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NEUROLOGY BOARD REVIEW MANUAL Neurodegenerative Disorders: Parkinson’s Disease Catherine L. Gallagher, MD INTRODUCTION As the population ages, adult-onset neurodegenerative disorders will be encountered even more frequently by clinical neurologists. New treatments will continue to emerge as scientific understanding of the molecular genetic and pathophysiologic basis of these disorders evolves. Volume 8 of the Hospital Physician Neurology Board Review Manual will focus on the diagnosis and management of neurodegenerative disorders. Because many excellent comprehensive reviews of these topics have been written, the goal is to provide an outline for review of basic concepts and to stimulate critical thinking. This manual is devoted to a discussion of Parkinson’s disease. Future manuals in this volume will address parkinsonian syndromes, dementia, and neurodegenerative conditions of the peripheral nervous system and muscle. CLINICAL AND PATHOLOGIC FEATURES Movement disorders are classified as hyperkinetic (ie, abnormal forms of excess movement are the dominant feature) or hypokinetic (ie, decreased movement is the essential feature). Parkinson’s disease is the most common hypokinetic disorder and the second most common late-life neurodegenerative disease, affecting 1% of persons older than 65 years.1 Idiopathic Parkinson’s disease is characterized clinically by the triad of resting tremor, bradykinesia, and rigidity and pathologically by loss of dopaminergic neurons in the pars compacta (dorsal portion) of the substantia nigra. CLINICAL PRESENTATION The clinical presentation of Parkinson’s disease is heterogeneous. As in many neurodegenerative conditions, clinical signs of disease appear when cerebral reserve has been exhausted. Several prodromal symptoms seem to occur more frequently in individuals who develop Parkinson’s disease. These symptoms include late-life depres- 2 Hospital Physician Board Review Manual sion,2 rapid eye movement sleep (REMS) behavior disorder,3 constipation,4 and anosmia. At initial presentation, patients may describe classic symptoms of tremor, micrographia, extreme slowness in completing activities of daily living, voice changes, or difficulty maneuvering in bed. They also may present with nonspecific complaints, such as stiffness, pain, weakness, fatigability, mild incoordination, or poor balance.5 Motor Symptoms A clinical diagnosis of Parkinson’s disease is based on the presence of 3 of 4 cardinal signs (tremor, rigidity, bradykinesia, and impaired postural reflexes) or the presence of 2 signs if tremor, rigidity, or bradykinesia is asymmetric.6 The classic tremor is a unilateral pillrolling 3- to 5-Hz rest tremor that is most evident when the patient is walking or seated with hands relaxed. However, leg tremor that improves with weight bearing and action (postural) tremor that dampens transiently with assumption of a new posture (reemergent rest tremor) are frequently observed. Chin tremor is common. The essential change in muscle tone in patients with Parkinson’s disease is rigidity. Rigidity is velocityindependent resistance to passive movement about a joint. Paratonia, in contrast, implies inability to voluntarily relax. Although the tone change in Parkinson’s disease may be termed cogwheeling, a physician flexing and extending the arm of any patient with tremor may note a ratcheting quality to the movement. In patients with Parkinson’s disease, rigidity should be detectable in addition to cogwheeling. Rigidity may be confirmed by asking the patient to perform a voluntary (“mirror”) movement in the contralateral limb. Parkinson’s disease causes slowness and reduced amplitude of movements, appearing in the spectrum of hypokinesia, bradykinesia, and akinesia. Specific manifestations include bradyphrenia (slow verbal responses), hypophonia, hypomimia (masked facies), micrographia, digital impedance (tendency for rapid alternating movements to “block” or assume the rhythm of the tremor),6 and decreased arm swing. Later, more severe symptoms appear, including freezing (inability to Neurodegenerative Disorders: Parkinson’s Disease Table 1. Modified Hoehn and Yahr Staging Scale for Parkinson’s Disease Stage 0 1 1.5 2 2.5 Description No signs of disease Unilateral disease Unilateral disease with axial involvement A B Bilateral disease without postural instability Early signs of postural instability (recovery on “pull test”) 3 Bilateral disease with postural instability, physically independent 4 Severe disability but still able to stand or walk unassisted 5 Confinement to wheelchair or bed Adapted from Hoehn MM. The natural history of Parkinson’s disease in the pre-levodopa and post-levodopa eras. Neurol Clin 1992;10: 331–9. Reprinted with permission from Elsevier Science. initiate gait, especially when turning or passing through a doorway), retropulsion (more than 2 steps required for recovery on the “pull test”),7 and difficulty arising from a chair without rocking back and forth or using the arms. Although slightly flexed posture is normal in elderly persons, the flexed position is more exaggerated in Parkinson’s disease. Dystonia—especially involving the brow (blepharospasm), toes, or feet—is common. Oculomotor findings may include slow saccades, insufficient convergence, and reduced blink rate. Glabellar reflex (Myerson’s sign) is frequently present. Nonmotor Symptoms Approximately 30% of patients develop cognitive dysfunction that has been characterized as subcortical, because the affected individuals predominantly display elements of poor motivation, slow thought, and executive dysfunction, with relative preservation of language and memory. The cognitive abilities of patients with advanced Parkinson’s disease are frequently underestimated due to bradyphrenia. Additional nonmotor symptoms include dysautonomia (resulting in excessive sweating, orthostatic hypotension, sexual dysfunction, urinary dysfunction, and