Background

BACKGROUND Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (see the following image). Most cases of Parkinson disease (idiopathic Parkinson disease [IPD]) are hypothesized to be due to a combination of genetic and environmental factors. However, no environmental cause of Parkinson disease has yet been proven. A known genetic cause can be identified in approximately 10% of cases, and these are more common in younger-onset patients. [1] The classic motor features of Parkinson disease typically start insidiously and emerge slowly over weeks or months, with tremor being the most common initial symptom. The 3 cardinal signs of Parkinson disease are resting tremor, rigidity, and bradykinesia. Postural instability (balance impairment) is sometimes listed as the fourth cardinal feature. However, balance impairment in Parkinson disease is a late phenomenon, and in fact, prominent balance impairment in the first few years suggests that Parkinson disease is not the correct diagnosis[1]. When a patient presents with tremor, the clinician evaluates the patient's history and physical examination findings to differentiate Parkinson disease tremor from other types of tremor. In patients with parkinsonism, careful attention to the history is necessary to exclude causes such as drugs, toxins, or trauma. Other common causes of tremor include essential tremor, physiologic tremor, and dystonic tremor. No laboratory or imaging study is required in patients with a typical presentation of Parkinson disease. Such patients are aged 55 years or older and have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity. There are no red flags such as prominent autonomic dysfunction, balance impairment, dementia, or eye-movement abnormalities. In such cases, the diagnosis is ultimately considered confirmed once the patient goes on dopaminergic therapy (levodopa or a dopamine agonist) as needed for motor symptom control and exhibits a robust and sustained benefit [1]. Imaging studies can be considered, depending on the differential diagnosis. Magnetic resonance imaging (MRI) of the brain can be considered to evaluate possible cerebrovascular disease (including multi-infarct state), space-occupying lesions, normal-pressure hydrocephalus, and other disorders. Levodopa coupled with a peripheral decarboxylase inhibitor (PDI), such as carbidopa, remains the gold standard of symptomatic treatment of motor features of Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, its long-term use is associated with the development of fluctuations and dyskinesias. Moreover, the disease continues to progress, and patients accumulate long-term disability. Dopamine agonists such as pramipexole (Mirapex) and ropinirole (Requip) can be used as monotherapy to improve symptoms in early Parkinson disease or as adjuncts to levodopa in patients who are experiencing motor fluctuations. Monoamine oxidase (MAO)-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Azilect) provide mild benefit as monotherapy in early disease and as adjuncts to levodopa in patients with motor fluctuations. Entacapone (Comtan), a catechol-o-methyltransferase (COMT) inhibitor, reduces the peripheral metabolism of levodopa, thereby making more levodopa 1

available to enter the brain over a longer period; this agent is used as an adjunct to levodopa in patients with motor fluctuations. ANATOMY Parkinson disease is predominantly a disorder of the basal ganglia, which are a group of nuclei situated at the base of the forebrain. The striatum, composed of the caudate and putamen, is the largest nuclear complex of the basal ganglia. The striatum receives excitatory input from several areas of the cerebral cortex, as well as inhibitory and excitatory input from the dopaminergic cells of the substantia nigra pars compacta (SNc). These cortical and nigral inputs are received by the spiny projection neurons, which are of 2 types: those that project directly to the internal segment of the globus pallidus (GPi), the major output site of the basal ganglia; and those that project to the external segment of the globus pallidus (GPe), establishing an indirect pathway to the GPi via the subthalamic nucleus (STN). The actions of the direct and indirect pathways regulate the neuronal output from the GPi, which provides tonic inhibitory input to the thalamic nuclei that project to the primary and supplementary motor areas [2]. PATHOPHYSIOLOGY No specific, standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as the specificity and sensitivity of its characteristic findings have not been clearly established. However, the following are the 2 major neuropathologic findings in Parkinson disease [2]:
• •

Loss of pigmented dopaminergic neurons of the substantia nigra pars compacta The presence of Lewy bodies and Lewy neurites The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease emerge. Some individuals who were thought to be normal neurologically at the time of their deaths are found to have Lewy bodies on autopsy examination. These incidental Lewy bodies have been hypothesized to represent the presymptomatic phase of Parkinson disease. The prevalence of incidental Lewy bodies increases with age. Note that Lewy bodies are not specific to Parkinson disease, as they are found in some cases of atypical parkinsonism, Hallervorden-Spatz disease, and other disorders. Nonetheless, they are a characteristic pathology finding of Parkinson disease.

2

Motor circuit in Parkinson disease

Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motor circuit and return to the same area via a feedback pathway. Output from the motor circuit is directed through the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). This inhibitory output is directed to the thalamocortical pathway and suppresses movement. Two pathways exist within the basal ganglia circuit, the direct and indirect pathways, as follows:
•

In the direct pathway, outflow from the striatum directly inhibits the GPi and SNr; striatal neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr

3

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The indirect pathway contains inhibitory connections between the striatum and the external segment of the globus pallidus (GPe) and between the GPe and the subthalamic nucleus (STN); striatal neurons with D2 receptors are part of the indirect pathway and project to the GPe The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory output to the ventral lateral nucleus (VL) of the thalamus. Dopamine is released from nigrostriatal (substantia nigra pars compacta [SNpc]) neurons to activate the direct pathway and inhibit the indirect pathway. In Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr via both the direct and indirect pathways (see the following image).

