PARKINSONS DISEASE

INTRODUCTION
Parkinson's disease may be one of the most baffling and complex of the neurological disorders. Its cause remains a mystery but research in this area is active, with new and intriguing findings constantly being reported. Parkinson's disease was first described in 1817 by James Parkinson, a British physician who published a paper on what he called "the shaking palsy.". In the early 1960s, researchers identified a fundamental brain defect that is a hallmark of the disease: the loss of brain cells that produce a chemical -dopamine -- that helps direct muscle activity. This discovery pointed to the first successful treatment for Parkinson's disease and suggested ways of devising new and even more effective therapies. Parkinson's disease belongs to a group of conditions called motor system disorders. The four primary symptoms are tremor or trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; bradykinesia or slowness of movement; and postural instability or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. The disease is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. It is not contagious nor is it usually inherited -- that is, it does not pass directly from one family member or generation to the next. Parkinson's disease is the most common form of parkinsonismThese disorders share the four primary symptoms described above, and all are the result of the loss of dopamine-producing brain cells. Parkinson's disease is also called primary parkinsonism or idiopathic Parkinson's disease; idiopathic is a term describing a disorder for which no cause has yet been found. In the other forms of parkinsonism either the cause is known or suspected or the disorder occurs as a secondary effect of another, primary neurological disorder.

ETIOLOGY

Parkinson's disease occurs when certain nerve cells, or neurons, in an area of the brain known as the substantia nigra die or become impaired. Normally, these neurons produce an important brain chemical known as dopamine. Dopamine is a chemical messenger responsible for transmitting signals between the substantia nigra and the next "relay station" of the brain, the corpus striatum, to produce smooth, purposeful muscle activity. Loss of dopamine causes the nerve cells of the striatum to fire out of control, leaving patients unable to direct or control their movements in a normal manner. Studies have shown that Parkinson's patients have a loss of 80 percent or more of dopamineproducing cells in the substantia nigra. Unstable and potentially damaging molecules generated by normal chemical reactions in the body -- may contribute to nerve cell death thereby leading to Parkinson's disease. Free radicals are unstable because they lack one electron; in an attempt to replace this missing electron, free radicals react with neighboring molecules (especially metals such as iron), in a process called oxidation. Oxidation is thought to cause damage to tissues, including neurons.

Normally, free radical damage is kept under control by antioxidants, chemicals that protect cells from this damage. Evidence that oxidative mechanisms may cause or contribute to Parkinson's disease includes the finding that patients with the disease have increased brain levels of iron, especially in the substantia nigra, and decreased levels of ferritin, which serves as a protective mechanism by chelating or forming a ring around the iron, and isolating it.

Parkinson's disease may occur when either an external or an internal toxin selectively destroys dopaminergic neurons. An environmental risk factor such as exposure to pesticides or a toxin in the food supply is an example of the kind of external trigger that could cause Parkinson's disease. The theory is based on the fact that there are a number of toxins, such as 1-methyl-4-phenyl-1,2,3,6,tetrahydropyridine (MPTP) and neuroleptic drugs, known to induce parkinsonian symptoms in humans. So far, however, no research has provided conclusive proof that a toxin is the cause of the disease.

The role of genetic factors in the development of Parkinson's disease. Fifteen to twenty percent of Parkinson's patients have a close relative who has experienced parkinsonian symptoms (such as a tremor).Parkinson's disease occurs when, for unknown reasons, the normal, age-related wearing away of dopamine-producing neurons accelerates in certain individuals.

INCIDENCE AND PREVALENCE

About 50,000 Indians are diagnosed with Parkinson's disease each year, with more than half a million Indians affected at any one time. Getting an accurate count of the number of cases may be impossible however, because many people in the early stages of the disease assume their symptoms are the result of normal aging. African-Americans and Asians are less likely than whites to develop Parkinson's disease.

TYPES OF PARKINSONS DISEASE

Postencephalitic parkinsonism. Just after the first World War, a viral disease, encephalitis lethargica, attacked almost 5 million people throughout the world, and then suddenly disappeared in the 1920s. Known as sleeping sickness, this disease killed one third of its victims and in many others led to post-encephalitic parkinsonism, a particularly severe form of movement disorder in which some patients developed, often years after the acute phase of the illness, disabling neurological disorders, including various forms of catatonia.

Drug-induced parkinsonism. A reversible form of parkinsonism sometimes results from use of certain drugs -- chlorpromazine and haloperidol, for example -- prescribed for patients with psychiatric disorders. Some drugs used for stomach disorders (metoclopramide) and high blood pressure (reserpine) may also produce parkinsonian symptoms.

Striatonigral degeneration. In this form of parkinsonism, the substantia nigra is only mildly affected, while other brain areas show more severe damage than occurs in patients with primary Parkinson's disease. People with this type of parkinsonism tend to show more rigidity and the disease progresses more rapidly.

Arteriosclerotic parkinsonism. Sometimes known as pseudoparkinsonism, arteriosclerotic parkinsonism involves damage to brain vessels due to multiple small strokes. Tremor is rare in this type of parkinsonism, while dementia -- the loss of mental skills and abilities -- is common. Antiparkinsonian drugs are of little help to patients with this form of parkinsonism.

Toxin-induced parkinsonism. Some toxins -- such as manganese dust, carbon disulfide, and carbon monoxide -- can also cause parkinsonism. A chemical known as MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine)

causes a permanent form of parkinsonism that closely resembles Parkinson's disease.

Parkinsonism-dementia complex of Guam. This form occurs among the Chamorro populations of Guam and the Mariana Islands and may be accompanied by a disease resembling amyotrophic lateral sclerosis (Lou Gehrig's disease). The course of the disease is rapid, with death typically occurring within 5 years. Some investigators suspect an environmental cause, perhaps the use of flour from the highly toxic seed of the cycad plant. This flour was a dietary staple for many years when rice and other food supplies were unavailable in this region, particularly during World War II.

Parkinsonism accompanying other conditions. Parkinsonian symptoms may also appear in patients with other, clearly distinct neurological disorders such as Shy-Drager syndrome (sometimes called multiple system atrophy), progressive supranuclear palsy, Wilson's disease, Huntington's disease, Hallervorden-Spatz syndrome, Alzheimer's disease, Creutzfeldt-Jakob disease, olivopontocerebellar atrophy, and posttraumatic encephalopathy

ANATOMY AND PHYSIOLOGY OF PARKINSONS DISEASE

OVERVIEW OF BRAIN PATHOLOGY INVOLVED IN PARKINSONS DISEASE

Lobes Occipital Parietal Temporal

Function Perception & Memory of Vision Perception & Memory of Space, Proprioception, and Somatosensory Perception & Memory of Sound

In order to initiate movement, the brain must have current information about the environment. Through the sensory organs, this information is collected, projected to its proper location in the brain, and analysed. As seen in

the chart below, the sensory information and function of the areas involved are shown:

The frontal lobe gathers this information and uses it to plan movements.The specific area in the frontal lobe that is involved with motion is the prefrontal cortex, which is located rostral to the premotor cortex and supplementary motor area. These two areas are located adjacent and rostral to the primary motor cortex. The prefrontal cortex is of particular interest because this is the area that executes planned movement. Once the information has been analyzed at the prefrontal cortex, it is projected to the premotor cortex and supplementary motor area, and then to the primary motor cortex. Direct electrical stimulation of the primary motor cortex results in movement of specific areas of the body. Consequently, the signal is sent to the spinal cord and then to the appropriate area for movement.

CORTICAL-BASAL GANGLIA LOOP The basal ganglia plays an integral role in movement. It is composed of the following nuclei: the caudate nucleus, putamen, and the globus pallidus. Inputs from the cerebral cortex, especially the primary motor strip and primary somatosensory cortex, are received in the basal ganglia and the substantia nigra. The outputs of these two areas are the primary motor cortex, supplementary motor area, the motor nuclei of the brain stem, and via the thalamus, the premotor cortex. The location of these nuclei and pathway for

movement is a circular loop which enables the basal ganglia to receive information about planned movements and motion that is performed by the primary motor cortex as seen on below . With this knowledge, the basal ganglia controls the motor cortex. The diagram below illustrates the planned and executed aspects of movement.

The inputs from the primary motor cortex and the primary somatosensory cortex are projected to the the putamen. Next, the signal is sent to the caudate and then to globus pallidis, which has two different outputs: the motor nuclei of the brain stem and the subthalamic nucleus. From the globus pallidus, the signal is then projected to the motor cortex via the ventrolateral thalamus. The feedback loop is complete when information from the primary motor and primary somatosensory cortex are sent to the putamen.

Specifically, the loop is maintained by two neurotransmitters: glutamate and GABA. The substantia nigra via dopamine sends both excitatory and inhibitory signals to the caudate, which innervates different areas of the putamen. The inhibitory signal has been received in the putamen, and it is relayed to the external globus pallidus. As a result, an IPSP is produced at the subthalmic nucleus. This inhibition results in an EPSP at the internal globus pallidus. Consequently, an inhibitory signal is sent to the thalamus, which produces an EPSP. This excitatory message is then projected to the motor cortex, which results in motor movement.

