PARKINSON DISEASE

PARKINSON DISEASE

Current diagnosis

•   Clinical diagnosis

•   Rigidity

•   Bradykinesia

•   Resting “pill-rolling” tremor

•   Postural instability

•   Sustained response to carbidopa/levodopa or dopamine agonist

•   Frequent re-evaluation

•   Imaging

•   Single photon emission computer tomography (SPECT) to differentiate essential tremor

•   Functional magnetic resonance imaging (fMRI) progressive supranuclear palsy

Current therapy

•   Early disease

•   Patients over age 70: levodopa/carbidopa

•   Patient under age 60: dopamine agonist or monoamineoxidase B (MAO-B) inhibitor

•   Patients between 60 and 70: one of above agents

•   On-off phenomenon

•   Levodopa/carbidopa with dopamine agonist or catechol-O- methyltransferase (COM-T) inhibitor

•   Dyskinesias

•   Amantadine

•   Advanced disease

•   Deep brain stimulation of subthalamic nucleus or globus pallidus interna

Parkinson disease (PD) is a common degenerative neurologic disorder characterized by bradykinesia and pathologically defined by the presence of Lewy bodies in the dopaminergic neurons of the substantia nigra.

Epidemiology

PD is rare in patients below 60 years of age. The prevalence is approximately 1% in people aged 60 and older. The prevalence among African Americans and Asian Americans is about half that of the white population. With a growing elderly population, the number of PD sufferers is expected to double by 2030. PD is not distributed equally across geographic areas. In the United States, higher rates of PD are found in the Midwest/Great Lakes region and in the Northeast Seaboard.

Risk Factors

Epidemiologic studies have consistently shown an association between exposure to pesticides and herbicides and risk of PD. Nicotine exposure, primarily through cigarette smoking, is associated with a lower risk of PD. Coffee drinkers also have lower rates of PD. First-degree relatives of PD patients have a two-fold increased risk.

Pathophysiology

The etiology of PD is not understood. While there are several genetic mutations implicated in sporadic PD, including LRRK2 and Parkin, their role is unclear. At this time, it seems likely that PD arises as a result of complex interactions between genes that promote or inhibit development of PD and environmental factors.

Post-mortem analysis of PD patients’ brains show neuronal loss and Lewy bodies in the substantia nigra. Lewy bodies are intracytoplasmic inclusions containing α-synuclein and ubiquitin. While the striatum, which receives neuronal inputs from the substantia nigra, appears normal, the loss of dopaminergic input into the striatum from the substantia nigra leads to the motor symptoms of PD, which typically begin when 70% to 80% of the dopaminergic neurons in the substantia nigra are lost.

Prevention

Although there are no measures proven to prevent PD, given the observed epidemiology, it is reasonable to recommend that people minimize exposure to herbicides and pesticides.

Clinical Manifestations

PD first manifests with the hallmark symptoms of bradykinesia, tremor, rigidity, and postural instability. Symptoms begin on one side and gradually progress.

Bradykinesia refers to generalized slowness of movement.

Bradykinesia makes it difficult for patients to perform fine motor tasks, such as key-boarding or writing, as well as initiating movement with large muscle groups. Patients may complain of trouble turning over in bed or standing up from a chair, as well as weakness or fatigue.

The “pill-rolling” tremor of PD is a resting tremor with a frequency of 3 to 7 Hz, and is most noticeable when the patient is sitting quietly or walking. Less commonly, the tremor can be present in the legs, lips, jaws, or tongue. The tremor improves with action and with sleep.

Rigidity is increased resistance to passive range of motion about a joint. Rigidity can be focal or widespread, and may lead to complaints of pain and stiffness.

Diagnosis

The diagnosis of PD is made clinically, and is suggested by the presence of tremor, rigidity, bradykinesia, postural instability, gradual progression, and a sustained response to levodopa. The London brain bank criteria have been found to have good predictive value in advanced disease, but there are no good clinical prediction rules for diagnosis of early disease.

