Medical Management, Orofacial Findings, and Dental Care for the Patient with Parkinson’s Disease

Epidemiology

Parkinson’s disease (PD) is a progressive, chronic, incurable neurodegenerative disease characterized by the atrophy of neuromelanin-containing dopaminergic neurons in the pars compacta of the substantia nigra (SN).¹ Currently, PD is the second most prevalent neurodegenerative disorder in North America after Alzheimer’s disease. According to the 2014 Canadian Health Report on PD, over 84 000 Canadian adults are living with PD.² The prevalence of PD increases with age; however, this trend may not apply to patients > 80 years because of an increase in disease severity and mortality rate.² The mean onset age of PD is 60 years; however, young-onset PD may develop before age 40 and is believed to account for 5–10% of those diagnosed with PD.³

Across all age groups, gender differences may exist among those with PD. Although men are more likely to have PD than women, information is insufficient to explain this difference. The annual incidence of PD has been reported to be as high as 20 cases per 100 000 people, and an estimated 8.7–9.3 million people worldwide will be diagnosed with PD by 2030.^2,4-6 With a marked proportion of the population affected by PD, it is pertinent for dentists to be familiar with its orofacial manifestations to appropriately accommodate patients, facilitate treatment planning and optimize dental care.

Etiology and Neuromuscular Pathology

The neuromuscular system is a highly sophisticated network of neural and muscular fibers that work synergistically to facilitate movement. Normally, motor signals are initiated in the motor cortex of the brain and forwarded to the basal ganglia via motor neurons.⁷ The striatum of the basal ganglia carries these motor signals to the SN, where dopaminergic neurons are highly concentrated, and movement is regulated. Dopamine plays an important role in producing involuntary motion via motor pathways. Also, dopaminergic neurons in the SN influence the expression of neuromelanin, a substance that helps protect these neurons from oxidative stress.⁸ When pathologies arise within these pathways, they can manifest systemically with neuromuscular symptoms of rigidity, akinesia or dyskinesia, which are among the most prominent signs of PD.^9,10

PD results in an overall deficiency of dopamine because of atrophy of the melanin-containing dopaminergic neurons within the SN and other pigmented nuclei of the brainstem.¹ This reduction in pigmented nuclei is the hallmark sign of PD.² Patients with PD may present with up to 80–90% depletion in dopaminergic neurons, which significantly impairs motor regulation in the SN resulting in delayed or uncoordinated movements. The precise mechanism leading to PD is unknown, and it is thought to be better classified as a syndrome of multiple etiologies rather than a stand-alone disease.¹¹

Generally, the etiology of PD includes idiopathic, environmental and genetic factors. Idiopathic PD accounts for over 95% of cases and includes atrophy of dopaminergic neurons resulting from the accumulation of Lewy bodies.¹² Lewy bodies are noxious, abnormal aggregations of proteins that develop within the SN and are believed to be causal factors in neuronal atrophy.¹² Ultimately, the degeneration of dopaminergic and non-dopaminergic neurons in the SN is a consequence of the presence of Lewy bodies and results in impaired motor control. Therefore, idiopathic Lewy body aggregates are thought to be the most common culprit in the initiation and progression of PD.

Genetic and environmental etiologies may also play a role in the initiation and progression of PD. Genetic onset of PD accounts for 3–5% of cases and involves several monogenic forms caused by a single mutation in an inherited dominant or recessive gene.¹³ Environmental factors may include oxidative damage via transition metals (iron, chromium, copper, zinc), which can exacerbate the progression of PD via neuromelanin atrophy.¹ Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine has also been identified as a potential risk factor¹⁴; however, environmental exposure to noxious substances is the least common etiology of PD.²

Clinical Presentation

The clinical presentation of PD varies with disease severity, which is based on the extent of dopaminergic neuron atrophy in the SN.¹⁵ In early stages, clinical signs and symptoms are usually absent. This asymptomatic pre-clinical phase may last for 5–20 years from the initiation of dopaminergic neurodegeneration. The clinical onset of PD unfolds once approximately 70–80% of the dopaminergic neurons in the SN have been depleted.⁷ At this point, systemic signs and symptoms will be prominent (Table 1).

Neuromuscular motor dysfunction presents clinically in PD patients as resting muscle tremors and muscle rigidity. Camptocormia is an abnormal thoracolumbar spinal flexion, or bent spine syndrome, and another clinical feature in patients with PD.¹⁶ Muscle rigidity is common and is mainly a result of oxidative stress resulting from mitochondrial complex I dysfunction and skeletal muscle damage.⁷ Sarcopenia, or muscle loss, may be seen in conjunction with muscle rigidity in PD patients because of skeletal muscle atrophy.¹⁷ Slow movements, bradykinesia, or lack of movement altogether (akinesia) are also characteristic neuromuscular motor signs of PD.^7,9 Although most PD symptoms manifest as neuromuscular motor impairments, several non-motor signs and symptoms include neuropsychiatric deficits, postural inadequacies, stomatognathic deficiencies, autonomic dysfunction and oral complications (Table 1).

