Movement Disorders
Lewis Sudarsky
PARKINSON DISEASE AND RELATED DISORDERSBackground
1. Parkinson disease (PD) was described in 1817 by James Parkinson, who observed the characteristic features of slowness, rigidity, rest tremor, and shuffling gait.
2. PD is the second most common neurodegenerative disorder after Alzheimer disease, affecting a half million people in the United States.
3. The incidence of the disease is age related; it occurs infrequently before age 40. Prevalence is roughly 1% at age 65 and 3% at age 85.
4. It is primarily a motor control disorder, although a variety of nonmotor symptoms also occur.
5. It is the most frequent reason for referral to a movement disorder specialist.
Pathophysiology
1. PD results in a loss of the dopamine innervation of the basal ganglia. Pathology shows deficiency of pigmented cells in the pars compacta of the substantia nigra; these cells contain neuromelanin and produce neurotransmitter dopamine. The dopamine projections to the caudate and putamen facilitate movement. When cell loss exceeds 60%, there is a critical deficiency of dopamine in the forebrain, resulting in motor symptoms.
2. The cause of the disease is not known.
a. Some degenerating nigral neurons contain inclusions (Lewy bodies), with aggregates of α-synuclein protein and ubiquitin.
b. PD is considered a complex disorder, product of a number of genetic and environmental factors.
c. While typical PD with onset after age 50 is not inherited, there are single gene mutations that cause a form of Parkinson. Examples include the α-synuclein mutations, and mutations of the parkin gene on chromosome 6, and the LRRK-2 mutation on chromosome 12. These genetic PD syndromes often have younger onset.
Prognosis
1. Dopamine cell loss in PD is progressive, beginning several years before clinical symptoms and continuing over 15 years or longer.
a. The rate of progression is variable, and mobility can be supported with dopamine replacement therapy.
b. Motor fluctuations develop in 40% to 50% of patients on levodopa at 5 years, 75% to 80% at 10 years. Most patients have accumulated significant disability at 15 years, while others retain a stable medication response, good balance, and preservation of cognitive function.
c. Dementia (30%) and falls emerge as treatment-limiting issues in patients with long-standing PD.
2. The progression of the disease can be followed using clinical measures, such as the unified PD rating scale (UPDRS, available at www.wemove.org), or through imaging tests like positive emission tomography (PET scan) or single photon emission computed tomography (SPECT) using radioisotope labeled markers. The dopamine cells do not create a visible footprint on magnetic resonance imaging (MRI).
Diagnosis
1. Diagnosis is made on clinical grounds; there are no laboratory tests. Onset is typically asymmetric. The cardinal clinical features are:
a. Tremor at rest: Typically a pill-rolling tremor of the hands, sometimes affecting the lower limbs or jaw.
b. Bradykinesia: Slowness of movement, difficulty initiating movement. This is the major source of disability, sometimes described by the patient as weakness or heaviness.
c. Rigidity with cogwheeling: A physical sign that is observed as the patient is passively moved. Cogwheeling is most easily appreciated at the wrist and neck.
d. Flexed posture/shuffling gait: A stooped posture is characteristic of PD. Shuffling gait is also typical, but the least specific feature in differential diagnosis.
2. The typical case begins asymmetrically in the limbs with a rest tremor. A diagnosis of PD is also based on a number of more impressionistic findings: Loss of facial expression, hypophonic dysarthria, drooling, micrographia.
3. Nonmotor symptoms like constipation, reduced sense of smell, and rapid eye movement (REM) sleep behavior disorder can occur early, before rigidity and tremor.
4. There is a degree of imprecision in clinical diagnosis. Ten percent to 15% of patients in a PD clinic will turn out to have a related disorder. Early occurrence (within a year) of imbalance and falls should suggest an alternate diagnosis. Failure to respond to levodopa often indicates another diagnosis. The differential diagnosis of PD is reviewed in Table 13-1.
