Movement disorders represent a group of neurologic disorders where there is either “too much” movement or hyperkinesias, or “too little” movement or hypokinesias. Some movement disorders combine features of both, such as parkinsonism where there is tremor (a hyperkinetic phenomenon) and rigidity or bradykinesia (both hypokinetic phenomena). While a significant proportion of movement disorders are “extrapyramidal” or resulting from basal ganglia dysfunction, a number of other movement disorders can involve any portion of the neuraxis from the cerebrum to the peripheral nerves. Therefore, movement disorders should no longer be considered synonymous to extrapyramidal or basal ganglia disorders.
The most important step in the diagnosis of these disorders is the recognition and classification of the abnormal movement (see Table 34-1). The most common hypokinetic phenomenology is parkinsonism, whereas among the hyperkinetic disorders, the most common ones are tremors, dystonias, choreas, tics, restless legs, and myoclonus.
Classification of Movement Disorders
| Hypokinesias | Hyperkinesias |
|---|---|
| Parkinsonian syndromes | Tremor |
| Cataplexy and drop attacks | Dystonia |
| Catatonia | Ataxia |
| Freezing phenomenon | Chorea |
| Hypothyroid slowness | Athetosis |
| Ballism | |
| Myoclonus | |
| Jumping stumps | |
| Paroxysmal dyskinesia | |
| Hyperekplexia | |
| Myokymia | |
| Stereotypy | |
| Tics | |
| Restless legs | |
| Periodic movements in sleep | |
| Myorhythmia |
CASE 34-1
You receive a neurology consult regarding a 60-year-old man who just had a right hip replacement but is not recovering as expected. He has noted having great difficulty ambulating and not moving his right arm well. Your colleague in Orthopedics thinks he has had “a minor stroke.” He was in good health preopearatively with all his gait difficulties attributed to his bad right hip. His wife mentions to you that he had been complaining of pain in the right shoulder in the preceeding 8 months, and had difficulties raising the arm above his head. However, repeated x-rays had not revealed any abnormalities. You also notice an intermittent rest tremor in both hands, more prominent on the right.
Parkinsonism is a clinical syndrome defined by the presence of bradykinesia and one or more of the following motor features: rest tremor, rigidity, and postural instability (that is not caused by other identifiable etiologies such as neuropathy, vestibulopathy, etc).
The major differential diagnoses of parkinsonism include primary or idiopathic parkinsonism (such as Parkinson disease), “atypical” or Parkinson-plus syndromes, vascular parkinsonism, and drug-induced parkinsonism.
Parkinson disease (PD) is a neurodegenerative disorder characterized by the gradual and progressive onset of parkinsonism pathologically characterized by degeneration of pigmented brainstem nuclei (specifically, the pars compacta of the substantia nigra) presence of intraneuronal alpha synuclein-positive Lewy bodies in the remaining nerve cells.1
PD is the second most common neurodegenerative disease after Alzheimer disease (AD) with a prevalence of 1–2 % for people 65 years or older.
Age is the most important risk factor for PD. While most PD is sporadic, there are genetic and familiar forms that typically present at a younger age, often below 50 years.
The motor phenotype of PD can be of 2 general varieties:
Tremor-predominant PD (generally suggestive of slower disease progression)
Akinetic-rigid PD or the postural instability gait dysfunction (PIGD) subtype (which is suggestive of more progressive disease course).
Currently there is no definitive test to diagnose PD in a living patient (neither are there tests to differentiate one form of parkinsonism from the other). All PD confirmations have occurred postmortem to date. Therefore, diagnosis of PD in a living patient remains a clinical one.
Bradykinesia (akinesia)
This is the most important clinical sign that must be present for a definition of parkinsonism.
It is defined as slowness of initiation with progressive reduction in speed and amplitude of repetitive action.
Bradykinesia can be tested in the clinical setting by repetitive finger tapping, repetitive hand opening, and foot or toe tapping, and during the performance of these actions, a diminution in the amplitude of movements is noticed (ie, fatiguing/decrement).
