Basal Ganglia Diseases And Their Treatment
Parkinson’s disease
Parkinson’s
disease is a
degenerative disorder that typically affects people in the sixth and seventh
decades of life. The primary pathological event is the loss of the dopaminergic
nigrostriatal tract, with the formation of characteristic histological inclusion
bodies, known as Lewy bodies. In the vast majority of cases the disease
develops for reasons that are not clear (idiopathic Parkinson’s disease; see
Chapter 60). However, in some cases clear aetiological agents are identified,
such as vascular lesions in the region of the nigrostriatal pathway,
administration of the antidopaminergic drugs in schizophrenia (see Chapter 59)
or genetic abnormalities in young patients and some rare families.
Over 50–60% of the
dopaminergic nigrostriatal neurones need to be lost before the classical
clinical features of idiopathic Parkinson’s disease are clearly manifest: slowness
to move (bradykinesia); increased tone in the muscles (cogwheel rigidity); and
rest tremor. However, most patients also display a range of cognitive,
affective and autonomic abnormalities, which relates to pathological changes at
other sites.
Neurophysiologically,
these patients have increased activity of the neurones in the GPi with a
disturbed pattern of discharge, which results from increased activity in the
STN secondary to the loss of the predominantly inhibitory dopaminergic input to
the neostriatum (NS). The increased inhibitory output from the GPi and SNr to
the ventroanterior–ventrolateral nuclei of the thalamus
(VA–VL) results in
reduced activation of the supplementary motor area (SMA) and other adjacent
cortical areas. Thus, patients with Parkinson’s disease are unable to initiate
movement because of their failure to activate the SMA.
Antiparkinsonian
drugs
Currently, no drugs have
been shown to slow the progression of Parkinson’s disease. For most patients, dopamine
replacement therapy with levodopa (L-dopa) or dopamine
agonists is the treatment of choice (dopamine itself does not pass the
blood–brain barrier).
· L-dopa is the immediate precursor of dopamine
and is converted in the brain by decarboxylation to dopamine. Orally
administered L-dopa is largely metabolized outside the brain and so it
is given with an extracerebral decarboxylase inhibitor (carbidopa or benserazide),
which greatly reduces the effective dose and peripheral adverse effects (e.g.
hypotension, nausea). L-dopa frequently produces adverse effects that
are mainly caused by widespread stimulation of dopamine receptors. After five
years’ treatment about half of the patients will experience some of these
complications. In some the akinesia gradually recurs producing so-called
wearing off effects, while in others various dyskinesias may appear in response
to L-dopa (so-called L-dopa-induced dyskinesias). These latter
problems may lead to rapid changes in the motor state of the individual
(‘on–off’ problems) and are found in all cases of advanced PD.
· Selegiline and rasagiline are selective
monoamine oxidase type B (MAOB) inhibitors that reduce the
metabolism of dopamine in the brain and potentiate the action of L-dopa.
They may be used in conjunction with L-dopa to reduce ‘end of dose’
deterioration.
· Catecholamine-O-methyltransferase
(COMT) inhibitors such as entacapone reduce the peripheral (and also
central in the case of tolcapone) metabolism of L-dopa and by so doing
increase the amount that can enter the brain.
· Dopamine agonists (e.g. ropinirole, pramipexole) are
also used often as first-line treatment in young patients or in combination
with L-dopa in the later stages of Parkinson’s disease. Dopamine
agonists directly bind to the dopamine receptors in the striatum (and
substantia nigra) and by so doing activate the postsynaptic output neurones of
the striatum.
· Other drugs that can be used in
Parkinson’s disease include antimuscarinic drugs (e.g. trihexyphenidyl
[benzhexol], procyclidine) in the early stages where tremor predominates and in
some young patients with PD. These drugs are believed to correct a relative overactivity
of central cholinergic activation that results from the progressive decrease of
(inhibitory) dopaminergic activity. Adverse effects are common.
Surgical therapies
Although most patients
with Parkinson’s disease are best treated with drugs, surgical approaches have
been undertaken in advanced disease. Initially this took the form of lesions of
the GPi (pallidotomy) but more recently the insertion of electrodes for deep-
brain stimulation especially into the STN. This latter approach may work by generating
a temporary lesion, possibly by inducing a conduction blocks, although this is
not proven.
An alternative surgical
approach is the implantation of dopamine-rich tissue into the striatum to
replace and possibly restore the damaged nigrostriatal pathway. The
efficacy of this approach is still debatable, as is the use of
growth factors such as glial cell line derived neurotrophic factor (GDNF).
Huntington’s disease
Huntington’s
disease is an
inherited autosomal dominant disorder associated with a trinucleotide expansion
in the gene coding for the protein huntingtin on chromosome 4 (see Chapter 63),
and as such affected individuals can be diagnosed with certainty using a simple
genetic test on the blood.
The disease presents
typically in mid-life with a progressive dementia and abnormal movements which
usually take the form of chorea – rapid dance-like movements. This type of
movement is described as being hyperkinetic in nature, unlike the hypokinetic
deficits seen in Parkinson’s disease, and reflects the fact that the primary
pathology is the loss of the output neurones of the stria- tum. This results in
relative inhibition of the STN and thus reduced inhibitory outflow from the GPi
and SNr, which leads to the cortical motor areas being overactivated, generating
an excess of movements.
Treatment of the
movement disorder in Huntington’s disease is designed to reduce the level of
dopaminergic stimulation within the basal ganglia. However, there are no
treatments for the cognitive deficits in Huntington’s disease, although mood
disturbances in this condition often do respond to drugs such as
antidepressants (see Chapter 57).
Other disorders of
the basal ganglia
• Another
example of a hyperkinetic movement disorder is hemiballismus,
which is the rapid flailing movements of the limbs contralateral to damage to
the STN.
• A
number of other conditions can affect the basal ganglia including Wilson’s
disease (an autosomal recessive condition associated with copper
deposition); Sydenham’s chorea (a sequela of rheumatic fever);
defects in mitochondrial function (mitochondrial cytopathies; see
Chapter 63); a number of toxins (e.g. carbon monoxide and manganese); and choreoathetoid
cerebral palsy (athetosis is defined as an abnormal involuntary slow
writhing movement).
• The
spectrum of movement disorders seen with these diseases is variable because the
damage is rarely confined to one structure so patients may exhibit either parkinsonism,
chorea and ballismus, or dystonia,
where a limb is held in an abnormal fixed posture.
• Many
of these conditions, including Parkinson’s disease and Huntington’s disease,
have a cognitive impairment – if not frank dementia – and while this relates to
additional damage in the cerebral cortex, there is increasing evidence that it
may in part be as a direct result of basal ganglia damage. In this respect the
ventral extension of the basal ganglia may be important.
• The
basal ganglia have a major role in the control of eye movements (see Chapter
56) and so many patients with diseases of the basal ganglia have abnormal eye
movements, which may be helpful in establishing their clinical
diagnosis.
