia.

 

Pathogenetic treatment for all types of meningitis

1.    Desintoxication

2.    Dehydratation

3.    Desensibilization

4.    Hormones

5.    Nootrops

 

Prevention To liquidate mice in the houses.

Multiple sclerosis is a demyelinating disease of the central nervous system (CNS) caused by an autoim­mune reaction that is the result of a complex interac­tion of genetic and environmental factors.

 

Epidemiology

Multiple sclerosis is more common in women, with a female:male ratio of 2.1:1. The disease is rare in children and has a peak incidence at 30 to 33 years of age, with a decline in the late forties. The upper limit of age at onset has usually been accepted as 59 years, but late onset of multiple sclerosis after the age of 60 years is reported. However, these cases probably rep­resent late occurrence of overt symptoms in individu­als who have had the disease in a subclinical or un­recognized fashion for many years.

The natural history of multiple sclerosis has been studied extensively and it is clearly a disease of temperate zones, with an increase in the prevalence gradient south to north in the northern hemisphere, and north to south in the southern hemisphere. Three zones of high, medium, and low prevalence rates can be recognized. High-frequency prevalence rates of more than 30 per 100,000 population occur in areas lying between latitudes 45° and 65° north or south. This includes northern Europe, southern Canada, the northern United States, New Zealand, and southern Australia. These areas of high frequency are bounded by areas of medium frequency with preva­lence rates of 5 to 25 per 100,000 and include south­ern Europe, the southern United States, and most of Australia. Tropical areas of Asia, Africa, and South America have low prevalence rates of less than 5 per 100,000. Anomalies do occur, however, with levels as high as 170 per 100,000 reported in Switzerland, 53 per 100,000 in southern Spain, 59 per 100,000 in Sardinia, and 32 to 58 per 100,000 in Italy and Sicily.

These figures cannot be attributed to climate alone, however, because there are well-documented ethnic differences. Multiple sclerosis predominantly affects people of northern European extraction. In the United States, African-American men are less likely to develop multiple sclerosis when compared to white men in the same geographic area. Studies in Japan, Korea, and Hong Kong indicate a very low prevalence in populations in these countries. Simi­larly, persons of Asian extraction who have lived for several generations in the United States have a low prevalence rate for multiple sclerosis.

Such findings suggest a genetic factor in multi­ple sclerosis, and family studies have demonstrated that the risk of multiple sclerosis is increased for rela­tives of patients with the disease. Studies in Vancou­ver, British Columbia indicate a family rate for multi­ple sclerosis approaching 20 percent, with a lifetime age-correlated risk for the sibling of a patient of more than 25 times the lifetime risk in the general popula­tion. Twin studies indicate a concordance of 26 per­cent for monozygotic pairs compared to 2.4 percent in like-sex dizygotic twins—a figure similar to that for nontwin siblings of multiple sclerosis patients. This supports the view that differences in monozy­gotic and dizygotic twins have a genetic basis.

At the present time, evidence suggests that mul­tiple sclerosis is influenced by several genes, the ma­jor histocompatibility (MHC) complex class 2, HLA-DRII allele having the strongest association with the disease iorthern European populations. However, the association of different class 1 and class 2 alleles has been reported in other populations. Consequently, the current impression is that multiple sclerosis is probably polygenic, the result of complex genetic factors involving the interaction of genes and coding within and outside of the MHC complex. However, epidemiologic studies in Israel and the Faroe Is­lands point to involvement of environmental factors in multiple sclerosis. The ongoing study of the dis­ease in the inhabitants of the Faroe Islands—now ex­periencing a fourth epidemic of multiple sclerosis — suggests that multiple sclerosis is the result of an unidentified infection transmitted person to person and requiring a prolonged exposure of at least 2 years. Susceptibility is limited to ages 11 years to 45 years at the start of exposure and a further 6 years to onset in those who develop clinical signs of multi­ple sclerosis. However, these figures are the results of a study in one isolated community, and although they express findings in that community, they should not be extrapolated to multiple sclerosis on a global scale, because multiple sclerosis has been clearly demonstrated in children as young as 5 years.

At the present time, it is considered probable that both genetic and environmental factors are in­volved in multiple sclerosis, with infection as the major environmental agent, in that both viral and bacterial infections can initiate or precipitate attacks of multiple sclerosis. Evidence for a direct involve­ment of a viral agent such as human T-cell lymphotropic virus (HTLV)-l, herpes simplex virus (HSV)-l, HSV-6, scrapie, parainfluenza virus 1, measles virus, coronavirus, simian virus, chimpanzee cytomegalovirus, and LM7 retrovirus in multiple sclerosis is less compelling. The role of environ­mental factors other than infection has been studied, including the relationship of trauma and multiple sclerosis, indicating that patients are at no greater risk to experience an exacerbation of multiple sclerosis af­ter trauma than at other times, nor is it likely that trauma is ever a causal factor in initiating the disease process. The role of emotional stress in multiple sclerosis is more controversial because stress is diffi­cult to define and quantitate.

 

Etiology, Pathology, and Pathogenesis

The etiology is unknown. The pathological changes in multiple sclerosis show variation, depending on the age of focal demyelination (the plaque). In the acute state, there is active demyelination with accumulation of sudanophilic myelin breakdown products. The area is edematous and there is marked perivascular cuffing around veins and venules by lymphocytes and macrophages. Plaques are frequently located in the periventricular distribution, particularly in the cere­bral hemispheres, but plaques can occur at any site in the white matter and often penetrate into the gray matter of the cortex and deeper gray matter structures in the cerebrum and cerebellum. Because multiple sclerosis is a disease of the CNS, plaque formation is not uncommon in the brainstem, cerebellum, spinal cord, and the optic nerves, which are structurally part of the CNS, in which the oligodendrocytes are anti-genically similar to the oligodendrocytes in the spinal cord.

All multiple sclerosis lesions show a variable degree of axonal loss, ranging from 10 to 20 percent in milder forms of the disease, to 80 percent in se­vere, acute multiple sclerosis.

Epidemiologic studies support the concept that multiple sclerosis results from an aberrant immune reactivity occurring in a genetically susceptible host who has acquired a specific, or one or more nonspe­cific, neurotropic infections at a critical age. Ge­netic susceptibility is thought to be associated with genes within or close to the HLA-DR DQ subregion, located in the short arm of chromosome 6. This primary infection results in a self-sustaining, organ-specific autoimmune disorder that remains latent until activated by a subsequent infection years after the primary event. An alternative explanation suggests that the mechanism is one of persistent systemic viral infection, which contributes to the changes in the CNS periodically, or to a persistent CNS viral infec­tion that is targeted by T cells unpredictably, resulting in an inflammatory response producing myelin dam­age (bystander response). The common factor in any one of these theoretical situations is the activation of an autoimmune event within the CNS, directed against myelin antigen-specific T cells, but no spe­cific antigen has as yet been identified. Antibodies to myelin basic protein appear to be the most frequent finding in multiple sclerosis, but reactivity to other myelin antigens is a possibility. Candidates include proteolipid protein, the most abundant myelin protein in humans, myelin oligodendrocyte glycoprotein, myelin-associated protein, minor myelin proteins, or heat shock proteins.

The autoimmune reaction probably begins with a systemic infection that is associated with liberation of γ-interferon, resulting in activation of CD4 T lym­phocytes. The lymphocytes attach to adhesion mole­cules on the surface endothelium of postcapillary venules, roll along the surface of the endothelium, producing endothelial cell activation, followed by passage of the CD4 T lymphocytes into the CNS—in effect, disrupting the blood-brain barrier. Once within the CNS, the T-lymphocyte receptors respond to antigen presented by MHC class 2 molecules on macrophages and astrocytes, but oligodendrocytes are usually preserved at this stage. The antigen T-cell receptor interaction is followed by stimulation of helper T cells, T-cell proliferation, and B-cell and macrophage activation, with release of cytokines such as •γ-interferon, tissue necrosis factor, interleukin-12, and proteases. The cytokines induce a local inflam­matory reaction with further disruption of the blood-brain barrier, followed by a major influx of CD4 lymphocytes and monocytes into the lesion. Myelin damage results from the combined effect of cytotoxic cytokines, particularly tissue necrosis factor and cytotoxic cells.

Oligodendrocytes appear to survive and prolif­erate in the presence of acute demyelination and in­teract with hypertrophied astrocytes, an association that may represent a short-term protective mecha­nism. Consequently, active demyelination and remyelination can occur in acute lesions. Oligodendro­cyte depletion in chronic multiple sclerosis lesions may be a slow, insidious process, spanning a pro­tracted period during which there is gradual cell dropout.

 

Classification of Multiple Sclerosis

Although multiple sclerosis can affect any site in the CNS, it is possible to recognize eight types of the dis­ease (Table 7-1):

1.    Relapsing-remitting multiple sclerosis. This is the classical form of multiple sclerosis that often be­gins in the late teens or twenties with a severe attack followed by complete or incomplete recovery. Approx­imately 70 percent of patients with multiple sclerosis experience a relapsing-remitting course initially.³⁸ Fur­ther attacks occur at unpredictable intervals, each fol­lowed by increasing disability. The relapsing-remitting pattern tends to change into the secondary progressive form of the disease in the late thirties.