TABLE 13-1 Differential Diagnosis of Parkinson Disease
Neurodegenerative disorders with atypical parkinsonism
Progressive supranuclear palsy
Multiple-system atrophy
Shy-Drager syndrome
Olivopontocerebellar atrophy (MSA-C)
Dementia with Lewy bodies
Corticobasal degeneration
Frontotemporal dementia with parkinsonism
Alzheimer-Parkinson overlap syndrome
Parkinson-amyotrophic lateral sclerosis-dementia of Guam
Huntington disease: Rigid variant
Hallervorden-Spatz disease
Pure akinesia syndrome
Primary progressive freezing gait
Secondary parkinsonism
Toxic
MPTP (methyl-4-phenyl-tetrahydropyridine)
Manganese
Carbon monoxide
Drug-induced
Neuroleptic drugs
Metaclopramide, prochlorperazine
Reserpine
Vascular disease (arteriosclerotic parkinsonism)
Basal ganglia lacunes
Binswanger disease
Hydrocephalus
Trauma
Tumor
Chronic hepatocerebral degeneration
Wilson disease
Infectious
Postencephalitic parkinsonism
Creutzfeldt-Jakob disease
HIV/AIDS
5. Several clues aid in the recognition of related neurodegenerative disorders:
a. Multiple-system atrophy (MSA)
1) MSA is a synucleinopathy, with pathology involving the nigrostriatal system, the cerebellum, and the autonomic nervous system. It is a more aggressive disease with progression to death in 5 to 10 years, and a partial or waning response to dopaminergic treatment.
2) Manifestations: Consensus criteria for a diagnosis of MSA are reviewed in Table 13-2.
a) Signs of autonomic failure (prominent orthostatic hypotension, urogenital dysfunction)
b) Progressive ataxia
c) Other “red flags” supporting diagnosis: Sleep apnea, stridor, anterocollis.
b. Dementia with Lewy bodies (DLB)
1) DLB is part of the PD spectrum, with more extensive pathology in the forebrain.
2) Manifestations
a) Dementia, behavioral disorders, and intermittent psychosis present within the first 2 years
b) Sleep disturbance and REM sleep behavior disorder
c) Parkinsonism
c. Progressive supranuclear palsy (PSP)
1) In PSP, there is neurodegeneration of structures in the upper brainstem and diencephalon, with accumulation of neurofibrillary tau proteins.
2) Manifestations
a) Early imbalance or falls
b) Axial dystonia
c) Oculomotor abnormalities (particularly failure of conjugate downward gaze)
d. Corticobasal degeneration
1) Corticobasal degeneration is also a “tauopathy,” with asymmetric onset.
2) Manifestations
a) Apraxia
b) Cortical sensory loss
c) “Alien limb” movements
d) There is often focal cerebral volume loss (lobar atrophy) on imaging.
6. Occasionally, patients will have an axial parkinsonian syndrome and gait disorder (“lower body parkinsons”) related to cerebrovascular small-vessel disease. Secondary parkinsonism from neuroleptic exposure (drug-induced parkinsonism) should always be considered as it is a treatable disorder. Drugs such as metoclopramide
(Reglan), prochlorperazine (Compazine), and the atypical antipsychotics should not be overlooked. Neuroleptic drugs are highly tissue bound, and motor signs can persist 4 to 12 weeks after these drugs have been discontinued. Toxin-induced PD related to manganese, carbon monoxide, or MPTP should be considered when environmental exposures have occurred.
TABLE 13-2 Consensus Criteria for Diagnosis of Probable Multiple-System Atrophy | ||||||||||
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Treatment
There are three components to therapy: (1) initial therapy of PD includes the initiation of dopaminergic medication during a “honeymoon period” of medication responsiveness, lasting 3 to 6 years; (2) management of more advanced disease, including motor fluctuations and dyskinesias; and (3) management of nonmotor symptoms and mental status change. There is no algorithm; treatment should always be individualized.
