The pipeline for Parkinson’s disease (PD) medications is extremely crowded these days, with multiple medications at various stages of research and development. Currently most of the approved medications for PD address the motor symptoms of PD – tremor, slowness, stiffness, and walking difficulties. Medications are also available to help people overcome OFF time or improve dyskinesias.
Clinical Trials for Non-Motor Symptoms of PD
One of the major unmet needs in PD treatment is therapies for non-motor symptoms (such as cognitive issues, psychosis, constipation and others) as these can have a significant effect on daily quality of life for both the person living with PD and their care partner. Therefore, it is particularly exciting to witness compounds being studied in clinical trials for these symptoms. Many of the currently active clinical trials for non-motor symptoms involve studying medications that are already approved for other diseases or uses, in hopes of determining if the medication also works for a particular symptom in the context of PD. Although these trials are crucial, this blog will focus on clinical trials of newly developed compounds aimed to specifically treat non-motor symptoms in PD.
If you are interested in getting involved in a clinical trial, Clinicaltrials.gov is a website that you should know about. It is a database of all clinical trials for all diseases worldwide. When a clinical trial is registered with the site, it is assigned a unique number called the National Clinical Trial (NCT) number. I will be referring to these numbers as I outline the clinical trials that are being conducted for newly developed compounds for non-motor symptoms of Parkinson’s disease so that you can learn more about them if you’re interested in participating in the trial.
Treating Non-Motor Symptoms of Parkinson’s Disease
Treatment of cognitive difficulties in PD is a major unmet need. There is only one medication approved for PD dementia, called rivastigmine, and its effects are mild. Research efforts are focused on trying to develop new therapies to improve this symptom.
SAGE-718 is an NMDA receptor positive allosteric modulator, a molecule that enhances the activity of the NMDA receptor. It is currently being studied in a Phase 2 open label trial (meaning that everyone receives the active compound and no one receives a placebo) for people with PD and mild cognitive impairment (NCT04476017). In order to be considered for the trial, participants must have a Montreal cognitive assessment (MoCA) of 20-25 (a range of scores meant to target people with mild cognitive impairment.)
This molecule has previously been tested in Phase I clinical trials, in both healthy people and people with Huntington’s disease (HD). Healthy people were given a molecule that blocks the NMDA receptor before administration of SAGE-718 or placebo. Those receiving SAGE-718 showed a statistically significant improvement of measures of working memory and complex problem solving. The molecule was also tested in six people with HD, a neurodegenerative condition that often results in dementia and although is very distinct from PD, does share some of its features. This study was open label (no placebo group). Participants
Today I will address the potential link between Parkinson’s disease and a common neurologic condition called peripheral neuropathy. This topic was submitted via the Suggest a Topic portal. I am grateful for your suggestions so please continue to let us know what you’d like to learn more about!
In order to understand what peripheral neuropathy is and what symptoms it can cause, we will briefly review the components of the nervous system.
Central nervous system vs. peripheral nervous system
Neurologic control of the body is very broadly divided into two systems – the central nervous system which consists of the brain and the spinal cord – and the peripheral nervous system which consists of the network of nerves that are outside the brain and spinal cord, and innervate the limbs and the organs of the body.
The peripheral nervous system is composed of three types of nerves: autonomic nerves, sensory nerves and motor nerves. Different types of nerves have varying diameters and are generally divided into those that are small and those that are large.
Autonomic nerves exert control over functions that are not under conscious direction such as respiration, heart function, blood pressure, digestion, urination, sexual function, pupillary response, and much more. This information is conveyed on small fibers.
Motor nerves carry information on limb movement from the brain and spinal cord to the limbs. This information is conveyed on large fibers.
Sensory nerves carry information on the various sensations felt by the limb to the brain and spinal cord. There are two main types of sensory nerves:
Pain and temperature fibers which are small fibers
Vibration and joint position sense fibers which are large fibers
The peripheral nervous system and Parkinson’s disease
It is well-established that the autonomic nervous system can be significantly affected in PD causing symptoms such as constipation, urinary dysfunction and orthostatic hypotension. The autonomic nerves that bring signals to the gut for example, can be directly affected by Lewy body-like accumulations and neurodegeneration. (This is not the only way that automatic functions of the body are affected in PD however. There can also be Lewy bodies and neurodegeneration in the parts of the brain that control these functions.)