2.    Primary progressive multiple sclerosis. The disease runs a steady deteriorating course that may be interrupted by periods of quiescence without improvement. The rate of progression is variable; at its most severe, this form of multiple sclerosis can termi­nate in death within a few years. In contrast, the more chronic form of progressive multiple sclerosis is simi­lar to the benign form of the disease.

 

Table 7-1

Eight Types of Multiple Sclerosis

1.  Relapsing-remitting

2.  Primary progressive

3.  Secondary progressive

4.  Relapsing progressive

5.  Benign

6.  Spinal form

7.  Neuromyelitis optica (Devic disease)

8.  Marburg variant

 

3.    Secondary progressive multiple sclerosis. The relapsing-remitting form of the disease fre­quently develops into secondary progressive multiple sclerosis after a variable period of time but usually in the late thirties.

4.    Relapsing progressive multiple sclerosis. Occasional cases are encountered where patients with a progressive form of multiple sclerosis have super­imposed relapses with no significant recovery.

5.    Benign multiple sclerosis. About 20 per­cent of cases have the benign form of multiple sclero­sis. This may be defined as multiple sclerosis in which the patient is able to function at the level of full employment or provide care of home and family independently 10 years after the appearance of the first symptoms. It is extremely unlikely that these pa­tients will ever be incapacitated by the disease and they should continue to live a full life span with only occasional minor symptoms.

The existence of a benign form of multiple sclerosis increases the importance of recording the date of the first symptoms in patients who appear to have few residual abnormal signs several years after the onset of the disease. These patients may be in­formed that they have a benign form of multiple scle­rosis 10 years following their first recorded symptom and that the benign course will continue in the years ahead.

6.    Spinal form of multiple sclerosis.  This form of multiple sclerosis presents with symptoms and signs of predominantly spinal cord involvement from the beginning and maintains this pattern. There may be a clear-cut pattern of relapse and remission initially, followed by the secondary progressive form of the disease after several years, or the presentation may be one of steady deterioration from the onset.

7.    Neuromyelitis  optica (Devic syndrome). Most cases of this syndrome are believed to be exam­ples of multiple sclerosis presenting with acute trans­verse myelitis followed by optic neuritis. Many pa­tients follow a relapsing-remitting course indistin­guishable from multiple sclerosis.

8.    Marburg variant. This rare and malignant form of multiple sclerosis is associated with a fulmi­nating course of progressive impairment of con­sciousness, severe visual loss, dysarthria, dysphagia, respiratory insufficiency, and rapid deterioration. It is indistinguishable from acute disseminated encepha­lomyelitis. The Marburg variant may result from the autoimmune process of multiple sclerosis occurring in  an  individual  with  developmentally  immature myelin basic protein.

 

Clinical Features

The diagnosis of multiple sclerosis is based on the clinical demonstration of multiple levels of involve­ment of the CNS. Symptoms may be grouped under several headings.

 

Sensory Symptoms

Sensory symptoms are the most common symptoms experienced by patients with multiple sclerosis. These symptoms are often forgotten or ignored by both patient and physician. Even prolonged sensory symptoms fail to evoke con­cern, in contrast to the almost immediate response that occurs with weakness or paralysis. Consequently, many patients date the onset of multiple sclerosis from the first appearance of weakness, visual loss, or other symptoms of dramatic onset rather than forgot­ten or poorly recorded sensory symptoms.

Sensory symptoms include impairment of sen­sation (hypesthesia), tingling (paresthesias), and uncomfortable sensations (dysesthesias) often referred to as “burning,” which may be present for days, weeks, or months without objective abnormalities. All patients with suspected multiple sclerosis should be carefully questioned about the occurrence of pre­vious sensory symptoms.

 

Motor Symptoms

Paralysis or paresis of upper or lower limbs is the most common presenting symptom in patients with multiple sclerosis. Paraparesis is a common early complaint when the patient gives a history of increasing weakness and stiffness of the lower extremities, associated with progressive impair­ment of gait. Examination shows signs of upper mo­tor neuron involvement with spasticity, increased ten­don reflexes, and extensor plantar responses. These findings may be quite subtle in the early states of the disease.

 

Visual Symptoms

Optic neuritis presents with sudden visual loss and pain on eye movement and a unilateral headache. The condition may be followed by a rapid progression to total loss of vision in the af­fected eye (Fig. 7-1) When vision is preserved, there is monocular blurring; a central, paracentral, or centrocecal scotoma; and impairment of color vision. In optic neuritis, there may be edema of the optic discs, but the appearance can be normal in retrobulbar neu­ritis, when the inflammatory response is localized and located proximally in the optic nerve. Temporal pal­lor is a later development because of demyelination of the maculopapular bundle. However, subclinical involvement of the optic nerve can occur and may be present without symptoms, when the patient first pre­sents with signs of multiple sclerosis or may be iden­tified when the patient presents with the first symp­toms of optic neuritis, indicating prior subclinical involvement of the optic nerve.

Recovery from optic neuritis is unpredictable. Many patients experience no further problems for several years and then develop symptoms of brain or spinal cord involvement, indicating multiple sclero­sis. However, not all optic neuritis is multiple sclero­sis, and only 50 percent of adolescents and young adults who present with the sudden onset of optic neuritis   subsequently   develop   multiple   sclerosis.

 

 

Those with a large time interval between the optic neuritis and the development of additional symptoms have a better prognosis. The clinician should always inquire about the possibility of preceding symptoms in any patient who presents with optic neuritis be­cause the presence of symptoms some years before the more dramatic visual symptoms might indicate a more benign prognosis.

Diplopia is indicative of third or sixth nerve in­volvement in the brainstem. The fourth nerve is rarely involved in isolation. Intemuclear ophthalmoplegia is pathognomonic of multiple sclerosis and rarely has another etiology. Unilateral or bilateral Marcus Gunn pupil is often present in optic or retrobulbar neuritis.

 

Bladder Involvement

The early symptoms of bladder dysfunction consist of occasional urgency of micturition followed by mild nocturia occurring once a night. The events gradually increase ium­ber, disturbing the sleep of the patient and the bed partner. There is a concomitant increase in urinary frequency and urgency during the day, ultimately resulting in incontinence. Impaired bladder control is usually the result of spinal cord involvement in multiple sclerosis and decreasing bladder control usually parallels increasing paraparesis. However, this is not an inevitable relationship and some pa­tients retain adequate bladder function even when paraplegic.

The anatomical center for bladder control lies in the tegmentum of the pons. The center is under the influence of a higher level of control located in the medial aspect of the frontal lobes. Thus, the frontal lobes can signal the pontine bladder control center to inhibit bladder function or to initiate bladder empty­ing at will or when convenient. The pontine center then inhibits or permits bladder contraction through connections that traverse the spinal cord and exit through the parasympathetic outflow in the S2-S4 sacral nerves supplying the bladder.

A number of abnormal responses are associated with interruption of bulbar or spinal cord connections in multiple sclerosis.

1. Detrusor hyperreflexia. The interruption of the afferent impulses from the detrusor muscle of the bladder to the pontine micturition center by spinal cord disease results in an uninhibited reflex at the sacral cord level. The detrusor muscle is no longer inhibited as bladder volume increases and detrusor contraction is initiated in response to smaller volumes of urine, resulting in increasing frequency.

2.  Detrusor sphincter dyssynergia. The normal pat­tern of voiding is disturbed. The normal relaxation of the external sphincter is impaired and detrusor contraction is poorly coordinated and accompa­nied by contraction rather than relaxation of the external sphincter. The result is poor flow of urine and incomplete emptying of the bladder.

3.  Detrusor hypocontractility is a failure to empty the bladder secondary to insufficient detrusor pressure or a fading contraction on voiding.

 

Cerebellar Symptoms

Tremor, dysarthria, trun­cal ataxia, and limb ataxia are frequent symptoms of multiple sclerosis. Occasionally, cerebellar dysfunc­tion is the dominant feature in multiple sclerosis, when a patient presents with adequate vision and muscle strength shows serious disability from the cu­mulative effects of the several forms of cerebellar ataxia.

 

Brainstem Symptoms

Many patients with mul­tiple sclerosis develop signs of brainstem involve­ment. Involvement of the oculomotor and sixth cra­nial nerves as they traverse the substance of the brainstem results in diplopia. Intemuclear ophthalmo­plegia due to involvement of the interaxial fibers con­necting the third, fourth, and sixth nerve nuclei is not uncommon. Sensory loss over the face indicates in­volvement of the afferent fibers entering the pons from the trigeminal nucleus. Facial weakness may be due to involvement of the seventh nerve in the pons. Episodic dysarthria and dysphagia indicate involve­ment of the vagus nerve in the medulla, and dysarthria may be due to involvement of the vagus nerve, the glossopharyngeal nerve, and the hypoglos­sal nerve as they course through the medulla. Involve­ment of the corticospinal tracts in the brainstem can produce a progressive spastic quadriparesis; involve­ment of the cerebellar connections results in limb and truncal ataxia.

