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...

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...

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...

Initiation Of Dopamine Agonist Therapy

Dopamine agonists provide substantial improvement in PD symptoms while delaying the development of motor fluctuations and dyskinesia (32,42,58). Similar trials comparing dopamine agonists (pergolide, pramipexole, ropinirole) to levodopa in a randomized fashion suggest possible long-term benefit according to the functional imaging measures (2,3). The reduction in striatal and nigral decline in F-dopa and -CIT uptake suggest these agents have some benefit over levodopa for up to 46 months of...

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...

Bilateral Pallidotomy

Laitinen (57) and Iacono et al. (70) reported early good outcomes in 12 and 10 bilaterally operated patients, respectively. There are, however, concerns regarding permanent cognitive and bulbar side effects of bilateral pallidotomy, which have been confirmed in a study of four patients in whom bilateral pallidotomy was performed (71). Despite a 40 improvement in motor UPDRS scores and resolution of dyski-nesia, one patient developed dysarthria, dysphagia, and eyelid opening apraxia, TABLE 1...

References

An Essay on the Shaking Palsy. London Sherwood, Neely, and Jones, 1817. 2. Lang AE, Obeso JA. Challenges in Parkinson's disease restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol 2004 3 309-16. 3. Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson's disease diagnosis and management. Lancet Neurol 2006 5 235-45. 4. Ford B, Louis ED, Greene P, Fahn S. Oral and genital pain syndromes in Parkinson's disease. Mov Disord 1996 11 421-426. 5....

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...

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...

Hypertensive Crisis

Tyramine is a sympathomimetic amine normally metabolized by gut MAO-A. When tyramine rich foods such as red wines, pickled herring, or aged cheeses are ingested by someone taking an irreversible MAO-A inhibitor (clorgyline) or nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine), the tyramine is absorbed rather than metabolized, causing norepinephrine release and potentially hypertensive crisis (26). This is known as the cheese effect. Levodopa is contraindicated with MAO-A or...

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...

Globus Pallidus Internal Segment Suppression Theory

This theory posits that the loss of SNpc dopamine neurons causes decreased activity in the striatal neurons of the direct pathway. This results in a reduction of inhibition of GPi neurons, which in turn results in increased inhibition of the VL thalamus and a reduction of excitation of the MC and SMA, thus providing an explanation of loss and slowing of movements (Fig. 1). Loss of SNpc dopaminergic drive to striatal neurons of the indirect pathway results in decreased inhibition of these...

Corticobasal Degeneration

Corticobasal degeneration (CBD) is only rarely mistaken for PD due to characteristic focal cortical signs that are the clinical hallmark of this disorder. Common clinical presentations include progressive asymmetrical rigidity and apraxia, progressive aphasia, and progressive frontal lobe dementia (43). Most cases also have some degree of parkinsonism, with bradykinesia, rigidity, and dystonia more common than tremor. Given the prominent cortical findings on clinical evaluations, it is not...

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...

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...

Unilateral Subthalamic Nucleotomy

The occurrence of cognitive deficits that have been reported with thalamotomy and pallidotomy, and the failure of thalamotomy to improve features other than tremor, has driven an interest in trying to find alternative targets to lesion, especially for patients who require bilateral procedures and are not suitable for DBS. The realization that the neurons of the STN in parkinsonian monkeys are over-active led to an interest in this nucleus as a possible target for PD (98). Surgeons had...

Unilateral Thalamotomy

Thalamotomy has been performed since the 1950s when some surgeons noted excellent relief of tremor compared with pallidotomy (anterodorsal). Hassler et al. (77) reported the successful treatment of a patient by making a lesion in the ventral tier of lateral thalamus, and Cooper also advocated that this was the optimal target (14). The VL region of the thalamus contains at least three important motor nuclei. According to Hassler's classification and running from anterior to posterior, these are...

Symptoms And Management Of Autonomic Dysfunction In Parkinsons Disease Orthostatic Hypotension

A significant drop in systolic blood pressure when moving from sitting or lying to the standing position is undoubtedly one of the most important symptoms of autonomic failure seen in PD. Orthostatism can be either symptomatic, in which patients complain of lightheadedness, dizziness or actual syncope, or asymptomatic in spite of significant drops in systolic blood pressure. When symptomatic, orthostatic hypotension can lead to significant disability including wheelchair or even bed...

Mentation Behavior And Mood History

Consistent forgetfulness with partial recollection of events and no other 2 Moderate memory loss, with disorientation and moderate difficulty handling complex problems. Mild but definite impairment of function at home with need of occasional prompting. 3 Severe memory loss with disorientation for time and often to place. Severe 4 Severe memory loss with orientation preserved to person only. Unable to make judgments or solve problems. Requires much help with personal care. Cannot be left...

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...

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...

Lsvt 5 Concepts And Techniques

(voice focus, high effort, intensive, sensory calibration, quantification) problems sustaining attention problems shifting cognitive set problems in procedural memory Laryngeal valving (ROM, stability) LOUD (effort, coordination) FIGURE 2 This figure graphically summarizes the rationale underlying the five essential concepts and techniques of the Lee Silverman Voice Treatment (LSVT ) from a neural, speech mechanism physiology, motor learning, muscle training, neuropsychological, and compliance...

Therapy Evaluation

Evaluation of the PD patient is focused on determining the patient's functional limitations. Range of motion, strength and balance deficits, postural deviations, general mobility, and level of conditioning are all assessed to determine their contribution to the patient's overall activity level. The evaluation consists of three parts the history, physical examination, and the functional assessment. This information is then utilized to determine a plan of care (11). The first component of both...

