Parkinson Disease Handbook

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. Continue reading...

The ParkinsonsReversing Breakthrough Summary


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Highly Recommended

I usually find books written on this category hard to understand and full of jargon. But the writer was capable of presenting advanced techniques in an extremely easy to understand language.

This e-book served its purpose to the maximum level. I am glad that I purchased it. If you are interested in this field, this is a must have.

Impairment of the Agentic Self in Parkinson s Disease Cognitive Deficits in Parkinson s Disease

In previous chapters, I have defined the nature and functions of the agentic self. In this chapter, I will show that selective cognitive subcomponents of the agentic self are impaired in PD and that this information helps us to understand both the normal cognitive operations of the agentic self and the symptomatology and functional impairments associated with several of the neuropsychiatric disorders of PD. I suggest that many of the symptoms of the psychiatric disorders seen in some PD patients can best be explained as impairments in the agentic self. That is, these patients are best described as suffering impairments in the agentic self rather than as suffering impairments in executive functions or in decision making, and so forth. Why attempt to understand neuropsychiatric symptoms as breakdowns in the functioning of the self rather than as isolated impairments in various cognitive processes like decision making or executive cognitive functioning For one thing, characterizing the...

Parkinsons Disease with Dementia

There are several forms of primary degenerative parkinsonism, including idiopathic (or sporadic) PD, sporadic PD with superimposed pathological features of AD, familial PD (or parkinsonian syndromes), and Parkinson's-ALS- dementia complex of Guam. Pathological substrates differ among these conditions, as do the frequency of cognitive disturbances. In patients with pathological evidence of AD, dementia is usually (but not invariably) present. In familial cases, genetic defects and pathological changes differ between kindreds, so it is difficult to generalize to sporadic PD. In each case of PD, however, when dementia is described, it is most consistent with a subcortical pattern to distinguish it from typical Alzheimer-type dementia. Pathogenesis and Pathophysiology. Memory performance in nondemented and demented patients with PD is qualitatively different, y , y suggesting that cognitive impairment in nondemented and demented PD patients reflects different anatomical or neurochemical...

Evolutionary Perspectives on the Agentic Self Its Neural Networks and Parkinson s Disease

The long 7 repeats allele (L-DRD4) has also been identified in clinical and non-clinical populations with ECF deficits including set-shifting and sustained attention (Kieling, Roman, Doyle, Hutz, & Rohde, 2006), spatial working memory (Froehlicha et al., 2007), and verbal fluency deficits (Alfimova et al., 2007). These clinical populations very often score high on impulsivity scales. It is possible that the L-DRD4 enhances extraverted personality traits when individuals are young, but then these individuals find it harder to develop strategies to inhibit the impulsive traits they were born with, and thus, they perform poorly on ECF tasks as adults. Enhanced impulsivity in the context of ECF deficit can lead to severe behavioral disturbances in PD (Voon et al., 2007 Weintraub et al., 2006). Although persons at risk for PD and PD patients themselves are not characteristically impulsive, they can become so when they are put on DA agonists. Once this occurs, the individual has an...

Sleep Disorders of Parkinson s Disease

In the past few chapters, we have been looking at the earliest predictors of PD. We have seen that an anxious personality in young adulthood significantly predicts risk for developing PD decades later. In middle age, a certain personality profile of anxiousness, harm avoidance, ambitiousness, inflexibility, punctuality, and reduced novelty seeking is also a significant predictor for later development of parkinsonism. Data uncovered in the past couple of decades have now shown that specific types of sleep disorders often develop 10-20 years before onset of motor symptoms of PD. That is, certain types of sleep dysfunction predict PD onset in some individuals about two decades later (see table 9.1). From the point of view of the self, agentic and executive control systems come progressively under attack by the disease process that culminates in PD. There is an initial genetic, or epigenetic, vulnerability that weakens the agentic self system and manifests in generalized anxiety very...

Mood Disorders and Apathy in Parkinson s Disease

If the reader has come with me this far, he or she will not be surprised at the predictions I offer concerning the origins, symptomatology, and nature of the mood disorders (anxiety and depression) that commonly occur in PD. I will also offer a brief review the symptom complex called apathy of PD. I review the symptoms of the major mood disorders of PD in this chapter and offer an explanatory model for those symptoms that derives from the larger theory of the agentic self system in PD that I have outlined in previous chapters. Hyperactivity within the amygdala is theorized to play a central role in mood disorders of PD. How can hyperactivity within the amygdala lead to such a wide variety of mood disorders Depression is a very different experience than anxiety, for example, yet both, to some extent, derive from aberrant activity in the amygdala along with dysfunction in prefrontal systems. Apathy, in turn is different from both depression and anxiety. How, then, does aberrant activity...

How shall cell therapy be developed in PD

The clinical trials with embryonic mesencephalic grafts in PD patients have provided proof-of-principle that cell replacement can restore function in the parkinsonian brain. However, a clinically competitive cell therapy has to provide advantages over currently available treatments for alleviation of motor symptoms in PD patients. Cell-based approaches should thus give rise to long-lasting, major improvements of mobility and suppression of dyskinesias without the need for further therapeutic interventions. Alternatively, the cells should improve symptoms that are largely resistant to current treatments such as postural and non-motor disturbances. So far, the improvements after intrastriatal transplantation of DA neurons in patients (Lindvall and Hagell, 2000 Freed et al., 2001 Olanow et al., 2003) have not exceeded those found with subthalamic deep brain stimulation (Vitek, 2002), and there is no convincing evidence that drug-resistant symptoms are reversed by these grafts (Lindvall...

On Parkinson s Disease

This book presents a theory concerning certain symptoms associated with the major neuropsychiatrie disorders of Parkinson's disease (PD). We will, therefore, need to present the basics of PD for readers not familiar with the condition. PD is a progressive neurodegenerative disorder that most commonly strikes people over 60 years of age. The mean duration of the disease is approximately 13 years, and the mean age at death is approximately 73. Its cardinal clinical manifestations are four major motor deficits resting tremor, rigidity, bradykinesia, and gait dysfunction. I will discuss these fundamental motor problems more thoroughly later. PD, however, is also associated with many nonmotor deficits, including autonomic dysfunction, pain, mood disorders, sleep problems, and cognitive impairment. Both the motor and the nonmotor deficits of PD are due, in part, to degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNc) coupled with intracytoplasmic...

Impulse Control Disorders in Parkinson s Disease

An impulse control disorder (ICD) occurs when a patient loses control of his impulses around food, sex, money, gambling, and the like. What are the anatomic correlates of ICDs in PD and how does the agentic self fit into the picture of causal factors for ICDs in PD Here is one potential explanation of the anatomic correlates of ICDs in PD The agentic self system is in mutual inhibitory balance with the minimal self system. Anatomically, when the dorsal PFC-basal ganglia loop is impaired, the ventral and orbitofrontal (OF)-limbic loop is disinhibited. Because the latter mediates fundamental drives of sex, food, and aggression, impulses associated with these drives are to varying degrees released from regulatory controls. When this situation occurs, the risk for developing ICDs increases significantly. These ICDs may involve compulsive gambling, hypersexuality, compulsive eating or spending, and the development of peculiar special interests such as special hobbies (Wolters, van der...

The Agentic Self and Personality Changes in Parkinson s Disease

One of the fascinating things about personality characteristics of PD is that there is fairly good evidence that the personality can be recognized decades before the onset of the motor symptoms of PD. This evidence for a premorbid personality of PD as well as similar findings with respect to depressive and anxious affect appearing decades before the motor problems appear suggest that the illness really begins in forebrain centers rather than in the brain stem or rather that forebrain centers are implicated along with brain-stem pathology right from the beginning of the disease process. Whatever the merits of this conjecture, there is now no question but that there are certain personality traits that are characteristic of someone with parkinsonism. It will be my claim that these personality traits are due to the weak Evidence for a Premorbid Personality in PD Eatough, Kempster, Stern, and Lees (1990) studied personality profiles of young-onset patients with PD. They found that these...

Have been reported with PD pathophysiology

Amygdala Pathophysiology

Anxiety can become independent of stimuli as in PD, be associated with benign stimuli as in phobias, or continue beyond the stimulus duration as in GAD. The precise mechanism by which these changes occur is unknown, but much has been discovered regarding how this may be regulated by treatment (Fig. 40-1).

Parkinsonism Plus Syndromes

In addition to Parkinson's disease, parkinsonism is one of the major clinical features in several other primary neurodegenerative conditions. However, because they all have additional features not typical of Parkinson's disease and share an overall worse prognosis and poorer response to antiparkinsonian therapy, they are often grouped together under the conglomerate term parkinsonism-plus syndromes. Within this group, each condition has distinctive characteristics that must be recognized and distinguished from one another and from PD. Pathogenesis and Pathophysiology. Progressive supranuclear palsy (PSP) is the most common and best recognized entity among the parkinsonism-plus syndromes. PSP is an idiopathic condition with no known precipitant or strong genetic component. Postmortem analysis of the brains of PSP patients show neuronal loss, gliosis, and neurofibrillary tangles composed of straight and paired helical filaments. y The SN, subthalamic nucleus, globus pallidus, superior...

