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PARKINSONISM &MOVEMENT DISORDERS DR.DOHA RASHEEDY ALY LECTURER OF GERIATRIC MEDICINE DEPARTMENT OF GERIATRIC AND GERONTOLOGY AIN SHAMS UNIVERSITY IDIOPATHIC PARKINSON’S DISEASE& OTHER PARKINSONIAN SYNDROMES IDIOPATHIC PARKINSON’S DISEASE Risk factors a. Age b. Sex (M > F) c. Family history d. History of exposure to toxins: higher risk with exposure to pesticides, herbicides, welding (manganese poisoning), or for agricultural workers e. History of head trauma 2. Inherited parkinsonism The onset is usually asymmetric, and tremor is the most common presenting sign a. Tremor 1) Characterized as rest tremor 2) May also be a postural or kinetic tremor (rest tremor typically dampens with posture or action) 3) Usually unilateral onset in an extremity 4) Tremor may spread to involve contiguous extremities b. Rigidity 1) Not velocity-dependent or direction-dependent 2) “Cogwheeling”: usually indicative of superimposed tremor c. Bradykinesia 1) Reduced arm swing 2) Generalized slowness in movements 3) Slowness and difficulty with manual dexterity 4) Micrographia 5) Masked facies (hypomimia) 6) Sialorrhea because of bulbar bradykinesia d. Postural instability 1) Loss of postural reflexes 2) Retropulsion as may be found on the “pull test” e. Gait disturbance 1) Stooped posture: characteristic “shuffling” festinating gait with short stride, with tendency to lean forward 2) Propulsion: involuntary and unwanted forward acceleration when patient wants to stop 3) Difficulty initiating gait and gait “freezing” after gait already initiated (sudden inability to take another step) 4) Difficulty with turns f. Associated features 1) Hypokinetic speech: characterized by reduced amplitude and sometimes acceleration of rate 2) Autonomic features a) Most commonly, orthostatism, usually not a presenting feature b) Other less common features: urinary symptoms (hesitancy, nocturia, incontinence), sexual dysfunction, intermittent increased sweating 3) Behavioral and cognitive features a) Bradyphrenia (mental slowing), with difficulty with attention, and poor initiation and working memory b) Depression in up to 2/3 of patients and anxiety (especially associated with akinetic “off” state) c) Dementia may develop after many years i) Difficulty with frontal lobe executive and visuospatial functions, with some language deficits ii) Difficulty with attentional tasks and those involving timed responses 4. Sleep disorders. REM behavior may precede onset of parkinsonism by several years in IPD or DLB. Restless legs syndrome (RLS) and/or periodic limb movements during sleep may be associated with IPD. Discomfort due to rigidity and inability to turn in bed can cause sleep fragmentation Neuroimaging a. Magnetic resonance imaging (MRI): generally not helpful b. Fluorodopa positron emission tomography (PET): reduced uptake in dopaminergic striatal and nigrostriatal pathways, proportional to severity of disease and pathology HISTOPATHOLOGY a. Macroscopic pigmentary loss and microscopic neuronal loss of substantia nigra pars compacta, with microglial activation and cytoplasmic pigmentation of macrophages b. Locus ceruleus, intermediolateral cell column, and dorsal motor nucleus of the vagus nerve may be affected c. Lewy bodies in surviving neurons in areas affected (sparing neocortex): cytoplasmic inclusions with dense eosinophilic core containing hyperphosphorylated neurofilament proteins, lipids, iron, ubiquitin, and α- synuclein MANAGEMENT PHARMACOTHERAPY A. LEVODOPA Should be taken on empty stomach because it competes with amino acids in crossing the blood-brain barrier by a transporter. Formulations: Immediate release (IR) carbidopa-levodopa& Controlled-release (CR) carbidopa-levodopa Increments in dose should be made weekly because a week is required to determine cumulative effect of drug. Simpler to use and initiate than the agonists. Most efficacious and potent medical