Fatigue and Limbic Dysfunction in Parkinson's Disease - Essay Example

Critique for Client I have additionally edited this document for reference cites that were not originally provided. The cites needed to be double checked as well because the volume numbers of journal entries were missing. The cites that I found referenced in the paper, I added to the reference page, however, many of the cites you provided, I did not find referenced to in the paper, so those were omitted. Also, I did not see cites for the "figures" you mention in the paper so I presume you have these "figures" to add to the paper. I cannot guarantee the document to be plagiarism free because you did not have quotation marks around areas that you took directly from other sources, however, with cites in place, this should not be an issue. In essence, I did the best I could with what I was provided. Please enjoy your comprehensively edited document. Introduction: Summary of Purpose and Thesis Parkinson's disease (PD), first described by James Parkinson in 1817 (Figure 1), is one of the most prevalent disabling illnesses that can occur later in life. It is estimated to affect 1% of 70-year-olds, but is also seen in younger people, with 10% of cases occurring before the age of 50. The disease has become the pathfinder for other neurodegenerative disorders, since discovery of dopamine deficiency within the basal ganglia led to the development of the first effective treatment for a progressive neurodegenerative condition. Dopamine replacement therapy substantially reduces the symptoms of Parkinson's disease in most patients, improving their quality of life and initially appearing to decrease mortality. My paper will attempt to hypothesize that: Patients with PD can be subdivided into categories including central fatigue and those without central fatigue. Fatigue will be present independent of daytime sleepiness, often confused with fatigue. Fatigue will correlate with indices of cardiovascular autonomic function and cardiac sympathetic imaging with MIBG SPECT scan in a subset of PD patients. Patients with PD who experience such central fatigue have pathology causing reductions in dopamine and serotonin turnover within the basal ganglia and limbic circuits. These are the structures, which facilitate the link between emotion/motivation (limbic system) and motor response. Demonstrating an association between fatigue and limbic dysfunction in PD will help rationalise treatment approaches for this disabling illness and its symptoms. Incidence and Prevalence Estimates of the annual incidence of Parkinson's disease are in the range of 4-20 per 100,000 individuals. A widely accepted figure for the prevalence of Parkinson's disease is approximately 200 per 100,000 populations. In the Unite States, it is estimated that between 750,000 and 1.5 million people have the disease. In the United Kingdom, there are approximately 120,000-130,000 diagnosed cases, but there may be many more that remain undiagnosed. Age, Sex, and Ethnicity Both the incidence and prevalence of Parkinson's disease increase with age, and the prevalence may be as high as 1 in 50 for patients over the age of 80 years. Men are 1.5 times more likely than women to develop the condition are. Hospital-based studies have suggested that Parkinson's disease is less common in the Black population, than in other groups. Pathology The main pathological feature of Parkinson's disease is the degeneration of neuromelanin-containing neurons in the pars compacta of the substantia nigra (Figure 1.1). Examination with the naked eye reveals pallor of this area, which is confirmed microscopically by a marked decrease in the number of neuromelanin-containing cells and the presence of Lewy bodies in the remaining nigral neurons. Degeneration of pigmented neurons in the brainstem is not limited to the nigra but extends to the locus ceruleus and the dorsal motor nucleus of the vagus. Lewy bodies are intracytoplasmic eosinophilic inclusions, which are typically found in the neurons of the substantia nigra (Figure 1.2). They are a pathological hallmark of idiopathic Parkinson's disease and are found in other neurodegenerative diseases, such as dementia with Lewy bodies and Alzheimer's disease. Neuronal degeneration The cause of neuronal degeneration in Parkinson's disease is unknown. The susceptible neurons are located in astroglial-poor regions such as the ventral tier. Glia may offer neuroprotection by providing neurotrophic factors that prevent cell death. Several hypotheses for neuronal degeneration have been proposed, including: Oxidative stress, induced by dopamine metabolism or other factors; Defective mitochondrial energy metabolism; Excitotoxin- and