Rigidity
It is defined by increased tone or resistance, independent of the velocity of the movement, giving a lead-pipe quality or a cogwheel quality (when there is superimposed tremor).
In the clinical setting, this is tested by slowly moving and extending the joints (neck, wrist, elbow, and knees) through their full range of movement with the patient at rest.
Rest tremor
In itself it is a hyperkinetic movement, but when accompanied by bradykinesia and rigidity, it represents “parkinsonism.”
It is characterized by its asymmetry, low frequency (4–7 Hz), and the classic pronation-supination pattern and “pill-rolling” pattern.
It commonly affects the hands but can also affect the legs and head, with chin tremor being very discriminatory for PD.
It predominates at rest, increasing in amplitude when performing tasks that require mental concentration.
It is best examined with the patient seated and arms supported (either on pillows or laps or arms of the chair); sometimes mental/cognitive tasking is needed to accentuate the tremor (such as asking the patient to count backward or reciting months of the year backward). The patient is then asked to stretch out the arms looking for any dystonic posturing, myoclonus, or postural tremor (the importance of these will be seen in the section on atypical parkinsonian syndromes).
Beware of a “re-emergent” tremor in PD that can be confused with the postural tremor that is typically seen in essential tremor. Re-emergent tremor in PD usually is of the same amplitude as the rest tremor and “re-appears” after a short latency period about 5–10 seconds after adopting a new posture. Do not conclude that a patient does not have a rest tremor until after you have examined for a tremor while walking.
Postural instability
Although one of the 4 signs of parkinsonism, postural instability, is usually a sign of advanced PD, it can be an early sign or a “red flag” for atypical parkinsonian syndromes, especially progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).
This is usually accompanied by a disturbance of gait.
Examination for postural instability includes inspecting how the patient stands up from a chair unassisted, posture (such as any stoop or scoliosis; correctable on request or not), gait including base, speed, stride, arm swing, and assessment of freezing (ask patient to turn 360 degrees in both directions).
Postural response is examined using the Pull test, which is performed by having the patient stand with feet no more than shoulder width apart, then the examiner giving a good tug from behind with enough force to displace the patient’s center of gravity (up to 2 half steps is considered a normal postural response); a word of caution when performing this test is that the examiner must be prepared to catch the patient!
Assessment of patients presenting with parkinsonism begins with clinically confirming a diagnosis of “probable” PD and ruling out the other differential diagnoses. A useful guide in clinical practice is the United Kingdom Parkinson’s Disease Society Brain Bank Clinical Criteria (UKPDBBCC).2
A complete history is very important including,
Course of symptoms
Progression
Gradual progression is suggestive of neurodegenerative parkinsonism.
Sudden onset is suggestive of other etiologies:
Vascular parkinsonism
Exposure to toxins and medications, especially neuroleptic use, which could suggest drug-induced parkinsonism.
A thorough neurologic evaluation basically involves 3 steps according to the UKPDBBCC:
Confirm parkinsonism with the presence of bradykinesia and one or more of tremor, rigidity, and postural instability.
Exclude other causes of parkinsonism by looking for the presence of red flags such as early (ie, within 1 year of parkinsonism) dementia (seen in dementia with Lewy bodies; and sometimes PSP and corticobasal degeneration), cerebellar signs (suggestive of MSA), strictly unilateral signs (seen in hemiatrophy-hemiparkinsonism syndrome), and structural lesions that could account for symptoms on imaging (eg, NPH).
Presence of supportive criteria including presence of persistent parkinsonism throughout disease course, predominantly asymmetrical, unequivocal levodopa response, presence of dyskinesias, etc.
A patient with a clinical diagnosis of PD should have clear parkinsonism, absence of red flags, and the presence of at least 3 of the supportive characteristics of PD. Sometimes repeated examination and follow-up are required during diagnostic evaluation, as some of the red flags may not develop early and some of the atypical parkinsonian syndromes will have an (initial) excellent response to levodopa.
