Cure for Parkinsons

The Parkinson's-Reversing Breakthrough

The Parkinson's Breakthrough Program entails the most effective and natural strategies people can use to heal the root cause of Parkinson's Disease. It is a digital manual aimed at showing the users the most effective method for overcoming Parkinson's without high-priced prescription drugs riddled with harmful side effects.The program was not created to be a quick fix. In fact, like different programs, it is tasking. Yet, you will not have to spend a lot of time dealing with it. The system requires your full attention, perseverance, and discipline. For the period of its usage, you will have the opportunity to use to eat some food ingredients that will detoxify you.The methods employed in this book are natural ones that have been proven by many specialists. The users will be privy to what to do and what not to do to treat the underlying root cause of their Parkinson's and the way they can reverse the symptoms naturally and effectively. The system comes with bonus E-books- Lessons from The Miracle Doctors, Mind Control in the USA', and 10 Deadly Health Myths of The 21st Century. The book is in a digital format (PDF) and has been created at a very affordable price. More here...

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Author: Matt Traverso
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Neurologic Aspects of Dementia with Lewy Bodies and Parkinsons Disease with Dementia

The two most common neurodegenerative disorders in the elderly are Alzheimer's disease (AD) and Parkinson's disease (PD). While each has well-defined clinical and pathologic features and specific criteria for clinical and pathological diagnosis, some degree of overlap between these two disorders exists. Some AD patients develop extrapyramidal signs and symptoms characteristic of PD, some patients with typical PD develop a dementia, and both disorders can co-occur in the same individual. This, however, does not explain all or even most of the cases of PD with dementia. Another entity known as dementia with Lewy bodies (DLB) has been estimated to account for 15 to 20 of late-onset dementias and has been only more recently recognized as the second most common cause of dementia after AD (McKeith, Perry, & Perry, 1999 McKeith et al., 1996). In this chapter, we focus on the dementias associated with both DLB and PD with dementia.

The Role Of Neuropsychology In The Management Of Parkinsons Disease

Neuropsychology provides an important contribution to the management of patients with PD. Neuropsychological evaluation delineates the nature and extent of cognitive changes, if any, and a profile of relative neuropsychological strengths and weaknesses. Such knowledge is helpful in Given the prevalence of cognitive and behavioral changes in PD, every patient would, in ideal circumstances, receive a baseline evaluation when first diagnosed with PD. Such a baseline neuropsychological evaluation would facilitate the accurate detection and diagnosis of subsequent neurobehavioral changes and permit the evaluation of treatment effects. This, however, occurs rarely and probably reflects cost-effectiveness issues in a managed care environment and the reluctance of many patients to contemplate in the early disease stages the threat of later, possibly significant, cognitive compromise. In the absence of an early baseline evaluation, a neuropsychological evaluation in the context of cognitive...

Pathologic Anatomic Correlates of Cognitive Behavioral Disturbances in PD

The classic neuropathologic findings of PD consist of degenerative lesions affecting the pigmented cells in the substantia nigra (SN) and other pig-mented nuclei in the brain stem. Lewy bodies (eosinophilic cytoplasmic inclusions) in cells of the SN and locus ceruleus (LC) are present in almost all cases. There may also be cell loss in the nucleus basalis of Meynert, and some cases exhibit neurofibrillary tangles (NFT), senile plaques (SP), and granulovacuolar degeneration. The nature of the histopathologic changes associated with PD with dementia continues to be debated. Although the dementia in PD might be explained by the co-occurrence of AD, mounting evidence argues against this as the sole explanation. AD and PD frequently develop in the same age group. One large study looked at NFT SP counts in PD patients at autopsy versus age-matched controls and demonstrated that AD changes were six times more frequent in the PD population (allowing for senile plaques only to make a diagnosis...

Parkinsons Disease Progression

The rate of clinical progression of PD is highly variable and unpredictable (77). In clinical studies, several clinical endpoints for progressive functional decline in PD have been used, including the Unified Parkinson's Disease Rating Scale (UPDRS) in the defined off state or after drug washout up to two weeks, time to need for dopaminergic therapy, or time to development of motor fluctuations (85-89). Clinical rating scales are extremely useful, but ratings may be investigator-dependent and are frequently confounded by changes in symptomatic treatment. Pathological studies investigating rate of progression have been limited and rely entirely on cross-sectional data (63,64). These studies have in general considered patients with severe illness of long duration. In vivo imaging studies provide the opportunity to evaluate patients longitudinally from early to late disease using an objective biomarker for dopaminergic degeneration. In several studies, neuroreceptor imaging of the...

Preclinical Parkinsons Disease

Estimates based on postmortem studies suggest that for every patient who presents with PD, there may be up to 15 cases of preclinical PD (development of Lewy body pathology without clinical signs of PD) (111). Neuroreceptor imaging studies provide a window into this preclinical period of PD, the time during which neurodegeneration has begun, but symptoms have not yet become manifest. Preclinical identification of affected subjects is particularly important if intervention exists, which may prevent progression of disease. The most extensive preclinical imaging data is from studies imaging patients with hemi-PD. In several imaging studies, there is a significant reduction in putamen DAT or 18F-DOPA uptake of about 25 to 30 in the presymptomatic striatum in these patients who are known to progress to bilateral disease (11,66,67). Most studies of the preclinical period have focused on potential at risk individuals for PD, such as family members or unaffected twins of PD patients. In a...

Parkinsons Disease Dementia

Pathological findings considered to account for dementia in PD include severe pathology in monoaminergic and cholinergic nuclei that project to the cortex producing a subcortical dementia (39 ), coexistent Alzheimer's disease (AD) (29 ), and diffuse cortical Lewy bodies (26 ) (22). The basal forebrain cholinergic system is the subcortical region most often implicated in dementia, and neurons in this region are damaged in both AD and Lewy body dementia. Neuronal loss in the basal nucleus is consistently found in PD, especially PD with dementia (23). Cholinergic deficits are common in PD (24) and they may contribute to dementia in PD in those cases that do not have concurrent AD or cortical Lewy bodies. While virtually all PD brains have a few cortical Lewy bodies (22), they are usually neither widespread nor numerous in PD patients who were not demented. Several studies have shown, however, that cortical Lewy bodies are numerous and widespread in PD with dementia (25-27) and that the...

Postencephalitic Parkinsonism

Parkinsonism following encephalitis lethargica during the influenza pandemic between 1916 and 1926 is known as postencephalitic parkinsonism (PEP). During the recovery phase of the acute viral encephalitis, parkinsonian rigidity developed with the most characteristic clinical features being oculogyric crises. The PEP brain has NFTs in the cortex, basal ganglia, thalamus, hypothalamus, substantia nigra, brainstem tegmentum, and cerebellar dentate nucleus (48). The distribution of the pathology overlaps with PSP and, in some studies, it has not been possible to distinguish the two disorders by histopathologic analysis alone (48). Biochemical studies of abnormal insoluble tau in PEP have features similar to AD with three major bands (68, 64 and 60 kDa) on western blot studies, and electron microscopy shows paired helical filaments similar to those in AD (49).

Multiple System Atrophy and Striatonigral Degeneration

MSA is a variant of PD characterized by a combination of clinical symptoms involving cerebellar, extra-pyramidal, and autonomic systems. The predominant subtype of MSA is striatonigral degeneration (SND), a form of levodopa unresponsive parkin-sonism. Neuropathological changes of SND include degeneration of the nigrostri-atal pathway, medium spiny striatal GABAergic projection pathways (putamen greater then caudate), as well as other regions of the brainstem, cerebellum, and spinal cord. Inclusion-like aggregates that immuno-stain for ubiquitin and alpha-synuclein are seen in oligodendrocytes and neurons. The basis for developing an animal model for SND emerged from established animal models for both parkinsonism having SNpc pathology and Huntington's disease (HD) with striatal pathology. For example, rodent models for SND have been Motor deficits in models for MSA and SND are assessed by ipsilateral and contralateral motor tasks (including stepping response, impaired paw reaching,...

Familial Parkinsonism

While most parkinsonian disorders are sporadic, rare familial forms have been described and mutations have been found or genetic linkage analyses have suggested a strong genetic factor in their etiology (58). Perhaps the most common cause of early onset familial PD is autosomal recessive juvenile PD (ARJP). The clinical features are somewhat atypical in that dystonia is common in ARJP (59). The pathology of ARJP is based upon only a few autopsy reports. Initial studies emphasized severe neuronal loss in the substantia nigra with no Lewy bodies, but a more recent report of an individual who died prematurely of an automobile accident had Lewy bodies in the substantia nigra and other vulnerable regions (60,61). Even in sporadic PD there is an inverse relationship between the disease duration and the number of Lewy bodies in the sub-stantia nigra. When the disease is very severe, there are very few residual neurons. Since Lewy bodies are intraneuronal inclusions that are phagocytosed...

Mortality of Parkinsons Disease with Levodopa

Several studies performed in the 1970s demonstrated that levodopa therapy improved mortality in PD. These studies compared the survival of levodopa-treated patients to the mortality rate demonstrated in the pre-levodopa Hoehn and Yahr study (122), which demonstrated that mortality was three times greater than the normal population. Nearly all studies indicated that levodopa improved survival with rates of 1.4 to 2.4 (119,120,123,124). Some investigators suggested that survival approached normal, whereas others indicated that the effect was only seen in the early years of therapy and then disappeared, suggesting that improvement was based on symptomatic responses. However, many of the studies have been criticized due to methodological flaws, problems with patient selection, and possible biases. One study (125) utilized a population-based study design (retrospective) to avoid many of these flaws and examined the change in survival related to levodopa therapy. The study included patients...

Other Trials in Early Parkinsons Disease

Palhagen et al. (72) reported a study of selegiline in 157 de novo PD subjects. Selegiline 10 mg day delayed the need for levodopa by four months compared with placebo (P 0.028). There was a wash-in effect at six weeks and three months, with total and motor UPDRS scores significantly better in the selegiline group. At six months, the rate of disease progression was significantly slower for both total UPDRS (-1.9 vs. 3.5 P < 0.001) and motor UPDRS (-1.5 vs. 2.5 P < 0.001) (negative numbers refer to improvement and positive numbers refer to worsening). Between baseline and the end of an eight week washout period, there was significantly slower progression of total UPDRS scores in the selegiline group (11.3) compared with the placebo group (14.2), when length of time to reach the endpoint was used as a covariate (P 0.033) (72). The French Selegiline Multicenter Trial (77) randomized 93 de novo PD subjects to selegiline 10 mg day or placebo. Significant improvements in total and motor...

