Movement Disorders
Barbara Kelly Changizi
Vikram Khurana
MOVEMENT DISORDERS DEFINITION AND BACKGROUND
1. Movement Disorders are neurological conditions that affect the quality and abundance of movement. A broad subdivision of movement disorders is hyperkinetic disorders, which include chorea, myoclonus, tics, dystonia, and tremor, and hypokinetic disorders, which include the parkinsonian syndromes. Movement disorders are caused by impairment of basal ganglia circuitry. The basal ganglia include the substantia nigra (SN), striatum (caudate and putamen), subthalamic nucleus (STN), thalamus, and globus pallidus (GP). This chapter also discusses ataxia, which is incoordination resulting from impairment of the cerebellum or its connections.
PARKINSON DISEASE AND RELATED DISORDERS
Background
1. Parkinson disease (PD) was first 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. PD affects more than 6.1 million people worldwide.
3. It is primarily a motor control disorder, although a variety of nonmotor symptoms also occur, including sleep disorders, depression, cognitive impairment, and dysautonomia.
Pathophysiology of PD
1. The etiology of the disease is not known.
Pathology shows neuronal cell loss and depigmentation of cells in the pars compacta of the substantia nigra (SNp); these cells contain neuromelanin and produce the neurotransmitter dopamine that projects to the caudate and putamen. These degenerating nigral neurons contain inclusions (Lewy bodies), with aggregates of α-synuclein protein and ubiquitin.
2. PD results in a gradual loss of the dopamine innervation of the basal ganglia, causing major disruptions of the output pathways of the basal ganglia that facilitate movement. When cell loss exceeds 60%, there is a critical deficiency of dopamine in the forebrain, resulting in motor symptoms of PD.
3. One model of basal ganglia dysfunction in PD involves the direct and indirect pathways of the basal ganglia. The direct pathway is pro-movement, whereas the indirect pathway opposes movement. These two pathways are balanced in a normal brain to allow for appropriate abundance and initiation of movement.
a. In the direct pathway, the substantia nigra provides excitatory input via dopamine onto striatal D1 receptors. The putamen projects inhibitory input to the GP internal segment, which then inhibits the thalamus. The thalamus provides excitatory
input to the cortex that is promovement. Excitation of D1 receptors in the striatum ultimately inhibits the inhibition of the thalamus, facilitating movement.
b. In the indirect pathway, the SN projects dopamine onto inhibitory D2 receptors in the striatum. These neurons project inhibitory input to the GP external segment, which in turn inhibits the STN. The STN projects excitatory input to the GP internal segment. The net effect of excitation of the indirect pathway is increased inhibition of the thalamus, which suppresses movement.
1) In PD, reduction in dopaminergic neurons in the SN results in relative overactivity of the indirect pathway.
4. The above model is likely more complex and involves pathological firing patterns within the diseased basal ganglia. For example, synchronized oscillatory activity in the 10 to 50 hz range, called the beta-band, has been associated with bradykinesia and tremor in PD patients. Suppression of this electrical firing pattern also suppresses symptoms of PD.
a. Epidemiological studies have identified multiple risk factors.
b. Age is the greatest risk factor for developing PD. PD risk increases with age, reaching a prevalence of 2.6% in people aged 85 to 89 years. Mean onset of PD is age 60. PD occurs infrequently before age 40, although young-onset cases are observed.
c. Other risk factors for PD include diabetes, low plasma urate level, physical inactivity, pesticide exposure, high consumption of dairy products, use of well water, farming or agricultural work, low 25-OH vitamin D levels, and high iron intake.
d. Exposure to trichloroethylene (TCE), manganese, and MPTP have been associated with parkinsonism.
e. Caffeine, nicotine, calcium channel blocker use may reduce risk of PD.
5. Although the majority of PD with onset after age 50 is sporadic, there are several single gene mutations that have been identified.
a. Examples include point mutations, duplications, and triplications of the gene for α-synuclein (PARK 1 and PARK 4), mutations of the Parkin gene on chromosome 6 (PARK 2), and the LRRK-2 (PARK 8) mutation on chromosome 12. These genetic PD syndromes often have younger onset and an informative family history. Genetic testing for these disorders is increasingly available, although a role for gene testing in clinical practice has not yet been established.