treatment. Greater incidence of motor fluctuations and dyskinesias than with dopamine agonists Response to medications. Absence of benefit from adequate dosages of dopaminergic drugs, especially levodopa, casts doubt on the diagnosis of IPD and suggests a diagnosis of secondary causes of parkinsonism or one of the Parkinson-plus syndromes Adverse effects a) Nausea i) Due to premature conversion of levodopa to dopamine in the circulation by the peripheral dopa decarboxylase enzyme (L-aromatic amino acid decarboxylase) May be treated with dry bread or cracker (low protein), adding carbidopa to each dose, domperidone (Motilium) b)Dyskinesias i) Dystonia (parkinsonian) ii) Choreiform (levodopa-induced): reduce dose of levodopa for peak-dose dyskinesias c) Orthostatic hypotension d) Visual hallucinations and psychosis e) Insomnia and vivid dreams DOPAMINE AGONISTS 1) Directly activate dopamine receptors 2) More likely than levodopa to produce psychosis, hallucinations, and orthostatic hypotention 3) Less likely than levodopa to produce dyskinesias 4) Synergistic effect with concomitant use of levodopa to exacerbate dyskinesias while reducing the “off” state, necessitating a lower levodopa dose Pergolide and bromocriptine: Ergot derivatives, higher chance of ergot side effects such as potential for vasoconstriction (e.g., Reynaud’s phenomenon), erythromelalgia, fibrotic degeneration of cardiac valves, pulmonary and retroperitoneal fibrosis Pramipexole and ropinirole: nonergolines, have lower rate of adverse effects than traditional dopamine agonists above; may rarely cause sleep attacks and leg edema COMT INHIBITORS 1) They inhibit catechol O-methyltransferase (COMT) and increase plasma level of levodopa. They act to prolong “on” time. Have predisposition to levodopa-induced dyskinesias and other adverse effects (e.g., nausea), sometimes requiring decrease in levodopa dose 2) Formulations: a) Tolcapone (Tasmar) i) Rarely used because of reported cases of acute fulminant liver failure, requiring frequent monitoring of liver function enzymes ii) Reversible central- and peripheral-acting COMT inhibitor b) Entacapone (Comtan) i) Reversible peripheral-acting (including gastrointestinal tract, erythrocytes, and liver) ii) Shorter duration of action than tolcapone iii) Given as 200-mg dose with each dose of levodopa Other adverse effects: abdominal cramps, abdominal pain, severe diarrhea (1.3% of patients) related to allergic hypersensitivity— otherwise, well tolerated ANTICHOLINERGIC AGENTS 1) Usually less effective than levodopa or dopamine agonists 2) May be selectively more effective for tremor and dystonia poorly responsive to levodopa or dopamine agonist when added 3) Most commonly used formulations: trihexyphenidyl (Artane) and benztropine mesylate (Cogentin) 4) Adverse effects: dry mouth, blurred vision, urinary retention, forgetfulness, hallucinations, psychosis ADJUNCTIVE THERAPY 1) Amantadine a) Used in early stages: may delay need for levodopa b) Used as adjunctive therapy: reduce the required doses of dopaminergic treatment c) May be effective in reducing levodopa-induced dyskinesias d) Excreted unchanged in the urine: dose needs to be reduced in patients with renal impairment and in elderly e) Can cause cognitive impairment 2) Selegiline: a) Selectively inhibits monoamine oxidase (MAO)-B and not MAO-A at doses below 10 mg daily b) Daily dose above 10 mg can inhibit MAO-A and may induce hypertensive crisis with ingestion of tyramine-containing food c) Delays the need for levodopa if started early, but no long-term benefit d) Unclear if it has neuroprotective effect e) Metabolized to amphetamine and methamphetamine f) May have a synergistic effect with levodopa GENERAL APPROACH TO INITIAL SYMPTOMATIC TREATMENT IN MILD TO MODERATE PARKINSONISM 1) Consider treatment with levodopa or dopamine agonist if symptoms interfere with daily activity 2) If minimal interference with daily