 

Spinal Cord Symptoms

Most patients with es­tablished multiple sclerosis have signs of spinal cord involvement. These signs include some degree of spastic paraparesis with increased tone in both lower limbs, bilateral ankle clonus, increased tendon re­flexes, and bilateral extensor plantar responses. It is not unusual to see a progression of paraparesis with increasing disability. This does not necessarily indi­cate progression of the disease but may be due to pro­gressive gliosis of plaques in the spinal cord. This scarring produces increasing traction on and destruc­tion of axons descending from higher centers in the CNS and results in increasing spasticity and para­paresis.

 

Abnormal Bowel Function

Constipation may be a major problem in advanced multiple sclerosis. Bowel incontinence can be a devastating experience to a patient with multiple sclerosis, particularly if the loss of control occurs in a social situation or in a crowded area such as a shopping center. Many pa­tients react to the incident with reluctance to leave home and are extremely apprehensive if they do so.

 

Memory Deficits and Dementia

Impaired cog­nitive processing is not unusual in multiple sclerosis when patients often display a verbal working memory deficit owing to a central processing problem. This has a significant impact on reading or other tasks that require the maintenance of verbal information over a short period of time. Dementia occurs in approxi­mately 50 percent of cases, with less cognitive im­pairment in patients with relapsing-remitting disease than in those with the progressive form. The disease can, however, remain predominantly spinobulbar in form, with little involvement of the white matter in the cerebral hemispheres and preservation of intel­lect. Patients with demyelination in the periventricu­lar white matter of the brain often show an explosive emotional response with inappropriate laughter or oc­casional crying during conversation. This condition results from the interruption of an inhibitory dopaminergic pathway connecting the thalamus and the frontal lobe. Despite the laughter, which has been incorrectly termed euphoria, many patients are de­pressed and are embarrassed by the inability to con­trol this often incongruous response.

 

Depression

Depression, or bipolar affective dis­order, is clearly associated with multiple sclerosis and may precede the onset of symptoms of multiple scle­rosis in some cases. Character or personality changes with impulsiveness or less inhibition in so­cial interactions may present problems or embar­rassment to family members.

 

Sexual Dysfunction

Sexual dysfunction is not uncommon in both men and women with multiple sclerosis. Men experience difficulty in achieving an erection because of diminished penile sensation or difficulty maintaining an erection. Others report fail­ure of orgasm. Sexual dysfunction in women with multiple sclerosis includes lower limb spasticity, lack of vaginal lubrication, and diminished vaginal sensa­tion, any of which can interfere with sexual function­ing.

 

Seizures

Epilepsy occurs in 1 to 5 percent of pa­tients with multiple sclerosis, a higher frequency than in the normal population. Seizures are associated with lesions in the cortical or subcortical area and the onset is usually associated with the presence of new lesions in the cortical gray matter or in subcortical re­gions. When seizures are associated with clinical re­lapse, the seizures rarely recur. Seizures not related to clinical relapse tend to recur occasionally but control is usually straightforward. Patients with multiple sclerosis, seizures, and progressive cognitive decline have a poor prognosis and are susceptible to status epilepticus.

 

Tonic Spasms

Tonic spasms are paroxysmal, uni­lateral stereotypical spasms of short duration precipi­tated by movement or hyperventilation, lasting 30 to 90 s and involving part or the whole of one side of the body. The attacks may be heralded by brief clonic movements. During an attack, the affected limb or limbs are usually extended, but the hands, fingers, feet, and toes may be drawn into a pseudodystonic posture. There may be a spread to the face on the same side with head turning. Speech may be affected by the distortion of the face. The patient is fully alert and usually experiences minimal pain or discomfort. The affected limbs may have a slight degree of weak­ness after an attack. The condition is believed to be the result of acute demyelination involving the corti­cospinal tracts in the brainstem or spinal cord.

 

Lhermitte’s Sign

Flexion of the head may result in an electric-like shock passing down the spine and into the limbs. This phenomenon, known as Lhermitte’s sign, while not pathognomonic, is highly sug­gestive of multiple sclerosis and may also precede the development of other symptoms by months or years in some cases.

 

Spasticity

The majority of patients with multiple sclerosis will show some evidence of spasticity, which may vary from a slight increase in tone to se­vere spastic paraplegia in flexion with limbs held in a permanent flexed posture at the knees and hips. In the mildest of cases, spasticity may present with no more than a slight increase in tendon reflexes and extensor plantar responses. In the most severe cases, spasticity may dominate the clinical picture and be responsible for severe disability.

 

Psychiatric Symptoms

Psychosis can occur in both chronic, progressive and relapsing-remitting forms of multiple sclerosis when it heralds increasing activity of the disease process. Paranoia or halluci­nations are unusual and are occasionally prominent symptoms when there is extensive involvement of both frontal and temporal lobes.

 

Fatigue

The majority of patients experience fa­tigue. The onset may be sudden and debilitating, with inability to continue even the simplest of tasks. Fatigue tends to be provoked by a high atmospheric temperature and many patients relate difficulties in functioning in the summer. Some are extremely sensi­tive to heat and report profound weakness after a hot bath or shower. A febrile illness has the same effect, with the appearance of symptoms suggesting a re­lapse of the disease. However, there is rapid return to the prefebrile state once the fever subsides.

 

Pain

Multiple sclerosis is not a painless disease and pain is occasionally a prominent feature. As many as 80 percent of patients experience painful muscle spasms, intermittent or constant limb pain, or spinal pain. Primary pain is usually dysesthetic, oc­curring most commonly in the lower limbs. However, truncal and upper limb dysesthesias can occur. The dysesthesias may be augmented by tic-like pains, tonic seizures are occasionally painful, and in some cases, Lhermitte’s sign is experienced as pain rather than paresthesias. Chronic pain can occur as a dyses­thesia in the extremities, in girdle-like fashion around the waist or abdomen, as low back pain or pain in the shoulders due to disuse with capsular adhesions.

Trigeminal neuralgia or atypical facial pain can occur at any stage of the disease. The occurrence of trigeminal neuralgia in a young person should always arouse the suspicion of multiple sclerosis.

Debilitated patients who use a wheelchair often develop joint pains from abnormal posture or from propelling the wheelchair manually. Spasticity and muscle cramps can cause severe pain.

 

Headache

 Migraine headaches are not unusual in multiple sclerosis. Retro-orbital pain presenting as a dull ache, and increasing on eye movement, occurs in optic and retrobulbar neuritis.

 

Respiratory Impairment

The incidence of respi­ratory failure in multiple sclerosis is low and usu­ally occurs in the presence of extensive spinal cord or brainstem involvement. Clinical indications of im­pending respiratory failure include orthopnea, para­doxical movements of the chest wall and abdominal muscles during respiration, and use of accessory muscles of respiration. Patients with suspected im­pairment of pulmonary function should be monitored carefully with a number of pulmonary function tests, including force vital capacity (FVC), maximal voluntary ventilation (MVV), and maximal expiratory pres­sure (MEP), coupled with the index score for pul­monary function, which provides a clinical tool for the rapid assessment of significant respiratory dys­function in multiple sclerosis.

 

Pregnancy

Multiple sclerosis does not reduce fer­tility. An apparent reduction in fertility may be sec­ondary to physical disability and to counseling against pregnancy by physicians. Other factors in­clude a decision by women with multiple sclerosis to forego marriage, to have fewer children, or to un­dergo sterilization. Multiple sclerosis does not affect the course of pregnancy and there is no difference in the duration of labor or frequency of difficult deliv­ery, premature labor or stillbirth.

Relapse rates of multiple sclerosis during preg­nancy are significantly reduced, particularly in the third trimester, but there is a significant increase in relapse rates during the first 3 months postpartum. Consequently, these facts should be discussed with a woman seeking advice prior to pregnancy and to her partner, explaining the present knowledge concerning pregnancy and multiple sclerosis. It is important that the partner realize that he will have to assume more responsibility for child care and reduce the burden of responsibility on the mother.

There is an apparent beneficial effect of preg­nancy in autoimmune diseases such as rheumatoid arthritis, suggesting that the beneficial effects of preg­nancy could be the result of immunomodulation or immunosuppression. However, the explanation for the alteration in the immune system remains illusive.

 

Diagnostic Procedures

1.    The diagnosis of multiple sclerosis is es­tablished by careful interpretation of clinical signs and symptoms. These indicate multiple levels of CNS involvement. The diagnosis may be strengthened by interpretation of other findings discussed below, but diagnosis remains a matter of clinical judgment.

2.    All patients should be fully investigated for the presence of infection. This includes aerobic and anaerobic blood cultures, urinalysis, culture and sen­sitivity, and chest x-ray to rule out pneumonia. Many patients have infections that are latent or occult. This dramatically affects response to treatment unless in­fection is eradicated. Patients with decubitus ulcers, which are chronic and deep, should receive bone scans to rule out the presence of osteomyelitis.

3.    Magnetic resonance imaging (MRI). An MRI scan of the brain is abnormal in 95 percent of definite cases of multiple sclerosis, but abnormal MRI findings alone are not sufficient to confirm a di­agnosis of multiple sclerosis without compatible clinical abnormalities.⁶⁰ MRI scans are abnormal in only 70 percent of patients with probable multiple sclero­sis and 30 to 50 percent of patients with possible multiple sclerosis, and some patients with multiple sclerosis may have normal MRI findings.

