Dementia

Cognitive impairment is common in PD, especially in the domain of executive function (28). Such deficits are usually the earliest cognitive signs in PD (117). Patients or caregivers often report difficulties with decision making, planning, and completion of goal-directed behaviors. When these cognitive deficits worsen, and patients have impairment of occupational or social functioning, a diagnosis of dementia is made (13). At this point, it is unclear whether the presence of early cognitive...

Considering a Patient for a Surgical Procedure

Prior to enrolling a patient into a surgical program, it is generally recommended that patients are assessed by a neurologist with experience in movement disorders since it is essential to document that the patient does indeed have PD which cannot be medically managed. There have been a few case reports of the use of lesion surgery in the management of Parkinson-plus syndromes and the success rates are generally disappointing (23,24). Additionally, it is necessary to show that a patient has a...

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...

Measuring Sleep Disorders

Until 2002, there were no specific instruments to clinically assess sleep problems of PD in a comprehensive and holistic fashion. Existing sleep scales for other disorders, such as the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale, or the Karolinska Sleepiness Scale, are not specific for PD and have problems related to scale clinimetrics in relation to complexity and face validity when these are used in PD (66, 71-73). For instance, the PSQI, although quantifiable, does not...

Bradykinesia

Bradykinesia, or slowness of movement, is often used interchangeably with hypokinesia (poverty of movement) and akinesia (absence of movement). Bradykinesia is the most characteristic symptom of basal ganglia dysfunction in PD (19). It may be manifested by a delay in the initiation and slowness of execution of a movement. Other aspects of bradykinesia include a delay in arresting movement, decrementing amplitude and speed of repetitive movement, and an inability to execute simultaneous or...

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...

Nonwestern Medical Systems Traditional Chinese Medicine

Traditional Chinese Medicine (TCM) has existed for thousands of years, long before Western medicine. Rather than following the disease model of Western medicine, TCM focuses on a symptom approach such that a person with PD who has mostly tremor would be evaluated and treated differently than another person whose symptoms were mostly gait and balance difficulty with no tremor. The specific symptoms of the individual signal a deficiency in the body fluids blood that is unable to properly nourish...

Basal Ganglia Selection Theory

This theory posits that the basal ganglia are involved in the selection of motor programs. Bradykinesia and akinesia of PD results in the failure to select or engage appropriate motor programs, whereas levodopa-induced dyskinesia and other hyperkinetic disorders of the basal ganglia fail to suppress inappropriate motor programs (33). The genesis of this theory lies in the observations that most all interactions between nuclei of the basal ganglia are inhibitory with the exception of the output...

Ayurvedic Medicine

Ayurvedic medicine is the traditional medical system in India, which has existed for over 5000 years. The term Ayurveda literally means science of life or life knowledge. PD is documented to have existed in ancient India and was called Kampavata. Similar to the TCM system, physical illness is thought to result from emotional imbalance, unhealthy lifestyle, and toxins that ultimately upset the balance of the three doshas or regulatory systems of a person (5). These three doshas are vata, which...

Deep Brain Stimulation Of The Subthalamic Nucleus

Multiple reports have demonstrated the short-term benefits of STN DBS in controlling the cardinal features of PD and reducing dyskinesia and antiparkinsonian medications (16,24-31). One of the largest studies was conducted by the Deep Brain Stimulation for Parkinson's Disease Study Group (16). This was a multicenter study in which 96 PD patients received bilateral STN DBS and 91 completed the six-month follow-up visit. In the medication off stimulation on condition at six months compared to the...

Detection and Assessment

There are no reliable and empirically derived criteria for recognition of depression in PD. Therefore, it is not surprising that depression remains under-detected and under-treated in the PD population (15,71). In a clinic-based study, nearly two-thirds of patients with clinically significant depressive symptomatology were not receiving antidepressant therapy (11). Older individuals often underreport depressive symptoms and are likely to focus on somatic or vegetative complaints (e.g., fatigue...

Progressive Supranuclear Palsy

Prevalence rates of dementia in PSP range from 50 to 80 , but some authors contend that these numbers reflect over-diagnosis due to bradyphrenia, emotional problems, and visual dysfunction that accompany PSP. Cognitive deficits are seen in approximately 50 of patients with PSP (172), with the neuropsychological profile being typical of diseases with subcortical involvement, including slowed information processing, executive dysfunction, and information retrieval deficits (173). As compared to...

