Parkinson's disease: pathophysiology, symptoms, and treatment

Perampanel Therapy, Cognitive Behavioral Therapy and Physical Therapy as Interventions for the Treatment of Parkinson's Disease

Clinicians and researchers have been constantly searching for more information on how to treat the symptoms of Parkinson's disease. This paper's aim is to outline three types of therapy that qualify as valid attempts, namely pharmacologically-oriented perampanel endeavors, cognitive behaviour therapy or CBT, and finally, physical therapy. The present paper will review the relevant research pertaining to these three forms of treatment, in terms of effectiveness, validity, safety, and other filters, before suggesting how one approach might be the most effective in the treatment of Parkinson's disease.

The first clinical signs of the degenerative neurological disorder named Parkinson's disease appear only at such time as approximately 60-80% of the dopamine-producing cells of the substantia nigra has already degenerated. Data from across the European continent indicated that about 1.8 of 100 inhabitants over the age of 65 are diagnosed with Parkinson, whereas in the 65-69 years age category, the disease affects 2.4 out of 100, and in the 85-89 years age group, its incidence amounts to a peak of 2.6 of 100 inhabitants (Kwakkel et al., 2007, p. S478).

Treatment of Parkinson's disease is a challenge, insomuch as multidisciplinary efforts have been directed at managing the motor and non-motor symptoms without impairing cognitive function or inducing unwanted side effects (Eggert et al., 2010, p. 897). Pharmacologically, the condition is presently treated through the prescription of L-dopa and other dopaminergic medications, such as dopamine agonists, catechol-O-methyltransferase inhibitors, and monoamine oxidase B. inhibitors. Yet, the use of such therapies is limited by the risk of adverse drug reactions, out of which gastrointestinal and cardiovascular problems, dyskinesias and motor fluctuations, and neuropsychiatric syndromes stand out (Rascol et al., 2012, p. 15). Therefore, alternative non-dopaminergic medicating solutions are required in the treatment of Parkinson's disease.

For this purpose, Perampanel, a potent, selective, noncompetitive a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-type glutamate receptor antagonist, appears to have shown evidence of efficacy in reducing motor symptoms when tested on afflicted rat and monkey models (Eggert et al., 2010, p. 897).

Clinical studies based on patients situated in an early phase 2 of Parkinson's disease indicated that perampanel was well tolerated at dosages ranging from 0.5 to 4 mg/d and might in the future, at higher dosages, reduce the patients' off-state time (Rascol et al., 2012, p. 16). However, based on current empirical evidence, Perampanel has no relevant impact on the L-dopa plasma concentrations, which were identical both at baseline, and at the end of the trials (Eggert et al., 2010, p. 902).

In fact, both primary and secondary efficacy analyses have failed to prove any given benefit to the perampanel groups, when compared to those who received placebos. Hence, no improvement in dyskinesias or notable difference in off-time reducton was apparent in the perampanel-treated groups vs. placebo, yet just as importantly, no significant worsening was registered (Eggert et al., 2010, p. 903). All in all, it can be affirmed that conducted randomized placebo-controlled studies failed to show any significant anti-parkinsonian efficacy of perampanel, even during those who employed the high value of 4 mg/d of substance (Rascol et al., 2012, p. 18).

Regarding safety, the largest difference recorded during therapy between the placebo and perampanel groups was the incidence of somnolence, dizziness, dyskinesia, and falls, with each event having at least a 3% higher prevalence for the perampanel group (Rascol et al., 2012, p. 17), and all such dopaminergic-like side effects were not accompanied by positive effects in terms of efficacy (Rascol et al., 2012, p. 19). Consequently, it can be asserted that perampanel-based pharmacological therapy is not successful.

S.J. Enright was the first to contend that "there is no psychological or physical problem that cannot potentially be assisted by the cognitive behavioural approach" (Cole & Vaughan, 2005, p. 272). Parkinson's disease is a chronic medical illness with a high incidence of psychiatric co-morbidity due to depression and anxiety. For the majority of patients, depression is left untreated, and those who are treated are not treated adequately (Veazey et al., 2009, p. 243). People suffering from Parkinson's-related depression and anxiety not only have to adjust to various and continuous impairments, but they also have to deal with negative thoughts that can be entirely justified, and moreover their affect may be of a biological nature, and influenced by the neurodegenerative changes (Cole & Vaughan, 2005, p. 274).