Prognosis of PD
1. There is no cure for PD; therapies are symptomatic. The disease typically has a slow progression toward disability over years. PD is associated with increased mortality. A large meta-analysis of 88 studies on mortality in PD found that mean duration until death ranged from 6.9 to 14.3 years. There was major heterogeneity in the longevity findings, with increasing age and presence of dementia associated with increased mortality.
2. Motor fluctuations develop in 40% to 50% of patients on levodopa at 5 years, 60% at 10 years. Motor fluctuations are the phenomenon of dopaminergic therapy having decreasing duration of effect, with peak dose dyskinesia. Later-stage PD patients may require dopaminergic medications every 2 to 3 hours while awake.
3. Freezing of gait (FOG) appears as the disease progresses, which is the inability to move the feet when attempting to move forwards (and differs from slow, shuffling gait).
4. There is progressive imbalance leading to postural instability and falls in later stages of PD.
5. Nonmotor symptoms may present as the disease progresses. These include depression, anxiety, hallucinations (often visual), orthostatic hypotension, urinary dysfunction, constipation.
6. The progression of the disease can be followed using clinical measures, such as the Unified Parkinson Disease Rating Scale (UPDRS).
7. As the disease progresses, it is typical for patients to require a “cocktail” of medications including dopaminergic therapies aimed at minimizing motor fluctuations, medications to treat dyskinesia, and therapies to treat nonmotor symptoms. Advanced patients may be candidates for more invasive procedures such as deep brain stimulation surgery or jejunostomy pumps to infuse liquid levodopa continuously to the gut (see therapy section).
Diagnosis of PD
1. The Movement Disorders Society put forth diagnostic criteria in 2015. These require bradykinesia with either resting tremor, rigidity, or both. Onset is typically asymmetric.
a. Bradykinesia is slowness of movement, difficulty initiating movement. Bradykinesia presents with decreased blink, loss of facial expression, soft voice, shuffling gait, lack of arm swing while ambulating, poor dexterity with rapid movements, and micrographia. This is often the major source of disability, sometimes described by the patient as weakness or heaviness.
b. Tremor is classically a resting tremor of 4 to 6 Hz, asymmetrical, with pill-rolling quality when in the hand. There may be a chin or tongue tremor.
c. Rigidity is increased resistance of the limb or neck to passive movement. This may be cogwheeling when tremor is superimposed.
d. Other supportive clinical features of parkinsonism include stooped posture, postural instability, and gait freezing.
e. There are three clinically defined subtypes of PD: Tremor-dominant, akinetic-rigid, and postural instability and gait difficulty (PIGD). Patients may change in subtype over time.
f. There is now recognition of a prodromal stage for PD, which may occur years before the motor manifestations of parkinsonism. These include hyposmia, constipation (defined as bowel movements occurring less frequently than every 2 days, or need for a weekly laxative), and rapid eye movement (REM) sleep behavior disorder (RBD). RBD is a parasomnia in which the patient reenacts vivid reams with vocalizations and/or body movements.
g. Brain imaging using conventional CT or MRI is typically normal in PD. Brain imaging is often performed to evaluate for other causes of shuffling gait or secondary parkinsonism, such as strokes or tumors in the basal ganglia, normal pressure hydrocephalus, or parkinsonian syndromes.
h. There are several ancillary tests that may support the diagnosis of PD. These are not required for diagnosis but may provide supportive evidence in the appropriate clinical setting.
1) The dopamine transporter SPECT, or DATscan, is a nuclear imaging study that detects loss of dopaminergic terminals in the caudate and putamen. Dopamine dysfunction is seen in the DATscan in PD but also in parkinsonian syndromes (see below). An abnormal study may support the specific diagnosis of PD when combined with the clinical history and exam.