N.B. It is not uncommon for patients to present with initial symptoms of parkinsonism (such as resting tremors, etc) while admitted to hospital for a medical illness or while recovering from surgery (just like the clinical vignette). When parkinsonism seems to present rather acutely, diligent workup to rule out other potential etiologies (such as reviewing the medication list for drug-induced parkinsonism, brain imaging to rule out vascular parkinsonism, etc) is warranted before a diagnosis of neurodegenerative parkinsonism is made.
Imaging and other ancillary tests have been utilized either in the clinical setting or in research to help confirm the diagnosis of PD. Recently DaT scans were approved by the USA Food and Drug Administration (FDA) to differentiate neurodegenerative parkinsonism from non-neurodegenerative causes (such as ET, vascular parkinsonism, or drug-induced parkinsonism). However, DaT scans are unable to differentiate PD from atypical parkinsonian syndromes. DaT scans have been in use for several years in many European countries and in several clinical trials in PD.
This is also clinically derived. Several decades past this was accomplished only by the use of the Hoehn and Yahr staging.3
Stage 1—unilateral parkinsonian signs
Stage 2—bilateral signs without gait or postural impairment
Stage 3—with postural impairment
Stage 4—with significant gait dysfunction and postural instability but can walk unaided
Stage 5—where patient is wheelchair-bound unless otherwise aided.
Although this staging is easy to use, it does not account for many differences between patients within the same stage. Other rating scales in clinical and research include the Unified Parkinson’s Disease Rating Scale (UPDRS) and Schwab and England scale.4
To clarify ambiguous items in the UPDRS and account for new features (especially nonmotor features) that were not recognized before the creation of the scale, the UPDRS has been recently updated by the Movement Disorders Society, with the new version named as the “Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).”5
CASE 34-2
You are called in the middle of the night by a nurse regarding a patient who is yelling and screaming while he is asleep and disturbing his roommate. You find the patient to be asleep, and when you wake him up, he does not remember the event. His wife notes that he has been doing that for years occasionally falling out of bed and she has got used to it. He has a history of PD. He also notes a history of constipation, some fatigue, lost sense of smell a long time ago, and some worsening depression. The wife is starting to get concerned that he may be having some memory problems as well.
The nonmotor symptoms of PD are very important to address in all patients. These symptoms can become quite debilitating and, oftentimes, are more problematic than the motor symptoms. It is important to delineate if symptoms are occurring just in the “off” state and resolve when the patient is “on” or if they occur regardless. If the latter is true, the symptoms require specified treatment that is distinct from strategies used to alleviate motor fluctuations. The patient above is experiencing multiple nonmotor symptoms of PD. While patients with PD are in the hospital, these problems are important to address.
Sleep can become problematic in most PD patients. Examples of common sleep disturbances include insomnia, excessive daytime sleepiness, REM sleep behavioral disorder (RBD), and restless legs syndrome (RLS).
RLS is over-represented in the PD population, and has been shown to occur in 8–22% of patients.6
It is postulated that loss of dopaminergic neurons in the midbrain contributes to the symptoms of RLS.
The treatment is discussed in the RLS section.
RBD has been shown in up to 50% of patients with PD. Moreover, the 10-year estimated risk of developing PD in patients who have had idiopathic RBD ranges from 40 to 65%.7
RBD consists of episodes of yelling, screaming, shouting, and thrashing around while a patient is in the REM phase of sleep, whereas normally a patient would be atonic during REM.
Generally, patients are unaware that they are doing this, and so it is important to obtain this information from caregivers.
Treatment of RBD includes low-dose clonazepam and physical barriers for patients who fall out of bed.
Other sleep disorders include excessive daytime sleepiness (EDS), which is usually medication-induced. PD patients on treatment with a dopamine agonist can experience excessive daytime sleepiness as a medication side effect. Along with EDS, insomnia can also become problematic. With a limited number of randomized controlled trials on PD insomnia, most patients are empirically treated using strategies such as improving sleep hygiene and the use of melatonin or sedating medications such as tricyclic antidepressants, benzodiazepines, and so forth. Insomnia can become a problem while a patient is admitted to a hospital due to various distractions and, therefore using any of the above as treatment options can be helpful.