activity: may start with selegiline, amantadine, or anticholinergic agent 3) Onset of symptoms at young age (<40-50 years): many prefer to start with dopamine agonist (no motor fluctuations or dyskinesias in absence of levodopa, much less potent than levodopa) or combination therapy (levodopa and dopamine agonist) 4) Onset of symptoms at older age: start with levodopa IR 25/100 3 times daily 1 hour before meals and titrate weekly or consider an agonist; initial dose may be smaller and titration slower if nausea or other prominent adverse effects GENERAL APPROACH TO ADVANCING PARKINSON’S DISEASE 1) “Wearing off” effect a) Most common type of motor fluctuation in advancing disease b) Recurrence of parkinsonian symptoms and clinical deterioration before next dose c) If response to levodopa during the “on” phase is adequate, move next dose to an earlier time and shorten the time between doses d) If response to levodopa during the “on” phase is inadequate, increase individual levodopa dose before making any adjustment in timing of next dose e) Addition of dopamine agonist after adjustments to levodopa regimen has been made reduces motor fluctuations f) Addition of COMT inhibitors may also increase the “on” phase but predispose to levodopa-induced adverse effects (e.g., dyskinesias) 2) Dyskinesias a) Dystonic in absence of chorea: usually parkinsonian (most commonly, early morning or nocturnal dystonia such as painful foot cramps) b) Choreiform with or without dystonia: usually levodopa-induced c) Usually peak-dose (Off-On-Dyskinesia-On-Off) and rarely biphasic (Off-Dyskinesia-On- Dyskinesia-Off) TTT 1) Peak-dose dyskinesias: reduce amount of levodopa IR and consider discontinuing adjunctive selegiline or COMT inhibitors, Consider addition of amantadine 2) Rapid motor fluctuations with alternating dyskinesias and “off” states, consider addition of an agonist (use adequate dose and avoid rapid titration of dose) 3) Biphasic dykinesias (true biphasic dyskinesias are rare): shortening the time between doses 3) “On-Off” phenomenon a) Unpredictable, abrupt episodes of parkinsonism b) Usually treated with increasing levodopa dose or addition of dopamine agonists 4) Freezing a) Usually occurs because of rigidity and bradykinesia,represents difficulty with initiating movements (walking, getting up from a seated position, etc.) b) “Off” phase, end-dose freezing responds to shortening the time between levodopa doses and taking the next dose at earlier time, addition of a COMT inhibitor or agonist c) If clinical response to levodopa is inadequate, treatment is to increase the respective levodopa dose d) Liquid levodopa as “rescue therapy” can be effective given relatively short onset of symptoms SURGICAL TREATMENT OF PARKINSON’S DISEASE THALAMOTOMY a) Now obsolete b) Alleviates or abolishes contralateral rest tremor or rigidity in 80% to 90% of patients c) Also effective for contralateral dyskinesias d) No effect on bradykinesia, postural instability, or other axial symptoms e) Complications: weakness, numbness, paresthesias, dysarthria, delayed-onset dystonia (more common with bilateral procedures previously done) UNILATERAL PALLIDOTOMY a) Improves rigidity, postural instability, and bradykinesia (as opposed to thalamotomy), although not much greater benefit over L-dopa treatment. b) Most important benefit: dyskinesias (both levodopa- induced chorea type and parkinsonian dystonic type) c) Complications: hemiparesis, aphasia, facial weakness (more common with bilateral procedures) DEEP BRAIN STIMULATION a) Electrodes implanted in ventralis intermedius nucleus of thalamus, subthalamic nucleus, globus pallidus interna, and other subcortical nuclei b) Components: lead, power source (implantable pulse generator), and extension wire connecting the two c) Implantable pulse generator is usually subcutaneous in infraclavicular area d) Stimulator implanted in thalamus, usually unilaterally e) Stimulator