xenobiotic-related cell death Programmed cell death (apoptosis). (Figure 1.4). Pathophysiology Nigral degeneration results in loss of dopamine in the nigrostriatal tract. Nigrostriatal dopaminergic transmission influences motor function through a complex route involving parallel circuits, some of which are inhibitory while others are facilitatory (Figure 1.5). The final common pathway of movement is the motor unit that is influenced through many cortical, reticulospinal and corticospinal tracts. The striatum influences the supplementary motor area through its connections with the ventrolateral nucleus of the thalamus. The striatal output uses -aminobutyric acid (GABA) and is entirely inhibitory. The striatum projects to the medial globus pallidus via two pathways, one indirect and the other direct. Dopamine is inhibitory to the indirect striatopallidal pathway, which first projects to the lateral globus pallidus. The lateral globus pallidus in turn sends another inhibitory projection to the subthalamic nucleus, using GABA as a neurotransmitter. The subthalamic nucleus sends an excitatory glutamatergic output to the medial globus pallidus. Dopamine is excitatory via the D1 receptors to the direct striatopallidal pathway. With Parkinson's disease, there is a relative lack of dopamine, which leads to defective excitation of the direct circuit and, therefore, decreased GABA-mediated inhibition. This results in over activity of the neurons of the medial globus pallidus. In addition, because of the lack of dopamine there is defective D2-mediated striatal inhibition (indirect pathway), accentuated striatal inhibition of the lateral pallidus and disinhibition of the subthalamic nucleus because of the under activity of GABAergic lateral globus pallidus outflow. The over activity of the subthalamic nucleus then overexcites the medial globus pallidus. The net result of both the direct and the indirect pathways in the absence of dopamine is over excitation of the medial globus pallidus, leading to excessive inhibition of the thalamus. If the thalamus cannot excite the cerebral cortex, this leads to akinesia (absence of body movements) and other symptoms of Parkinson's disease. Diagnosis of Parkinsonism An essential feature of motor systems is used to diagnose PD, including Bradykinesia and tremor (resting), and/or rigidity (cogwheel or lead-pipe). Additional features that may be present are: Postural imbalance Fixed, stooped posture Dystonic postures, e.g. striatal hand Hypomimia ('masked' face) Shuffling, short-step gait (with or without festination) Freezing episodes (sometimes known as paradoxical akinesia) Neuropsychiatric Symptoms There are also non-motor symptom complexes related to PD, including depression, apathy, anxiety; anhedonia; attention deficity; hallucinations, illusions, delusions; dementia; obsess ional and repetitive behaviour; confusion; delirium (possibly drug induced); and panic attacks. Sleep Disorders Sleep disorders related to PD include restless legs and periodic limb movements; rapid eye movement (REM) behaviour disorder and REM loss of atonia; non-REM sleep-related movement disorders; excessive daytime somnolence; vivid dreaming; insomnia; and sleep-disordered breathing. Autonomic Symptoms PD autonomic symptoms include: Bladder disturbances: Urgency, nocturnia, and frequency Sweating Orthostatic hypotension (OH): Related to falls, and coat hunger pains Sexual dysfunction: Hyper sexuality (likely drug induced), and/or erectile dysfunction or impotence Dry eyes (xerostomia) Gastrointestinal symptoms Symptoms that are representative of gastrointestinal nature are dribbling of saliva; ageusia; dysphagia/choking; reflux, vomiting; nausea; constipation; unsatisfactory voiding of bowel; and fecal incontinence. Sensory symptoms Symptoms affecting the sensory system include pain, paresthesia, and olfactory disturbances. Other Symptoms Various other symptoms may also be present, such as diplopia; blurred vision; seborrhoea; weight loss; and weight gain (possibly drug induced). Fatigue Fatigue is defined in the Fatigue Assessment Inventory (FAI) as "a sense of tiredness, lack of energy or total body give out." In contrast, a dictionary definition defines fatigue as "weariness caused by hard work or effort" but uses "lassitude," "languor," and "exhaustion" as synonyms (Krup, LaRocca, Muir-Nash, & Steinberg 1989; The World Book Dictionary 1987). Fatigue is a common problem in virtually all chronic medical and many psychiatric disorders. (Figure 1-6). Excessive fatigue is a common complaint in those suffering from PD, occurring in up to 40% of patients. Fatigue has a significant negative impact on patients' quality of life impairing their ability to work and