The increased inhibition of the thalamocortical pathway suppresses movement. Via the direct pathway, decreased striatal dopamine stimulation causes decreased inhibition of the GPi/SNr. Via the indirect pathway, decreased dopamine inhibition causes increased inhibition of the GPe, resulting in disinhibition of the STN. Increased STN output increases GPi/SNr inhibitory output to the thalamus

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ETIOLOGY[3,4] Although the etiology of Parkinson disease is still unclear, most cases are hypothesized to be due to a combination of genetic and environmental factors. Currently known genetic causes of Parkinson disease account for approximately 10% of cases. Environmental causes Environmental risk factors commonly associated with the development of Parkinson disease include use of pesticides, living in a rural environment, consumption of well water, exposure to herbicides, and proximity to industrial plants or quarries.[4] The National Institutes of Health-AARP Diet and Health Study, as well as a meta-analysis of prospective studies, found that higher caffeine intake was associated with lower risk of Parkinson disease in both men and women. A similar association was found for smoking and Parkinson disease risk.[5] The biological mechanisms underlying the inverse relationship between caffeine or smoking and Parkinson disease risk are not well elucidated. MPTP interference with mitochondrial function Several individuals were identified who developed parkinsonism after self-injection of 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity, and tremor, which progressed over several weeks and improved with dopamine replacement therapy. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B.[3] MPP+ accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A chemical resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like environmental toxin might be a cause of Parkinson disease, but no specific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced in Parkinson disease, suggesting a common pathway with MPTP-induced parkinsonism. Oxidation hypothesis The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative metabolism, plays a role in the development or progression of Parkinson disease. The oxidative metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Normally, hydrogen peroxide is cleared rapidly by glutathione, but if hydrogen peroxide is not cleared adequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage. In Parkinson disease, levels of reduced glutathione are decreased, suggesting a loss of protection against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons, thereby promoting the formation of free radicals [4]. Parkinson disease is associated with increased dopamine turnover, decreased protective mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation. This hypothesis has raised concern that increased dopamine turnover due to levodopa administration 5

could increase oxidative damage and accelerate loss of dopamine neurons. However, there is no clear evidence that levodopa accelerates disease progression. Genetic factors[4] If genetic factors are important in a particular disease, concordance in genetically identical monozygotic (MZ) twins will be greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early Parkinson disease twin studies generally found low and similar concordance rates for MZ and DZ pairs. However, genetic factors in Parkinson disease appear to be very important when the disease begins at or before age 50 years. In a study of 193 twins, overall concordance for MZ and DZ pairs was similar, but in 16 pairs of twins in whom Parkinson disease was diagnosed at or before age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant. The identification of a few families with familial Parkinson disease sparked further interest in the genetics of the disease. In one large family in Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein gene. Termed PD-1, this mutation codes for a substitution of threonine for alanine at amino acid 53. These individuals were characterized by early age of disease onset (mean age, 47.5 years), rapid progression (mean age at death, 56.1 years), lack of tremor, and good response to levodopa therapy.[8] Five small Greek kindreds were also found to have the PD-1 mutation. In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that mutations in the alpha-synuclein gene can cause Parkinson disease. [9] A few additional familial mutations in the alpha-synuclein gene have been identified and are collectively called PARK1. It is now clear that these mutations are an exceedingly rare cause of Parkinson disease. A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations within 6 of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are well-validated causes of familial parkinsonism.[10] Inheritance is autosomal dominant for SNCA and LRRK2 (although LRRK2 mutations exhibit variable penetrance). Inheritance is autosomal recessive for PRKN, DJ1, PINK1, and ATP13A2. In addition, polymorphisms within SNCA and LRRK2, as well as variations in MAPT and GBA, are risk factors for Parkinson disease.[10] Although the mechanisms by which genetic mutations cause Parkinson disease is not known, evidence to date converges on mechanisms related to abnormal protein aggregation, defective ubiquitin-mediated protein degradation, mitochondrial dysfunction, and oxidative damage. Alpha-synuclein conformational changes and aggregation[8] Abnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are characteristic pathologic findings in Parkinson disease. Missense mutations and multiplications in the SNCA gene that encodes alpha-synuclein, although rare, cause autosomal dominant Parkinson disease. However, genome-wide association studies have also demonstrated a link between SNCA and sporadic Parkinson disease. 6

Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson disease, and understanding its relationship to the disease process holds major promise for the development of a cure. Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH. However, when bound to membranes or vesicles containing acidic phospholipids, it takes on an alphahelical structure. Normally, alpha-synuclein is found mainly in neuronal presynaptic terminals and may play a role in assembly and function of SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) proteins that are involved in neurotransmitter release. Under certain conditions, alpha-synuclein aggregates into oligomers that are gradually converted to the beta–sheet-rich fibrillary structures that form Lewy bodies and neurites in Parkinson disease. Most evidence currently suggests that it is the intermediate soluble oligomers that are toxic to neurons.Multiple mechanisms have been suggested as to how abnormally aggregated alpha-synuclein could exert neurotoxicity. One hypothesis suggests that oligomeric alpha-synuclein can promote formation of ionpermeable pores on neuronal membranes, leading to increased calcium influx. Aberrant pore formation could also lead to neurotransmitter leaks from synaptic vesicles into the cytosol. In addition, overexpression of alpha-synuclein has been demonstrated to impair mitochondrial complex I activity, and oligomeric alpha-synuclein may have a direct effect on mitochondrial membranes. Other lines of evidence suggest that oligomerization of alpha-synuclein could cause cytoskeletal disruption, possibly by an effect on the microtubule-stabilizing protein, tau. Elevated levels of alpha-synuclein promote abnormal aggregation. levels are normally regulated by a balance between synthesis and degradation. SNCAmultiplications lead to increased synthesis of alpha-synuclein and can cause Parkinson disease. Alpha-synuclein appears to be degraded by the ubiquitin proteasome system and the autophagy-lysosome pathway. Several genetic mutations associated with Parkinson disease may lead to decreased alpha-synuclein degradation. For example, increased risk of Parkinson disease in carriers of GBA (beta-glucocerebrosidase gene) mutations, which encode for the lysosomal enzyme glucocerebrosidase, may be due to lysosomal dysfunction and consequent alphasynuclein accumulation and oligomerization. How the Parkinson disease process begins is not known. Once it is initiated, however, it may propagate by a prionlike process in which misconformed proteins induce the templated misfolding of other protein molecules. In Parkinson disease, synuclein pathology begins in the lower brainstem and olfactory bulb, ascends up the midbrain, and eventually affects the neocortex. One set of observations in support of a prionlike process comes from experience with fetal dopaminergic grafts transplanted into the striata of patients with Parkinson disease, because these grafts develop Lewy bodies, suggesting host-graft transmission of disease Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowing or stopping Parkinson disease progression.