Sensory complaints are common in PD. Olfaction can be impaired in up to 90% of patients and can even predate motor symptoms of PD by many years.8 Other sensory symptoms include fatigue, pain, and paresthesias.4
Autonomic dysfunction in PD patients can include symptoms such as orthostatic hypotension, constipation, gastroparesis, urinary incontinence, erectile dysfunction, sweating, and drooling. All of these can significantly affect a patient’s quality of life and therefore require close monitoring.
Orthostatic hypotension in PD patients can result in worsening or precipitation of falls.
Furthermore, PD medications can also lower blood pressure and, occasionally, can worsen hypotensive symptoms.
Treatment for orthostatic hypotension includes increasing fluid intake, increasing salt intake, and minimizing/eliminating any antihypertensive medications.
Patients should be advised to shift slowly between positions, especially from supine to sitting or standing. If these maneuvers are ineffective, medications such as fludrocortisone, midodrine, pyridostigmine, and droxidopa can be used.
Compression stockings are also effective. However, they need to be up to the abdomen to be effective and this is usually uncomfortable for patients.
Fall precautions should always be employed when a PD patient is admitted to the hospital.
Constipation and gastroparesis can occur in PD due to multiple reasons.
Patients with PD are generally less mobile and therefore at increased risk for constipation.
In addition, constipation can arise as a side effect of anticholinergic medications that they might be on.
Patients are encouraged to do as much physical exercise as they can tolerate, as well as have adequate intake of fluid, fruits, and fibers.
Laxatives and stool softeners may also be used.
Isosmotic macrogol electrolyte solution is currently the only treatment of constipation in PD that has been proven to be efficacious and well tolerated in a randomized placebo-controlled study.9
Excessive drooling can also become quite difficult and embarrassing for patients.
When bothersome, treatment with botulinum toxin type A or B has been shown to be effective in randomized clinical trials.10
Anticholinergic medication can be used; however, side effects usually inhibit use (confusion, worsening constipation).
On the other hand, glycopyrrolate exhibits minimal central side effects and has been effective and safe in PD patients with sialorrhea.
Up to 61% of PD patients can have at least one psychiatric symptom, of which depression is the most common.11 Dopaminergic circuits in the mesolimbic and mesocortical areas play important roles in reward, affect control, and impulsivity, and disruption of these can have tremendous effects on behavior and thought content.12PD with major depression is associated with increased disease severity, poorer motor function, and worse performance in their activities of daily living. Furthermore, there is an association of depression with the severity of bradykinesia and axial rigidity.11Anxiety also is very prevalent in PD patients, with one study reporting up to 49% of PD patients having a lifetime prevalence of anxiety.12
Treatment for depression and anxiety should be tailored to the severity of the disease:
Mild depression can be treated with supportive psychotherapy and cognitive behavioral therapy.
Moderate-to-severe depression and anxiety may require pharmacotherapy.
The strongest evidence for effectiveness in depression has been shown with tricyclic antidepressants (TCAs); however, these can be difficult to tolerate due to anticholinergic effects.13
Selective serotonin reuptake inhibitors (SSRIs) can help with both the anxiety and depressive symptoms.
Recent studies have also shown effectiveness in using selective noradrenergic reuptake inhibitors (SNRIs).14
Apathy in PD appears to be related to the underlying disease process, and 13% of PD patients can experience apathy alone.15 It is characterized by symptoms of poor motivation and initiative, hopelessness, or anhedonia, which can be independent of depression. Sometimes, optimization of motor symptoms with dopamine agonists and levodopa to induce “on-states” may help; however, most treatments are minimally effective.
Cognitive decline has been found in 84% of PD patients, with close to 50% of patients meeting criteria for dementia when followed up for more than 10–15 years.16
Although this can be a late feature of the disease, impairment in attention, episodic memory, category fluency, and psychomotor function may be detected even in early stages of the disease.12
Most common cognitive deficits seen using formal testing include deficits in attention, active memory, and executive and visuospatial functions, whereas verbal functions, thinking, and reasoning are relatively spared.12
Clinical evaluation using the Montreal Cognitive Assessment (MoCA) can detect early cognitive decline and can be used to establish baseline in PD patients when being evaluated and monitored, as anti-parkinsonian medications often require readjustment with further cognitive decline due to side effects.