When patients have a diagnosis of probable multiple sclerosis, a positive MRI scan will raise the category to definite in about 50 percent of cases. The results of positive MRI scanning in those categorized as possibly having multiple sclerosis are less impres­sive, with only 5 percent changing category from pos­sible to definite. Nevertheless, progression to definite multiple sclerosis is more likely in those with dissem­inated MRI lesions at presentation and less likely in those without disseminated lesions. Other character­istic features are immediate proximity to the ventri­cles, lesions greater than 6 mm in diameter, and the presence of infratentorial lesions. Lesions present as multiple areas of increased signal intensity on proton density or T2-weighted image and as hypointense im­ages using Tl-weighted images. These lesions are situated predominantly in a periventricular distribu­tion around the lateral ventricles and in the white matter of the brainstem, cerebellum, and spinal cord (Figs. 7-2, 7-3). Lesions in the corpus callosum, which may show atrophy on sagittal images, are more specific for multiple sclerosis. However, the diagnosis of multiple sclerosis requires a history of two attacks with clinical evidence of two separate lesions. An MRI abnormality caow substitute for one of these lesions when it is clearly not related to the other clini­cally defined lesion. However, an individual who has had a single attack with a single lesion on MRI scan cannot be said to have definite multiple sclerosis and may have a monophasic acute disseminated en­cephalomyelitis. A repeat MRI scan taken 6 weeks later and demonstrating new lesions would justify a diagnosis of probable multiple sclerosis and lead to additional studies, including evoked potentials and examination for IgG and oligoclonal bands in the cerebrospinal fluid beyond 3 months.

Frequent interval MRI scans have shown that newly encountered lesions found on T2-weighted images have a transient enhancement following ad­ministration of gadolinium. In about two-thirds of the cases, these enhancing lesions will continue to show faded enhancement for 4 to 6 weeks with less than 2 percent showing enhancement beyond 3 months. Enhanced lesions tend to appear in clusters over time and lesions seen in T2-weighted MRI scans can regress in size but are unlikely to disappear. Serial studies have shown that the MRI attack rate greatly exceeds the clinical attack rate. There is a much lower rate of new lesions defined by MRI in primary pro­gressive multiple sclerosis than in secondary progres­sive multiple sclerosis and in the relapsing-remitting form of the disease.

Serial studies have also shown a considerable amount of clinically silent disease activity in relapsing-remitting and secondary progressive multiple sclero­sis, but there is a lack of correlation between MRI and clinical disability. Nevertheless, MRI as a measure of multiple sclerosis activity is now widely accepted as a surrogate marker of disease in treatment trials of evolv­ing therapies.

§        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.

§        According to the accepted criteria there should be at least 3 focuses in MRI (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.

§       

 

         

 

4. Examination of the cerebrospinal fluid (CSF). Acute exacerbations of multiple sclerosis may be accompanied by a lymphocytic or polymorphonu­clear pleocytosis in the CSF. This is short-lived and does not usually exceed 200 cells per cubic millime­ter. The CSF protein is elevated, particularly in early cases and during acute exacerbations. The level rarely exceeds 100 mg/dL. Gamma globulin elevation is seen in many cases and exceeds 13 percent of the to­tal protein content. About 70 percent of patients have evidence of abnormal intrathecal IgG synthesis, as demonstrated by the IgG index.

 

IgG CSF/IgG serum albumin CSF/albumin serum

 

An index greater than 0.7 indicates synthesis of IgG within the CNS. The presence of IgG oligoclonal bands is a more sensitive measure of local IgG pro­duction.  However,  this  finding is  nonspecific  and oligoclonal bands in the CSF have been seen in pa­tients suffering from cerebral infarction, brain tu­mors, paraneoplastic syndromes, diabetes mellitus, borreliosis, neurosyphilis, human immunodeficiency virus (HIV) infection, various connective tissue dis­eases, and hypothyroidism. Consequently, testing must include both serum and CSF. Detection in CSF alone or primarily in the CSF is an indication of local IgG synthesis, which is usually associated with multi­ple sclerosis. Oligoclonal bands (Table 7-2) are de­tected in 90 percent of the patients with clinically definite multiple sclerosis. This figure drops to 50 percent in optic neuritis and isolated brainstem and spinal cord disease. Elevation of myelin basic protein is present in approximately 80 percent of cases of acute multiple sclerosis or multiple sclerosis in exac­erbation. Antibodies to myelin, myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG), and prote-olipid protein (PLP) are present in cells in the CSF but are not specific for multiple sclerosis.

5. Visual evoked potentials are positive in about 80 percent of patients with multiple sclerosis. Many of these patients have not had any visual symp­toms. Similarly, auditory evoked potentials are posi­tive in about 70 percent of patients with multiple scle­rosis and a number of these cases do not show clinical signs of brainstem involvement. Somatosen­sory evoked potentials are positive in about 60 per­cent of cases of multiple sclerosis. The presence of abnormal evoked potentials provide additional objec­tive evidence of a heterogenous involvement of the CNS.

Table 7-2

Oligoclonal Bands

Not specific for multiple sclerosis. Can occur in any disease with demyelination. Multiple sclerosis Neurosyphilis Viral encephalitis Bacterial meningitis Cerebral lupus erythematosus Lyme disease Neurosarcoidosis

6.    Neuropsychological testing is useful, par­ticularly in the early stages of apparent intellectual and cognitive failure, when it is necessary to distin­guish between early dementia and depression.

7.    Urological evaluation. Patients with estab­lished symptoms of urgency and frequency of mic­turition sufficient to cause inconvenience should have a limited urological evaluation with measurement of postvoid residual urine and a cystometrogram.

8.    Ophthalmology   evaluation.   An   opinion from an ophthalmologist should be obtained in the event of visual problems. Baseline evaluations of vi­sual acuity, visual fields, color vision and the pres­ence of scotomata are determined accurately and can be used for a comparison should visual deterioration continue.

 

Differential Diagnosis

Multiple sclerosis can mimic almost any chronic dis­ease affecting the CNS. The diagnosis is usually not difficult in well established cases, with evidence of multiple areas of involvement in the CNS, but early cases often present a problem in diagnosis. Various conditions (Table 7-3) can be confused with multiple sclerosis.

1.    The leukodystrophies. The adult forms of metachromatic  leukodystrophy,  Fabry  disease,  X-linked adrenaleukodystrophy,  globoid leukodystro­phy, and leukodystrophy with diffuse Rosenthal fiber formation can present with progressive deterioration and evidence of multiple areas of involvement in the CNS. There is a peripheral neuropathy with slowing of nerve  conduction  velocities  in  metachromatic leukodystrophy, which is not present in multiple scle­rosis. The demonstration of metachromatic material, low levels of arylsulfatase, and very long-chain fatty acids will establish the diagnosis. The diagnosis of leukodystrophy with diffuse Rosenthal fiber forma­tion can be made only by brain biopsy.

2.    Spinocerebellar degenerations. Autosomal dominant   spinocerebellar   degenerations,   sporadic late-onset olivopontocerebellar atrophies (multisys­tem disease), and Friedrich’s ataxia are occasionally misdiagnosed as multiple sclerosis. Diagnostic proce­dures in late-onset ataxias include MRI scanning of the brain and spinal cord and nerve conduction stud­ies. Metabolic evaluation consists of peripheral blood smears for acanthocytosis; determination of plasma amino acids, vitamin E, lactate and pyruvate levels; lipid and lipoprotein determination; and urinary or­ganic acid to identify abetalipoproteinemia, hypobetalipoproteinemia, vitamin E dysmetabolism, mito­chondrial cytopathies, and organic acidemias.

 

Table 7-3

MRI-Detected Abnormalities in White Matter Resembling Changes in Multiple Sclerosis

Acute disseminated encephalomyelitis

Adult-onset leukodystrophies

Multisystem disease

Spinocerebellar degeneration

Closed head injury

HIV encephalitis

HTLV-1 myelitis

Progressive multifocal leukoencephalopathy

Neurobrucellosis

Chronic granulomas

Beh§et disease

Sjogren syndrome

Brain tumors

Lymphoma

Cerebrovascular disease

Migraine ischemia

Cerebral vasculitis

B₁₂ deficiency

Moyamoya

Aging

Drug-induced encephalopathy

Cerebral lupus erythematosus

Neurosarcoidosis

Effects of radiation therapy

3.    Syphilis.   Both   meningeal   and   vascular syphilis may mimic multiple sclerosis. The diagnosis is established by abnormalities in the CSF and a posi­tive serologic test for syphilis.

4.    Wilson disease (hepatolenticular degenera­tion) usually presents with symptoms and signs of he­patic   involvement   and   neurological   dysfunction. However, a number of patients have minimal hepatic involvement with a broad range of neurological signs, including dysarthria, involuntary movements, and deteriorating coordination, followed by progressive de­mentia and behavioral abnormalities. A misdiagnosis of multiple sclerosis, particularly in those with marked cerebellar ataxia or psychiatric disorder, is not uncommon. Diagnosis is established by a positive slit lamp examination for Kayser-Fleischer rings, cataracts, and determination of serum, copper and ceruloplasmin, and of 24-hour urinary excretion of copper.

