Download MINISTRY OF HEALTH OF UKRAINE VINNYTSIA NATIONAL

MINISTRY OF HEALTH OF UKRAINE
VINNYTSIA NATIONAL MEDICAL UNIVERSITY
NAMED AFTER M.I.PIROGOV
NEUROLOGY DEPARTMENT
Stomatology Faculty
Lesson # 11
Demyelization of the Nervous System. Multiple Sclerosis.
1. Goals:
1.1. To study the Neurological fundamentals of the
Demyelization in the Nervous System.
1.2. To study the Neurological fundamentals of the Multiple
Sclerosis.
2. Basic questions:
2.1. Multiple sclerosis:
2.1.1. Etiology. Pathogenesis. Pathological Anatomy.
Clinical Features. Clinical Courses.
Diagnostic
evaluation. Treatment. Prognosis.
Literature:
Mark Mumenthaler, M.D., Heinrich Mattle, M.D. Fundamentals
of Neurology. – P. 156-159.
Fundamentals
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), 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.
Multiple Sclerosis
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 “sclerose 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 occurs 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.
According to this hypothesis, CNS demyelination and the generation of
antibodies against myelin are merely secondary consequences of the
disease process, rather than the cause of MS. An effect of the primary
infection outside the central nervous system might explain the
lymphocyte abnormalities that are also observed in MS.
Another hypothesis is that an infection induces a (cellmediated)
autoimmune reaction against normal or virally infected components of
the nervous system. In any case, multiple sclerosis clearly involves a
reactive process that can be set in motion by more than one precipitating
factor. This explains why foci can arise in such diverse locations in the
central nervous system and why the temporal course of the disease is so
variable.
Many different exogenous factors have been proposed as putative
causes of MS, but no clear causal relationship has yet been demonstrated
for any of them.
Course. The temporal course of multiple sclerosis (Fig. 8.1) can
be characterized:
_ by the episodic appearance of new neurological deficits (relapsing
type), which can then:
_ remit completely or almost completely,
_ leave residual deficits of greater or lesser severity, or
_ (rarely) fail to regress at all;
_ by episodic worsening at first, followed by steady progression
(secondary progressive type);
_ by steady progression from the beginning (primary progressive type),
as is most commonly seen in older patients with paraparesis; or
_ by steady progression with interspersed episodes of acute worsening
(progressive relapsing type).
Clinical manifestations and neurological findings. The general
clinical features of MS are summarized in Table 8.1.
The neurological deficits present in each individual patient
depend on the number and location of the demyelinating foci. The
following are among the more characteristic disease manifestations and
physical findings:
Retrobulbar neuritis is usually unilateral. Over the course of a
few days, the patient develops an impairment of color vision, followed
by a marked impairment of visual acuity (finger counting is barely
possible). Orbital pain is often present and the patient may see flashes of
light on movement of the globe. These problems begin to improve in one
or two weeks and usually resolve completely. The temporal side of the
optic disc becomes pale three or four weeks after the onset of symptoms.
Retrobulbar neuritis rarely affects both eyes, either at the same time or in
rapid succession. Recurrences are rare. If retrobulbar neuritis is an
isolated event in a patient otherwise free of neurological disease, the
probability that other clinical signs of multiple sclerosis will appear in
the future is roughly 50%. This probability is greater if pathological
changes are seen in the CSF (see below) or on an MRI scan (Fig. 8.3).
Disturbances of ocular motility. Diplopia, particularly due to
abducens palsy, is a common early symptom but nearly always resolves
spontaneously. Later, typical findings are nystagmus (often dissociated)
and internuclear ophthalmoplegia, often without any subjective
correlate. Internuclear ophthalmoplegia in a young patient is relatively
specific for multiple sclerosis.
Lhermitte sign (positive neck-flexion sign). Active or passive
forward flexion of the neck induces an “electric” paresthesia running
down the spine and/or into the limbs.
! Retrobulbar neuritis, disturbances of ocular motility, sensory
deficits, and Lhermitte sign are common early findings in multiple
sclerosis.
Pyramidal tract signs and exaggerated intrinsic muscle reflexes
may be present early in the course of the disease. The abdominal
cutaneous reflexes are absent. Later on, in almost all patients, spastic
paraparesis or quadriparesis develops.
Cerebellar signs are practically always present in advanced MS,
including impaired coordination, ataxia, and, frequently, a very
characteristic intention tremor (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.
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.
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.
Fig. 8.2 Common physical findings in multiple sclerosis (diagram).
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.
_ 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 relapses are
treated over the long term with the immune modulator β-interferon, at
a dose of (for example) 8 × 106 IU s.c. q.i.d. for three or four days every
week. This lowers the number of relapses per year by about 30%.
Copolymer-1, a synthetic mixture of amino acids, has a comparable
effect when injected subcutaneously every day. _-Interferon is also
thought to be an effective treatment for the secondary progressive forms
of MS. In general, these drugs can slow the progression of the disease,
but they cannot stop it. Thus, general treatment measures remain very
important: patient education, symptomatic treatments (antispasmodic
drugs, treatment of bladder infections, etc.), psychological and
rehabilitative treatment (especially physical therapy).
Differential diagnosis. Generally speaking, when a patient
presents with an isolated neurological deficit that would be typical of
MS, the differential diagnosis must include all other conditions that
could produce that deficit (cerebral tumor, vascular spinal cord and brain
lesions, posttraumatic brain injure etc.)
Prognosis. Patient survival 10 years after the onset of MS is
nearly the same as that of a normal control population, and the total life
span is reduced by no more than a few years. Advanced age at the onset
of disease confers a worse prognosis, but only the disease takes a
primary or secondary progressive course. Further unfavorable prognostic
factors include cerebellar and brainstem signs, rapid initial progression,
and a brief interval between the onset of disease and the first relapse. The
patient’s condition five years after onset is closely correlated with their
condition 10 and 15 years after onset, particularly with respect to
cerebellar and pyramidal tract signs. About one-third of patients have no
major disability 10 years after onset and a few percent still have none 25
years later.
! Multiple sclerosis sometimes takes a “benign” course.