constipation), sialorrhea, dysphagia, sleep disorders (restless legs syndrome, excessive daytime sleepiness, REMS behavior disorder, and obstructive and central sleep apnea), neuropsychiatric symptoms (depression, psychosis, and anxiety), and anosmia. Subjective sensory symptoms—such as pain, numbness, tingling, and burning—occur in 40% of patients.8 Figure 1. Gross pathology of Parkinson’s disease. Comparison between normal (A) and Parkinson’s (B) midbrain, showing depigmentation of the substantia nigra with maximal cell loss in the lateral nigra (inset, arrow). (Photograph courtesy of M. Shahriar Salamat, MD, PhD.) Clinical Staging The most widely used disability/disease progression scales include the Hoehn and Yahr9 staging system (Table 1) and the Unified Parkinson’s Disease Rating Scale (UPDRS).10 The 6 subsections of the UPDRS comprise the Hoehn and Yahr staging system and the Schwab and England Activities of Daily Living Scale. Although time consuming to administer, the UPDRS is the principal outcome measure used in many clinical studies. PATHOLOGY Characteristic pathologic features of Parkinson’s disease are cell loss and Lewy body formation in the substantia nigra and other pigmented brainstem nuclei. The pattern of neuronal loss in the substantia nigra is opposite (beginning in the lateral ventral pars compacta) to the pattern seen in normal aging (Figure 1).11 Functional imaging and autopsy studies suggest that at least 30% of nigral dopaminergic neurons are lost before disease expression occurs.12 Degeneration of other neuronal populations occurs, including neurons of the nucleus basalis of Meynert; hypothalamic neurons; small cortical neurons in the cingulate gyrus and entorhinal cortex; neurons of the olfactory bulb, sympathetic ganglia, and dorsal motor nucleus of the vagus; and parasympathetic neurons in the gastrointestinal tract.13 Lewy bodies (ie, neuronal cytoplasmic inclusions consisting of radially arranged, intermediate filaments [Figure 2]) accumulate in neurons of the substantia nigra, brainstem nuclei, hippocampus, cerebral cortex, myenteric plexus, and olfactory bulb. Typically, a hematoxylin and eosin stain is used to reveal these round, eosinophilic, cytoplasmic inclusions that are surrounded by a pale halo. Lewy bodies are ubiquitinpositive. The presence of Lewy bodies is nonspecific for Neurology Volume 8, Part 1 3 Neurodegenerative Disorders: Parkinson’s Disease Table 2. Exclusion Criteria for Parkinson’s Disease Figure 2. Hematoxylin and eosin stain demonstrating Lewy bodies (arrows) within pigmented nigral neurons. (Photograph courtesy of M. Shahriar Salamat, MD, PhD.) idiopathic Parkinson’s disease; they also are found in multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and other neurodegenerative syndromes with additional pathologic features. A few Lewy bodies are found incidentally in 4% to 13% of aged brains.11 PREMORBID DIAGNOSTIC ACCURACY Clinicopathologic studies published in the 1990s reported that a neurologist’s clinical diagnosis of idiopathic Parkinson’s disease corresponded with the pathologic diagnosis in only 76% of cases.14,15 However, a more recent assessment of 73 pathologic cases revealed considerably higher accuracy of diagnosis in movement disorders clinics.16 Features that improve diagnostic accuracy include asymmetric onset, resting tremor, and clinical response to levodopa. Features that suggest an alternative diagnosis include history or signs suggestive of another hypokinetic-rigid syndrome or druginduced parkinsonism (Table 2).8 ETIOLOGY LOSS OF NIGRAL DOPAMINERGIC OUTPUT Catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine) are synthesized from tyrosine in tissues that express the necessary biosynthetic enzymes (Figure 3). For example, dopamine β-hydroxylase is expressed in locus ceruleus and postganglionic sympathetic neurons, whereas phenylethanolamine-N-methyltransferase (PNMT) is expressed 4 Hospital Physician Board Review Manual Disease Criteria Vascular parkinsonism Step-wise progression, gait apraxia MPTP toxicity Abrupt onset of symptoms Medication-induced parkinsonism Remitting course, neuroleptic therapy within the previous year Postencephalitic parkinsonism History of encephalitis Progressive supranuclear palsy Supranuclear gaze palsy Multiple system atrophy Cerebellar signs, severe autonomic failure, unexplained pyramidal (upper motor neuron) signs Pantothenate kinase– associated disorders Unexplained pyramidal signs Lewy body dementia Early dementia, hallucinations Corticobasal degeneration Unilateral apraxia with cortical sensory loss MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. (Adapted with permission from Koller WC. How accurately can Parkinson’s disease be diagnosed? Neurology 1992;42[Suppl 1]:6–16.) in the adrenal medulla. Melanin also is synthesized from tyrosine (not surprising when one considers that both melanocytes and neurons are neural crest derivatives), accumulates in mesencephalic catecholaminesynthesizing reticular neurons with age, and is present even in albinos.17 Central and peripheral dopamine receptors are classified differently. Peripheral receptors include DA1 and DA2 subtypes. DA1 receptors mediate vasodilation of mesenteric, renal, and coronary beds, whereas DA2 receptors mediate reduction of norepinephrine and aldosterone release. Central nervous system (CNS) dopamine receptors include the D1,D5 family and the D2,D3,D4 family. D1and D2-receptor activation have opposite effects on adenylate cyclase activity and thus on levels of intracellular cyclic adenosine monophosphate.18 Of the 4 major dopaminergic CNS tracts, 3 arise in the substantia nigra; the fourth is the projection from the hypothalamic arcuate nucleus to the pituitary gland.19 The substantia nigra gives rise to mesolimbic and mesocortical tracts (implicated in schizophrenia) and the nigrostriatal pathway (implicated in Parkinson’s disease). Loss of nigral dopaminergic projections produces Neurodegenerative Disorders: Parkinson’s Disease Tyrosine Norepinephrine Dopamine Levodopa TH DDC DBH Epinephrine PNMT Figure 3. Catecholamine synthesis from tyrosine. DBH = dopamine β-hydroxylase; DDC = dihydroxyphenylalanine decarboxylase (ie, DOPA decarboxylase or aromatic amino acid decarboxylase); PNMT = phenyl-ethanolamine-N-methyltransferase; TH = tyrosine hydroxylase (rate-limiting step). symptoms of Parkinson’s disease. Circuitry of the basal nuclei (ganglia) is complex and has been reproduced in multiple diagrams that are modified frequently as understanding evolves (Figure 4). Some simplified rules follow: CONTRIBUTING FACTORS Cumulative genetic and environmental factors probably play a role in the pathogenesis of Parkinson’s disease. 