Minimizing and simplifying the anti-parkinsonian regimen should be the first step with removal of anticholinergics, MAO-B inhibitors, and amantadine, followed by dopamine agonists and COMT-inhibitors if necessary.
Treatment with cholinesterase inhibitors is indicated for mild-to-moderate dementia. In a randomized placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with PD.17
In the inpatient setting, confusion can be the presentation of a urinary tract infection, pneumonia, electrolyte imbalance, or some other medical illness. A thorough medical/infectious workup is always required in the setting of acute delirum in a patient with Parkinson disease. Similarly, while in the inpatient for any medical or surgical illness, it is not uncommon for PD patients with known cognitive impairment to transiently decline while in the hospital. This can also be accompanied by psychosis.
In addition, psychosis, including visual and auditory hallucinations, paranoia, and illusions have been reported and associated with other psychiatric comorbidities including depression, anxiety, and apathy.
Risk factors for the development of hallucinations include cognitive impairment, age, duration of disease, medication side effects, delirium, environmental changes, and/or poor visual acuity.18
Usually the hallucinations are visual and nonthreatening and patients have insight to them when cognitive function is preserved.
As the disease progresses, delusions can appear and are usually persecutory in nature, often involving themes of jealousy and infidelity. This is generally associated with cognitive decline.
If patients still have insight, usually treatment is not necessary.
As the hallucinations and delusions become more threatening, treatment becomes paramount.
Simplifying the anti-parkinsonian regimen is a key first step. If a neuroleptic agent is needed, an atypical antipsychotic medication, such as quetipine or clozapine, may be beneficial.19
Risperidone, ziprasidone, aripiprazole, and olanzapine, while marketed as an atypical antipsychotic, behave like a typical antipsychotic in the PD population and should be avoided.
Patients on clozapine should be carefully monitored for agranulocytosis with weekly complete blood counts for 6 months, every other week for the next 6 months, and monthly thereafter. If absolute neutrophil count falls below 2000 mm3 and/or the white blood cell count is below 3.6 mm3, clozapine should be discontinued.
It is important to note that all antipsychotic medications carry a black box warning of increased mortality, especially in the cognitively impaired elderly population.
Admitted PD patients are at a higher risk for developing (or worsening of ongoing) hallucinations or delusions. It is advisable to resist using any antipsychotic agent (except quetiapine or clozapine), to review the medication list and eliminate any psychotropic medications that can potentially precipitate psychosis, and to simplify the Parkinson regimen, in cases of polypharmacy.
Finally, impulse control disorders (ICDs) are very critical to detect and treat immediately, as they can be detrimental for families.
These are a family of neuropsychiatric conditions that have a central feature of uncontrollable need to engage in repetitive behaviors, often to a maladaptive degree.
The most common behaviors include compulsive gambling, hypersexuality, binge eating, and uncontrolled spending.
Patients being treated with dopamine agonists are at a much increased risk for developing ICDs,20 whereas patients with levodopa are at an increased risk of developing dopamine dysregulation syndrome (DDS).
DDS occurs when patients take higher and more frequent doses of levodopa than they actually need to stay in the “on” state.
In addition, they can also experience hypersexuality and compulsions. Early recognition is key, as patients are unlikely to volunteer these symptoms.
When initiating dopamine agonists, it is important to discuss the possibility of ICDs with the patient and the family, as the family can monitor for symptoms and report what they have experienced.
When observed, tapering and/or discontinuing the offending agent can improve or eliminate ICDs, although this is often easier said than done.