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CLINICAL PRESENTATION[3] Onset of motor signs in Parkinson disease is typically asymmetric, with the most common initial finding being an asymmetric resting tremor in an upper extremity. Over time, patients notice symptoms related to progressive bradykinesia, rigidity, and gait difficulty. The first affected arm may not swing fully when walking, and the foot on the same side may scrape the floor. Over time, axial posture becomes progressively flexed and strides become shorter. Some nonmotor symptoms commonly precede motor signs in Parkinson disease. Most Parkinson disease patients have a substantial reduction in olfactory function (smell) by the time motor signs emerge. However, either this is not noticed by the patients or patients may not realize that it is part of the disease. Another common premotor symptom is rapid eye movement (REM) behavior disorder (RBD). In this condition, individuals exhibit movements during REM sleep that are often described as hitting or kicking motions. There are also a number of midlife risk factors for the later development of Parkinson disease. These include constipation and excessive daytime sleepiness, although they are far from specific for Parkinson disease. In a British study, the frequency of nonmotor symptoms in 159 patients with newly diagnosed Parkinson’s disease was found to be significantly greater than that in 99 healthy age-matched control patients (mean, 8.4 vs 2.8). The most commonly experienced nonmotor symptoms in patients with early Parkinson disease in this study included the following :
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Excessive saliva Forgetfulness Urinary urgency Hyposmia Constipation

Initial clinical symptoms in Parkinson disease include the following:
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Tremor A subtle decrease in dexterity; for example, a lack of coordination with activities such as playing golf or dressing (about 20% of patients first experience clumsiness in one hand) Decreased arm swing on the first-involved side Soft voice Decreased facial expression Sleep disturbances 8

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RBD, in which there is a loss of normal atonia during REM sleep: In one study, 38% of 50-yearold men with RBD and no neurologic signs went on to develop parkinsonism ; patients “act out their dreams” and may kick, hit, talk, or cry out in their sleep Decreased sense of smell Symptoms of autonomic dysfunction, including constipation, sweating abnormalities, sexual dysfunction, and seborrheic dermatitis A general feeling of weakness, malaise, or lassitude Depression or anhedonia Slowness in thinking

• •

• • •

Common early motor signs of Parkinson disease include tremor, bradykinesia, rigidity, and dystonia. Tremor Although tremor is the most common initial symptom in Parkinson disease, occurring in approximately 70% of patients, it does not have to be present to make the diagnosis. Tremor is most often described by patients as shakiness or nervousness and usually begins in one upper extremity and initially may be intermittent. Upper extremity tremor generally begins in the fingers or thumb, but it can also start in the forearm or wrist. After several months or years, the tremor may spread to the ipsilateral lower extremity or the contralateral upper extremity before becoming more generalized; however, asymmetry is usually maintained. Tremor can vary considerably, emerging only with stress, anxiety, or fatigue. Classically, the tremor of Parkinson disease is a resting tremor (occurring with the limb in a resting position) and disappears with action or use of the limb, but this is not seen in all patients. Initially, the tremor may be noticed during activities such as eating or reading a newspaper. Although Parkinson disease is a rare cause of tremor affecting the head or neck, tremors of the chin, lip, or tongue are not uncommon. As with other tremors, the amplitude increases with stress and resolves during sleep. Bradykinesia Bradykinesia refers to slowness of movement. Symptoms of bradykinesia are varied and can be described by patients in different ways. These may include a subjective sense of weakness, without true weakness on physical examination; loss of dexterity, sometimes described by patients as the "message not getting to the limb"; fatigability; or achiness when performing repeated actions. Facial bradykinesia is characterized by decreased blink rate and facial expression. Speech may become softer, less distinct, or more monotonal. In more advanced cases, speech is slurred, poorly articulated, and difficult to understand. Drooling is an uncommon initial symptom in isolation but is reported commonly (especially nighttime drooling) later in the disease course.

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Truncal bradykinesia results in slowness or difficulty in rising from a chair, turning in bed, or walking. If walking is affected, patients may take smaller steps and gait cadence is reduced. Some patients experience a transient inability to walk, as though their feet are frozen to the floor. This "freezing" is seen commonly in patients with more advanced disease; it is more prominent as patients attempt to navigate doorways or narrow areas and can result in patients getting trapped behind furniture or being unable to cross a door threshold easily. In the upper extremities, bradykinesia can cause small, effortful handwriting (ie, micrographia) and difficulty using the hand for fine dexterous activities such as using a key or kitchen utensils. In the lower extremities, unilateral bradykinesia commonly causes scuffing of that foot on the ground, as it is not picked up during leg swing. This may also be described as dragging of one leg. Rigidity Some patients may describe stiffness in the limbs, but this may reflect bradykinesia more than rigidity. Occasionally, individuals may describe a feeling of ratchety stiffness when moving a limb, which may be a manifestation of cogwheel rigidity. Dystonia Dystonia is a common initial symptom in young-onset Parkinson disease, which is defined as symptom onset before age 40 years. Dystonia in Parkinson disease commonly consists of a foot involuntary turning in (inversion) or down (plantar flexion), often associated with cramping or aching in the leg. Dorsiflexion of the big toe may also occur. Another common dystonia in Parkinson disease is adduction of the arm and elbow, causing the hand to rest in front of the abdomen or chest. Dystonic postures can wax and wane, occurring with fatigue or exertion. Whether stooped posture is due to truncal dystonia is a matter of debate. One study suggests that the stooped posture may be due to vertebral fractures resulting from vitamin D deficiency with compensatory hyperparathyroidism. Vitamin D supplementation may reduce the risk for stooped posture.