Treatment

There is a poor evidence base for the treatment of sleep problems in PD, and the issue is complicated by the fact that treatment of sleep problems in PD needs to take into account the multifactorial nature of sleep disturbances in PD. A review by the Movement Disorder Society Task Force reported that there were no robust trials of dopaminergic agents for the treatment of nonmotor symptoms in PD, including sleep (80). Only modafinil (for EDS) and melatonin (for insomnia) have been studied in...

Chelation

Chelation is typically used as an intravenous therapy (sometimes oral) to remove a particular substance that is found to occur at a toxic level in the body such as lead, copper, mercury, or arsenic. The amino acid complex, ethylene-diamine-tetra-acetic acid, is the most commonly used chelating agent, though herbs and supplements may sometimes be used. Though there is a higher incidence of PD occurring in persons with chronic exposure to heavy metals such as manganese and copper and also with...

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)....

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...

Naturopathy

Naturopathic doctors exist in large numbers in Europe, but are growing in the United States with established four-year accredited naturopathic schools and now over 1000 naturopaths practicing in America. Naturopathy incorporates many of the modalities of TCM and Ayurveda, such as acupuncture, herbs, nutrition, massage, and homeopathy with the goal of achieving a balance between one's physical, emotional, mental, and spiritual health by allowing the body and mind to heal itself through its own...

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)...

Specific Occupations And Parkinsonism

Numerous epidemiologic studies have attempted to detect occupations at high risk for developing PD. Fall et al. (65) performed an occupation case-control study and found an increased risk of PD in carpenters (OR 3.9), cabinet-makers (OR 11), and cleaners (OR 6.7), compared to a population-based control group. Tanner et al. (66) performed a case-control study (nonpopulation-based) of occupational exposures and PD in People's Republic of China and found that occupations involving industrial...

Autonomic Testing

An exhaustive review of the various tests of autonomic function in PD is beyond the scope of this chapter. Briefly, the tests that have been commonly employed in the study of PD autonomic failure include heart rate variation (with deep breathing and valsalva), tilt table testing for orthostatism, sudomotor axon reflex testing, and thermoregulatory sweat testing. Abnormalities may be seen in one or more of these depending on the presenting symptoms. Several studies have suggested that as a...

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...

Autonomic Dysfunction and Management

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Although Parkinson's disease (PD) is commonly regarded as a disorder of dopamine deficiency, it is actually a multisystem degenerative disorder. As nondopaminergic brain pathways are involved in the genesis of many symptoms, these cannot be successfully treated by merely increasing brain dopaminergic stimulation. The auto-nomic symptoms fall into this category, and thus management is often...

Other Motor Manifestations

There are many other motor findings in PD (Table 1), most of which are directly related to one of the cardinal signs. For example, the loss of facial expression (hypomimia, masked facies) and the bulbar symptoms (dysarthria, hypophonia, dysphagia, and sialorrhea) result from orofacial-laryngeal bradykinesia and rigidity (96). Respiratory difficulties result from a variety of mechanisms, including a restrictive component due to rigid respiratory muscles and levodopa-induced respiratory...

Conclusion

Sleep disorders in patients with PD are common (94). They are a key component of the nonmotor symptom complex of PD and remain under-diagnosed and under-treated. Sleep problems may arise from uncontrolled motor symptoms, degeneration of the neuroanatomical substrates responsible for the sleep-wake cycle or unwanted medication side effects. Routine assessment of patients with PD should include inquiry regarding the quality of sleep and sleep-related symptoms. Use of validated bedside clinical...

Dopamine Agonists And Dopamine Receptors

The dopamine agonists used in the treatment of PD include apomorphine, bromocrip-tine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, and rotigotine. All of these agents activate D2 receptors, whereas pergolide has been shown to be a mild D1 agonist, and pramipexole may have higher affinity for D3 receptors (Table 1). Five subtypes of dopamine agonist receptors have been identified and may be classified into striatal (D1 and D2) receptors or cortical (D3, D4, and D5) receptors. The...

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...