1. The striatum (caudate and putamen) is the main recipient of excitatory (glutamatergic) inputs from the cerebral cortex. Of striatal neurons, 90% to 95% are medium-spiny projection neurons. A few striatal neurons are inhibitory interneurons, some of which synthesize acetylcholine. Environmental Factors The environmental toxin most directly linked to Parkinson’s disease is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This substance was discovered accidentally in the late 1970s, when illegally synthesized meperidine containing MPTP produced clinical and pathologic features of Parkinson’s disease (with the exception of Lewy bodies) in young persons who used the substance. When infused, lipophilic MPTP readily crosses the blood-brain barrier and is metabolized to 1-methyl-4-phenylpyridinium (MPP+) in astrocytes and serotonergic neurons that contain monoamine oxidase B (MAOB). Subsequently, MPP+ is transported into the extracellular space, where it is selectively taken up by dopaminergic neurons via the plasma membrane dopamine transporter. Intracellularly, MPP+ inhibits mitochondrial complex I and α-ketoglutarate dehydrogenase of the tricarboxylic acid cycle; this results in energy failure, with its sequelae—intraneuronal calcium overload, glutamate release, and impaired detoxification of reactive oxygen and nitrogen species—leading to cell death in a dose-dependent manner.20 Therefore, inhibition of either MAOB or dopamine transporter function is protective against MPTP-induced parkinsonism. Under normal conditions, reactive oxygen species generated during metabolism of dopamine via MAOB are “detoxified” by reduced glutathione and superoxide dismutase. These observations have led to the evaluation of MAOB inhibitors as neuroprotective agents. Other factors that have been shown in animal models or through epidemiologic studies to be potentially related to the development of Parkinson’s disease include exposure to pesticides (particularly organophosphates and rotenone, which is a mitochondrial complex I inhibitor), rural living, well water, and exposure to metals (aluminum, copper, iron, and manganese).21 Occupational welders exposed to volatilized metals for 10 or more years develop Parkinson’s disease at a younger age than controls.22 Other substances that may 2. Major output nuclei include the functionally related internal segment of globus pallidus (GPi) and substantia nigra reticularis (SNr). In the resting state, these nuclei are tonically active, maintaining cortical inhibition. 3. Within the subcortical circuit, almost all nuclei have inhibitory outputs mediated by the neurotransmitter γ-aminobutyric acid. Notable excitatory projections include the substantia nigra dopaminergic D1-receptor pathway and the subthalamic nucleus (STN) glutamatergic pathway. 4. Increased activity of the STN augments inhibitory output from the GPi and SNr. 5. Dopaminergic projections from the substantia nigra pars compacta (dorsal nigra) influence output from the basal nuclei via a direct (D1-receptor mediated) and an indirect (D2 -receptor mediated) pathway. Direct: Striatum → GPi Indirect: Striatum → GPe (globus pallidus externa) → STN → GPi The direct and indirect pathways have inverse influences on GPi and thus on thalamocortical activation. In Parkinson’s disease, decreased dopaminergic output from the substantia nigra pars compacta produces decreased excitation of the direct pathway and decreased inhibition of the indirect pathway, overactivity of both STN and GPi, and thus akinesia. Neurology Volume 8, Part 1 5 Neurodegenerative Disorders: Parkinson’s Disease Permission to electronically reproduce this figure not granted by copyright holder. produce parkinsonism through specific toxic effects on the globus pallidus include carbon monoxide, manganese, carbon disulfide, and cyanide.6 Genetic Factors Genetic susceptibility is suggested by the observation that not all persons exposed to MPTP develop parkinsonism.23 Familial aggregation of both early-onset and late-onset Parkinson’s disease is observed.24 However, a large twin study found that concordance for Parkinson’s disease was higher for monozygotic twins than for dizygotic twins only when symptom onset occurred at an age younger than 50 years.25 Early-onset familial Parkinson’s disease has been linked to mutations in genes encoding α-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 (UCHL1).26 The ubiquitin-proteasomal pathway (UPP) provides controlled degradation of proteins tagged with ubiquitin within eukaryotic cells. Ubiquitinpositive inclusions are found in several neurodegenerative disorders, suggesting that alterations in the structure or quantity of the substrate proteins or alterations in the 6 Hospital Physician Board Review Manual Figure 4. A simplified version of basal nuclear (ganglia) connections. Black projections are excitatory; white connections are inhibitory. D1, D2 = dopamine receptors; DA = dopamine; ENK = enkephalin; GABA = γ-aminobutyric acid; GLU = glutamatergic inputs; GPe = external segment of the globus pallidus; GPi = internal segment of the globus pallidus; SNc = substantia nigra compacta; SNr = substantia nigra reticularis; STN = subthalamic nucleus; SubstP = substance P; VA/VL = ventral anterior/ventral lateral nuclei of the thalamus. (Adapted from Riley DE, Lang AE. Movement disorders. In: Bradley WG, Daroff RB, Fenichel GM, Janikovic J, editors. Neurology in clinical practice: principles of diagnosis and management. Vol 2. 