Etiology

The basal ganglia are a complex of deep gray-matter nuclei that includes the corpus striatum, globus pallidus, and substantia nigra. These structures regulate the initiation and control of movement. Patients with Parkinson disease have typically lost 80% or more of the dopamine-producing neurons in the substantia nigra. Depletion of dopamine in the complex nigrostriatal pathway produces an imbalance in inhibitory and excitatory neuronal signals, leading to the cardinal signs of Parkinson disease.

Although most cases are sporadic, genetic factors are implicated in the pathogenesis, especially in early-onset cases. At least 5 possible causative genes have been identified, and the number of Parkinson-like disorders associated with specific genetic defects is increasing. Many of these defects appear to be involved in cellular protein metabolism. Overall, Parkinson disease seems to have a multifactorial etiology that includes genetic predisposition, environmental factors, and age-related changes in neuron metabolism.

Symptoms

The first symptom of Parkinson disease is usually tremor of a limb at rest. Other common symptoms include bradykinesia, rigidity, a shuffling gait, postural instability, and stooped posture. Persons with Parkinson disease often have reduced facial expressions and speak in a soft voice. The disease is associated with nonmotor features such as depression (in up to 50% of cases), dementia, personality changes, sexual difficulties, sleep disorders, and hallucinations.

Treatment

There is currently no cure for Parkinson disease. Dopamine replacement, with medications such as levodopa, is the main treatment. Dopamine itself cannot be given because it does not cross the blood–brain barrier. Although levodopa helps at least three-fourths of patients with Parkinson disease, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, whereas tremor may only be marginally reduced. Problems with balance and other symptoms may not be alleviated at all. Patients are often given levodopa combined with carbidopa. The combination of the 2 together delays the conversion of levodopa into dopamine until it reaches the brain, diminishing some of the adverse effects that often accompany levodopa therapy alone.

After years of therapy, patients may experience a “wearing-off” effect that occurs about 4 hours after a dose of levodopa, when symptoms may return. Catechol O-methyltransferase inhibitors such as entacapone extend the duration of the levodopa effect and reduce the “off ” time by inhibiting the methylation of levodopa and dopamine.

Several additional therapies for Parkinson disease exist, and research is dedicated to finding more effective modalities. Dopamine agonists (bromocriptine, pramipexole, ropinirole, rotigotine, and apomorphine) stimulate dopamine receptors in the brain and may delay the need for levodopa. The monoamine oxidase (MAO) type B inhibitors selegiline, rasagiline, and safinamide may modestly improve symptoms of Parkinson disease. Based on information obtained from animal studies, the first 2 may also have neuroprotective properties and are therefore considered to be potential disease-modifying agents. The glucagon-like peptide-1 (GLP-1) drug exenatide, which is used in the treatment of type 2 diabetes mellitus, has also demonstrated some potential neuroprotective effect and is currently being studied. Anticholinergic drugs such as trihexyphenidyl and benztropine have a short-lived effect controlling tremor and rigidity. However, only about half of patients respond to anticholinergics, and typical anticholinergic adverse effects can be problematic.

Amantadine, an antiviral drug, may be used during the early stages of the disease, either alone or in combination with anticholinergics or levodopa. After several months, the effectiveness of amantadine wears off in one-third to one-half of patients.

Modern surgical treatments consist primarily of deep-brain stimulation and pallidotomy or thalamotomy. The dopamine deficiency in patients with Parkinson disease results in excitation of the globus pallidus, which in turn inhibits thalamic activity. Both surgical techniques serve to suppress this excessive globus pallidus activity. Deep-brain stimulation is initially safer than pallidotomy but requires intensive adjustments and lifelong maintenance, given the risk of hardware complications and infection. Pallidotomy carries the risk of complications such as stroke and hemorrhage, as well as the risk of irreversible adverse effects, and is seldom performed.

• Ferreira M, Massano J. An updated review of Parkinson’s disease genetics and clinicopathological correlations. Acta Neurol Scand. 2017;135(3):273–284.

• Kalia LV, Kalia, SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Mov Disord. 2015;30(11):1442–1450.

Ophthalmic considerations Patients with Parkinson disease may present with numerous ophthalmologic findings. These findings can be divided into eyelid disorders and ocular motor abnormalities. Eyelid disorders include seborrheic dermatitis and blepharitis, apraxia of eyelid opening, eyelid retraction, decreased blinking (with secondary dry eye), and blepharospasm. Ocular motor abnormalities include convergence insufficiency, limitation of upgaze, saccadic abnormalities, square-wave jerks, and oculogyric crisis. Patients commonly report difficulty with reading and symptoms related to ocular surface abnormalities.

Drug-related adverse effects may also be superimposed, especially for patients on anticholinergic medications, which may exacerbate dry eyes and cause accommodative changes or precipitate angle-closure glaucoma. Over 30% of patients with coexisting ocular disease and reduced vision may experience formed recurrent hallucinations characteristic of Charles Bonnet syndrome. However, this syndrome is not specific to Parkinson disease because it can be seen with other neurodegenerative conditions. Likewise, visual hallucinations can also occur as a result of treatment. This adverse effect has been reported in particular with the use of levodopa and anticholinergic agents. The drug amantadine has been reported to cause corneal infiltrates and edema in rare cases.

Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.