Theme: Demyelination diseases of nervous system: multiply sclerosis (MS), acute disseminated encephalomyelitis (ADEM), optic encephalomyelitis, encephalomyelopolyradiculoneuritis, polyencephalomyelitis, disseminated myelitis

Theme: Demyelination diseases of nervous system: multiply sclerosis (MS), acute disseminated encephalomyelitis (ADEM), optic encephalomyelitis, encephalomyelopolyradiculoneuritis, polyencephalomyelitis, disseminated myelitis. Acute myelitis.

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 in northern 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.

Plate 104

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 in number, 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 can now 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 CSFbut 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.

Theme: Demyelination diseases of nervous system: multiply sclerosis (MS), acute disseminated encephalomyelitis (ADEM), optic encephalomyelitis, encephalomyelopolyradiculoneuritis, polyencephalomyelitis, disseminated myelitis

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

Plate 104

Etiology, Pathology, and Pathogenesis

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.

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):

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

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.

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

Motor Symptoms

Visual Symptoms

Bladder Involvement

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

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

Cerebellar Symptoms

Brainstem Symptoms

Spinal Cord Symptoms

Abnormal Bowel Function

Memory Deficits and Dementia

Depression

Sexual Dysfunction

Seizures

Tonic Spasms

Lhermitte's Sign

Spasticity

Psychiatric Symptoms

Fatigue

Pain

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

Pregnancy

Diagnostic Procedures

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.

IgG CSF/IgG serum albumin CSF/albumin serum

Table 7-2

Oligoclonal Bands

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.

Differential Diagnosis

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.

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 often not 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 agentwith 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 been no 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 cyclophosphamidemay 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.

Students’ practical Study Program.

Step I. Aim: To put clinical diagnosis. For this purpose it is necessary:

1. To determine clinical form of multiply sclerosis, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis, acute myelitis by mean of scheme of differential diagnosis.

2. To define basic clinical syndromes of locomotors, sensitive, coordinative dysfunction, cranial innervation.

3. Carry out differential diagnosis between multiplex sclerosis and acute disseminated encephalomyelitis.

4. To formulate clinical diagnosis, for example:

a) Multiply sclerosis, cerebral-spinal form with presence of lower spastic paralysis, degree III, progradientive course

b) Acute disseminated encephalomyelitis (encephalomyelopolyradiculoneuritis) with presence of mixed tetraparesis and disturbed sensation of radicular and polyneuritic type.

Step II. Aim: To prescribe therapy. For this it is necessary to pay attention to pathogenetic mechanism of demyelination diseases of nervous system, clinical forms, course of disease, presence of remission, acute periods, est.

For the treatment of multiply sclerosis prescribe:

- general-clamping drags (ATPh, Cocarboxylase);

- vitamins group B (B₁, B₆, B₁₂), ascorbinic acid (Vit C), nicotinic acid (PP);

- hormones (prednisolone, metipred, dexamethazone, polcortolone) in onset of disease;

- desensibilisation drugs (dimedrol, pipolphene, diazoline, claritin, hormones);

- immunostimulators (T-activine, Thymaline, Sinacten-depo, Echinacea);

- pyrogenic drugs (pyrogenal);

- immunodepressors (hormones, asathyoprine);

- myorelaxation drugs (Midocalm, Mellictine, Bactrophene);

- biostimulators (aloe, vitreous body);

- plasmapheresis.

In causes of ADEM also it is necessary to prescribe course of antibiotics therapy (series of penicillin, cephasolin), enzymes (desoxyribonucleinase, ribonucleinase) and antivirus remedies such as Reapherone, Acyclovir, Zovirax, hormones, desensibilisation medicines. Independently prescribes medicines for therapy of amyotrophic lateral sclerosis.

Step III. Aim: To fulfill preventive-examinative measures.