What remains unclear is if motor and sensory nerves are also affected in PD.
What is peripheral neuropathy?
Peripheral neuropathy (PN) is a condition in which there is damage to peripheral nerves. Symptoms depend on which type of nerves are affected and can result in:
Imbalance with walking
Pain or paresthesias (sensations such as burning or tingling) in the limbs
The legs are more commonly affected than the arms because the nerves to the legs are longer than the arms and therefore more prone to damage.
Symptoms of peripheral neuropathy
The symptoms of PN can be non-specific, and a person therefore may not be able to distinguish on their own whether his/her symptoms are due to PN or another condition. PN, however, often results in specific findings on a neurologic exam, such as decreased sensation to pin prick or vibration or the lack of ability to discern which way a toe is being pointed without looking.
I’m so thankful to those of you who submit potential topics for my blog as it helps me understand what you would like to know more about. A frequent topic that I am asked about is symptoms of Parkinson’s disease (PD) that are caused by medications. So today, I will address drug-induced parkinsonism.
Common symptoms of drug-induced parkinsonism
The motor features of PD are often (but not always) very easy to see via a neurologic exam in a doctor’s office. Rest tremor (which is a tremor that goes away with movement, but often returns when the limb is at rest) for example, is seen in virtually no other illness and can therefore be very important in diagnosing PD. But there is one other common condition that induces the symptoms of PD, including a rest tremor, which must be considered every time PD is being considered as a diagnosis, and that is drug-induced parkinsonism.
Parkinsonism is not technically a diagnosis, but rather a set of symptoms including slowness, stiffness, rest tremor, and problems with walking and balance. This set of symptoms can be caused by PD, but also can occur as a side effect of certain prescription medications (that have nothing to do with PD).
A number of medications can cause parkinsonism because they block the dopamine receptor and thereby mimic the symptoms of PD that are caused by loss of dopamine neurons in the brain. Reviewing a patient’s medications is therefore a critical step for a neurologist when seeing someone with parkinsonism. Anti-psychotics and anti-nausea treatments make up the bulk of the problematic medications, although there are other medications that can also cause parkinsonism. The primary treatment for this type of parkinsonism is weaning off of the offending medication, if possible.
For some people, it is not possible to stop the problematic medication. For example, some people with bipolar disorder or schizophrenia have tried multiple medications to control their mental health issues and the one that works best also causes parkinsonism. In these difficult situations, some amount of parkinsonism might be tolerated in order to maximize the person’s mental health. This is a tricky clinical situation, and one that typically requires the psychiatrist and neurologist to work together to optimize the circumstances.
The connection between PD and drug-induced parkinsonism
In addition to potentially causing parkinsonism in the general population, these medications should definitely be avoided in people who have parkinsonism from other causes, such as PD. APDA has created a list of Medications to be Avoided or Used With Caution in Parkinson’s Disease. It is important to note that there are anti-psychotics and anti-nausea medications which do not cause parkinsonism and can be used safely by people with PD.
Sometimes, a person without a diagnosis of PD is prescribed a medication which leads to a side effect of drug-induced parkinsonism. The prescribing physician may stop the new medication, but the parkinsonism does not resolve. The patient remains off the medication with continuing symptoms, and eventually is given a diagnosis of PD. In this scenario, that person most likely had dopamine depletion in the brain (prior
Atypical parkinsonian syndromes
Progressive Supranuclear Palsy and Corticobasal Degeneration
As part of our Planning for the What Ifs series, today we expand the definition of advanced Parkinson’s disease (PD) by discussing atypical parkinsonian syndromes (APS), neurodegenerative disorders that are related to PD. Our guest author, Dr. Pravin Khemani, a Movement disorders neurologist at Swedish Medical Center in Seattle and Medical Director of the APDA Northwest Chapter, will discuss two of these disorders – progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).
