Understanding the Significant Role of Secondary Symptoms of Parkinson Disease

Parkinson disease (PD), a progressive neurodegenerative disorder involving multiple neurotransmitter pathways in the brain and autonomic nervous system, has been typically characterized by motor symptoms including tremor, bradykinesia, rigidity, and postural reflex disturbance. Although these dopaminergic motor symptoms are a major part of the clinical management of the disease, a growing number of patients have expressed that the nonmotor, secondary symptoms affect their quality of life even more.

There are a number of nonmotor symptoms associated with the disease, including anxiety, apathy, cognitive changes, constipation and nausea, dementia, depression, fatigue, hallucinations/delusions, loss of smell, pain, skeletal and bone health, sleep disorders, speech and swallowing issues, urinary incontinence, and vision changes, among various others. Some of these symptoms, such as loss of smell, constipation, depression, and REM sleep behavior disorder (RBD), can even occur years before patients receive a diagnosis of PD.¹

Though much of the recent drug development has been geared towards improving the OFF and ON stages of the disease, education and awareness of nonmotor symptoms are equally as critical, Christopher Tarolli, MD, told NeurologyLive^®.

"While many patients think I’m here to discuss their tremor or motor symptoms, I want to make sure my patients recognize that all these symptoms [motor and nonmotor] are parts of the disease and things we should be discussing at their visits," he said. "There are a lot of symptoms, and there’s no way that we’re going to be able to discuss each of those in detail in a single, relatively short follow-up visit. And so, I ask my patients to think about the things that are most impactful and most bothersome for them."

Tarolli, an associate professor of neurology at the University of Rochester, also spends his time as a movement disorder specialist, primarily seeing patients with PD in clinical practice. Like many other PD specialists, he feels that early recognition and communication are key to attenuating the impacts of nonmotor symptoms on quality of life.

Constipation

Constipation, defined as fewer than 3 bowel movements per week and frequently accompanied by straining, hard stools, or a sensation of incomplete emptying, has been considered the most widely recognized gastrointestinal symptom of PD. For some patients, constipation may occur because of an improper functioning of the autonomic nervous system, which is responsible for regulating smooth muscle activity of the gut.

Over the years, there has been increasing evidence that constipation is one of the major nonmotor symptoms to predate PD. One of the first studies that shed light on this, conducted in 2009, revealed that constipation preceding PD or the index year was more common in cases than in controls, with an OR of 2.48 (95% CI, 1.49-4.11; P = .0005). Not only did this association remain after adjusting for smoking and coffee consumption, but the association remained significant in analyses restricted to constipation documented 20 or more years before the onset of motor symptoms.²

To date, there are no prescription drugs specific for PD constipation. Many patients start by focusing on diet and lifestyle adjustments, including increasing daily water intake, adding more fiber to the food regimen, eating smaller meals each day, and exercising regularly.³ Clinicians often take an aggressive approach to managing constipation considering its effect on the gut microbiome and downstream impact of how medications are absorbed and the efficiency with which they work.

As patients understand more about the lingering effects of constipation, they become more proactive in the decisions they make. "If you explain the ‘why’ to them, they’re more likely to get on board and say, ‘OK, I understand why I’m constipated, it’s part of the disease that my gut has slowed, just like my arm. And if I don’t treat it, all these pills are going to get stuck in the stomach,’" Maria Christina (MC) Ospina, MD, MBA, explained to NeurologyLive.

Ospina, who serves as a medical director for a regional Parkinson center in Phoenix, Arizona, added, "They may not like prunes, but if they understand [more about their constipation] they may be more diligent in eating at least 5 prunes every night. When they take their Rytary (carbidopa/levodopa; Amneal), it actually kicks in. I’m not having to take so many other medicines like Inbrija (levodopa; Merz) or Apokyn (apomorphine; Supernus), medicines that are so expensive to try to bypass the gut that’s very slow."

Medications for PD, including levodopa and dopamine agonists, as well as amantadine and trihexyphenidyl, may also cause or contribute to constipation.¹ Other causes may include not drinking enough water, a diet low in fiber, lack of exercise, and weakness of the pelvic floor muscles. Certain other medications, such as iron supplements, opioid pain medications, antiacid medications containing calcium or aluminum, and therapies for blood pressure, have also been shown to contribute.