On reason from clinical diagnosis and effect of therapy to define prognosis about life, work, recovering, to take preventive measures, to fulfill medical labor examination and military medical examination.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a chronic progressive disease of nervous system and is defined pathologically as one in which there is degeneration of both upper and lower motor neurons of brain and spinal cord. It is characterized by unfavourable prognosis. The disease was first described by Charcot and Joffroy in 1869.

Epidemiology

The incidence rate of Amyotrophic Lateral Sclerosis of 2 – 5 cases per 100 000 population has been found in many countries. As many as 60 000 - 70 000 begin_of_the_skype_highlighting 60 000 - 70 000 FREE end_of_the_skype_highlighting patients have this disease at any one time all over the world.

The disease is one of middle and late life. Only 10% of cases begin before age 40 years; 5% begin before age 30. In most series, men are effected one to two times more often than women. There is no known ethnic predilection.

The disease is found worldwide in roughly the same prevalence. However, about 50 times that number were found on the island of Guam.

Etiology and pathogenesis

The cause of ALS is not known. Most of scientists consider this disease to be a polietiologic one.

The main theories:

1. Connection of ALS with Prion Diseases. This can be proved by high content of Arginaza in the brain of animals in experiment and in the CSF of patients with ALS. Besides this we can find morphologic changes in the brain of such patients. They are spongiosis and synapse degeneration. This can be explained by the deficiency of Argininum.

2. Autoimmune theory. There are certain changes in cell – mediated and humoral immunity.

3. Genetic theory. The patients with familial forms of ALS have changes of gene, located in the 21^st chromosome. This gene is responsible for the production of endogenous antioxidants. The deficiency of such antioxidants can cause activation of free radical oxidation that leads to the death of neurons of anterior horn.

4. Amino acids, neuromediators, neuropeptides metabolism disorders. And those chemical substances are responsible for the apoptosis. That’s why the patients with ALS have low content of Mg, Mn, AL, Se in biologic fluids.

The main reasons of ALS development are:

1. Insufficiency of spinal blood circulation.

2. Vertebrogenous pathology

3. Trauma

4. Infections

5. Demyelination

6. Metabolic disorders

7. Tumours (rarely)

8. Radiation

Pathomorphology

The pathologic process is localized in

· Anterior horns of the spinal cord

· Pyramidal tract

· Motor neurons of IX, X, XI, XII CN’s, sometimes - V, VII

There is degeneration of third and fifth cortex layers of the anterior central gyrus (small and large pyramidal cells).

Besides there is demyelination of pyramidal tracts (in the internal capsule, lateral and anterior horns of the spinal cord) that cause the death of axial cylinder. That means that the fibres irreversibly die.

Classification

There are three forms of the disease:

1. Classical or sporadic ALS

2. Familial ALS which is usually associated with

· Dementia

· Extrapyramidal disorders

· Extrapyramidal and cerebellar disorders

· Extrapyramidal and sensory disorders

· Peripheral neuropathy

3. Complex – ALS – Parkinson disease – Dementia

Familial ALS usually begins at the age of 45 – 48. This form can be inherited as autosomal dominant and autosomal recessive one.

According to the localization of the process at the beginning of the disease we can diffea such clinical forms:

1. Cerebral

2. Bulbar

3. Cervical - thoracic

4. Lumbar – sacral

Clinical features of the main forms of ALS and its diagnostics

According to the International Neurologic Community in 1990 the main criteria of ALS were established:

· The symptoms of lower motor neuron lesion

· The symptoms of upper motor neuron lesion

· Progressive course of the disease (during 6 months and more)

· No effects from medicines and physiotherapeutic treatment

ALS is ruled out at:

· Sensory disorders

· Pelvic disorders

· Eye movements disorders

· Autonomic disturbances

· Also if it is not a familial form - in case of Parkinson disease and Dementia

1. Anamnesis of the disease.

The first symptoms of the disease are weakness, especially in extremities (hands in particular), awkwardness during the performance of acute movements, reduced muscles of thenar and hypothenar, fasciculations. Forerunner symptoms of ALS are crumpies (painful tension of calf muscles). These symptoms were observed in 30% of patients 3 – 6 months before the other signs of the disease.