2) The Syn-one skin biopsy detects abnormally phosphorylated alpha-synuclein in the cutaneous nerves of the skin. The test may be positive in PD, dementia with Lewy bodies, and multiple system atrophy. It can support the diagnosis of PD in the appropriate clinical setting.
3) The cardiac metaiodobenzylguanidine (MIBG) scintigraphy study evaluates cardiac sympathetic denervation. The ligand is MIBG. MIBG is taken up and stored in presynaptic vesicles similar to norepinephrine, then released into the synaptic cleft. If there is postganglionic cardiac sympathetic denervation, there is decreased uptake of MIBG in the heart. Abnormal MIBG cardiac uptake is considered supportive of the diagnosis of PD per the 2015 consensus criteria of the Movement Disorders Society.
i. There is a degree of imprecision in clinical diagnosis. 10 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 14-1.
Table 14-1 Differential Diagnosis of Parkinson Disease | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Parkinsonian Syndromes and Secondary Parkinsonism
1. Multiple-system atrophy (MSA)
a. MSA is a parkinsonian syndrome with a more aggressive course than PD, with progression to death in 5 to 10 years, and a poor or rapidly waning response to dopaminergic treatment.
b. There are two forms of MSA: MSA-P, which presents predominantly with parkinsonian phenotype and dysautonomia, and MSA-C, which presents with cerebellar disease and dysautonomia. These two subtypes may overlap.
c. Consensus criteria for a diagnosis of MSA were published in 2022 by the Movement Disorders Society. These are reviewed in Table 14-2.
d. Dysautonomia presents as constipation, voiding difficulties with either post-void urinary retention or urinary urge incontinence, sexual impotence, and neurogenic orthostatic hypotension.
e. The cerebellar syndrome presents as gait ataxia, limb ataxia, cerebellar dysarthria, or oculomotor findings.
f. Parkinsonian symptoms are poorly L-dopa responsive or benefits are short-lived with rapid onset to motor fluctuations followed by lack of efficacy.
g. MSA is a synucleinopathy, with pathology involving glial cytoplasmic inclusions of α-synuclein found in the striatum, the cerebellum, and the autonomic nervous system. The prodromal signs of REM Sleep Behavior Disorder may precede MSA by years. Dysautonomia may be the earliest symptom of MSA.
h. MRI markers of MSA include atrophy of the putamen, middle cerebellar peduncle, pons, and cerebellum, the “hot cross bun” sign in the pons on axial images, and increased diffusivity of the putamen or middle cerebellar peduncles.
2. Dementia with Lewy bodies (DLB)
a. DLB presents with a combination of parkinsonism as well as dementia, behavioral disorders, fluctuation of alertness and attention, and intermittent psychosis (typically visual hallucinations) within the first 2 years. In PD, cognitive impairment and hallucinations typically occur later in the course.
b. DLB is a synucleinopathy, and thus may also have a prodromal period with hyposmia and REM sleep behavior disorder. There is more extensive pathology in the forebrain.
c. The DLB Consortium published consensus criteria for the clinical diagnosis of DLB in 2017 to improve diagnostic sensitivity and specificity. These are reviewed in Table 14-3.
3. Progressive supranuclear palsy (PSP)
a. PSP is a parkinsonian syndrome. The original description of classic PSP, also known as PSP-Richardson syndrome, was first described in 1964. It described a clinical syndrome of postural instability, parkinsonism with axial rigidity, frontal cognitive impairment, and vertical supranuclear gaze palsy.
b. We now know that the phenotype of PSP is much broader, and that classical PSP may only comprise 50% of PSP cases. PSP is now believed to have several phenotype presentations that share a consistent pathology of microtubule-associated protein tau aggregates in astrocytic tufts, oligodendrocytes, and neurofibrillary tangles. The most common brain areas with tau pathology are the midbrain (including the substantia nigra, oculomotor complex, rostral interstitial nucleus of the medial longitudinal fasciculus, periaqueductal gray, superior colliculi), subthalamic nucleus, globus pallidus internal segment, dentate nucleus of the cerebellum, and prefrontal cortex.