socialise. PD patients who experience chronic fatigue describe it as an overwhelming sense of tiredness, lack of energy and feeling of exhaustion and for many it is the worst aspect of their parkinsonian symptoms. Actual recognition of fatigue as a common problem in parkinsons disease (PD) has been relatively recent . The first papers on fatigue in PD were published in 1993, (7, 8) and the earliest reference to it appears to be from 1967 (Van Hilten, Hoogland, & Van der Velde 1993; Friedman & Friedman 1993). The impact of fatigue in PD is generally underappreciated, and its treatment is empiric (Shulman, Taback, Rabinstein, & Weiner 2002). Pathophysiology of Fatigue in Parkinsons Disease Although there is information on muscle fatigue, virtually nothing is known about the pathophysiology of central fatigue in PD. The concept of primary and secondary fatigue is relevant as many patients may experience fatigue because of depression, whereas others may experience fatigue without associated comorbidities. Shulman and colleagues (2001) reported the frequent concurrence of discrete nonmotor symptoms. Nonmotor symptoms are more likely to occur together when they share the same pathogenesis or when they are secondary or reactive phenomena with similar triggers. Covington (2002) described a feedback loop in which pain, depression, fatigue, inactivity, and deconditioning act synergistically to increase disability. The presence of a high concurrence of nonmotor symptoms in PD may be illus- trative of this cycle. These interrelationships may have important therapeutic implications, because intervention at different points in the feedback loop may have synergistic benefits. Thus, treating comorbid symptoms should be attempted first (Shulman, Taback, Bean, & Weiner 2001). Fatigue appears to have both emotional and physiological components. Role of Basalganglia in Fatigue The basal ganglia are subcortical brain nuclei that act to filter and focus, or bind, cognitive, emotional, motivational, sensory and motor information arising from the cortex and periphery into efficient thought and action. Structural lesions and/or biochemical changes in the neurotransmitter balance within the basal ganglia can disrupt the usual process of integration of the limbic input (emotion and motivation) and motor function. This may result in a failure to initiate and/or sustain attentional tasks and physical activities requiring self-motivation, and lead to the experience of a feeling of fatigue by patients. Along with the loss of nigrostriatal dopamine, which characterizes the disease, cellular loss occurs in other non-motor dopaminergic pathways including the mesolimbic and mesocortical dopamine systems, and, to a lesser extent, the noradrenaline (locus ceruleus) and serotonin (median raphe) systems projecting to frontal and limbic areas. In support of a role for the basal ganglia in generating fatigue in PD, in a recent study patients who reported excessive fatigue showed reduced putamen glucose metabolism. In another study, bilateral pallidotomy in PD was followed by profound fatigue, sleepiness, changes in behaviour, and poor initiative in executive functions despite improvement in motor control. Overlap of Fatigue with Other Conditions Fatigue and depression are sometimes confused and mistaken for one another when a diagnosis is administered. Dutch study reported that 43% of 90 non-depressed PD patients (50 men) reported fatigue, half of them developing it before onset of PD. A total of 15% rated fatigue their worst symptom, and 54% rated it as severe as their other PD symptoms (Kerkhof, Roos, Van der Velde, Van Djjk, Van Hilten, & Weggeman 1993). A Norwegian study showed that Fatigue was significantly associated with depression, but not with disease severity. Of note, fatigue was found to affect nondepressed, nondemented, and nonsleepy PD patients as much as those with these problems (Jorgensen, Karlsen, Larsen, & Tandberg 1999) A Japanese study compared nondemented PD patients to non-neurological patients and found that the PD patients were significantly more fatigued and that fatigue did not correlate with depression (Karlsen, Larsen, & Tandberg 1999; Friedman, Oakes, & Shiffito 2006). In most reports to date, fatigue did not correlate with motor dysfunction.22 One third of early PD patients enrolled in a clinical trial (ELLDOPA) who were untreated, nondemented, and nondepressed suffered from fatigue (Friedman, Oakes, & Shiffito 2006). Although it is uncertain if fatigue is related to depression, it is clear that nondepressed patients also frequently suffer from fatigue. It is also clear that fatigue may predate disease onset, is relatively independent of disease motor severity, and may be