Speech and Language Deficits of Parkinson s Disease

I have been arguing that the core cognitive deficit of PD is a weak activation of the agentic self system that is mediated by striatal-DLPFC and frontopolar cortical networks. This failure to fully activate the agentic self leads to hyperactivity in the minimal self system, which is subserved by limbic and orbitofrontal networks. The imbalance of activation between the agentic and the minimal self systems ultimately contributes to the executive control cognitive deficits of PD and the disabling symptoms of the neuropsychiatric disorders of PD (as I will discuss in the chapters on neuropsychiatric syndromes of PD). Recent studies of language functions in PD are consistent with the idea of a weakly activated agentic self system in PD. I will argue that these language deficits of PD are best understood as an inability to use language efficiently to accomplish actions. Characterization of the Language Deficit in PD Patients with PD exhibit inordinate difficulties in what is called the...

Psychosis and Dementia in Parkinson s Disease

As the neurodegenerative process that underlies PD progresses, risk for developing psychotic ideation and a dementing illness increase significantly. At least 75 of PD patients who survive for more than 10 years will develop some form of PD dementia (PDD Aarsland & Kurz, 2010), but there is huge variation with some individuals not developing dementia at all, some developing a relatively mild form of dementia, and some not developing dementia until very late in the disease. The mean time from onset of PD to dementia is approximately 10 years. The strongest predictors for development of early dementia in PD are old age, postural and gait disturbances, and impairment in frontal ECFs (Janvin et al. 2006 Kulisevsky & Pagonabarraga, 2010 Marder, 2010). Because the ECFs are treated in this book as part of the agentic self system, in our terms, severe impairment in the agentic self system increases risk for later dementia in PD. Thus, if the agentic self system can be exercised so that...

Parkinsons Disease

Parkinson's disease is a degenerative neurologic disease with a long chronic, progressive course evidenced by akinesia, rigidity, and tremor. The goal of therapy is to reduce symptoms and maintain or improve quality of life. Palliative care provides support to both the patient and caregiving system as patients become more disabled and as neuro-psychiatric problems arise. Symptoms that frequently occur are skin infections and breakdown, constipation, pain, depression, hallucinations, and confusion. Individuals with Parkinson's disease often die from bronchial pneumonia due to dysphagia and complication from falls (see Chap. 32).

The Nature and Functions of the Agentic Self

We will be examining the neuropsychiatric syndromes that one sees in PD through the lens of the agentic self. The agentic self is that component of a person's identity or unified self that makes decisions and acts. The agentic self deliberates, plans, learns, and acts. It has been called by many names including the executive self, the active self, the actor, the goal-driven self, the purpose-driven self, and many others besides (see review on self systems by Boyer, Robins, & Jack, 2005). The idea though is simple The agentic self is that part of the self that formulates goals, makes decisions, and acts. As Bandura (2001, p. 2) summarized in his exhaustive review on the topic, Agency embodies the endowments, belief systems, self-regulatory capabilities and distributed structures and functions through which personal influence is exercised, rather than residing as a discrete entity in a particular place. Although we cannot point to a particular place in the brain and say There is the...

The Neurology of the Agentic Self

We are bombarded with all kinds of sensory impressions, stimuli, information, choices, and potential goals toward which we strive. Every agent has to sift through the welter of impressions, choices, and potential goals to strive for to identify those choices that will yield the highest value for the agent. No agent can be considered competent and truly an agent unless he can identify things of value around which to organize his actions and his goals. How is this identification of values accomplished cognitively and neurobiologically Although it may turn out that this component process of the agentic self is not impaired in PD, we will still need to be aware of the basics of the valuation process to understand the other subcomponent processes of the agentic self. Unfortunately, little is known about the cognitive and neurobiological correlates of values identification. Rangel et al. (2008) have proposed the existence of three different types of valuation systems Pavlovian, habitual,...

Rehabilitation of the Agentic Self

Up to this point in the book, I have described an array of neuropsychiatric disorders that are sometimes seen in PD. However, I do not want to leave the reader with the impression that PD is nothing but a catalogue of deficits. Instead, one of the benefits of looking at PD from the point of view of the agentic self is that we can see that it is a person, an individual, who copes with an array of challenges including functional deficits. The individual is not a syndrome. The person, not the syndrome, lives in the face of and despite these deficits. When we focus on the agentic self, or the acting person, new opportunities for treatment and rehabilitation open up. Social-Cognitive Deficits in PD Social cognition primarily involves attempts to model the beliefs, emotions, intentions, desires, and thoughts of other minds or persons (Anderson & Chen, 2002 Baldwin, 2003 Decety, 2007 Decety & Grezes, 2006 Josephs & Ribbert, 2003 Keysers & Gazzola, 2007 Lieberman, 2007 Uddin,...

Directed Neurological Examination

The examiner should also ask whether the patient is hearing or seeing things that aren't there and assess whether these hallucinations are interfering with complete cooperation. Delusions should be probed but not countered. Since the delusion is an irrational belief, argument over its logic is fruitless, but the examiner should not agree with it. Depending on the situation, either an explanation that the belief is a delusion but appears real to the patient can be given, or the clinician can simply take note of it and pass on to other subjects. In the case of drug-induced psychosis in Parkinson's disease, the most common delusion is of spousal infidelity, a problem that is often not shared with the neurologist owing to embarrassment by both the patient and the spouse. In this situation and occasionally in others, specific delusions should be asked about.

Brain Diseases with BBB Dysfunction

Dysfunction of the BBB may be in the form of increased permeability or BBB breakdown to large and small molecules in brain diseases and or may take the form of alterations in endothelial transport mechanisms. Well documented in the literature is the increased BBB permeability to plasma proteins, which occurs in conditions associated with vasogenic edema such as ischemic and hemorrhagic stroke, infections, inflammation, seizures, trauma, tumors, epilepsy, and hypertensive encephalopathy (182, 183). Increased permeability to C14 sucrose implying increased ionic permeability has been reported in peripheral inflammatory pain (184). Increased BBB permeability to ions and plasma proteins has been reported in human and experimental diabetes (184, 185). Global vascular changes and altered expression of Pg-p have been implicated in the pathogenesis of degenerative diseases such as Alzheimer's disease (186, 187) and Parkinson's disease (188) as reviewed previously (136, 189).

Anxiety and Obsessive Compulsive Disorder Syndromes

Anxiety is an extremely common occurrence that affects everyone at some time and is characterized by an unpleasant and unjustified sense of fear that is usually associated with autonomic symptoms including hypervigilance, palpitations, sweating, lightheadedness, hyperventilation, diarrhea, and urinary frequency as well as fatigue and insomnia. Anxiety is thought to be mediated through the limbic system, particularly the cingulate gyrus and the septal-hippocampal pathway, as well as the frontal and temporal cortex. The term anxiety disorder is used to denote significant distress and dysfunction resulting from anxiety, including panic attacks and anxiety with specific phobias. Chronic, moderately severe anxiety tends to run in families and may be associated with other anxiety disorders or depression. The differential diagnosis of anxiety states includes other psychiatric conditions such as anxious depression as well as schizophrenia, which may present as a panic attack with disordered...

Carol Jagger And Antony J Arthur

By 2010 in most of the developed countries, the 65+ age group will form over 15 of the total population and over 20 in Japan. In the UK, those aged 65 years and over make up 18 of the population but they receive nearly half of all prescriptions.2 Despite this, few trials, unless specially designed and conducted in this age group, have sufficient numbers of older people, particularly the 'oldest-old', to provide evidence of efficacy, even for treatments of diseases and conditions that are seen predominantly in later life. A recent review of clinical trials in Parkinson's disease, where prevalence increases with age and incidence peaks between 70 and

History and Physiology of the Blood Brain Barrier in Relation to Delivery of Drugs to the Brain

The l transporter at the blood-brain barrier has somewhat different Km values for its substrate amino acids than the Km values exhibited in other tissues hence it is regarded as a separate isoform and has been designated L1 (14). The general l transporter has recently been sequenced (15) and the three-dimensional structure of the binding site for neutral amino acids at the blood-brain barrier has been largely established by computer modeling (16). Marked preference for phenylalanine analogues was exhibited when a neutral substituent was at the meta position. The anticancer drugs melphalan and d,l-2-NAM-7 are appreciably transported by the L1 process. The latter drug has an exceptionally high affinity for the transporter, with a Km of about 0.2 j.M (17). The transporter also has pharmaceutical significance in that it carries l-Dopa, used in the therapy of Parkinson's disease.

Instrumental learning

Beginning with the extraordinary discovery by James Olds that animals would self-stimulate the reward circuit in the brain, we have learned a good deal about this circuitry (Kelley, 2004 Schultz, 2000). In brief, a system called the medial forebrain bundle projects dopamine containing neuron axons from the midbrain to forebrain structures, particularly the nucleus accumbens, the striatum and the prefrontal cortex. This system is activated by all types of rewarding stimuli, from food and water to sex. Importantly, this circuit, particularly the accumbens nucleus, is activated by all drugs of addiction. These drugs cause release of dopamine in the accumbens. Analysis of this reward-memory circuitry is a major field of research today. The dopamine projection to the striatum is of course essentially involved in Parkinson's disease and the projections to the prefrontal cortex and other higher brain regions are thought to be critically involved in schizophrenia.

Alexias And Agraphias Languagerelated Disorders

Extrapyramidal disease is often associated with either hypokinetic or hyperkinetic dysarthria. Hypokinetic dysarthria occurs in Parkinson's disease and other rigid types of extrapyramidal disorders. This speech abnormality is characterized by rapid utterances, slurring of words, and decrescendo volume at the ends of sentences. The voice is low pitched and monotonous, lacking both inflection and volume (hypokinetic and hypophonic). In advanced states only whispering is possible.