Exercise

An endless list of available exercises to consider for overall health promotion exists (i.e., weight lifting, conditioning, isometric pilates, aerobic, stretching, martial arts, specific sports, etc.). Exercise can positively impact any person's health and in particular a person with PD by increasing muscle strength (thereby increasing one's ability to get up, walk, swallow, speak, and breath), flexibility (reducing muscle rigidity joint stiffness and increasing range of motion), and bone...

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

Vesicular transporters transport neurotransmitters into vesicles of nerve terminals and neuroendocrine cells and make them available for regulated release. VMAT1 is localized predominantly in the neuroendocrine cells, whereas VMAT2 is widely distributed in monoaminergic terminals and dendrites. In the dopaminergic nerve terminal, VMAT2 transports cytoplasmic dopamine and 1-methyl-4-phenylpyridium (MPP+) into the vesicles (16). Dopamine that is not incorporated into the vesicles gets oxidized...

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 rate are the incidence of new cases and life expectancy. Crude prevalence rates are greatly affected by the age distribution of the source population age-adjusted...

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...

Kelly E Lyons and Rajesh Pahwa

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A. Stereotactic surgeries for movement disorders were introduced in the late 1940s (1-3) but were not widely accepted due to significant morbidity, mortality, and limited knowledge of the appropriate target for symptomatic benefit. With advances in pharmacological therapy, particularly the availability of levodopa, these surgeries were rarely performed for Parkinson's disease (PD) until the late 1980s (4)....

Cholinesterase Inhibitors

In multiple AD trials, cholinesterase inhibitors had mild-to-moderate benefits in both cognition and psychosis (101,102). Cholinesterase inhibitors are also effective for psychosis in DLB patients and are a potential alternative to the atypical antipsy-chotics for PD psychosis. An early open-label study with tacrine showed that five of seven demented PD patients had complete resolution of psychotic symptoms (103) however, the use of this drug has been limited because of hepatic toxicity....

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...

Sleep Benefit and Sleep Hygiene

Sleep benefit is a common phenomenon of variable duration ranging from 30 minutes to 3 hours in PD and implies improvement in mobility and motor state in the morning and after drug intake at night (98). The mechanism of sleep benefit is unknown, and possible causes include (i) recovery of dopaminergic function and storage during sleep, (ii) a circadian rhythm-related phenomenon, or (iii) a pharmacological response to dopaminergic drugs (7,30). Good sleep hygiene is also useful. Activities such...

Transcription Factor Pitx3

Yet another clue to the factor(s) that render the dopamine neurons of the SNpc vulnerable to neurodegeneration in PD is obtained from the studies on the role of the transcription factor Pitx3 in aphakic mice. Aphakic mice have small eyes with no lens and a loss of development of the anterior chamber of the eye (57,58). The clinical features of the aphakic mice result from a deletion of a large segment of the promotor region, exon 1, and intron regions of the Pitx3 gene (58). In addition to the...

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is an effective treatment for primary psychiatric disorders, especially treatment-resistant depression. Experience with ECT for PD psychosis, however, is limited to case studies. ECT has been demonstrated to be beneficial in PD patients with psychosis (112-114), and can transiently improve parkinsonian motor symptoms, but may require a period of hospitalization, and result in significant confusion. ECT should only be considered when patients are resistant to...

Common Approaches To Neuropsychological Evaluation

Neuropsychological assessment approaches fall broadly into three categories (i) the fixed battery (or cognitive-metric) approach (ii) the process (or hypothesis-testing) approach and (iii) the flexible battery approach. These approaches can readily be conceptualized as differing along two dimensions test selection and administration interpretation. Test selection may be fixed or flexible administration and interpretation are characterized, respectively, as standardized and actuarial at one...

Benzodiazepines

Although benzodiazepines are commonly used in the management of anxiety, only one randomized controlled trial addressed this in the PD population (40). Bromazepam, a long-acting benzodiazepine, was reported to improve psychic and somatic (i.e., tremor) symptoms of anxiety. Anecdotally, other benzodiazepines have also been noted to be effective. Clonazepam was reported to be effective in a patient with anxiety and panic attacks that were refractory to alprazolam, lorazepam, and numerous...

