8Multiple Sclerosis and Other Myelinopathies

The common feature of all diseases affecting myelin is a pathological abnormality or total destruction of myelin sheaths, primarily in the central nervous system. Deficient myelin formation is caused by congenital enzyme defects in a small subgroup of these diseases (the leukodystrophies, p. 121), but, in most of them, myelin is lost later in life, for reasons that are currently not well understood. Immunological (autoimmune) processes and metabolic disturbances appear to play important roles. The most common demyelinating disease is multiple sclerosis.

Myelin

Most axons are surrounded by a myelin sheath. The myelin sheaths of the central nervous system are composed of the cell membrane of oligodendroglia, which is wrapped around the axon to form a multilaminar structure, as seen in the illustration on p. 2.

The myelin sheath enables the axon to conduct impulses more rapidly (see p. 4); thus, loss of myelin lowers conduction velocity, producing clinical manifestations of neuronal dysfunction. The myelination of the central nervous system reaches its final extent in the first few years of postnatal life. Each layer of a myelin sheath is 7.5 microns thick and is composed of two lipoid and two proteinaceous monomolecular layers. In the genetic myelinopathies, the primary development of myelin is deficient; in the metabolic and autoimmune demyelinating diseases, originally intact myelin is attacked and destroyed. The most common demyelinating disease, multiple sclerosis, is described in further detail below.

Multiple sclerosis (MS) is a chronic disease of the central nervous system. It usually presents with episodic neurological deficits, which, later on in the course of the disease, tend not to reverse fully, leaving increasingly severe residual deficits whose summation causes progressively severe disability.

The clinical manifestations are very diverse because widely separated areas of the CNS are affected and the temporal course of the disease is variable.

“Disseminated encephalomyelitis” is a synonym for multiple sclerosis. In French, the disease is called “sclérose en plaques,” as it was named by Charcot; related terms are used in the other Romance languages.

Epidemiology. The incidence in temperate zones is four to six new cases per 100 000 persons per year and the prevalence is greater than 100 per 100 000. MS is particularly common in northern Europe, Switzerland, Russia, the northern U.S.A., southern Canada, New Zealand, and southwest Australia. Women are affected about four times as commonly as men. The initial attack usually oc-

curs in the second or third decade, only rarely in a child or older adult.

!After ischemic stroke, multiple sclerosis ranks second among all neurological diseases as a cause of chronic disability.

Pathological anatomy. There are disseminated foci of demyelination in the central nervous system (brain and spinal cord), sometimes with destruction of axons as well. Local, reactive gliosis is found at the sites of older foci. Thus, “sclerosis” develops at “multiple” locations, giving the disease its English name.

Pathogenesis. The pathogenetic mechanisms underlying MS are still poorly understood. The most promising hypothesis at present is that an infection of neurons and glia occurs in childhood, after which the genome of the pathogenic organism remains in the nervous system. The pathogenic genome is then reactivated on multiple occasions through influences of various kinds; this reactivation, in turn, impairs the functioning of the oligodendroglia, producing episodes of demyelination. Ac-

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Cerebellar signs are practically always present in advanced MS, including impaired coordination, ataxia, and, frequently, a very characteristic intention tremor (Fig. 3.20 [p. 28], Fig. 8.2).

Gait impairment often becomes severe early in the course of the disease. Typically, the combination of spastic paraparesis and ataxia results in a spastic−ataxic, uneven, uncoordinated, and stiff gait (p. 14, Fig. 3.2).

Sensory deficits are found early in the course of the disease in about half of all patients. Vibration sense in the lower limbs is nearly always impaired. Pain is not uncommon; sometimes there is even a dissociated sensory deficit.

Bladder dysfunction is present in about three-quarters of all patients (generally in association with spasticity); disturbances of defecation are much rarer. Bladder dysfunction is sometimes an early manifestation of the disease. Urge incontinence is highly characteristic, i. e., a sudden, almost uncontrollable need to urinate, perhaps leading to “accidents” and bedwetting. Patients often do not mention bladder dysfunction until they are directly asked about it.

Ictal phenomena of various types are not uncommon. It is still debated whether MS causes epileptic seizures. About 1.5 % of persons with MS suffer from trigeminal neuralgia, which may alternate from one side to the other. Acute dizzy spells can occur, as can paroxysmal dystonia, dysarthria, or ataxia. The characteristic socalled tonic brainstem seizures consist of paroxysmal, often painful, tonic stiffness of the muscles on one side of the body. The lower limb is hyperextended, the upper limb flexed (Wernicke−Mann posture). The patient re-

mains fully conscious. Tonic brainstem seizures are often provoked by a change of position; they last less than one minute and are followed by a refractory period of a half hour or more in which no further seizures can occur. Tonic brainstem seizures and most other MS-as- sociated ictal phenomena respond to treatment with carbamazepine or other antiepileptic drugs.

Mental disturbances are not severe early in the course of the disease. Later on, however, many patients develop psycho-organic changes and psychoreactive and depressive disturbances. Psychosis is very rare.

The typical clinical findings in multiple sclerosis are shown schematically in Fig. 8.2.

Diagnostic evaluation. The typical physical findings

(see above) reveal the involvement of multiple areas of the nervous system by lesions separated in space and time. The following ancillary tests are also useful:

Neuroimaging studies, particularly MRI, typically reveal abnormal white matter signal in the periventricular regions and the corpus callosum. Active MS plaques take up contrast medium (Fig. 8.3).

Cerebrospinal fluid examination reveals a mild elevation of the total protein concentration, mild lymphocytic and plasma cell pleocytosis, and, in 90 % of patients, oligoclonal banding (demonstrable by isoelectric focusing, Fig. 8.4).

Electrophysiological testing: delayed latency of the visual evoked potentials is typical.

Treatment. Individual acute episodes (relapses) are treated with high-dose steroids, e. g., methylprednisolone 500 mg i. v. per day for five days, followed by oral prednisone, initially 100 mg per day and then in tapering doses, for two weeks. Patients with frequent re-

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