CASE 34-3
A 55-year-old left-handed woman presents with intermittent tremor of her right hand of 1-year duration. The tremor is mainly noticeable when she walks and tends “to act up” when she is watching television; it does not interfere with her day-to-day activities. Her handwriting has changed recently—no matter how big she starts out, writing her script eventually becomes smaller in the end. There is no history of slowness and no difficulty with fine motor skills. Examination reveals bilateral tremor (more prominent on the right, only noticeable on the left with mental distraction). She has mild reduction in finger tapping on the right, no rigidity, and reduced arm swing bilaterally.
CASE 34-4
A 67-year-old right-handed man presents with a 5-year history of shuffling while walking and difficulty turning in bed that wakes him up intermittently during the night. He has become slower in his movements, and it takes him twice as long to complete his daily chores. He feels as if “he is all thumbs,” as he finds it difficult to carry out tasks requiring fine motor skills and he cannot play his guitar as he used to. He has had tremors in his right hand for the past 3 years, which was initially not bothersome, but in the last 1 year, it has become very bothersome to him and now affects his left hand and makes him very self-conscious. He retired the previous year, and since his retirement, his wife has noticed a lack of interest in his hobbies and a gradual withdrawal from their social circle because of the tremors.
To date, PD is a progressive disorder that has no known cure and no available therapy to slow down the rate of disease progression.
The therapeutic goal should be to keep the patient as independent and as functional for as long as possible.
Daily exercise—encourages the patient to remain active and mobile
Individualized therapy
Treatment of motor symptoms only when they become bothersome or interfere with activities of daily living
Recognize and treat motor fluctuations
Recognize and treat nonmotor features
Medications such as trihexiphenydyl and benztropine continue to be used to treat tremors in PD.
They are not effective against other motor symptoms and have an unfavorable side effect profile, particularly in the elderly (confusion, hallucinations).
This class of medications have limited utility in the management of PD but can be considered for younger patients with medication-resistant tremor-predominant PD.
These include selegiline, zydis selegiline and rasagiline.
These are selective, irreversible monoamine oxidase (MAO) type 2 inhibitors.
They can be used for mild symptomatic monotherapy in early PD, and also used as an adjunct to levodopa in patients with motor fluctuations.
They were evaluated as possible neuroprotective agents, but studies have remained inconclusive for both selegiline and rasagiline.21,22
The usual dose for selegiline is 5 mg in the morning and noon.
Doses should be avoided later in the day because of potential for insomnia.
When selegiline dose is >10 mg per day, it becomes a nonselective MAO inhibitor and can potentially cause a tyramine effect (ie, hypertensive crisis with concomitant ingestion of high-tyramine meals).
Selegiline has been reported to prevent the development of freezing.
Rasagiline is given at a dose of 1 mg daily
At doses greater than 2 mg, it will also inhibit MAO-A.
At the recommended doses, there is no longer any dietary restriction.
In general, all MAO inhibitors including rasagiline and selegiline should be avoided or tapered prior to the administration of meperidine or similar anesthetic compounds that could result in serotonin syndrome when preparing a PD patient for surgery.
Its mechanism of action is not clearly understood but is largely viewed as a N-methyl-D-aspartate (NMDA) antagonist that also inhibits dopamine uptake at nerve terminals and may stimulate dopamine receptors. It also has an antimuscarinic effect (which contributes to anticholinergic side effects in some patients).
It generally provides mild antiparkinsonian benefit.
It also symptomatically reduces levodopa-induced dyskinesia,23 although it may not be sustained.
Amantadine is usually given at a starting dose of 100 mg twice daily, which can be titrated up to 400 mg total per day.
Side effects include livedo reticularis, leg swelling, confusion, and visual hallucinations; therefore, it has to be used with caution in elderly patients and those with pre-existing dementia.
It should also be used with caution among patients with renal insufficiency.
They are largely viewed as the second most efficacious class of drugs available for the treatment of PD motor symptoms. There are 2 types: ergot and nonergot. The ergot dopamine agonists are no longer in use in the United States, although bromocriptine is still being used in other countries. The nonergot medications include pramipexole, ropinirole, rotigotine, and apomorphine.