Proteasome Inhibitors

An important regulatory system within cells is the ubiquitin proteasome system (UPS), a large enzymatic complex involved in detoxification and degradation of ubiquitin-tagged proteins (125,126). Inhibition of the UPS can lead to the inability to remove toxic protein moieties, accumulation of protein aggregates, neuronal dysfunction, and cell death (127,128). The identification of genes involved in familial forms of parkinsonism, especially parkin (an E3 ligase of UPS) and UCH-L1 (ubiq-uitin...

Physiologic Measures of Laryngeal Dysfunction in Parkinsons Disease

Disordered laryngeal function has been documented in a number of videoendo-scopic and videostroboscopic studies. Hansen et al. (22) reported vocal fold bowing resulting in poor glottic closure in 94 of 32 PD patients, together with greater amplitude of vibration and laryngeal asymmetry. Smith et al. (41), using videostro-boscopic observations, found that 57 of 21 PD patients had a form of glottal incompetence (bowing, anterior or posterior chink) on fiberoptic examination. Perez et al. (42)...

Sexual Dysfunction

Though PD patients rarely complain of sexual difficulties, if specifically asked, dysfunction in this area is very common. Bronner et al. (65) performed a comprehensive assessment of sexuality in 75 patients (32 women, 43 men) with PD who did not complain of problems in this area. Using specific sexual function scales, they asked patients to rate their sexuality currently and retrospectively before the onset of their PD. They found that in men, 68 had erectile dysfunction, 65 were dissatisfied...

Neurotoxicantinduced Models Of Parkinsons Disease 6Hydroxydopamine

6-OHDA or 2,4,5-trihydroxyphenylethylamine is a specific catecholaminergic neu-rotoxin structurally analogous to both dopamine and noradrenalin. Acting as a false-substrate, 6-OHDA is rapidly accumulated in catecholaminergic neurons. The mechanism of 6-OHDA toxicity is complex and involves alkylation rapid auto-oxidization leading to the generation of hydrogen peroxide, superoxide, and hydroxyl radicals and impairment of mitochondrial energy production (5,6). The 6-OHDA-induced rat model of PD...

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...

Neuronal Mechanisms Of Subthalamic Nucleus Deep Brain Stimulation

One of the first hypotheses regarding the neuronal mechanism of action of DBS is that DBS inhibits activities within the stimulated target. A number of studies demonstrated that activity in structures receiving input from the DBS target was consistent with increased, not decreased, output from the stimulated structure. An example of GPi activity before, during, and after STN DBS in a nonhuman primate is shown in Figure 4. Note in this example, there is a significant reduction of neuronal...

Alpha MethylPara Tyrosine

Although less commonly used, AMPT, like reserpine, serves as an effective catecholamine-depleting agent (4). By directly inhibiting tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, the nascent synthesis of dopamine in neurons of the SNpc and ventral tegmental area (VTA) is prevented. Both reserpine and AMPT have been used to discover new dopaminomimet-ics for the treatment of PD, but since their effects are transient (hours to days), these models are primarily useful for...

Anxiety Epidemiology

In James Parkinson's original monograph, An Essay on the Shaking Palsy, little mention was made of the nonmotor symptoms of anxiety and depression (14). However, it is now known that clinically significant anxiety symptoms occur in 20 to 52 of PD patients, a frequency greater than that found in community dwelling age-matched controls (1,15-17). Menza et al. (18) reported a depressive disorder in 92 of PD patients diagnosed with an anxiety disorder, and an anxiety disorder was present in 67 of...

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...

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...

Other Pharmacologic Agents

Few other pharmacologic strategies for specifically treating dementia in PD have even been reported. Because noradrenergic depletion could contribute to executive dysfunction in PD, Bedard et al. (170) conducted a trial of naphtoxazine (SDZ-NVI-085), a selective noradrenergic alpha 1 agonist, versus placebo in nondemented patients with PD. The results of the study demonstrated improved performance on tasks of set-shifting and cognitive flexibility, such as the Stroop and Odd-Man-Out tests....

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...

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...

