MOVEMENT DISORDERS
Three disorders of the body's motor systems will be
presented, to show how the various components of the motor
pathways may be disrupted by disease or environmental insults. The
cases discussed here - Parkinson's Disease, Huntington's Chorea
and Tardive Dyskinesia - all involve dysfunctions of the basal
ganglia.
Anatomy of basal ganglia
The basal ganglia are subcortical nuclei known as the
caudate, putamen, substantia nigra, globus pallidus and
subthalamus. The caudate and putamen are called the striatum; they
are derived from the same telencephalic structure. The globus
pallidus is derived from the diencephalon.
The caudate nuclei are two large, ring-shaped structures extending
from the putamen to the amygdala on each side of the brain. In
transverse section (Figure 2), the caudate can be seen just below
the lateral ventricle. Also visible are the putamen, globus
pallidus and subthalamic nucleus.
A schematic of the neural connections between the basal ganglia is
shown in Figure 3. These ganglia are highly interconnected and
play a significant role in the regulation of muscle tone and motor
function.
Parkinson's Disease
Parkinson's disease, or paralysis agitans, affects
approximately 500,000 patients in the US. Symptoms include a
rhythmic tremor at rest, increased muscle tone or rigidity –
sometimes of the cogwheel type, slowness of initiation of movement
(akinesia) and slow execution of movement (bradykinesia),
drooling, slowness of thinking, and depression. The classical
three symptoms are tremor, rigidity and poverty of movement.
The pathophysiology of Parkinson's includes (1) degeneration
of the nigrostriatal pathway, which is dopaminergic. The CalneLangston theory suggests that ingestion of enviromental toxins
accelerates the normal rate of killing of domaminergic neurons
(see handout); (2) degeneration of raphe nuclei (see Figure 5):
These are primarily serotonergic neurons that project widely to
the nervous system, and apparently have a diffuse modulatory role
in sleep and wakefulness; (3) degeneration of neurons in the locus
ceruleus:
The LC and the raphe nucleus are involved in anxiety production,
through norepinephrine-containing neurons. Degeneration may cause
depression; (4) degeneration of the motor nucleus of X; this
sometimes causes drooling.
Some chemical changes with parkinsonism include a reduction
of dopamine, serotonin, and norepinephrine. Most of the
catecholamine in the brain, including dopamine, is located in the
basal ganglia. Parkinson patients have very low levels of these
biogenic amines at autopsy. Treatment is with L-DOPA
(dihydroxyphenylalanine), but it only controls some of the
symptoms and not the course of the disease. Parkinsonism has also
been successfully treated with transplantation of fetal nigral
tissue into the striatum of patients.
The masked facies of parkinsonism is shown in Figure 7.
The facial muscles show an unusual immobility. The eyes have a
staring appearance, and ocular movements or blinking are rare.
Huntington's Chorea
Chorea means involuntary, purposeless and irregular movements
of the body affecting proximal or distal joints. It may include
unpredictable grimacing, twitching or writhing of the limbs and
head. It is a symptom of basal ganglia disease. Huntington's
Chorea appears at an age of 30-40 years, and includes symptoms of
chorea and dementia. It is autosomally dominant, and affected
patients usually succumb due to respiratory difficulties within 15
years of onset. The pathophysiology of Huntington's Chorea
includes degeneration of intrastriatal (caudate and putamen) GABAergic neurons.
Chemical changes include a reduction of choline
acetyltransferase, glutamic acid decarboxylase, and GABA (gamma
aminobutyric acid).
Tardive Dyskinesia
The symptoms are involuntary movements, esp. of face &
tongue. This condition is caused by long-term treatment with
antipsychotic drugs - phenothiazines e.g.chlorpromazine and
butyrophenones e.g. haloperidol (Haldol).
The pathophysiology of tardive dyskinesia is that chronically
administered antipsychotic drugs block dopaminergic cells, and
then the cells become hypersensitive to dopamine. Antipsychotics
exert calming effect by blocking dopaminergic cells in the cortex
and elsewhere. Unfortunately, they also do the same thing in the
basal ganglia, producing rhythmic movements as a side effect.
Klawans (1973) proposed that dopamine antagonists used as
antipsychotics cause upregulation of dopamine receptors in the
striatum. When the antagonists are withdrawn, the hypersensitivity
to dopamine causes excessive movement. About 20% of patients in
who have been in long-term treatment develop TD. The new drug
clozapine appears to have less of this effect.