2. Typical clinical picture

· Flaccid and spastic paralysis

· Muscles atrophy

· Bulbar and pseudobulbar signs

The reflexes at the beginning are very high with wide reflexogenic zones. There are all the groups of pathologic reflexes. But :

Abdominal reflexes are preserved for a long time
There are no pelvic disorders

Clinical picture of high (cerebral) form of ALS

It is observed in 1-2% of all patients with ALS. It is characterized by spastic tetraparesis and pseudobulbar syndrome. Sometimes at this form Extrapyramidal nervous system (the signs of Parkinson disease) and cortex of frontal lobe (the signs of Dementia ) is involved.

Clinical picture of bulbar form of ALS

It is observed in 25 % of all patients with ALS. At the beginning the process is localized in the medulla oblongata and causes the lesion of IX, X, XI, XII CN’s that leads to the classic bulbar syndrome. Then it is joined by anterior horns amyotrophy and pyramidal disorders.

Clinical picture of cervical - thoracic form of ALS

It is observed in 50 % of all patients with ALS. The disease begins with the weakness and reduced muscles of proximal and later distal parts of the upper extremities. There is well – expressed hypotrophy, increased muscle tone according to the spastic type, hyperreflexia, pathologic signs. That means that there is a mixed paresis. In the course of the disease the reflexes fade away, the peripheral palsy dominates, bulbar symptoms are joined.

Clinical picture of lumbar – sacral form of ALS

It is observed in 25 % of all patients with ALS. The first signs of the disease are connected with the peroneal muscle group lesion. This is associated with high stretch reflexes, pathologic signs. This form is characterized by slow progress.

Depending on the combination or domination of some clinical signs there are:

1. Classical type – when anterior horns and lateral columns are involved in pathologic process in equal way.

2. Poliomyelitic type – in 10 – 12 % of all cases the lesion of anterior horns (that means amyotrophy) dominates.

3. Spastic type – the conductive disorders dominate.

The stages of the disease

I. There are only subjective signs (complains). This stage lasts for about 2 – 3 years.

II. There are the clinical signs of the disease – focal and bulbar disorders. This stage lasts for about 6 months – 2 years.

III. The process involves neighbour regions. This stage lasts for about 4 months – 2 years.

IV.Terminal stage. The patients need somebody’s care. This stage lasts for about 3 months – 1 year.

The additional methods of diagnostics

ENMG:

Regular rhythmical fasciculations
Decreased speed of impulse conductance along motor fibres but preserved speed of impulse conductance along sensory fibres.

This method is very important in the diagnostics. Due to it we can:

Localize the process
To find out its expansion
The degree of lower and upper motor neurons lesion
To register fasciculations as usually it is one of the first symptoms of the disease.

MRI

We can diagnose atrophy and bilateral degeneration of cortico – spinal tracts. In case of high lesion we can find the focus in the posterior crus of the internal capsule.

PET

One can register the low content of glucosa in the region of anterior central gyrus. This sign by itself doesn’t have very important meaning.

CSF – examination

Increased protein level
Increased activity of Arginaza

Differential diagnosis should be made with following diseases:

1. Chronic stage of Acaridan encephalitis

2. Cervical ischemic myelopathy, which is characterized by slow progress and often with the termination of the process

· Limited fasciculations, which are non – rhythmical

· A great attention should be paid to the X- ray – examination, MRI, ENMG

3. Subacute poliomyelitis which is characterized by the absence of pyramidal tract lesion

4. Spinal amyotrophy, which is characterized by slow benign course. Pyramidal signs are very rare at this disease

5. Syringomyelia (anterior horns form). There are sensory and segmental trophic disorders

6. The tumours of the cervical part of the spinal cord – intramedullar. Only MRI and CT examination can diffe those pathologies at early stages

7. Radiculoischemia on the lumbar level is characterized by peculiarities of development, vertebrogenous syndrome, radicular syndrome and partial regress in case of treatment

The course of the disease and prognosis

There is progressive course of the disease. The result of ALS in most cases is death of the patient. Sometimes the periods of stable symptoms can be observed during 1 – 3 years.