implanted in subthalamic nucleus and globus pallidus interna, usually bilaterally f) Mechanism of action thought to involve i) Depolarization inhibition and block ii) Activation of inhibitory pathways iii) Desynchronization of tremor-causing intrinsic pacemaker activity of excitatory neurons Generally, good surgical candidates: younger than 75; multiple antiparkinsonian agents, including combinations, have been tried; no dementia, behavioral problems, or mood disorders OTHER PARKINSONIAN SYNDROMES This is a group of parkinsonian syndromes distinguished from IPD by the presence of additional prominent neurologic abnormalities. In these conditions, there may be cerebellar, autonomic, pyramidal, oculomotor, cortical sensory, bulbar, cognitive, and psychiatric dysfunction, as well as apraxia and movement disorders not typically seen in untreated IPD such as myoclonus, dystonia, or chorea. Despite the apparent clinical differences between IPD and the Parkinson-plus syndromes,differentiation between the two can be difficult. MULTIPLE SYSTEM ATROPHY (MSA) Often multiple overlapping clinical features: 1)Autonomic features: Shy-Drager syndrome Most common presenting symptoms: orthostatism and urinary incontinence, Postural hypotension, Postprandial hypotension, Anhidrosis, Urinary incontinence (Detrusor hypofunction and denervation, Detrusor hyperreflexia, Sphincter weakness from involvement of Onuf’s nucleus (sacral cord)), Male impotence, Iris atrophy, Constipation. 2)Extrapyramidal features: Most often bradykinesia and rigidity, less often tremor, Severe hypophonia, Postural myoclonus: jerking of outstretched hands Up to 30% of patients may respond to levodopa: response is usually brief and limited, Levodopa- induced dyskinesias are usually dystonic 3)Cerebellar features: olivopontocerebellar atrophy a. Presenting feature in only about 5% of patients b. Eventually develops in up to half of patients c. Appendicular and axial dysmetria are more common than oculomotor dysmetria 4) Other features a. Stridor (as well as sleep apnea and other sleep-related breathing disorders) 1) Due to abductor weakness of vocal cords 2) May cause sudden nocturnal death b. Pyramidal features: long-tract signs include spasticity, extensor plantar responses, hyperreflexia HISTOPATHOLOGY a. Neuronal loss and gliosis in inferior olivary nucleus,pons, cerebellum, intermediolateral cell column of thoracic cord, putamen, and substantia nigra b. Glial and neuronal inclusions INVESTIGATIONS a. MRI 1) Rule out other disorders 2) T2 imaging: putaminal hypointensity and atrophyand nigral atrophy—not specific 3) Atrophy of cerebellum, cerebellar peduncles, pons (may see “hot-cross-bun sign” with pontine atrophy) b. Functional imaging 1) Fluorodopa PET: decreased uptake in striatonigral projections, reduced metabolism in putamen and caudate c. Thermoregulatory sweat test and autonomic testing d. Sleep study for evaluation of stridor E. Electromyography (EMG) of the external urethra or anal sphincter: long duration, high-amplitude neurogenic potentials indicating denervation and involvement of Onuf’s nucleus (segments S2 and S3) Treatment a. Orthostatism 1) Discontinuation of agents exacerbating orthostatic hypotension 2) Increase fluid and salt intake in diet 3) Elevate head of bed at 30 degrees (to increase renin secretion) 4) Compressive elastic stockings 5) Medications ( Fludrocortisone, Midodrine) b. Urinary incontinence 1) Bedside urinal or condom catheter (males) for simple urge incontinence 2) Intermittent self-catheterization for urinary retention 3) Anticholinergic agents (oxybutynin 2.5-5 mg 2-3 times daily) or propantheline bromide (15-60 mg daily) for detrusor hyperreflexia 4) Indwelling catheters 5) Surgery (last resort) c. Anhidrosis: patients warned against extreme heat (environmental or during exercise) d. Other measures 1) Physical therapy 2) Stridor: continuous positive pressure or tracheostomy for refractory