Intracerebral Drug Infusion Glial Cell Line Derived Neurotrophic Factor

Glial cell line-derived neurotrophic factor (GDNF) was first identified in the early 1990s as a member of the transforming growth factor (TGF)-beta superfamily with potent effects on embryonic neuronal cultures and specifically on dopaminergic cell lines (29). It was subsequently found to be potently expressed in the developing rodent striatum (30). Its potential as a possible agent for the protection of dopamin-ergic projections was quickly recognized and there was investigation into the...

Assessment Of Disability

The assessment of PD is difficult, because it is expressed variably in an individual patient at different times and it is influenced by emotional state, response to medication, and other variables. Moreover, there is a marked interpatient variability of symptoms and signs. To study this heterogeneity and to determine possible patterns of clinical associations, we analyzed the clinical findings in 334 patients with PD and identified at least two distinct clinical populations of parkinsonian...

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...

Excessive Daytime Sleepiness

In PD, severe EDS needs treatment, and first concurrent medications that may be sedating should be eliminated or reduced (Table 5). Modafinil (100-400 mg day), a nonaddictive sleep-wake cycle activator, is nonstimulating and the only drug that has shown efficacy in improving EDS in double-blind, placebo-controlled trials (87,88). A seven-week, double-blind, placebo-crossover study of modafinil (200 mg) followed by a four-week open-label extension (200 and 400 mg) study by Adler et al. (88)...

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...

Urinary Bladder Dysfunction

The most frequent urinary complaints in PD patients are frequency, urgency, urge incontinence, and nocturia. Hobson et al. (58) performed a community-based questionnaire survey in Wales, U.K., and found that bladder problems were reported in 51 of 123 PD patients returning the survey compared to 31 of 92 controls. The calculated relative risk of developing bladder symptoms in PD patients compared to controls was 2.4. Lemack et al. (59) performed a similar questionnaire-based assessment of...

Anticholinergics and Cholinesterase Inhibitors

Anticholinergic medications used to treat motor symptoms in PD potentially produce adverse effects on memory, executive functions, and global cognitive abilities. In placebo-controlled studies, Bedard et al. (114,115) found anticholinergics to induce executive deficits in PD, but not in control participants. Although anticholinergic-induced memory decrements are observable even in patients without preexisting cognitive impairments (116), Saint-Cyr (117) found that confusional states are more...

Massage Therapy

Massage therapy involves the use of a therapist's hands and sometimes elbows and knees or in some cases hand-held wooden thumbs or rocks along with special ointments and aromas that are directly applied to the body's muscles and soft tissues (5). Its origins date back to over 4000 years as a form of TCM therapy to promote health and prevent disease. It is also a primary treatment in the Ayurvedic system. Similar to acupuncture theory, the direct manipulation of the body tissues is thought to...

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...

Chiropractic

Chiropractic theory is similar to TCM and Ayurveda in that it views the body as having an innate ability to heal itself and naturally adapt to changes in its internal and external environments to maintain a natural state of health. Chiropractic practitioners focus on the nervous system knowing that the brain sends messages through the spinal cord to all the organs, muscles, blood vessels, and cells of the body. The nervous system helps to coordinate and regulate a vast array of chemical...

Girk2 Mutation

Phenotypically, the weaver mouse exhibits profound ataxia resulting from a near total loss of granule cells in the cerebellum (76-78) tremor resulting from a 70 loss of dopamine in the dorsolateral striatum due to selective degeneration of dopamine neurons of the SNpc (79) male infertility due to degeneration of Sertoli and sper-matogenic cells (80) and seizures possibly due to hippocampal abnormalities and hypothyroidism (81,82). An A153G point mutation, in the pore forming the H5 region of a...

Selegiline and Rasagiline

Selegiline and rasagiline, selective monoamine oxidase-B (MAO-B) inhibitors, have been hypothesized to exert a neuroprotective effect in PD by way of reducing physiologic stress associated with MAO-B oxidation of dopamine. Along with improvement in motor functions, several small, uncontrolled studies have found selegiline to be associated with improved global cognitive functioning, P300 latencies, and or memory in patients with PD (137-140). In contrast, selegiline was reported not to...

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...