The duration of life in such patients depending on the clinical form of the disease:

1. Cerebral form – 4 – 6 years.

2. Bulbar form – 1 – 3 years

3. Cervical – thoracic form – 6 – 8 years

4. Lumbar – sacral form – 10 – 12, 9 – 16 years.

The main principles of treatment:

1. For the examination and diagnosis putting the patients are sent to the neurologic hospital

2. There is no effective treatment for ALS

3. For the stabilization of the process there are used :

· Vit B (2 – 4 ml per day during 30 days)

· Vit E 1500 mg per day

· Biostimulators

· Anabolics (Nerobol 5 – 10 mg twice a day during 1.5 – 2 months, Retabolil – 1 ml (50 mg) once a week)

· As pathogenetic treatment we prescribe Delargil 2 mg twice a day i/v during 10 days, then i/m up to 1 month.

· Tireotropinum i/v by drops 500 mg

· Riluzan 100 mg per kg during 12 months.

· At increased tonus myorelaxants are used.

· Dipheninum is prescribed at crampy

· Antidepressive medicines

· Electro – therapy is excluded

· The patients in the third and fourth stage need somebody’s care. Sometimes fixative equipments are used. At bulbar disorders the patients get food in a special way.

Motor Neuron Disease (Amyotrophic Lateral Sclerosis)

Definition Motor neuron disease (amyotrophic lateral sclerosis—ALS) is a chronic disease characterized by progressive degeneration of motor neurons of the anterior horn of the spinal cord, motor nuclei in the brainstem, and neurons in the motor area of the posterior aspect of the frontal lobe.

Etiology and Pathology

The etiology is unknown. The disease is familial in 10 percent of cases, when it is inherited as an autosomal dominant or autosomal recessive trait. Dominant familial ALS has a penetrance of less than 100 percent by age 70 yearsand may be lower than 50 percent by age 63.⁸⁵ This is the most common form of familial ALS, with the responsible gene located on chromosome 21, whereas some families with recessive ALS show linkage to markers on chromosome 2 or 21. The mutations are associated with an abnormality in the superoxide dis-mutases, which are a group of isoenzymes that catalyze the conversion of superoxide free radical ions to hydrogen peroxide and oxygen. Failure of this reaction permits free radicals, which are highly toxic, to accumulate in motor neurons, producing free radical toxicity and accelerated cell death.

Some 90 percent of patients with ALS are without evidence of chromosomal abnormality with superoxide dismutases mutations present in a small percentage. In the majority, however, the disease may be the result of exotoxicity. This process postulates overactivity of the glutamate system, in which the normal amino acid is converted into an exotoxin which produces glutamate overstimulation of the five subtypes of the glutamate receptors on the neuronal membrane, resulting in increased calcium entry into neurons, overproduction of free radicals, and premature cell death.

Evidence for an autoimmune mechanism producing neuronal loss or the role of positive viral agents such as the poliovirus are unproven. Failure of axonal transport with accumulation of neurofilaments, which are known to be increased in ALS, could indicate a failure of axonal transport, leading to dendritic atrophy and death of the perikaryon.