Historical features that increase the likelihood of PD include tremor of head or limbs; bradykinesia and rigidity; decreased facial expression; difficulty arising from a chair, loss of balance, feet freezing; shuffling gait, trouble turning in bed and opening jars, and micrographia. The absence of rigidity and bradykinesia make PD less likely, as do a history of falls.

On examination, the clinician should look for the typical tremor with the patient sitting and hands resting in the lap. Having the patient do mental calculations or move the contralateral limb may increase a tremor or bring out a latent tremor. The tremor will improve with use of the affected limb. Bradykinesia can be observed via several maneuvers. Perform a get-up and go test, and watch for difficulty arising from a chair, decreased arm swing, and decreased stride length, as well as difficulty turning. Provocative maneuvers— repeatedly circling the hands in front of the body; pinching the thumb and forefinger together repeatedly with the right hand and then with the left hand, circling one hand and then the other, and then pinching thumb and forefinger together with one hand while circling with the other can reveal bradykinesia, as will asking the patient to repeatedly tap their heel to the floor. The examiner can detect rigidity by passively rotating the wrist and/or flexing and extending the forearm, and noting resistance. Jerky resistance is typical of “cogwheel” rigidity, whereas smooth resistance is typical of lead-pipe rigidity: both can be present in PD. A positive glabellar tap test also increases the likelihood of PD.

A sustained response to levodopa/carbidopa (Sinemet) or a dopamine agonist helps confirm the diagnosis. The “acute challenge test,” using either levodopa/carbidopa or apomorphine (Apokyn) is no longer recommended.

Imaging is not routinely needed. In rare instances, magnetic resonance imaging can help differentiate PD from multisystem atrophy, and single-photon emission computed tomography may distinguish PD from essential tremor.

PD shares features with a number of other conditions, making diagnosis, particularly in the early stages, challenging. Repeated evaluation over the course of the illness is important, as is careful attention to response to treatment. The absence of a sustained response to appropriate therapy early in the course of the illness should lead to re-evaluation. Uncertainty about the diagnosis warrants consulting a clinician experienced in diagnosis.

Differential Diagnosis

Diseases with a tremor, parkinsonian symptoms or gait impairment should be considered in the differential of a patient with suspected PD. Diseases that are most commonly mistaken for PD by primary care physicians include essential tremor, vascular parkinsonism, progressive supranuclear palsy and drug-induced parkinsonism.

These conditions, as well as differentiating signs and symptoms, are listed in Table 1.

Table 1

Characteristics of Conditions Considered in Differential Diagnosis of Parkinsonism

Condition                            Features
Essential tremor Symmetric postural tremor; worsens with movement; affects distal extremities, head and speech; family history common
Vascular parkinsonism May have focal neurologic finding; stepwise progression; poor response to carbidopa/levodopa; basal ganglia and/or thalamic infarcts present on CNS imaging
Drug-induced parkinsonism Clinical features similar to PD; symptoms improve after withdrawal of medicine; anti-emetics and psychotropic drugs most common cause
Dementia with Lewy bodies Onset of dementia and hallucinations at same time as motor symptoms; fluctuating mental status; poor response  to carbidopa/levodopa
Progressive supranuclear palsy Parkinsonism accompanied by falls and minimal response to dopaminergic treatment, with later development of supranuclear gaze palsy
Multiple system atrophy Parkinsonism accompanied by early autonomic dysfunction and poor response to dopaminergic treatment and ataxia
Corticobasal degeneration Cognitive impairment, asymmetrical limb dysfunction and minimal response to dopaminergic treatment, with absence of tremor

Findings that make a diagnosis of PD less likely include a history of traumatic, vascular or infectious brain injury and use of antidopaminergic drugs within the previous 6 months. The time course of disease progression is helpful in distinguishing PD from other neurologic diseases. Presentation of dementia, significant autonomic insufficiency, frequent falls, and apraxia early in the disease course make PD unlikely. Symmetric findings on examination, as well as cerebellar signs, spasticity and hyper-reflexia, and inability to name objects despite intact sensation all point away from PD. Individuals less than age 50 who present with PD may have an inherited form of the disorder, and should also be evaluated for

Wilson disease. Younger adults and adolescents who present with parkinsonian features likely have dopa-responsive dystonia.