Respiratory Dysfunction in Parkinsons Disease

A number of studies have provided evidence, through various aerodynamic measurements, for disordered respiratory function in individuals with PD. These disorders include reduced vital capacity, reduced total amount of air expended during maximum phonation tasks, reduced intraoral air pressure during consonant vowel productions, and abnormal airflow patterns (48-50). The origins of these airflow abnormalities are not clear but they may be related to variations in airflow resistance due to abnormal movements of the vocal folds and supralaryngeal area (50) or abnormal chest wall movements and respiratory muscle activation patterns (23,48,51). Articulatory and Velopharyngeal Disorders Acoustic and Kinematic Correlates of Articulatory Abnormalities in Parkinson's Disease Acoustic correlates of disordered articulation include problems with timing of vocal onsets and offsets (voicing during normally voiceless closure intervals of voiceless stops) (24) and spirantization (presence of...

Sensorimotor and Perceptual Deficits Underlying Motor Dysfunction in Parkinsons Disease

Sensory problems in PD have been recognized for years (66), and these problems may underlie some of the disorders of the speech system. Sensorimotor deficits in the orofacial system (62,63,67) and abnormal auditory, temporal, and perceptual processing of voice and speech (26,27,53,68) have been documented in PD (28,63) and have been implicated as important etiologic factors in hypokinetic dysarthria secondary to PD (69). Schneider et al. (63) found marked sensorimotor deficits in the orofacial and limb systems of individuals with PD. They observed that individuals with PD, compared with age-matched controls, showed greater deficits in tests of sensory function and sensorimotor integration. They suggested that PD patients might have complex deficits in the utilization of specific sensory inputs to organize and guide movements due to abnormal sensory gating or filtering associated with basal ganglia motor dysfunction. Caliguiri and Abbs (62) described abnormal orofacial reflexes in some...

Effect Of Surgical Treatments For Parkinsons Disease On Speech And Swallowing Deep Brain Stimulation

Many studies of deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus internus (GPi), and ventral intermediate (Vim) nucleus of the thalamus have reported dysarthria and dysphagia as side effects (88-90). Several studies examined specific aspects of voice, speech, swallowing and related orofacial, and respira-tory-laryngeal functions associated with DBS treatment of PD. Santens et al. (91) found that left-brain stimulation had a profound negative effect on prosody, articulation, and intelligibility not seen with right-brain stimulation. With bilateral stimulation, no differences in speech characteristics were observed on- and off-stimulation. Wang et al. (92) also studied the effects of unilateral STN DBS on respiratory phonatory subsystems of speech production in PD. Speech recordings were made in the medication-off state at baseline and three months post-DBS with stimulation-on and -off, in six right-handed patients. Three patients who received left-brain...

Behavioral Speech Voice And Swallowing Treatment For Parkinsons Disease

Although the incidence of speech and voice disorders in individuals with PD is extremely high, only 3 to 4 receive speech treatment (112). One explanation for this is that carryover and long-term treatment outcomes have been disappointing and consequently the primary challenges in the treatment of hypokinetic dysarthria associated with PD. Clinicians have long been aware that when dysarthric PD patients are receiving direct stimulation, prodding, or feedback from the speech clinician or an external cue (113,114), they are likely to show a dramatic improvement in speech and voice production and overall intelligibility. However, maintaining these improvements without these external cues is extremely difficult for most of these individuals. One explanation for the inability of individuals with PD to maximize and maintain treatment gains may be their deficits in internal cueing, vigilance, scaling amplitude of vocal output, and self-perception and self-regulation of vocal loudness and...

Levodopa Challenge Test

It can be difficult to accurately differentiate PD from other forms of parkinsonism, especially during the early stages of disease. Levodopa administration can be used for diagnostic purposes, as PD patients respond more frequently and robustly to levodopa compared with other forms of parkinsonism. Clarke and Davies (145) reviewed 13 studies that examined whether an acute levodopa or apomorphine challenge test could aid in the diagnosis of PD. Four studies examined de novo patients and nine examined patients with clinically established PD. Although there was significant variability in the methodologies employed, abstracted sensitivity and specificity data were summarized from the studies and the two challenge tests compared as to their ability to accurately predict patients' diagnosis. The sensitivity for the diagnosis of established PD for apomorphine was 0.86 95 confidence interval (CI) , acute levodopa 0.75 (95 CI), and chronic levodopa therapy 0.91 (95 CI). The specificity for the...

Does Tolerance Develop to Levodopa

The lay literature is replete with information suggesting that levodopa loses its effect after about five years. This leads to some trepidation on the part of the patient and physician in initiating therapy. If that were the case, it would indicate that tolerance is a possible concern and would argue for delaying treatment. It is conceivable that, when all nigrostriatal cells are depleted, levodopa would lose all effectiveness since these are the cells that convert levodopa and release dopamine. Lesser et al. (70) found that longer duration of disease did not appear to adversely affect response to levodopa at the time of initiation of therapy, yet they demonstrated deterioration in response that did not correlate with duration of disease. Those receiving levodopa longer had more severe disease. The assumption made by the authors was that PD patients developed tolerance. Despite these findings, the authors did not rule out the possibility that those receiving levodopa longer had a more...

Resonance Problems in Parkinsons Disease

Resonance problems are not common in PD, but when they are present, the voice often sounds like a foghorn. The acoustic and physiologic nature of this phenomenon is not clear, and perceptually, it is difficult to determine whether the voice is hypernasal or hyponasal. Aerodynamic and kinematic studies suggest that velopharyngeal movements may be reduced in some of these individuals (22,52,56). Abnormal tongue posture may also contribute to the resonance in parkinsonian speech. The abnormal resonance may also reflect motor symptoms not directly caused by PD such as pharmacologically induced dystonic or dyskinetic movements of the velopharyngeal and or tongue muscles.

Gender And Parkinsonism

The available evidence indicates that men have a slightly higher risk of parkinson-ism than women, with the exception of drug-induced parkinsonism (59,60). According to a meta-analysis, relative risk of parkinsonism for men compared to women is 1.5 (61). Suggested reasons for this risk included differential exposure to external risk factors, an X-linked genetic factor, and mitochondrial dysfunction. The lifetime risk of parkinsonism is greater in men than in women (4.4 vs. 3.7 ) (32). In older patients, 65 to 84 years, the male to female incidence ratio was 1.66 for parkinsonism and 2.13 for PD (19). Interestingly, although women have a longer life expectancy than men, women with PD have the same mortality rates as men with PD (60). GEOGRAPHY, ETHNICITY, RACE, AND PARKINSONISM Parkinsonism has been reported in all countries and in all races. In most countries, geography, ethnicity, and race are intertwined. Comparing immigrants to residents of their homeland is one way to evaluate the...

Parkinsonism In Young Adults

The onset of parkinsonism under the age of 40 is usually called young onset parkinsonism. When symptoms begin under the age of 20, the term juvenile parkinsonism is sometimes used (111). Under the age of 20, parkinsonism typically occurs as a component of a more widespread degenerative disorder. However, parkin mutations have been described in some young patients (2). There is a significant overlap in young patients with dystonia and parkinsonism. Patients with young onset parkinsonism manifest dystonia that may be responsive to dopaminergic drugs (112). However, the response may deteriorate upon long-term fol-lowup. Patients with hereditary dopa responsive dystonia have an excellent and sustained response to low doses of levodopa (113). In addition, PET scans show markedly reduced 6-fluorodopa uptake in patients with young onset PD, whereas the fluo-rodopa uptake is normal in patients with dopa responsive dystonia (114). Patients with dopa responsive dystonia have a guanosine...

Acoustic Measures of Abnormal Voice and Speech in Parkinsons Disease

Acoustic analyses of voice and speech in individuals with PD have confirmed the perceptual descriptions of hypokinetic dysarthria. Fox and Ramig (33) documented reduced vocal sound pressure level (vocSPL) by 2 to 4 dB (at 30 cm) on a number of speech tasks in 29 individuals with PD, compared with age- and gender-matched controls, which is equal to a 40 change in vocal loudness. Ho et al. (34) found vocSPL in PD to decay much faster than in neurologically normal speakers. They interpreted this fading as symptomatic of frontostriatal dysfunction. Rosen et al. (35) examined intensity decay in the phonation of persons with and without PD on various speech tasks. They found that vocSPL declined more rapidly in PD than in normal, age-matched speakers during syllable repetition speech diadochokinesis (DDK) . They also found that in some of the individuals with PD, there were abnormally abrupt changes in vocSPL during conversation. However, during sustained vowel phonation, vocSPL did not...

Life Expectancy In Parkinsonism

All of the parkinsonism variants limit mobility, and the increased tendency for falls and dysphagia predisposes these patients to life-threatening complications (33,34). Life expectancy prior to the widespread use of levodopa was significantly reduced. In one hospital based parkinsonism series during the 1950s and 1960s, the mean survival after onset was 10.8 years (35). Excluding postencephalitic parkinsonism, the mean survival was 9.42 years, which is frequently cited as the yardstick for the prelevodopa era life expectancy (35). Mean survival in the contemporary parkinsonism cases cannot be compared with that study. There have been significant social and health care advances leading to longer life in the general population, and one would expect that parkinsonism patients would share these survival gains. Comparisons for survival should be made matching for year of birth, gender, and region country. Kurtzke et al. (36) noted that patients in the 1980s were, on an average, five years...

Geographic Differences In Rates Of Parkinsons Disease

Although the findings are inconsistent, a higher prevalence of PD in urban areas argues for byproducts of industrialization as risk factors for PD. Several studies suggest that increasing industrialization may increase PD risk. Schoenberg et al. compared the prevalence of PD in Copiah County, Mississippi, U.S.A. (341 100,000 over age 39) to Igbo-Ora, Nigeria (67 100,000 over age 39) using similar methodology, and studying genetically similar populations. They concluded that environmental factors may be responsible for the observed higher prevalence in the industrialized U.S. population (26). In contrast, a study (27) of PD in Estonia found a similar prevalence of PD in urban and rural regions, although the definitions of urban and rural were unclear. A small study (25) conducted in a health district in Canada found a lower risk of PD in industrialized areas of the district. In a population-based mortality study, Rybicki et al. (28) demonstrated that counties in Michigan, U.S.A. with a...