The excitatory input from the substantia nigra has a somewhat similar pathway. Like the inhibitory pathway, an IPSP is produced at the globus pallidus, but at a different location, the internal globus pallidus. From this area, the mechanism is like the one previously described. The diagram below illustrates the corto-basal ganglia loop (Carlson, 244). The red arrows indicate inhibitory pathways; the black arrow are excitatory connections.

CLINICAL FEATURES OF PARKINSONS DISEASE Signs and symptoms of Parkinson's disease are varied. Parkinson's disease affects movement, producing motor symptoms.[1] Non-motor symptoms, which include autonomic dysfunction, cognitive and neurobehavioral problems, and sensory and sleep difficulties, are also common. Motor symptoms Parkinsonian Gait

Parkinson's disease patient showing a flexed walking posture Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability. Other motor symptoms include gait and posture disturbances such as decreased arm swing, a forward-flexed posture and the use of small steps when walking; speech and swallowing disturbances; and other symptoms such as a mask-like face expression or small handwriting are examples of the range of common motor problems that can appear.

Cardinal symptoms

Four symptoms are considered cardinal in PD: tremor, rigidity, bradykinesia and postural instability.

Tremor is the most apparent and well-known symptom. It is also the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses. It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep. It affects to a greater extent the most distal part of the limb, and at onset typically appears in only a single arm or leg, becoming bilateral later.

Frequency of PD tremor is between 4 and 6hertzs (cycles per second). It is a pronation-supination tremor that is described as "pill-rolling"; a term used to describe the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement. Such term was given due to the similarity of the movement in PD patients with the former pharmaceutical technique of manually making pills. PD tremor is not improved with alcohol intake, as opposed to essential tremor.

Rigidity is a characterized by an increased muscle tone (an excessive and continuous contraction of the muscles) which produces stiffness and resistance to movement in joints. Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease. When limbs of the person with PD are passively moved by others a "cogwheel rigidity" is commonly seen. Cogwheel-like refers to the ratchety jerks by which the articulation is moved as opposed to the normal fluid movement: when a muscle is externally tried to move it resists at first but with enough force it is partially moved until it resists again and only with further force it will be move. The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.

Bradykinesia and akinesia: the former refers to slowness of movement while the latter to the absence of it. It is the most characteristic clinical feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement. The performance of sequential and simultaneous movements is also hindered. Bradykinesia is the most disabling symptom in the early stages of the disease. Initial manifestations of bradykinesia are problems when performing daily life tasks requiring fine motor control such as writing, sewing or getting dressed. Clinical evaluation is based in similar tasks consisting such as alternating movements between both hands or feet Bradykinesia is not equal for all movements or times. It is modified by the activity or emotional state of the subject to the point of some patients barely able to walk being capable of riding a bicycle. Generally patients have less difficulties when some short of external cue is provided.

Immobile patients who become excited may be able to make quick movements such as catching a ball (or may be able to suddenly run if someone screams "fire"). This phenomenon (kinesia paradoxica) suggests that patients with PD have intact motor programmes but have difficulties accessing them without an external trigger, such as a loud noise, marching music or a visual cue requiring them to step over an obstacle.

Postural instability: In the late stages postural instability is typical, which leads to impaired balance and frequent falls, and secondarily to bone fractures. Instability is often absent in the initial stages, especially in younger people. Up to 40% of the patients may experience falls and around 10% may have falls weekly, with number of falls being related to the severity of PD. It is produced by a failure of postural reflexes, along other disease related factors such as orthostatic hypotension or cognitive andsensory changes

Other motor symptoms

Drawing of a Parkinson's disease patient face showinghypomimia. Depiction appeared inNouvelle iconographie de la Salptrire, vol 1 (1888)

Text accompanying image stated "The strokes forming the letters are very irregular and sinuous, whilst the irregularities and sinuosities are of a very limited width. On a careful examination of this specimen of writing it will be perceived that the down-strokes are all, with the exception of the first letter, made with comparative firmness and are, in fact, nearly normal the finer upstrokes, on the contrary, are all tremulous in appearance, and it is to the unsteadiness of these lines that the peculiar character of the writing here is principally due."

Other motor symptoms include:

Gait and posture disturbances: Shuffling gait: gait is characterized by short steps, with feet barely leaving the ground. Small obstacles tend to cause the patient to trip. Decreased arm-swing. Turning "en bloc": rather than the usual twisting of the neck and trunk and pivoting on the toes, PD patients keep their neck and trunk rigid, requiring multiple small steps to accomplish a turn. Camptocormia: stooped, forward-flexed posture. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk.[7] Festination: A combination of stooped posture, imbalance, and short steps. It leads to a gait that gets progressively faster and faster, often ending in a fall. Gait freezing: also called motor blocks, is a manifestation of akinesia. Gait freezing is characterized by a sudden inability to move the lower extremities which usually lasts less than 10 seconds. It may worsen in tight, cluttered spaces, when attempting to initiate gait or turning around, or when approaching a destination. Freezing improves with treatment and also with behavioral techniques such as marching to command or following a given rhythm. Dystonia: abnormal, sustained, painful twisting muscle contractions, often affecting the foot and ankle (mainly toe flexion and foot inversion) which often interferes with gait. Scoliosis Speech and swallowing disturbances. Hypophonia: soft speech. Monotonic speech: Speech quality tends to be soft, hoarse, and monotonous. Festinating speech: excessively rapid, soft, poorly-intelligible speech. Drooling: most likely caused by a weak, infrequent swallow. Dysphagia: impaired ability to swallow; which in the case of PD is probably related to an inability to initiate the swallowing reflex or by a too long laryngeal or oesophageal movement. Can lead to aspiration pneumonia.

Dysarthria

Other motor symptoms and signs:

Fatigue Hypomimia: a mask-like face Difficulty rolling in bed or rising from a seated position. Micrographia:[1] small, cramped handwriting. IImpaired fine motor dexterity and motor coordination. Impaired gross motor coordination. Akathisia: an unpleasant desire to move. Reemergence of primitive reflexes. Glabellar reflex

Neuropsychiatric
Pathologic gambling can appear in PD patients as a manifestation of a dopamine dysregulation syndrome Parkinson's disease causes neuropsychiatric disturbances, which include mainly cognition, mood and behavior problems and can be as disabling as motor symptoms.[1] Cognitive disturbances occur even in the initial stages of the disease in some cases.[9] A very high proportion of sufferers will have mild cognitive impairment as the disease advances.[1] Most common deficits in non-demented patients are:

Executive dysfunction, which translates into impaired set shifting, poor problem solving, and uctuations in attention among other difficulties. Slowed cognitive speed (Bradyphrenia). Memory problems; specifically in recalling learned information, with an important improvement with cues. Recognition is less impaired than free recall pointing towards a retrieving more than to an encoding problem. Regarding language, patients are found to have problems in verbal fluency tests. Visuospatial skills difficulties, which are seen when the person with PD is for example asked to perform tests of facial recognition and perception of line orientation.

Deficits tend to aggravate with time, developing in many cases into dementia. A person with PD has a sixfold increased risk of suffering it, and the overall rate in people with the disease is around 30%.Moreover, prevalence of dementia increases in relation to disease duration, going up to 80%. Dementia has been associated with a reduced quality of life in disease sufferers and caregivers, increased mortality and a higher probability of attending a nursing home. Cognitive problems and dementia are usually accompanied by behavior and mood alterations, although these kind of changes are also more common in those patients without cognitive impairment than in the general population. Most frequent mood difficulties include:

Depression: Depression is well recognized in PD, having been identified as "melancholia" by James Parkinson in his original report of the disease in 1817. Estimated prevalence rates of depression vary widely according to the population sampled and methodology used although prevalence at a given time is most probably around 31%; which doubles the numbers in the general population. There is an increased risk for any individual with depression to go on to develop Parkinson's disease at a later date. It is increasingly thought to be a consequence of the disease rather than an emotional reaction to disability. Since Parkinson's affects many areas of the brain that control mood (specifically the frontal lobe as well as those areas that produce serotonin, norepinephrine and dopamine), depression may result. Depression is one of the most common neuropsychiatric conditions found in patients who have Parkinson's disease, and it is associated with more rapid progression of physical symptoms and a greater decline in cognitive skills. Depression in patients with PD was found to be more predictive of overall disability than was the motor disability from the PD. An interesting finding is that although there is a high rate of depression in patients with PD, the incidence of suicide is lower in this group of patients. Many of the symptoms of PD may overlap with those of depression, making diagnosis a difficult issue. Apathy Anxiety: Seventy percent of individuals with Parkinson's disease diagnosed with pre-existing depression go on to develop anxiety. Ninety percent of Parkinson's disease patients with pre-existing anxiety subsequently develop depression; apathy or abulia.