Associated Neurological Findings

Attention to ataxia, apraxia for orolingual movements, oculomotor abnormalities, coordination problems, gait disturbances, tremor, bradykinesia, and rigidity is critical, since alterations in the ability to smell are present in some patients with Huntington's chorea and multiple sclerosis, and in approximately 90 percent of patients with early-stage Parkinson's disease. In Korsakoff's syndrome, ataxia of the trunk but not of the limbs is frequently present, as are signs of acute alcohol withdrawal (e.g., tremor, delirium, and tachycardia).

Emotional Regulatory Network

The prefrontal syndrome includes deficits in motor programming, especially evident in alternating, reciprocal, and sequential motor tasks. Executive function impairments include the inability to generate hypotheses and show flexibility in maintaining or shifting sets required by changes in the demands of a task. Patients also exhibit poor organizational strategies for learning tasks and copying complex designs, as well as diminished verbal and drawing fluency. Lesions span the circuit from BA 9 and 10 to the dorsolateral caudate nucleus, to the globus pallidus, and to the ventral anterior and dorsomedian thalamus and back to DLPFC. This circuit is shown to be hypometabolic in Figure 3-3 after an anterior thalamic stroke. Indirect pathways extend from globus pallidus externa to lateral subthalamic nucleus, then to globus pallidus interna and substantia nigra.

The Electrocardiogram

The P wave (atrial activity) and the QRS complex (ventricular activity) are completely independent, with no arithmetic relationship between the two (see Fig. 4-5). In acquired complete heart block, periods of synchronization called accrochage sometimes occur,64,66,74 a phenomenon seldom witnessed in cases of congenital complete heart block (see Fig. 4-7).104 Although atrial depolarization does not activate the ventricles, examples of change from partial to complete heart block,23 as well as from complete to partial heart block, are occasionally encountered (see Fig. 4-3).13,15,16,26,71 A neonate with congenital complete heart block experienced intermittent 1 1 atrioventricular conduction through a Wolff-Parkinson-White accessory pathway.78

Changing Concepts of the Reticular Activating System Arousal Revisited

The monoamine and acetylcholine nuclei are the classical neuromodulatory systems upon which psychiatry has focused much of its clinical intervention and research. They include three monoamine systems with differential projection targets and differential global modulatory functions. There are direct noradren-ergic (NE) and serotonergic (5-HT) projections from the locus coeruleus lateral tegmental area and rostral raphe systems, respectively, which spread to the cortical mantle. Dopaminergic (DA) projections are more targeted toward pre-frontal and paralimbic systems, with projections from the substantia nigra to putamen, caudate nucleus, nucleus accumbens, along with DA projections from the midbrain VTA to many cortical areas, with strong predominance toward prefrontal, cingulate, insular, and other paleocortical regions. There are also projections from brainstem DA, NE, and 5-HT nuclei to the basal forebrain, regulating key cholinergic systems in the basal forebrain. Cholinergic...

Visual Hallucinations

Peduncular hallucinations, consisting of vivid and life-like visual images of concrete objects, are rare sequelae of ventral midbrain injury. The hallucinations are frequently accompanied by sleep and cognitive disturbances. One clinicopathological study y suggested that their expression requires bilateral destruction of the medial substantia nigra pars reticulata. Illicit drug use (cocaine, lysergic acid diethylamide LSD , marijuana), medications (digoxin, anticholinergics, and dopaminergics), and parasympatholytic eye drops (atropine) may also be responsible for visual hallucinations. A psychotic psychiatric disorder is suggested when complex visual hallucinations are accompanied by occasional auditory hallucinations. y Normal people may experience both formed and unformed visual images upon wakening (hypnopompic) or upon going to sleep (hypnagogic). A number of degenerative neurological diseases (Parkinson's disease, progressive supranuclear palsy), in the setting of medication use...

Case Study 32 Bilateral ILN LesionA Progressive Walk Through of the Taxonomy of Disorders of Consciousness1

CT Scan of ILN patient and Schematic Graphic of Mesodiencephalic Regions. Key for Mesodiencephalic Graphic CA anterior commissure CP posterior commissure ANT anterior thalamus IL intralaminar region CEM centromedian ILN VTA ventral tegmental area NRT reticular thalamus DL VL dorsolateral ventrolateral thalamus DM dorsomedial thalamus SN substantia nigra MT mamillothalamic tract EW Edinger-Westphal nucleus CS superior colliculus CI inferior colliculus F fornix, P pulvinar BAS basilar artery ACA anterior communicating artery ACP posterior communicating artery. (From van Domburg, P., ten Donkelaar, HJ, Notermans, SH 1996, with permission from Elsevier Science). Figure 3.2. CT Scan of ILN patient and Schematic Graphic of Mesodiencephalic Regions. Key for Mesodiencephalic Graphic CA anterior commissure CP posterior commissure ANT anterior thalamus IL intralaminar region CEM centromedian ILN VTA ventral tegmental area NRT reticular thalamus DL VL dorsolateral ventrolateral...

Osseous Site Management

Unfortunately, the behavior of the alveolar bone post-tooth extraction complicates the routine implant installation procedures, due to the reduced bone volume and the approximation from the anatomical landmarks that might limit the optimized implant placement. It has been reported that the alveolar bone loses almost 30 of its size within two years following tooth extraction (Lam 1967). Both the maxilla and mandible have distinctive resorption patterns that affect both the width and height of the alveolar bone (Parkinson 1978, Pietrokovski et al.

Therapeutic Uses Of Botulinum Toxin

However paradoxical it may seem, botulinum toxin has over the past decade risen to the status of 'wonder drug'.47,48 It is used to treat a variety of diseases characterized by spasm or overactivity of a particular muscle or group of muscles. In many of these illnesses the muscular hyperactivity is the primary disorder (e.g., cervical dystonia), while in others, it is secondary to another disease (e.g., rigidity and tremor in Parkinson's disease). In most of these conditions intramuscular injection of botulinum toxin has become the treatment of choice and has replaced previous and much less satisfactory surgical or pharmacological alternatives. Clinically effective paralysis with type A botulinum toxin typically lasts three or four months, but it can be longer.47,48

Other Transport Systems Responsible for Drug Transport at the Blood Brain Barrier

Although it has not been established whether the Na+-dependent hexose transporter SGLT is expressed at the BBB, a recent report suggested a participation of SGLT in the BBB transport of cycasin (58). Cycasin, methylazoxy-methanol-d-glucoside, is proposed to be a significant etiologic factor for the prototypical neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and for Parkinsonism-dementia complex. Cycasin is taken up into primary-cultured bovine BCECs in a dose-dependent manner with maximal uptake at a concentration of 10 j.M. Since cycasin uptake was significantly inhibited by a-methyl-d-glucoside, a specific analogue for the Na+-dependent glucose transporter, SGLT, as well as by phlorizin (a SGLT inhibitor), replacement of extracellular NaCl with LiCl, and dinitrophenol (an inhibitor of energy metabolism), cycasin is suggested to be transported across the BBB via a Na+ energy-dependent SGLT (58).

Studies of Cerebral Metabolism and Blood Flow in Anxiety Disorders

In a 15O PET study, Meyer et al. (2000) found an increased left posterior parietal-temporal cortex activation after a challenge with D-fenfluramine in 17 women with panic disorder. In particular, they found hypoactivity in the precentral gyrus, the inferior frontal gyrus, the right amygdala, and the anterior insula during anticipatory anxiety in PD patients. Hyperactivity in patients compared to control subjects was observed in the parahippocampal gyrus, the superior temporal lobe, the hypothalamus, the anterior cin-gulate gyrus, and the midbrain. After the fenfluramine challenge, the patients showed decreases compared to the control subjects in the precentral gyrus, the inferior frontal gyrus, and the anterior insula. Regions of increased activity in the patients compared to the control subjects were the parahippocampal gyrus, the superior temporal lobe, the anterior cingulate gyrus, and the midbrain. Another 15O PET study described specific rCBF differences between panic disorder...

Basal ganglia oiling the wheels of movement

Deep within the brain, towards its base, is a series of grey matter structures, the basal ganglia, whose components include the caudate, putamen and globus pallidus. The basal ganglia have a critical role in motor function, acting on a large scale. The major neurotransmitter substance involved in this role is dopamine. It is produced in a part of the brain that appears darker then the surrounding tissue and is therefore termed the substantia nigra (black substance). The degeneration of this part of the brain was first described in 1817 by the British physician James Parkinson (1755 1828). Parkinson's disease is characterized by slowness of movements, often with difficulty in starting off. The normally smooth contraction and relaxation of muscles is lost and generalized rigidity occurs. Imbalances in the control of muscle movements can also lead to tremor. It is possible to treat Parkinson's disease by giving the drug L-dopa, which is able to cross into the brain, where it is converted...