Frequency Of Autonomic Dysfunction In Parkinsons Disease

Although the focus of routine follow-up visits between PD patients and neurologists is typically on motor symptoms of the disease, autonomic problems are frequently present and can be identified if patients are specifically asked. In one study of 48 men with PD, 89 had at least one autonomic symptom compared with 43 of elderly control subjects (2). Autonomic symptoms seen in these men with PD included erectile dysfunction (60 ), urinary urgency (46 ), constipation (44 ), dysphagia (23 ), and orthostatism (22 ), and each of these symptoms was more common in PD patients than controls. Siddiqui et al. (3) performed a comprehensive symptom survey of autonomic symptoms in 44 patients with PD, comparing the frequency and severity of these symptoms with 24 aged-matched controls. Using a five point scale to rate symptom severity, the authors tabulated the severity of symptoms in each of five areas GI, urinary, sexual dysfunction, cardiovascular, and thermoregulatory. They found that PD...

Risk Factors for Dementia in Parkinsons Disease

TABLE 3 Risk Factors for Dementia in Parkinson's Disease Lower socioeconomic status Family history of Parkinson's dementia Disease severity Susceptibility to levodopa-induced psychosis or confusion patients with PD on verbal fluency, attentional, and visuospatial tasks was associated with subsequent development of dementia. Woods and Tr ster (93) found that nondemented PD patients who met criteria for dementia at one-year follow-up evaluation demonstrated poorer baseline performance on measures of word-list learning and recognition, complex auditory attention, and executive function.

Pharmacologicalinduced Models Of Parkinsons Disease

Pharmacological manipulation of the dopaminergic system can take on two basic forms either targeting dopamine biosynthesis or destruction of nigrostriatal dopaminergic neurons. Both reserpine and alpha-methyl-para-tyrosine (AMPT) interfere with dopamine production and result in a temporary dopamine depletion lasting hours to days, whereas neurotoxicants such as 6-hydroxydopamine (6-OHDA) and (MPTP) result in midbrain dopaminergic cell death. Methamphetamine (METH) is a class of compound that selectively destroys axonal terminals of nigrostriatal dopaminergic neurons usually without significant cell death. Recently, other compounds, particularly pesticides and proteasome inhibitors, have been utilized as selective toxins targeting the dopaminergic system since the mitochondria of these cells display enhanced vulnerability during chronic exposure. The utility of compounds to generate animal models of parkinsonism are discussed in the following sections.

Does Levodopa Cause Motor Fluctuations

It has been known since the early days of levodopa therapy for PD that motor fluctuations and dyskinesia were associated with drug therapy (12). Barbeau (61) referred to it as the long-term levodopa syndrome. At that time, with no alternative treatments available, he indicated that its existence did not counterbalance the great usefulness of the drug. The questions are what causes their onset and progression and what are the key risk factors The main issues in the debate address whether they are a result of disease progression or primarily levodopa itself (or the manner in which it is delivered to the brain) or both. The answer is not totally clear, but this question has been examined extensively by (i) evaluating patient populations and examining which of the two factors correlates with the onset of fluctuations and dyskinesia and (ii) examining the actual response fluctuations in a controlled setting to determine possible etiologic explanations. In a retrospective study, Lesser et...

Incidence Of Parkinsonism

In the Western countries, some of the most reliable incidence studies are those from Rochester Minnesota using the record system of the Mayo Clinic, which combines case ascertainment with diagnosis by neurologists. Four different incidence reports based on the Rochester population have been published (15-18). Since drug-induced parkinsonism was not recognized until the early 1960s (28), we excluded drug-induced parkinsonism from each study for the purpose of comparison. The rates for 1945-1954 (15), 1935-1966 (16), 1967-1979 (17), and 1976-1990 (18) were 20.5, 18.5, 18.2, and 20.5 105, respectively. There was no significant change in incidence over 55 years. The latest study (18) revealed overall incidence of parkinsonism of 25.6 105, including drug-induced parkinsonism. Incidence increases with increasing age. The incidence of parkinsonism was 0.8 105 in those aged 0 to 29 years, 25.6 105 in those 50 to 59 years and, more than 11 times higher (304.8 105) in the 80- to 99-year age...

Neuropsychological Dysfunction in Parkinsons Disease Without Dementia

In reviewing the PD literature, Lieberman (29) reported that 17 to 53 of treated and untreated PD patients without dementia demonstrate cognitive dysfunction. Unfortunately, few of the studies reported formal criteria for determining what did or did not constitute dementia, thus making it difficult to determine whether patients were in the early stages of dementia. As noted earlier, more recent studies suggest that formal neuropsychological testing may uncover mild cognitive deficits in 25 to 36 of PD patients at the time of diagnosis (22,23). When present in early PD, cognitive dysfunction is typically mild and most commonly involves bradyphre-nia (a slowness of thought) and subtle deficits in executive functions, recall, and or visuoperceptual spatial functions (30).

Neuropsychological Dysfunction in Parkinsons Disease with Dementia

The annual incidence of clinically diagnosed dementia in PD (PDD) is about 3 for individuals younger than 60 years and 15 or less for those 80 years and older (66,67). Estimates of dementia prevalence in patients with PD vary between 9 and 93 , depending on which diagnostic criteria, ascertainment methods, and sampling methods are implemented (24). The methodologically soundest studies yield prevalence estimates of about 25 (68). Dementia is very rarely present early in the disease course moreover, dementia that precedes or accompanies the evolution of motor symptoms should raise concern that the dementia might be related to factors other than PD, for example, AD, LBD, or depression. Recently revised diagnostic criteria for LBD (69) propose that the clinical diagnostic term PD with dementia be reserved for individuals who have a clinical diagnosis of PD and have had only motor symptoms for at least 12 months before developing fluctuating cognition and other neuropsychiatric symptoms...

Is There an Association Between Levodopa Therapy and Melanoma

The connection between levodopa therapy, PD, and malignant melanoma has been a matter of debate for three decades. It originally derived from the biochemistry of the drug. Levodopa is a substrate for the development of dopamine, which, in turn, develops into neuromelanin in CNS nigral neurons. It is the dopaquinones derived from levodopa that are oxidized to form neuromelanin in these cells (126). Hence, it has been proposed that levodopa may also affect the activity of melanocytes in the skin, possibly promoting malignant transformation, although this connection has never been proven. In addition, it is now known that 70 of melanoma cases in the general population appear to be connected with a genetic mutation unrelated to PD. Thus, it would seem unlikely that there would be a connection between PD, lev-odopa, and melanoma. Nevertheless, reports of melanoma in patients treated in the 1970s led the FDA to require language in the package insert that cautions against the use of levodopa...

Disordered vs Compensated Rate of Speech in Parkinsons Disease

Disordered rate of speech has been reported in some individuals with PD, and rapid rate or short rushes of speech have been reported in 6 to 13 of individuals with PD. Palilalia or stuttering-like speech disfluencies have been observed in a small percent of individuals with parkinsonism (30,31). The discrepant findings of speech rate in parkinsonian speech (slow vs. rapid) may be related to the presence or absence of compensatory mechanisms. Caliguiri (55) found, using kinematic analyses, that lip movements were normal when individuals with PD spoke at a rate of 3 to 5 syllable sec, but hypokinetic when the rate increased to 5 to 7 syllable sec, which is the typical rate of conversational speech. Similarly, Ackermann et al. (53) described a

Inclusion Criteria For Parkinson Epidemiology

The two major considerations for inclusion in parkinsonism epidemiology are 1. Does this individual have parkinsonism, normal aging, or another disorder 2. Does this person have idiopathic Parkinson's disease (PD) or another variant of parkinsonism Primitive reflexes, slowed motor functions, flexed posture, and impaired postural reflexes characteristic of parkinsonism are also a part of normal aging (2). In general, age-related abnormalities are symmetrical while parkinsonism is often asymmetrical. Rest tremor, a common early feature of parkinsonism, is not part of normal aging and hence is the single most reliable feature of this disorder (3). The most common tremor disorder misdiagnosed as PD is essential tremor (ET). Typically, ET is present on positioning a limb against gravity and during activity. ET is usually restricted to the upper limbs and or head. By contrast, resting tremor is characteristic of parkinsonism and may involve the upper and lower limbs. Nearly one-third of ET...

Perceptual and Phonetic Characteristics of Voice and Speech Disorders in Parkinsons Disease

Darley et al. (3) reported one of the first systematic descriptions of perceptual characteristics of speech and voice in individuals with PD (3,31,32). They identified reduced loudness, monopitch, monoloudness, reduced stress, breathy, hoarse voice quality, imprecise articulation, and short rushes of speech as the most characteristic of the speech and voice disorders in PD. They termed these symptoms hypoki-netic dysarthria. Logemann et al. (2) used phonetic and perceptual analyses to characterize voice and speech abnormalities in 200 nonmedicated individuals with PD. Of these individuals, 89 were found to have voice quality problems such as breathiness, hoarseness, roughness, and tremor and 45 also had speech prosody or articulation problems. Ho et al. (1) used perceptual and phonetic methods to characterize voice and speech problems in 200 individuals with PD. They found that voice problems were first to occur, with other speech problems (prosody, articulation, and fluency)...

Complementary Therapies For Parkinsons Disease What Do We Really Know

There are very few well-designed studies and consequently very little evidence to support or refute the use of most complementary therapies for the treatment of PD. This does not mean that alternative therapies cannot help someone with PD, but for Western-trained healthcare providers treating someone with PD who is considering alternative therapies, it is difficult to know what and how to advise them. The first rule in medicine is do no harm, so if a particular therapy such as massage therapy is not thought to be harmful then it might be recommended. On the other hand, ingesting an herb, injecting glutathione, or ingesting a homeopathic remedy without any proof that it is beneficial and without knowing the potential harmful effects or drug interactions may not be in the best interest of a person with PD. Specific complementary therapies that are commonly prescribed by alternative practitioners are reviewed in the following section. As the majority of these therapies, especially those...