Obsessivecompulsive behaviors such as craving, binge eating, hypersexuality, pathological gambling, or other, can also appear in PD, and have been related to a dopamine dysregulation syndrome associated with the medications for the disease. Psychotic symptoms are common in PD, generally associated with dopamine therapy. Symptoms of psychosis, or impaired reality testing, are either hallucinations, typically visual, less commonly auditory, and rarely in other domains including tactile, gustatory or olafactory, or delusions, that is, irrational beliefs. Hallucinations are generally stereotyped and without emotional content. Initially patients usually have insight so that the hallucinations are benign in terms of their immediate impact but have poor prognostic implications, with increased risk of dementia, worsened psychotic symptoms and mortality. Delusions occur in about 5-10% of treated patients, and are considerably more disruptive, being paranoid in nature, of spousal infidelity or family abandonment. Psychosis is an independent risk factor for nursing home placement.

Hallucinations can occur in Parkinsonian syndromes for a variety of reasons. There is an overlap between Parkinson's disease and Lewy body dementia, so that where Lewy bodies are present in the visual cortex, hallucinations may result. Hallucinations can also be brought about by excessive dopaminergic stimulation. Most hallucinations are visual in nature, often formed as familiar people or animals, and are generally non-threatening in nature. Some patients find them comforting; however their carers often find this part of the disease most disturbing and the occurrence of hallucinations is a major risk factor for hospitalisation. Treatment options consist of modifying the dosage of dopaminergic drugs taken each day, adding an antipsychotic drug like quetiapine, or offering carers a psychosocial intervention to help them cope with the hallucinations.

Sleep

Rapid eye movement sleep (REM) is altered in PD as opposed to the shown EEGpolysomnographic record representing normal REM Sleep problems can be worsened by medications for PD, but they are a core feature of the disease. Some common symptoms are:

Excessive daytime somnolence. Insomnia, characterized mostly by sleep fragmentation. Disturbances in REM sleep: disturbingly vivid dreams, and rapid eye movement behavior disorder, characterized by acting out of dream content.[1] It appears in a third of the patients and it is a risk factor for Parkinson's disease in the overall population.[1]

Perception
Impaired proprioception (the awareness of bodily position in threedimensional space). Reduction or loss of sense of smell (hyposmia or anosmia).[1] It may be an early marker of the disease. Pain: Neuropathic, muscle, joints, and tendons, attributable to tension, dystonia, rigidity, joint stiffness, and injuries associated with attempts at accommodation. Paresthesias.

Autonomic

Orthostatic hypotension, leading to dizziness and fainting Oily skin Urinary incontinence (typically in later disease progression) and nocturia (getting up in the night to pass urine) Altered sexual function: characterized by profound impairment of sexual arousal, behavior, orgasm, and drive is found in mid and late Parkinson disease. Excessive sweating

Gastrointestinal

Parkinson' disease causes constipation and gastric dysmotility that is severe enough to endanger comfort and even health.[18] A factor in this is the appearance of Lewy bodies and Lewy neurites even before these affect the functioning of the substantia nigra in the neurons in the enteric nervous system that control gut functions.[19]

Neuro-ophthalmological

PD is related to different ophthalmological abnormalities produced by the neurological changes. Among them are:

Decreased blink rate Irritation of the eye surface Alteration in the tear film Visual hallucinations Decreased eye convergence Blepharospasm Abnormalities in ocular pursuit and saccadic movements Difficulties to open the eye-lidsThis can have particular relevance when driving. People with Parkinson's have been shown to be less accurate in spotting landmarks and roadsigns whilst driving.

Limitations in the upward gaze Blurred vision Diplopia (double vision), produced by a reduced eye convergence.

DIFFERENTIAL DIAGNOSIS
There are a number of factors useful in separating an atypical form of parkinsonism from idiopathic Parkinson's disease. Patients with early-onset or rapidly progressive dementia coupled with parkinsonian features are more likely to have diffuse Lewy body disease (also called Lewy body dementia) or Alzheimer's disease. In addition, a history of a rapidly progressive course should trigger the clinician to look for other parkinsonian syndromes. The presence of supranuclear gaze palsy, especially a downgaze palsy, suggests progressive supranuclear palsy (PSP), a parkinsonism-plus syndrome.

Common Misdiagnoses

Distinguishing features

Essential tremor (ET) Tremor (action/postural) is the only or predominant feature; no response to PD drugs Progressive supranuclear palsy (PSP) Multiple system atrophy (MSA) Supranuclear downgaze palsy; square-wave jerks; upright posture; pseudobulbar affect; early gait instability; dysphagia Autonomic disturbance, cerebellar signs, relative absence of tremor; early gait instability; dysphagia

Corticobasal Limb apraxia; cortical sensory abnormalities; coarse degeneration (CBD) unilateral tremor; early dementia Diffuse Lewy body dementia (LBD) Early dementia; psychosis; agitation

Alzheimer's disease Dementia is the primary symptom Drug-induced parkinsonism Vascular parkinsonism Exposure to dopamine-blocking drugs; lack of rest tremor and asymmetry History of chronic hypertension; stepwise progression (if any); unilateral; imaging

Evidence of upper motor neuron involvement, such as Babinski's sign and pathological hyperreflexia, suggests corticospinal pathway involvement. Patients exhibiting cerebellar signs such as dysmetria, ataxia, nystagmus, titubation, or gait ataxia need to be evaluated further for cerebellar diseases. Patients with early onset of urinary incontinence should be evaluated for normal pressure hydrocephalus or other possible symptomatic or secondary causes of parkinsonism.

Early symptomatic postural hypotension is rare in PD, and suggests the possibility of multiple system atrophy.

Other Disorders

Wilson's disease Huntington's disease DRPLA SCA-3 Metabolic disorder Structural lesion Hydrocephalus Infectious encephalitis

INVESTIGATIONS

A diagnosis of Parkinson's disease is based on your medical historyand a thorough neurological exam. Your doctor also may check your sense of smell. Sometimes, your doctor will have you try a medicine for Parkinson's disease. If that medicine helps your symptoms, it may help the doctor find out if you have Parkinson's disease. There are no lab tests that can diagnose Parkinson's disease. If your symptoms and the doctor's findings during the examination are not entirely typical of Parkinson's disease, certain tests may be done to help diagnose other conditions with similar symptoms. For instance, blood tests may be done to

check for

abnormal thyroid hormone levels or liver damage. An imaging test (such as a CT scan or an MRI) may be used to check for signs of a stroke or brain tumor. Another type of imaging test, called PET, sometimes may detect low levels of dopamine in the brain, a key feature of Parkinson's disease. But PET scanning is not commonly used to evaluate Parkinson's disease because it is very expensive, is not available in many hospitals, and is only used experimentally. Investigators became interested in the possibility that impairment in mitochondrial DNA may be the cause of Parkinson's disease. Mitochondria are essential organelles found in all animal cells that convert the energy in food into fuel for the cells Early detection For some diseases, doctors can do tests to look for problems or diseases before you have any symptoms. This is called screening. But there is no screening test for Parkinson's disease at this time.

TREATMENT
Unlike many other neurodegenerative diseases, there is effective symptomatic therapy for Parkinson's disease that can provide most patients with several years of satisfactory quality of life and response to treatment. Key points in PD therapy include: No therapy has yet been shown to slow or reverse the disease, although clinical trials of several candidates have shown intriguing results. Levodopa continues to be the most effective treatment for motor symptoms, and all patients eventually require it. Long-term complications of dopaminergic therapy are a concern that drives decision-making early in the treatment program. Non-motor symptoms, especially depression and anxiety, are important targets of therapy. Surgical treatment has become a mainstay of late-stage management, although not all patients can afford it or are appropriate candidates. Cell transplant therapies are still experimental. Non-pharmacological treatments remain an important part of a comprehensive treatment program.

Drug Classes

Five classes of drugs comprise the pharmacological armamentarium for the motor symptoms of PD: Levodopa

Levodopa was introduced as a PD therapy in the 1960s, and remains the most effective therapy for motor symptoms. It alleviates all the cardinal motor symptoms of PD, including bradykinesia, which is generally the most disabling motor feature of the disease. Carbidopa (in the United States ) or benserazide (not available in the US ) are included in the standard oral formulation to inhibit conversion of levodopa to dopamine outside of the brain (in the periphery). Carbidopa does not cross the blood-brain-barrier. Levodopa is a large neutral amino acid, which is absorbed in the gut and transported across the blood-brain barrier by the large neutral amino acid transporter. Thus, it competes with dietary amino acids for transport, and patients with advanced PD may need to schedule the administration of their doses far from meal times, or reduce the protein content of their meals.

Legend: Levodopa Metabolism BBB = Blood brain barrier AADC = amino acid decarboxylase COMT = catechol Omethyltransferase MAO = monoamine oxidase

Adverse effects
Nausea and vomiting are the most common side effects, and are due to accumulation of dopamine in the blood stream (periphery). Orthostatic hypotension also occurs. The risk of hallucinations and paranoia increases over time, especially with advanced age. Compulsive behavior, including gambling and hypersexuality, is a rare adverse effect. Drowsiness is a common adverse effect of levodopa and other dopaminergic therapies, and daytime somnolence and sudden sleep onset is possible. Patients may not experience any warning signs of sudden sleep onset; when such therapy is prescribed by a physician, patients need to be counseled

and warned about this possibility of sudden sleep onset. In addition, patients should be reminded of this warning when doses are increased or when switching agents. No one agent appears to be more likely than others to cause these effects.