5.    The   antiphospholipid   syndrome,   which usually presents with deep venous thrombosis or stroke, can mimic multiple sclerosis when repeated minor strokes produce focal deficits and optic neuritis in a young adult.⁷⁴ Moreover, some patients will show the presence of areas of increased signal inten­sity in the periventricular area on a T2-weighted MRI. The diagnosis of the antiphospholipid syn­drome is established by a positive anticardiolipin and lupus anticoagulant in the serum.

6.    Lyme disease is of major concern in the eastern United States and appears to be spreading south and west. The disease is the cause of intermit­tent neurological symptoms. In the mildest form, it causes  Bell’s  palsy,  but  there  is  a  chronic  en­cephalomyelitis with intermittent signs of CNS in­volvement.

There may be a history of tick bite followed by a migratory rash and arthralgias. Lyme titers or Lyme polymerase chain reaction in the blood or spinal fluid will be positive in these patients.

7.    Behcet disease. The presence of cranial neuropathies, cerebellar ataxia, hemiparesis, quadri-paresis, pseudobulbar palsy, and peripheral neuropa­thy in an individual with oral ulcers, genital ulcers, and uveitis suggests Behcet disease. An MRI may re­veal findings resembling those seen in multiple scle­rosis.

8.    HTLV-1 infection. This retrovirus produces a myelopathy and spastic paraparesis and is an occa­sional cause of more widespread white matter dis­ease. Under these circumstances, it may be difficult to distinguish HTLV-1 infection from multiple sclerosis and appropriate antibody detection in both blood and CSF is necessary.

9.    Subacute combined degeneration of the spinal cord may resemble multiple sclerosis, particu­larly if there is an associated dementia and optic atro­phy. Serum B₁₂ levels are low in this condition. Al­though most cases of serum B₁₂ deficiency are acquired, inherited defects have been described in in­fants and children. Late-onset adult cases mimicking multiple sclerosis have occurred, suggesting that pa­tients diagnosed with multiple sclerosis should be screened for B₁₂ deficiency. Similarly, folate dysme-tabolism in the rare hereditary adult presentation may resemble multiple sclerosis.

10.    Brain tumor. The presence of a fixed sin­gle neurologic deficit in a young adult should always suggest the possibility of a brain tumor rather than multiple sclerosis. The diagnosis is established by MRI or computed tomography (CT) scanning.

11.    The arteritides. Both polyarteritis nodosa and systemic lupus erythematosus can produce multiple lesions in the CNS. However, other organs are often in­volved and there is evidence of peripheral neuropathy with an elevated sedimentation rate, abnormal nerve conduction velocities, and a positive nerve biopsy. Ab­normal antibodies in lupus erythematosus should reveal the presence of this condition, but abnormal antibodies are not always present in isolated cerebral lupus erythe­matosus. Similarly, isolated cranial arteritis can mimic multiple sclerosis and is often accompanied by a nor­mal sedimentation rate and a lack of any abnormal serum antibody levels. Diagnosis of this condition is es­tablished by angiography, which reveals beading and ir­regularity in the lumen of the intracranial arteries.

12.    Transverse myelitis. Multiple sclerosis is a relatively rare cause of transverse myelitis. Unless there is definite evidence of multiple areas of involve­ment of the CNS, other conditions causing transverse myelitis should be considered.

13.    Mitochondrial disorders. The association of optic atrophy, ataxia, spasticity, and hyperreflexia, usually associated with multiple sclerosis, can occur in Leber’s optic atrophy, now believed to be the result of mitochondrial DNA mutations. An electrocardio­gram and molecular diagnostic tests are suggested in suspected cases of Leber disease.

Other mitochondrial metabolic disorders can mimic multiple sclerosis, including MELAS syn­drome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), chronic milder forms of the MEERF syndrome (myoclonus epilepsy and ragged red fibers), and the adult form of Leigh syn­drome.

14.    Sjogren syndrome. There is a marked sim­ilarity in the clinical presentation of multiple sclerosis and Sjogren syndrome with CNS involvement. Both conditions may have optic neuritis, spinal cord in­volvement,    psychiatric    manifestations,    abnormal evoked potentials, similar CSF profiles, and indistin­guishable abnormalities on MRI and CT scans. Fea­tures that may distinguish Sjogren syndrome include the sicca complex, xerophthalmia, xerostomia, or re­current salivary gland enlargement, peripheral neu­ropathy, vasculitis in skin or muscle, elevated sedi­mentation    rate,    abnormal    antinuclear    antibody, positive rheumatoid factor, anti-RO(SSA)  or anti-LA(SSB) antibodies and decreased complement.

15.    Hereditary spastic paraparesis with pro­gressive lower limb weakness and spasticity, hyper­reflexia, and urinary incontinence can mimic multiple sclerosis, particularly when there is an associated op­tic atrophy. A positive family history suggesting an autosomal dominant trait and the slow progression of the disease should lead to the exclusion of multiple sclerosis.

 

Treatment

1.    Infection. Because there is strong evidence that the first attack or exacerbation of multiple sclero­sis may be caused by viral or bacterial infection, all infections should be treated promptly.

2.    Bed rest. Patients with acute multiple scle­rosis or an acute exacerbation of multiple sclerosis benefit from complete bed rest. Patients who are re­moved from the necessity of self-care and added wor­ries of the home environment improve with rest. However, the period of rest should not be protracted and no more than a few days in the great majority of patients. Once the patient shows improvement, the in­stitution of a graded program of physical therapy be­comes paramount.

3.    Corticosteroids.   Evidence   suggests   that high doses of intravenous corticosteroids (glucocorti­coids) may arrest the progress of multiple sclerosis.

Corticosteroids have several beneficial effects, in­cluding inhibition of secretion by antigen-presenting cells and T cells of the cytokines, tumor necrosis fac­tor a, and interleukin-6. An additional effect may be inhibition of secretion of 7-interferon and inter-leukin-12 by T cells.

About 85 percent of patients with relapsing-remitting multiple sclerosis shows objective signs of neurological improvement during treatment with in­travenous corticosteroids. Fifty percent of patients with progressive multiple sclerosis are improved by intravenous corticosteroids, although for many, the response is limited to a reduction in spasticity. This figure may improve if attention is paid to prevention of infection in the posttreatment period.

The short-term use of intravenous cortico­steroids is attended by few side effects. Some patients experience insomnia during treatment, a few show signs of euphoria; gastric upset with epigastric pain responds to ranitidine 150 mg ql2h. Hypomania or depression are unusual events. The daily dose and du­ration of therapy have not been determined, but an in­travenous dose of 1000 mg methylprednisolone over 3 h daily for 7 days, followed by alternate-day oral methylprednisolone, beginning with 96 mg (16 mg tablets X 6) at breakfast, and reducing by 8 mg q.o.d., will allow the hypothalamic-pituitary-adrenal axis to recover by the end of therapy. In the majority, this regimen will result in at least 6 months’ remission and several months or even years in many cases. The treatment can be repeated if relapse occurs.

As indicated under Diagnostic Procedures, all patients will have received full investigation for in­fection, including blood cultures, urinalysis, culture and sensitivity, and chest x-ray to rule out pneumonia before receiving corticosteroid therapy. Infections should be treated before and during treatment with corticosteroids. One of the major causes of failure or poor response to corticosteroids is the presence of a concomitant, untreated infection.

4. Immunosuppressive therapy. Long-term treatment with immunosuppressants may reduce the frequency of relapses in patients with multiple sclero­sis. Azathioprine is probably the safest drug in this category and has reduced relapse to 70 percent in 3 years, compared to 80 percent in the placebo group.

Azathioprine has few adverse effects and has not been shown to carry an increased risk of inducing neoplasia, unlike the more powerful immunosup­pressive therapies used to prevent transplant rejection.

Methotrexate, a drug used widely in the treat­ment of chronic autoimmune diseases such as rheumatoid arthritis and psoriasis, will reduce pro­gression of disability in chronic progressive multiple sclerosis. Low-dose therapy using 7.5 mg per week orally is effective, and adverse effects are few, but regular monitoring with complete blood counts and liver function tests is advised. Currently, low-dose oral methotrexate appears to be the best therapy for slowing deterioration in chronic progressive multiple sclerosis.

Cladribine, a specific antilymphocytic agent that is incorporated into DNA and induces lympho­cyte apoptosis, is reported to produce improvement in patients with chronic progressive multiple sclerosis. The drug, which is administered intravenously, has been reported to induce lymphopenia and severe but reversible aplastic anemia; the safety of cladribine has yet to be determined.

Results of studies of cyclosporine in multiple sclerosis have been equivocal. The drug may be bene­ficial in patients with frequently recurring or nearly continuous disease activity but unacceptable toxic­ity and marginal benefit have limited the use of cyclosporine in multiple sclerosis.

5.    Total lymphoid irradiation, originally intro­duced for the treatment of Hodgkin disease, has theo­retical benefits in multiple sclerosis, in that treatment produces a significant reduction in CD4 and CD8 lymphocytes. Potential risks of therapy, such as ma­lignancy, have limited the use of this modality, and the results of some studies have been equivocal.

6.    Plasmapheresis  has   marginal  benefit in multiple sclerosis and has not been accepted as an established therapy for this disease.