Clinical Trials Of Levodopa

The initial therapeutic studies of levodopa in PD were carried out in the 1960s and early 1970s. The subjects were of varying disease durations, some quite advanced with dementia, and standard measures such as the Unified Parkinson's Disease Rating Scale (UPDRS) were not yet devised however, the results were dramatic (3). In 1967, Cotzias et al. (11) demonstrated the definitive effectiveness of high-dose L-Dopa (as opposed to D, L-Dopa). These investigators examined 28 patients in an open-label manner with intermittent blinded replacement with placebo and utilized levodopa without a dopa decarboxylase inhibitor. The duration of disease ranged from 1 to 30 years (mean 10 years). All patients responded, with 20 having a marked to dramatic improvement. All motor features improved. Some patients developed fluctuations and dyskinesia quickly and it was suggested that these problems related to duration of disease. Many studies followed which supported these findings (13,42-44). An example...

Spontaneous Rodent Models for Parkinsons Disease

There are several naturally occurring spontaneous mutations in rodents that are of particular interest in PD. Spontaneous rodent models include the weaver, lurcher, reeler, Tshrhyt, tottering, and coloboma mice and the AS AGU and circling (ci) rat. These models possess unique characteristics that may provide insight into neurodegener-ative processes of PD and related disorders. Several of these spontaneous rodent models display altered dopaminergic function or neurodegeneration, and have Another naturally occurring mutation is the aphakia mouse. This mutation affects a gene called Pitx3, which is a developmentally regulated homeobox containing transcription factor necessary for the establishment of midbrain dopaminer-gic neurons (138). Mice carrying mutations in Pitx3 display behavioral and neurochemical characteristics similar to the anatomical and functional deficits seen in PD, including cell loss in the substantia nigra dopaminergic neurons, a feature not seen in most transgenic...

Swallowing Treatment for Parkinsons Disease

Treatment of swallowing disorders in PD has not been well studied. Conventional techniques have included oral motor exercises to improve muscle strength, range of motion and coordination, and behavioral modifications such as effortful breath-hold, chin positioning, double swallow, the Mendelsohn maneuver, swallow cough, effortful swallow, and diet and liquid modifications (13,127). Effectiveness of these techniques varies and can be dependent on patient motivation and cooperation, family support, and the timeliness of the referral for a swallowing evaluation. Efficacy studies of the impact of behavioral treatment on dysphagia in PD are lacking (128). The effects of LSVT on swallowing dysfunction in individuals with PD have been studied by Sharkawi et al. (8). These researchers found that the LSVT reduced swallowing motility disorders by 51 . Some temporal measures of swallowing were also reduced, as was the amount of residue. This is the first study to find positive changes in both...

Advanced Parkinsons Disease

Selegiline has mild to moderate benefit as adjunct therapy to levodopa in advanced PD patients and is approved by the FDA in the United States for this indication. In a small double-blind placebo-controlled trial (79) of selegiline 10mg day in PD subjects (n 38) on stable levodopa doses, selegiline reduced daily levodopa dosage requirements (P < 0.05) and significantly improved tremor (P 0.02) over eight weeks. Thirty subjects (selegiline n 18, placebo n 12) completed a 16-month follow-up (79). Both mean levodopa dosage (-133 mg day) and dosing frequency were significantly reduced in the selegiline-treated group. Significantly less end-of-dose akinesia was reported in double-blind crossover trials with selegiline (80,81). Golbe et al. (82) randomized 96 PD patients with motor fluctuations that could not be improved with levodopa adjustments to selegiline 10 mg day or placebo. Mean hourly symptom control in subjects randomized to selegiline was significantly improved compared to...

Common Diseases With Abnormal Gait Parkinsonism

In patients with parkinsonism, walking is slower than normal, cautious, and contained. The steps get smaller and the patient will eventually shuffle. In more advanced disease, she is flexed at the knees and hips and walks on her toes while sliding her feet forward. Her arms are adducted and flexed at the elbow, with her hands held in front of her thigh or abdomen.

Levodopa And Homocysteine

An evolving concern with levodopa therapy relates to its association with elevated homocysteine (HC) levels. Since the late 1990s, several studies have indicated that levodopa dose correlates with elevation of HC. Postuma and Lang (131) reviewed this literature, and the relevance of the increase of HC to PD and patient health remains unclear. The concern relates to data suggesting that elevated HC levels increase the risk of stroke, coronary artery disease, and dementia (132-134). HC is metabolized from dietary methionine through two intermediates SAM (s-adenosylmethionine) and SAH (s-adenosylhomocysteine). HC is metabolized back to methionine via methylene tetrahydrofolate reductase (MTHFR) or to cysteine via other mechanisms. These enzymatic reactions occur in the presence of folate and vitamins B12 and B6. Hence, deficiency of any of these could lead to elevated HC. This is true for the presence of the C677T MTHFR polymorphism, which decreases metabolism of HC. In PD, it is the...

Effect Of Medical Treatments For Parkinsons Disease On Speech And Swallowing

Although neuropharmacologic and neurosurgical approaches have had positive effects on the primary symptoms of PD, their effects on voice, speech, and swallowing have been inconsistent. Several studies have assessed the effects of levodopa and dopamine agonists on voice and speech functions in PD. Gallena et al. (47) studied the effects of levodopa on laryngeal function in six persons with early PD who were not receiving medication. They found that levodopa reduced excessive laryngeal muscle activity and vocal fold bowing and improved voice onset and offset control during speech in some patients. De Letter et al. (80) reported significant improvement in speech intelligibility with levodopa. Goberman et al. (81) examined the acoustic-phonatory characteristics of speech in nine individuals with PD and motor fluctuations before and after taking levodopa. They found that the voice F0 variability in vowels and mean F0 were higher, and intensity range was lower when on-medication, compared...

Neurotoxicantinduced Models Of Parkinsons Disease 6Hydroxydopamine

Hydroxyl radicals and impairment of mitochondrial energy production (5,6). The 6-OHDA-induced rat model of PD was initially carried out by Ungerstedt in 1968, using stereotaxic bilateral intracerebral injections into the substantia nigra or lateral hypothalamus targeting the medial forebrain bundle (7). The bilateral administration of 6-OHDA resulted in catalepsy, generalized inactivity, aphagia, adipsia, and a high degree of animal morbidity and mortality. Consequently, the administration of 6-OHDA was modified to a unilateral intracerebral lesion targeting the substantia nigra and or medial forebrain bundle. With unilateral lesioning, there was minimal postoperative morbidity, behavioral asymmetry, and a nonlesioned side to serve as a control (8,9). An additional modification of 6-OHDA administration is using chronic low dose striatal injections. This can lead to progressive dopaminergic cell death thought to more closely resemble the human condition (10). An important caveat of...

Physiologic Measures of Laryngeal Dysfunction in Parkinsons Disease

Additional data to support the laryngeal closure problems in PD come from analyses of EGG signals. Gerratt et al. (43) reported abnormally large speed quotient and poorly defined closing period in PD patients. Blumin et al. (44) used videostro-boscopy and fiberoptic endoscopic techniques, as well as a voice handicap index (VHI) questionnaire, to assess laryngeal function in 15 individuals with severe PD. Of these individuals, 13 (87 ) had significant vocal fold bowing and 14 (93 ) self-reported significant voice handicap. These observations were consistent with the slow vocal fold opening relative to the rate of closure and incomplete closure of the vocal folds. EMG studies of the laryngeal muscles provided further information regarding laryngeal pathology in PD. Hirose and Joshita (45) studied the EMG data from the thyroarytenoid (TA) muscles in an individual with PD who had limited vocal fold movement. They observed no reduction in the number of motor unit discharges and no...

Neuropsychological Findings In Parkinsons Disease

Parkinson (20) contended that patients with shaking palsy did not exhibit significant intellectual changes however, by the late 1800s, investigators had begun to recognize the presence of cognitive deficits in patients with PD (21). Mild neuropsychological changes are widely accepted to occur in early PD. Increasingly, it is recognized that cognitive alterations, especially in executive functions and or memory, may already be present at the time of disease diagnosis. Recent studies estimate that one-quarter to one-third of patients may have deficits detectable on careful neuropsychological testing at the time of disease diagnosis (22,23). Cognitive declines early in the disease most often include deficient information processing speed, visuospatial abilities, verbal fluency, recall, and executive functions (24,25). The neuropsychological dysfunction associated with early PD is hypothesized to reflect nigrostriatal dopamine depletion and disruption of mesocortical and mesolimbic...

High Field Neuroimaging in Parkinsons Disease

Until recently, standard neuroimaging techniques have had a marginal role in the diagnosis and follow-up of Parkinson's disease (PD). The diagnosis of PD is essentially based on clinical data (neurological examination and evaluation of therapeutic response) (UK Parkinson's Disease Brain Bank criteria). In the earlyphase the magnetic resonance (MR) examination may be negative. In other words MR is not sufficiently sensitive to the damage caused by PD. One-fourth of patients with a clinical diagnosis of idiopathic PD are subsequently found to have other degenerative disorders 11 . Like clinical examination, standard MR is scarcely specific and has a secondary role that is in fact limited to gross differential diagnosis with other neurological disorders. We examine the rationale of standard MR diagnostic imaging, the more advanced quantification techniques and the advantages and drawbacks of 3.0 T magnetic fields in PD.

Parkinsons Disease Differential Diagnosis And Severity

The initial questions of an imaging ligand are whether it reliably distinguishes between subjects with and without a known pathology (a marker for disease trait) and whether the changes in the imaging outcomes correlate with disease severity (a marker for disease state). In several studies, dopamine and vesicular transporter ligands and 18F-DOPA discriminated between individuals with PD and healthy subjects, with a sensitivity greater than 95 (11,13,20,72-74). These studies take advantage of the relatively greater dopaminergic loss in the putamen to enhance the discriminant function. Furthermore, the reduction in both dopamine and vesicular transporter and 18F-DOPA imaging activity correlated with well-defined clinical rating scales of PD severity (16,20,28,75). Interestingly, when specific PD symptoms were compared, the loss of dopaminergic activity measured by imaging correlated with bradykinesia but not with tremor (20,76). Cross-sectional studies show that In clinical practice,...

Prevalence Of Parkinsonism

The prevalence rate is defined as the number of patients in the population at a given time. This can be difficult to ascertain, as approximately 15 of people in the community self-reporting a PD diagnosis do not actually have PD and 20 of people with PD have not been diagnosed (46). The two main factors that determine the Prevalence rates can be estimated by multiplying incidence rate and the mean survival. Most observers regard Rochester, Minnesota, incidence rates as representative for North America. The latest annual incidence of parkinsonism in Rochester is 25.6 105 (18). The survival in parkinsonism has increased substantially during the last three decades. A conservative estimate of mean survival in contemporary parkinsonism is 15 years, though an average PD case would survive longer. Thus, the minimum prevalence rate in the North American general population is estimated at 384 105. Other methods have been used to determine prevalence rates for parkinson-ism. A state registry in...