The most troubling adverse effect from long-term levodopa use is dyskinesias, or uncontrolled movements. These typically begin to develop in a relatively mild form after three to five years of treatment and become more severe after five to 10 years of treatment. As the disease progresses, the dose required for symptomatic control approaches that which induces intolerable dyskinesias, thus narrowing the therapeutic window and limiting the continuing utility of levodopa. At this point, surgery may be the only effective option.

Delaying commencement of levodopa therapy may be an appropriate strategy in younger patients, as discussed in the section entitled "Approaches to Treatment." Early concern that levodopa may be neurotoxic in vivo does not seem to be borne out by clinical experience or recent research.

Dosing and Other Formulations

Theoretical and experimental evidence suggests that continuous, versus pulsatile, delivery of levodopa may reduce or delay the risk for dyskinesias. While controlled-release preparations have not proven effective, newer formulations, including duodenal delivery, may hold promise in this regard. Immediate-release levodopa/carbidopa is formulated in doses of 10/100, 25/100, and 25/250 milligram pills. Onset of action is usually 20 to 40 minutes. Early-stage PD patients typically experience a smooth and sustained benefit from intermittent dosing. In more advanced PD patients, duration of benefit is 2 to 4 hours. An orally disintegrating tablet of levodopa and carbidopa (Parcopa) is also available in the same doses as the swallowed pill. This formulation does not need to be taken with water. Dissolving the tablets in orange juice is a possible strategy for speeding the onset of effect, although this reduces the duration of benefit.

Dopamine Agonists A variety of dopamine agonists are available; these differ in their duration of action, method of delivery, and adverse effect profile. The currently available agonists are listed in the table below.

Dopamine Agonists: Half-lives and Monotherapy Dosages Name T1/2 Dosage (monotherapy) 30 min 6 hr 8 hr 4 hr 2-100 mg/day

Apomorphine

Bromocriptine Pramipexole Ropinirole Rotigotine Cabergoline

7.5-30 mg/day 1-4.5 mg/day 3-24 mg/day

5-7 hr 4-6 mg/day 65+ hr 2-5 mg/day

Lisuride

2-4 hr 1-5 mg/day

Dopamine agonists directly stimulate dopamine receptors, and do not require metabolic conversion within the degenerating cells of the substantia nigra. Despite this theoretical advantage, dopamine agonist monotherapy is not an effective substitute for levodopa in the long-term, with the possible exception of apomorphine infusion.

Clinical trials of both pramipexole and ropinirole have shown their ability to delay motor complications when used as monotherapy early in the disease. These trials have also shown that the dopamine agonists provide less complete symptomatic control than levodopa, although it is possible this difference is simply an artifact of the evaluation tools used. Dopamine agonists tend to produce more edema and psychosis than levodopa, effects which may be more clinically significant than mild dyskinesias, especially in older patients.

The reason for the delay in motor complications has been the subject of much study and controversy. While some preclinical evidence supports the possibility that dopamine agonists are neuroprotective, no unequivocal clinical evidence for this effect exists. In the agonist-levodopa trials, intensity of neuroimaging markers declined less quickly on the agonists. While neuroprotection is one possible explanation, there is also evidence that differential pharmacological effects on the remaining cells, such as upregulation by the agonist or down regulation by levodopa, may play a part.

Adverse Effects
Drowsiness is a common adverse effect of dopamine agonists and levodopa, and sudden sleep onset is possible. Patients may not experience any warning signs of sudden sleep onset, and should be warned about this possibility at the commencement of therapy, when increasing doses, or switching agents. Other significant adverse effects of dopamine agonists include nausea, vomiting, and orthostatic hypotension. A rare but potentially serious adverse effect is development of impulse control disorders, most often manifested as hypersexuality, excessive gambling, compulsive shopping, or obsessive hobby activity. Fibrosis is a risk from the ergot-derived dopamine agonists, which are pergolide, bromocriptine, cabergoline, and lisuride. Pulmonary and retroperitoneal fibrosis are rare, while recent studies suggest fibrosis of the heart valves may be common enough to warrant monitoring of all patients on ergot-derived agonists, and switching to a non-ergot agonist when possible. Pergolide was withdrawn from the US market in March 2007 over concern for this effect.

Apomorphine Rescue Therapy

The receptor activation profile of apomorphine most closely matches that of levodopa, and it can provide a quality of symptomatic benefit that is equivalent to that of levodopa. It is not orally available, and must be administered parenterally. Subcutaneously injected apomorphine (Apokyn) is used as a "rescue" therapy for patients with off episodes. Its onset of effect is approximately 10

minutes, and lasts approximately 90 minutes. Guidelines from frequent prescribers indicate it can be used up to 10 times per day; if more frequent dosing is needed, continuous infusion is recommended if the patient is to remain on apomorphine. Injection-site reactions may occur, but are generally well tolerated.

Continuous subcutaneous apomorphine infusion is possible as an alternative to other forms of therapy. This continuous delivery has been shown to reduce dyskinesias in clinical trials. Skin nodules at the infusion site are a major complication, but may be minimized by regular rotation of the needle site.

COMT Inhibitors
Inhibition of catechol O-methyltransferase (COMT) prevents conversion of levodopa to 3 O-methyldopa in the periphery, thus increasing the levodopa available for transport into the brain. Two COMT inhibitors are approved in the United States , entacapone and tolcapone. Neither has significant activity in the CNS. Both have been shown to decrease the duration of "off" time in patients with significant off time. Tolcapone is more effective than entacapone, reducing off time in clinical trials by 2 to 3 hours, versus 1 to 2 hours for entacapone. Both treatments usually allow reduction of levodopa dose in the range of 20% to 25%. Physicians often choose to commence COMT inhibitor therapy early in the week to be available by phone to help patients reduce their levodopa dose if dyskinesias develop. Entacapone (Comtan) is dosed at 200 mg with each levodopa dose. Diarrhea is the most common side effect, which may require stopping treatment in approximately 5% of patients. Diarrhea usually begins one to two weeks after therapy initiation. A combination of levodopa, carbidopa, and entacapone in a single pill (Stalevo) is also available, with a similar side effect profile to the agents used alone. Pills are available in a range of levodopa/carbidopa doses, each of which contains 200 mg entacapone. Tolcapone (Tasmar) is dosed at 100 or 200 mg tid. Side effects include diarrhea, which may preclude treatment in up to 15% of patients. Four cases of acute fulminant hepatic necrosis, with three deaths, have been reported, and led the FDA to issue a "black box" warning on tolcapone. This warning recommends that physicians only prescribe tolcapone for patients whose symptoms cannot be adequately controlled without it. MAO-B Inhibitors Monoamine oxidase B acts in the brain to degrade dopamine. Thus,

inhibiting MAO-B is a therapeutic strategy for treatment of PD. Two selective MAO-B inhibitors are available in the United States and elsewhere: selegiline and rasagiline. Both are irreversible inhibitors of the enzyme.

Rasagiline
Rasagiline (Azilect) is approved for the treatment of signs and symptoms of Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. It is available in 0.5 mg and 1.0 mg tablets. As monotherapy, it may reduce parkinsonian disability. As adjunctive therapy, it may reduce off time and increase dyskinesia-free on time. As monotherapy, the recommended dose is 1.0 mg once daily. As adjunctive therapy, the recommended dose is 0.5 mg once daily, with the option of increasing to 1.0 mg daily if sufficient clinical response is not obtained with the lower dose. The risk of hypertensive crisis increases above the prescribed dose. Side effects include insomnia, hallucinations, and orthostatic hypotension.

Selegiline
Selegiline is available as a swallowed pill (Eldepryl and generics), and as an orally disintegrating tablet (Zelapar ODT), which is not swallowed and does not require water. Selegiline is approved for the treatment of signs and symptoms of Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. As monotherapy, it may reduce parkinsonian disability. As adjunctive therapy, it may reduce off time and increase dyskinesia-free on time. Selegiline in pill form is dosed at 5 mg once daily. Zelapar is dosed at 1.25-2.5 mg once daily. The risk of hypertensive crisis increases above the prescribed dose. Side effects include insomnia, hallucinations, and orthostatic hypotension.

Hypertensive Crisis
Nonselective MAO inhibition (i.e., inhibition of both MAO-A and MAO-B) may lead to life-threatening hypertensive crisis when tyramine-containing foods

or drugs are consumed. While selegiline and rasagiline are selective MAO-B inhibitors, at doses above the prescribed dose, the risk of hypertensive crisis increases. Foods to avoid include air-dried or fermented meats, pickled herring, fava beans, soy beans and soy products (including soy sauce), aged cheeses, red wine, non-pasteurized beer, sauerkraut, and yeast extracts. Drugs to avoid include sympathomimetic amines including pseudoephedrine, phenylephrine, phenylproanolamine, and ephedrine.