PSP and CBD can mimic each other and can also mimic PD early in the clinical course, so it can be confusing and difficult to diagnose. As the diseases progress however, they produce clinical signs and symptoms which assist in their distinction as separate neurodegenerative disorders. Because there can be a significant overlap between PSP and CBD, it makes sense to discuss them together. Both diseases are caused by abnormal deposition and spread of misfolded tau protein in the brain. Hence, they are referred to as tauopathies.
CBD is less common than PSP, and both are significantly less common than PD. Based on one recent study, the combined number of new cases of PSP and CBD per 100,000 people per year was between 3 and 5. Based on these results, PD is about 5 times more common than these two diseases combined. However these diseases are still seen relatively frequently in Movement disorders clinics and many of our readers are grappling with these conditions.
Progressive supranuclear palsy (PSP):
Since its recognition as a distinct neurodegenerative disorder in 1964, PSP has undergone more than one reorganization into various subtypes based on the increased recognition of its clinical symptoms. In PSP, the distribution of tau protein in specific brain regions is associated with progressive death of neurons which causes clinical signs and symptoms unique to this disorder. The most recent consensus classifies PSP into several clinical subtypes (Table 1). However, the following four primary clinical signs are key features in a majority of cases, although they may not be present all at once in every patient:
Eye movement abnormalities
These are detected by a careful examination which can reveal difficulty shifting the eyes down when not moving the head. Patients may also complain of difficulty walking downstairs, double vision, blurred vision or light sensitivity, and frequent involuntary blinking or forceful closure of eyelids (or blepharospasm).
Early in the disease course when turning, starting to walk or changing position; falls can occur in any direction, but falling backwards is suspicious for PSP.
A feature of PD which can be presented with slowness on one or both sides of the body, soft speech, reduced expression, and stiffness. However, a classic PD rest tremor is uncommon in PSP, and mobility does not show long-term improvement with Levodopa.
Behavioral, speech and cognitive problems early in the course:
impulsive and socially inappropriate behavior
apathy which can be misconstrued as indifference or lack of compassion
inflexibility of thought
laughing or crying out of context (also known as pseudobulbar affect)
difficulty following the steps in a task
stuttering speech with words running into each
Restless Legs Syndrome (RLS) is a neurologic and sleep-related condition characterized by an irresistible urge to move the legs. The symptoms respond to dopaminergic medications such as dopamine agonists or levodopa, which are also used to treat Parkinson’s disease (PD), making an association between RLS and PD likely. Here we explore RLS and its potential connections with PD. This post was adapted from content originally written by Dr. J Steven Poceta, neurologist and sleep medicine specialist.
What is Restless Leg Syndrome (RLS)?
Characteristics of Restless Leg Syndrome
There are certain features of RLS that make it a unique and specific disorder.
- The hallmark of RLS is a feeling of restlessness, usually in the legs. The restlessness is often accompanied by additional sensations such as tingling, “creepy-crawly” or electric sensations, usually located in the legs. The symptoms are usually not restricted to the toes or feet, as in peripheral neuropathy, but rather are present more generally in the legs, often the calves or thighs.
- The restlessness is worse when the person is at rest or not moving. This feature makes it hard for people with RLS to get to sleep and can also interfere with the ability to sit still in order to read, relax, or do desk work.
- Symptoms are improved with moving, particularly walking. Unfortunately, the relief lasts only as long as the movement continues, which makes some people “pace the floor” for hours when the condition is severe. Besides walking, sometimes providing other stimuli to the legs is helpful, such as rubbing, massage, or stretching.
- RLS symptoms usually occur in the evening and night and are absent in the daytime. This is the reason that RLS is considered a sleep disorder. If the symptoms are present in the daytime, the intensity of the sensations are usually less than in the evening and night. Most people with the condition have the onset of the feeling in the hours after dinner and before bedtime. The restlessness might impede the onset of sleep or cause the person to wake up frequently, but usually the restlessness goes away during the latter portion of the night and is gone by morning. RLS can cause significant sleep deprivation and anxiety related to trying to fall asleep — and poor sleep can have significant ramifications on health and wellbeing.