c. The International Parkinson and Movement Disorder Society (MDS)-endorsed PSP Study group developed new diagnostic PSP criteria in 2017. These criteria mention four functional domains of impairment: ocular, postural instability, akinesia, and cognitive dysfunction. There are currently 8 subtypes of PSP recognized:
1) PSP RS or classic PSP
2) PSP-P with predominant parkinsonism
3) PSP-F with predominant frontal presentation of cognitive impairment
4) PSP-PGF with progressive gait freezing
5) PSP-CBS with predominant corticobasal syndrome
6) PSP-SL with predominant speech language disorder
7) PSP-OM with predominant ocular motor dysfunction
8) PSP-PI with predominant postural instability
d. MRI findings in class PSP-RS are midbrain atrophy, or the “hummingbird” or “penguin” signs on midsagittal images, and the “mickey mouse” or “morning glory” sign on axial images.
4. Corticobasal Syndrome (CBS) and Corticobasal Degeneration (CBD)
a. Corticobasal syndrome (CBS) presents with asymmetric parkinsonism (bradykinesia, rigidity, and dystonia) but also hallmark cortical findings of ideomotor apraxia, cortical myoclonus, cortical sensory loss, and alien limb. Features of CBS are:
1) Apraxia, which may be limb ideomotor apraxia or speech apraxia
2) Cortical myoclonus in a limb
3) Asymmetric parkinsonism with bradykinesia or rigidity
4) Focal dystonia
5) Alien limb meaning lack of awareness of the movement of the limb, sometimes with the patient denying or showing disgust that the limb is their own
6) Cortical sensory loss of astereognosis or agraphesthesia
7) Cognitive impairment, sometimes with aphasia
b. Corticobasal degeneration (CBD) is the clinical syndrome of CBS, but with confirmatory pathology at autopsy of hyperphosphorylated 4-repeat tau inclusions in astrocytes, glia, and neurons. These are in astrocytic plaques, compared to the tufted astrocytes found in PSP.
c. Brain MRI may show atrophy in the frontal and parietal regions.
5. Occasionally, patients have an axial parkinsonian syndrome and gait disorder (“lower body Parkinsonism”) related to cerebrovascular small-vessel disease. Secondary parkinsonism from neuroleptic exposure (drug-induced parkinsonism) should always be considered because 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 up to 12 weeks after these drugs have been discontinued. Toxin-induced PD related to manganese, carbon monoxide, or methyl-4-phenyl-tetrahydropyridine (MPTP) should be considered when environmental exposures have occurred.
Table 14-2 Consensus Criteria for Diagnosis of Probable Multiple-System Atrophy | ||||||||
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Table 14-3 DLB Consortium Revised Criteria for Diagnosis of Dementia With Lewy Bodies (DLB) | ||||||||||||||||||||
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PD Treatment Principles
1. Medical treatment for PD can be divided into three parts:
a. Initiation of dopaminergic medication
b. Management of motor complications, including motor fluctuations and dyskinesias
c. Management of nonmotor symptoms and mental status changes
2. Exercise and physical therapy have been shown to provide benefit to motor symptoms during all stages of the illness and are imperative to address early and continually with patients. Exercise may also slow disease progression.
3. Therapy should always be individualized with every patient, addressing lifestyle goals and functional disability versus side effects of medications at each stage of the illness.
4. Dopamine replacement therapy is generally provided for patients who have some difficulty in daily activities, difficulty with walking, or patients who are having difficulty with maintaining their occupation. There is no advantage to delaying pharmacotherapy; in fact, suitable treatment of motor symptoms allows the patient to exercise, which may be neuroprotective.
5. 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. There is controversy over whether complications of motor fluctuations and dyskinesia may be delayed with use of dopamine agonists rather than L-dopa. Levodopa remains the preferred initial therapy for older patients (older than 65 years), patients prone to hypotension, and those with cognitive and behavioral problems.