Neurotransmitter Imaging of the Dopamine System

Even more important than their role in elucidating the primary pathology of schizophrenia, studies using SPECT and PET significantly advanced our knowledge of basic mechanisms of actions of antipsychotic drugs. The D2 receptor is thought to be key for both the clinically desired antipsychotic effects and unwanted motor side effects. Using PET or SPECT to investigate the relative proportion of receptors occupied by a drug versus the available (i.e., drug-free) receptors, which is termed receptor occupancy of a given drug, it has been possible to establish a minimal threshold necessary for clinical antipsychotic effects with typical neuroleptics. Also established are upper thresholds with high risks for drug-induced extrapyramidal motor side effects (EPS) such as dystonic reactions, drug-induced parkinsonism, akathisia, tardive dyskinesia, or the consequences of increased prolactin secretion such as galactorrhea, amenorrhea, and impaired libido. Although...

Brainstem the bridge to the outside world

This is the point at which the large outbound motor pathways, the corticospinal tracts, merge into the brainstem, one column from each side. It is also the location of the substantia nigra (see page 57). There is also a very important group of nerve cells, which are the final stage of the system controlling eye movements. We have already discussed the importance of eye movement co-ordination with other systems but, crucially, the eyes must co-ordinate with each other otherwise double vision will ensue. Specific nerve pathways link the movements of the two eyeballs together and these can become disrupted in certain diseases of the brainstem such as strokes, multiple sclerosis and brain tumours.

Upon completion of the chapter the reader will be able to

Explain the etiology of Parkinson's disease (PD). 2. Explain the pathologic and biochemical changes in patients with PD. 4. Explain the desired therapeutic goals for patients with PD. 5. Recommend lifestyle modifications and pharmacotherapy interventions for treating motor symptoms of patients with PD. 6. Recommend drug and nondrug interventions for treating the nonmotor symptoms of patients with PD.

Epidemiology And Etiology

PD affects approximately one million Americans (1 of people over 60 years of age). The average age of onset is 60 years of age, and PD is fairly uncommon in those under age 40. About 15 of patients with PD have a first-degree relative with the disease. The pathogenesis of cell death (neuron degeneration) may be due to oxidative stress, mitochondrial dysfunction, increased concentrations of excitotoxic aminoacids and in In PD there is a loss of pigmented cells in the substantia nigra that make and store dopamine. When patients are diagnosed with PD, they have lost 50 to 60 of their dopamine neurons in the substantia nigra, and the remaining neurons may not function well, as they have lost about 80 of their activity in the striatum. There may be cortical Lewy bodies along with Lewy neurites seen in microscopic samples from The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus,...

Response Fluctuations

Response fluctuations occur with disease progression, as the patient's dopamine reserves are depleted in the brain, and as a complication of PD treatment. Motor fluctuations include delayed peak response, early wearing off, random unpredictable on-off, and freezing. Dyskinesias include chorea, dystonia, and diphasic dyskinesia. Wearing off can be visualized by imagining the therapeutic window of dopamine narrowing over time. The therapeutic window is defined as the minimum effective concentration of dopamine required to control PD symptoms (on without dyskinesia) and the maximum concentration before experiencing side effects from too much dopam-ine (on with dyskinesia). Early in the disease, a dose of levodopa is administered, and the plasma concentrations are supplemented by the brain's supply of dopamine. Thus, although the plasma half-life of levodopa is 1.5 to 2 hours, the therapeutic effect lasts about 5 hours, and the patient experiences no dopamine side effects. As the disease...

Differential Diagnosis

While depression is generally thought of as a primary psychiatric disorder, it is also commonly seen with a variety of neurological and medical illnesses (Starkstein and Robinson, 1993 Glassman and Shapiro, 1998 Meyers and Scheibel, 1990). Recognition of these comorbid conditions is critical since different treatment strategies may be necessary for optimal clinical response in different populations. In evaluating a newly depressed patient, drug-induced mood changes, comorbid general medical illnesses, and substance abuse should always be considered, particularly in patients whose symptoms are atypical or of uncharacteristic onset. A related problem is the recognition of depression in patients with certain neurological disorders such as dementia or Parkinson's disease, where the diagnosis of depression may be obscured by neurological findings such as inattention, memory loss, apathy, motor slowing, or bradyphrenia (Marin, 1990 Starkstein et al., 1990a). Similarly, the presence of these...

Anatomy Of The Basal Ganglia

Collectively known as the striatum the globus pallidus (both internal and external segments, termed GP i and GPe ) the subthalamic nucleus and the substantia nigra (pars compacta and pars reticulata). Figure 16-2 Cross section of a human midbrain with the black band of dark melanin-rich substantia nigra (SN) and the pyramidal tract that lies anteriorally.

Dance Creativity and Research

Treatment practices in patients with neurological disorders such as Parkinson's disease and related movement disorders. Scientific dance research investigates the implications of dance training and dance styles on the type, degree, and rate of injuries, as well as the psychological make-up of dancers working in this frequently brief and stressful profession. These investigations also examine the specific biomechanics and motor learning employed during the execution of dance skills. Research topics that remain at the forefront include investigations on the distinction between perfectionism and neurotic perfectionism denial of pain and exhaustion that frequently cause career ending injuries and body image and eating disorders, especially in the adolescent dancer who is vulnerable to disruptions in normal hormonal and bone development. Researchers such as Donna Krasnow, Linda Mainwaring, and Gretchen Kerr have demonstrated a clear link between excessive perfectionism and dance injuries...

The somatic marker hypothesis Cognition meets emotion

The apathetic abulic negative disorder of drive pattern of personality change has been noted in a number of neuropsychiatric conditions including TBI, stroke, Parkinson's disease, Huntington's disease, Alzheimer's disease, and disorders involving the frontal-subcortical circuitry including the thalamus, and the basal ganglia (Lichter & Cummings, 2001 Crowe & Hoogenraad, 2000), as well as compromise of the dorsolateral prefrontal cortex.

Reviews And Selected Updates

Lansek R, Bradshaw J, Phillips J, et al The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson's disease. Brain 1995 118 1613-1617. Levy R, Hazrati LN, Herrero MT Reevaluation of the functional anatomy of the basal ganglia in normal and parkinsonian states. Neuroscience 1997 76 335-343.

Adjunct Pharmacologic Treatments

Antidepressants may be useful for patients with depressive symptoms that are not due to negative symptomatology or emotional blunting secondary to parkinsonian-type side effects. Since suicide and depression are linked, aggressive treatment is necessary when depression is present. Selective serotonin reuptake inhibitors (SSRIs) are the preferred agents, but may inhibit the CYP450 enzymes, thus raising plasma concentrations of clozapine, olanzapine, and haloperidol. Mood stabilizers, such as lithium and the anticonvulsants, have long been used adjunctively with antipsychotics to treat the affective component of schizoaffective disorder. Lastly, much research is currently underway to develop better treatments for primary negative symptoms and cognitive impairment however, no approved treatments are yet available.

Clinical Manifestations and Diagnosis Clinical Manifestations

Benson (1983) suggest that all forms of dementia other than Alzheimer's and Pick's disease show signs of subcortical dysfunction in addition to more obvious cortical signs. This is especially true of dementia associated with basal ganglia disease, which regularly produces the characteristic subcortical pattern of slowed thinking, attention deficit, memory impairment, and apathy. Subcortical dementia occurs in 20 to 40 percent of patients with Parkinson's disease (Marttila and Rinne 1976) and is also observed in progressive supranuclear palsy, Huntington's chorea, and Wilson's disease. Symptomatic treatment of basal ganglia disease occasionally improves the associated dementia. Antidepressants may improve cognition as well as any associated depression (Albert, Feldman, and Willis 1974).

Mechanisms Of Action Regulation

Rather, Redgrave et al. suggest that there is a more elementary role of the dopamine projections, to facilitate neostriatal behavioral switching operations in response to significant events. Others have also proposed a similar view of dopaminergic function (Spanagel and Weiss, 1999). Although the dopamine modulation is understood primarily in the neostriatum, this might be extended to dopamine targets in limbic cortex, such as the ACC. The finding that patients with Parkinson's disease exhibit smaller ERN amplitudes (Falkenstein et al., 2001) is particularly relevant within this context. Gurney et al., (2001) have argued that the circuits within the neostriatum may be differentiated, with certain neural populations specialized for behavioral switching functions and others for the control of those switching functions. This sort of mechanism would be well suited to motivational control of action selection.

Motivational Control Of Action Regulation

Although we have considered the possibility that dopaminergic activity may contribute to phase-resetting of the theta rhythm, the exact locus of action remains to be clarified. One candidate is the medial septum-diagonal band complex. Cells from the VTA and substantia nigra have been shown to project to cholinergic cells of the medial septum-diagonal band complex (Gaykema and Zaborszky, 1996), which is believed to be the pacemaker of the theta rhythm. Miura et al. (1987) injected dopamine into the medial septum and found an increase in hippocampal theta activity. Therefore, it is possible that during an error response, a decrease of dopaminergic input into the medial septum or diagonal band results in a pause (or reduction) in cholinergic activity. This pause results in a phase resetting of the theta rhythm to the error event. Interestingly, this mechanism would involve a dopamine influence at the basal forebrain rather than in the ACC. It is entirely possible, however, that phase...

Somatic Treatments For Major Depression Electroconvulsive Therapy ECT

There is no widespread agreement on the underlying mechanism of action of ECT. Electrophysiological studies (Ishihara and Sasa, 1999) have shown that ECT increases the sensitivity of 5-HT3 receptors in the hippocampus, resulting in an increased release of glutamate and GABA. However, tryptophan depletion failed to reverse the improvement in mood seen in depressed patients after ECT (Cassidy et al., 1997) and does not support a primarily 5-HT-dependent mechanism. ECT has been shown to decrease the sensitivity of the noradrenergic and DA autoreceptors in the locus coeruleus and substantia nigra, resulting in an increased release of NE and DA (Ishihara and Sasa, 1999). Support for a noradrenergic mechanism also arises from a study showing a normalization of platelet alpha-2 receptors after a course of ECT (Werstiuk et al., 1996). However, the fact that ECT has efficacy in patients that fail treatment with medications argues against ECT having a similar mechanism of action (Persad, 1990)....