2nd ed. Butterworth-Heinemann; 1996:1892. Reprinted with permission from Elsevier Ltd.) efficiency of UPP function lead to abnormal protein accumulation (Table 3).27 α-Synuclein is degraded via the UPP pathway; ubiquitin, parkin, and UCHL1 are involved in the degradation of α-synuclein. Additional genetic factors that seem to play a role in Parkinson’s disease include deficient mitochondrial complex I function28 and polymorphisms in enzymes that degrade dopamine, including N-acetyltransferase 2,29 MAOB, and catechol-O-methyltransferase (COMT).30 Other Causes of Parkinsonism Postinfectious parkinsonism. In 1917, von Economo described parkinsonism as a complication of encephalitis lethargica. Postencephalitic parkinsonism differed from idiopathic Parkinson’s disease in its slow progression, tendency to produce associated hyperkinetic movements, pyramidal tract signs, behavioral features, and response to anticholinergics.31 West Nile encephalitis may cause parkinsonism and other movement disorders. Iatrogenic parkinsonism. Iatrogenic parkinsonism is associated with use of neuroleptics (most of which are Neurodegenerative Disorders: Parkinson’s Disease Table 3. Representative Neurodegenerative Diseases with Ubiquitin-Positive Inclusion Bodies Disease Gene Mutations Pathology AD APP, PS1, PS2 Missense Amyloid plaques, neurofibrillary tangles FTDP MAPT Missense Tau inclusions Pick’s MAPT ALS SOD Missense Lewy body–like inclusions PD α-Synuclein, UCHL1, Parkin Missense Lewy bodies DLB α-Synuclein Lewy bodies MSA α-Synuclein GCIs Prion* Prion Missense PrP plaques DRPLA Atrophin 1 Polyglutamine Nuclear inclusions HD Huntington Polyglutamine Nuclear inclusions SCA1 Ataxin 1 Polyglutamine Nuclear inclusions SCA3/MJD Ataxin 3 Polyglutamine Nuclear inclusions SCA7 Ataxin 7 Polyglutamine Nuclear inclusions Pick bodies AD = Alzheimer’s disease; ALS = amyotrophic lateral sclerosis; APP = amyloid precursor protein; DLB = dementia with Lewy bodies; DRPLA = dentatorubral-pallidolluysian atrophy; FTDP = frontotemporal dementia with parkinsonism; GCIs = glial cytoplasmic inclusions; HD = Huntington’s disease; MAPT = microtubule-associated protein tau; MJD = Machado-Joseph disease; MSA = multiple system atrophy; PD = Parkinson’s disease; PrP = prion protein; PS = presenilin; SCA = spinocerebellar ataxia; SOD = superoxide dismutase; UCHL1 = ubiquitin C-terminal hydrolase L1. *Data regarding prion from Dagher A. Functional imaging in Parkinson’s disease. Semin Neurol 2001;21:23–32. antagonists of D1 or D2 receptors), reserpine, amiodarone, metoclopramide, divalproex, pyridostigmine, cyclosporine, lithium, and fluoxetine. Iatrogenic parkinsonism may be distinguished from Parkinson’s disease by subacute onset, symmetry, response to anticholinergics, and resolution of symptoms usually within weeks to months after discontinuation of the offending agent.32 MANAGEMENT NONPHARMACOLOGIC THERAPY There is good evidence that regular exercise and physical therapy improve UPDRS scores.33 Interventions that help control freezing include use of targets near the floor (eg, a specialized cane), marching to music, and counting. Many devices have been invented to assist with activities of daily living as well. PHARMACOLOGIC THERAPY Motor Symptoms Medications available in the United States for treatment of motor symptoms are shown in Figure 5. In humans, these medications have been shown to provide symptomatic relief rather than to delay progression of the disease. Dopamine replacement improves bradykinesia, tremor, and rigidity; it is less effective for cognitive changes, dysarthria, sialorrhea, postural instability, and dysautonomia.34 Levodopa is taken up into the brain by the amino acid transporter, so restriction of oral protein intake when taking levodopa enhances bioavailability. Taking levodopa with acid and without protein also enhances absorption from the gastrointestinal tract. Bioavailability of extendedrelease levodopa is approximately 80% of immediaterelease levodopa. Levodopa is administered with a DOPA (dihydroxyphenylalanine) decarboxylase (DDC) inhibitor to enhance passage into the CNS. Initially, 75 mg of carbidopa was felt to be sufficient to inhibit peripheral DDC in all patients; however, it now appears that patients with significant peripheral side effects may benefit from a higher dose. Doses higher than 150 mg may cross the blood-brain barrier, inhibiting central DDC and limiting levodopa central bioavailability.34 The dopamine agonists (pergolide, bromocriptine, pramipexole, ropinirole) have highest agonist activity for D2 and D3 receptors. Bromocriptine is also a D1-receptor antagonist.35 Amantadine has various proposed mechanisms of action, including enhancement of dopamine Neurology Volume 8, Part 1 7 Neurodegenerative Disorders: Parkinson’s Disease BRAIN D1, D2 receptors (striatum) Pramipexole Ropinirole Bromocriptine Pergolide Cholinergic interneurons (striatum) Trihexyphenidyl Benztropine Tolcapone Dopamine MAOB Selegiline Levodopa 3-O-methyl-dopa COMT DDC (substantia nigra) Free radicals BLOOD-BRAIN BARRIER LNAA transporter Tolcapone Entacapone BODY Levodopa COMT DDC Methylated levodopa Carbidopa Dopamine Figure 5. A schematic diagram of standard pharmacologic options for treating Parkinson’s motor symptoms. Note: Amantadine is not shown because it has several mechanisms of action. COMT = catechol-O-methyltransferase; DDC = dihydroxyphenylalanine decarboxylase; LNAA = large neutral amino acid; MAOB = monoamine oxidase B. Table 4. Side Effects of Levodopa Side Effect Proposed Cause Nausea Stimulation of peripheral dopamine receptors in the area postrema Dyskinetic movements Unbalanced stimulation of the direct pathway and inhibition of the indirect pathway Psychological symptoms