Cognitive Behavioral Therapy is a structured therapy which aims to help patients recognize the maladaptive thoughts which contribute to emotional discomfort, and replace them with other images. This goal is reached though a process of collaborative empiricism, which implies that the therapist and client join efforts in exploring the implications of the patient's various beliefs. As part of this process, Socratic questioning is used to guide the individual towards singling out, scrutinizing and modifying harmful thoughts. In addition, this therapy also employs behavioral tools, such as activity scheduling, graded exposure and experiments, which are altogether designed to address beliefs' authenticity or lack thereof (Cole & Vaughan, 2005, p. 270).

Some patients will experience mood swings during the off-period, together with feelings of doom, helplessness, hopelessness and sorrow. Various hypotheses have been issued regarding these mood variations, ranging from psychological reaction, to the inability to control illness events, to changes in dopamine levels. Even though basal ganglia dysfunction is the primary trait of this condition, the effects of degeneration may be widespread due to neural circuit connections between brain systems, particularly those extending to the prefrontal cortex, which would explain why cognitive problems traditionally associated with the frontal lobe such as deficient problem solving ability, inability to shift attention, concrete thought and impaired memory processes, occur frequently (Cole & Vaughan, 2005, p. 272).

Qualitative data suggests that physical symptoms, such as tremor, difficulties writing and drooling can result in people commenting that they are too ashamed to be seen in public, and reports of feeling stigmatized have been linked to depression severity. The therapist might help the individual to prepare in advance for the type of cognitive distortions likely to occur during the off-period and attempt more encouraging alternatives. In this sense, the use of cognitive methods may enable the individual to break depressive or anxiety patterns, regardless of their origin. In this case, the focus would not be on curing low mood, but on finding a way to manage the reactive responses in order to maintain the most optimistic outlook (Cole & Vaughan, 2005, p. 273).

Cognitive behavioral therapy has been reported to be successful in reducing symptoms of depression and anxiety in "people with diverse chronic medical and neurological conditions" (Cole & Vaughan, 2005, p. 269). Admittedly, there are solid clinical reasons which support the use of this type of therapy for depression associated with Parkinson's disease. Among these, there is the fact that depression affects a large number of subjects, on an equal or even higher level than that associated with other chronic ailments. What is more, depression is often left untreated, and apart from that, pharmacological treatment approaches do not always seem to work (Cole & Vaughan, 2005, p. 270).

However, there is no research consensus that indisputably identifies the mechanisms of change during Cognitive Behavioral Therapy. Instead, there are only general assumptions, including the belief that improvement is achieved through the transformation of cognitive structures, the acquisition of new skills, or the consequence of activating more adaptive ways of interpreting experience. In equal measure, there is no sound evidence about which components of cognitive therapy actually alleviate low mood. While several studies have emphasized behavioral activation, others have focused on the cognitive elements involved in appraising thoughts, and finally some entertain the notion that non-specific elements of the therapy, such as the quality of the therapeutic alliance, play a great part in the recovery process.

Other elements believed to compromise Cognitive Behavioral Therapy are entrenched personality styles, poor motivation, low acceptance of personal responsibility for change, and pessimism regarding therapy outcome (Cole & Vaughan, 2005, p. 270). Nonetheless, seeing as Parkinson's disease is progressive and degenerative in nature, and that there is still no viable cure for it, cognitive processing of what it means to live with this condition might be an appropriate adjuvant approach, insofar as such strategy would involve that people accept and reflect on what it means to them and to their world that they have Parkinson's disease (Veazey et al., 2009, p. 252).