Anatomy The Basics For Circuitry

This section reviews the basic anatomical interconnections between neurons that make up the basal ganglia-thalamic-cortical circuits. The anatomy is discussed only to a level of detail necessary for conceptual understanding of current models of function and dysfunction and for possible futures theories. This section will neither cover a fine-grained analysis of interconnections nor the histology for reviews see Refs. (8-12) . Traditional approaches to the anatomy of the basal ganglia have been...

Surgical Complications

Surgical complications are those that occur within 30 days of surgery. These complications are typical of those seen with other intracranial stereotactic procedures and generally occur in less than 5 of the patients. These complications include hemorrhage, ischemic lesions, seizures, infections, and misplaced leads. Several studies have focused on the examination of surgical complications related to DBS. Beric et al. (46) reported 86 patients who received 149 DBS implants in the VIM nucleus of...

Psychosis

Psychosis is a disorder characterized by hallucinations, delusions, or disorganized thinking (13), and is estimated to occur in 20 to 40 of PD patients (14,15). The most common manifestations of psychosis in PD are visual hallucinations (14,16-18). Although visual hallucinations are a common feature of patients with dementia with Lewy bodies (DLB), and may occasionally occur in demented PD patients who are not taking medications, the vast majority of PD patients who develop psychotic symptoms...

Atypical Antipsychotics

Atypical antipsychotics are typically used to treat psychosis in PD. Table 1 provides a summary of atypical antipsychotic studies in PD. The United States Food and Drug Administration (FDA) recently asked all atypical antipsychotic manufacturers to add a boxed warning to their product labels, saying that atypical antipsychotics, when used in elderly patients with dementia, were associated with a higher risk of mortality (54). However, since the deaths were primarily due to cardiovascular or...

Welding

Some materials safety data sheets (MSDS) for welding consumables list parkinsonism as a potential hazard of welding, although the data upon which this claim is based is unclear. There are several clinical reports (80,83-85) of parkinsonism in welders, although many patients had atypical features, including cognitive abnormalities, disturbances of sleep, peripheral nerve complaints, and mild motor slowing. In a study of magnetic field exposed workers, Noonan et al. (70) found that welders were...

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...

Epidemiology And Symptoms

Sleep dysfunction in PD is multifactorial, and as many as 98 of patients with PD may suffer at some time from nocturnal symptoms that can disturb their sleep (2). Overall prevalence figures range from 25 to 98 (2-4). A community-based study reported 60 of PD patients with sleep problems, compared with 33 of age- and sex-matched healthy controls (4). The NMSQuest study in 123 PD patients across all age groups and 96 age-matched controls, using a validated nonmotor symptom questionnaire in an...

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,...

[123IMetaiodobenzylguanidine Scintigraphy

123I Metaiodobenzylguanidine (MIBG) is a norepinephrine analog, which is transported into and stored in the terminals of sympathetic nerve endings. MIBG uptake is expressed as a ratio of single photon emission computed tomography signal in heart to that of the upper mediastinum. The lower the ratio, the fewer are the functioning sympathetic nerve terminals in the heart. A number of studies have looked at the sympathetic innervation of cardiac muscle in PD patients using this technique, and all...

Detection and Recognition

No standardized tool or method has been specifically developed to detect and assess anxiety in the PD population. Detection may be problematic, because several symptoms of anxiety overlap with mental and somatic symptoms commonly associated with PD. The Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for GAD in the general population includes a period of at least six months with prominent tension, worry, and feelings of apprehension about everyday events...

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...

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...

Deep Brain Stimulation

Nonablative surgical procedures for treatment of PD involve either unilateral or bilateral implantation of high-frequency stimulation electrodes into deep brain nuclei. Studies detailing neuropsychological outcomes after unilateral globus pallidus (GPi) deep brain stimulation (DBS) have supported the neurobehavioral safety of this technique (113,157), although a few studies have demonstrated minor postoperative declines in verbal fluency (158-160). The majority of studies indicate that even...

Incidence Of Parkinsonism

Incidence is defined as the number of new cases per year and is usually described per 100,000 people. Conducting an incidence study requires not only defining cases but also determining which are the new cases. Some new onset cases that ought to be included may not be recognized until sometime later. As well, the number of new cases in a community may vary from one year to the next. Consequently, incidence studies require a long period of observations in the same community using consistent case...

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...