- RLS can be accompanied by a related disorder called Periodic Limb Movements of Sleep (PLMS) which are repetitive leg movements that occur during sleep.
Causes of Restless Leg Syndrome
- Although the cause of RLS in many people remains unknown, about half of people with RLS have a family history of the condition. Despite this, no specific gene has been identified.
- RLS can also be secondary to other medical conditions such as iron deficiency, neuropathy and renal failure.
Parkinson’s & Restless Leg Syndrome: Using Dopaminergic Medication
Because RLS is well-treated by medications that also treat PD, it is likely that some aspect of brain dopamine function is altered in RLS. However, unlike in PD, in which the deficit in substantia nigra dopamine-producing cells can be proven in many ways, no such abnormality has been shown in RLS. For example, studies show that DaTscan results are not abnormal in RLS.
Using dopaminergic medications to treat RLS however can be tricky. In some people they can lead to a phenomenon known as augmentation, in which long term use of dopaminergic medications can worsen the symptoms – making them appear earlier in the day or migrating to the upper body in addition to the legs.
Does having RLS increase the risk of developing PD?
Since RLS affects as much as 4-10% of the US adult population, it is clear that the vast majority of those with RLS do not ever develop PD.
Despite this, it still might be the case that RLS increases the risk of subsequently developing PD. There have been many studies trying to figure this out – with conflicting results. Some studies show that there is no increased risk and others show that having RLS confers about a two-fold increased risk of developing PD over the general population.
Is RLS more common in PD?
But what about the other possibility? Do patients with PD have an increased risk of RLS over the general population? Is it the same RLS as the person without PD has, or is it different? These questions have been difficult to answer. Of course, since PD affects about 1.5% of the elderly, and RLS in about 4-10% of the population, there will be some coincidental overlap. In addition to this however, patients with PD can have sensations that feel like RLS when their dose of dopamine medication is wearing off. These sensations are not truly RLS since they do not have the key features of RLS described above (more common at night, improves with movement, etc) and fluctuate with medication timing, but they can be easily confused with RLS by the person with PD.
Studies of people with PD that assess for RLS and compare to a control group are hindered by the fact that the majority of patients with significant PD are under treatment with medications that affect RLS. Over the years, there have been multiple studies investigating whether RLS is more common in PD than in the general population. Different studies come to different conclusions. Studies conducted in which a group of people with PD are directly compared to a group of people without PD (case-control study) typically show that RLS is more common in PD than the general population.
To complicate matters, some researchers of this topic explain that the experience of people with PD is not actually RLS but rather something else called leg motor restlessness (LMR). The difference between the two is that RLS is worse when the legs are not moving and temporarily relieved by movement whereas leg motor restlessness is not worse when the legs are not moving and not relieved by movement. LMR may be increased in people with PD, whereas true RLS may not be.
Treatment of RLS in PD
Regardless of the above discussion, it is clear that many people with PD have difficulty falling asleep because of annoying sensations in the legs accompanied by a sometimes unbearable sense of restlessness in the legs. For these people, taking dopamine agonists before bed can be helpful. Caution is in order, of course, because in some patients with PD, especially older or more advanced patients, these medications can cause confusion and hallucinations and are thus not well-tolerated. A long-acting levodopa formulation or medications such as gabapentin, gabapentin enacarbil and pregabalin can also be effective. Trying to address sleep issues such as RLS in patients who have sleep complaints can be an important aspect of maximizing therapy for PD.
Tips and Takeaways
- Restless leg syndrome (RLS) causes a feeling of restlessness in the evening hours, usually in the legs, when the limbs are at rest. The restlessness is relieved by movement.
- RLS is a common condition in the general population and may have an increased incidence among people with PD, but studies have been inconsistent.
- Dopamine agonists, levodopa, gabapentin, gabapentin enacarbil, and pregabalin, can be tried to help relieve RLS symptoms, but should be used with caution (as with all medications) due to potential side effects.
- Sleep disorders including RLS are very common in PD and often interfere with getting a restful night sleep. Poor sleep can have significant impacts on your health and wellbeing, so talk with your doctor about these symptoms or any symptoms that interfere with your sleep.
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