ranging from vivid dreams and “benign visual hallucinations” to psychosis Possibly related to stimulation of the mesolimbic and mesocortical dopaminergic pathways Orthostatic hypotension Vasodilation, norepinephrine antagonism Spontaneous erections and possibly hypersexual behavior Central D2-receptor agonism, oxytocin release Cardiac arrhythmias Stimulation of cardiac α1, α2, and β1 receptors release from central stores, inhibition of dopamine reuptake, and glutamate antagonism. COMT inhibitors block a different dopamine degradation pathway than that blocked by carbidopa; tolcapone has both central and peripheral action (but has been associated with severe hepatotoxicity); entacapone acts peripherally. All medications except anticholinergics and possibly amantadine have side effect profiles similar to levodopa (Table 4). Muscarinic cholinergic antagonists (trihexyphenidyl, benztropine) may produce dry mucous membranes, constipation, blurred vision (due to paralysis of accommodation), decreased sweating, and psy- 8 Hospital Physician Board Review Manual chosis, particularly in elderly persons. Amantadine may cause peripheral edema, livedo reticularis, and visual dysfunction. COMT inhibitors may turn the urine orange. In addition, certain medications have potential idiosyncratic side effects. Bromocriptine and pergolide are ergot-derived dopamine agonists, posing a small risk of retroperitoneal fibrosis. Some studies have shown a higher incidence of hallucinations and daytime sleepiness in patients taking dopamine agonists when compared with those taking levodopa.36,37 Pergolide also has been associated with an increased risk of cardiac valvular abnormalities. Neurodegenerative Disorders: Parkinson’s Disease Table 5. Treatment of Nonmotor Symptoms in Patients with Parkinson’s Disease Condition Symptom Pharmacologic Therapy Nonpharmacologic Therapy Dysautonomia Constipation Usual interventions Orthostatic hypotension Sialorrhea Eliminate antihypertensives Midodrine Fludrocortisone Second-line agents (eg, erythropoietin)* Eliminate offending medications, treat depression Yohimbine* Sildenafil β-Blockers* Focal botulinum toxin injections* Oxybutynin Tolterodine Parotid botulinum toxin injections* Oral atropine drops* Increase exercise and fluid and fiber intake Increase salt and fluid intake Elevate head at night Compression stockings Dysphagia Treatment of bradykinesia Swallowing evaluation and technique instruction Depression SSRIs, others Exercise Counseling Anxiety Dementia SSRIs, benzodiazepines Donepezil,* rivastigmine,* galantamine* Decrease levodopa equivalent dose Clozapine Quetiapine ?Donepezil* Aripiprazole Impotence Excessive sweating Urinary frequency Neuropsychiatric symptoms Psychosis Sleep disorders Restless legs/PLMS REMS behavior disorder Daytime sleepiness Modify fluid intake Bedtime dopamine agonist or CR* levodopa Clonazepam* Modafinil,* methylphenidate* Pain Tricyclic antidepressants* Anticonvulsants* Seborrhea Steroid cream Improve sleep hygiene CR = controlled release; PLMS = periodic limb movements during sleep; REMS = rapid eye movement sleep; SSRIs = selective serotonin reuptake inhibitors; ? = questionable because only one study indicates improvement. *These agents are not approved by the Food and Drug Administration for this indication. Nonmotor Symptoms A variety of nonmotor symptoms afflict patients with Parkinson’s disease. Potential therapies for these symptoms are outlined in Table 5.38,39 Natural History of Medically Treated Disease The introduction of levodopa therapy in the early 1960s revolutionized treatment of Parkinson’s disease. However, it is now clear that in most patients, response Neurology Volume 8, Part 1 9 Neurodegenerative Disorders: Parkinson’s Disease On dyskinesia Off bradykinesia 6–8 hr 3–5 hr 0.5–2 hr Early Moderate Advanced Parkinson’s disease Figure 6. Motor fluctuations in treated Parkinson’s disease. Dark grey = therapeutic window. (Adapted with permission from Jankovic J. Levodopa strengths and weaknesses. Neurology 2002;58[4 Suppl 1]:S23.) to pharmacologic therapy ultimately becomes inadequate because of the emergence of motor fluctuations. Motor fluctuations include wearing off (a shorter duration of medication efficacy), dyskinesias (hyperkinetic writhing movements typically involving limbs, face, and neck), and freezing. Rarely, dyskinesias affect ocular, respiratory, and abdominal muscles. Dyskinesias are classified as peak dose (monophasic, present at maximum levodopa serum level) or as diphasic (present with wearing on and wearing off of medication effect). Patients become painfully aware of the disparity in their motor abilities in the on state (ie, during times of maximum medication efficacy) versus the off state (ie, when the medication is depleted). As motor fluctuations progress, time spent in the on state becomes shorter, and the transition from on to off becomes more precipitous and less predictable (Figure 6). Careful observation reveals that most patients treated with levodopa develop some motor fluctuations within 1 year of starting therapy.40 With progressive attrition of dopaminergic neurons, the ability of the substantia nigra to metabolize and store dopamine declines; therapeutic response to the levodopa more and more closely reflects its serum half-life (about 60 minutes). Whether the administration of levodopa alters disease progression is a matter of debate; however, several studies have shown that the use of longer-acting dopamine receptor agonists is associated with a lower risk of developing motor fluctuations.36,37 As a result, the American Academy of Neurology now recommends dopamine agonists as first-line therapy for patients with Parkinson’s disease.41 However, the wisdom of this recommendation for all patients remains controversial among neurologists because (1) levodopa produces the greatest improvement in UPDRS scores,36,37 (2) dopamine agonists require prolonged titration sched- 10 Hospital Physician Board