Vesicular Monoamine Transporter And Dopamine Transporters In The Substantia Nigra Pars Compacta

The dopaminergic synaptic transmission is terminated by the transportation of 95 of synaptic dopamine into the nigrostriatal terminals by the dopamine transporter (DAT) molecule (20). DAT also plays a major role in the neurotoxic effects of MPTP by transporting MPP+, the active mitochondrial toxic metabolite of MPTP, into the dopamine neuron terminals. DAT is an important and a specific marker for dopaminergic neurons (20,21). The intensity of expression of DAT mRNA in primate and human nigra is maximal at the caudal, ventral, and lateral group of dopamine neurons and gradually decreases medially in the VTA regions (19-23), corresponding with the pattern of dopaminergic cells that are highly melanized in the SNpc. The SNpc cells that express DAT very densely are the most severely affected in PD, and those VTA neurons expressing DAT less intensely demonstrate a less severe pattern of degeneration. The level of expression of DAT mRNA in the dopaminergic neurons of the arcuate and...

Tremors can be classified as follows Resting tremorParkinsonian

The tremor of Parkinson's disease is present at rest. The hand tremor is most marked with the arms supported on the lap and during walking. The characteristic movement is 'pill-rolling' where movement of the fingers at the metacarpophalangeal joints is combined with movements of the thumb. The resting tremor decreases on finger-nose testing but a faster action tremor may supervene. The best way to evoke the tremor is to distract the patient, such as focusing attention on the left hand with a view to 'examining' the right hand or by turning the head.

Levodopa and Dopamine Agonists

Findings concerning the impact of levodopa on cognitive functions are inconsistent, with studies showing improvement, decrements, and an absence of significant cognitive changes associated with levodopa therapy or its withdrawal (124). Despite these inconsistent findings, evidence is accumulating that levodopa has short-term effects on certain aspects of memory and executive functions, perhaps as mediated by disease stage. Kulisevsky et al. (125) reported that short-term improvements in learning and memory, visuoperception, and certain executive functions were associated with dopamine replacement therapies, but stated that these cognitive improvements were not maintained over time. Owen et al. (126) found that only certain aspects of executive functioning (i.e., planning accuracy) were improved with levodopa therapy early in the disease, whereas other aspects (response latency) remained relatively unaffected. That levodopa affects only certain components of cognitive functions is...

Levodopa Methyl Ester

Levodopa methyl-ester carbidopa effervescent tablets (CNP-1512) are currently approved for rescue therapy in PD in Italy (Chiesi Farmaceutici). Outside of Italy, the drug (V1512) is owned by Vernalis Pharmaceuticals. This preparation is approximately 250 times more soluble in water and can thus be easily dissolved and orally administered. Studies comparing the drug with standard levodopa preparations demonstrate a faster onset of action (by a mean of 8.5 minutes) and a longer total duration of action (mean 15 minutes longer) with fewer dose failures. A large 39-center European trial compared levodopa methyl-ester with standard levodopa in patients already on levodopa who were experiencing at least two hours of off time. At 12 weeks, subjects on levodopa methyl-ester tended to have less off time than levodopa (-39.4 vs. +3.4 minutes, P 0.07). No unexpected adverse events have been noted. Phase III North American and European studies are planned (4).

Intensive Voice Treatment for Parkinsons Disease

It is hypothesized that there are three features underlying the voice disorder in individuals with PD (i) an overall amplitude scale down (75,76) to the speech mechanism (reduced amplitude of neural drive to the muscles of the speech mechanism), which results in hypophonia, hypoprosodia, and hypokinetic articulation (ii) problems in the perception of vocal loudness and effort (77), which prevent the individuals with PD from accurately monitoring and scaling their vocal output and (iii) difficulty in independently generating (internal cueing scaling) the right amount of effort (78) to produce adequate vocal output (loudness, prosodic inflection, and amplitude of articulatory movement). The LSVT has been designed to address these problems.

Parkinsons Disease Diagnosis Accuracy

The diagnosis of PD is currently based primarily on clinical judgment. However, the variability of disease presentation, progression, and response to medications often makes the diagnosis uncertain. In a population-based study, at least 15 of patients with a diagnosis of PD did not meet strict diagnostic criteria, and approximately 20 of patients with PD who had medical attention had not been diagnosed with PD (48). Prevalence studies of parkinsonism suggest a diagnostic accuracy of 80 after examination and application of clinical diagnostic criteria (49-51). Long-term clinico-pathologic studies evaluating the diagnostic accuracy of PD demonstrate that the diagnoses most commonly mistaken for PD are progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (52,53). However, early in the course of PD, the most common misdiagnoses include essential tremor, vascular parkinsonism, drug-induced parkinsonism, and Alzheimer's disease (54,55). It has been estimated that the...

Neuropsychological Characteristics of Dementia in PD

Cognitive disturbances may range from relative circumscribed deficits to global dementia. Mild cognitive deficits are common in idiopathic Parkinson's disease (IPD) and are characterized by impaired cognitive flexibility, psychomotor slowing, reduced ability to learn and retrieve new information, and impaired visuospatial skills. The concept of subdividing dementias on clinical grounds into cortical and subcortical dementias has been adapted Explicit verbal memory (word lists, paired associate learning, brief prose passages) is disturbed in PD patients with dementia however, the quality of this memory impairment is different from that seen in AD. Most often, the deficit is in memory retrieval (where patients are able to develop a normal learning curve but exhibit increased rates of forgetting on delayed recall and are much better at recognition). This differential recall recognition is seen for PD patients over a broad range of mental status changes. Explicit nonverbal memory...

Guam Parkinsondementia Complex

A characteristic parkinsonism with dementia Parkinson dementia complex (PDC) with a number of features that overlap with PSP (50) has been reported in the native Chamorro population of Guam since the 1950s (51). The frequency of PDC is declining in recent years for unknown reasons, and the etiology is unknown. The gross findings in PDC are notable for cortical atrophy affecting frontal and temporal lobes, as well as atrophy of the hippocampus and the tegmentum of the rostral brainstem (52). These areas typically have neuronal loss and gliosis with many NFTs in residual neurons.

Levodopa Preparations

Levodopa is available with carbidopa as immediate release carbidopa levodopa 10 100, 25 100, and 25 250. It is also available in a sustained-release form as car-bidopa levodopa 25 100 and 50 200. An orally dissolvable form of immediate release carbidopa levodopa (Parcopa ) is available as 10 100, 25 100, and 25 250. Finally, levodopa is available with the COMT inhibitor, entacapone, in the following combinations Stalevo 50 (carbidopa 12.5mg levodopa 50mg entacapone 200 mg), Stalevo 100 (carbidopa 25 levodopa 100 entacapone 200), and Stalevo 150 (carbidopa 37.5 levodopa 150 entacapone 200).

Neuropsychological Aspects Of Parkinsonplus Syndromes And Essential Tremor

Parkinson-plus syndromes traditionally include PSP, MSA, and corticobasal degeneration (CBD). Although sparse, preliminary neuropsychological studies indicate that the cognitive impairment profiles likely differ across the parkinson-plus syndromes (172). A summary of key differences is presented in Table 4. TABLE 4 Comparison of Neurobehavioral Features of Parkinson's Disease with Dementia, Lewy Body Dementia, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Multiple System Atrophy TABLE 4 Comparison of Neurobehavioral Features of Parkinson's Disease with Dementia, Lewy Body Dementia, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Multiple System Atrophy

Anxiety in PD

These investigators also found that 43 of IPD patients had a depressive disorder an additional 14 had depressive symptoms. It has been suggested that anxiety may be secondary in part to the antiparkinson-ian medications. A study by Maricle, Nutt, and Carter (1995) investigated mood and anxiety fluctuations associated with L-dopa infusion therapy in a small series of patients and found that mood and anxiety symptoms slightly preceded but temporarily paralleled fluctuations in motor tapping scores. The effects of L-dopa on mood and anxiety were not related to relief of parkinsonism. Mood change preceded changes in tapping scores and started dropping before tapping scores deteriorated. There was no relationship between the amount of mood change, severity of parkinsonism, and the extent to which IPD improved during L-dopa infusion.

Parkinsons Disease

The clinical features of Parkinson's disease (PD) include bradykinesia, rigidity, tremor, postural instability, autonomic dysfunction, and bradyphrenia. The most frequent pathologic substrate for PD is Lewy body disease (2). Some cases of otherwise clinically typical PD have other disorders, such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) or vascular disease, but these are uncommon, especially when the clinical diagnosis is made after several years of clinical follow-up (3,4). The diagnostic accuracy rate has approached 90 in some series (5). The brain is usually grossly normal when viewed from the outer surface. There may be mild frontal atrophy is some cases, but this is variable. The most obvious morphologic change in PD is only visible after the brainstem is sectioned. The loss of neu-romelanin pigmentation in the substantia nigra and locus ceruleus is usually grossly apparent and may be associated with a rust color in the pars reticulata, which...

Depression in PD

The specific population assessed and the rating scales used. Of these, approximately half met criteria for major depression and the other half had chronic dysthymia. Another recent literature review between 1922 and 1998 by Slaughter, Slaughter, Nichols, and Martens (2001) found an overall prevalence of depression of 31 in patients with IPD. Between 20 and 60 of patients with IPD experience affective changes sometime during the course of their illness. Santamaria and Valles (1986) found that in 50 of the cases, depression preceded the motor manifestations by an average of five years. In general, depressed patients had a younger age of onset and were less physically disabled. Starkstein (1992) found depression to be more common in IPD with onset before age 55. Depressed patients with IPD have greater frontal lobe dysfunction and greater involvement of dopaminergic and noradrenergic systems than nondepressed patients with PD (Cummings, 1992). Although depression is more common among...