Treatment

Early Disease

Treatment begins when symptoms impair an individual’s ability to carry out their usual daily routine. Three classes of medications are effective for early disease: levodopa/carbidopa (Sinemet), dopamine agonists, and monoamine oxidase inhibitors (Table 2).

Levodopa/carbidopa is the most effective of these three classes of medications, but motor-related complications, such as dyskinesias, develop at a rate of 10% per year, and are more problematic in younger patients. Dopamine agonists, which directly stimulate dopamine receptors, are less likely to lead to dyskinesias in head to head comparisons with levodopa/carbidopa. However, these same trials demonstrated that they are less effective and resulted in a higher drop-out rate than levodopa/carbidopa. Monoamine oxidase inhibitors are the best tolerated but least effective. There are no drugs that slow progressive neuron loss in PD. The initial choice of medication should be made taking into account the severity of the patient’s symptoms and age, after a discussion of benefits and burdens with patients. Most experts recommend initiating therapy with a dopamine agonist for patients younger than 60 years old, and levodopa/carbidopa for patients over the age of 70. For patients between these ages, the initial choice of medication is less clear. The evidence does not support the use of combination therapy in early disease to delay the development of dyskinesias.

Table 2

Drugs for Parkinson Disease

2  Exceeds dosage recommended by the  manufacturer.

Levodopa/carbidopa is started at a dose of ½ to 1 tablet of the 25/100 immediate release tablet three times a day. The dose can be titrated to 2 to 3 tablets of the 25/100 tablet, increasing the dose weekly by a half-tablet at all doses, until the patient’s symptoms are controlled. In early disease, patients will develop a sustained response to dopamine, with good control of symptoms throughout the day. Patients should take levodopa/carbidopa on an empty stomach, as dietary protein competes with dopamine for receptors sites on trans- gut amino acid transporters. The main side effects of levodopa/carbidopa that patients will experience are nausea and orthostatic hypotension. For nausea, patients may try taking their medication with a small nonprotein snack, such as saltine crackers.

Adding additional carbidopa to each dose of levodopa/carbidopa can also help. Trimethobenzamide (Tigan)1 and ondansetron (Zofran),1 nondopamine blocking nausea agents may be effective. There is no benefit to use of sustained release levodopa/carbidopa.

The oral dopamine agonists, pramipexole (Mirapex) and ropinirole (Requip), and the transdermal agonist rotigotine (Neupro) are started at the lowest dose and titrated slowly to effect. In addition to nausea, these agents can cause sleepiness, edema, and hallucinations, as well as compulsive repetitive behaviors, pathologic gambling or shopping, and hypersexuality. Older dopamine agonists, such as bromocriptine (Parlodel), can cause pleural and retroperitoneal fibrosis and cardiac valvulopathies and should not be used. Rasagiline (Azilect) and selegiline (Eldepryl) are monoamine oxidase B (MAO-B) inhibitors that can delay use of levodopa/carbidopa in patients with mild disease, but also cause nausea and orthostatic hypotension.

Later Disease

As the disease progresses, bradykinesia, rigidity and tremor worsen. For patients taking dopamine agonists or MAO-B inhibitor increasing the dose may help, but these patients will eventually require the addition of levodopa/carbidopa. Patients taking levodopa/carbidopa will eventually develop motor fluctuations and will initially notice that the symptoms recur near the end of dosing intervals (“wearing off”). For these patients, increase the frequency of the effective dose, not the amount of the dose. Eventually, patients will notice more abrupt and sudden fluctuations in effect (“on-off” phenomenon).