Review Manual ules, (3) dopamine agonists are still under patent protection and therefore are more expensive than levodopa, and (4) patients with late-onset Parkinson’s disease may not live long enough for motor fluctuations to produce significant disability. Therefore, choice of initial therapy should be individualized. SURGICAL INTERVENTION Indications Between 1939 and the early 1960s, ablative surgeries of the globus pallidus and thalamus were used to control symptoms of Parkinson’s disease. With growing awareness of the natural history of pharmacologically treated Parkinson’s disease, interest in surgical treatment of patients with disabling motor complications has reemerged. Patients should be considered for surgical intervention if they develop medication-refractory motor complications, their symptoms are responsive to levodopa, they are cognitively intact, and they are good surgical candidates. Surgical Procedures Ablative therapy refers to stereotactic lesioning of a target structure within the basal nuclei (typically thalamus or GPi). Ablative procedures are seldom used bilaterally because of the potential complications of dysarthria and dysphagia. The intraoperative risk of ablative procedures is generally higher than that of deep brain stimulator (DBS) placement. However, postoperative risks with DBS include wire breakage, erosion of the overlying skin, and infection of the implanted hardware. The DBS electrode has several contacts within the target structure, allowing some flexibility in subsequent therapy. Patients usually require numerous postoperative visits for “tuning” of the device and medication adjustment. The subcutaneous battery pack must be replaced approximately every 5 years. Surgical Targets and Expected Outcomes Stimulation or lesioning of the GPi and STN benefits most symptoms of Parkinson’s disease. GPi procedures directly suppress dyskinesia, whereas STN procedures suppress dyskinesia both directly and indirectly by allowing reduction in the levodopa dose (≥ 60%). A recent multicenter prospective randomized trial of STN versus GPi stimulation for Parkinson’s disease found that the median UPDRS motor score improved by 49% with STN stimulation and by 37% with GPi stimulation.42 The decrease in the UPDRS motor off score for STN DBS is typically greater than 50%.43 However, dramatic improvements in motor on function should not be expected. DBS (Figure 7) appears to suppress or Neurodegenerative Disorders: Parkinson’s Disease restore a more normal pattern of output from GPi and STN, allowing medication doses to be decreased accordingly. Stimulation also has an additive effect with levodopa in terms of producing dyskinetic side effects. Surgical Procedures in Development Transplantation of dopamine-producing progenitor cells into the striatum has been tried using several different procedures. Allogeneic transplantation of fetal ventral mesencephalic tissue into the striatum of Parkinson’s patients produced long-term graft survival (demonstrated by positron emission tomography [PET] and autopsy), a 20% reduction in levodopa dose, a 44% reduction in off time, and a 26% improvement in UPDRS off motor score 2 years after transplantation.44 Unilateral transplants may provide some benefit for motor symptoms in ipsilateral limbs and do not seem to require lifelong immunosuppression.44 However, disabling dyskinesias have consistently appeared in a few patients even when not taking medication. Additional potential sources of tissue include porcine mesencephalon, human carotid body, adrenal chromaffin cells, retinal pigment epithelium, and bone marrow. Intraventricular infusion of growth factors intended to encourage precursor cells to differentiate into dopamineproducing neurons have not produced significant clinical benefit.43 However, direct infusion into the putamen appears more promising (trials ongoing). NEUROPROTECTIVE THERAPIES Distinction should be made between the terms neuroprotection and neurorescue.12 Neurorescue implies restoring the organism to its former healthy state (thus, restoring function of lost cells); neuroprotection implies slowing the disease course or preventing things from getting worse. So far, none of the medications used to treat motor symptoms of Parkinson’s disease has been conclusively proven to offer neuroprotection. The Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s (DATATOP)45 study seems to indicate a modest protective role for selegiline. However, subsequent analysis has suggested that the apparent benefit may have been related to residual symptomatic improvement; the washout period may have been too short to allow full regeneration of central MAOB activity. Dopamine agonists have several theoretical neuroprotective activities. A recent study using oral coenzyme Q 10 (which is intended to bolster mitochondrial function) showed that patients given coenzyme Q 10 during a period of 16 months experienced dose-dependent protection against decline in UPDRS scores, especially activities of daily living.46 Other potential neuroprotective therapies currently under investigation Figure 7. Sagittal T1-weighted magnetic resonance image of a patient with a deep brain stimulator (arrow) in the subthalamic nucleus. include antiglutamatergic agents (remacemide, rilutek, amantadine), trophic factors (glial-derived neurotrophic factor), MAOB inhibitors (rasagiline), adenosine receptor antagonists, and dopamine agonists.47 Smoking and caffeine ingestion are associated with a decreased risk for developing Parkinson’s disease.48 CASE STUDIES FOR SELF-ASSESSMENT CASE 1 Presentation A 34-year-old right-handed man presents for evaluation of a 2-year history of left hand and left leg resting tremor that has slightly increased in amplitude since onset. The patient also describes symptoms of poor coordination in his left hand, mild solid dysphagia, and increased tremor when he is nervous or during physical exertion. He denies any slowness, weakness, hallucinations, falls, change