General Treatment of Dementia

Similar to the guidelines governing the general treatment of psychosis, any sudden change in cognition or behavior is most likely due to a medical cause. Therefore, infections, metabolic and endocrine derangements, and hypoperfusion states should be considered and treated if present. A switch to an unfamiliar environment may also precipitate an acute deterioration in cognitive status, and can be helped to a small degree with reassurance and frequent orientation. Substance abuse, including...

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...

Clinical Uses

Amantadine is generally considered as a mild antiparkinsonian agent, with effects on tremor, rigidity, and bradykinesia, and a well-tolerated side-effect profile. It is used in early PD when considering levodopa sparing strategies or when symptoms are mild enough not to warrant more aggressive therapy. Amantadine has been studied in early PD as monotherapy, and in combination with anticholinergics in limited series and small controlled studies, with relatively short follow-up (18-20). However,...

Assessment of Efficacy

Overall, based on clinical experience and the available scientific data, SSRIs and TCAs may be considered useful for the treatment of depression in PD, and the agent that provides the best overall clinical benefit-to-risk profile should be selected (168). Amoxapine and lithium should be avoided, given the propensity of these agents to worsen motor symptoms and the availability of safer agents (169,170). Additionally, the nonselective MAO inhibitors (e.g., isocarboxazid, phenelzine, and...

Antioxidants CellSupporting Agents

A number of theories as to what causes PD at the cellular level include oxidative stress and free radical formation, mitochondrial impairment, intracellular protein clumping, inflammation, apoptosis (programmed cell death), and excitotoxicity (5). Many of the prescribed supplements, minerals, and vitamins by alternative practitioners are based upon these theories and the belief or hope that cellular function will be restored and or future brain cell injury prevented with their use. Currently,...

Constipation

Constipation is a very common complaint among patients with PD and is probably multifactorial in origin. Frequency estimates vary, but in one study of 94 patients, 71 were constipated as defined by less than one bowel movement in three days (44). Although the neuropathology of PD itself is a major causative factor, these authors pointed out in addition that PD patients have a significantly reduced water intake per day when compared with controls. Further questioning of these constipated PD...

Risk Factors for Dementia in Parkinsons Disease

Various demographic and disease variables predict PDD (Table 3). More recent work suggests that neuropsychological evaluation may also facilitate early identification of PDD. Jacobs et al. (91) and Mahieux et al. (92) noted that poorer performance by TABLE 3 Risk Factors for Dementia in Parkinson's Disease Diminished cognitive test performance Executive Attention Verbal fluency Visuoperceptual List learning Lower socioeconomic status Family history of Parkinson's dementia Disease severity...

Drugs For Dyskinesia Sarizotan

Sarizotan (Merck KgaA) is a novel compound belonging to the aminomethyl chro-mane chemical group, which was initially developed as an atypical antipsychotic, but is now being evaluated to treat dopaminergic-induced dyskinesia in PD. The drug has affinity for 5-HT1A, D2, D3, and D4 receptors. After oral ingestion, it is rapidly absorbed and highly protein bound, but readily crosses the blood-brain barrier. The terminal serum T1 2 is approximately seven hours, and the drug is extensively...

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...

Hardware Related Complications

Several reports have also focused on hardware complications related to DBS. Beric et al. (46) examined complications for 86 DBS patients and found electrode failure in 3.5 (n 3), extension wire failure in 4.7 (n 4), IPG malfunction in 1.2 (n 1), and pain at the IPG in 1.2 (n 1). Kondziolka et al. (49) examined hardware complications in 66 patients undergoing unilateral thalamic DBS for either essential tremor, parkinsonian tremor, multiple sclerosis, or other forms of tremor. There were a total...

General Treatment of Psychosis

The management of the psychotic PD patient begins by searching for correctable causes, including infection, metabolic derangements, social stress, and drug toxicity. Infections may not always cause fevers in the geriatric population, so a search for urinary tract infections or pneumonias is warranted. Some PD patients who did not manifest psychotic symptoms at home may decompensate upon moving into the hospital environment. In many of these cases, moving the patient into a secure familiar...