"Usually, I recommend starting with a stool softener most days or every day and then if that's not enough I recommend adding in an [over-the-counter] laxative as needed; and if they find that they need both daily then that's OK from my standpoint," Tim Leichliter, MD, a neurologist at Allegheny Health Network, told NeurologyLive. "If that's not enough to keep them relatively regular then I can either try prescription medications off-label like linaclotide or will refer them to a gastroenterologist for a more comprehensive look and further recommendations."

To date, there are no prescription drugs specific for PD constipation; however, there are marketed therapies for “chronic idiopathic constipation,” or constipation because of an unknown medical cause or medication. Some of these therapies, like linaclotide (Linzess; AbbVie), lubiprostone (Amitiza; Takeda), and plecanatide (Trulance; Salix), may be considered after diet changes, exercise, and over-the-counter therapies have failed.

It has been suggested that gut microbiota influence PD via the gut-brain axis. Compared with healthy controls, patients with PD exhibit gut microbiome characterized by a decrease in putative short-chain fatty acid-producing bacteria, such as Butyricicocuccus, and Coprococcus, as well as an increase in putative proinflammatory bacteria, such as the genera Akkermansia.4In addition, there have been reports of different microbiome features in patients with PD based on a phenotype that is more tremor-predominant vs rigid-predominant.⁵

At this moment, there still needs to be more research understanding the good and bad influence of gut microbiome, Ospina said. “We know that the good guys like to eat fiber, so the more fiber we give that gut, the more we’re going to push the ‘bad people’ in the microbiome and grow the good microbiome,” she told NeurologyLive.

"We’re at that stage where we don’t know well enough that [something like] fecal transplant is going to make you better. In 10 years from now, especially as we start to treat PD in the pre-motor phase—where we treat RBD, constipation, and osmium using a positive alpha-synuclein biopsy—our treatments are going to be disease-modifying that have some change to your microbiome,” Ospina added.

Hallucinations, Delusions, and Psychosis

Between 20% to 40% of patients with PD report the experience of hallucinations or delusions. As the disease continues to progress, this number typically increases. Although often initially benign, these hallucinations almost invariably involve perception of people and animals, often in vivid detail, with some patients describing scenes of Victorian women and small children playing.

"When I’m managing hallucinations or delusions of PD, I want to make sure that it’s following the pattern that I would expect, which is a slow escalation of symptoms over time," Tarolli said. "If I see a patient who has a sudden worsening of cognitive changes or sudden onset of delusions or hallucinations, that makes me think that something else is going on. Do they have something like a urinary tract infection or pneumonia? Is something wrong with their electrolytes? Is there something else going on that we can manage that’s bringing out those hallucinations that wouldn’t otherwise be there?"

There are several PD medications, including carbidopa-levodopa and dopamine agonists which are designed to increase dopamine levels, that inadvertently cause symptoms of psychosis. Other medications used to treat PD can also cause these symptoms by lowering levels of acetylcholine, shifting its balance with dopamine. In addition, dementia, a term associated with a decline in memory and thinking, and delirium, a reversible change in a person’s level of attention and concentration, have both been linked the development of psychosis in PD.⁶

Typically, clinicians will try to decrease dosages of other PD medications first before turning to antipsychotics; however, this becomes often difficult because of the movement problems patients experience. The management for PD psychosis has typically involved off-label antipsychotic medications such as quetiapine (Seroquel) and clozapine, as well as pimavanserin (Nuplazid; Acadia), the only FDA-approved medication specific to PD psychosis. Most antipsychotics used directly block dopamine D2 receptors, which can lead to significantly worsening motor symptoms in patients with PD. Notably, all 3 of these drugs carry a Black Box warning, indicating an increased risk for death in patients aged 65 and older.

The Importance of Open Communication in Patient Care

Kelly Papesh, DNP, APRN, FNP-BC, executive director of the Association of Movement Disorder Advanced Practice Providers, discussed how effective patient care in movement disorders can lead to better management and treatment outcomes. Papesh, who also serves as a nurse practitioner and the clinical director at PMD Alliance, talked about the challenges in addressing nonmotor symptoms or hidden features in patient care, and how these can be mitigated. Furthermore, she spoke about how cultural sensitivity, language barriers, and gender preferences can impact patient-provider communication, and how shared strategies that can improve this interaction.