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PHYSICAL EXAMINATION There are 4 cardinal signs of Parkinson disease, with 2 of the first 3 listed below required to make the clinical diagnosis. The fourth cardinal sign, postural instability (balance difficulty), emerges late in the disease, usually after 8 years or more.
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Resting tremor Rigidity Bradykinesia Postural instability

Resting tremor Resting tremor is assessed by having patients relax their arms in their lap while in a seated position. Having patients count aloud backward from 10 may help bring out the tremor. The arms should also be observed in an outstretched position to assess postural tremor, and kinetic tremor (tremor with voluntary movement) can be observed during the finger-to-nose test. Although a resting tremor is the tremor characteristic of Parkinson disease, many Parkinson disease patients also have some postural and/or kinetic tremor. Rigidity Rigidity refers to an increase in resistance to passive movement about a joint. The resistance can be either smooth (lead pipe) or oscillating (cogwheeling). Cogwheeling is thought to reflect tremor rather than rigidity and may be present with tremors not associated with an increase in tone (ie, essential tremor). Rigidity is usually tested by flexing and extending the patient's relaxed wrist and can be made more obvious by having the patient perform voluntary movements, such as tapping, with the contralateral limb. Bradykinesia Bradykinesia refers to slowness of movement but also includes reduced spontaneous movements and decreased amplitude of movement. Bradykinesia is also expressed as micrographia (small handwriting), hypomimia (decreased facial expression), decreased blink rate, and hypophonia (soft speech). Thus, the patient’s blink rate and facial expression should be observed. In addition, speed and amplitude of movements are assessed by having the patient open his or her hand (each limb is assessed individually) and tap his or her thumb and index finger repetitively, trying to perform the movement as big and as fast as possible. Similarly, the patient should be asked to tap the toes of each foot as big and as fast as possible. Finally, the patient should be asked to arise from a seated position with the arms crossed to assess the ability to arise from a chair. The patient is then observed while walking to assess stride length and speed, as well as arm swing.

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Postural instability Postural instability refers to imbalance and loss of righting reflexes. Its emergence in a patient with Parkinson disease is an important milestone, because it is poorly amenable to treatment and a common source of disability in late disease. Postural stability is typically assessed by having patients stand with their eyes open and then pulling their shoulders back toward the examiner. Patients are told to be ready for the displacement and to regain their balance as quickly as possible. Taking 1 or 2 steps backward to regain balance is considered normal. The examiner should be ready to catch patients if they are unable to regain balance. Laryngeal dysfunction and dysphagia As the patient is speaking, the vocal loudness, intonation, and quality, including fluidity of speech and articulation, should be assessed. Sustaining vowel phonation (eg, "ah") for maximum duration, counting to 50, and reading a passage that tests articulation (eg, the rainbow passage) provide reasonable speech samples. Closely listening for reduced or diminishing loudness and intonation and increasing breathiness and hoarseness helps differentiate Parkinson disease from hyperkinetic disorders such as spasmodic dysphonia. A soft, monotone voice, vocal tremor, poor articulation, variable speech rate, trouble with the initiation of speech, and stuttering-like qualities are all characteristics of Parkinson disease. Perhaps the most telling vocal symptom is the marked contrast between habitual vocal volume (soft and diminishing) and the patient's response to a request to increase loudness. A request to "say that again, twice as loud" often results in increased loudness, improved voice quality, and a dramatic improvement in speech intelligibility. Dysphagia is common, especially in advanced Parkinson disease. Manifestations may range from drooling to aspiration. The larynx is evaluated for vocal fold mobility, paresis or paralysis, coordination of movement, agility, fatigability, flexibility, and use of accessory muscles during phonation while the patient says various phrases and syllables. Hyperfunctional and hypofunctional disorders can often be differentiated by isolating the abductor and adductor muscle groups. The larynx is also visualized at rest. Pooling of secretions, decreased sensation, and aspiration are also characterizations of the Parkinson disease larynx. A paralyzed vocal fold suggests Parkinson-plus syndrome (PPS) as the etiology for the parkinsonism if other aspects of the diagnosis are present. Autonomic dysfunction Autonomic dysfunction is common in patients with Parkinson disease. Orthostatic hypotension often becomes a concern in late disease, and impaired intestinal motility can lead to constipation and, sometimes, vomiting or impaired absorption. Urinary symptoms, retention, and bladder infection can occur, and erectile dysfunction is not uncommon. In addition, many patients note episodes of sweating. Prominent autonomic dysfunction, especially frank urinary incontinence or profound orthostatic hypotension, may suggest multiple system atrophy (MSA) rather than Parkinson disease. 12

Cardiopulmonary impairment The flexed posture of patients with Parkinson disease can lead to kyphosis, cause a reduction in pulmonary capacity, and produce a restrictive lung disease pattern.