Is Levodopa Toxic

The notion that levodopa may be toxic to dopaminergic neurons leading to more rapid nigral degeneration has been a controversy for 25 years. It is based on a body of evidence that suggests that oxyradicals play an important role in the pathogenesis of cell death in PD (87). Evidence includes decreased glutathione, increased Fe2+, increased malondialdehyde, and decreased mitochondrial complex I activity in the substantia nigra (SN) (77). These changes appear to lead to apoptotic mechanisms of cell death (88). Dopamine, when metabolized by monoamine oxidase (MAO) or auto-oxidized, forms H2O2, a precursor to the toxic hydroxyl radical. In PD, after loss of a substantial number of nigral cells, those surviving neurons increase their dopamine metabolism, thus possibly increasing the risk of further free radical formation and neurodegeneration, especially in an environment where protective mechanisms such as glutathione are diminished and iron has accumulated. The use of levodopa may lead...

Jeanmartin Charcot And The Salpetriere School

Deformity Posture Parkinson

Working in Paris, in the second half of the 19th century, Charcot knew of Parkinson's description and studied the disorder in the large Salpetriere hospital that housed elderly and destitute women. He identified the cardinal features of Parkinson's disease and specifically separated bradykinesia from rigidity (5,16) FIGURE 12 Jean-Martin Charcot. Working in Paris, in the second half of the 19th century, Charcot knew of Parkinson's description and studied the disorder in the large Salpetriere hospital that housed elderly and destitute women. He identified the cardinal features of Parkinson's disease and specifically separated bradykinesia from rigidity (5,16) FIGURE 13 Statue of a parkinsonian woman by Paul Richer. Richer worked with Charcot, and, as an artist and sculptor, produced several works that depicted the habitus, joint deformities and postural abnormalities of patients with Parkinson's disease (14,17). FIGURE 13 Statue of a parkinsonian woman by...

Attention and Executive Functions

Attention and executive deficits in PD are most often ascribed to frontal lobe dysfunction secondary to striatofrontal deafferentation and, in particular, pathophysio-logical alterations in the basal ganglionic-dorsolateral frontal loops with medial nigral dopamine depletion impacting the caudate and its frontal projections (31). Performance on simple tasks of attention, for example, forward digit span, is most often preserved in patients with PD (32). On the other hand, deficits on tasks, requiring complex attention, planning, reasoning, abstraction, conceptualization, and cognitive flexibility, are more readily identified in PD. Deficits are most apparent on tasks that require spontaneous, self-directed information, processing strategy formulation and deployment (33). Executive dysfunction may account for some of the deficits observed on recall, verbal fluency, and visuoperceptual tasks (34), but it is unlikely that executive deficits alone can explain the range of cognitive changes...

Visuospatial Perception

Visuoperceptual impairments are thought to occur in early PD, even when motoric task demands are minimized (62,63) however, some argue that visuoperceptual impairments are secondary to deficits in set-shifting, spatial memory, bradyphrenia, and dexterity (34,64). Visuospatial impairments do not appear to improve with dopamine replacement and do not reliably vary with motor on and off periods. Thus, if dopamine impacts visuoperceptual abnormalities in PD, it is probably in conjunction with other neurochemical or pathophysiological processes (65).

Selective Serotonin Reuptake Inhibitors

Results from uncontrolled studies suggest that SSRIs are effective for anxiety in PD (42-44). In an open-label study (n 10), Menza et al. (42) reported that citalopram (mean dose 19mg d) improved anxiety in depressed PD patients. In a study of 30 patients, paroxetine (20 mg twice daily) reduced psychic and somatic anxiety symptoms, as well as depressive symptoms after six weeks (43). Sertraline was also found to have anxiolytic effects in PD patients (44). Although these data are derived from uncontrolled studies, many specialists prefer to use SSRIs for managing anxiety and depression in PD (49). The SSRIs are relatively well tolerated, although acute, treatment-emergent side effects such as agitation, diarrhea loose stools, insomnia, nausea, and sedation may occur. Occasionally, SSRIs may worsen tremor, and chronic use is associated with an increased risk of developing endocrinologic and metabolic adverse effects, such as hyponatremia, sexual dysfunction, and weight gain (Table 1)...

Neuropsychology Behavioral Neurology And Neuropsychiatry

Sir William Osler first used the term neuropsychology in 1913 however, neuropsychology, at least as a clinical endeavor, did not emerge as a subdiscipline of psychology until the 1940s, largely in response to demands for the assessment and rehabilitation of brain-injured soldiers in World War II (1). The likely first published use of a clinical neuropsychological test with persons having parkinsonian syndrome is Shaskin et al.'s (2) administration of the Wechsler Bellevue Scale, an intelligence scale, to postencephalitic parkinsonians. Neuropsychology shares with behavioral neurology and neuropsychiatry the goal of relating behavior to underlying brain structure and function (3). However, neuropsychology's principal clinical method, namely its standardized, quantitative, norm-referenced approach to the evaluation

Long Term Outcome of Treatment for Psychosis

Goetz and Stebbins (5) described 11 PD patients in a nursing home with hallucinations, all of whom were never discharged from the nursing home and died within two years. In an open-label extension of the U.S. double-blind clozapine trial, only 25 of completers died over a 26-month observational period. Forty-two percent were in nursing homes, 68 were demented, and 69 were still psychotic (4). A separate study of 39 parkinsonian patients, treated with clozapine for psychosis, found that only 15 had died over a span of five years and 33 had been admitted to nursing homes (115).

Progressive Supranuclear Palsy

PSP is an atypical parkinsonian disorder associated with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia first described by Steele-Richard-son-Olszewski (35). Frontal lobe syndrome and subcortical dementia are present in some cases. In contrast to PD, gross examination of the brain often has distinctive features. Most cases have varying degrees of frontal atrophy that may involve the precentral gyrus. The midbrain, especially the midbrain tectum, and to a lesser extent the pons, shows atrophy. The third ventricle and aqueduct of Sylvius may be dilated. The substantia nigra shows loss of pigment, whereas the locus ceruleus is often better preserved. The subthalamic nucleus is smaller than expected and may have a gray discoloration. The superior cerebellar peduncle and the hilus of the cere-bellar dentate nucleus are usually atrophic and have a gray color due to myelinated fiber loss (36). Microscopic findings include neuronal loss, gliosis and NFTs affecting...

Freezing And Other Gait Abnormalities

A slow, shuffling, narrow-based gait is one of the most characteristic features of PD (83). The parkinsonian gait reveals certain features that overlap with the gait disturbance associated with normal pressure hydrocephalus (84,85). In a study of 50 subjects older than 70 years, Sudarsky and Ronthal (86) established a principal cause of the gait disorder in all but seven subjects (essential gait disorder). They, but not others (87), suggested that this senile gait is related to normal pressure hydrocephalus. The gait and postural problems associated with PD probably result from a combination of bradykinesia, rigidity, loss of anticipatory proprioceptive reflexes, loss of protective reaction to a fall, gait and axial apraxia, ataxia, vestibular dysfunction, and orthostatic hypotension. When gait disorder, with or without freezing and postural instability, is the dominant motor dysfunction, lower body parkinsonism should be considered in the differential diagnosis (88). This syndrome is...

Transgenic Mouse Models

The development of transgenic animal models is dependent on identifying the potential role of genes of interest to the etiology of PD. A transgenic mouse is an animal in which a specific gene of interest has been altered through one of several techniques, including (i) the excision of the host gene (knock-out), (ii) the introduction of a mutant gene (knock-in), and (iii) the alteration of gene expression (knock-down, null, or over-expression). In PD, one source of transgenic targeting is derived from genes identified through epidemiological and linkage analysis studies. Alpha-synuclein and parkin are examples of genes that have been identified through linkage analysis in familial forms of parkinsonism. Once the transgene has been constructed, the degree of its expression and its impact on the phenotype of the animal depends on many factors, including the selection of sequence (mutant vs. wild-type), site of genomic integration, number of copies recombined, selection of transcription...

Tauopathies Including Progressive Supranuclear Palsy and Other Tau Related Disorders

The low molecular weight microtubule-associated protein tau has been implicated in a number of neurodegenerative diseases, including Alzheimer's disease, PSP, Pick's disease, frontotemporal dementia with parkinsonism (FTDP), and amyotrophic lateral sclerosis parkinsonism-dementia complex (ALS PDC) of Guam. Together these neurodegenerative diseases are referred to as tauopathies since they share common neuropathological features, including abnormal hyper-phosphorylation and filamentous accumulation of aggregated tau proteins (224). Reports have implicated either alternative RNA splicing (generating different isoforms) or missense mutations as mechanisms underlying many of the tauopathies. Therefore, transgenic mice have been generated that over-express specific splice variants or missense mutation

Epidemiologic Studies

Epidemiologic studies indicate a genetic contribution to the pathogenesis of PD. Laz-zarini et al. (11) found that the likelihood of persons in New Jersey having PD at age 80 years was about 2 for the general population and about 5 to 6 if a parent or sibling was affected. However, if both a parent and a sibling were affected, the probability of having PD increased to 20 to 40 . Marder et al. (12) assessed the risk of PD among first-degree relatives living in the same geographic region (northern Manhattan, New York, U.S.A.). They found a 2 cumulative incidence of PD to age 75 years among first-degree relatives of patients with PD compared with a 1 incidence among first-degree relatives of control subjects. The risk of PD was greater in male than in female first-degree relatives relative risk, 2.0 95 confidence interval (CI) 1.1-3.4 . The risk of PD in any first-degree relative was also higher for whites than for African Americans or Hispanics (relative risk, 2.4 95 CI 1.4-4.1). Rocca...

Evaluation Of Kindreds

Kindreds with a parkinsonian phenotype have been reported in the world medical literature since the 19th century (27). In a 1926 literature review, Bell and Clark (28) described 10 families with shaking palsy believed to be hereditary. They also provided 20 references of earlier accounts of familial paralysis agitans. In 1937, Allen (29) detailed an additional 25 families with inherited parkinsonism and speculated that the inheritance was autosomal dominant and probably the result of a single autosomal gene in about two-thirds of these kindreds. In 1949, Mjones (30) detailed eight pedigrees with inherited parkinsonism, some with atypical features such as myoclonic epilepsy. In the levodopa era (from the early 1960s to now), numerous reports described families with PD and parkinsonism-plus syndrome (31), including two large multigenerational kindreds known as the Contursi (32) and Family C (German-American) (33) kindreds. As molecular genetic techniques have improved, the importance of...