"It comes down to juggling the hallucinations and motor symptoms of PD and finding a balance with the medications, which is not always easy," Leichliter added.

Pimavanserin, a 5-HT2A receptor antagonist/inverse agonist, has been on the market since 2016. 5-HT2A, a subtype of the 5-HT2 receptor, is believed to be the most excitatory receptor subtype among the serotonin receptors. More recently, in late 2023, the FDA updated pimavanserin’s packaging label to clarify that the medication may be used for patients with PD psychosis with or without dementia.⁷

According to a published meta-analysis of 19 unique studies assessing antipsychotics in patients with PD psychosis, results showed that pimavanserin (standardized mean differences [SMD], –4.81; 95% CI, –5.39 to –4.24) and clozapine (SMD, –4.25; 95% CI, –5.24 to –3.26) showed the most significant ability to improve symptoms relative to placebo.⁸ Despite the data, cost and questions about its long-term efficacy have deterred some from using pimavanserin.

"As the disease progresses, pimavanserin just can’t hold that psychosis,” Ospina said. "Eventually it gets to a point where now there’s more trouble at night and we haven’t been able to mitigate their symptoms by either reducing their other medicines like amantadine or Mirapex, that sort of thing. At that point, we either add quetiapine or switch them to quetiapine, where we can go up to 300 mg and treat them before we start talking about adding another person to the caregiver."

Serotonergic agents like pimavanserin have gained considerable attention as candidate drug treatments for hallucinations, as they offer an alternative approach that is not mediated via direct antagonism of dopamine D2/3 receptors. Ondansetron, an alternative serotonergic agent that showed promise in treating visual hallucinations in PD in the early 1990s, was being investigated in the TOP HAT trial; however, the study was closed early in April of this year after a Data Monitoring and Ethics Committee found greater safety concerns with the agent than placebo.⁹

Promise on the Horizon

The clinical pipeline for PD remains quite fluid, with 139 clinical trials for drug therapies currently registered as of 2023. Of these, 55% (n = 76) were considered symptomatic treatments and 45% (n = 63) were designated disease-modifying. Similar to previous years, approximately one-third of the studies were in phase 1 (n = 47; 34%), half (n = 72; 52%) were in phase 2, and 20 (14%) were in phase 3. Novel therapies again represented the most dominant group of experimental treatments, with 58 (42%) trials testing new agents.¹⁰

In terms of symptomatic therapies in development, there are 15 (19.7%) trials focused on motor and nonmotor symptoms of the disease, slightly less than the amount for motor symptoms (n = 22; 29%). There are 6 trials for agents targeting cognition, 5 for gait and balance, 4 for depression, 1 for constipation, and 1 for psychosis. In addition, there are 4 studies investigating neurotrophic factors: sargramostim, talineurin, ATH-1017, and an adeno-associated vector-driven GDNF gene therapy agent.

Enterin’s ENT-01, a positively charged molecule, is currently in development as a treatment of various nonmotor symptoms of PD, including psychosis, dementia, and potentially constipation. It’s designed to enter enteric nerve cells and electrostatically displaces exiting alpha-synuclein aggregates bound to the inner membrane. In a 2022 study, patients with PD with constipation saw weekly complete spontaneous bowel movements (SBMs) per week increase from 0.7 to 3.2 while on treatment in comparison to increases of 0.7 to 1.2 in the placebo group (P <.001). Patients on the drug also saw improvement in other secondary outcomes, including SBMs (P = .002), stool consistency (P <.001), ease of passage (P = .006), and laxative use (P = .041).¹¹

As the research and understanding of both motor and nonmotor symptoms improves, several in the field believe disease-modifying types of treatments will soon be on the horizon. There are currently a number of levodopa-based agents and investigational pumps that are nearing potential approval, with others on the way. Overall, the diversity of therapeutic options being explored in terms of differing targets, mechanisms, and drug delivery systems presents promise for those living with PD.