The clinical signs of Parkinson's disease include rigidity, bradykinesia, tremor, and loss of postural control. These impairments altogether effect a downfall in a person's functional status, as suffering individuals have increasing difficulty performing usual tasks, such as walking, rising from a chair, and moving in bed. This decline in functionality often results in dependence and a low quality of life (Ellis et al., 2005, p. 626). As their diseases evolve, most patients with Parkinson's register a set of escalating mobility deficits, including difficulties in transfer, posture, balance, and walking. This often leads to injury or inactivity, which is easily conducive to social isolation and a high probability of osteoporosis or cardiovascular disease. These mobility deficits are difficult to treat with drugs or neurosurgery, yet physical therapy has the potential to improve these aspects by training patients in the use of pure or compensatory movement (Keus et al., 2007, p. 453).

Clinical trials settled for six targeted areas of focus during physical therapy for antiparkinsonian purposes, namely transfers, posture, reaching and grasping, balance, gait, and physical capacity; and four specific treatment recommendations were derived from them, namely cueing strategies designed to improve gait, cognitive movement strategies designed to improve transfers, exercises for balance, and active exercise for joint mobility, muscle power, and an improved physical capacity (Keus et al., 2007, p. 451). Several methods, such as mobility exercises, motor and gait training with external cues, training of daily activities, relaxation techniques, karate exercises, have been employed in these trials, but specific delimitations are scant in the absence of any general consensus regarding a rehabilitation program specific for Parkinson's disease patients (Pellecchia et al., 2003, p. 597).

Balance disturbance represents one of the most prevalent signs in Parkinson's disease. After adopting a long-term therapy comprised of sessions where a sequence of specific physical therapy exercises are aimed at cognitive and motor stimulation, positive values can be observed at the implementation of the Berg Balance Scale and the Timed Get Up and Go test for individuals with this condition, and finally the incidence of falls is diminished (Christofoletti et al., 2010, p. S58).

Overall benefits of patients' undergoing physical therapy were observed in the functional status and quality of life related to physical mobility, but not in global quality of life or in the level of impairment (Ellis et al., 2005, p. 630). On the other hand, results indicate significant improvements in the sickness impact profile motor score, in the Unified Parkinson's Disease Rating Scale, Comfortable Walking Speed, with the most positive values in the field of gait speed and daily living activities, such as cooking, making coffee and outdoor activities like shopping (Kwakkel et al., 2007, p. S483). Improvements in stride length, step cadence, gait initiation, walking velocity, and daily living activities are consistently reported in the literature after patients' participation in a rehabilitation program (Ellis et al., 2005, p. 631).

Interestingly, subjects who took part in high-intensity sessions of physical therapy portrayed a post-exercise increase in gait speed, step and stride length, and improved weight distribution during sit-to-stand tasks, all of which lacked from low- and zero-intensity groups. A high-intensity session mostly consists of a gradual increase of treadmill exercise speed from self-selected velocity of comfortable values, to speeds above over-ground walking velocity (Fisher et al., 2008, p. 1221).

Subjects undergoing high repetition, velocity, or complexity physical programs also showed considerable lengthening of the cortical silent period, together with enhancing the neuroplasticity of the impaired brain, including the basal ganglia (Fisher et al., 2008, p. 1221). The actual mechanism that stands behind the lengthening of cortical silent period duration in people with Parkinson's disease who participate in high-intensity exercise is unclear. However, the cortical silent period is mainly mediated by ?-aminobutyric acid-B receptors, major inhibitory neurotransmitters in the basal ganglia. Abnormalities of GABAergic transmission are key aspects of the pathophysiology of movement disorders that involve the basal ganglia (Fisher et al., 2008, p. 1226).

In addition, an active form of physical therapy can increase levels of the brain-derived neurotrophic factor, which has neurotrophic and neuroprotective properties, can enhance brain plasticity, and appears to be responsible for the long-term benefits of physical exercise on the brain, while also potentiating synaptogenesis and neurogenesis. What is more, evidence has shown that BDNF modulates the level of functional inhibition in an activity-dependent manner by regulating the number of GABAergic interneurons. Despite the fact that the role of BDNF in modulating GABA-mediated inhibitory transmission is not yet entirely comprehended, it is feasible that the exercise-induced, prolonged cortical silence period is linked with an exercise-related increase in BDNF (Fisher et al., 2008, p. 1227).