Pathological changes consist of loss of motor neurons in the spinal cord, brainstem, and cerebral cortex. Surviving neurons are atrophic with abnormalities of dendritic pattern on Golgi staining and show reduced levels of RNA. Inclusion bodies, identified as hyalin inclusions, Lewy bodies, basophilic inclusions, and Bunani bodies, occur in motor neurons in familial and nonfamilial ALS. A filamentous neuronal inclusion body has been identified in nonfamilial ALS in both motor and nonmotor neurons in < the brain, suggesting that ALS should be considered a ' multisystem disease. '

Clinical Features Amyotrophic lateral sclera- | sis is a rare disease with a prevalence of approxi- j mately 2 per 100,000 and a male-to-female ratio of i 1.1:1. The median age of onset is 66 years. ]

The fundamental disease process in ALS involves loss of motor neurons in the cerebral cortex, the motor nuclei of the cranial nerves, and the anterior horn cells of the spinal cord. Consequently, the classical division of ALS into those with bulbar onset (progressive bulbar palsy) and those with involvement of the spinal cord motor neurons (progressive muscular atrophy) may well be artificial because careful neurological examination will reveal evidence of lower motor neuron involvement in patients with predominantly bulbar symptoms, whereas those with < spinal motor neuron signs of wasting and fasciculations usually present with increased tendon reflexes and extensor plantar responses, indicating that the pathological process includes the corticospinal tracts. It is probable that ALS consists of a spectrum of disease extending from primary lateral sclerosis to spinal muscular atrophy and that ultimately, if the patient survives, signs of both upper and lower motor neuron disease will be apparent.

The disease often begins with progressive loss of motor neurons in the anterior horns of the spinal cord. When the neurons of the cervical cord are involved, there will be progressive weakness, wasting, and fasciculations involving the small muscles of the hands. However, the loss may occur at any site in the spinal cord. The sensory examination is normal. Initially, there may be no clinical evidence of corticospinal tract or bulbar involvement, which will inevitably develop later as the disease progresses.

Alternatively, the disease may begin with involvement of the motor neurons of the cranial nerve nuclei. Under these circumstances, there is progressive weakness and wasting involving the pharyngeal musculature, the tongue, and the facial muscles. The patient develops progressive dysarthria and dysphagia. Fasciculations of the tongue are usually prominent and can be seen when the tongue is examined, lying quietly on the floor of the mouth. The oculomotor nuclei are usually not involved.

Signs indicating spinal motor neuron disease with wasting, fasciculations, the development of corticospinal tract dysfunction, increased tendon reflexes and extensor plantar responses, ultimately occur in patients who survive for more than a few months.

A combined form of upper motor neuron disease and anterior horn cell involvement, plus corticospinal tract dysfunction, is the most common form of ALS. The patient complains of increasing weakness and examination reveals atrophy, fasciculations, and wasting of the muscles in both upper and lower limbs, associated with increased reflexes and extensor plantar responses. Eventually the brainstem nuclei are involved, resulting in dysphagia, dysarthria, and facial weakness. There are no sensory changes.

Diagnostic Procedures

1. Electromyography (EMG) as an extension of the clinical examination, is the single most useful test in evaluating disease of the lower motor neurons.The EMG will demonstrate abnormalities in upper and lower extremities and thoracic paraspinal muscles and the presence of normal nerve conduction velocities.

2. Muscle biopsy shows the typical appearance of denervation atrophy with atrophic fascicles coexisting with normal fascicles.

3. Muscle enzymes such as creatinine phosphokinase (CK) may be elevated in rapidly progressive cases.

4. The CSF is normal.

5. There are no MRI, CT, or myelographic abnormalities.

Differential Diagnosis

1. With mass lesions impinging on the spinal cord (e.g., tumors, spondylosis, abscess), the weakness, wasting, and fasciculations are confined to one or more myotomes, and there is appropriate sensory loss in the affected dermatomes.

2. Multifocal motor neuropathy with conduction block can be differentiated by EMG and the presence of GM_: antibodies in this disease.

3. Combined cervical myeloradiculopathy and lumbosacral radiculopathy with both upper and lower motor neuron signs can be excluded if brainstem cervical, thoracic, and lumbosacral areas are included in the EMG evaluation.

4. Benign fasciculations, myokymia. Benign fasciculations are not at all uncommon and are often diffuse. There are no other signs of neurological involvement, and the general physical examination and neurological examination are perfectly normal. Follow-up examinations remain normal.