They stimulate dopamine receptors in the striatum and have long half-lives (6 hours) as compared to levodopa.
They can be used as monotherapy for early PD or as an adjunct to levodopa therapy for reducing wearing-off.
Pramipexole
Available as generic immediate-release and extended-release formulations.
Maximum dose is 4.5 mg/day.
The usual therapeutic dose starts at 1.5 mg per day.
Ropinirole
Available as immediate-release and extended-release.
Starting dose is 0.25 mg 3 times daily and this can be titrated up to a maximum of 24 mg per day.
The usual therapeutic dose starts between 9 to 12 mg per day.
The maximum doses are the same for the immediate- as well as the extended-release formulations.
Apomorphine
This is an injectable dopamine agonist that is used as a “rescue” medication in PD patients with severe motor fluctuations.
It is injected subcutaneously, and because of a penchant to induce emesis, patients have to be pretreated with an antiemetic agent.
Rotigotine
This is a transdermal formulation that is available as a patch.
The recommended dose is 6 mg/day for early monotherapy and up to 8 mg/day for patients with motor fluctuations.
Side effects
All dopamine agonists cause drowsiness, “sleep attacks” (ie, sudden onset of sleep without warning), leg swelling, and weight gain.
Other side effects include punding (repetitive, unproductive actions) and impulse control disorders such as pathologic gambling or sweet cravings.20
Patients being started on these agents have to be warned about the potential for these idiosyncratic side effects.
This has been the mainstay of dopaminergic therapy, and remains the most efficacious oral agent for PD since its introduction more than 5 decades ago. It is combined with a peripheral dopa decarboxylase inhibitor (carbidopa or benserazide). This reduces the peripheral conversion of levodopa to dopamine, limiting some of its side effects especially nausea, and increasing the delivery of levodopa to the brain. In the brain, levodopa is converted into dopamine and stored in the dopaminergic neurons where it is released as needed.
Carbidopa/levodopa is available as immediate release (25/100 mg, 10/100 mg, and 25/250 mg) and controlled release (25/100 mg and 50/200 mg).
Short half-life of 90 min means that levodopa has to be given in multiple doses throughout the day.
The initial starting dose is typically 1 tablet of the 25/100 immediate-release formulation 3 times a day, titrated slowly upward to the minimum dose that makes the patient functional with the least amount of side effects.
Short-term side effects include nausea (which may require additional carbidopa, marketed as lodosyn, with each dose of carbidopa/levodopa), drowsiness, and hypotension.
The long-term side effects of levodopa are important markers for advancing disease in the parkinsonian patient, which includes
Wearing-off: when the benefits of medication no longer last until the next dose
Dyskinesias
These are usually choreic, but can also be dystonic or ballistic.
They are typically seen during the peak effect of levodopa (termed peak dose dyskinesia), but can also be seen as the medication starts working or when it begins to wear off (termed diphasic dyskinesias).
There is a higher incidence of developing these motor fluctuations with chronic levodopa use as compared to any other class of drug used in PD. This has been the basis for various “levodopa-sparing strategies” used by some clinicians.
Abrupt withdrawal of levodopa can lead to a neuroleptic malignant-like syndrome, a life-threatening condition characterized by confusion, hyperpyrexia, rigidity, rhabdomyolysis, and significant blood pressure fluctuations, that requires intensive care unit monitoring. Therefore, when levodopa adjustments are needed, a slow taper is always recommended.
COMT is the enzyme that metabolizes levodopa to inactive 3-O-methyldopa, and by blocking the activity of COMT, there is an increase in the available plasma and brain levels of levodopa and subsequently dopamine.
These medications do not have any antiparkinsonian activity on their own but are effective when wearing-off becomes a problem.
The 2 COMT inhibitors in the market are entacapone and tolcapone.
Entacapone is given at a dose of 200 mg with each levodopa dose (maximum of 1600 mg daily) while tolcapone is given as 100–200 mg 3 times a day.
Despite the less frequent dosing, tolcapone is less frequently used as it requires frequent liver monitoring, because of the rare potential to cause acute (sometimes fulminant) liver dysfunction.