Cognitive decline and dementia are common neuropsychiatric features of PD, which often occur in conjunction with each other.¹⁸ Postural inadequacies, including facial impassiveness, postural instability, shuffling gait and retropulsion, may present at diagnosis, but become more prevalent with the advancement of PD and related morbidities. Postural imbalances are extremely debilitating and often associated with increased falls and loss of independence.¹⁹ Postural deformities may also affect the functionality of the extremities, shoulder, head and neck, compromising the patient’s ability to walk, lift, rotate and reach. This hindrance of movement makes performing activities of daily living, such as oral hygiene, extremely challenging.^20,21

The prevalence and clinical presentation of orofacial manifestations also increases with the progression of PD.²⁰ Patients are prone to the development of stomatognathic deficiencies, which alter their masticatory function.²² Alterations of the stomatognathic system in PD patients may lead to temporomandibular joint disorders (TMDs), along with difficulties swallowing, chewing and speaking.^22,23 Several autonomic effects may also manifest clinically, including sialorrhea, fatigue, constipation, sexual dysfunction and orthostatic hypotension.^20,24-26 In addition, dental-specific manifestations of PD include xerostomia, dysphagia, bruxism and an increased incidence of root caries.²⁰

Diagnosis and Classification

The diagnosis of PD is based on several factors including patient history, physical examination, clinical presentation of signs and symptoms and a sustained response to dopaminergic medications, such as levodopa.^2,7 PD may present with a plethora of signs and symptoms; however, the cardinal neuromuscular signs that dentists and physicians should recognize include the “classical triad” of resting tremor, cogwheel rigidity and bradykinesia (or akinesia).^2,7,10,20 There is some crossover between the secondary motor symptoms of PD and those of similar neurodegenerative diseases and related Parkinsonian disorders.¹⁰ Thus, it is important for clinicians to be able to differentiate PD from non-Parkinsonian disorders by recognizing these classical signs and symptoms. Although there are no definitive tests to confirm or rule out PD,⁷ the absence of tremor, postural instability, dementia, and other key factors, such as poor response to levodopa, might suggest other diagnoses.¹⁰ Therefore, a thorough and nuanced approach should be used, and the broad spectrum of clinical manifestations considered to reach an accurate diagnosis.

Medical imaging modalities may aid physicians in evaluating patients who are suspected to be suffering from PD. Specifically, dopaminergic uptake of the ¹²³I-Ioflupane radiotracer in nigrostriatal tracts may be visualized with single photon-emission computed tomography. This facilitates the detection of PD and may provide insight regarding disease severity and duration.²⁷ The stage of PD can be evaluated by determining the extent of the uptake of ¹²³I-Ioflupane at the presynaptic terminal of dopaminergic neurons, which reflects the extent of functional dopaminergic neurons present. In early stages of PD, there is a relative decrease in the intensity of tracer uptake bilaterally, whereas, in advanced stages of the disease, this decrease in uptake becomes more noticeable.^15,18 Patients with unilateral neurodegeneration of dopaminergic neurons will also reflect these changes in diagnostic imaging, and may present clinically with contralateral motor dysfunction.

Several scales have been used to rate and categorize the severity of PD based on the extent to which patients experience related signs and symptoms. The Hoehn and Yahr scale is the grandfather of these evaluation scales and is most commonly used to provide a general assessment of the progression of PD in terms of neuromuscular deficiency (Table 2).²⁸ Currently, the most widely employed and well-established system for assessing disability and impairment among PD patients is the Unified Parkinson’s Disease Rating Scale (UPDRS), which was revised in 2007.^29-31 The UPDRS has 4 major components: (1) mental state, behaviour and mood, (2) activities of daily living, (3) motor symptoms and (4) complications of therapy.³⁰ The UPDRS provides additional information over the Hoehn and Yahr scale, implying variable differences in the rate of progression of PD, specifically during earlier stages. The progression of PD is not linear and requires robust medical and dental management strategies to maximize patient comfort and attain patient-specific treatment goals.^10,32

Medical Management

Unfortunately, there is not yet a cure for PD. Currently, we are limited to treating the symptoms of PD by addressing its hallmark sign: an absolute decrease in dopaminergic neurons in the SN.³³ Various methods exist to increase the concentration of dopamine and, therefore, combat the dopamine-dependent signs and symptoms of PD; they include pharmacotherapy, lifestyle changes and surgical intervention.²⁰ Here, we discuss current pharmacological interventions useful for the management of PD along with their associated systemic and orofacial implications.