Initial Therapy of Parkinson Disease
1. After confirmation of diagnosis, consider whether the patient has disability sufficient to warrant some form of dopamine replacement. Dopamine replacement therapy is provided for patients who have some difficulty in daily activities, difficulty with walking, or patients whose employment is compromised.
2. For patients with newly diagnosed PD, not yet requiring dopamine replacement, there is a range of therapeutic options:
a. Rasagiline: This drug is a monoamine B inhibitor, with mild symptomatic benefits in early PD. In clinical trials, it delayed progression of motor disability in the first 2 years. The starting dose is 0.5 mg, which can be increased to 1.0 mg after a week. The dose should be reduced back to 0.5 mg once levodopa is added. As the MAO inhibition is selective, the drug can be used together with levodopa, and tyramine reaction is quite rare in patients on a standard diet. Side effects include sleep disturbance and hyper- or hypotension. It should generally not be given with meperidine or selective serotonin reuptake inhibitor (SSRI) antidepressants.
b. Selegiline: Another monoamine oxidase B enzyme inhibitor, with some symptomatic benefits in early PD. It can elevate mood and help with fatigue. In one large clinical trial, selegiline delayed the introduction of levodopa by a year. Five milligrams are usually sufficient, given once a day in the morning. No special diet is required at doses under 15 mg. Infrequent side effects include insomnia, nausea, and hypotension. The drug is not well tolerated by confused patients. As with rasagiline, adverse interactions have been described with meperidine and SSRI antidepressants. An orally disintegrating, rapidly absorbed form of selegiline (Zelepar) avoids first pass hepatic metabolism. Dose is reduced accordingly (1.25 to 2.5 mg).
c. Amantadine: This older drug is a dopamine releaser and glutamate receptor antagonist. It is often helpful, particularly with tremor in early patients. In more advanced PD it can help reduce dyskinesia. The dose is 100 to 300 mg; side effects include livido reticularis and hallucination.
d. Anticholinergic drugs: For younger patients with tremor as the major presenting symptom, trihexyphenidyl (Artane 2 mg three times a day [t.i.d.]), benztropine (Cogentin 0.5 mg twice a day [b.i.d.]), or ethopropazine (Parsitan 50 to 100 mg t.i.d.) can be helpful. These drugs can precipitate urinary retention or aggravate confusion, and are poorly tolerated in older patients. Other side effects include dry mouth.
e. Neuroprotection options: There is presently no evidence that any of the drugs retard dopamine cell loss in PD, although several promising drugs are in clinical trials. Coenzyme Q (CoQ)-10 at 1,200 mg/d had some effect on progression of ADL scores in a small pilot study.
3. For patients whose PD has begun to affect their daily activities, and who have a degree of disability as a result, some form of dopamine replacement is indicated.
The threshold for starting dopamine replacement therapy is somewhat subjective, as determined by the doctor and patient. The options include levodopa, or the use of a synthetic, direct-acting dopamine agonist. Half of the patients with new PD can be successfully treated with a dopamine agonist as monotherapy for 3 to 5 years. Motor complications may be delayed, a particular advantage for younger patients. Levodopa remains the preferred initial therapy for older patients (older than 65 years), medically fragile patients, and those with cognitive and behavioral problems.
a. Dopamine agonists (ropinirole, pramipexole)
1) Advantages
a) Motor complications are delayed.
b) Better outcome with surrogate markers (imaging) in randomized clinical trials.
2) Disadvantages
a) Greater cost
b) More adverse events
c) Somnolence, sudden sleep attacks
b. Levodopa preparations (Sinemet, Sinemet CR, Stalevo)
1) Advantages
a) Easier to use (may be titrated)
b) Superior efficacy
c) Better tolerated in frail, elderly patients and those with cognitive or behavioral changes
2) Disadvantage: Treatment-emergent side effects (fluctuations, dyskinesias)
4. Medications used for dopamine replacement
a. Carbidopa/levodopa (Sinemet): Mainstay of therapy for most patients with PD, and the drug with the best therapeutic index. Sinemet is a combination of levodopa with carbidopa, a peripheral DOPA decarboxylase inhibitor. At doses above 75 mg, carbidopa reduces the peripheral decarboxylation of levodopa, increases fourfold the central nervous system (CNS) delivery, and reduces nausea and hypotension. Sinemet comes in 25/100, 10/100, and 25/250 tablets. The usual initial dosage of levodopa is 50 to 100 mg b.i.d. to t.i.d., increasing as required to 300 to 600 mg. Side effects include nausea, hypotension, constipation, confusion, and hallucinations. No intravenous (IV) preparation is available for surgical patients, but Sinemet tablets can be administered, crushed, by nasogastric (NG) tube.