5. Chronic inflammation of the meninges or spinal cord (e.g. adhesive arachnoiditis). In this condition, the CSF is abnormal. The MRI and CT scans with myelography may be abnormal.

Treatment

There is no effective treatment for this disease and the course is one of progressive deterioration, with a mean survival of 3 years. Immunosuppressant and intravenous immunoglobulin therapies are not effective. Selegiline does not modify the progression of ALS. Ceftriaxone is without benefit. Lamotrigine and gabapentin, which inhibit glutamate release, do not alter the course of this disease. Neither dextromethorphan, physostigmine,branch-chain amino acids, 3,4-aminopyridine,nor acetylcysteine has had a significant effect on ALS. Recombinant human insulin-like growth factor-1 is reported to slow the progression of ALS and deterioration in the quality of life.

Riluzole, a glutamate antagonist, is reported to increase survival in ALS and appears to be most effective in patients with disease of bulbar onset. The drug is taken by mouth, 50 mg ql2h, 1 h before or 2 h after a meal. Adverse effects include nausea, weight loss, and headache.

There should be close support by physicians, nurses, social workers, and psychologists to help the patient face the ravages of this disease. The family should be informed of the course complications and prognosis of the disease. Community resources should be obtained through the help of a social worker because the family will require increasing support as the patient becomes increasingly dependent. When dysphagia prevents normal feeding, feedings should be continued through a plastic naso-gastrostomy or jejunostomy tube, using a pureed diet and ultimately the use of a percutaneous gastronomy (PEG) tube. The weakness and wasting often produce painful subluxation of the scapulohumeral joints, and the arms should be supported by hemiplegic slings. Adequate analgesia for pain control is essential. Aggressive symptomatic treatment should focus on the goal of maintaining the patient's functional independence as long as possible. This requires an ongoing program of physical rehabilitation, including physical and occupational therapies, the use of assistive devices, the provision of home equipment, and nutritional, communication, respiratory, and psychological support.

When respiratory failure occurs, the family should be assured that the patient will pass quietly into a carbon dioxide narcosis, followed by coma and death, and should be urged to avoid the use of a mechanical respirator in most cases. However, a number of patients develop respiratory failure at an early stage, when there is still adequate function in the upper limbs. These individuals may lead a useful life of

2 or more years, in some cases, with portable mechanical ventilator support. Death occurs from pulmonary infection as the patient becomes immobilized by muscle weakness.

The bulbar musculature tends to lose function at a slower rate than the muscles of the upper limbs, but bulbar involvement is more critical because of the dangers of aspiration pneumonia.

Prognosis

The course is one of steady progression until death. Life expectancy of patients with dysphagia is less than that of patients with limb weakness, presumably because of the higher risk of aspiration pneumonia in the dysphagia group. Occasionally, the process seems to be arrested for a period of several months before continuing a downhill course. Mean survival in the familial form of ALS is 3 years, with mean survival of 4 years in sporadic cases of ALS.

Primary Lateral Sclerosis

Definition This is a slowly progressive disorder of nonfamilial form, in which there is a gradual development of spastic paraparesis over a period of many years.

Etiology and Pathology

The etiology is unknown. Pathological changes consist of frontal lobe atrophy with neuronal loss and corresponding reduction in subcortical white matter, involving the precentral gyrus, the premotor areas, and the supplementary motor areas, with degeneration of the corticospinal and corticobulbar axons. The pathological changes suggest that there may be an overlap with ALS and frontotemporal dementia.

Clinical Features

The condition presents in adults with a gradual development of spasticity in the lower limbs, producing progressive impairment of gait and eventual requirement of a cane or walker. The upper limbs are spared but show hyperreflexia. The tendon reflexes are increased in the lower limbs, and bilateral extensor plantar responses are present. Spastic dysarthria and mild dysphagia are late developments. There is no evidence of amyotrophy, fasciculations, optic atrophy, hearing loss, sensory change, or pes cavus. There are no sphincter problems, no urgency of micturition, and absence of any evidence of a segmental lesion.