Research on Neuroprotection
Selegiline was the subject of a major neuroprotective trial in PD, the DATATOP trial. While the results appeared to indicate that selegiline slowed the disease, the time required to wash out selegiline's symptomatic effect was greater than the washout period allotted in the trial, thus making these results inconclusive. In a 2004 trial of rasagiline with a different trial design, patients who were treated for rasagiline for 12 months had slightly better activities of daily living scores than those treated for only 6 months, suggesting the potential for a disease-modifying effect. This study will need to be repeated and expanded before firm conclusions can be drawn. Frequent liver function monitoring is required for patients commencing therapy. This requires a blood test every 2-4 weeks for the first 6 months, to be sure that certain critical liver function values are not rising. After that, blood tests are recommended at intervals deemed clinically relevant. Treatment should be discontinued if the ALT/AST levels rise above twice the upper limit of norma

Anticholinergics
Anticholinergics have a limited role in the treatment of PD. They are primarily effective against tremor and rigidity, and their side effects may be especially significant in elderly patients. Doses should begin low and increase slowly. Typical doses for common anticholinergics are: Trihexyphenidyl (Artane): 2-15 mg/day Benztropine: 1.0-4.5 mg/day

 Ethopropazine: 10-200 mg/day Common side effects are memory loss, dry mouth, urinary retention, constipation, sedation, delirium, and hallucinations

Amantadine
Amantadine (Symmetrel, generics) has a mild symptomatic effect on the motor symptoms of PD, but a more significant effect on the reduction of dyskinesias. It is believed to act through blockade of N-methyl-D-aspartate (NMDA) receptors. It is usually dosed at 100 mg 2-4 times per day. Side effects include hallucinations, insomnia, agitation, and difficulty concentrating, as well as ankle edema, dry mouth and mottled skin. Amantadine may be ineffective for dyskinesias in up to one third of patients.

Treatment Decision-Making
Early Disease The central questions in commencing treatment of PD are when to begin, and with what agent or combination of agents.

Potential Neuroprotection

If and when a clearly neuroprotective agent is identified, it will likely become the first treatment offered, and will be started as early in the course of the disease as possible. As of late 2006, no agent has been definitively shown to offer neuroprotection. Selegiline has a mild symptomatic effect, and is often used early for this reason, as well as its equivocal and much debated effects on slowing disease progression. Rasagiline is also used for the same purposes, based on its proven mild symptomatic effect and suggestion of a diseaseslowing effect from a single trial. Coenzyme Q10, available over the counter, is also used early, based on a single trial whose results suggested a mild neuroprotective effect. Most PD experts believe the results of this trial are too preliminary and not robust enough to change early treatment practices without replication. CW Shults, D Oakes, K Kieburtz, et al., and the Parkinson Study Group. Effects of coenzyme Q10 in early Parkinson disease: Evidence of slowing of the functional decline.Arch Neurol 2002;59:1541-1550

Commencing Symptomatic Therapy

The decision as to when to begin symptomatic therapy is an individual one made between patient and physician. Factors include: Degree of functional impairment Effect of symptoms on employment Patient attitudes towards medications Fully educating the patient regarding the benefits and limitations of specific therapies allows the patient to be a full partner in the decision-making process. The obvious benefits of this collaborative decision-making process are especially important in PD, since treatment must be reevaluated and adjusted so often during the course of the disease, based on the changing condition of the patient and the response to previous therapy. It is in the interest of both patient and physician to develop such a partnership from the very beginning.

Initial Treatment Options

The choice of initial treatment is strongly influenced by patient age and condition. Levodopa is the usual treatment of choice in the elderly patient, because of its lower risk for psychiatric complications as compared to dopamine agonists. A dopamine agonist may be preferable in the younger patient, who is likely to be more tolerant of its side effects, and for whom delaying motor complications is an important goal, given the longer treatment horizon. An MAOB inhibitor, amantadine, or an anticholinergic may also be appropriate initial treatment for mild symptoms, provided the side effects can be tolerated. Depression and anxiety may also be early debilitating symptoms, and therefore can become the object of initial therapy.

Surgery

Brain surgery is an option for advanced PD patients whose symptoms can no longer be adequately managed pharmacologically. The best surgical candidate is someone who responds well to dopaminergic therapy but has motor complications (off periods and dyskinesias) that are limiting factors, and who is otherwise healthy and a good surgical risk. Advanced age is not necessarily a barrier to surgery; however, impaired cognition and brain atrophy increase surgical risk and decrease the likelihood of an optimal outcome. Depending on the patient, procedure, and skill of the operating team, cognition may be mildly impaired or largely unaffected. The most commonly reported adverse neuropsychiatric effects are reduced executive function and language impairments.

Types of Surgery

There are two surgical procedureslesioning and deep brain stimulation and three target locations in PD surgery: thalamus, globus pallidum internus (GPi), and subthalamic nucleus (STN). Deep brain stimulation (DBS) uses implanted electrodes to create a functional thalamotomy, pallidotomy or subthalamotomy. Lesion procedures (pallidotomy, thalamotomy) deliver radiofrequency energy to heat and ablate a pea-sized region within the target. Cell transplants, gene therapy, and neurotrophic factor delivery remain experimental procedures for the treatment of PD.

Deep Brain Stimulation (DBS)

DBS uses a programmable stimulator implanted in the chest wall, connected by subcutaneous leads to implanted, bipolar electrodes in the brain. The stimulator can be turned on and off by a magnet. Batteries can be replaced as needed, generally after 5 years. The high-frequency stimulation simulates a lesion, although the exact mechanism is not known. There are a large number of methodological issues that affect the efficacy of the procedure, including: The target chosen The ability to accurately locate the electrode in the target The variables of stimulation, and Post-operative changes in medication.

Adjusting the stimulation parameters after electrode implantation is a major time commitment on the part of the neurological team and patient.

Thalamic DBS
Like thalamotomy, thalamic DBS is primarily effective against tremor. Bilateral procedures are possible, but with a higher risk of adverse effects. Compared to thalamotomy, thalamic DBS has less morbidity.

GPi DBS
Effects of GPi DBS tend to mimic those of pallidotomy. Dyskinesia improvement is a major effect, along with some improvement in the cardinal motor signs of PD, primarily in the off-medication state. Bilateral DBS is better tolerated than bilateral pallidotomy.

Subthalamic DBS
The subthalamic nucleus (STN) has become a major target for DBS, with many teams considering it the target of choice for control of PD. It leads to improvement of all cardinal features of PD, with improvement of motor scores of 40% to 60% in the off condition, and 10% in the on condition. Levodopa dosage reduction is typically 30%, with resulting improvement in dyskinesias. Bilateral procedures appear to be superior to unilateral, with only a slightly increased risk of complications.

As DBS has become more common, rare but serious neuropsychiatric adverse events have been increasingly reported. Onset or worsening of depression occurs post-operatively in a small percentage of patients, often in those who prospectively are at increased risk for neuropsychiatric complications. Suicide, a well-known risk in depressed patients, has been reported in a small number of patients. Pre-operative neuropsychiatric evaluation is essential and post-operative follow-up is also a critical part of patient care.

Pallidotomy
Until the late 1990s, pallidotomy was the most common type of PD surgery (DBS is now more commonly performed). The target is located using microelectrode stimulation, with care taken to avoid the nearby optic tract. A microelectrode is then used to confirm placement, based on the globus pallidum internus (GPi)

firing pattern; therefore, the precise location of the GPi is identified by the characteristic electrical patterns of the GPi. Radiofrequency lesioning is then performed. Effects are apparent almost immediately. Depending on the center and the study, improvements from pallidotomy range from 70% to 90% for dyskinesias and dystonia, and 25% to 50% for tremor, rigidity, bradykinesia, and gait. Dyskinesia improvement is based partly on the reduction in levodopa dose made possible by the surgery. Improvements are primarily contralateral to the lesioned side and observed more while off medication than while on medication. Bilateral surgery is possible and improves dyskinesias further, but greatly increases the risk for worsening cognitive and bulbar effects, and is rarely performed today. Adverse effects of pallidotomy may include: Hemorrhage (2% to 6%) Weakness (2% to 8%) Visual field deficit (0% to 12%) Confusion (0% to 8%) Weight gain (50% to 70%)

Thalamotomy
Thalamotomy is primarily effective for tremor, and is therefore indicated mainly in patients for whom tremor is the only disabling symptom. Bilateral procedures are poorly tolerated because of increased complication risks, especially visual field deficits and language impairment. The procedure has largely been replaced by thalamic DBS in PD patients in the United States (but remains a useful treatment for medically intractable essential tremor).

Experimental Therapies
Cell Transplant Therapy

Transplant of fetal substantia nigra cells has been performed in several hundred patients to date in multiple centers throughout the world. While results have been encouraging in some individual patients, two double-blind placebocontrolled studies showed that consistent benefit was only seen in younger PD patients (age 60 or below), and side effects in some patients were significant. In particular, some patients developed off-medication dyskinesias even without any levodopa or other dopaminergic medication. The lack of consistently good results and the significant side effects encountered have been interpreted by the scientific and medical community to indicate that further research in animal models of PD is needed to improve upon what has been observed to date before more studies in PD patients are undertaken. Another cell transplant technique that shows some promise is the use of retinal pigment epithelial cells. These cells are derived from tissue at the back of the eye, and they produce and release dopamine. An open-label trial in six advanced PD patients has shown promise, and as of mid-2004, a double-blind trial is underway.