Geographic Differences In Rates Of Parkinsons Disease

Population-based prevalence and incidence studies can provide an indirect indication of potential environmental etiologies of PD, although it is impossible to compare between studies of different populations, given that genetic differences could account for the differing prevalence. Within a population, however, these studies can provide critical clues to environmental risk factors. A higher prevalence of PD in rural environments implicates regional farming practices, including pesticides,...

Incidence Prevalence and Risk Factors

Estimates of incidence and prevalence of dementia in PD vary widely because of different definitions, methods of ascertainment, and study designs. Prevalence rates of dementia in hospital- or clinic-based cohort studies range from 11 to 22 (123-125), whereas population-based estimates are somewhat higher, ranging from 18 to 44 (9,126-129), perhaps reflecting referral bias. A recent systematic review of the literature estimated that the prevalence of dementia in PD ranges from 25 to 31 (130)....

Neuroprotective Effects Of Monoamine Oxidase Inhibitors

Neuroprotective effects of the MAO-B inhibitors, selegiline and rasagiline, are dependent on their propargyl moiety and independent of their MAO inhibitory properties. The selegiline metabolite, desmethylselegiline, is responsible for the potential neuroprotective effects of selegiline. The S-isomer of rasagiline, TVP 1022, is one thousand times less potent at inhibiting MAO-B, yet demonstrates similar potential neuroprotective effects (27). Both selegiline and rasagiline have demonstrated...

Pathophysiology of Dementia

There is controversy regarding which features are the primary contributors to dementia in PD. PD is characterized by cell loss in the substantia nigra pars compacta (SNc), resulting in loss of dopaminergic input into the striatum. Several pathological and functional imaging studies have shown that in PD, there is greater depletion in the lateral compartment of the SNc, which projects to the putamen, than in the medial compartment, which projects to the caudate (139-141). Cognitive impairment is...

Sialorrhea

The presence of excessive saliva in the mouth with resultant drooling is a common problem in PD with estimates of up to 77 of patients being affected (31). When severe, patients will often complain bitterly about the problem and may request drug treatment to deal with it. Although the clinical impression of the physician is often that the patient has too much saliva, this turns out not to be the case. Proulx et al. (38) studied 83 PD patients and 55 controls by collecting saliva secreted over a...

Summary

Autonomic symptoms are common in patients with PD, though often under-recognized. As in the case of constipation, evidence for autonomic dysfunction may precede the onset of motor features by years however, most autonomic symptoms increase in severity with the progression of motor disability. Careful attention by treating physicians to the autonomic features of PD is necessary in order to recognize these problems early and begin treatment in a timely fashion. In most areas of autonomic...

Anxiety

Anxiety disorders are seen in approximately 40 of patients with PD (109). Despite their frequent occurrence and contribution to morbidity and caregiver burden (11), anxiety symptoms in PD have received relatively little attention, perhaps because they overlap with symptoms of depression, PD, and medication effects, and are thus difficult to measure (110). The relationship between anxiety and cognition in PD has received virtually no attention. Ryder et al. (111) found that self-reported...

Mechanisms

The underlying mechanism for depression in PD remains poorly understood, but the phenotypic expression of depressive disorders has been attributed to a combination of medical, neurochemical, and psychosocial phenomena. Depression may be a reactive response or demoralization phenomenon associated with the diagnosis of PD and its relative disability. However, when compared with patients with other chronic disabling conditions matched for functional disability, patients with PD exhibit greater...

Methyl4Phenyl1236Tetrahydropyridine

The inadvertent self-administration of MPTP by heroin addicts in the 1980s induced an acute form of parkinsonism whose clinical and biochemical features were indistinguishable from idiopathic PD (35,36). Like PD, this MPTP cohort demonstrated an excellent response to levodopa and dopamine agonist treatment but developed motor complications within weeks. The rapidity with which these motor complications appeared presumably reflected the severity of substantia nigra neuronal degeneration induced...

Pathophysiology of Psychosis and Risk Factors

The pathophysiology of psychosis in PD is poorly understood, but dopaminergic and serotonergic mechanisms have been proposed. One theory is that chronic excessive stimulation of dopamine receptors, particularly in the mesolimbic mesocorti-cal pathways, causes hypersensitization, resulting in psychosis when patients are treated with dopaminergic agents (36). However, exogenous dopamine supplementation by itself is not the only factor in the development of psychosis since all PD medications...