There are three classes of medications that can be added to increase “on time” to patients on levodopa/carbidopa: monoamine oxidase inhibitors, dopamine agonists, and catechol O-methyltransferase (COM-T) inhibitors, which decrease peripheral dopamine metabolism. The COM-T inhibitor entacapone (Comtan) is preferred to tolcapone (Tasmar), which can cause fatal hepatotoxicity. In addition to oral and transdermal dopamine agonists, an injectable agonist, apomorphine (Apokyn), is effective in reducing off-time; its use should be supervised by a specialist in movement disorders. Dopamine agonists are probably the most effective medications for reducing off-time.

With addition of any of these agents, the dose of levodopa/carbidopa can often be reduced. All of these agents increase the occurrence of dyskinesias.

Dyskinesias eventually develop, often around the same time that wearing-off or on-off symptoms begin. Dyskinesias are choreaform movements affecting a limb, trunk, head, neck, or a combination of areas. Dyskinesias are due to excessive dopamine stimulation. If patients find them bothersome, treat them by reducing the dose of levodopa/carbidopa and decreasing the dosing interval.

Unfortunately this will often lead to worsening of other parkinsonian motor symptoms. Amantadine (Symmetrel) can also reduce dyskinesias, although the effect is modest.

For patients whose symptoms cannot be adequately controlled by optimal medical therapy, consider referral for deep brain stimulation, which targets either the subthalamic nucleus or the globus pallidus interna. Patients who have had a good response to levodopa/carbidopa, few comorbidities, no cognitive impairment, and either no depression or who have well controlled depression are likely to have a good response. Patients who have surgery have gains in on- time and improvements in motor function and quality of life. Surgery does not slow disease progression, however, and patients will ultimately develop treatment resistant symptoms. Surgical risks include intracranial hemorrhage, stroke, infection, lead migration, misplacement or fracture, and death. Patients undergoing surgery area are at increased risk for depression.

Physical therapy is an important intervention in both early and later disease. For patients with mobility impairment, physical therapy improves balance, motor strength and walking speed. Speech therapy aimed at increasing speech volume is effective in patients with hypophonia. While lacking evidence of effectiveness, occupational therapy might help patients maintain work, family, or social roles.

Complications

In addition to functional impairment and disability from motor disease, PD also has cognitive, neuropsychiatric, and autonomic nervous system manifestations. Sleep disturbances occur in almost half of PD patients, including insomnia, nightmares, excessive daytime sleepiness, and rapid-eye movement sleep behavior disorder. Sleep disturbances are often due to sleep fragmentation, and may respond to usual treatments for insomnia. For patients who have difficulty with bed mobility or tremor that affects sleep, prescribe a night-time dose of levodopa/carbidopa. Restless leg syndrome is common in PD and responds to the usual treatments. Rapid eye movement sleep disorder occurs commonly and can occur prior to the onset of motor symptoms. It is characterized by dream-enactment behaviors such as kicking and screaming. Confirm the diagnosis with polysomnography and treat with benzodiazepines.

Fatigue is present in up to a third of patients with PD at the time of diagnosis and may respond to methylphenidate (Ritalin).1 Daytime drowsiness in PD may be due to sleep disorders and the effect of PD medication. Modefinil (Provigil)1 has improved scores on the Eppworth sleepiness scale, but has not actually improved sleep parameters in PD patients. There is no effective treatment for sleep attacks in patients with PD. Counsel these patients to avoid driving or operating machinery.

Depression has been reported in up to 80% of PD patients, and can be difficult to distinguish from apathy. The motor symptoms of PD can mimic signs of depression, such as psychomotor slowing. Use of a depression inventory can aid in diagnosis. Desipramine (Norpramin) and nortriptyline (Pamelor) have effectively treated depression in PD; however, their side effect profiles complicate their use. Select a medication for depression—a tricyclic antidepressant (TCA), serotonin-norepinephrine (SNRI) or selective serotonin reuptake inhibitors (SSRI)—based on the patient’s co-morbidities and risk for drug interactions.