in facial expression or voice amplitude, or difficulty turning in bed. His medical history is unremarkable. He has no history of depression, constipation, sexual dysfunction, orthostasis, or urinary urgency. The patient was raised in a rural community; he denies any history of using illegal substances. His family history is negative for neurodegenerative disorders and tremor. Examination reveals a normally developed, intelligent, cooperative patient. His weight is 189 lb. His Neurology Volume 8, Part 1 11 Neurodegenerative Disorders: Parkinson’s Disease A B Figure 8. Fluorodopa positron emission tomography scan of (A) normal control and (B) case 1 patient. The scan shows markedly decreased tracer in the striatum (arrow) compared with the control, a finding consistent with significant loss of dopaminergic neurons. blood pressure is 132/84 mm Hg when sitting and 128/82 mm Hg when standing. Pulse is 64 bpm. Mental status and cranial nerve examinations are normal with the exception of mild masking of facial expressions. No chin tremor is present. Motor examination shows mild rigidity of left wrist and elbow flexion/extension. the patient also has decreased amplitude and loss of rhythmicity of rapid movements when using his left hand. Left hand and left leg resting tremor occurs intermittently. Deep tendon reflexes are 2+ and symmetrical. Sensory examination is intact to pinprick, vibration, and proprioception. Coordination testing is normal with finger-to-nose and heel-shin maneuvers. Gait examination demonstrates decreased left arm swing. • What is the most likely diagnosis? A) Essential tremor B) Parkinson’s disease C) Iatrogenic parkinsonism D) Wilson’s disease Discussion The best answer is B. Parkinson’s disease with onset before age 20 years is considered juvenile Parkinson’s disease; onset before age 40 years is considered early- 12 Hospital Physician Board Review Manual onset Parkinson’s disease. In a patient with early-onset parkinsonism, exclusion of Wilson’s disease (slit lamp examination for Kayser-Fleischer rings, serum ceruloplasmin, 24-hour urine copper, and liver function tests) and Huntington’s disease (family history, evaluation of chromosome for trinucleotide repeat) is recommended. However, this patient’s neurologic examination and the lack of psychiatric symptoms are inconsistent with these diagnoses. Essential tremor is distinguished from idiopathic Parkinson’s disease by symmetry, postural rather than resting tremor, and the absence of tone changes and bradykinesia. Recent use of antidopaminergic therapies would suggest iatrogenic parkinsonism. • What diagnostic test is most likely to be helpful in confirming the diagnosis? A) α-Synuclein gene mutation B) Ceruloplasmin and 24-hour urine copper C) Fluorodopa PET scan D) Magnetic resonance imaging (MRI) of the brain Discussion The best answer is C. Several radiotracers have been developed to evaluate the function of nigral projections and dopamine receptors. After intravenous injection, fluorodopa crosses the blood-brain barrier and is taken up by nigral neurons, metabolized to [18F]-dopamine by DDC, and stored in nerve terminals.49 The fluorodopa PET scan done in this patient shows markedly decreased and asymmetric tracer uptake in the striatum compared with the control, a finding consistent with significant loss of nigral dopaminergic projections (Figure 8). Relative preservation of tracer uptake in the caudate head compared with the posterior putamen distinguishes idiopathic Parkinson’s disease from other forms of parkinsonism. Although functional MRI is under development for use in Parkinson’s disease, anatomic images are typically without diagnostic structural characteristics. Mutations in parkin, α-synuclein, or UCHL1 genes have only been found in a small fraction of patients with familial Parkinson’s disease and, therefore, are unlikely to harbor a mutation. • What is the best initial therapy for this patient? A) Acetazolamide 250 mg twice daily (BID) B) Carbidopa/levodopa 25/100 mg three times daily (TID) C) Pramipexole 0.125 mg TID D) Propranolol 20 mg TID Neurodegenerative Disorders: Parkinson’s Disease Discussion The best answer is C. Especially in young patients, best options for initial symptomatic therapy include selegiline and dopamine agonists because of the decreased risk of producing motor fluctuations when compared with levodopa. Propranolol and acetazolamide are used in the treatment of essential tremor. CASE 2 Presentation A 70-year-old man has an 11-year history of resting tremor, bradykinesia, and rigidity. Although his symptoms are responsive to dopamine replacement therapy, the duration of therapeutic benefit has become shorter and shorter over time. His medications include carbidopa/levodopa 25/100 mg every 2 hours, pramipexole 1.5 mg TID, and selegiline 5 mg BID. About 30 minutes after a carbidopa/levodopa dose, the patient develops writhing movements of his face, arms, and torso. He is able to move fluidly, and his gait stability is unaffected. These movements resolve approximately 1 hour later, at which time the patient develops predictable freezing. When in the off state, he is unable to arise from a chair. The patient is examined 40 minutes after a dose of carbidopa/levodopa. His blood pressure is 125/70 mm Hg when sitting, and his pulse is 75 bpm. Choreic movements of his face, arms, and legs are pronounced. Mental status and language are normal. No tremor and only minimal rigidity of wrist flexion/ extension are detected. The patient is able to arise from a chair and walk unassisted without freezing, festination, or loss of balance. During the gait examination, however, choreic movements of his upper limbs persist. • What is the correct term for this patient’s excess movement? A) Diphasic dyskinesia B) Peak-dose dyskinesia C) Latent Huntington’s disease D) Freezing Discussion The best answer is B. Peak-dose dyskinesia is characteristically asymmetric and choreic in nature and parallels