7.    Interferon β. Interferon β-lb (Betaseron) is reportedly effective in reducing clinical attacks of multiple sclerosis by approximately 30 percent over 24 months, when compared to placebo. Treatment reduces frequency of major attacks by 50 percent and produces immediate and significant reduction in contrast-enhanced MRI lesions and fewer new le­sions in patients receiving interferon B. The dose is 8 million units subcutaneously every other day.

Interferon β-la (Avonex) is also an available al­ternative therapeutic agent. It also lowers multiple sclerosis attack frequency by 30 percent and de­creases disease activity, measured by gadolinium-enhanced MRI. The dose is 6 million units intra­muscularly, once weekly.

Adverse effects of interferons include fever, chills, headache, and myalgia. These “flu-like” symp­toms begin 4 to 6 h after injection and last for a few hours. The response tends to resolve after a few weeks of therapy but can persist for several months in a minority of cases. Acetaminophen or ibuprofen, given 1 h before injection, reduces the flu-like re­sponse. The dose of acetominophen or ibuprofen can be repeated, should the flu-like symptoms still occur. The persistence of adverse effects requires reduction of the dose by 50 percent, that is, 4 million units of Betaseron and gradually increasing the dose to 8 mil­lion units over a period of 4 weeks. Prednisone 20 mg given 2 h before the injection of interferon 3 is also effective in reducing adverse effects.

Other adverse effects include redness at injec­tion sites, which occurs in many patients receiving Betaseron. The local reaction lasts for many weeks before resolution. Necrosis at the injection site is rare, but persistence of painful skin reactions requires the cessation of treatment.

Interferon β has been associated with depres­sion, which usually responds to a serotonin uptake in­hibitor such as fluoxetine. Inquiry should be made re­garding thoughts of suicide, which, if present, are an indication to stop treatment with interferon p.

The development of virus-neutralizing antibod­ies has been reported in 35 percent of multiple sclero­sis patients receiving interferon β-lb. The appearance of antibodies has minimal effect on clinical response and does not appear to be a reason for discontinuing therapy. The action of interferon β in multiple sclero­sis appears to be multifactorial, including sequestra­tion of T lymphocytes into lymphoid tissue and im­paired migration of T lymphocytes through the blood-brain barrier by inhibition of adhesion molecules on endothelial cells; decreased release of cy­tokines, including ^-interferon, from T lymphocytes; decreased tissue necrosis factor production by macrophages; and paradoxically, increased inter-leukin-6 production.

8.    Copolymer 1. The development of copoly­mer 1 was based on the premise that myelin basic protein is encephalitogenic and can cause experimen­tal allergic encephalomyelitis   (EAE) in animals. However, although some regions of the protein are encephalitogenic, other regions will suppress the de­velopment of EAE. This led to the synthesis and test­ing of several copolymers of amino acids, based on the amino acid composition of myelin basic protein. One such copolymer, designated copolymer 1, sup­pressed EAE in guinea pigs and other animals. The mechanism of suppression is not certain, but copoly­mer 1 seems to inhibit human T-cell lines specific for myelin basic protein. Consequently, the application of copolymer 1 to multiple sclerosis was a natural de­velopment   in   therapy.   A   double-blind   placebo-controlled trial of copolymer 1 in patients with re-lapsing-remitting multiple sclerosis over a 24-month period indicated a statistically significant reduction in the   copolymer   treated   group,   compared   to   the placebo group. The dose is 30 mg copolymer 1 daily by subcutaneous injection.  Side effects are mild, consisting of a local reaction at the site of injec­tion and rare transient palpitations, flushing, sweat­ing, or a feeling of chest tightness and anxiety.

9.    Immunoglobulin therapy. Treatment with intravenous immunoglobulin has received some atten­tion in recent years and there is some indication that IVIG may be safe and effective in reducing the fre­quency of exacerbations in relapsing-remitting multi­ple sclerosis.

10.    Physical therapy. All patients with multi­ple sclerosis should be evaluated by a physiatrist and should be placed in a graded program of physical therapy. This program should be under constant re­view so it can be modified, depending on the results of corticosteroid and other therapies, as well as the benefit of the physical therapy itself.

11.     Spasticity. Increased muscle tone, exag­gerated tendon reflexes, clonus, and spontaneous muscle spasms are often present in patients with ad­vanced multiple sclerosis. An acute increase in spas­ticity can occur during an exacerbation of multiple sclerosis, or spasticity may present as an insidious de­terioration over a period of months, when the deterio­ration is ofteot apparent to patient or therapist. Baclofen (Lioresal) is effective in reducing spasticity and can be given in doses up to 120 mg daily. The tendency is to underdose. The medication should be given in an initial dose of 20 mg ql2h orally, with gradual increments over several weeks to an ef­fective level. High doses, although reducing spastic­ity, may increase weakness in some cases. Diazepam (Valium) or clonazepam (Klonopin) are potent spas­molytic agents. The tendency to drowsiness can be mitigated by beginning with a low dose and only in­creasing when the patient is comfortable, that is, not drowsy.

Dantrolene sodium (Dantrium) is effective in reducing spasticity but has limited applications be­cause it almost invariably causes weakness. However, it can be useful for treatment of spasticity in nonam­bulatory patients with severe prolonged muscle con­tractions, who will not be adversely affected by the decrease in voluntary muscle power associated with the use of this drug. Adverse effects include damage to the liver, drowsiness, and light-headedness. An ini­tial dose of 25 mg/day may be increased by 25 mg in­crements every week, to a maximum dose of 100 mg/day.

Tizanidine is an effective antispastic agent with an antispasticity effect comparable to ba­clofen. Tizanidine dosage should be titrated begin­ning with 2 mg at night and gradually increasing by 2 mg every 4 days in divided doses, until therapeutic goals have been achieved without adverse effects. The larger dose should be given at bedtime to mini­mize adverse effects. The average daily dose is 18 to 24 mg, and the total daily dose should not exceed 36 mg. Adverse effects include dry mouth, drowsi­ness, hypotension, light-headedness, abnormal liver function tests, and the rare occurrence of hallucina­tions. These adverse effects tend to decrease in inten­sity as the duration of therapy increases.

Sudden muscle spasms (charley horses), whether nocturnal or diurnal, often respond to clonazepam, which is particularly useful for nocturnal spasms, in that clonazepam not only reduces spasm but also in­duces sleep without contributing to fatigue the next day.

When patients fail to respond to oral medica­tion, intrathecal baclofen delivered through a pro­grammed pump placed in the abdominal wall, with an intrathecal catheter in the spinal canal, produces re­markable reduction of spasticity and spasms in pa­tients with severe spastic paraparesis. Potentially am­bulatory patients have returned to walking in some cases.

Botulinum toxin is effective in reducing spas­ticity when injected into selected muscles but has had limited application to date.

12.    Visual difficulties. Patients should be en­couraged to report visual deterioration at the onset of the problem.  Because optic neuritis can develop rapidly,   further   deterioration   should   be   treated promptly, with intravenous or oral corticosteroids in a high dose. In many cases, this produces rapid im­provement in symptoms or stabilizes the condition, with subsequent slower but steady improvement in visual acuity.

13.    Weakness. It is very difficult to strengthen a muscle  weakened by central  denervation.  The potassium channel blocking agents 4-aminopyridine and 3-4-diaminopyridine may improve action poten­tial provocation in demyelinated axons and improve neurological function. Body cooling, using cooling vests or repeated cold showers in the summer months, are effective in those who are heat sensitive.

14.    Fatigue may strike without warning. Fam­ilies should be informed about the fatigue factor and the unpredictable development of this symptom. This prevents resentment when the patient is suddenly un­able to attend a long-planned social function and when there is a need for extra rest periods during the day. The intense fatigue associated with a febrile ill­ness will respond once the body core temperature re­turns to normal. Every patient with recent onset of fa­tigue should be evaluated for depression, medication effect, or intercurrent illness.

A number of drugs may help eliminate fatigue, including amantadine 100 mg twice a day, pemoline (Cylert) 37.5 mg morning and noon, methylphenidate (Ritalin)   10   mg   morning   and   noon,   fluoxetine (Prozac) 20 mg every morning, or selegiline 5 mg ql2h orally.

15.    Pain is a common feature of multiple scle­rosis. The treatment consists of physical therapy, when appropriate, and medication. Mild chronic pain may respond to acetaminophen or propoxyphene and acetaminophen   (Darvocet-N).    Nonsteroidal   anti­inflammatory drugs should be used with caution to avoid gastric ulceration. Ibuprofen 600 mg, given with meals, is an effective analgesic. Tramadol (Ul-tram) 50 mg with misoprostol (Cytotec) 100 μg, to limit the risk of gastric ulceration, will control mod­erately severe pain. Gabapentin beginning 300 mg 12h and increasing, as tolerated, to as high as 2700 mg in divided doses, or amitriptyline 10 mg q.h.s., in­creasing slowly by 10-mg increments to 80 to 100 mg daily, are both useful in pain control. Trigeminal neu­ralgia usually responds to carbamazepine but the re­sponse is less predictable in atypical facial pain. A painful Lhermitte’s sign often shows response to car­bamazepine or clonazepam as do tic-like extremity pains.   If opioids  are  prescribed,   the  medication should be prescribed by one practitioner. The risk of addiction with oral opioids is low. but dependency can occur. Neurolytic nerve blocks are required occa­sionally, including epidural blocks for chronic sciatic pain.

