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This document discusses Parkinson disease (PD), including its history, symptoms, diagnosis, pathogenesis, treatment and differential diagnosis. It provides the following key points:
1. PD is characterized by a tetrad of symptoms including resting tremor, bradykinesia, rigidity, and loss of postural reflexes. Its pathogenesis involves degeneration of dopamine-producing cells in the substantia nigra.
2. Diagnosis is based on the clinical presentation and may be difficult in early stages. Features that predict pathological PD include resting tremor, asymmetric symptoms and a good response to levodopa.
3. Treatment aims to manage symptoms and potential neuroprotection. Dopamine agonists and levodopa
This document discusses Parkinson disease (PD), including its history, symptoms, diagnosis, pathogenesis, treatment and differential diagnosis. It provides the following key points:
1. PD is characterized by a tetrad of symptoms including resting tremor, bradykinesia, rigidity, and loss of postural reflexes. Its pathogenesis involves degeneration of dopamine-producing cells in the substantia nigra.
2. Diagnosis is based on the clinical presentation and may be difficult in early stages. Features that predict pathological PD include resting tremor, asymmetric symptoms and a good response to levodopa.
3. Treatment aims to manage symptoms and potential neuroprotection. Dopamine agonists and levodopa
This document discusses Parkinson disease (PD), including its history, symptoms, diagnosis, pathogenesis, treatment and differential diagnosis. It provides the following key points:
1. PD is characterized by a tetrad of symptoms including resting tremor, bradykinesia, rigidity, and loss of postural reflexes. Its pathogenesis involves degeneration of dopamine-producing cells in the substantia nigra.
2. Diagnosis is based on the clinical presentation and may be difficult in early stages. Features that predict pathological PD include resting tremor, asymmetric symptoms and a good response to levodopa.
3. Treatment aims to manage symptoms and potential neuroprotection. Dopamine agonists and levodopa
PARKINSON DISEASE - SPECT [123I]-beta CIT scans – used to measure presynaptic
Noreen T. Trinidad, MD, FPCP, FPNA dopaminergic activity
- Functional MRI and MR spectroscopy James Parkinson (1755-1824) 1817… ESSAY ON THE SHAKING PALSY “…involuntary tremulous motion, with lessened muscular power, in parts not in actionand even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured.” CLINICAL DIAGNOSIS - TETRAD: o Resting tremor, o bradykinesia, o rigidity, o loss of postural reflexes - Prototype parkinsonian disorder; parkinsonism occurs in isolation without other evidence of neuropathologic change - Distinguishing Parkinson disease clinically from other parkinsonian disorders: o Asymmetry of parkinsonian signs o marked rest tremor o clinically significant response to levodopa o little or no balance problems in the first months and years of the disease ETIOLOGY - The cause of Parkinson disease is unknown. - Current research efforts: o Hereditary factors (including several genetic defects) o Environmental toxins that could damage substantia nigra cells selectively INITIAL SYMPTOMS IN PD Tremor 70% Gait disturbance 11% Stiffness 10% (Left) Horizontal sections through the midbrain and pons of a 79- Slowness 10% year-old male (control) and (right) 79-year-old male patient with Muscle aches 8% Parkinson disease. Note the difference in pigmentation of the Loss of dexterity 7% substantia nigra and locus ceruleus. Handwriting disturbance 5% Depression, nervousness, psychiatric disturbance 4% Speech disturbance 3% PATHOGENESIS AND PATHOPHYSIOLOGY - Degeneration of dopamine producing cells in the pars compacta of the substantia nigra - Cell loss in other pigmented brainstem nuclei, autonomic nuclei, and pyramidal cells in the presupplementary cortex - Glial cells do not regenerate Low-power photomicrographs of substantia nigra. Note o Activation in the midst of neuronal loss may play a difference of neuronal density between the normal protective role through the release of trophic factors substantia nigra (left) and the patient with Parkinson - Free radical toxicity from oxidative reactions disease (right). (Hematoxylin-eosin; x31.25) o Oxidative stress o Anti-oxidant therapy may slow down nigral DIFFERENTIAL DIAGNOSES degeneration in PD - Essential tremor - PET – one of the most important tools for studying the - Parkinsonism-plus syndromes – additional neurologic signs pathogenesis and pathophysiology of changes in dopamine beside parkinsonism neurochemistry in sporadic Parkinson disease and familial o PSP (conjugate gaze