Nonpharmacologic Therapy

Patients with PD should be counseled to avoid stimulant agents (e.g., decongestants, diet pills, and caffeine) that may precipitate a panic attack. CBT consists of psy-choeducation, continuous panic monitoring, breathing retraining, cognitive restructuring, and exposure to fear cues.50 CBT may involve these features to varying degree. Panic-focused psychodynamic psychotherapy (PFPP) focuses on underlying meaning of panic symptoms (e.g., they have a specific emotional significance) and on current social and emotional functioning.50 PFPP may be used alone or with other modalities. Exposure therapy is useful for patients with phobic avoidance. CBT is considered a first-line treatment of PD, with efficacy similar to that of pharmacotherapy. In a large placebo-controlled trial comparing CBT with imipramine or combination (CBT + imi-pramine), CBT was as effective as the antidepressant after 12 weeks. Patients receiving CBT were less likely to relapse during the 6 months after treatment...

Interim Moratorium on Fetal Tissue Transplantation Research

In March 1988, in response to a growing political controversy surrounding the publicity over Mexican and Swedish attempts at grafting fetal CNS tissue into Parkinson's patients, Robert Windom, assistant secretary for Health, imposed a moratorium on federal support for fetal tissue transplantation applications, pending a report from a special panel he directed NIH to convene in order to answer ethical and legal questions posed by a proposal for transplanting fetal brain tissue into patients with Parkinson's disease. In September 1988,

Summary And Conclusions

During this period, the focus of psychiatric research was on understanding the role of monoamine systems in the pathophysiology of mental illnesses. These efforts were greatly influenced by the discovery of the CNS DA deficiency in patients suffering from Parkinson's disease (Ehringer and Hornykiewicz, 1960) and the remarkable therapeutic effects of l-DOPA treatment (Cotzias et al., 1967). The discovery of a DA deficiency in Parkinson's disease led psychiatric investigators to hope that the pathophysiology of mental disorders would be discovered by understanding the pharmacology of our treatments. The research of the past 30 years suggests that new, more complex models are in order. We have begun to understand that mood disorders are not simply the result of a deficiency on monoamine neurotransmitters and that we have to better understand the anatomy and function of brain circuits regulating emotion and cognition as well as the molecular events that modulate the function and viability...

Neuropathological Abnormalities

One of the challenges of postmortem neuroanatomical observations in schizophrenia is that the changes that are seen are widespread and usually subtle (Harrison, 1999 Powers, 1999). There is no gross lesion that is typical of a schizophrenia brain such as that seen in Huntington's disease or Parkinson's disease. Moreover, many of the abnormalities that are detected in the brains of patients with schizophrenia are not selective and are associated with other psychiatric conditions as well. Finally, there

Approaches for Walking

Ambulation is often the highest immediate rehabilitative priority for patients following a stroke, the Guillain-Barre syndrome, and brain or spinal cord injury. Patients with progressive diseases such as multiple sclerosis, Parkinson's disease, and myopathies, as well as the elderly who develop proximal weakness and imbalance associated with deconditioning, arthritic pain, contractures or a spinal stenosis aim for continued independent walking, in part to lessen the burden of care they may pose for significant others.

The Use of Chiral Reagents and Catalysts

The main disadvantage of using a chiral auxiliary is that additional steps are required in the synthesis for appendage and removal of the chiral group. One method of overcoming this is to use a chiral catalyst to promote the conversion of an achiral starting material into a chiral product. By definition, the advantage is that only a small molar ratio of catalyst is required, which can be recovered and reused. One of the most widely exploited areas of catalytic asymmetric synthesis is hydrogenation using a chiral transition metal complex. Two important ligands in this area are BINAP and DIPAMP (Figure 5.14), which are often complexed to rhodium (II) or ruthenium (II) acetate. DIPAMP is used in the industrial synthesis of (S)-3,4-dihydroxyphenylalanine (l-DOPA), an anti-Parkinson's agent.

Neurological Applications in Diagnosis and Treatment

Characteristic patterns of decreased regional glucose metabolism within the parietal and temporal lobes have been described in patients with AD.y In these patients there is a relative preservation of the calcarine fissure region, sensory motor region, cerebellum, and the basal ganglion region. Decreased metabolic rates for oxygen have also been reported in the same regions that demonstrate areas of decreased glucose metabolism in patients with Alzheimer's disease. Patients with progressive Parkinson's disease have a similar pattern, as seen in patients with Alzheimer's disease. Multiple-infarct dementia occurs after multiple lacunar infarctions. PET generally demonstrates multifocal regions of decreased glucose metabolism y that typically correlate to focal lesions demonstrated on CT scans and MR images. A significant decrease in glucose metabolism within the frontal and temporal lobes has been described in patients with Pick's disease. y Patients with...

Other conditions of the salivary glands

Drooling is a normal phenonomen when it is associated with teething in childhood, but at most other times it is abnormal. It is often seen in patients with cerebral palsy but it also may be seen in adults with neurological diseases such as Parkinson's disease. It can be caused by the overproduction of saliva or the presence of an abnormal swallowing reflex. Various surgical treatments have been described for the treatment of drooling, including rerouting of the submandibular ducts to drain into the tonsil fossae and also excision of the submandibular glands with rerouting of the parotid ducts, with varying degrees of success. Tympanic neurectomy also has been shown to be of benefit in the short term but, like all autonomic nerve surgery, its long-term results are disappointing.

Neurogenic versus nonneurogenic regions in the adult brain

In the olfactory system, precursor cells reside in the sub-ventricular zone (SVZ sometimes also called the sub-ependymal zone) in the walls of the lateral ventricles, migrate via chain migration through a structure surrounding the obliterated olfactory ventricle (the rostral migratory stream (RMS)) into the olfactory bulb, and differentiate into two types of interneurons in the granule cell layer and peri-glomerular regions of the bulb (Lois and Alvarez-Buylla, 1993 Luskin, 1993 Goldman, 1995 Doetsch et al., 1999). In the DG of the hippocampus, the precursor cell population is found in the sub-granular zone of the DG. Here, new granule cell neurons are produced. These two brain regions are referred to as the neurogenic regions. Additionally, there have been controversial isolated reports of adult neurogenesis in the amygdala (Bernier et al., 2002), area CA1 of the hippocampus (Rietze et al., 2000), and the substantia nigra (Zhao et al., 2003), though this last...

Methodological issues

Guze and Gitlin (1994) have drawn a distinction in the way in which affective disorders relate to brain disorder. They contend that the relationship between the neurological condition and the affective state presents three possible aetiologies integral, reactive, and independent. In the case of Parkinson's disease (PD) for example, they contend that depression is an integral component of the disease (presumably as a consequence of the effect of the disease on the neuromodula-tory mechanisms of dopaminergic, noradrenergic, and serotonergic functioning). Patients with PD-related affective disorders are thus considered to show a true secondary mood disorder. These individuals often show a negative family and personal history of affective disorders and they have usually been euthymic up until the onset of their PD.

Formation of Reactive Metabolites

The metabolism of neurotransmitter amines by cerebral MAO-A and -B produces equivalent amounts of the corresponding aldehydes, and ammonia. Both products are considered to be neurotoxic and could participate in the progressive neuronal death that occurs during senescence. Moreover, implication of MAOs in xenobiotic metabolism was definitely assessed by the demonstration that MPTP, a meperidine analogue promoting a parkinsonian-like syndrome in humans (66), monkeys (67), and mice (68), was a substrate of MAO-B in most mammalian species assayed (69). The precise mechanism by which MPTP administration induces selective dopaminergic neuronal death in the pars compacta of the substantia nigra is still a subject of debate. Exposure to MPTP results in the formation of MPP+, which is actively taken up by dopaminergic neurons and kills them either by blocking complex 1 of the mitochondrial respiratory chain or by promoting the formation of superoxide and hydroxyl radicals (for a recent review,...

Ionexchange materials

Conaghey et al. (1998) studied the in vitro iontophoretic transdermal delivery of nicotine by ion-exchange resins in agar hydrogel. Both strong and weak resins were used and the heterogeneous vehicles were shown to have advantages over comparable simple hydrogel vehicles in their versatility, in their capacities to store the drug, and to control the delivery rate during iontophoresis. Kankkunen et al. (2000, 2002, 2004) studied controlled transdermal delivery of the zwitterionic levodopa by iontophoresis and ion-exchange fiber. Ion-exchange kinetics and transdermal permeation of a cationic (presumably more stable) model drug, metaraminol, were compared to the corresponding data for levodopa. Levodopa was rapidly oxidized in the presence of water, especially at basic pH. At acidic pH, stability was improved significantly. Ion-exchange groups and pH had a clear effect on the release of both the levodopa and metaraminol from the ionexchange fiber. Iontophoretic enhancement of drug...