DEMENTIA Hoops et al found that in Parkinson disease, the Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for screening for mild cognitive impairment or dementia. [26] MoCA and MMSE demonstrated similar overall discriminant validity for detection of any cognitive disorder, but as a screening instrument, MoCA was better than MMSE (64% vs 54% correct diagnoses). [6] The prevalence of dementia in Parkinson disease ranges from 20-40%, with the disease conferring a 2- to 6-fold increased risk compared with control populations. [7] Many patients with Parkinson disease have some executive function impairment, even early in the disease. [7] Substantial cognitive impairment and dementia typically occur 8 years or more after the onset of motor features. Dementia generally occurs late in Parkinson disease; substantial cognitive dysfunction within 1 year of onset of motor features suggests a diagnosis of Lewy body disease, a disease closely related to Parkinson disease and marked by the presence of cortical Lewy bodies. In the affected age group, comorbidity with other neurodegenerative disorders, particularly Alzheimer disease and cerebrovascular disease, is common. The relatively high prevalence of depression in patients with Parkinson disease is another confounder in the diagnosis of Parkinson disease dementia. Executive function, short-term memory, and visuospatial ability may be impaired in patients with Parkinson disease dementia, but aphasia is not present. In a long-term Australian study that compared neuropsychologic measures between patients with Parkinson disease who had early dementia (< 10 years of disease onset) and those with late dementia, investigators reported that dementia in parkinsonism appears to occur at about age 70 years regardless of the time of onset of Parkinson disease. [28] However, although early and late dementia had similar effects in cognitive domains, individuals with early onset of parkinsonism had a preserved linguistic ability before the onset of dementia. [8] DIAGNOSTIC CONSIDERATION The most common tremor disorders are Parkinson disease and essential tremor. When a patient presents with tremor, the clinician should pay particular attention to the body parts involved, positions/conditions in which the tremor occurs (ie, resting, postural, kinetic, intention), and the frequency of the tremor. It is also critical to look for potential associated signs. The patient should be examined for evidence of parkinsonism (bradykinesia, rigidity, postural instability), dystonia, and other neurologic signs. An 8-12 Hz action (postural/kinetic) tremor of the upper extremities that is temporarily relieved by drinking alcohol is characteristic of essential tremor, whereas the presence of a pill-rolling rest tremor, bradykinesia, and rigidity is consistent with Parkinson disease and argues against essential tremor. In patients with parkinsonism, careful attention to the history is necessary to exclude secondary causes such as medications, toxins, or trauma. Medications that block striatal dopamine receptors, such as 13

metoclopramide and neuroleptics, can cause drug-induced parkinsonism. Certain toxins such as MPTP (1methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and manganese (at high levels of exposure) can also cause parkinsonism. Early clinical features that suggest an atypical parkinsonism rather than Parkinson disease include the following[1] :
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Falls at presentation or early in the disease Poor response to levodopa Symmetry at disease onset Rapid disease progression No tremor Dysautonomia (eg, urinary incontinence, fecal incontinence, catheterization for urinary retention, persistent erectile failure, prominent symptomatic orthostatic hypotension)

The atypical parkinsonisms are usually associated with little or no tremor, relatively early speech and balance difficulty, and little or no response to dopaminergic medications. Multiple system atrophy (MSA) is relatively symmetric and characterized by parkinsonism, often with some combination of autonomic, corticospinal, and cerebellar dysfunction. Progressive supranuclear palsy (PSP) is relatively symmetric and characterized by parkinsonism with early falls (often in the first year) and a supranuclear gaze palsy in which the patient has difficulty with voluntary down-gaze. Corticobasal ganglionic degeneration (CBD) is typically very asymmetric and characterized by both cortical (difficulty identifying objects, apraxias) and basal ganglionic (usually marked rigidity in an arm) features. Lewy body disease is characterized by substantial cognitive dysfunction within 1 year of onset of parkinsonism. Hallucinations are common. Patients with onset of parkinsonism before age 40 years should be tested for Wilson disease, starting with serum ceruloplasmin measurement and ophthalmologic evaluation for Kayser-Fleischer rings.

Differential Diagnoses
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Alzheimer Disease Cardioembolic Stroke Chorea in Adults Cortical Basal Ganglionic Degeneration Dementia With Lewy Bodies 14

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Huntington Disease Multiple System Atrophy Vascular Dementia

WORKUP Magnetic resonance imaging Magnetic resonance imaging (MRI) is useful to exclude strokes, tumors, multi-infarct state, hydrocephalus, and the lesions of Wilson disease. MRI should be obtained in patients whose clinical presentation does not allow a high degree of diagnostic certainty, including those who lack tremor, have an acute or stepwise progression, or are younger than 55 years. HISTOLOGIC FINDING Classic pathologic findings in Parkinson disease include degeneration of the neurons containing neuromelanin, especially in the substantia nigra and the locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic inclusions called Lewy bodies (see the following image). The primary biochemical defects are loss of striatal dopamine, which results from degeneration of dopamineproducing cells in the substantia nigra, as well as hyperactivity of the cholinergic neurons in the caudate nucleus. Alpha-synuclein is a major structural component of Lewy bodies; all Lewy bodies stain for alphasynuclein, and most also stain for ubiquitin. Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and dense cores. The presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic, but not pathognomonic, of Parkinson disease. Lewy bodies are also found in the cortex, nucleus basalis, locus ceruleus, intermediolateral column of the spinal cord, and other areas. According to the Braak hypothesis, Lewy body pathology in the brain begins in the olfactory bulb and lower brainstem and slowly ascends to affect dopamine neurons in the substantia nigra and, ultimately, the cerebral cortex.[3] Lewy body pathology is also observed in autonomic nerves of the gut and heart.

