Parkinsonism

PARKINSONISM

Parkinsonism is a term that describes a group of disorders in which patients present with varying combinations of tremor, muscle rigidity, slowed movements (bradykinesia), and postural disturbances, including falls. In addition to these signs (not all of which need to be present), patients with parkinsonism also exhibit other neurological symptoms. Parkinsonism needs to be distinguished from idiopathic Parkinson's disease, in which the cardinal diagnostic features of tremor, rigidity, bradykinesia, and postural disturbance are present. To make a diagnosis of Parkinson's disease, each of these symptoms must be present and responsive to levodopa, a medication that is converted to dopamine, which is a natural substance depleted in Parkinson's disease. In addition, from a neuropathological point of view, patients with idiopathic Parkinson's disease have dopaminergic cell degeneration in substantia nigra, an area found in the deep part of the brain, and these cells contain characteristic debris within the nuclei of the cells, called Lewy bodies. Patients with parkinsonism, in general, do not have these neuropathological findings in the substantia nigra to the same extent and, clinically, they are poorly responsive to levodopa.

Clinical syndromes

There are a wide variety of clinical syndromes that exhibit symptoms of parkinsonism, including various neurodegenerative disorders such as multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal ganglionic degeneration (CBGD), and progressive supranuclear Palsy (PSP). Vascular changes can also cause parkinsonism. The other group of disorders that demonstrate parkinsonism include drug-induced parkinsonism, resulting from dopamine-receptor blockade (i.e. neuroleptics, such as thioridazine or haloperidol). Certain toxins, such as manganese and MPTP (an impurity found in certain recreational drugs) also cause parkinsonism. Metabolic disorders, such as Wilson's disease, in which copper accumulates in the brain and elsewhere, also causes parkinsonism.

Clinical features of parkinsonism

Tremor. The characteristic tremor of Parkinson's disease is a 3 to 6 hertz (hz) rest tremor with pill-rolling quality, that is, the tremor is more pronounced when the person is at rest and, when looking at the hands, the thumb and index finger move in a circular motion. This too can be seen in patients with other parkinsonian syndromes. For example, up to 80 percent of patients with multiple system atrophy, have tremor. In DLB, tremor occurs in 25 to 76 percent of patients.

Rigidity. Muscle rigidity occurs in 89 to 99 percent of patients with Parkinson's disease, and it is also seen in patients with other parkinsonian syndromes. Patients with rigidity have the sensation of stiffness. Clinicians who examine them find that the muscles feel rigid when they are put through passive movement.

Bradykinesia. Bradykinesia is defined as slowness of movement and an inability to maintain a motor act. It is present in 77 to 98 percent of patients with Parkinson's disease, and can also occur in all other parkonsonian syndromes.

Postural instability. While postural instability is one of the cardinal features of Parkinson's disease, it occurs in many other parkinsonian syndromes. In the aging population, because of multiple sensory deficits, including musculoskeletal problems, postural instability results in a sense of poor balance and tendency to fall.

Asymetric onset. Asymmetric onset: that is, onset of symptoms such as tremor or rigidity, on one side, is found in most patients with Parkinson's disease, and in many other parkinsonian syndromes. For example, up to 42 percent of patients with asymmetric onset of parkinsonism had a diagnosis other than Parkinson's disease.

Speech disturbance. Many patients with Parkinson's disease have low volume of speech (hypophonia). They may also have stuttering or involuntary repetition of phrase with increased rapidity (palilalia). These speech disturbances are also seen in other disorders, such as PSP, in which a pronounced change in voice may be an early feature.

Dementia. While dementia has been estimated to occur in between 25 to 40 percent of patients with Parkinson's disease, the cognitive deficits are not as prominent as in other parkinsonian syndromes. So-called dementia subcortical syndrome (with mental slowing and decreased mood) can occur in other parkinsonian syndromes, such as PSP and MSA. Mood and psychotic disorders do occur in some patients with Parkinson's disease, but can be more common in other parkinsonian syndromes.