Oxygen Reduction Products

MAO activity involves the formation of hydrogen peroxide, and this enzyme has been suspected to participate in the global increase of oxidized products in the aged brain (94) and in oxidative damage to the substantia nigra observed in Parkinson's disease (95). Therefore, deprenyl, a specific MAO-B inhibitor, and also a molecule protecting dopamine neurons from peroxyni-trite-promoted apoptosis (96), is frequently coadministered with dopamine agonists for the treatment of Parkinson's disease (73).

Nonenzymatic Oxidation of Drugs

The nonenzymatic autoxidation of catecholamines also plays an important role in the physiology and aging of the CNS. Dopamine, like most catecholamines, can be easily oxidized by molecular oxygen in physiological solutions (i.e., at neutral pH and in the presence of transition metal traces) (104). During autoxidation, both semiquinones and quinones are formed, and they react with molecular oxygen to produce reactive oxygen species. Numerous data suggest that the cytotoxicity of levodopa, a dopamine precursor used for long-term therapy of Parkinson's disease, is likely due to the action of free radicals formed as a result of its autoxidation (105, 106). Moreover, quinoid compounds derived from the autoxidation of endogenous catechols polymerize to form neuromelanin, which contributes to the vulnerability of dopaminergic neurons in Parkinson's disease (107). Finally, quinoids products can crosslink with neurofilament proteins (108) and with cysteine to form cytotoxic cysteinylcatechols...

Nutrition And Dysphagia

Neurogenic dysphagia means dysfunction in the mechanisms that deliver a food or liquid bolus into the esophagus. Aspiration, respiratory compromise, malnutrition, and dehydration are the serious consequences. Indeed, dys-phagia is the potential cause of a pulmonary infection in any patient with stroke, TBI, motor neuron disease, cerebral palsy, MS, advanced Parkinson's disease, cervicomedullary pathologies such as a syrinx, the Guillain-Barre syndrome, myasthenia gravis, and most neuro-muscular diseases. Dysphagia occurs in approximately one-third of patients with serious TBI, eventually in up to one-half of patients with MS, in nearly all patients with ALS, and in people with myasthe-nia gravis that affects oral muscles, the velopha-ryngeal port, and the pharynx. Aspiration is also common in people with Parkinson's disease. Fatigability may impede swallowing in any patient with a neurologic disease, but is especially apt to affect people with myasthenia. Oral secretions colonized by...

Degenerative Diseases

Tive therapeutic treatment is able to ameliorate symptoms to a significant degree (except for Parkinson's disease), or even to halt the progress of the disease. The molecular level is not readily accessible to ERPs, therefore ERPs have not yet played a significant role in therapeutic research. Whether there is a role for ERPs in diagnosis and prognosis and in understanding consequences of diseases with respect to cognition is discussed in the following sections.

Basal Ganglia Dysfunction

Evidence for basal ganglia dysfunction is provided by neuroimaging studies and the association of OCD with neurologic disorders known to involve basal ganglia structures, including Tourette syndrome, Sydenham chorea, and Huntington's chorea (Cummings and Cunningham, 1992). The first description of neurologically based OCD comes from Constantin von Economo's 1931 treatise on postencephalitic Parkinson's disease, wherein patients suffered basal ganglia destruction as a result of severe Figure 13.1. In this model, the primary area of dysfunction is in the striatum, reducing its inhibition of the globus pallidus externa (GPe indirect pathway), which causes the GPe to increase its inhibition of the subthalamic nucleus, thus reducing the subthalamic nucleus' STN's stimulation of the globus pallidus interna substantia nigra (pars reticulata) (GPi SNr). This causes a reduction in GPi SNr inhibition of the thalamus, which then can increase its stimulation of the frontal cortex (t, glutamate -,...

Different types of memory and learning are processed and stored in functionally distinct brain regions

Not all learning is impaired by hippocampal lesions, because patients with such lesions can learn new motor skills perfectly well, and repeat their performance when requested to do so. However, they have no awareness or recollection that they have learned a new skill 12, 13 . In contrast, patients with Parkinson's disease affecting the basal ganglia circuits are deficient in learning cognitive skills, but not tasks involving declarative memory 16 . Similarly, learning conditional responses such as the association between the sound of a horn and the approach of a vehicle involves several parts of the brain. The amygdala (Fig. 7.2), which is part of the medial temporal lobe, plays a crucial role in conditional emotional responses 12, 13, 17, 18 .

Huntingtons Disease

Besides HD, other less common heredofamilial choreas include hereditary benign chorea and neuroacanthocytosis (see later discussion in this chapter). If a family history of choreic or psychiatric disorders is lacking, numerous other disorders should be considered, including tardive dyskinesia, CNS vasculitis, Wilson's disease (WD), Sydenham's chorea, and toxin exposure. Drugs causing chorea include oral contraceptives, levodopa, CNS stimulants, neuroleptics, phenytoin, carbamazepine, and ethosuximide. If the diagnosis is approached from the perspective of genetic testing, other hereditary neurodegenerative conditions with expanded trinucleotide repeats of CAG include Kennedy's syndrome (X-linked spinal and bulbar muscular atrophy), myotonic dystrophy, spinocerebellar atrophy type 1, and dentato-rubro-pallidal- luysian atrophy ( ,Xa bJ ,.3.4-4 ). Management. DA receptor-blocking agents (e.g., haloperidol or fluphenazine) and dopamine-depleting agents (e.g.,...

Other Forms of Primary Dystonia

Several other forms of primary inherited degenerative syndromes are associated with dystonia. y Like the parkinsonism-plus syndromes, the major hallmark in these dystonia-plus syndromes is dystonia, but this is accompanied by movement disorders. Dopa-responsive dystonia (DRD) is also an autosomal dominant disorder caused by a mutation in the GTP cyclohydrolase I gene on chromosome 14q, which causes a defect in dihydrobiopterin synthesis. These patients present with dystonia and parkinsonism that has a marked diurnal fluctuation. In the early morning they may be symptom-free or only mildly affected, but then a progressive gait disorder and cramping and rigidity develop during the day. These patients are markedly sensitive to low doses of levodopa, and often doses of Sinemet as low as 25 100 mg day are effective in obliterating clinical signs. For this reason, it is particularly important to recognize DRD, and all children with dystonia and adults with leg or trunk dystonia deserve a...

Hallervorden Spatz Disease

Hallervorden- Spatz disease (HSD) is a rare autosomal recessive disorder associated with excessive iron deposition in the globus pallidus (GP). y The most striking autopsy finding in HSD patients is the asymmetrical rust-brown pigmentation of the GP and zona reticulata of the substantia nigra (SN). The iron pigmentation occurs both extracellularly and intracellularly but is predominantly found in astrocytes, microglia, and neurons. Mulberry concretions are also typically present in the extracellular space. Numerous and large spheroid bodies, identified by myelin staining and surrounded by pigment granules, are typically present throughout the medial GP, SN zona reticulata, cortex, and subthalamic nucleus. y The spheroid bodies apparently represent degenerating myelinated axons. developed athetosis, tremor, and visual difficulties. Dystonia and rigidity are the major hallmarks of this childhood illness, but other associated features include gait and...

MalingeringTo Be or Not to Be

Evaluator noted that the evaluee spoke very little and did not appear to be taking the evaluation seriously. After spending 15 minutes with the evaluee, the evaluator issued a brief report recommending that the defendant be committed to a forensic psychiatric hospital for further evaluation with a primary rule-out diagnosis of malingering. The forensic evaluator at the hospital noted that the evaluee was taking moderate doses of a typical antipsychotic and that he presented with what appeared to be prominent negative symptoms of schizophrenia and extrapyramidal side effects (parkinsonian tremor). He had a markedly restricted range of emotional expression and very little spontaneous speech, but when he spoke, he did so in a linear fashion. The evaluee denied current hallucinations, did not speak with any delusional material being evident, and denied any history of psychotic symptoms.

Examination and Test Findings

An extended office or bedside cognitive examination will reveal difficulties with recent memory, language, visuospatial abilities, and calculations as discussed above. As AD progresses and the frontal lobes are affected, executive dysfunction will also be seen. The neurological examination in AD is normal until the disease becomes advanced. Parkinsonism can be seen in the later stages of the illness. In the late stages of AD, the posture becomes markedly flexed and the limbs rigid, leading to contractures. Neurofibrillary tangles (NFTs) are the other hallmark histological finding of AD, although they are also observed in other neurodegenerative diseases and to a lesser extent in normal aging (Wisniewski et al., 1979). NFTs are found in a wide variety of locations in AD including the cortex, medial temporal structures, substantia nigra, locus ceruleus, raphe nuclei, and nucleus basalis of Meynert. NFTs are aggregations of cytoskeletal proteins and are composed mainly of paired helical...

Ken Nakamura1 and Un Jung Kang2

Replacement of missing neurotransmitters, augmenting the phenotypes of remaining neurons, promotion of neuronal regeneration, and prevention of further degeneration by delivering genes that impede cell death pathways. Although the replacement of missing transmitters has been an effective approach for diseases such as Parkinson's disease (PD Volume II, Chapter 35), the underlying degenerative process is not impeded. In many cases, our understanding of disease pathophysiology is insufficient to allow more direct interventions. In other diseases such as stroke (see Volume II, Chapter 36) and spinal cord injury (see Volume II, Chapter 37), the primary insult has already occurred at the time of clinical presentation. This chapter examines the rational, therapeutic potential, strategies, and obstacles to the delivery of neuro-trophic factors using gene therapy for the treatment of neurologic diseases.