6. Motor fluctuations occur within a few years of disease onset. This phenomenon involves shortened duration of effect of dopaminergic medication (“wearing off”), dose failures, delayed kicking-in of effect, and peak-dose dyskinesia. The duration of benefit from L-dopa becomes more abrupt, erratic, and unpredictable. Management of motor fluctuations involves frequent dosing of dopaminergic medication, adjunct medications such as monoamine oxidase B or catechol-O-methyltransferase (COMT) enzyme inhibitors to prolong dopamine levels in the brain. Other options involve concurrent use of long-acting dopamine agonists, and transition to long-acting L-dopa formulation Rytary. When best medical management is failing, we move forward with more invasive interventions such as deep brain stimulation (DBS) or jejunostomy pumps to infuse constant levodopa to the gut.
7. NMDA-receptor antagonists may be used to curb dyskinesia that occurs with motor fluctuations.
8. Difficulty with gait initiation or freezing is a particularly challenging 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.
9. 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. Deep brain stimulation surgery does not reliably improve the “on” period gait freezing or prevent falls. The best treatment for this problem is a physical therapy-based intervention to improve axial mobility and balance. These programs typically utilize auditory and visual cueing to overcome freezing (in the United States, Lee Silverman Voice Training BIG and LOUD therapy).
10. Neuroprotection options: There is presently no universally established evidence that any of the drugs delay dopamine cell loss in PD.
Pharmacotherapy for PD
1. Monoamine oxidase B enzyme inhibitors (MAOI-B). These drugs include rasagiline, selegiline, and safinamide. Because the monoamine oxidase inhibitor (MAO) inhibition is selective for dopamine, tyramine reaction is quite rare in patients on a standard diet. These drugs provide mild benefit for early disease or may be used as adjunct therapy in more advanced disease to smooth motor fluctuations. Side effects include hyper- or hypotension. Caution is advised when prescribed concurrently with serotonergic drugs such as selective serotonin reuptake inhibitor (SSRI) antidepressants because of the risk of serotonin syndrome. Selegiline is metabolized to desmethylselegiline and methamphetamine, which are then metabolized to amphetamine; thus selegiline can be used to help fatigue in PD (at the risk of insomnia). An orally disintegrating, rapidly absorbed form of selegiline (Zelapar) avoids first pass hepatic metabolism.
2. Amantadine and extended-release amantadine (Gocovri). These drugs have mixed mechanism of action including dopamine releaser, N-methyl-D-aspartate (NMDA) receptor antagonist, and anticholinergic properties. These drugs may help with tremor in early patients. In more advanced PD, the NMDA receptor antagonism can reduce dyskinesia. The drugs are renally cleared and adjusted dosing in renal insufficiency is recommended. Side effects include livedo reticularis, insomnia, hallucinations or psychosis, anticholinergic side effects of confusion, constipation, etc., and rarely corneal edema. Livedo reticularis is typically asymptomatic and reversible and thus does not mandate discontinuation of the drug.
3. Anticholinergic drugs: For younger patients with tremor as the major presenting symptom, trihexyphenidyl (Artane 2 mg three times a day [tid]), benztropine (Cogentin 0.5 mg twice a day [bid]) can be helpful. Anticholinergic side effects include urinary retention, constipation, confusion, memory loss, dry mouth, and blurry vision. These are commonly poorly tolerated in older patients or in patients with advanced PD. Use of anticholinergics may increase the risk of dementia.
4. Dopamine agonists (ropinirole, pramipexole, rotigotine)
a. Available in immediate release oral formulation, extended release once daily oral formulations, and a patch (rotigotine)
b. Interestingly, potency is not as strong as L-dopa and yet dopamine agonists may be more prone to cause side effects.
c. Side effects: nausea, orthostatic hypotension, leg swelling, fatigue, sleep attacks, impulse control disorders (hypersexuality, excessive eating, shopping, gambling, or substance-use that is impairing). The rotigotine patch has an additional risk of skin reactions.
d. Pramipexole (Mirapex, Mirapex ER): A D2 and D3 oral dopamine agonist. Used for initial monotherapy, or as adjunctive therapy of PD (with levodopa).