Gene Therapy

As of 2007, gene therapy has been tried in only a few PD patients. The only publicized trial is of delivery of the gene for glutamic acid decarboxylase (GAD) to the STN. GAD is a key enzyme in the production of the inhibitory neurotransmitter GABA. Gene therapy with GAD is meant to increase GABA production, reducing subthalamic nucleus (STN) activity in the manner of STN DBS. A very small phase I trial indicates that 12 months of treatment appears to be safe, and may improve motor symptoms.

Growth Factor Delivery

Glial cell-derived neurotrophic factor (GDNF) stimulates sprouting of dopaminergic neurons in animal models. Delivery of GDNF to the ventricles in PD patients has proven unsuccessful, possibly because GDNF cannot migrate far enough to reach the nigral cells. Direct delivery of GDNF to the striatum has

produced promising results in an open trial in a small number of patients; however, a larger, double-blind trial failed to show efficacy, and the manufacturerwithdrew GDNF from trials over concerns for safety.

Nonpharmacologic Treatments
A wide variety of problems in PD may respond to nonpharmacological treatments. These include: Motor, balance, posture, gait, and mobility Difficulties with activities of daily living (ADL) Speech and swallowing Inadequate nutrition Sleep disturbance Pain Constipation Sexual dysfunction Depression

In all cases, an individualized approach is needed to identify the problems and determine a treatment plan. Multiple members of the treatment team physical therapists, occupational therapists, speech-language pathologists, gerontologists, neurologists, psychologists, and othersmay be involved. Effective treatment may reduce the need for medications and improve quality of life.

Physical and Occupational Therapy

Goals of physical therapy include maintaining or increasing activity levels, decreasing rigidity and bradykinesia, optimizing gait, and improving balance and motor coordination. Features of the PT program may include: Regular exercise, such as walking (1+ miles/day), swimming, golf, or

dancing, depending on the patient's preferences and abilities Stretching and strengthening Exaggerated or patterned movements, such as high stepping and weight shifting Mobility aids, orthotics Training in transfer techniques Training in techniques to improve posture and walking Occupational therapy

Goals of occupational therapy include maximizing fine motor coordination, especially of the upper extremities, reducing energy expenditure, increasing safety and independence, and improving quality of life and efficiency of activities of daily living. Features of the OT program may include:

Use of orthoses and adaptive equipment Home and workplace modification, such as improving accessibility and removing obstructions Adaptation and simplification of utensils, toileting articles, beds, etc.

Speech and swallowing

Hypophonia often occurs in PD and deserves specific attention from the treatment team. Several PD-specific voice training programs have been developed, which share an emphasis on consciously increasing voice volume as a key strategy. Other features may include modification of speech patterns such as use of shorter sentences, breathing exercises, and range-of-motion exercises for the muscles of speech. Sialorrhea can be a feature of advanced PD. The genesis of the problem is not in increased saliva production, but reduced ability to swallow. Awareness of the problem, and consciously swallowing more often, may be effective. If not, treatments may include sublingual anticholinergics or botulinum toxin injection into the salivary glands. Management of swallowing difficulties may include instructions to take smaller bites, to completely empty the mouth before taking the next bite, and eating softer foods.

Sexuality
Sexual dysfunction affects a large proportion of patients with PD and their spouses. Difficulties include erectile dysfunction in men, vaginal dryness in women, and loss of libido. Hypersexuality from dopaminergic drugs also occurs. Most PD patients will not volunteer these problems unless specifically asked. Sildenafil (Viagra) has been shown to be safe and effective in men with PD to treat erectile dysfunction. Patients should always have a thorough urological or gynecological exam to rule out non-PD related causes.

Constipation
A good bowel regimen can greatly reduce constipation. Increased fluid intake, a diet rich in vegetables and fruits, use of stool softeners, and increased dietary and/or supplemental fiber are just some interventions that can help. Working with one's physician and/or a gastroenterologist is the approach to take.

Driving
PD patients tend to do worse than controls on tests of driving safety, because of increased reaction times and movement times caused by PD. Vehicular control skills are generally well preserved; however, attention to safety landmarks declines. A decline in vehicular performance correlates with worsening of motor abilities. Patients tend not to be good judges of their loss of driving safety and family members may need to intervene. A good way to determine driving capability is to have the patient undergo a driving examination at a rehabilitation facility.

Locomotor disturbance is an early sign of PD, (2,3) yet it can easily be overlooked in elderly people. Due to a progressive loss of substantia nigra neurons that produce dopamine, neurotransmitter imbalances occur in the basal ganglia. (4) Once around 80% of neurons have been lost, PD becomes evident and people begin to experience difficulties with motor skills, cognition, and autonomic function. (5) Sensory, emotional, and perceptual signs also are observed in some individuals. (6) Footsteps become asymmetrical and underscaled in size and speed (hypokinesia), difficult to activate (akinesia), and difficult to terminate and show progressive diminution as the locomotor

sequence progresses. (6-9) Resting tremor, rigidity, and, later in the disease process, postural instability and falls also are characteristic of PD. (10,11) These impairments of body structure and body function are associated with limitations in activities such as walking in the home and community, moving from a lying to sitting to standing position, and turning. (12) Functional activities that require the performance of motor skills become compromised even though the ability to perform simple movements is retained. This is because simple movements are controlled by frontal, cerebellar, and brain-stem regions rather than the basal ganglia, (13) and these regions are not affected in the early stages of PD.

Secondary to aging, immobility, and disuse, locomotion also can be affected by musculoskeletal impairments such as weakness, reduced flexibility of joints, and deformity as well as cardiopulmonary impairments such as reduced aerobic capacity. (14,15) In turn, these impairments and activity limitations restrict the person's ability to participate in societal roles related to work, family life, education, civic life, and leisure. (16) Although levodopa and other PD medications are initially very effective in reducing the severity of movement disorders, some gait disorders persist despite optimal medication. (17,18) The Figure summarizes these interactions and shows how performance within these domains of the ICF is influenced by individual factors such as the person's age, disease duration, PD medication, and socioeconomic status in addition to environmental factors such as their level of supervision and the physical environment in which locomotor tasks are performed.

Locomotion in Parkinson Disease

Even before the diagnosis of PD has been confirmed by a neurologist, most people with the disease find that they are walking more slowly than usual and with short steps. Their shoes frequently scuff the ground, and they are susceptible to tripping on obstacles. (26) The trunk is held rigidly, the width of the base of support narrows, and there is a high stepping rate. (27) In addition, people with PD can experience difficulty initiating and terminating a step (akinesia). (28) As the disease progresses, there is asymmetry and reduced amplitude of arm swing. (29) Overall, gait patterns become increasingly stereotyped, and there is reduced flexibility in adapting to new environments or task conditions.

These gait disorders are most pronounced for well-learned locomotor sequences, such as walking and turning or walking while performing a secondary task such as talking, carrying a tray, or transferring coins from one pocket to another. Reduced gait speed and shortened step length tend to be more accentuated in the "off phase" of the levodopa cycle, when the neurotransmitter imbalance in the basal ganglia is most pronounced.Other gait variables, such as footstep timing, are less affected by PD and are less responsive to PD medication. Gait disorders also vary according to the environment in which movement occurs. Although people with PD can walk relatively quickly and easily in open spaces or very familiar environments, the slow-stepped shuffling gait pattern that is so characteristic of the disease re-emerges in novel environments orcongested spaces. This is because the role of the caudate in processing multiple sensory stimuli and motor skill learning is disrupted. (37,38) Unexpected changes in the ground surface, walking slope, pathway width, or lighting conditions can be problematic, particularly in elderly people with advanced disease who have postural instability. Changing the goals or complexity of the locomotor task can be challenging when there is insufficient time to use intact frontal cortex regions to plan adaptations to the stepping pattern. The defective basal ganglia also compromise the person's ability to quickly shift from one mode of locomotor behavior to another. (39-41) For this reason, people with PD can experience difficulties in changing from walking slowly to walking quickly, making the transition from hard to soft floor surfaces, or veering to avoid an obstacle.

Physical Therapy for Patients With Newly Diagnosed Parkinson Disease

In the early months after diagnosis, physical therapists have considerable scope to teach people with PD strategies to optimize locomotor performance and physical activity prior to the commencement of levodopa medication. Uniquely, in the "de novo" stage, there is an opportunity to assess the person's baseline levels of impairments, activity limitations, and participation restrictions before medications have commenced. The natural variability in the person's capabilities, therefore, can be mapped without the confounding effects of pharmacological therapies. Baseline data can be retained for future use in evaluating disease progression. (42) Core strategies can be learned for moving quickly and easily with large-amplitude movements, (19,43) and these strategies can be retained for when they are needed later in the disease

process.