The clinical course is slow, with a median survival of several years. Some patients show evidence of muscle wasting late in the course of the disease, suggesting that primary lateral sclerosis is a forme fruste of ALS or frontotemporal dementia.

Diagnostic Procedures

1. An MRI or CT scan should be obtained to exclude malformations at the craniocervical junction, cervical spondylosis, spinal canal or canal tumors, and multiple sclerosis.

2. The CSF is normal.

3. A SPECT or PET scan shows bilateral posterior frontal lobe hypoperfusion/hypometabolism.

4. Neuropsychological testing may reveal minor cognitive deficits that escape detection in a brief mental status evaluation.

Treatment

Oral baclofen or a baclofen pump may be useful in reducing spasticity. Adequate evalu ation will avoid unnecessary surgery for higher cervical cord compression.

TRANSVERSE MYELITIS (MYELOPATHY)

Definition

Transverse myelitis is a syndrome characterized by acute spinal cord dysfunction involving both halves of the cord in transverse section.

Etiology and Pathology

The various etiologies of transverse myelitis are outlined in Table 12-2. The condition may be a periinfectious or postinfectious process and has been associated with many viral infections, including poliovirus, echovirus, and Coxsackieviruses.¹² In some patients, there is direct viral involvement of the spinal cord, whereas others present with a postinfectious process, probably the result of inflammation, edema, or an autoimmune response to viral infection. Transverse myelitis has been associated with measles, varicella, mumps, rabies, typhoid, systemic lupus erythematosus, and a reaction to sulfonamides. Transverse myelitis has also followed vaccination and immunization against rubella, diphtheria, and poliomyelitis. Vascular occlusion with softening of the cord may occur in syphilitic arteritis and in the arteritis associated with collagen vascular diseases. Arterial occlusion due to a dissecting aneurysm of the aorta or after surgical resection of an aortic aneurysm are other possible causes. Acute transverse myelitis in heroin addicts is probably due to focal arteritis. Transverse myelitis may occur as an acute demyelinating process in multiple sclerosis and a severe acute myelitis as a remote effect of carcinoma. The increasing survival of patients with treated neoplasms has led to the recognition of increasing numbers of cases of acute transverse myelitis secondary to radiation therapy.

Table 12-2

Etiologies of transverse myelitis

1. Congenital—vascular malformation

2. Infectious—viral infection

3. Autoimmune—peri-infectious, postinfectious, or vaccinial myelitis

4. Multiple sclerosis

5. Neoplastic—paraneoplastic necrosis

6. Toxic—secondary to heroin injections

7. Vascular—vascular insufficiency—arteritis, dissecting aneurysm, aorta resection, aortic aneurysm

8. Degenerative—irradiation

9. Idiopathic

Sudden bleeding from vascular malformations or capillary telangiectasia may produce a similar picture.

The pathological changes vary. In most cases, there is necrosis of the cord, often involving several segments. The necrosis is maximal in the center of the cord and even in severe cases, there is always a thin rim of surviving tissue at the periphery. The posterior nerve roots and posterior root ganglia are occasionally involved in the process. In cases of vascular etiology, there is infarction of the spinal cord.

Clinical Features

A history of recent acute illness suggesting a viral or bacterial infection may be obtained in about one-third of the patients. The most common complaint is a history of upper respiratory tract infection or a flu-like illness. Transverse myelitis is occasionally preceded by a gastrointestinal illness. Patients with transverse myelitis occurring as a paraneoplastic condition have a history of pre-existing neoplasia that is frequently metastatic. Radiation transverse myelitis occurs several months to a year after radiation therapy.

Transverse myelitis presents with symptoms and signs indicating involvement of gray matter and the corticospinal and spinothalamic tracts.

1. Paresthesias, which are often described as numbness, tingling, or pins and needles, usually begin in the toes or the feet and extend up the lower limbs into the trunk, with eventual involvement of the upper limbs in cervical transverse myelitis.