the motor response to levodopa. Diphasic dyskinesia occurs at transition times between levodopa effectiveness and wearing off and thus is characterized by a pattern of dyskinesia-improvement-dyskinesia. Diphasic dyskinesia may incorporate dystonic elements and be more disabling than peak-dose dyskinesia. In some cases, dyskinesia can be treated by adding amantadine, a dopamine agonist, or clozapine.34 Huntington’s disease causes unremitting chorea. Freezing implies inability to initiate movement. • What is the best initial therapeutic intervention to prolong the effective half-life of levodopa for this patient? A) Apomorphine rescue B) Add entacapone 200 mg BID C) Discontinue selegiline D) Deep brain stimulation (DBS) Discussion The best answer is B. An excellent initial intervention for this patient would be to slightly reduce the dose of levodopa and to prolong its activity by adding a COMT inhibitor. Another acceptable option would be to replace some doses of immediate-release carbidopa/ levodopa with a slightly larger dose of extended-release levodopa. Parenteral apomorphine (2 to 5 mg subcutaneously) has been used to “rescue” Parkinson’s patients who are frozen. If modification of the medical regimen is unsuccessful in treating the patient’s motor fluctuations, DBS should be considered. CASE 3 Presentation A 73-year-old man with a history of ischemic cardiomyopathy, congestive heart failure, and Parkinson’s disease presents for evaluation of hallucinations and freezing episodes. The patient developed unilateral levodopa-responsive hand tremor 5 years ago. Since that time, he has developed bilateral hand tremor and mild postural instability with infrequent falls. However, he is plagued by daily visual hallucinations. He does not experience these hallucinations as distressing and may express insight into their illusory nature. He frequently describes “smoking men in the curtains” and “monkeys crossing the lawn.” His motor symptoms are fairly well controlled, although he develops freezing if he misses a medication dose. Ambulation also is limited by marked orthostatic dizziness that is so severe at times that he has “blacked out,” precipitating a fall with injury. His medications include controlled-release carbidopa/levodopa 50/200 mg TID, carbidopa/levodopa 10/100 mg every 3 hours, and ropinirole 1 mg TID. Physical examination reveals an alert patient. After 3 minutes of standing, his blood pressure is 100/65 mm Hg and his pulse is 80 bpm. His supine blood pressure and pulse are 150/70 mm Hg and 80 bpm, respectively. Mini-mental status examination Neurology Volume 8, Part 1 13 Neurodegenerative Disorders: Parkinson’s Disease score is 27 out of 30. Cranial nerve and motor examinations are significant for mild dyskinetic movements of the face and arms. Muscle tone is normal. No tremor is present. His gait is fluid, with mildly decreased left arm swing. Deep tendon reflexes and plantar responses are normal. • What is the best option for treatment of this patient’s hallucinations? A) Quetiapine 25 mg at night B) Haloperidol 1 mg TID C) Risperidone 0.5 mg BID D) Olanzapine 5 mg daily Discussion The best answer is A. The best initial intervention would be a reduction in the ropinirole or levodopa dose. If this intervention produced intolerable motor decline, one of the atypical antipsychotic medications (ie, clozapine or quetiapine) could be added, as these agents do not exacerbate parkinsonism. However, quetiapine may exacerbate orthostatic hypotension, and clozapine requires lifelong weekly monitoring for agranulocytosis. Risperidone and olanzapine may exacerbate parkinsonism. • What would you recommend for treatment of this patient’s orthostatic hypotension? A) Alprazolam 0.5 mg BID B) Fludrocortisone 0.2 mg every morning C) Midodrine 2.5 mg in the morning and at noon D) Salt tablets Discussion The best answer is C. Neurogenic orthostatic hypotension can be successfully treated with behavior modification, compression stockings, liberalization of fluid and salt intake, and mineralocorticoid analogs (fludrocortisone). However, some of these therapies would be a poor choice in this patient because of his history of congestive heart failure. Vasoconstricting agents, such as midodrine (a peripheral α1-receptor agonist), should be taken early in the day because of the risk of supine hypertension. SUMMARY POINTS • Parkinson’s disease is the most common akineticrigid syndrome and the second most common adult neurodegenerative disease, affecting 1% of persons older than 65 years. 14 Hospital Physician Board Review Manual • Parkinson’s disease is characterized by selective loss of cells and accumulation of Lewy bodies in pigmented brainstem nuclei, especially substantia nigra, with resulting insufficient function of nigrostriatal dopaminergic projections. The ultimate consequence is bradykinesia, rigidity, and tremor. • Most neurodegenerative disorders, including Parkinson’s disease, have a long preclinical phase. By the time symptoms emerge, significant cerebral reserve has been lost. • Environmental factors appear to influence development of Parkinson’s disease in genetically susceptible individuals. • Replacement of central dopamine is the mainstay of Parkinson’s disease treatment but is an imperfect solution because of continued attrition of dopaminergic neurons and emergence of motor fluctuations. Several pharmacologic and surgical interventions are available as palliative therapy for Parkinson’s disease • Especially in young patients, best options for initial symptomatic therapy include selegiline and dopamine agonists because of the decreased risk of producing motor fluctuations when compared with levodopa. ACKNOWLEDGMENT Figures 1 and 2 are courtesy of M. Shahriar Salamat, MD, PhD, Department of Pathology, University of Wisconsin, Madison, WI. REFERENCES 1. Tanner CM, Goldman SM. Epidemiology of Parkinson’s disease. Neurol Clin 1996;14:317–5. 2. 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