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...

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...

Sweating Dysfunction

Hyperhidrosis is a problem in some patients with PD, and when severe, this symptom can be severely disabling. Little is known about the problem due to a paucity of careful studies. A small study (71) demonstrated that PD patients generate more sweat when exposed to heat than control patients and that excessive sweating increases with disease severity. Swinn et al. (72) recruited 77 consecutive PD patients and 40 controls for a study of sweating. The authors designed their own questionnaire to...

The Basal Ganglia ThalamicCortical System as Nested Nonlinear Reentrant Oscillators in a Loosely Coupled Network

One could view the basal ganglia-thalamic-cortical system as a set of nested oscillators, as shown in Figure 3. The dynamics of such a configuration and the alternations associated with PD comprise an alternative theory termed the oscillatory theory (7). This theory posits the basal ganglia-thalamic-cortical system to be organized as a large set of nested oscillators loosely coupled in a network. Within each set of nested oscillators, individual oscillators are made up of different combinations...

Swallowing Disorders

Swallowing disorders occur in up to 90 of individuals with PD (69) and may be among the first, though subtle or covert, signs of the disease (9). Identification of swallowing disorders is extremely important in this population, given the ramifications on nutrition and the ability to take oral medication appropriately. Silent aspiration may be observed and pneumonia can be a cause of death in advanced PD. Swallowing abnormalities have been reported in all stages of PD (79) and many individuals...

Treatment

Patients with PD and untreated depression experience reduced quality of life compared with those who are depressed and taking antidepressant medications (62). Additionally, depression in PD patients often persists or worsens longitudinally, and untreated minor depression commonly progresses to major depression. Therefore, even mild depressive disturbances should be considered clinically significant and should warrant monitoring if not definitive treatment. The efficacy and safety of various...

Clinical Molecular Genetic Testing

At present, diagnostic molecular genetic testing is commercially available for parkin and PINK1 gene mutations and can be done for selected patients. However, appropriate counseling should be provided either by the treating physician or a clinical geneticist, along with psychological support. 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...

Summary

The genetics of PD and related conditions are complex, even in monogenic parkin-sonism. The discovery of mutations in the genes for SNCA, parkin, UCHL1, PINK1, DJ-1, and LRRK2 has created a unique glimpse into the basic mechanisms responsible for this neurodegenerative process. Further genetic studies of already known PD loci will undoubtedly uncover more mutations in more genes. Subsequent clinical FIGURE 1 Genes and mutations associated with parkinsonism. Gene names are indicated in italics...

Herbs

A variety of herbs may be useful to treat the motor symptoms of PD as well as some of the associated symptoms or possible side effects from PD medications (14). Mucuna pruriens is a natural plant, indigenous to India, which contains levodopa. It is also called kawach, cowage, cowhage, or velvet bean. It has been studied extensively and shown to reduce the motor symptoms of PD similar to carbidopa lev-odopa (15). In fact, mucuna seeds have been prescribed by Ayurvedic physicians in India for...

Largo

The LARGO (Lasting Effect in Adjunct Therapy with Rasagiline Given Once Daily) study evaluated once daily rasagiline and entacapone administered with each levodopa dose, compared with placebo as adjuncts to levodopa in patients with motor fluctuations. In this 18-week, double-blind, parallel-group trial (97), 687 subjects were randomized to receive rasagiline 1mg daily, entacapone 200 mg with each levodopa dose, or placebo. Off hours were significantly reduced in both the rasagiline (-1.2 hours...

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...

Rasagiline Adverse Events

Adverse events were no more common with rasagiline than placebo in the TEMPO study (94) of early patients the two most common adverse events were infection and headache. In the active treatment phase, there were no significant differences in the most common adverse events occurring in the second six months of the study (infection, headache, unintentional injury, and dizziness). There were eight newly diagnosed malignancies detected over the 12 months of the TEMPO study including six skin...

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...

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...

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...

Irans Rich Foods In Vegetables

What a person ingests can have a dramatic impact upon the person's health for better or for worse. Ayurvedics, TCM, and naturopaths believe that diet is critical to disease prevention and health promotion. Most holistic practitioners would prescribe a specific diet based upon the individual's particular body type and imbalance and their specific training. A review of the many Eastern diet approaches is well beyond the scope of this chapter. It is therefore recommended that persons with PD seek...

The Parasomnias

Rapid Eye Movement Sleep Behavior Disorder REM sleep behavior disorder (RBD) was first reported by Schenck et al. in 1986 and is a parasomnia, which is typically characterized by vivid and usually frightening dreams or nightmares associated with a paradoxical simple or complex movement during REM sleep when muscles are usually atonic (13,23). RBD is thought to have a population prevalence of 0.5 . During REM sleep, patients enact their dreams, which can be vivid or unpleasant, and partners...

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...

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...

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....

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...

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...

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 delivery...

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...

Melanized Midbrain Dopamine Neurons

The midbrain dopaminergic neurons are characterized by the presence of neurome-lanin. Neuromelanin is distributed mostly in cells that synthesize dopamine, norep-inephrine, but not epinephrine, and it is derived from dopamine, dopaquinone, and their oxidized products as well as catecholamines that are not stored in the vesicles 8 . Tetrabenazine and reserpine, drugs that block incorporation of dopamine in the presynaptic vesicles, increase accumulation of neuromelanin and over-expression of...