16.    Ankle edema. Swelling of the ankles in patients with limited walking or in those who are nonambulatory and confined to a wheelchair is a gravity effect with fluid accumulating in the depen­dent tissues of the feet and ankles. Consequently, the use of diuretics is of little value. The patient should lie supine for several hours a day, with the ankles ele­vated above the level of the heart. This can be accom­plished by having the patient lie supine with the feet elevated on a firm cushion or over the armrest of a sofa, thus permitting gravity-driven drainage over the lower limbs. The use of leotards or elastic stockings may also be helpful.

17.    Restricted mobility. Many patients with limited mobility resist the use of a wheelchair and re­quire a great deal of persuasion to use an electric cart. The idea that this will lead to further weakening is frequently expressed and is, of course, not true. The severe paraparetic with good upper limb function should be encouraged to use an electric cart. The in­creased mobility and broadening of the patient’s so­cial contacts is truly remarkable, once this is ac­cepted, and the electric cart is an essential therapeutic tool in many cases.

18.    Decubitus ulcers. Skin care is one of the paramount needs in the wheelchair-bound paraplegic patient or in those who are bedridden. With few ex­ceptions, skin breakdown and the development of de­cubitus ulcers is the result of neglect by caregivers. Treatment requires removal of pressure in the af­fected area and bacterial culture, followed by the use of appropriate antibiotics when the ulcer is infected. When the ulcer fails to heal or when the patient ap­pears to be deteriorating, the suspicion of an underly­ing osteomyelitis indicates the need for a radioactive bone scan to confirm this diagnosis. A protracted course of intravenous antibiotics is indicated in such cases. Deep (third degree) decubitus ulcers usually require debridement and plastic surgery with surgical reconstruction.

19.    Urinary tract infection. Cystitis is com­mon in female patients with multiple sclerosis and has an increased frequency in male patients using self-catheterization. Although pyelonephritis is un­common, it can occur in severely debilitated patients and is a potent factor in chronic illness, with ane­mia, weight loss, and fatigue. Urinary tract infec­tions require urinary culture and sensitivity testing, with the use of appropriate antibiotic therapy. Atten­tion to the symptoms of infection and immediate treatment facilitates the use of a Foley catheter or suprapubic catheter and increases the safety of self-catheterization.

20.    Management of bladder dysfunction.

A. Detrusor hyperreflexia. The early symptoms of bladder dysfunction are usu­ally caused by detrusor hyperreflexia, with urgency, frequency, and occasional nocturia. Most patients can be managed with an anticholinergic such as oxybutynin chloride 5 mg ql2h and increasing to 5 mg q8h if necessary. Tolterodine (Detrol) 2 mg ql2h is equally effective and has fewer adverse effects. Imipramine PM 75 to 100 mg q.h.s. is a useful alternative, particularly when nocturia is a problem. Pro-Banthine 15 mg with meals and at bedtime is an effective alternative. Hyoscyamine time release 0.375 mg at night is also effective in reducing noc­turia.

B.    Sphincter    detrusor    dyssynergia with poor flow, interrupted stream, and increased postvoid residual responds to prazosin 0.5 mg/day, increasing by 0.5-mg increments to an effective dose, if there are no hypotensive effects. Doxa­zosin mesylate tablets 1 mg q.h.s., in­creasing by increments to effect, are also helpful.

C.    Incomplete emptying with a post-micturition residual volume greater than 150 mL  requires intermittent self-catheterization. This technique has revo­lutionized the management of bladder dysfunction in multiple sclerosis but re­quires instruction and is a clean rather than sterile procedure. Repeated bladder infections are not unusual during the first few months of self-catheterization but are reduced as the bladder begins to tolerate the presence of bacteria and clean tech­nique improves. Anticholinergic drugs can be continued in patients performing intermittent self-catheterization.

D.    Surgical procedures. Severe or total incontinence requires the use of an in­dwelling catheter or suprapubic catheter. There seems to be little difference in the development of infection in these two tech­niques, but some patients find a suprapubic catheter with continuous drainage into a catheter bag more convenient than the transurethral   catheter,   and   the   choice should be offered, when appropriate.

Augmentation cystoplasty to in­crease the storage volume in a severely contracted hyperreflexic bladder is of oc­casional benefit for patients who can per­form self-catheterization.

21.    Intention tremor is a common sign in multiple sclerosis and many patients develop resting tremor enhanced by action in the later stages of the disease. These are difficult symptoms to control. De­vices to dampen tremor, such as weights applied to the wrists, are of limited benefit. Medication is unpre­dictable. Propranolol (Inderal) beginning 20 mg tid and increasing to as high as 240 mg/day when the long-acting preparation can be used, may be effective in some cases. Other drugs of occasional benefit in­clude clonazepam, primidone, and hydroxyzine. Car­bonic anhydrase inhibitors such as acetazolamide and Neptazane may help in some cases, and isoniazid in high doses has been reported to decrease tremor, but adverse effects are not uncommon. In many cases, a combination of drugs is the most effective approach to this problem.

22.    Unsteadiness (ataxia). No medications are available to modify ataxia. The physician must per­suade the patient who is at risk from falling to take reasonable precautions to reduce the effects of ataxia. Light-weight wheeled vehicles with hand brakes are useful, rather than the standard walker, which is slow and cumbersome. Severe ataxia is an indication for the use of an electric cart, even though the patient has little or no weakness, and this should be encouraged at an early stage, because improvement in ataxia is unusual.

23.    Contractures. Paraplegia and flexion with knee and hip contractures are common manifestations of neglect and should not happen in a well planned treatment program. Contractures can be prevented by physical therapy, appropriate splinting, and the use of antispasticity agents such as baclofen or tizanidine. If contractures are established, early surgical interven­tion is necessary to release joints and restore normal limb posture. The baclofen pump has major benefit when contractures are the result of severe flexor spasticity.

24.    Diplopia is often temporary during an ex­acerbation of multiple sclerosis and should be treated by patching one eye. The patch should be alternated over each eye daily. When diplopia is an established symptom, the use of prisms in eyeglasses may help. Surgical correction by an ophthalmologist is needed occasionally.

25.    Impairment of bowel control. Bowel in­continence can be a devastating event in patients with multiple sclerosis, sufficient in some cases to convert an outgoing, gregarious patient into a recluse. The problem can be solved by development of the innate but dormant gastrocolic reflex. The patient is in­structed to attempt bowel movements immediately af­ter breakfast each day. The reflex may not function for several weeks, but eventually, it will return and bowel evacuation becomes an automatic function in the morning. The patient is then free of worry about incontinence for the rest of the day.

Constipation is a common complaint. A stool softener such as docosate sodium 100 mg b.i.d. or bulk agents such as Metamucil may suffice in mild cases. When constipation is established, the patient should take 30 mL Milk of Magnesia, plus 2 senna tablets (Senokot) at night, if there has beeo bowel movement for 2 days. This should result in a bowel movement after breakfast the next morning. An alter­native method is to use lactulose syrup 1 to 2 table­spoons daily. In refractory cases, bisacodyl supposi­tory (Dulcolax) 10 mg can be used in the morning. Failure of bowel movement after these measures re­quires the periodic use of an enema.

Fecal impaction is a problem in bedridden or immobile patients. Manual removal of fecal material followed by enemas may be necessary. The venerable but extremely effective milk and molasses enema is recommended as a last resort.

26.    Sexual dysfunction. Sexual dysfunction is not uncommon in both men and women with multiple sclerosis, occurring in almost 80 percent of men with advanced multiple sclerosis and in approximately 50 percent of women with similar disability.

In men, failure to achieve erection rarely re­sponds to oral therapy with yohimbine or hormonal replacement, with parenteral testosterone which, in reality, should only be used for hypogonadal disor­ders. Penile prostheses are cumbersome and subject to infection. Intercavernous injection of alprostadil (prostaglandin E) or propiverine combined with phentolamine increases arterial inflow into the penis, while decreasing venous outflow. Both methods are effective, with restoration of ability to achieve satis­factory intercourse in the majority of cases. Adverse effects include mild pain and dizziness. The dose of alprostadil or propiverine should be titrated to achieve a satisfactory but not prolonged erection. Ad­verse effects are infrequent and include prolonged erection, priapism, hematoma, hypotension, and fibrosis.

Another method using transurethral supposito­ries of alprostadil is an equally successful alternative therapy, with fewer adverse effects. It is probable that sildenafil citrate tablets will supersede most methods for improving erectile function in males. The use of this drug is effective in most cases of erec­tile dysfunction with few serious adverse effects, the most common of which are headache in 16% of pa­tients, flushing in 10%, and dyspepsia in 7%.

Female sexual problems include loss of vaginal sensation or lubrication. The latter can be treated with vaginal lubricant. Loss of vaginal sensation requires empathy and understanding by a concerned partner who is prepared to assist in the development of satis­factory sexual foreplay.

Loss of vaginal sensation can be treated in some cases with a vibrator, which enhances sensation in the vaginal area.