b. Sinemet CR (50/200 and 25/100): Carbidopa/levodopa in a polymer matrix designed to produce delayed enteric absorption and a 3- to 4-hour half-life. Absorption is incomplete, and onset of effect often takes 40 to 60 minutes. Some patients find this drug variable or unreliable.
c. Benserazide/levodopa (Madopar 50/100): An alternative tocarbidopa/levodopa, using a different decarboxylase inhibitor. It is sold primarily in Europe.
d. Pramipexole (Mirapex): A D2 and D3 dopamine agonist. Used for initial monotherapy, or as adjunctive therapy of PD (with levodopa). Initial titration begins at 0.125 mg t.i.d., proceeds slowly over 2 to 3 weeks to achieve 0.5 to 0.75 mg t.i.d.; 3 mg/d or above are often required for monotherapy after the first year. Adverse effects include nausea, somnolence, leg edema, confusion, and hallucinations. There are case reports of patients on pramipexole and ropinirole falling asleep while driving. Patients should not drive if somnolence is reported. There are also reports of impulse control difficulties like compulsive gambling.
e. Ropinirole (Requip): A D2 and D3 dopamine agonist. Used for initial monotherapy or as adjunctive therapy of PD (with levodopa). There is a very large dynamic range, with doses as high as 27 mg/d and above. Initial titration
begins at 0.25 mg t.i.d., proceeds slowly over 2 to 3 weeks to achieve 1 to 3 mg t.i.d.; 16 mg/d or above often required for monotherapy after the first year. Adverse effects include nausea, somnolence, leg edema, confusion, and hallucinations. This drug is metabolized by CYP1A2 enzymes in the liver, and can interact with other medications that share this pathway. There are case reports of patients on pramipexole and ropinirole falling asleep while driving. Patients should not drive if somnolence is reported. Ropinirole is now available in a sustained release form (Requip XL), which has stable 24-hour kinetics, is easier to titrate, can be started at 2 mg/d, and advanced by 2 mg/d/wk. There is less nausea and sleep disturbance, but it is more costly.
f. Bromocriptine: An older ergot-derived dopamine agonist used in initial therapy and adjunctive therapy of PD. Used alone, starting dose should be small (2.5 mg; a half tablet b.i.d.), creeping up over weeks to a therapeutic target of 5 mg t.i.d. Doses as high as 30 to 60 mg may be required for monotherapy after the first year. Side effects include nausea, hypotension, confusion, hallucinations, leg edema, erythromelalgia; rarely pulmonary or retroperitoneal fibrosis. Cardiac valve changes have also been reported, and annual monitoring of cardiac echo is advised. (Given the other options, this drug is not recommended.)
g. Pergolide: An older ergot-derived dopamine agonist used as monotherapy for early Parkinsons, as well as adjunctive therapy for more advanced disease. Starting dose is 0.05 mg t.i.d., titrating slowly to 0.5 mg t.i.d. or above. Side effects include nausea, hypotension, confusion, hallucinations, leg edema, erythromelalgia; rarely pulmonary or retroperitoneal fibrosis. Cardiac valve changes have also been reported, and annual monitoring using cardiac ultrasound is advised. (Given the other options, this drug is not recommended.)
h. Cabergoline: A newer ergot-derived dopamine agonist, which can be used as monotherapy for early PD, although not approved by the Food and Drug Administration (FDA) for this purpose in the United States. This drug has a long half-life, and can be given twice a week. Side effects include nausea, hypotension, confusion, leg edema, rare pulmonary, or retroperitoneal fibrosis. Cardiac valve changes have also been reported, and annual monitoring using cardiac ultrasound is advised.
