The Treatment of Akinesia using Virtual Images

by Jerrold D. Prothero

The Treatment of Parkinson's Disease

Parkinson's disease is related to a reduction of dopamine in the brain and damage to the dopaminergic pathway from the substantia nigra to the striatum [32]. The search for a cure for Parkinson's disease is complicated by the fact that its cause is unknown. The most prominent risk factor is age, with symptoms usually appearing after the age of 50 [8], although one third of patients develop the disease before the age of 50 and 10% before the age of 40 [27]. At present, all therapies for Parkinson's disease are palliative, and treatment failures are eventually experienced by patients given the primary antiparkinsonian drug, levodopa [8].

Tremor is the usual first symptom which leads to the patient seeking medical advice, although more subtle clues may have been present earlier [27]. Untreated, the progression of Parkinson's disease has been broken into five stages [28] (see also [27]):

Stage I: The symptoms occur on one side, usually in an extremity. During Stage I, the disease is primarily an inconvenience. The median duration of illness at Stage I is about 3 years.
Stage II: The disease spreads and becomes generalized. The site of onset remains most severely affected. The median duration of illness at Stage II is about 6 years [27].
``In addition to tremor, rigidity and impaired mobility on the opposite side, during Stage II the posture may become mildly flexed with adduction of the limbs. Facial masking, monotonous and hypophonic speech, mild disturbance of gait, generalized slowness, decreased associated and spontaneous movement and easy fatigability usually begin to make an appearance. However, these signs are mild, and balance is still intact.''
Stage III: In this stage, ``disequilibrium with impairment of balance and of postural and righting reflexes'' occurs. The median duration of illness at Stage III is 7 years, but with wide variation.
Stage IV: The patient begins to require help with everyday tasks such as walking, dressing, bathing and feeding. ``The disease is fully developed, generalized and advanced.'' While other symptoms become worse, tremor may be less severe. The median duration of illness at Stage IV is 9 years with wide variation.
Stage V: ``The patient is severely disabled and confined to a wheelchair or bed unless aided.'' The median duration of illness at Stage V is 14 years.

The introduction of levodopa (L-DOPA) in the late 1960's marked a milestone in the treatment of Parkinson's disease, although the reasons for its effectiveness are not well understood [9]. Eighty-five percent of patients initially show clinically significant benefit [58] (see also [43,62]). The effect is so noticeable that a response to it is often used as a diagnostic criteria for Parkinson's disease [26].

Unfortunately, according to Peppe et al. [58],

``this salutary response generally does not last. Within a few years, the stable antiparkinsonian action of L-DOPA gives way to motor fluctuations of gradually increasing severity. In addition, abnormal involuntary movements, especially of the choreoform type, begin to spoil periods of peak drug efficacy [41]. It has been reported that two-thirds of parkinsonian patients develop one or both of these motor response complications within 6 years of L-DOPA initiation [71].''

Peppe et al. conclude that

``motor response complications reflect alterations in striatal systems due to the loss of dopaminergic inputs and subsequent exposure to fluctuating dopamine levels as a result of intermittent L-DOPA administration.''

At least three classes of abnormal involuntary movements can result from chronic levodopa therapy. These include choreoform movements (termed dyskinesia), dystonia, and myoclonus [37].

Dyskinesias are clearly related to the duration of high dosage levodopa therapy [36]. Boshes [3] reports finding dyskinesia in 37% of levodopa-treated patients at 6 months, in 66% of patients at 18 months, and in 70% of patients at 24 months.

Peak dosage dystonia occurs in about 10% of patients [36] (see also [55]).

Monoclonus also appears to be directly related to levodopa dosage and duration of treatment [36,37].

Besides levodopa, another treatment for Parkinson's disease is stereotaxic surgery, which involves precisely locating structures in the brain for ablation. Stereotaxic surgery was common in the period from 1957 to 1972, but fell off sharply with the advent of levodopa [52]. This reflects the preference of patients and physicians for medication instead of surgery and the (relatively slight) risks involved in surgery.

Fahn [19] mentions that the stereotaxic thalamotomy of the 1950s and 1960s

``was particularly effective for controlling tremor, somewhat effective for rigidity, and less so for bradykinesia. It probably had no effect on loss of postural reflexes.... The procedure did not slow progression of the disease, and elderly patients were prone to develop complications of stroke.''

Stereotaxic techniques have continued to improve, however, becoming more selective and accurate, with minimal complications and side-effects [52].

A recent paper by Fahn [19] lists five directions for future treatments in Parkinson's disease:

Attempts to slow the progression of the disease: This will proceed in two directions. The first is the investigation of trophic factors associated with the growth and nourishment of the dopaminergic nigrostriatal system. The second will look at oxidative stress, which has been proposed as a mechanism for dopaminergic neuronal death in Parkinson's disease.
Attempts to overcome complications from current therapies: Particularly clinical response fluctuations associated with long-term L-DOPA usage.
Attempts to treat other neurotransmitter and chemical defects: Some Parkinson's disease problems (for instance, freezing and loss of postural reflexes) do not respond to dopaminergic agents. These may be treatable with drugs acting on other neurotransmitter sites, although no such drugs are currently available.
Attempts to control symptoms by noncentral approaches: Tremor may be treatable outside of the brain, by muscle injections.
Attempts to control symptoms and progression by surgical approaches: In part due to problems with L-DOPA, thalamotomy is making something of a comeback, particularly for patients with intractable tremor. It may also be used to control L-DOPA-induced dyskinesias and to treat the ``off'' states, in which L-DOPA occasionally becomes ineffective. Two other types of surgery, stereotaxic ablative pallidotomy and surgical lesions of the subthalamic nucleus, also show promise. Fetal transplantation to provide more dopaminergic neurons is also being tried, but is very experimental.

It is also worth mentioning the recent isolation of ``glial cell line-derived neurotrophic factor'' (GDNF), which shows promise for keeping dopamine-producing cells alive [83], and research on the treatment of Parkinson's disease using magnetic fields [64].