Autonomic dysfunction. Autonomic dysfunction, such as blood pressure falling when the patient stands, occurs in some patients with Parkinson's disease and is exacerbated by medications. This, however, is not a prominent feature of Parkinsons' disease, but it can be a significant feature of other parkinsonian syndromes. For example, orthostatic hypotension is one of the hallmarks of MSA.

Eye movements. While patients with Parkinson's disease exhibit mild abnormalities in their eye movements, such abnormalities are a subtle feature and are often not readily evident in clinical examination. They can be a significant feature, however, in other parkinsonian syndromes, such as PSP, in which there is marked difficulty in looking down.

Neuroanatomical considerations

Patients with parkinsonism have pathologic involvement of the basal ganglia, which are structures found deep in the brain. The basal ganglia have specific connections with other structures, in particular the thalamus and the cerebral cortex. Several basal ganglia thalamocortical circuits have been described, but it is the motor circuit that is predominantly involved in patients with parkinsonism. In general, there are two parallel motor circuits; one called the direct circuit and the other called the indirect circuit. These circuits serve to turn off various basal ganglia structures, so that, acting with other parts of the brain, human movements (especially of the hands) can be finely controlled. Both of these circuits include cells in the cerebral cortex that have connections with the basal ganglia, the latter structures being the ones not functioning properly in parkinsonism. In the direct pathway, cells expressing GABA (gamma aminobutyric acid) and substance P-chemicals used by these cells to communicate with other cells, project to (globus pallidus interna and substantia nigra pars reticulata) certain parts of the basal ganglia where they have an inhibitory effect on the cell structures. Various feedback mechanisms are required, so that, from these structures there are GABAergic inhibitory projections to the thalamus, which, in turn, has an excitatory projection back to the cortex. In the indirect pathway, there is excitatory projection from the cerebral cortex to another part of the basal ganglia, the striatum. Then, from the striatum there is GABAergic/ enkephalinergic inhibitory projection to the globus pallidus pars externa, which, in turn, a GABAergic inhibitory projection to the subthalamic nucleus. Other feedback loops exist; for example, from the subthalamic nucleus there is excitatory projection to the globus pallidus pars interna and substantia nigra pars reticulatta. Once again, from these structures there is an inhibitory GABAergic projection to the thalamus and the circuit is completed by an excitatory projection from the thalamus back to the cortex. Perhaps the best known of the basal ganglia loops in parkinsonism involves the substantia nigra pars compacta, which uses the neurotransmitter dopamine. This is the neurotransmitter that is reduced in Parkinson's disease—and replaced to provide benefits to patients with the disorder. Again, there is a balance of pathways: the direct pathway has an excitatory influence on the cortex which results in increased movement; while the indirect pathway has an inhibitory influence on the cortex that reduces movement. In parkinsonism there is a general reduction of excitatory input to the cortex, resulting in reduced movement. For example, involvement of substantia nigra pars compacta (as in Parkinson's disease) leads to reduction in dopamine going to the striatum. In parkinsonism, reduction in cells in the substantia nigra pars compacta leads to a reduction in input to the motor cortex, which leads to reduction in movement. Blockage of dopaminergic receptors in the striatum by neuroleptic drugs, such as thioridazine and haloperidol, has a similar effect, leading to drug-induced parkinsonism.

Treatment

Most patients with Parkinson's disease respond to levodopa, which is, in fact, essential in diagnosis. By contrast, the response to levodopa is not as reliable as a diagnostic tool in other parkinsonian syndromes. For example, only a minority of patients with PSP respond to levodopa temporarily. While most patients with multiple system atrophy have an initial response to levodopa, this response is usually not sustained. Up to 87 percent of patients with DLB respond to levodopa temporarily.

Prognosis

Parkinsonism, either alone, (as in Parkinson's disease) or in association with other neurological illnesses, appears to reduce life expectancy in older adults. How this occurs is not clear, nor is it clear what role treatment plays. These and other issues suggest that further research is needed to come to grips with the challenge of parkinsonism in an aging society.

Sultan Darvesh

See also Balance and Mobility; Brain; Dementia; Dementia with Lewy Bodies; Frailty; Multiple Systems Atrophy; Speech; Tremor.

BIBLIOGRAPHY

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