5. For anorexia and nausea in patients on Sinemet, options include extra carbidopa (Lodosyn 25 mg). Patients with nausea often tolerate Sinemet CR better, as the drug peaks more gradually. Addition of an antiemetic such as trimethobenzamine (Tigan) 25 mg t.i.d., or domperidone (Motilium) 10 mg prior to each dose, may be necessary to counter gastrointestinal (GI) side effects of dopaminergic drugs.
Management of More Advanced Disease
1. As PD progresses over time, patients may have difficulty maintaining a stable therapeutic response and independence in daily activities. Motor complications such as wearing off fluctuations, on-off fluctuations, and dyskinesias develop with increasing frequency in patients after 5 to 6 years of levodopa therapy. Gait freezing and falls may also develop overtime, regardless of the choice of initial therapy.
2. Levodopa is a medication with a half-life of 90 to 120 minutes. Many patients with long-standing or advanced PD experience a wearing off of drug effect at 2 to 3 hours, as the bioavailability of the drug declines. With more advanced disease, motor fluctuations become more abrupt, erratic, and unpredictable. To extend the effect of levodopa, options include more frequent dosing, use of a longer acting levodopa preparation, or addition of a monoamine oxidase B or catechol-o-methyltransferase (COMT) enzyme inhibitor. The other major option is addition of a longer acting dopamine agonist as a second drug.
a. Rasagiline (Azilect): Retards the enzymatic degradation of levodopa and dopamine. Rasagiline is often used in treatment of early symptomatic PD, but
can be used as well to stabilize motor fluctuations. Given 0.5 mg once/d, it increases on time in fluctuating patients by 15%. Side effects include dizziness, BP fluctuations, and increased dyskinesia.
b. Entacapone (Comtan): Retards the enzymatic degradation of levodopa and dopamine, by a peripheral mechanism. It increases the CNS delivery of levodopa, and improves the kinetics. (It is ineffective without levodopa.) Dose is 200 mg, given with each dose of levodopa. No dose titration is required, although the dose can be reduced to 100 mg if necessary. It increases on time in clinical trials by 15%. Side effects include discoloration of the urine, infrequently diarrhea. It may increase dyskinesia.
c. Levodopa/carbidopa/entacapone (Stalevo): Combination drug that provides levodopa/carbidopa with entacapone in a fixed dose combination: 50/12.5/200, 75/18.75/200, 100/25/200, 125/22.25/200, 150/37.5/200, and 200/50/200. It affords extra convenience for patients taking entacapone.
d. Tolcapone (Tasmar): COMT inhibitor that is more potent than entacapone in clinical trials, and longer acting. The dosage is 100 to 200 mg t.i.d. Side effects include serious, occasionally fatal hepatotoxicity, and not infrequent diarrhea. Because of a small number of cases of sudden hepatic failure, an informed consent process is required, and liver function tests (LFTs) must be monitored every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months, and every 8 weeks thereafter.
3. Patients with troublesome dyskinesias sometimes do better with a dopamine agonist as primary therapy, and a small dose of Sinemet as needed to enhance the effect. Ropinirole can be pushed to 24 to 30 mg, pramipexole to 4.5 to 6 mg. Supplemental use of amantadine can reduce dyskinesia in many patients.
4. Deep brain stimulation (DBS), a neurosurgical procedure, is an option for patients with difficult motor fluctuations and disabling dyskinesias, and referral to a surgical program is sometimes appropriate. Surgical outcome is not good in patients with mental status changes, and surgery may exacerbate dysarthria.