TREATMENT 15

The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is not instituted at or shortly after diagnosis. [3] Symptomatic and neuroprotective therapy Pharmacologic treatment of Parkinson disease can be divided into symptomatic and neuroprotective (disease modifying) therapy. At this time, there is no proven neuroprotective or disease-modifying therapy. Medications commonly used for symptomatic benefit of motor symptoms in early Parkinson disease include levodopa, monoamine oxidase (MAO)-B inhibitors, and dopamine agonists. Levodopa[10] Levodopa, coupled with a peripheral dopa decarboxylase inhibitor such as carbidopa, remains the standard of symptomatic treatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, long-term use of levodopa is associated with the development of fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve. These adverse effects are the reason to consider delaying the initiation of levodopa if other alternatives are able to control symptoms. Levodopa/carbidopa is introduced at a low dose and escalated slowly. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for greater levodopa delivery into the central nervous system. Currently available levodopa preparations in the United States include levodopa/carbidopa immediaterelease (IR) tablets (Sinemet), levodopa/carbidopa controlled-release (CR) tablets (Sinemet CR), and levodopa/carbidopa orally disintegrating tablets (Parcopa). The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa IR, but it dissolves on the tongue without the need to swallow it with water. The orally disintegrating tablet is not absorbed in the mouth but travels in the saliva to absorption sites in the proximal small bowel (where other levodopa preparations are also absorbed). Levodopa/carbidopa is also available in combination with entacapone, a catechol-O-methyltransferase (COMT) inhibitor. When entacapone is given in conjunction with levodopa and carbidopa, plasma levels of levodopa are higher and more sustained than after administration of levodopa and carbidopa alone. Levodopa/carbidopa/entacapone is useful in advanced Parkinson disease in patients with motor fluctuations. In the STRIDE-PD (STalevo Reduction In Dyskinesia Evaluation) study, patients with early Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo) developed more dyskinesia than patients treated with levodopa/carbidopa; therefore, levodopa/carbidopa/entacapone is not recommended for treatment of early disease.

Levodopa in combination with a dopa decarboxylase inhibitor is started at a low dose and slowly titrated to control clinical symptoms. Most patients experience a good response on a daily levodopa dosage of 16

300-600 mg/day (usually divided 3 or 4 times daily) for 3-5 years or longer. Doses higher than those necessary to control symptoms adequately should be avoided, because higher doses increase the risk for the development of dyskinesia. If nausea occurs, the levodopa dose can be taken immediately following a meal. Additional measures to alleviate nausea include adding extra carbidopa or introducing domperidone (available outside the United States). Other side effects include dizziness and headache. In elderly patients, confusion, delusions, agitation, hallucinations, and psychosis may be more commonly seen. MAO-B inhibitors MAO-B inhibitors, such as selegiline and rasagiline, may be used for early symptomatic treatment of Parkinson disease. These medications provide mild symptomatic benefit, have excellent adverse effect profiles, and may improve long-term outcomes. These characteristics make MAO-B inhibitors a good choice as initial treatment for many patients. When the MAO-B inhibitor alone is not sufficient to provide good control of motor symptoms, another medication (eg, a dopamine agonist or levodopa) can be added. Selegiline is indicated as adjunctive therapy (5 mg every morning; maximum, 10 mg/day) in the treatment of Parkinson disease in patients being treated with levodopa/carbidopa. Rasagiline is indicated for the treatment of the signs and symptoms of Parkinson disease as initial monotherapy (1 mg/day) and as adjunctive therapy (0.5-1.0 mg/day) to levodopa. Potential side effects include nausea, headaches, and dizziness. Dopamine agonists Initial treatment with a dopamine agonist, to which levodopa can be added as necessary, is associated with fewer motor fluctuations and dyskinesias than levodopa alone in prospective, double-blind studies. Subsequent analyses of these studies indicate that the benefit of dopamine agonists in delaying motor symptoms is due to their ability to delay the need for levodopa/carbidopa. Commonly used dopamine agonists include pramipexole and ropinirole. Dopamine agonists provide symptomatic benefit that is comparable to that with levodopa/carbidopa in early disease, but these agents lack sufficient efficacy to control signs and symptoms by themselves in more advanced disease. Dopamine agonists provide moderate symptomatic benefit and rarely cause fluctuations and dyskinesias by themselves, but they have more adverse effects than levodopa, including sleepiness, hallucinations, edema, and impulse control disorders. However, these adverse effects resolve upon lowering the dose or discontinuing the medication. Dopamine agonists are commonly reserved for younger individuals (< 65-70 years) who are cognitively intact. When the dopamine agonist (with or without an MAO-B inhibitor) no longer provides good control of motor symptoms, levodopa can be added. However, dopamine agonists may provide good symptom control for several years before levodopa is required. For patients aged 65-70 years, the authors make a judgment based on general health and cognitive status. The more robust and cognitively intact the patient, the more likely the authors are to treat with a dopamine agonist before levodopa and add levodopa/carbidopa when necessary. For patients with cognitive impairment and those older than 70 years—who may be prone to adverse effects, such as hallucinations, from dopamine agonists—and for those likely to require treatment for only 17