e. Ropinirole (Requip, Requip XL): A D2 and D3 oral dopamine agonist. Used for initial monotherapy or as adjunctive therapy of PD (with levodopa). This drug is metabolized by CYP1A2 enzymes in the liver, and can interact with other medications that share this pathway.
f. Rotigotine (Neupro): A transdermal patch formulation D2 and D3 dopamine agonist. It has a similar side-effect profile to other dopamine agonists and can rarely precipitate skin reactions.
g. Apomorphine (Apokyn subcutaneous, and Kynmobi sublingual film): A unique, short-acting dopamine agonist that is available as a subcutaneous injection, or as a sublingual film. Apomorphine is used as a “rescue medication” for unpredictable off times or motor complications not controlled by other medications. Doses are variable and need to be titrated by the provider to monitor blood pressure and pulse, as well as efficacy. It provides rapid symptom relief, but side effects include profound nausea that needs pretreatment with antiemetics, hypotension, and dyskinesias.
5. Levodopa preparations
a. Carbidopa/levodopa (Sinemet IR): 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 more than 75 mg total daily, carbidopa reduces the peripheral decarboxylation of levodopa, increases fourfold the central nervous system delivery, and reduces nausea and hypotension. Sinemet IR comes in 25/100, 10/100, and 25/250 tablets. The usual initial dosage of levodopa is 100 mg tid with increasing amounts of 200 to 300 mg every few hours as tolerated for advanced disease. Side effects include nausea, orthostatic hypotension, fatigue, and hallucinations. No intravenous (IV) preparation is available for surgical patients, but Sinemet tablets can be administered, crushed, by nasogastric (NG) tube or dissolved in carbonated water.
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. Sinemet CR also is only 75% of equivalent immediate release (IR) because of delayed gastric absorption. Absorption is incomplete, and onset of effect often takes 40 to 60 minutes. Patients with motor fluctuations may find this drug absorption to be variable or unreliable. This medication is used in early disease, or at bedtime. It is not typically used for advanced motor fluctuations.
c. For anorexia and nausea in patients on Sinemet, an extra carbidopa (Lodosyn 25 mg) can help. Patients with nausea may tolerate Sinemet CR better because the drug peaks more gradually. Addition of an antiemetic such as trimethobenzamide (Tigan) 25 mg tid or ondansetron (Zofran) or domperidone (Motilium) 10 mg prior to each dose, may be necessary to counter gastrointestinal (GI) side effects of dopaminergic drugs. We avoid dopamine receptor blocking drugs as these can worsen parkinsonism.
d. Rytary (IPX066): A novel carbidopa/levodopa formulation approved by the FDA in January 2015. It is a capsule composed of immediate-release and
extended release beads that are absorbed at different rates in the GI tract. Studies have shown it improves wearing off between levodopa doses and improves the time between interval dosing. The capsules can be opened and the contents sprinkled on food or given via G-tube for patients with dysphagia. Pitfalls include high cost and occasional trouble with titration from standard regimens. (Dose conversion table is available online from the manufacturer.)
e. Inhaled L-dopa (Inbrija) is an oral inhalation form of L-dopa that is given through an oral inhaler. This may be useful in patients with dysphagia. It is approved for motor fluctuations in Parkinson disease, to reduce off time. The main side effect is cough. A small minority of patients may experience dopaminergic side effects of hallucinations, orthostatic hypotension, nausea, dyskinesia.
6. Catechol-O-methyltransferase (COMT) enzyme inhibitors
a. Entacapone and opicapone retard the enzymatic degradation of levodopa and dopamine by a peripheral mechanism. The result is increased delivery of levodopa to the brain, thus improving motor fluctuations. Side effects include discoloration of the urine, dopaminergic side effects of L-dopa, and diarrhea. It may increase dyskinesia.
b. 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.
c. Tolcapone (Tasmar) is a COMT inhibitor that is more potent than entacapone in clinical trials and longer acting. The dosage is 100 to 200 mg tid. However, side effects include serious, occasionally fatal hepatotoxicity, and not infrequent diarrhea. This is only rarely used in the clinic due to availability of superior methods to treat motor fluctuations. 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.Related posts:
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