Side effects include diarrhea, orange discoloration of body fluids (including urine), and, because it prolongs levodopa action, dyskinesias.
The patient in the 1st clinical vignette is relatively young and has early mild PD that is not functionally limiting, and she can be offered daily exercise with no medications for now or, if she wants to start medication, one of the MAO-B inhibitors. On the other hand, the patient described in the 2nd clinical vignette is already functionally limited by his symptoms, is older, and also has nonmotor symptoms (apathy). He can be offered levodopa therapy.
CASE 34-5
A 53-year-old man with a history of arterial hypertension presents to the Emergency Department because of a syncopal episode. He had just finished eating at a restaurant, stood up to greet a friend, and slumped suddenly. On arrival, his BP was 60/35 mmHg and he was diaphoretic. He had been experiencing recurrent light headedness with change of posture (especially when standing) over the past 18 months but had never lost consciousness prior to this. He has also been progressively slow over the past 2 years and sometimes has difficulty keeping up with his peers when walking. He sometimes feels stiff and has difficulty getting out of a car and out of his bed in the morning. There is no history of tremor. He has a history of erectile dysfunction over the past 2.5 years, which he attributed to the side effects of the antihypertensives he had been taking.
The atypical parkinsonian syndromes can be defined as neurodegenerative disorders characterized predominantly by parkinsonism, and are also known as Parkinson-plus syndromes.
They are typically more rapidly evolving and symmetric akinetic rigid in phenotype.
Except for corticobasal degeneration, which typically maintains its asymmetry.
They are associated with additional features such as
Early postural instability
Supranuclear gaze palsy
Early autonomic dysfunction
Apraxia
Pyramidal and cerebellar signs
An unsustained or absent response to levodopa
They can be pathologically divided into synucleinopathies and tauopathies:
Synucleinopathies
Dementia with Lewy bodies (DLB)
MSA
Tauopathies
PSP
Corticobasal degeneration (CBD)
Frontotemporal dementia with parkinsonism (FTD-P)
This is a neurodegenerative dementia characterized by fluctuations in cognition, attention, and alertness, recurrent visual hallucinations, and parkinsonism.
Possibly second most common cause of dementia in the elderly.
Onset is usually between the ages of 60–90 years, and no significant gender or ethnic differences in prevalence have been reported.
Clinical features consist of a central feature, core features, and suggestive and supportive features.24 Sometimes the clinical features overlap between AD and PD.
The central feature is a progressive dementia that is usually a combination of cortical and subcortical cognitive impairment.
It is typified by attentional deficits and prominent visuospatial and executive dysfunction compared to AD.
Memory is usually preserved especially in the early stages of the disease.
Core features are recurrent visual hallucinations, fluctuations in cognition, and motor parkinsonism.
The visual hallucinations are typically well formed, complex, and unrelated to medications.
The fluctuations in cognition are usually due to variations in alertness.
Motor parkinsonism in DLB is usually bilateral with mainly rigidity (including axial) and slowness. Rest tremor is not common in DLB.
Suggestive features include REM sleep behavior disorder (RBD), neuroleptic sensitivity, and low dopamine transporter uptake in the basal ganglia demonstrated by SPECT imaging.
RBD may antedate the presentation of DLB by several years, and because patients usually have no memory of the sleep behaviour, the history is dependent on the bed partner.
Sensitivity to D2 receptor blockers has been reported in up to half of DLB patients.
A low striatal DAT activity occurs in DLB, which can be used to differentiate it from Alzheimer disease.
Supportive features are those features that are present commonly but are not specific for DLB.
They include repeated falls and syncope, hallucinations in other modalities, autonomic dysfunction, delusions, and depression.
Because of underlying dementia, patients with DLB who are admitted to the hospital are at very high risk of developing delirium, psychosis, and worsening of parkinsonism. It is important to avoid using antipsychotic medications (except quetiapine or clozapine), antiemetic medications (except odansetron or domperidone), and increasing PD medications if the patient is not too uncomfortable motorically.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