Psychosis manifests commonly as visual hallucinations. Evaluate the patient for potential causes of delirium, and treat if present.

Reassure patients and families in regards to mild, nonfrightening hallucinations. Prescribe quetiapine (Seroquel) for psychosis that requires pharmacologic therapy. Clozapine (Clozaril) is more effective, but the risk of agranulocytosis and need for monitoring make it the second-line agent in the United States. Do not use other antipsychotics, which can worsen motor symptoms of PD. Pimavanserin is new antipsychotic agent that has been found, in one randomized controlled trial, to reduce psychotic symptoms (NNT = 7) and caregiver burden (NNT = 13). The FDA gave approval on April 26, 2016. It is sold under the brand name Nuplazid.

Autonomic symptoms include drooling, dysphagia, constipation, voiding dysfunction, erectile dysfunction and orthostatic hypotension. Treat drooling with glycopyrrolate (Robinul) or botulinum toxin type A (Botox).1 Dysphagia is worse during “off” times; adjusting PD medications to reduce “off” time may help, as may speech therapy. In a randomized trial, polyethylene glycol solution (Miralax) was effective in reducing constipation. No treatments are proven to affect urinary symptoms in PD. It is reasonable to try usual symptomatic treatments, such as antimuscarinic agents. Sildenafil (Viagra) has been shown to improve erectile dysfunction in PD. For patients with orthostatic hypotension, lower antihypertensive dosages if possible and encourage increased fluid and salt intake. Consider use of fludrocortisone1 or midodrine (Proamatine), even though there is no data to support their use in PD, and monitor for supine hypertension.

Cognitive impairment occurs frequently in PD, and up to 80% of patients will develop dementia at 20 years after diagnosis.

Rivastigmine (Exelon) is approved for use in PD. Donepezil (Aricept)1 is also effective, and it is generally better tolerated than rivastigmine. It is unclear which drug is more effective. Memantine (Namenda)1 is of uncertain benefit.

PD patients will experience progressive decline in motor and cognitive function, and have about a two-fold increased mortality risk. At age 70, men with PD have a median life expectancy of 8 years and women a median life expectancy of 11 years. Effective treatment can delay disability and improve quality of life.

References

1.     Ahlskog J.E. Cheaper, simpler, and better: Tips for treating seniors with Parkinson disease. Mayo Clin Proc. 2011;86:1211– 1216.

2.    Chou K.L. In the clinic: Parkinson disease. Ann Int Med. 2012;157:ITC5–1–16.

3.     Connolly B.S., Lang A.E. Pharmacological treatment of Parkinson disease: A review. JAMA. 2014;311:1670–1683.

4.    Cummings J., et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383:533–540.

5.     Drugs for Parkinson’s Disease. Treat Guidel Med Lett. 2013;11:101–106.

6.     Fritsch T., Smyth K.A., Wallendal M.S., et al. Parkinson disease: research update and clinical management. South Med J.   2012;105:650–656.

7.    Gazewood J.D., Richards R.R., Clebak K. Parkinson disease: an update. Am Fam Physician. 2013;87:267–273.

8.    Okun M.S. Deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2012;367:1529–1538.

9.     Rao G., Fisch L., Srinivasan S., et al. Does this patient have Parkinson disease? JAMA. 2003;289:347–353.

10.   Scottish Intercollegiate Guidelines Network. Diagnosis and Pharmacological Management of Parkinson’s disease: A National Clinical Guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; January, 2010. Available at http://www.sign.ac.uk/sign-113-diagnosis-and- pharmacological-management-of-parkinson-s-disease.html [accessed September 28, 2017].

11.    Stowe R., Ives N., Clarke C.E., et al. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson’s disease patients with motor complications. Cochrane Database Syst Rev. 2010;7: CD007166.

1  Not FDA approved for this  indication.

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