Clinical Molecular Genetic Testing

Commercial genetic testing for parkinsonian genes should be interpreted with caution. A positive finding contributes only to the probability that the person will become affected, because most mutations gain or lose function and are associated with age-dependent penetrance. Indeed, for most genes and mutations, the age-associated risk to carriers has yet to be formally described. Despite the explosive progress in genetic research, not all mutations in PD have been functionally validated and some rare variants could be benign polymorphisms. Technical problems in test-retest reliability may also occur. These issues should be carefully and comprehensively discussed with physicians and their patients who are seeking genetic advice, as well as with asymptomatic family members who are genealogically at risk. Patients and their families must continue contributing to genetic research to identify new genes, understand the molecular pathways affected, and develop new treatments. However, this...

Pharmacokinetics and Dosing

Anticholinergics are a diverse group of medications. The majority of the anticholiner-gic medications have good oral absorption, but precise figures on many are not known. In general, most have half-lives requiring at least twice and usually three times a day dosing. The antiparkinsonian effect of anticholinergics is largely attributed to centrally acting acetylcholine receptors (74). Most synthetic (tertiary) anticholinergics used in

Mechanisms of Action

Antiparkinsonian benefit is generally attributed to inhibition of central muscarinic acetylcholine receptors. For instance, Duvoisin and Katz reported an antiparkinsonian benefit to benztropine and scopolamine, both centrally acting anticholinergics, with an exacerbation of parkinsonism after a trial of physostigmine, a centrally acting anticholinesterase inhibitor. In contrast, peripheral anticholinergics (methyl scopolamine and propantheline) and a peripheral anticholinesterase (edrophonium) did not affect parkinsonian symptoms (74). Details of how centrally acting anticholinergics can modify PD symptoms, usually attributed to dopaminergic deficiency, remain unclear. Abnormalities in the central acetylcholine neurotransmitter system have been described in PD patients (87,88). An oversimplified, but clinically useful, conceptualization is that the anticholinergic use corrects an imbalance between dopamine and acetylcholine (89). The depleted nigrostriatal dopaminergic system in PD...

Introduction And History

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the cardinal motor manifestations of bradykinesia akinesia, rigidity, resting tremor, and postural instability, although nonmotor features play an important role as well, including cognitive, psychiatric, and autonomic features (1). Pathologically, there is a loss of nigrostriatal neurons in the substantia nigra pars compacta (SNpc), which is believed to represent a middle stage of the degenerative process that starts in the lower brainstem and olfactory nuclei and ascends throughout the cortex (2). Neuro-chemically, the key feature relating to current therapeutics and nigral cell death is a loss of dopamine (3). Levodopa (L-3,4-dihydroxyphenylalanine) is the cornerstone of symptomatic therapy for PD. It is a metabolic precursor of the neurotransmitter dopamine. Dopamine was synthesized in 1910 by Barger and Ewens, but not given its name until 1952, whereas D L Dopa racemate was first synthesized in 1911 (3-5)....

Motor Fluctuations And Dyskinesia Definitions

There is a loss of 50 to 60 of nigrostriatal neurons or a reduction in striatal dopamine concentrations of approximately 70 associated with the onset of clinical symptoms of PD (24). The surviving neurons can initially compensate with increased dopamine synthesis, but subsequently, with continued disease progression and neuronal loss, these mechanisms fail. What follows is the loss of the ability of nigrostri-atal neurons to store and release dopamine appropriately, followed by postsynaptic changes, both of which lead to a fluctuating response to levodopa (25). Glial cells can also convert levodopa to dopamine, but they lack the machinery for appropriate regulation (23). Hence, levodopa therapy leads to a substantial release of dopamine in the synapse in a pulsatile fashion. The levels of dopamine have been shown to be four-fold higher in the striatum of lesioned animals compared to normal, suggesting that a large pulse occurs in the synapse with oral medications in advanced disease...

Midbrain Dopamine Neurons That Express Calcium Binding Proteins

CR is closely related to CB and has significant similarities in the homology of the amino acid sequence (32,33). CR-immunoreactive neurons are much less frequently observed in the entire brain. Approximately 50 of CR-immunoreactive cells in the SN VTA complex also display TH-immunoreactivity (34,35). Within the midbrain, CR-immunoreactive cell bodies are more numerous in all the subdivisions of dopamine neurons of the VTA than in the SNpc. Within the SNpc, the CR-positive cells are more abundant in the dorsal tier of the SNpc than substantia nigra pars reticulate (SNpr) or substantia nigra pars lateralis (SNpl).

Historical And Literary Precedents

Boissier Sauvages

FIGURE 2 Fran ois Boissier de Sauvages de la Croix (1706-1767). Sauvages was cited by Parkinson himself and described patients with running disturbances of the limbs, scelotyrbe fes-tinans. Such subjects had difficulty in walking, moving with short and hasty steps. He considered the problem to be due to diminished flexibility of muscle fibers possibly his manner of describing rigidity (2,3). FIGURE 2 Fran ois Boissier de Sauvages de la Croix (1706-1767). Sauvages was cited by Parkinson himself and described patients with running disturbances of the limbs, scelotyrbe fes-tinans. Such subjects had difficulty in walking, moving with short and hasty steps. He considered the problem to be due to diminished flexibility of muscle fibers possibly his manner of describing rigidity (2,3). FIGURE 4 Wilhelm von Humboldt (1767-1835). The celebrated academic reformer and writer, von Humboldt, lived in the era of Parkinson and described his own neurological condition in a series of letters, analyzed...

Comparisons Between Dopamine Agonists

Tan and Jankovic (6) summarized 15 comparative trials between dopamine agonists, and reported conversion factors of 10 1 for bromocriptine to pergolide, 1 1 for pergolide to pramipexole, 1 6 for pergolide to ropinirole, and 10 6 for bromocriptine to ropinirole. Hanna et al. (56) followed 21 stable subjects on pergolide and switched them to pramipexole in a 1 1 ratio. Although not significant, levodopa dosages were reduced by 16.5 , and 13 of the 21 (62 ) subjects reported improvement with the change in regimen. Hauser et al. reported the conversion of stable subjects on levodopa and pramipexole to levodopa and ropinirole in a 1 3 mg ratio. A gradual transition was better tolerated than a rapid change (57). However, in retrospect, the difficulties reported by subjects may have been improved with a higher conversion factor for ropinirole. agonist potency would suggest bromocriptine x 10 pergolide pramipexole ropinirole x 6 on a mg mg basis. Perhaps a better measure of treatment response...

Clinical Trials Of Selegiline Datatop

The DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) study (70) evaluated 800 PD subjects randomized to receive selegiline 10mg day or placebo. The total Unified Parkinson's Disease Rating Scale (UPDRS) scores were improved in the selegiline-treated group compared with placebo at one month (2.1 vs. 0.1 P < 0.001) and at three months (1.6 vs. -1.3 P < 0.001). The motor UPDRS scores also improved significantly in the selegiline compared with the placebo group at one month (1.4 vs. 0.01, P < 0.001) and at three months (0.9 vs. -0.8 P < 0.001). In the DATATOP trial, selegiline delayed the need for levodopa by approximately nine months compared with placebo. Following selegiline withdrawal, there was no loss of benefit at one month but at two months, total UPDRS had worsened 3.2 points in selegiline-treated patients compared to 0.5 in placebo-treated patients (P < 0.001). Selegiline monotherapy slowed decline in parkinsonian disability in the DATATOP trial...

Selegiline And Mortality

The Parkinson's Disease Research Group of the United Kingdom (84) reported an increased mortality rate in PD patients randomized to levodopa and selegiline, compared to levodopa alone. Forty-four (17.7 ) deaths were observed in the lev-odopa group compared with 76 (28 ) deaths in the levodopa plus selegiline group, after a mean duration of 5.6 years (P 0.05). Methodologic questions were raised (85), and both groups had higher than expected mortality rates. Other studies have not reported higher mortality with selegiline. Analysis of the DATATOP trial and subsequent open-label extensions revealed an overall death rate of 17.1 (137 of 800), or 2.1 per year through a mean of 8.2 years of observation (86), and mortality rate was not affected by any of the treatments. Cumulative exposure to selegiline was not associated with increased mortality in the 13-year follow-up of the

Clinical Trials Of Rasagiline Tempo

Subjects with early PD (n 404) were evaluated in a phase III study called TEMPO (Rasagiline Mesylate TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients) (94). Subjects were randomized to receive rasagiline 1 mg day (n 134), rasagiline 2 mg day (n 132), or placebo (n 138), with the change in total UPDRS scores between baseline and 26 weeks as the primary outcome measure. Significant improvements in total UPDRS scores were observed for both rasagiline 1 mg day and rasagiline 2 mg day (-4.2 and -3.6, respectively) compared with placebo (P < 0.001 for each comparison) (94). Two-thirds of both rasagiline groups compared to approximately one-half of the placebo group were responders (defined as less than 3 points worsening in total UPDRS scores from baseline to week 26 P < 0.01 for each rasagiline group compared with placebo). Secondary endpoints including UPDRS motor and ADL subscales, and the Parkinson's disease quality of life scale (PDQUALIF), an assessment of quality...

First Generation Catecholomethyltransferase Inhibitors

Several of these early COMT inhibitors did undergo pilot testing in humans. N-butyl gallate (GPA 1714), a derivative of gallic acid, was found to be effective in alleviating signs and symptoms of PD when administered to 10 patients (28). The dose of levodopa was reduced by an average of 29 and the drug was also noted to alleviate nausea and vomiting. No significant adverse effects were noted in this initial study, but testing was eventually abandoned because of its toxicity (29). Another compound, 3,4-dihydroxy-2-methylpropiophenone (U-0521), demonstrated significant COMT inhibition in animal studies, but when it was administered orally to a single human in progressively increasing doses, it demonstrated no effect on ery-throcyte COMT activity (29).

Current Status Of Catecholomethyltransferase Inhibitors

Two COMT inhibitors are currently available for use as adjunctive therapy in PD, to be used in conjunction with levodopa and an AAAD inhibitor in patients, who have developed motor fluctuations with end-of-dose wearing off. Tolcapone is the more potent of the two and, with its longer T1 2 can be given on a TID basis. Its potential to produce hepatic failure has limited its use to individuals in whom entacapone has been ineffective or not tolerated (117). Because of the tolcapone-related safety issues, clinical use of COMT inhibition has largely centered on entacapone, despite its lesser relative potency. Because of its short T1 2 entacapone must be administered with each dose of levodopa. At first glance this seems inconvenient, but since it really does not entail any more frequent dosing than that already being employed for the levodopa, the inconvenience is more perceived than real. The additional one to two hours of on time per day that a COMT inhibitor typically affords to a...