paresis) parkinsonism o MSA (ataxia, dyssynergia, kinetic tremor) o SND (pyramidal signs) o CBD (apraxia and cortical sensory dysfunction) o One unconfirmed report of increased mortality in o Shy-Drager syndrome (marked dysautonomia) patients receiving levodopa plus selegiline o DLB (early dementia and hallucinations) o Primary progressive freezing gait - Vitamin E (α-tocopherol) - Hemiatrophy-hemiparkinsonism o No delay in disease progression detected - Iatrogenically-induced or exacerbated parkinsonism (DATATOP study) - Amyotrophic lateral sclerosis-parkinsonism-dementia o No basis for recommending megadoses of Vit E to complex PD patients at this time - X-linked Lubag syndrome ***APPENDIX B - Rigid form of Huntington disease PHARMACOLOGIC INTERVENTION: SYMPTOMATIC THERAPY - Wilson disease When to initiate symptomatic therapy? - Ischemic vascular disease - Early treatment to provide maximal clinical benefit - Post-encephalitic parkinsonism or - Vascular parkinsonism - Delay initiation of treatment to minimize risk of developing Parkinson Disease Cont motor complications or accelerating disease progression - diagnosis may be difficult in early stage consequent to oxidant radicals derived from levodopa - tremor, rigidity and bradykinesia metabolism - features that best predict pathological changes of General Agreement idiopathic PD - Appropriate to start treatment when patient begins to o resting tremor experience functional impairment o asymmetric presentation - Functional impairment o good response to levodopa o Impairment in managing activities of daily living ADL subscale of UPDRS is a most useful TREATMENT OF EARLY PARKINSON’S DISEASE way to assess disability - Patients with early untreated disease o Threatened loss of employability - even above criteria may not permit an accurate diagnosis Same degree of dysfunction is more likely because of the mild nature of parkinsonian features to cause disability in a patient who is - may show no observable effect with levodopa especially if working with tremor dominant form of disease o Development of gait disturbance with falling - may still be reasonable to introduce pharmacological Can lead to serious injuries treatment in any parkinsonian patient with functional disability Factors that influence determination of whether a patient has o Atypical parkinsonism patients – may have initial functional impairment benefit with dopaminergic replacement - whether symptoms affect the dominant or nondominant ***APPENDIX A hand - whether patient is employed or employable PHARMACOLOGIC INTERVENTION: NEUROPROTECTION - type of parkinsonian symptoms present (e.g. bradykinesia - An intervention that tends to be more disabling than tremor) o protects vulnerable neurons - individual patient sentiment o slows or stops disease progression - philosophy of the treating physician - Selegiline o selective monoamine oxidase (MAO)-B inhibitor PHARMACOLOGIC INTERVENTION: DRUG THERAPIES***APPENDIX C o capacity to block formation of free radicals derived DOPAMINE AGONISTS from oxidative metabolism of dopamine - Group of drugs w/ diverse physical and chemical properties o can prevent development of parkinsonian - Directly stimulate dopamine receptors syndrome induced by MPTP (experimental - Bromocriptine, pergolide, lisuride, apomorphine animals) - Cabergoline, pramipexole, ropinirole o doses of 5 mg bid delays emergence of disability o Pramipexole and ropinirole – non-ergot dopamine and progression of signs and symptoms in agonists that avoid ergot-related side-effects previously untreated PD patients Advantages Consistent with neuroprotective effect - Some antiparkinson effect - Advantages - Reduced incidence of levodopa-related adverse events o As adjunct to levodopa provides reduced motor - Selective stimulation of dopamine receptor subtypes fluctuations and increased “on” time - Do not generate oxidative metabolites o Levodopa-sparing effect - Levodopa-sparing effect o Neuroprotective in laboratory models - Potential neuroprotective benefits o May be neuroprotective in PD Disadvantages Disadvantages - Limited antiparkinson efficacy o Minimal antiparkinson effect - Specific side effects o Neuroprotection in PD not definitively established o Does not stop disease progression - Do not completely prevent development of levodopa- - Cholinergic drugs exacerbate and anticholinergic drugs related adverse events improve parkinsonian symptoms - Do not treat all features of PD, such as freezing, postural - Typically used in younger PD patients (<70 yrs) in whom instability, autonomic dysfunction, dementia tremor is the dominant clinical feature and cognitive - Do not stop disease progression function is preserved ***APPENDIX D - Useful