a few years, the authors may elect not to use a dopamine agonist and instead depend on levodopa/PDI (peripheral decarboxylase inhibitor) as primary symptomatic therapy. When introducing a dopamine agonist, it is important to start at a low dose and escalate slowly. The dose should be titrated upward until symptoms are controlled, the maximum dose is reached, or adverse effects emerge. The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations, somnolence, and impulse control disorders. Nausea can usually be reduced by having the patient take the medication after meals. Domperidone, a peripheral dopamine agonist available outside the United States, is very helpful in relieving refractory nausea. Patients on dopamine agonists should be routinely asked about sleepiness, sudden onset of sleep, and impulse control disorders such as pathologic gambling, shopping, internet use, and sexual activity. These adverse effects typically resolve with reduction in dose or discontinuation of the medication. Patients should be warned not to drive if they are experiencing undue sleepiness. They should also be warned about the possibility of impulse control disorders and the need to let their physician know if such an effect occurs. Anticholinergic agents Anticholinergic agents can be used for patients who have disability due to tremor that is not adequately controlled with dopaminergic medication, but these are not first-line drugs, because of their limited efficacy and the possibility of neuropsychiatric side effects. Anticholinergic medications provide good tremor relief in approximately 50% of patients but do not meaningfully improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication but not another, a second anticholinergic agent usually can be tried if the first is not successful. These medications should be introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in elderly persons. One of the most commonly used anticholinergic is trihexyphenidyl. The initial dose of trihexyphenidyl should be low and gradually increased. It is recommended to begin therapy with a single 1-mg dose. Dosage can be titrated by 1 mg each week or so, until a total of 4-6 mg is given daily or until satisfactory control is achieved. Some patients may require higher doses. Benztropine (Cogentin) is also commonly used, with an initial dose of 0.5-1 mg daily at bedtime. Dose can be titrated at weekly intervals in increments of 0.5 mg to a maximum of 6 mg/day. Amantadine Amantadine is an antiviral agent that has antiparkinsonian activity. Its mechanism of action is not fully understood, but amantadine appears to potentiate CNS dopaminergic responses. It may release dopamine and norepinephrine from storage sites and inhibit the reuptake of dopamine and norepinephrine. Amantadine may offer additional benefit in patients experiencing maximal or waning effects from levodopa. Amantadine is commonly introduced at a dose of 100 mg per day and slowly increased to an initial maintenance dose of 100 mg 2 or 3 times daily. The most concerning potential side effects of amantadine 18

are confusion and hallucinations. Common side effects include nausea, headache, dizziness, and insomnia. Less frequently reported side effects include anxiety and irritability, ataxia, livedo reticularis, peripheral edema, and orthostatic hypotension. In a small, double-blind crossover study, amantadine was found to ameliorate pathologic gambling associated with Parkinson disease.[41] However, in a large cross-sectional study, amantadine was associated with a higher prevalence of impulse control disorders, including gambling. Thus, further research is needed to understand the role of amantadine as a treatment or cause of impulse control disorders in patients with Parkinson disease.

Nonmotor symptoms It is now recognized that in Parkinson disease, nonmotor symptoms may be as troublesome as, or more troublesome than, motor symptoms. Nonmotor symptoms can be categorized as autonomic, cognitive/psychiatric, and sensory[34] and may include depression, dementia, hallucinations, rapid eye movement (REM) sleep behavior disorder (RMD), orthostatic hypotension, and constipation. Nonmotor symptoms can also fluctuate, especially depression, pain, numbness, paresthesia/dysesthesia, akathisia, and restless-legs syndrome. Recognition of nonmotor symptoms of Parkinson disease is essential for appropriate management.[10] Screen Parkinson disease patients for depression, and treat it when present. An evidence-based guideline from the American Academy of Neurology (AAN) reports that physician recognition of depression is low in Parkinson disease, at less than 30% of clinically proven cases. There are many factors that confound its diagnosis in these patients; and depression has the single largest effect on the quality of life of patients with Parkinson disease In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations included the following[11] :
• • •

Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction Polyethylene glycol may be considered to treat constipation Modafinil should be considered for patients who subjectively experience excessive daytime somnolence For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for poor sleep quality Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but there are insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that of restless-legs syndrome Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction) 19

•

•

•

•

Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety, and RMD

Reference 1. Mahlon R Delong,Jorge L. Juncos, Parkinson Disease, Harrisons Principles Of Internal Medicine Vol II 17th Edition, 2549-2559 2. Factor S, Weiner W, Parkinson’s disease: Diagnosis and Clinical Mangement, New York, 2007 3. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol. Jun 2011;26 Suppl 1:S1-58. 4. Anderson P. Cognitive Therapy Controls Impulse Behaviors in Parkinson's. Available athttp://www.medscape.com/viewarticle/779914. Accessed March 21, 2013. 5. Hauser RA, Grosset DG. [(123) I]FP-CIT (DaTscan) SPECT Brain Imaging in Patients with Suspected Parkinsonian Syndromes. J Neuroimaging. Mar 16 2011; 6. Liu R, Guo X, Park Y, Huang X, Sinha R, Freedman ND, et al. Caffeine Intake, Smoking, and Risk of Parkinson Disease in Men and Women. Am J Epidemiol. Apr 13 2012; 7. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology. Jul 1985;35(7):949-56. 20

8. Tanner CM, Ottman R, Goldman SM, Ellenberg J, Chan P, Mayeux R, et al. Parkinson disease in twins: an etiologic study. JAMA. Jan 27 1999;281(4):341-6. 9. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. Jun 27 1997;276(5321):2045-7 10. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. Feb 1998;18(2):106-8.