Pharmacotherapy

Pharmacological interventions are most commonly used to treat PD-related signs and symptoms. Several classes of drugs may be used to increase the concentration of dopamine in the brain by increasing the synthesis of dopamine, decreasing the metabolism of dopamine and increasing the presynaptic release of dopamine (Table 3). Levodopa (dopamine precursor) combined with carbidopa (DOPA decarboxylase inhibitor) is considered the gold standard therapy for early PD.³⁴ Novel pharmacological strategies target other neurotransmitters in addition to the dopaminergic system, including serotonin (5-HT), gamma aminobutyric acid (GABA) and acetylcholine (ACh). These have been proposed to treat symptoms associated with advanced stages of PD.³⁵

Nonetheless, all pharmacotherapies for PD rely on the fundamental principle of increasing the concentration of dopamine in the brain. This can be accomplished by either stimulating dopamine synthesis or inhibiting dopamine metabolism with monoamine oxidase (MAO-B) inhibitors or catechol-O-methyltransferase (COMT) inhibitors. Dental professionals should be wary of patients who are taking COMT-inhibitors because of potential interactions with vasoconstrictors, such as epinephrine and levonordefrin^36-38 and may, therefore, consider the use of dental anesthesia without vasoconstriction, when clinically applicable.²⁰

Dopamine Agonists and Levodopa

Dopamine replacement therapy is the most common first-line treatment for PD-related signs and symptoms.³⁹ Levodopa is a precursor to dopamine, which is naturally metabolized following decarboxylation. The metabolism of levodopa results in increased levels of serum dopamine because of the chemical equivalence between levodopa and dopamine. Unlike levodopa, dopaminergic agonists directly stimulate the postsynaptic dopamine receptors in the nigrostriatal system, rather than increase the production of dopamine.³⁹ Dopamine agonists are the first choice for mild rigidity; whereas dopamine precursors become necessary as signs and symptoms worsen.^34,39

Dopamine agonists are mainly derived from 2 subgroups: ergoline and non-ergoline.⁴⁰ Bromocriptine and cabergoline are ergoline-based drugs for anti-PD therapy, while pramipexole and ropinirole are non-ergoline derivatives (Table 3).^34,29,40 Although the differences in their mechanisms of action are unclear, ergoline derivatives are associated with more severe adverse effects with extended use, including retroperitoneal and pleuropulmonary fibrosis. Certain ergoline-based drugs, such as pergolide, may also cause valvular heart disease. Therefore, ergoline-derived medications are more often used as a second-line therapy for PD. Non-ergoline drugs may promote impulsive behaviour, such as gambling, and have a higher tendency to promote somnolence than ergoline-derived medications.⁴⁰ Both ergoline and non-ergoline derived dopamine agonists produce similar orofacial manifestations, as described in Table 3; however, the extent and severity of oral adverse effects seems to be on an individual drug basis rather than a subgroup trend.

DOPA Decarboxylase Inhibitors

Carbidopa is a DOPA decarboxylase inhibitor often prescribed in combination with levodopa (Sinemet). Research suggests the combination of carbidopa and levodopa may be the most effective treatment regimen to manage the dopaminergic symptoms of PD.⁴¹ The mechanism of action of Sinemet involves an increase in the post-synaptic release of dopamine, which is achieved by levodopa, while carbidopa prevents the peripheral conversion of levodopa into dopamine. This synergistic combination increases the half-life and bioavailability of levodopa in the brain.^39,41 The combination of levodopa and carbidopa is exceptional at inhibiting the metabolism of dopamine, though DOPA decarboxylase inhibition by carbidopa is non-specific. Therefore, the treatment of dopaminergic symptoms of PD using Sinemet is associated with various adverse effects, including but not limited to gastrointestinal upset, cardiac arrythmias and orthostatic hypotension (Table 3).

Monoamine Oxidase-B Inhibitors

Although dopamine agonists aim to sustain levels of dopamine by stimulating its postsynaptic release, monoamine oxidase inhibitors (MAOIs) reduce the metabolism of dopamine by MAO enzymes. Despite the difference in their mechanism of action, both dopamine agonists and MAOIs may be used alone as a first-line therapy or in combination with levodopa to synergistically control the motor symptoms of PD.³⁴ Rasagiline, selegiline and safinamide are anti-PD medications that specifically inhibit MAO-B, an enzyme responsible for the post-synaptic breakdown of dopamine (Table 3).⁴² Both selegiline and rasagiline have the potential to selectively and irreversibly inhibit MAO-B in PD treatment; however, selegiline seems to have a higher affinity.⁴² Furthermore, selegiline and rasagiline are both known to potentiate the release of dopamine by levodopa in combination therapy. Safinamide also has an inhibito…