related to sleepiness, but commonly affects PD patients who do not suffer from EDS or other sleep disorders. Symptoms of fatigue and sleep dysfunction sometimes overlap sufficiently to potentially confound studies of fatigue. In English, the word "tired" is used interchangeably with sleepiness and fatigue. Sleep disruption and EDS are frequent problems associated with PD. EDS has been described in 8% to 50% of patients.28, 37, 38. Both sleepiness and fatigue appear to be independent of motor response to medications (Jorgensen, Karlsen, Larsen, Tandberg 1999). Several studies suggest that fatigue is an independent symptom in PD, unrelated to the degree of sleepiness or to nocturnal sleep disturbance (Alves, Larsen, & Wentzel-Larsen 2004; Jorgensen, Karlsen, Larsen, Tandberg 1999). PD patients generally distinguish the two conditions, although they often suffer from both. Patients with fatigue remain fatigued after naps, whereas most people with sleep deficiency feel refreshed, albeit transiently, after a nap. Fatigue and dysautonomia is also a concern for PD patients. Recent studies have reported that PD patients have a high prevalence of loss of sympathetic innervation in the heart and other organs, and in PD, selective cardiac sympathetic denervation occurs early even in the absence of evidence of other markers of sympathetic failure (c) (Covington, Goodman, Schwid, & Segal 2002). A generalized sympathetic denervation has been suggested to contribute to symptoms of autonomic failure such as orthostatic hypotension and might potentially have a role in the genesis of fatigue. Sympathetic nervous system disorders resulted in markedly decreased cardiac uptake of 123) I-metaiodobenzylguanidine (MIBG) scintigraphy observed in PD cases. (b) Measuring of Fatigue Because fatigue is a symptom, it must be measured by self-report. The FSS is a nine-item questionnaire that assesses the effect of fatigue on daily living. Each item is a statement on fatigue that the subject rates from 1, 'completely disagree' to 7, 'completely agree'. Examples of the items in the questionnaire are: 'My motivation is lower when I am fatigued', 'Exercise brings on my fatigue' and 'I am easily fatigued.' It is brief, easy to administer, and demonstrates reliability and internal consistency. Patients with a mean score of 4 or more were defined as suffering from significant fatigue (C). The PFS-16 has specifically been designed to measure fatigue in a PD population taking in account possible overlapping with other motor and non-motor symptoms of PD. The scale allows one to distinguish between PD patients who experience fatigue from those who do not (score > 7) and to identify patients perceiving fatigue to be a problem (score > 8) (D). References ALVES, G., LARSEN, J.P., WENTZEL-LARSON, T. 2004. Is fatigue an independent and persistant symptom in patients with Parkinson's disease American Academy of Neurology, 63, pp. 1908-1911. COVINGTON, M., GOODMAN, A.D., SEGAL, B.M., SCHWID, S.R. 2002. Fatigue in multiple sclerosis: current understanding and future directions. Journal of Rehabilitation Research and Development, 39(2), pp. 211-224. FRIEDMAN, J.H., AND FRIEDMAN, H. 1993. Fatigue in Parkinson's disease. Neurology, 43, pp. 2016-2018. FRIEDMAN, J.H., OAKES, D, SHIFFITO, G., ET AL 2006. 'Fatigue in ELLDOPA'. World Congress on Parkinson's disease, Washington, DC. JORGENSEN, K., KARLSEN, K., TANBERG, E. 1999. Fatigue in patients with Parkinson's disease. Movement Disorders, 14(2), pp. 237-241. KARLSEN, K., LARSEN, J.P., TANDBERG, E. 2000. Clinical problems in non-fluctuating patients with Parkinson's disease: a community-based study. Movement Disorders, 15(5), pp. 826-859. KERKHOF, G.A., ROOS, R.A., VAN DER VELDE, E.A., VAN DJJK, J.G., VAN HILTEN, J.J., AND WEGGEMEN, M. 1993. Sleep, excessive daytime sleepiness and fatigue in Parkinson's disease. Journal of Neural Transmission, 5(3), pp. 235-244. KRUPP, L.B., LAROCCA, NG, MUIR-NASH, J., AND STEINBERG, A.D. 1989. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus, Arch Neurol, 46(10), pp. 1121-1123. SHULMAN, L.M., TABACK, R., RABINSTEIN, A.A., AND WEINER, W.J. 2001. Comorbitity of the non-motor symptoms of Parkinson's disease. Movement Disorders, 16(3), pp. 507-510. SHULMAN, L.M., TABACK, R., RABINSTEIN, A.A., AND WEINER, W.J. 2002. Non-recognition of depression and other non-motor symptoms in Parkinson's disease. Parkinsonism Related Disorders, 8(3), pp. 193-197. THE WORLD BOOK DICTIONARY. 1987. Chicago: Doubleday and Company, Inc. VAN HILTEN, J.J., HOOGLAND, G., VAN DER VELDE, E.A., ET AL. 1993. Diurnal effects of motor activity and fatigue in Parkinson's disease. Journal of Neurology, Neurosurgery, & Psychiatry, 56(8), pp. 874-877. Read More