CASE ILLUSTRATION Patient identity Name : Munir Age : 78 years

Address: Solok Medical Record No : 003578 ANAMNESIS A male patient aged 78 years came to the Neurology Polyclinic at the Solok District Hospital on 2 nd May 2013 Chief Complaint : Difficulty in walking Current medical history: 21

• • •

Patient was having difficulty in walking for the past 1 day. Pasien has difficulty to start walking and during walking feels unstable until the patient prefers to use the wheel chair Previously the patient complained his footsteps were getting narrower for the past 1 week. Patient always knocks into furniture at home while walking The patient also complains of tremor on both his hands which started getting worse since 3 months ago. At first the patient experienced trembling on his right hand for the past 10 years then the trembling continued on her left hand. The trembling worsens when the patient is at rest and reduces when the patient does physical activities The patient always has difficulty carrying out his daily activities such as wearing clothes, and is always forgetfull Urination and defeacation is normal

• •

Past medical history • • • • No history of trauma, falling sitting down No past history of hypertension, diabetes, and previous stroke Has never experienced this condition before No previous history of medicine usage

Family history • No family members has experienced or experiencing this sort of condition.

History of work, social economic and habits • Patients is a retiree and carries out sufficient physical activity

Physical Examination General State Awareness BP : looks moderately ill : compos mentis cooperative : 150/100 22

Pulse

: 84 beats per minute

Respiration rate : 21 times per minute Temperature Internal Status Thorax lungs : inspection Palpation Percussion Auscultation Heart : inspection Palpation Percussion Auscultation Abdomen inspection Palpation Percussion Auscultation Neurological status • • • GCS 15 (E4 M6 V5) Meningeal signs : (-) Increase intracranial pressure signs: (-) : symmetrical left and right : left fremitus same with right : sonar : vesicular no rhonchi, no wheezing : ictus not visible : ictus felt 1 finger medial to the mid clavicle line : heart borders are normal : no murmurs : no bulging : liver and spleen normal in size : tympanic : bowel sounds normal : 36.8 C ͦ

1. Cranial Nerves examination : NI NII : good sense of smell : good eyesight, normal field of vision

NII,IV,VI : pupils isokor, diameter both 3mm, light reflex +/+, eye movement free to all directions NV : normal sensory and motoric functions 23

NVII: face symmetrical, plica nasolabialis flat, eye closure +/+, forehead movement +/+, whistling +/+ NVIII: hearing normal NIX NX NXI : vomit reflex (+) : swallowing normal, clear articulation : head movement to all angles (+), lift up shoulder (+)

NXII: no tongue deviation 2. Motoric : Superior extremity Movement Strength Tone Trophy Inferior extremity Movement Strength Tone Trophy right active 555 hypertonus eutrophic right active 555 hypertonus eutrophic left active 555 hypertonus eutrophic left active 555 hypertonus eutrophic

Resting tremor (+) rigidity (+) a kinesis (+) 3. Sensory : normal sensory functions 4. Autonomic function : normal bladder and defecation 5. Dementia signs : glabella reflex (-) snout (-) sucking reflex (-) grasping (-) palm mental (-) 6. Physiologic reflexes a. Biseps ++/++ b. Triceps ++/++ c. Patella ++/++ d. Achilles ++/++ 24

7. Pathologic reflexes a. Babinski signs -/8. Parkinson signs : resting tremor (+) rigidity (+) akinesis (+) Parkinson face (-) narrow gait (+) delayed speech (+) dementia (-) 9. Noble functions : good Clinical diagnosis : Parkinson’s disease Topical diagnosis : substantia nigra pars compacta Etiological diagnosis : idiopathic Secondary diagnosis : -

Therapy : • • Dopaminergic- leparson 3x1 Anticholinergic – triheksifenidin 2x1

Case Discussion Reported a male patient aged 78 years old came to the Polyclinic on 2 nd may 2013 with the clinical diagnosis of Parkinson’s Disease. Diagnosis was made based on the patients history and physical examination. From the history the patient had difficulty in gait since a day ago, difficulty in starting to walk and during walking feels unstable till he prefers to use a wheel chair. Before this the patient complained his gait and footsteps were getting narrower in the past week. Patient always knocks into furniture at home while walking . The patient also complains of tremor on both his hands which started getting worse since 3 months ago. At first the patient experienced trembling on his right hand for the past 10 years then the trembling continued on her left hand. The trembling worsens when the patient is at rest and reduces when the patient does physical activities. He always has difficulty carrying out his daily activities such as wearing clothes, and is always forgetful. Based on the theory of Parkinson’s disease there is bradikinesia 25

and resting tremor on this patient. From both the manifestations it was enough to diagnose the patient with Parkinson’s disease. From the physical examination the muscles were hypertonic with Cog Wheel phenomena was (+) resting tremor (+) rigidity (+) akinesia (+) delayed speech, slowed and narrowed gait, there were no signs of dementia. Treatment for this patient is the usage of anticholinergic and dopaminergic as it is given to patients with Parkinson’s Disease. Anticholinergic drugs hampers cholinergic on basal ganglia and also hampers acetylcholine. It also creates a balance between dopamine-acetylcholine and prevents tremors. Examples of drugs used are Trihexyphenidyl and benztrophine. Dopaminergic such as Levodopa crosses blood brain barrier into the central nervous system. It goes through enzymatic conversion to form dopamine and hampers neuron activities in the basal ganglia. Levodopa reduces tremor, muscle rigidity, and improves movements.

Case report

PARKINSON’S DISEASE

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BY : Rifka Septia Putri 0810313229 Amirudin 0810311010 Khairati Ilda 0810311006 Maisyah Nelzima 0810311023 Syukri Alhamda 0810312119 Mirshad Aditya 07120013 Anisa Resfiana Putri 0810313230 Adil Makmur 06923074 Charan Pal Singh 810314156

PERCEPTORS : Prof Dr, H. Basjiruddin Ahmad SpS (K) Dr Hj Yuliarni Syafrita SpS

BAGIAN ILMU PENYAKIT SARAF FAKULTAS KEDOKTERAN UNIVERSITAS ANDALAS RSUD DR M DJAMIL PADANG 2013

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