At the time of diagnosis, disease progression is usually minimal, which arguably provides physical therapists with the best opportunity to take advantage of the capacity for motor skill learning. In the early stages of skill acquisition, frontal cortical regions are used to control movements using attentional processes. (13,44) With practice, control is relegated to the basal ganglia, allowing movements to be executed quickly, easily, and automatically. (37,44,45) When the basal ganglia are dysfunctional, as in PD, automaticity of movement is compromised and there is greater reliance on frontal-lobe attentional mechanisms to control movements. Thus, people with advanced PD have difficulty learning a skill, task, or strategy to the stage that it is retained over long periods and generalized to the performance of similar tasks. (46,47) The motor learning literature shows that skills are learned most effectively when they are practiced repeatedly in relation to meaningful goals, incorporating variations in the manner in which they are performed and varying the environment and task. (37,46,47) For example, if the goal is to train a person with gait hypokinesia to walk with long steps, this could be practiced repeatedly over short (eg, 10 m) and longer (eg, 40 m) distances on different walking surfaces (concrete, floor boards, carpet, grass, uneven ground, slopes) at slow,

medium, and fast speeds. The person with mild PD also could be encouraged to walk with long strides on wide and narrow pathways, incorporating turns of different magnitude (eg, 60[degrees], 120[degrees], 180[degrees]) rather than simply performing straight-line walks. (48)

If a person has gait hypokinesia, visual cues also can be used to enable him or her to walk with long steps. (29) Evidence has accumulated showing that visual cues can normalize step length for several minutes to several hours. (17,30,49,50) Moreover, a single-case study by Sidaway et al (51) showed that 4 weeks of daily gait training led to long-term improvements in step length and speed. Visual cues in the form of white strips can be very effective when taped to the floor (eg, in the corridor that leads from the bedroom to the toilet) or other areas where people fesfinate or have poor gait initiation. Some people find it useful to place small signs on the wall close to a door where troublesome freezing episodes occur to remind them to "take long steps." (52) Van Wegen et al (17) reported that rhythmically flashing lights as well as projection of virtual stripes on the floor could be used to enhance step length in people with PD. Of interest, in the early stages of the disease, people find ascending and descending steps relatively easy because the stairs act as visual cues that drive motor performance. (53) The attentional load is considered to be a key constraint to motor performance in PD. (45,54-56) For people with mild PD, it could be useful to encourage concurrent activities with the aim of enabling them to learn multitasking. Practicing walking with attention directed toward secondary tasks of increasing levels of complexity also could be built into the training regimen, provided that the person has sufficient cognitive ability to be able to learn how to safely perform more than one task at a time. (19) Examples include training people to maintain long strides while performing a secondary task such as talking on a cell phone, carrying a tray, or transferring coins from one pocket to another. (45) This type of intense, variable, and distributed practice regimen appears to provide the best conditions for acquiring and retaining flexibility and adaptability in locomotor control. (55,57) As will be discussed, when the disease has become advanced, it is safer to teach people with PD to avoid dual task intervention by focusing on performing only one movement at a time. Instructional sets (58,59) are another powerful determinant of performance in PD, and some walking trials can be performed while the physical therapist says "long strides," (30) "think big," (35) or "step out" and other walking trials could

be performed with the person using his or her own internally generated instructions or mental images of long steps. (29) In addition to practicing walking in the physical therapy clinic, the person could be encouraged to walk with long strides around the home and in the community. (35) Practice of both treadmill and overground walking also can be considered for people with mild PD, with or without a musical beat to motivate performance. There is preliminary evidence that treadmill training enhances stride length and gait speed in people without balance impairment, (60-63) although this awaits replication.

From the outset, it is recommended that information be provided about falls prevention, the future risk factors for falls, and how to modify the environment and task performance in order to avoid slipping, tripping, and falling. (19) Activities such as walking, cycling, golf, tai chi, and bowling also can be practiced. (19) Another priority is to educate people with PD and their "significant others" about the benefits of regular physical activity and how to incorporate into their life a daily exercise and mobility routine. (59) Progressive resistance strength training has been shown to have beneficial effects (64) even though weakness is secondary to disuse rather than a primary outcome of PD.

Physical Therapy After Levodopa Is Commenced

On commencement of levodopa or other PD medications, the physical therapist acquires several new roles. The first new role is to evaluate the person's response to the medication by conducting a dose-response trial. (65) We have provided details on how this involves measuring impairments of body function and activity limitations at close and regular intervals across a 24-hour period when the person is both "off" and "on" his or her medication. (65) For example, the neurologist might refer the person for evaluation of changes in walking speed, step length, tremor, dyskinesia, and balance at 15-minute intervals early in the morning after a 12-hour period in which medication has been withheld and then throughout the same day after the medication has been administered. By graphing or tabulating the person's response to medication for these variables, the physical therapist is able to provide medical practitioners and other health care professionals and the person with data about the positive or negative effects of medication. This can enable the type and dosage of medication to be carefully adjusted to the person's needs while avoiding undesirable movement disorders such as dyskinesia, dystonia, or hypokinesia. It also provides physical therapists with information about the residual movement disorders that are still apparent despite the best possible medication regimen. In turn, this can aid clinical decision making and assist the physical therapist and

patient in determining the priorities and goals of treatment together.

Another role is to educate the person about the presence and timing of symptoms and possible ways to overcome them. (19) Attentional strategies such as focusing attention on the key aspects of the gait pattern requiring improvement, avoiding the performance of a secondary motor or cognitive task that may compromise safety during gait, and breaking down long or complex locomotor sequences into component parts and concentrating on the performance of each part can enable people to walk more easily. (19,56) Visual cues continue to be helpful as gait hypokinesia and akinesia progress in severity. (29)

At this stage, gait freezing emerges as a problem in some individuals. Auditory cues that aim to normalize locomotor timing such as provided by a musical beat or rhythmical chanting can help some people move more easily. (66-70) Nieuwboer et al (68) found that premature timing of the tibialis anterior andgastrocnemius muscles occurs just before a gait freezing episode due to a disturbance of central locomotor timing mechanisms and that auditory cues provide one mechanism for overcoming this. Moreover, Fernandez del Olmo et al (71) reported reduced movement variability in 9 people with PD after a 4 week program of daily gait training using auditory cues, and this finding correlated

with changes in regional cerebral glucose utilization as shown by positron emission tomography scans.

With disease progression, some patients exhibit difficulties with gait termination. They show excessive diminution of the footstep size and speed prior to a planned stop and overshooting of step length at the termination point. For example, when approaching a chair with the intention of turning around to sit down, the person's footsteps are dramatically reduced in size and speed and freezing occurs prior to and during the turning maneuver. The person might benefit by planning and mentally rehearsing the procedure for terminating the straight-line walking sequence and performing the turning and sitting down components separately. (19) Freezing just short of a goal, such as sitting down, also can be avoided by focusing on the far arm of the chair when walking toward it.

Physical Therapy 5 to 8 Years After Medication Commences

Although levodopa and other PD medications are usually very effective initially, motor fluctuations eventually occur because the progressive death of substantia nigra cells continues despite optimal pharmacological interventions. Performance varies throughout the day and from one day to the next, (27,72) and the performance of complex motor tasks can become intermittently problematic. Physical therapy at this stage aims to teach people how to increase movement speed and amplitude, optimize postural alignment, and maintain postural stability at the times when the medication is not holding them within the normal range. Therapists also can train people with PD and their significant others to identify when movements, postural alignment, or balance are within a pathological range, as self-monitoring of motor performance is not always optimal. This is particularly relevant for people who are frequent fallers, who can benefit from being trained to deliberately monitor their walking patterns and balance during tasks such as turning to avoid tripping and falling.

Around 29% of community-dwelling older adults who are healthy fall each year, (73) compared with up to 60% of community-dwelling people with PD. (18,74,75) One study (76) showed that a quarter of people with PD experience fractures in the first 10 years after diagnosis. Most falls in the PD population occur during the day and indoors, when people are most active and at their best clinical condition at peak dose. (77) Fewer falls occur at the end of dose or during the "off" phase of the levodopa cycle, when patients are less mobile. Although gait parameters such as step length are responsive to levodopa, postural instability shows little change with medication. (78,79) Environmental

factors predict falls to a moderate extent in people with PD, whereas rapid turns, complex tasks, and transfers appear to be more highly correlated with falls. (77) To minimize the rate and severity of falls, home environments can be cleared of excessive furniture and trip hazards. (19) Changes in support surfaces (such as carpet to floorboards) can be highlighted by using brightly colored tape to direct the person's attention toward his or her footsteps, as changes in environmental context such as this (or a narrow doorway) appear to trigger freezing episodes that increase the risk of falls in people with akinesia. (80) When approaching doorways, short shuffling steps can re-emerge, and it can be useful to encourage people with this form of motor instability to look past the doorway at an object in order to avoid hypokinesia and freezing. In addition, footwear can be checked to ensure that it is supportive and not too tight or loose. Given the marked variability in performance that typically occurs after 5 to 8 years of PD medication, (29,81,82) there is a need to devise and evaluate locomotor training programs for both the "on" and "off" phases of the levodopa cycle. Even when patients are fully medicated and in the peak dose of the medication cycle, they still have gait disorders (27,34,83) and dual-task interference (45) that warrant treatment. This is the major reason why physical therapists and other allied health professionals provide gait training as an adjunct to pharmacological therapy in everyday clinical practice. Because most people with PD show differences in their performance when they are "on" compared with when they are "off" the medication cycle, it can be useful for the physical therapist to color code their assessment and treatment planning documentation and to teach them separate strategies for when they are "on" or "off" the medication cycle. (19,29) At the end of the dose, many patients experience gait hypokinesia (slowness with reduced amplitude), gait initiation and termination difficulties, and freezing. Some patients have dystonia of the plantar flexors, reduced arm swing, or rigidity of the trunk. (84-86) At peak dose, some people have no residual movement disorders, whereas others experience slowness and other impairments despite the best possible pharmacological regimen. It is very important to document the time of physical therapy measurements together with the times for PD medications on that day so that judgments can be made about whether a person's performance is better or worse for that point within the medication cycle. (19,29) Given the variability in performance in people with PD, it is necessary to know when assessments are made in order to judge whether they are responding favorably to treatment.