for treating resting tremor but of lesser value in treatment of akinesia or impaired postural reflexes LEVODOPA - Adverse effects are common and often limit their use - Most effective drug in the treatment of PD - Most important side effects - Treatment is associated with decreased morbidity and o Memory impairment mortality o Acute confusion - Virtually all patients benefit from treatment o Hallucinations - Routinely administered in combination with a - Adverse events most likely to occur in older individuals but decarboxylase inhibitor to prevent peripheral conversion of even younger parkinsonian patients without evident levodopa to dopamine resulting in nausea, vomiting and cognitive impairment can experience neuropsychiatric hypotension dysfunction during anticholinergic treatment - Employ lowest dose of levodopa that will provide a - Other CNS side effects: sedation, dysphoria satisfactory clinical response - Peripheral antimuscarinic side effects: dry mouth, blurred - Early stages of PD 300 – 500 mg/day of levodopa usually vision, constipation, nausea, urinary retention, impaired provides a satisfactory clinical response sweating and tachycardia - Sustained-release formulations of levodopa are less well absorbed than the regular formulation; doses 20 to 30% AMANTADINE - Antiviral agent discovered by chance to have antiparkinson higher may be needed to achieve the same clinical effect as activity the regular preparation of levodopa - Principal mechanism of action has not been established - Chronic treatment with levodopa is associated with - Known to increase dopamine release, block dopamine reuptake, development of adverse events in majority of patients stimulate dopamine receptors and, possibly to have peripheral (motor fluctuations, dyskinesias, neuropsychiatric anticholinergic properties problems) - Appears to be more effective than anticholinergic drugs with - With time, new features develop that do not respond to regard to akinesia and rigidity but is less effective with regard to levodopa therapy (falling, postural instability, freezing, tremor autonomic dysfunction, and dementia) - Most important side effects: confusion, hallucinations, insomnia and nightmares (more common in older patients but can be seen - Levodopa treatment may promote oxidative stress and in patients of any age) accelerate neuronal degeneration in PD because of potential to generate reactive oxidant species TREATMENT OF EARLY PARKINSON’S DISEASE - Pulsatile stimulation of dopamine receptors is believed to 1. Ensure that the correct diagnosis has been made. induce postsynaptic changes, resulting in development of 2. Consider neuroprotective therapy as soon as diagnosis is made. motor fluctuations and dyskinesia 3. Initiate symptomatic therapy with a dopamine agonist in appropriate patients. - Pharmacologic Intervention: 4. Supplement with levodopa when dopamine agonist monotherapy Drug therapies can no longer provide satisfactory clinical control. COMT (Catechol-O-methyltransferase) inhibitors 5. Consider introducing supplemental levodopa therapy in - Entacapone and tolcapone combination with a COMT inhibitor to extend its elimination half- - extends plasma half-life and duration of L-dopa life and further reduce the risk of motor complications. - prevents breakdown of levodopa FACTORS THAT MIGHT INFLUENCE CHOICE OF INITIAL THERAPY COMT inhibitors as an adjunct to levodopa Age Dopamine agonists in younger pxs (<70 yrs) Advantages - Levodopa + decarboxylaxe inhibitor in older pxs - Decreased “off” time in fluctuators and improved ADL o Concerns about cognitive dysfunction scores in nonfluctuators o Older pxs less likely to develop levodopa-related motor - Easy to administer complications - Increases levodopa availability to the brain - Anticholinergic drugs and amantadine - Smoother levodopa plasma levels may reduce risk of o Specifically discouraged in older patients (risk of aggravating underlying mental function) levodopa-related adverse events - Factors that might influence choice of initial therapy in PD Disadvantages Cognitive impairment - Dopaminergic side effects, especially dyskinesia - Most favor initiating treatment of PD sxs with levodopa + - Intolerable diarrhea in 5 to 6% of tolcapone-treated decarboxylase inhibitor in pxs with cognitive impairment patients regardless of age - Tolcapone patients require monitoring of liver function - Immediate-release formulation ***APPENDIX E o Simpler to initiate o Easier to adjust ANTICHOLINERGICS o Can avoid cumulative effects associated with controlled - In PD, dopamine depletion results in a state of relative release preparations and psychiatric problems cholinergic sensitivity associated with DA antagonist