The Future For Catecholomethyltransferase Inhibitors

The pathogenesis of motor fluctuations in individuals with PD receiving levodopa has been the subject of much speculation, but little certainty, over the years. Both peripheral and central mechanisms have been hypothesized. Both may actually be active, but it appears that most often the predominant mechanisms driving the pathogenic process are within the CNS. Evidence has begun to accumulate that with PD progression the dwindling number of surviving nigrostriatal dopaminergic neurons are unable to maintain the normal synaptic atmosphere of constant dopaminergic stimulation instead the environment becomes one in which dopamine receptor stimulation is intermittent, characterized by pulses of dopaminergic stimulation coincident with levodopa administration. It appears that this pulsatile stimulation may, in turn, incite a cascade of changes within the postsynaptic striatal spiny neurons that produces sensitization of glutamate receptors and altered motor responses (125,126). If this is...

Monoamine Oxidase Inhibitor Safinamide

A three-month controlled trial of safinamide in de novo and dopamine agonist treated patients was conducted (24). A median safinamide dose of 70 mg day (range 40-90 mg day) increased the percentage of parkinsonian patients that improved their motor scores by 30 compared to placebo (37.5 vs. 21.4 , P < 0.05). In a subgroup of 101 patients under stable treatment with a single dopamine agonist, addition of safinamide magnified the response (47.1 responders, mean 4.7-point motor score decrease P 0.05).

Agents With Novel Mechanisms Of Action

(GABA), enkephalin, and cholinergic (ACh) spiny neurons in the striatum. These neurons receive inhibitory dopaminergic input from the substantia nigra and then project to inhibit pallidal neurons as part of the indirect pathway of the basal ganglia. Therefore, in PD, dopaminergic cell loss results in disinhibition of striatal spiny neurons that subsequently overly inhibit the globus pallidus externus, which in turn overly stimulate the subthalamic and globus pallidus internus nuclei. This increased activity in the final basal ganglia outflow pathway finalizes PD symptoms. Antagonism of the adenosine A2A receptor appears to modulate GABA and ACh release in a manner that could counteract the deleterious effects of reduced dopaminergic stimulation (27).

Early Surgical Experiments

Lesion locations were varied, not just within the pallidum but within the basal ganglia. Some early evidence suggested the superiority of thalamotomy in resolving tremor and rigidity (7,14). These reports were later extended to specify ventrolateral (VL) and ventral intermediate thalamotomy (15,16). In 1967, the introduction of levodopa (17) led to a worldwide reduction in the use of pallido-tomy and thalamotomy to treat parkinsonism. Lesion surgery later re-emerged with a new role as a result of identification of new indications and new targets

Patient Selection Indications for Surgery

The modern incentive to re-evaluate surgical therapy for Parkinson's disease (PD) has been driven by the realization of the inadequacy of chronic dopaminergic replacement as a main strategy of treatment, namely that dopaminergic replacement treatment is associated with the development of disabling motor fluctuations and dyskinesia (21,22). With disease progression, in some patients, neither parkinsonism nor drug-related side effects can be managed optimally with medications and surgery may be warranted. The primary objective of the surgery is to alleviate dyski-nesia and motor fluctuations (pallidotomy or subthalamotomy) and tremor (thalamotomy).

Unilateral Pallidotomy

To date, the results of only two short, randomized, single-blinded trials of pallidotomy have been published. The most recent study showed improvements of 75 in contralateral dyskinesia, 45 with respect to complications of therapy (UPDRS IV), 36 in ipsilateral dyskinesia, and 34 in parkinsonism at six months follow-up compared with medical therapy in which these aspects generally worsened (41). In the other study (42), 37 patients, who were matched for age and severity of PD, were randomized to receive either unilateral pallidotomy within one month (n 19) or maximal medical therapy for six months (n 18). Although the nonoperated group showed an 8 deterioration of median UPDRS motor scores and no change in dyskinesia, the operated group showed 31 and 50 improvements in parkinsonism and dyskinesia scores, respectively. This group more recently showed that, as expected, unilateral pal-lidotomy is less efficacious in improving parkinsonism than bilateral subthalamic stimulation, reducing...

Unilateral Thalamotomy

There have been few long-term follow-up reports of thalamotomy in PD. Kelly (84) reported the 10-year follow-up of 60 parkinsonian patients who had thalamotomy between 1965 and 1967 and showed the sustained improvement in tremor and rigidity, but the continued progression of bradykinesia. Later, 12 patients were reported who also had a marked improvement or cessation in contralateral tremor without complications (15). A larger series of 103 patients operated between 1964 and 1969, also followed-up for 10 years, showed that overall 87 patients had a good effect and in only seven patients were tremor or rigidity not alleviated completely (29). In a more recent series from 1984 to 1989, all 36 patients underwent CT and microelectrode-guided VL thalamotomy and 86 showed complete cessation of tremor, with a further 5 showing a significant improvement up to 68 months of follow-up (85). The antitremor effect was shown to be maintained in one blinded retrospective study, following thalamotomy...

Bilateral Subthalamotomy

The effects of bilateral subthalamic nucleotomy were reported earlier than unilateral subthalamotomy. One early report of two patients claimed that small lesions in the dorsolateral STN could reduce the off motor UPDRS scores by over 68 , without inducing dyskinesia (111). Both patients were reported to have no complications and to have medication withdrawn. This group later reported that bilateral subthalam-otomy had been accomplished safely in five subjects (105). Detailed imaging was not presented. A larger series of seven staged bilateral and 11 simultaneous procedures was reported to show a 50 reduction in off parkinsonism, 36 reduction in on-period parkinsonian features, 50 reduction in dyskinesia, and 47 reduction in levodopa-equivalent medication at three years of follow-up. Three patients had severe long-term dysarthria, whereas 11 18 had intraoperative or transient postoperative mild chorea. In three cases, the chorea lasted for three to six months before resolving fully...

Deep Brain Stimulation Of The Thalamus

DBS of the thalamus has largely replaced thalamotomy as the preferred surgery for the treatment of medication resistant tremor. There are multiple reports demonstrating a significant reduction in tremor in 63 to 95 of patients receiving thalamic DBS for parkinsonian tremor (8-11) however, currently, it is rarely used for PD as the majority of the studies have reported that even though tremor is markedly improved, other symptoms continue to progress and cause significant disability (12,13). Therefore, this procedure is restricted to PD patients whose primary disability is tremor. Several studies have demonstrated long-term benefit in PD tremor with thal-amic DBS. Pollak et al. (14) reported 80 PD patients who had DBS of the thalamus for drug-resistant tremor. After up to seven years of follow-up (mean three years), global evaluations showed the best control for parkinsonian rest tremor and the least satisfactory control for action tremor. There was no dramatic effect on other symptoms...

Deep Brain Stimulation Of The Globus Pallidus Interna

Surgery targeting the internal segment of the globus pallidus has been shown to improve all of the cardinal features of PD including bradykinesia, rigidity, and tremor as well as levodopa-induced dyskinesia. Due to concerns of complications related to speech, balance, and cognition with bilateral pallidal lesions, bilateral DBS of the GPi is preferred to pallidotomy. Multiple studies have reported the efficacy of GPi stimulation for PD (15-20) (Table 1). Many of these studies have a small number of patients and or a relatively short follow-up period. Kumar et al. (19) reported 22 PD patients who were treated with either unilateral (n 5) or bilateral (n 17) GPi stimulation. Evaluations performed in the medication off stimulation on state at six months reported a 32 improvement in UPDRS motor scores and a 40 improvement in UPDRS activities of daily living (ADL) scores compared to baseline medication off scores. There was also a 68 reduction in dyskinesia. The Deep Brain Stimulation for...

Predictors Of Outcome After Subthalamic Nucleus Deep Brain Stimulation

Several studies have examined the factors predictive of a positive outcome after STN DBS (25,35,38-40). Charles et al. (38) examined 54 PD patients after bilateral STN DBS and found that age and preoperative levodopa response were the strongest predictors of outcome. In a study of 41 PD patients who had STN DBS, Welter et al. used regression analyses to identify age and disease duration as predictors of outcome. They found that patients 56 years of age or younger had a 71 improvement in UPDRS ADL and motor scores compared to improvements of 57 and 62 for those older than 56 years. Similarly, those with disease duration less than 16 years had significantly better responses to surgery than those with disease duration greater than 16 years. The authors concluded that in addition to age and disease duration, levodopa responsiveness was the strongest predictor of outcome after STN DBS. Kleiner-Fisman et al. (35) examined age, sex, disease duration, medication usage, dyskinesia, age of...

Deep Brain Stimulation Of The Globus Pallidus Interna Or The Subthalamic Nucleus

There are only a few studies that have directly compared patients who have undergone GPi or STN DBS and most of these studies are not randomized and the number of patients is small. Krack et al. (42) retrospectively compared eight patients who had STN DBS with five who had GPi DBS six months after surgery. In the medication off state, UPDRS motor scores improved by 71 with STN stimulation and by 39 with GPi stimulation and UPDRS ADL scores were also more improved in the STN group. Rigidity and tremor showed comparable improvement in both groups but bradykinesia was more improved in the STN group. There was a reduction in levodopa equivalence dose only in the STN group. Scotto di Luzio et al. (43) retrospectively compared nine patients who had undergone STN stimulation to five who had undergone GPi stimulation 12 months after surgery. UPDRS motor scores in the medication off stimulation on condition improved by 56.6 with STN stimulation and 41.7 with GPi stimulation. Both groups had a...

Patient Selection For Pallidal And Subthalamic Deep Brain Stimulation

The criteria for patient selection for DBS of the GPi and STN for PD are similar. The ideal candidate is a patient with idiopathic levodopa responsive PD who has medication resistant motor fluctuations and or dyskinesia. It is recommended that patients undergo a levodopa challenge. Generally, patients arrive at the clinic 12 hours after not taking any antiparkinsonian medications at which time they are evaluated with a complete UPDRS and other site-specific measures. After these evaluations either the regular dose of antiparkinsonian medication or at some sites a dose of levodopa 150 of the usual dose (without any other antiparkinsonian medication) is usually given and evaluations are repeated after the patient has reached the best medication on state. Usually, a 30 or greater improvement in UPDRS motor scores between the medication off and on conditions is required to recommend surgery. Patients older than 75 years are generally not considered candidates as they may have difficulty...

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