Basal Ganglia Diseases And Their Treatment
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.
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.
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 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.