vocal cord paresis e. Parkinsonism: carbidopa-levodopa (may worsen orthostatic hypotension) PROGRESSIVE SUPRANUCLEAR PALSY Clinical features a. Supranuclear ophthalmoplegia 1) Vertical saccades (especially downward) > horizontal saccades affected earlier than pursuit movements 2) Apraxia of eyelid movements (especially opening) 3) Reduced vestibulo-ocular reflex suppression 4)Eventually, complete bilateral ophthalmoplegia b. Parkinsonism and early falls 1) Prominent, early axial rigidity and early impairment of axial and postural reflexes with retropulsion 2) Prominent hyperextended posture during walking (as compared with antecollis in patients with multiple system atrophy) 3) Symmetric bradykinesia 4) Rest tremor is uncommon 5) Unresponsive or poor response to levodopa c. Pseudobulbar palsy 1) “Emotional incontinence”: crying or laughter inappropriate to context of conversation 2) Dysarthria: spastic and sometimes hypernasal speech 3) Dysphagia 4) Drooling 5) Increased jaw jerk d. Cognitive disturbance 1) Impaired attention and mental slowing 2) Frontal-executive dysfunction 3) Frontal release signs 4) Personality change: apathy, irritability, disinhibition e. Other:hypertension (presumably from degeneration of brainstem adrenergic nuclei) INVESTIGATIONS a. MRI 1) Localized midbrain atrophy (reduced anteroposterior diameter) 2) Enlarged third ventricle 3) Atrophy of red nucleus 4) Possibly frontal or temporal atrophy b. Functional imaging 1) Global metabolic reduction, including bilateral frontal lobes (especially anterior cingulate cortex), basal ganglia, thalamus, upper brainstem 2) Fluorodopa PET: reduction of 18F-dopa influx into caudate and putamen c. Polysomnography: diminished total sleep time and REM sleep HISTOPATHOLOGY a. Atrophy (with neuronal loss and gliosis) of upper brainstem structures, pallor of substantia nigra and locus ceruleus b. Other areas may be affected: periaqueductal gray matter, superior colliculus, substantia nigra, subthalamic nucleus, red nucleus, dentate nucleus, basal ganglia (globus pallidus > putamen), hippocampal structures c. Abnormal tau deposition, including neuropil threads(tau- positive fibers) and tau-positive tufted astrocytes d. Iron pigmentation of globus pallidus TREATMENT a. Few patients have response to dopaminergic agents: minimal response may be appreciated with bradykinesia and rigidity b. Trials of NMDA receptor antagonists (e.g., amantadine) and acetylcholinesterase inhibitors have been disappointing CORTICOBASAL DEGENERATION Clinical. This syndrome can present as a strikingly asymmetric or unilateral akinetic-rigid syndrome associated with limb apraxia, alien limb phenomenon, cortical sensory signs, stimulus sensitive myoclonus, dystonia, and postural or action tremor. Supranuclear gaze palsy, cognitive impairment, and pyramidal tract signs can also be seen. The alien limb phenomenon is present when a patient manifests uncontrollable grasping and manipulating of objects. This phenomenon may be present in CBD, ischemic strokes, or Creutzfeldt-Jakob disease (CJD). Neuroimaging MRI or CT of the brain are abnormal in some patients and reveal asymmetric frontoparietal atrophy NEUROPATHOLOGY Neuronal loss and gliosis is found in the frontoparietal regions and substantia nigra pars compacta. Swollen achromatic neurons and basophilic nigral inclusions, which represent an overlap with Pick's disease, are characteristic. Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated tau protein are found SECONDARY PARKINSONISM Parkinsonism can be induced by a wide spectrum of disease processes affecting the brain, especially the basal ganglia. These include infection, cerebrovascular disorders, toxins, metabolic disorders, trauma, neoplasm, drugs, hypoxemia, and hydrocephalus. Selected causes include: 1. Drug-induced parkinsonism. Neuroleptics and metoclopramide block striatal D-2 dopamine receptors, whereas reserpine depletes dopamine from presynaptic vesicles. The resolution of drug induced parkinsonism may take several months after discontinuation of the offending medication 2. Toxic parkinsonism a. Manganese: most common cause of environmental toxin b. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine c. Cyanide d. Methanol e. Carbon monoxide 3. Metabolic parkinsonism a. Hepatic encephalopathy: parkinsonism associated with asterixis, myoclonus, chorea, encephalopathy b. Postanoxic parkinsonism: associated with pallidal lesions (as in carbon monoxide poisoning) c. Hypoparathyroidism: associated with basal ganglia calcifications d. Hypothyroidism (not true parkinsonism): slowing of activity may mimic parkinsonism e. Central pontine myelinolysis: associated with extrapontine lesions that occur with rapid correction of hyponatremia 4. Vascular parkinsonism a. Multiple small lacunes in deep gray matter b. Parkinsonism primarily affecting gait and presenting as loss of postural stability and falls (primarily lower body involvement); apractic gait with difficulty initiating each step c. Pseudobulbar affect, urinary incontinence with subcortical dementia d. Associated with vascular dementia e. Pyramidal involvement is common: hyperreflexia and extensor plantar responses are more common than upper motor neuron distribution weakness f. Poor response to dopaminergic agents 5. Posttraumatic parkinsonism 6.Infectious and postencephalitic parkinsonism HEREDODEGENERATIVE DISEASES • Wilson's disease. An autosomal recessive condition associated with impairment of copper excretion due to a genetic defect in a copper transporting ATPase, resulting in copper accumulation in different organ systems including the central nervous system, liver (cirrhosis), cornea (Kayser- Fleischer ring), heart, and kidney. • Huntington's disease (HD). progressive autosomal dominant disorder characterized by dementia, psychiatric disturbance, and a variety of movement disorders. • familial calcification of the basal ganglia. (Fahr’s disease)Syndrome of progressive dementia and parkinsonism, schizophrenia-like psychosis extensive calcification of basal ganglia. Usually sporadic but may be inherited as autosomal dominant disorder (locus on chromosome 14) DEMENTIA WITH LEWY BODIES • Dementia with Lewy bodies, characterized by the presence of Lewy bodies in the cortical and subcortical areas, is now considered the second most common neuropathological cause of dementia after Alzheimer’s disease. Dementia, defined as progressive decline of memory andother cognitive functions causing impairment in functional ability, is an essential feature for the diagnosis. The dementia can have cortical and subcortical characteristics. Other features include fluctuation of symptoms, visual hallucination and spontaneous Parkinsonism. Fluctuation can be defined as a significant variation in a patient’s cognitive or functional abilities, or periods of confusion or decreased responsiveness alternating with reasonable lucidity .This is a distinctive characteristic and can vary in duration from minutes to days or weeks. Fluctuation can present as episodic confusion, inattention, decreased level of arousal, and even speech arrest. • Visual hallucinations are often a prominent feature and have been described in 40 to 75 percent of patients with DLB . The hallucinations are represented by vivid images of animals, people, or children and can be very disturbing to the patient. • Parkinsonian features are also found in DLB, particularly rigidity and bradykinesia and less commonly resting tremor. • Other clinical findings include syncope, loss of muscle tone, transient loss of consciousness, delusions, and so on. • Treatment: The treatment is symptomatic with the use of anticholinesterase and antipsychotic and neuroprotective agents. The response to levodopa is variable among subjects. Hypersensitivity to antipsychotics.
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