27.    Cognitive dysfunction. About 40 percent of patients have cognitive difficulties, which are usually mild. The main deficits relate to retention and recall, short-term memory, attention, and de­layed processing of information. When these difficul­ties interfere with the ability to function, neuropsy­chological testing should be performed to measure the extent of deterioration and to exclude depression, which is a major cause of impaired memory in multi­ple sclerosis. A small percentage of patients do show significant disability with cognitive impairment, suf­ficient to interfere with daily activities. These situa­tions can be treated with a cognitive rehabilitation program, allowing the patient to circumvent or mini­mize these difficulties. Dementia, if sufficient to pro­duce declining ability to function independently, is rare” and often associated with atrophy of the cor­pus callosum.

28.    Respiratory impairment treatment should be directed to the control of infection followed by in­travenous corticosteroid therapy. The dictum—if in doubt, don’t wait, intubate and place the patient on a ventilator—is applicable in these cases.

29.    Bulbar dysfunction. Dysarthria is not un­usual in multiple sclerosis but is rarely of sufficient magnitude to interfere with communication. Should this happen, the services of a speech pathologist are indicated.

Dysphagia is, however, common and often un­detected in patients with multiple sclerosis. This in­volves a disturbance of both the oral and pharyngeal phase of swallowing, and evaluation by a speech ther­apist, including radiological investigations with a bar­ium swallow and visual fluoroscopy, is indicated. The speech pathologist can then suggest changes in diet and the use of various maneuvers to facilitate swal­lowing. In advanced cases, when dysphagia is a ma­jor problem, the patient should be fed through a per­cutaneous gastrostomy tube.

30.    Community services. Patients with severe multiple sclerosis who are unable to continue their employment, or who become increasingly dependent on others, face the prospect of growing problems at home and in the community. Most are not equipped to cope with the stress of chronic illness and should receive social service assessment and advice when­ever possible. This results in a smoother transition from hospital to home and better adjustment to home conditions, with improved support for the patient and the family. To this end, identification and referral to community resources available to multiple sclerosis patients should be implemented in all cases with more than a minor degree of disability.

31.    Simple prophylactic measures.

A.    Combat infection. In many cases, a relapse occurs after an infection. It is prudent, therefore, to treat all infections in multiple sclerosis patients seriously and to resort to the early use of antibiotics. This will not have any effect on viral in­fections but antibiotic therapy will reduce the risk of secondary bacterial infections such as sinusitis, bronchitis and pneumo­nia.

B.    Avoid fatigue. Some patients note relapse following periods of unexpected exercise. Ambulatory patients with multi­ple sclerosis should avoid sudden unex­pected athletic activities or prolonged ex­ertion. Those who wish to exercise should develop an incremental program of activ­ity and stop whenever they experience fatigue.

C.    Emotional stress. As a group, mul­tiple sclerosis patients experience more emotional stress than those who are well There are  increased  rates  of divorce more financial problems, and fewer op­portunities for gainful employment. Sub­standard care for the chronically disablec and limitations on mobility because of ; lack of transportation or lack of propei building access adds to the emotional dis tress   of   multiple   sclerosis   sufferers Whether such stress leads to exacerbatioi is debatable, but every effort should b< made to reduce emotional distress by ap propriate treatment or referral to commu nity agencies.

Patients with depression will oftei benefit from the use of appropriate antide pressants such as fluoxetine (Prozac), ser traline (Zoloft), or paroxetine (Paxil) which can be combined with psychothet apy in appropriate cases.

D.    Avoid excessive, prolonged expo sure to sunlight. Patients with multipl sclerosis experience considerable weak ness with the reappearance of previou symptoms if exposed to a hot environ ment, in particular, after prolonged expo sure to sunlight. The patient should b warned about this possibility and reas sured that the  symptoms  will resolv once   the   body   core   temperature   de creases.

 

Prognosis                                        ^;

The prognosis in multiple sclerosis has im proved in the last two decades. The mean surviva is now 20 to 25 years. This can be attributed to bette treatment and control of infection in debilitated pa tients. The physician should be frank with the patient and relatives in discussing the prognosis. Multiple sclerosis resembles a chronic infectious disease in presentation and prognosis. Consequently, multiple sclerosis may be benign, relapsing and remitting, pri­mary or secondary progressive, severely disabling, or fatal. In general, patients who present with mild symptoms and who have several mild relapses tend to remain in the mild category and do not become se­verely disabled. Approximately 20 percent of patients remain fully active and fully employed 10 years after the diagnosis of multiple sclerosis and should be in­formed that they have a benign form of the disease and will not be disabled by multiple sclerosis. How­ever, these patients must also be informed that mild exacerbations of multiple sclerosis will continue at unpredictable times well past the fiftieth year. More than 50 percent of patients continue to work full-time, whereas 33 percent are paraparetic, para­plegic, or quadriplegic, and 25 percent require inter­mittent or constant catheterization for bladder dysfunction.

The prognosis of multiple sclerosis can be im­proved by avoiding any precipitating factors. The pa­tients should be advised to identify and treat infec­tions promptly, to avoid unusual physical or emotional stress, and to avoid prolonged exposure to sunlight. All infections should be treated with the early use of antibiotics. Patients with chronic multiple sclerosis who are bedridden or confined to a wheel­chair often experience slow deterioration, which is not appreciated by patients or by relatives. The prog­nosis can be improved in these cases by regular reevaluation at 6-month intervals, followed by prompt attention to obvious areas of deterioration. Patients with urinary tract problems should be reevaluated fre­quently. Loss of function in the limbs calls for prompt reinstitution of physical therapy and treatment with intravenous corticosteroids. Paraparesis should not render a patient bedridden. Prescription of the correct type of wheelchair and instruction in the proper trans­fer from bed to chair permit broader contact with friends and relatives, improve morale, and improve the long-term outlook for the patient. Pregnancy is associated with clinical stability in most cases, but the postpartum period carries a risk of exacerbation of multiple sclerosis by two or three times the ex­pected relapse rate. Patients should be told that there is some increased risk of multiple sclerosis in the off­spring if one parent has the disease, but the actual risk is small.

 

 

Acute Disseminated Encephalomyelitis

This condition is an acute demyelinating disease be­lieved to be an autoimmune response to a systemic viral infection. The illness may begin within a week or as long as 4 weeks after an acute viral infection such as measles, varicella, or rubella, and rarely fol­lowing mumps or influenza (postinfectious en­cephalomyelitis). In many cases, the infectious com­ponent is unrecorded or may present as a mild upper respiratory tract infection. Acute disseminated en­cephalomyelitis used to be a recognized complication of vaccination against rabies or smallpox (postvacci­nal encephalomyelitis), but this condition has largely been eliminated by the use of modern rabies vaccines and by the eradication of smallpox worldwide. Occa­sional cases may be seen following injection of tetanus antiserum or earlier forms of rabies vaccine, which are still in use in Third World countries.

 

Pathology

The brain and spinal cord show the presence of perivascular cuffing with lymphocytes and plasma cells and scattered areas of perivascular demyelination. The primary lesion is believed to be a vasculopathy and discrete areas of hemorrhage are seen in some cases. The condition has a similar pathological appearance to experimental allergic en­cephalomyelitis. In some fulminating cases, the brain is swollen and shows the presence of numerous pe­techial hemorrhages or hematoma formation. Micro­scopic changes consist of necrosis of blood vessel walls and the passage of fibrinous exudate into the perivascular spaces. There are marked white matter edema and infiltration of abnormal areas with inflam­matory cells. The affected blood vessels may be sur­rounded by areas of necrosis and demyelination or ball or ring-like hemorrhages (acute hemorrhagic en­cephalomyelitis).

 

Clinical Features

 The decrease in the incidence of acute disseminated encephalomyelitis has been at­tributed to increased vaccination and immunization against infectious diseases. The onset is usually abrupt, occurring within a week of clinical evidence of infection, but the first symptoms have been re­ported before any signs of infection, and as long as 2 or 3 months after infection. The early symptoms

consist of headache, fever, anorexia, and lethargy. The subsequent course shows considerable variation. The illness may resemble a mild encephalitis with complete recovery, or there may be rapid progression to stupor and coma. Psychiatric symptoms consisting of personality changes, hallucinations, or acute para­noia are not uncommon. Seizures, sensory or motor disturbances, or dysfunction of bladder or bowel may occur.

 

Differential Diagnosis

The disseminated in­volvement of the CNS in acute disseminated en­cephalomyelitis produces a clinical picture that mim­ics acute multiple sclerosis. The development of symptoms following documented infections, how­ever, suggests the diagnosis of acute disseminated en­cephalomyelitis.

 

Diagnostic Procedures                                                                                                  

1.    On lumbar puncture, the CSF is clear, with normal, slightly elevated pressure. There is a lympho­cytic pleocytosis and red blood cells are present in some cases. The protein and gamma globulin con­tents are elevated. The glucose content is normal.

2.    The EEG is abnormal in severe cerebral in­volvement, with diffuse slowing in the theta and delta range.

3.    The MRI scan shows the presence of nu­merous areas of increased signal intensity in the white matter of the brainstem and spinal cord, and in the gray matter of basal ganglia, thalamus, and tem­poral lobe cortex.

 

Treatment

1.    Plasmapheresis alone or combined with high-dose corticosteroids and cyclophosphamide may produce a successful recovery in some cases.

2.    The fulminating acute hemorrhagic form of the disease is associated with rapid increase in ICP and requires ICP monitoring, intravenous mannitol and high-dose barbiturate therapy.