Neurochemical Lesions

Experimental neurochemical lesions (to be distinguished from experimental or clinical neuroablation lesions or from thermo- or cryolesions) are used according to different experimental strategies. For example, it is possible to produce lesions selectively in one of the five nuclear groups that are interconnected to form the basal ganglia in the basal forebrain and involved in the modulation of voluntary movement. For instance, selective lesion of the substantia nigra (one of the nuclear groups of the basal ganglia) in primates has allowed partial models of Parkinson's disease to be advanced. Another strategy involving the use of experimental targeted lesions of the nervous system evaluates the protective effectiveness of certain drugs or natural factors (e.g., nerve growth factor) or of ganglioside molecules on the lesion. Molecular biology techniques have also been introduced to establish the relationship between the development of the lesion and the associated gene activation or...

Learningrelated neural activity in the striatum

Other studies, focusing on striatal interneurons that are tonically active, have led to a similar conclusion. Ann Graybiel and her colleagues identified a substantial population of tonically active neurons in the striatum that became responsive to an auditory cue only when the cue acquired predictive value for subsequent delivery of a reward. These cells did not respond to primary rewards, but did establish cued responses in expectation of a reward and maintained those conditioned responses for weeks. The conditioned responses were entirely dependent on dopamine inputs from the substantia nigra. Selective depletion of dopamine cells in the substantia nigra, another major part of this system that sends inputs to the striatum, resulted in a reduction of the cued responses of tonically active striatal neurons, to the same level as observed prior to conditioning. Subsequent systemic administration of a dopamine receptor agonist reinstated conditioned responses of these striatal cells....

Clinical Presentation

Although these lesions are in close association with the basal ganglia, involuntary movements are relatively uncommon. In series consisting of all age groups, movement disorders are present in less than 10 of cases.21 However, in pediatric series, these presenting signs have been reported in up to 25 of children with unilateral involvement and 36 of patients with bilateral involvement.24,36,46 These movement disorders most commonly take the form of a non-Parkinsonian tremor or focal dystonia. In rarer circumstances, hemichorea, hemiballismus, or hemiathetosis can also be found.

Dementia With Lewy Bodies History

While known previously, the disease now referred to as Parkinson's disease (PD) was first systematically described by James Parkinson in 1817. Parkinson noted that 3. Parkinsonism the disease was associated with a resting tremor, truncal flexion, and a festinating (accelerating) gait. Parkinson thought that in this disease the senses and intellect (are) uninjured despite the fact that neuropsychiatry symptoms were present in the cases he reported (Adams and Victor, 1993). Charcot was among the first to note that patients with this illness develop increasing cognitive dysfunction as the illness progresses. In 1912, Friedrich Lewy examined the brains of patients with PD and was the first to describe the neuronal inclusion bodies that now bear his name. It was not until 1961, though, that Okazaki and colleagues (1961) reported two cases of dementia associated with cortical Lewy bodies. Further cases of this illness appeared in the literature through the late 1980s, and by 1991 the first...

Clinical Features

In a study by Aarsland and colleagues (2001), parkinsonism was noted in 68 percent of a population of DLB patients with advanced disease. When compared to a community sample of PD patients, the DLB patients had more severe parkinsonism in general no difference was noted in resting tremor. The parkinsonism of DLB is usually characterized by bradykinesia, limb rigidity, and gait disturbance. Other physical problems associated with DLB include syncopal spells and falling these phenomena are seen in about one-third of DLB patients (McKeith, 2002). Cognitive. Cognitive problems observed in DLB overlap to some extent with both PD and AD reflecting the combination of subcortical and cortical pathology in the disease. Slowed psychomotor skills and information processing are commonly reported as is visuospatial dysfunction (Knopman and Selnes, 2003). Attentional impairment is also a frequent and prominent accompaniment of DLB (Cullum et al., 2003) and may be related to the periods of...

Improved Transporter Mediated Permeability

Another example of facilitating active absorption processes by the use of prodrugs is levodopa. Levodopa (or L-dopa) is a prodrug of the neurotransmitter dopamine and utilizes the L-aromatic amino acid transporter for permeation of the intestine and the blood-brain barrier. The active compound dopamine is regenerated by decarboxylation mediated by dopamine decarboxylase enzymes (Figure 9.13).

The neural bases of abstraction

In contrast to the precise (somatotopic) localization of motor and sensory functions in the brain cortex, the symptoms of patients with lesions in the prefrontal areas are associated with a broad range of cognitive functions, which include problem solving, planning, and managing work and personal life, as well as judging complex situations. These cognitive functions have been globally described as goal oriented behavior15 or executive functions. Brain imaging studies indicate that the prefrontal lobes (Fig. 4.2) are involved in such functions, but there is no general agreement on the details 45 . The symptoms shown by frontal lobe patients are variable and even restricted lesions produce deficits in several different cognitive tasks which are difficult to separate from general intelligence 46 . This is attributed to the interaction of anatomically and functionally distinct systems in the performance of complex tasks 47 . In addition, the ventromedial areas of the prefrontal cortex...

Intramuscular Depot Injections

Drug targeting to the brain has been investigated using uptake transporters in the blood-brain barrier as targets for prodrugs. For example, glucose and mannose derivatives of levodopa and dopamine have shown increased in vivo activity in animal models compared to parent compounds. This has been attributed to enhanced drug transport into the brain by prodrugs utilizing the glucose transporter in the blood-brain barrier. Other brain uptake systems such as the large amino acid transporter have been the target for prodrugs.

Research Evidence to Date

Music therapy also reduces self-reported levels of dental and postoperative pain. It assists the physical rehabilitation of patients with stroke and Parkinson's disease, improving the rate at which patients learn to walk when compared with no-music-therapy control patients. Stroke victims receiving music therapy also have reported lower levels of anxiety and higher scores on measures of psychological health when compared with control groups. Several small studies have shown that music therapy can improve speech among those with traumatic brain injuries. Researchers at the University of California at Irvine produced evidence that listening to Mozart produced short-term enhancement of spatial-temporal reasoning abilities in college students.

Clinical Manifestations

The cardinal features of Parkinson's disease are resting tremor, bradykinesia, rigidity, and postural instability. The resting tremor usually is 4 to 6 cycles per second and is present at rest and decreases with Figure VIII. 102.1. Scheme illustrating the mechanism of MPTP toxicity at nigral dopamine neurons in primates. MPTP, which is lipophilic, enters the brain where it is transformed into MPP+ by monoamine oxidase B located in glial cells or in serotonergic neurons. MPP+ is taken up into the dopaminergic (DA) neurons, where it accumulates, by dopamine reuptake mechanisms. The binding of MPP+ to neuromelanin might assist in the accumulation of MPP+, or might contribute to its toxicity. MPP+ within the neurons is assumed not to undergo redox cycling to reproduce free radical species but, rather, to be actively accumulated by mitochondria, where it inerferes with mitochondrial energy metabolism, leading to cell death. The precise mechanism of MPP+ toxicity remains unknown. The...

Deep Brain Stimulation

Deep brain stimulation is now routinely performed for refractory Parkinson's disease (PD), essential tremor, intention tremor and various chronic pain syndromes. There are three main targets used to treat PD ventrolateral thalamus (VL), globus pallidus internus (GPi), and subthalamic nucleus (STN) (Limousin et al., 1998). The FDA has now clinically approved all three sites. The detailed knowledge of the motor circuitry and the pathophysiology of PD are an achievement for researchers in psychiatric disorders to emulate. Since their original descriptions by Alexander and DeLong in the mid-1980s, the cortico-basal-ganglio-thalamic loops have offered a framework for such endeavors (Alexander et al., 1986). In PD, there are two overlapping loops, the motor and the associative. The loss of dopaminergic input to the striatum due to substantia nigral degeneration results in dysregulation in basal ganglia functions. The net effect is excessive inhibitory influence of the GPi on the ventralis...

Positron emission tomography brain meets antimatter

For example, since glucose is the major source of energy for the brain, glucose can be used as a tracer to look at brain activity. Currently, PET has a growing application in the detection of certain types of brain tumour and other cancers, but there are relatively few PET centres and in the main it is a research tool only. In this capacity it has an established reputation in neuroscience and has, in particular, led to a greater understanding of Parkinson's disease.

Mending the brain changing ourselves

Age-related brain changes are of several different types. Neurons daily die in huge numbers from the day we are born to the day we die. We lose about a neuron a second from the cerebral cortex, or thirty-one million a year. After the first few years of life, no more new neurons are made but because there are a hundred billion of them, the loss of a few million a year makes little difference. By the age of seventy, the average person still has ninety-seven per cent of the nerve cells they had at twenty-one. But, as we have seen, in the brain, location is everything. If the nerve loss is concentrated in an important area, it may give rise to symptoms once a critical level is reached. This could happen in some people sooner than others, because they had fewer neurons to start with or were affected by a disease that damaged the neurons already there. Another possibility is that this rate of nerve cell loss is programmed genetically. This sort of critical neuron loss is known as...