2. Pain is of sudden onset, usually severe and corresponding to the level of the cord involvement. Consequently, the pain is often in the intrascapular region.

3. Progressive lower limb weakness is noted, often presenting with "stumbling or weakness of one leg."

4. Urinary retention occasionally occurs as the initial complaint and is usually followed by lower limb weakness in a short period of time.

The course of transverse myelitis may vary:

1. A smooth progressive course often begins with involvement of the lower limbs followed by ascending paresthesias and weakness over a period of 2 weeks, at which time the condition stabilizes with paraplegia or quadriplegia and a well-defined sensory level.

2. In subacute progression the symptoms appear intermittently over a 10-day to 4-week period. During this time, the illness may appear to stabilize, only to be followed by the appearance of new symptoms after several days of apparent stabilization.

3. Progressive limb weakness often presents with stumbling or asymmetrical weakness of a lower limb or with upper limb paresthesias when there is cervical cord involvement.

4. An acute catastrophic illness with all symptoms develops within 12 h and sometimes in less than an hour after onset. This type of presentation is usually preceded by marked back pain. Recovery is slow and incomplete.

Examination of the patient reveals a flaccid paresis or paralysis with depressed or absent tendon reflexes suggesting involvement of anterior horn cells. There is bilateral symmetrical sensory loss extending to the upper level of cord involvement. This site commonly lies between T6 and T12, but there may be extension of the cervical cord in some cases. The sensory loss is usually total, involving touch, pinprick, vibration, and proprioception, or the loss may be dissociated, with loss of pinprick and preservation of posterior column functions. Bladder distention occurs early in the illness in the majority of patients and is followed by overflow incontinence. Fecal incontinence is less frequently encountered.

Diagnostic Procedures

1. The T2-weighted MRI scan shows areas of increased signal intensity involving gray matter and surrounding white matter.

2. Electromyography performed after 2 weeks will demonstrate motor axonopathy in keeping with anterior horn cell involvement.

3. Lumbar puncture. The CSF is abnormal with a pleocytosis in about 50 percent of cases, which varies from a mild increase in leukocytes to a white count as high as 300 cells per cubic millimeter. The cells are predominantly monocytic. Protein content is elevated in about 40 percent of cases.

Differential Diagnosis

See Table 12-1.

Treatment

The patient should be placed on bed rest and turned every 2 h to prevent the development of decubiti and also to promote drainage of the dependent portions of the lungs. The bladder should be catheterized and the urine cultured periodically to detect any infection. Appropriate antibiotics are inducted if infection occurs. The bowels should be moved once every 2 days and a diet with adequate bulk content given as soon as possible to prevent fecal impaction. Physical therapy with passive movements of all joints should be performed twice a day. Application of foam rubber splints to the lower limbs helps to prevent contraction deformities. Patients with involvement of the upper limbs require adequate splinting of the forearms,, wrists, and hands.

As recovery occurs, efforts should be made to I remove the bladder catheter as soon as possible and urological evaluation should be obtained to determine bladder function. Stimulants such as bethanechol chloride, a parasympathetic stimulant, 10 to 50 mg three or four times a day may help to initiate micturition and empty the bladder in patients with persistent | bladder paralysis.

Spasticity involving the lower limbs can be re-1 lieved by baclofen (Lioresal) 10 mg q6h, increasing slowly to as high as 100 to 120 mg/day. Severe spasticity will require the use of a baclofen pump with intrathecal injection of baclofen.

Physical therapy, beginning with passive therapy in the acute phase, should be changed gradually to a more active program as the patient recovers.

Prognosis

The majority of patients with transverse myelitis show some degree of recovery, which varies from complete to minimal. More than 50 percent of patients with the idiopathic form of the disease regain the ability to walk within a year, although a number will be dependent on orthopedic appliances. Twenty-five percent of patients show poor recovery and the majority of these give a history of severe back pain preceding a rapid catastrophic onset of transverse myelitis.