5. Difficulty with gait initiation or freezing is a particularly frustrating problem. Freezing is sometimes overcome by visual cues, and some patients can use an inverted cane to step over. (A variation in this technique is the use of a laser pointer to provide a visual target for step initiation.) The problem does not always yield to increasing doses of dopaminergic medication, although this should be attempted. Postural instability and recurrent falls may become a problem after 5 to 10 years of PD. Such patients have difficulty standing from a chair and are easily displaced backward. The unfortunate reality is that drug treatment does not always improve balance. As patients are mobilized by medication, they may be at increased risk for falls. Surgery does not reliably improve the “on” period gait freezing or falls. The best treatment for this problem is a physical therapy-based intervention to improve axial mobility and balance.
Nonmotor Symptoms. While motor complications can be managed with available medications and occasional use of functional neurosurgery (DBS), nonmotor symptoms are increasingly recognized as a contributing cause of disability in PD. Apathy and depression are common, and mental status changes occur more often in more advanced disease. A variety of autonomic nervous system problems, pain, and sleep disturbance can be major issues for some patients.
1. Postural hypotension occurs in PD because of autonomic involvement and the effects of medications. Decarboxylase inhibitors should be optimized, MAO-B inhibitors should be discontinued. Some patients require supplemental mineralocorticoid (Florinef, 0.1 to 0.3 mg/d) and elastic hose. Midodrine (Proamitine, 2.5 to 5 mg t.i.d.) is occasionally required.
2. Some patients require medication for bladder instability. Caution is advised as anticholinergic drugs can aggravate mental confusion.
3. GI motility is also a common problem in PD, and patients often require medication for constipation. Polyethylene glycol (MiraLax) is often effective when used daily: 17 g dissolved in 8 oz water.
4. Drooling results from a reduced rate of swallowing, and not from increased production of secretions. Nonetheless, reducing saliva is sometimes helpful. Options include injection of the parotid with botulinum toxin or sublingual use of a drop of atropine 1.0% ophthalmic solution b.i.d., or utilizing the transdermally absorbed scopolamine patch.
Management of Mental Status Changes
1. Cognitive difficulty, behavioral disturbance, and sleep disorder are not emphasized in classic descriptions of PD, but each poses a common therapeutic problem. Delirium in PD is generally transient and reversible, related to medications. All antiparkinsonian medications have the potential to cause delirium, even transient psychosis. It is best to minimize the use of anticholinergic drugs, MAO-B inhibitors, and dopamine agonists in patients with mental status changes. The preferred strategy in such patients is to avoid polypharmacy and focus on the single drug with the best therapeutic index (carbidopa/levodopa). Use the lowest dose that provides adequate mobility.
a. Clozapine (Clozaril): Clozapine in low dosage (12.5 to 75 mg at bedtime [hs]) has been useful when hallucinations, paranoid thinking, and nocturnal agitation persist on minimal levodopa. It can cause daytime sleepiness, but it does not appear to exacerbate motor symptoms of PD (tremor may actually improve). Patients must be monitored with weekly complete blood counts (CBCs) for leukopenia and agranulocytosis. The manufacturer maintains a national registry.
b. Other atypical antipsychotics (quetiapine 25 to 150 mg; risperidone 0.5 to 3 mg) are sometimes used in this context as they do not require monitoring of blood counts. Again low doses are recommended. With time, these drugs accumulate and motor symptoms may worsen. Sedation is the other major side effect. Older antipsychotics such as haloperidol and chlorpromazine should be avoided in PD.
c. Black box warning: In elderly patients with dementia the use of any of the atypical antipsychotics is associated with a slight increase in the risk of death from cardiovascular disease or pneumonia. These drugs should be used with caution and at low dose, but can reduce hallucinations and agitation, and help patients sleep at night.
2. Dementia occurs in 20% to 40% of patients with idiopathic PD by 10 to 15 years. Episodic confusion (even off medication), slowness, and frontal behavioral features are most often observed. Cholinesterase inhibitors (donepezil, galantamine, rivastigmine) have a beneficial effect on behavior in these patients, and produce measurable (although modest) improvements in cognitive function.