Classification and Pathophysiology

Dementia is usually divided into four main categories. Dementia of Alzheimer's type accounts for approximately 60 of cases dementia with Lewy bodies, 15 and vascular dementia, 15 . The remaining category includes multiple other forms, including mixed dementias that exhibit components of both Alzheimer's and vascular dementia and dementias resulting from CNS trauma, Parkinson's disease, Pick's disease, Creutzfeldt-Jakob disease, and Huntington's disease. Dementia with Lewy bodies is similar to Alzheimer's disease, but visual hallucinations and motor symptoms similar to parkinsonism develop early in the course of the disease. His-tologically, Lewy bodies are present, cytoplasmic inclusions found in the temporal, parietal, and paralimbic regions of the brain.

The real reason we could not live for ever

Would all be demented when we died and probably all have Parkinson's disease and motor neuron disease as well. Diseases that involve neurodegeneration were essentially nonexistent in human evolution, but will become more frequent as we gradually push back the frontiers of survival.

Acquired Movement Disorders

Movement disorders may follow serious TBI or repetitive concussions. Problems include rubral and other tremors, myoclonic jerks, and parkinsonism, particularly the punch-drunk syndrome of boxers. Less often, patients develop akinetic-rigid syndromes, chorea and ballismus, focal and more generalized dystonia, tics, psychogenic jerks, and other unwilled movements.71 These disorders can develop within weeks, months, or as long as 10 years after injury. Late evolution raises the possibility of ongoing changes within the basal ganglia and their connections, such as denervation hy-persensitivity, dendritic sprouting onto partially denervated target cells, and an accelerated decline in the number of striatal neurons as the patient ages.

Symptomatic effects of neural grafts

The main pathology underlying disease symptoms in PD is a rather selective degeneration of the nigrostriatal DA neuron system. An estimated number of 350 patients with PD have so far received intrastriatal implants of human embryonic mesencephalic tissue. The tissue has been taken from dead aborted human embryos, aged 6-9-week postconception. Several open-label trials have reported clinical benefit associated with graft survival (Lindvall et al., 1990 1992 1994 Sawle et al., 1992 Peschanski et al., 1994 Freeman et al., 1995 Remy et al., 1995 Defer et al., 1996 Wenning et al., 1997 Hagell et al., 1999 Hauser et al., 1999 Brundin et al., 2000 Mendez et al., 2000 2002 Cochen et al., 2003). In the most successful cases, patients have been able to withdraw L-dopa treatment during several years after transplantation (Wenning et al., 1997 Hagell et al., 1999 Piccini et al., 1999 Brundin et al., 2000). The magnitude of the overall clinical benefit at 10-24 months postoperatively in three...

Mechanisms of action of neural grafts

It is well established that human embryonic mesen-cephalic DA neurons survive transplantation into the brain of PD patients. Significant increases of FD uptake in the grafted striatum have been shown in several studies (Lindvall et al., 1990 1994 Sawle et al., 1992 Peschanski et al., 1994 Freeman et al., 1995 Remy et al., 1995 Wenning et al., 1997 Hagell et al., 1999 Hauser et al., 1999 Brundin et al., 2000 Mendez et al., 2000 2002 Freed et al., 2001 Cochen et al., 2003 Olanow et al., 2003), and in one patient, the uptake was completely normalized after transplantation (Wenning et al., 1997 Piccini et al., 1999). FD-PET has also demonstrated that the grafts can survive for at least 10 years despite an ongoing disease process and continuous antiparkinsonian drug Finally, the embryonic mesencephalic grafts can become functionally integrated into neural circuitries in the PD patient's brain. Normally, substan-tia nigra DA neurons are important regulators of cortico-striatal...

Adverse effects of neural grafts

The adverse events considered to have a possible or probable relationship with either the surgical procedure or the implanted tissue have generally been few, mild, and transient following neural transplantation in PD. In the recent double-blind clinical trial by Olanow et al. (2003), the overall rate of reported adverse events did not differ between either of the two grafted or the sham-operated groups of patients. In several studies, transient mental side effects, such as confusion, hallucination, disorientation, and frontal syndromes, have been observed during the immediate postoperative period (Defer et al., 1996 Hauser et al., 1999 Jaques et al., 1999 Brundin et al., 2000). These side effects have typically resolved spontaneously within the first month, and are likely to be related to the surgical trauma and subsequent edema along the trajectories. A few cases of postoperative seizures have been described (Hauser et al., 1999 Jaques et al., 1999) they have resolved without later...

How Common Is Epilepsy In The Elderly Population

Epidemiologic studies of several populations2-6 have shown that the incidence of seizures, epilepsy, or both is high within the first few years of life, stabilizes over the second through fifth decades, and then rises again, in some studies approaching or exceeding rates seen in infancy (Fig. 13.1). In the Rochester, Minnesota, population,5 newly diagnosed epilepsy was seen in 139 of 100,000 persons aged 75 or older, versus 44 per 100,000 throughout the lifespan. Scheuer and Cohen6 calculate, based on 1990 U.S. census data and incidence and prevalence data from the Mayo clinic, that in this country there are 331,000 persons aged 65 and older with epilepsy and that 41,700 of them have new-onset cases. These numbers are below those for stroke and dementia but comparable to those for such other age-related conditions as Parkinson's disease.7

Generation of large numbers of DA neurons in standardized and qualitycontrolled preparations

Using intrastriatal transplantation of porcine embryonic mesencephalic tissue in patients with PD (Schumacher et al., 2000 Watts et al., 2001) have not provided any evidence of graft survival or unequivocal clinical benefits. The main interest is now instead focused on the production of DA neurons from stem cells in culture and subsequent transplantation (Fig. 34.2). These neurons have to work, at least, as well as the primary DA neurons in the embryonic mesencephalic grafts used so far in PD patients. Based on results obtained with such transplants in animals and in patients, a set of requirements can be identified which probably have to be fulfilled also by stem cell-derived cells in order to induce marked clinical improvement 1 The cells should release DA in a regulated manner, and exhibit the molecular, morphological, and electrophysiological properties of substantia nigra neurons (Isacson et al., 2003).

Clinical Use and Adverse Effects of Specific Antiepileptic Drugs

Ethosuximide has been marketed in the United States since 1960 for the treatment of AS. It is the drug of choice in AE without TCS, against which it is ineffective. Ethosuximide blocks T-type Ca2+ channels that trigger and sustain rhythmical burst discharges in thalamic neurons. Trimethadione, which is no longer available in the United States, is the only other agent with a similar mechanism of action. Ethosuximide does not induce hepatic microsomal enzymes and is not protein-bound. Idiosyncratic reactions include headache, hiccups, blood dyscrasias, lupus-like syndromes, behavioral disturbances, and parkinsonism. Ethosuximide is available in 250 mg capsules and syrup (250 mg 5 ml).

Neurobiology and Genetics

The neurobiology of both depressive and anxiety disorders is complex and incompletely understood. In contrast to illnesses such as Parkinson's or Huntington's disease, no single area of brain pathology or anatomic lesion has been implicated in the development of anxiety or depression rather, these illnesses appear to be mediated by dysregula-tion of complex interactions between neural circuits (Nestler et al., 2002). In depression, most lines of investigation have involved dysregulation of the hypothalamic-pituitary axis (HPA) and hippocampus, along with investigations of neural circuitry mediating mood, reward, sleep, appetite, motivation, and cognition. In particular, hyperactivity of the HPA axis in some depressed patients has been found to lead to hippocampal volume reduction, likely by reduction of brain-derived neurotrophic factor (BDNF) and changes in the mechanisms that mediate BDNF expression. However, whether reduced hippocampal volume is a partial cause or merely a result...

Interaction of Depression Anxiety and Medical Illness

A complex and reciprocal relationship exists between medical illnesses and comorbid anxiety and depressive disorders. Medical illnesses are associated with higher prevalence rates of anxiety and depression, and anxiety and depression are associated with higher rates of comorbid medical illnesses. Studies of patients with diabetes, cancer, stroke, myocardial infarction, HIV-related illness, and Parkinson's disease have higher rates of depression compared to patients without such illnesses (Katon, 2003 a). Common medical disorders seen in primary care settings have high comorbidity with anxiety disorders as well. Cardiovascular disease is associated with a 1.5 times greater risk of both GAD and panic disorder (Goodwin et al., 2008). Patients with back pain or arthritis are almost twice as likely to have panic attacks or GAD (McWilliams et al., 2004), whereas patients with asthma (pediatric or adult) may have a 30 increased likelihood of anxiety disorders (Katon et al., 2004). The...

Restless Legs Syndrome and Periodic Limb Movement Disorder

Evening and bedtime doses of levodopacarbidopa or dopaminergic agonists provide the most benefit in RLS and PLM disorder. y Some patients require additional doses during the night or controlled-release formulations. Unfortunately, some patients develop tolerance and require increasing doses, whereas others develop increased daytime symptoms of restless legs. If necessary, levodopa-carbidopa can be given around the clock to such patients. Temporary withdrawal and reinstitution of therapy a few weeks later may improve efficacy.

Amyotrophic Lateral Sclerosis

In addition to range of motion and mild resistive and walking exercises, patients with ALS may need rehabilitative interventions for spas-ticity, foot-drop, hand paresis, dysarthia, and dysphagia. The inertia of a spastic paretic gait and spasms usually respond to baclofen, the benzodiazepines or other antispasticity agents (Table 8-10). All antispasticity medications can worsen bulbar function, however. Levodopa carbidopa, 25 100 mg, may relieve nocturnal movements and sometimes lessens hyper-tonicity. Standing can reduce leg tone temporarily. Anticholinesterase medications such as pyridostigmine, 30-120 mg, may modestly

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