Turning during locomotion is typically problematic in the early and middle stages of disease progression and can be associated with trips, falls, and freezing episodes. (12,29) Turning disorders and falls are presumably not as common in the advanced stages of disease progression because patients are not so mobile then. (87) Using 3-dimensional motion analysis, Huxham (87) measured selfpaced 60-degree turns during walking in people with PD compared with young and older adults without impairments. Those with PD showed shorter step lengths and reduced axial rotation at the pelvis as well as diminished counterbalancing activity at the thorax, even for this relatively small turning angle. Strategies to improve performance during gait include deliberately turning in a large arc of movement rather than rapidly swiveling on the spot, planning the turn so that it is performed using planned control mechanisms rather than attempting to turn automatically "on line," and using visual cues (such as looking at a chair or obstacle on the ground) to assist the direction change. (19,57) In addition to avoiding the performance of secondary tasks, the person can be encouraged to turn gradually rather than sharply. This appears to be the preferred strategy for all age groups when the turn path is not predefined.

Advanced Disease Progression

Because the loss of dopamine-producing neurons in the substantia nigra progresses over time, gait disorders become more severe and variable in their presentation in the advanced stages of the disease. (33) Severe gait hypokinesia is very common, and most people find that their footsteps are shortened and the ground clearance is diminished toward the end of dose or in the half hour after it has been taken, before a sufficient level of uptake has occurred. (19) The strategies for hypokinesia described earlier are applicable, although particular attention needs to be directed toward preventing trips during walking. Emphasizingdorsiflexion at heel-strike and strengthening the dorsiflexors using progressive resistance strength training may be productive. Other strategies include teaching the person how to deliberately increase the ground clearance by increasing the length of steps, planning the walking task, and carefully scanning the environment for hazards prior to and during walking. (19,29) The person can be educated about the ways in which multitask performance increases the risk of slips, trips, and falls, as well as the need to be particularly vigilant at the end of dose. After many years of anti-PD medication, some people experience extra movements such gait dyskinesia, whereby excessive large-amplitude choreiform movements occur. (29,88) On clinical examination, the steps appear to be very long, the base of support is wider than usual, the arm swing amplitude is increased, and the magnitude of trunk rotation is increased. Many people find these large-amplitude writhing movements disconcerting from a cosmetic point

of view and believe that they increase fatigue and lassitude. (89) For this reason, severe dyskinesia can be a key factor that restricts participation in social activities and community life. Unfortunately, little is known about the pathogenesis of gait dyskinesia or its response to physical therapy. There is a clinical impression that relaxation techniques are helpful for providing shortterm relief from dyskinesia, (99,89) although this has not yet been confirmed with controlled clinical trials. Focusing attention on keeping still, weight bearing, and compression reduce the size and frequency of extra movements, although the effects appear to be transient, lasting for less than 30 minutes. (19,29) Similarly, severe tremor appears to respond for brief periods to attentional strategies such thinking about keeping the limb still, mental imagery, and relaxation. 9,90) Dystonia also occurs in select muscle groups in some people with advanced disease. Prolonged stretch is reported to be useful for some people with dystonia, and sensory stimulation provided by a firmly fitting sock has been noted to be useful for short-term alleviation of dystonia. Assistive devices, such as wheeled walking frames, are an option for people who are at high risk for falls. They should be considered only after other physical therapy strategies for enhancing gait and balance have been attempted. Walking sticks (whether single-point or 4-point) usually provide little assistance for people with postural instability because they typically end up being carried by the person and can become a distracting source of dual-task interference. Walking frames that do not have wheels also can be difficult for people with PD to use because they require the person to pick up the frame, place it strategically, and then step forward in a sequential action that is difficult for people with basal ganglia dysfunction. Likewise, forearm crutches offer little help because they require the person to repeatedly perform a long action sequence. Sometimes walking frames with front wheels can be an effective tool for enabling the person to maintain balance while walking relatively easily. This appears to be particularly the case for people with cognitive impairment who cannot learn other strategies to maintain balance and safety. In some people with advanced disease who are troubled by disabling dyskinesia, tremor, or dystonia, brain surgery can be an option. Due to the usual risks associated with neurosurgery, most candidates are younger people with rapidly progressive PD or older adults who need surgery in order to maintain employment or other societal roles. Pallidotomies and subthalamic stimulation are commonly used, with varying outcomes. Reconstructive neurosurgery, such as inserting dopamine-producing neurons from porcine, fetal, or human tissue has been reported in the PD literature, although equivocal results have been obtained to date. This procedure is still considered to be experimental. Physical therapists play a role in assessing motor performance before and after brain surgery "on" and "off" levodopa and other medications. In addition, the physical

therapist can provide amount of change impairments, activity participation result of brain

data on the that occurs in limitations, and restrictions as a surgery.

Laboratory-based 3-dimensional gait analysis (3-DGA) is used to assist clinical decision making in a small proportion of people with PD, particularly those referred for neurosurgery. Although observational gait analysis provides data on the footstep patterns and gait kinematics (angular displacements of joints and motion of body segments over time), 3-DGA provides information on movement kinetics such as the underlying moments of force and power generation in different muscle groups that contribute to the disordered movement patterns. In gait laboratories throughout the world, specialized physical therapists now play a key role in measuring locomotor performance using 3-DGA in order to quantify the outcomes of therapy, surgery, and other interventions.

End-Stage Disease Management

A proportion of individuals with PD live well into very old age, and it is not unusual for a person diagnosed with PD at the age of 60 years to be coping with the interactions between long-term disease progression and aging when he or she is 85 or 90 years of age. By this time, the person has usually received physical therapy services interspersed over many years and is aware of which strategies remain helpful. Therapy now focuses on educating and supporting the

primary caregiver and optimizing the person's quality of life and participation in societal roles. Priorities include enabling participation in parenting and grandparenting roles as well as assisting them to maintain relationships with their spouse, friends, and community-based organizations. There is less emphasis on the treatment of impairments of body structure and body function, unless these impairments are causing particular problems such as pain, difficulty swallowing, or difficulty breathing. Strategies for minimizing activity limitations usually involve training nurses or family members how to help the person move from one position to another and to perform daily activities such as dressing, eating, and grooming. Toward the end of life, some people with PD lose the capacity to walk safely and benefit from being prescribed a wheelchair that enables them to continue to participate in family and community activities. As with the previous stages, the physical therapist works in partnership with people with PD, their families, and other members of the interprofessional team to set therapy goals that best meet their needs without raising hopes for unrealistic levels of movement recovery.

Clinical Research
Finally, it is recommended that physical therapists become more involved with clinical research, translational research, or collaborative basic science studies relevant to evidence-based practice in PD. This article has shown a paucity of physical therapy outcome studies, and there is an immediate need for controlled trials to determine optimal methods to reduce falls and enhance mobility in this debilitating disease.

Conclusion
This perspective article has integrated clinical research findings to provide clinicians with a practical guide to physical therapist management of locomotor disorders in people with PD. Although there is evidence in animal studies that aggressive learning-based activities can be neuroprotective, to date there are no longitudinal clinical studies confirming that a meticulous commitment to learning in a patient diagnosed with PD would actually slow down the progression of the disease. There are many characteristic features of PD gait, and large individual differences exist in the combinations of gait deviations seen and the extent to which locomotor performance fluctuates over time. Physical therapists assess people with PD individually, taking into account their medication status, their changing levels of performance, their goals, and the

needs of their "significant others." Goals are set and constantly modified in conjunction with the person, and therapy is regularly adjusted to minimize impairments and to increase the ability to perform functional activities. Part of the training program involves structuring the environment and controlling the ways in which tasks are performed to enhance performance. The ultimate goal is to optimize quality of life and participation in social roles pertaining to family life, leisure, work, education, and community service at appropriate stages in the life cycle. Physical therapists should collaborate with basic science researchers to improve our understanding of how movement strategies and exercise can be maximally protective and rehabilitative along with new technological and pharmaceutical interventions.

REFERENCE
Adler CH, and JE Ahlskog, eds. Parkinson's Disease and Movement Disorders. Totawa NJ :Human Press, 2000. Olanow CW, RL Watts, WC Koller, eds. An Algorithm (Decision Tree) for the Management of Parkinson's Disease (2001): Treatment Guidelines. Neurology 2001;56 (Suppl 5). Hauser R, T Zesiewicz. Parkinson's Disease: Questions and Answers, 2nd edition. Merit Publishing International, 1997.