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More on asymptomatic carriers and bad modeling by the POTUS

In a recent MPDN post about asymptomatic carriers  of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19 I noted that these people can be infected and infect others without ever knowing they are ill.  This is particularly concerning because we have not had enough testing in the state (or the country for that matter) to know the incidence of these cases.   It is also concerning because we are opening up businesses and many people do not take the most basic precautions to protect themselves and others, such as wearing a mask in public or practicing physical distancing.  We are also seeing an influx of tourists in our state and have no way of knowing who has actually been tested or quarantined.  Finally, there have been a variety of gatherings around the state and the country, such as the heavily televised campaign rally for the POTUS yesterday, in which masks were worn by very few, voices were loud, and people were crowded at an indoor location; conditions near ideal for spread from asymptomatic carriers. 

This past week a scientific letter published in Nature Medicine about asymptomatic carriers raised more concerns about COVID-19 that have a lot of bearing on all of this.  The cases were detected by the Chinese Wanzhou District Centers for Disease Control and Prevention (CDC), which conducted RT–PCR tests on 2,088 “close contacts under quarantine.” None of these people had symptoms in the two weeks prior to testing.  This is especially relevant because in the U.S. the standard is to have people who have had a close contact with a sick person go into isolation for two weeks.  If they develop no symptoms, they come out of isolation.  In this study, a positive test was detected in 178 patients.  All 178 were hospitalized and a variety of tests were conducted.  All patients were followed for several weeks.  Among these 178 cases, 37 (20.8%) remained asymptomatic.  Within the 37 asymptomatic cases, the average age was 41 years, and 22 were female. 

A younger average age is an interesting feature that might speak to the fact that younger people seem to do better with the virus if exposed.  However, that might also lead people to a false sense of security.  First, not all young people do so well.  Many younger people (including children) with COVID-19 in our country have died or suffered a variety of serious illnesses. Second, these people might spread disease, even if they are not so sick.  If one person infects two other people, and those two people infect two other people, it doesn’t take long for infection to grow to huge numbers.  For another example of exponential growth, see this post.

It is important to understand a little about how the testing was done to understand a couple other concerns.  Recall that polymerase chain reaction (PCR) is a test for genetic material.  PCR looks for the genetic material of the organism when the COVID-19 test is done, and in that case the only way for one to have a positive test is if the organism is present (an infection).  In this study, the amount of genetic material found in the 37 asymptomatic cases was compared against symptomatic cases and found to be the same. Similar to the prior post on asymptomatic cases, this tells us that viral shedding, or the amount of virus being emitted is probably about the same between symptomatic an asymptomatic people.  (footnote)

The authors also reported that asymptomatic carriers were found to shed virus for a period of time longer than people with symptomatic disease.  The average duration of viral shedding among these “silent spreaders” was 19 days, with a range of 15-26 days (versus an average of 14 days among symptomatic patients).  This longer duration may be related to another finding in the study, that asymptomatic carriers in this report had a less robust immune response than people with symptomatic disease.  This concept fits with the idea that much of the damage done to the body with severe cases is thought to be caused by an infected person’s own immune response. In other words, a person with a strong immune response to the virus might wind up severely ill, and if they survive, stop shedding virus faster than a person with a weaker immune response and fewer neutralizing antibodies.  Also, asymptomatic people in the report had  lower levels of pro- and anti-inflammatory cytokines.  The so-called “cytokine storm” is implicated in progression to severe disease in symptomatic cases. 

However, the longer duration of positive testing could have another meaning.  Again, a positive PCR test means genetic material is present, but does not necessarily imply viral infectivity is still possible.  It could be that after one has stopped being infectious a test could remain positive for a few days due to viral debris.  It is known in many other viral infections that the immune system can neutralize viruses by damaging the outer envelope or aggregating virus particles.  These acts prevent infection but do not destroy the nucleic acid, which degrades slowly over time.  One example is measles virus RNA, which can be detected for up to 8 weeks after the clearance of infectious virus.  As an analogy, if you thought there was a nest of hornets in your attic, and you had a test that picked up hornets, it might not distinguish between live hornets and the ones left behind after fogging the attic with hornet spray.  It would take a while for the hornets to disintegrate. 

Whatever the case, asymptomatic carriers reproduce and spread virus.  Being in the presence of someone who is slowly emitting virus by talking or breathing is much less risky if that person is wearing a mask.  It is also less risky if the encounter is kept brief, if you are wearing a mask also, and if are physically distanced at least 6 feet.  Indoor environments are less dangerous if air is being circulated away from you to the outside (windows open, air exchangers, or negative pressure rooms). 

So let’s close with a few words from the president yesterday.  To paraphrase, he stated he had asked for COVID-19 is a “flu,” that testing to be slowed down in this country, because if you test, you find cases.  He made a point that some cases are mild and should not have been counted.  He stated that he had probably saved hundreds of thousands of lives by acting as quickly as he did.   He was wrong on all counts, and several more I haven’t mentioned. What he said about COVID-19 so clearly illuminated his indifference to science and experts, failure to read daily briefings, inability to grasp or accept simple medical facts, and failure to lead in a health crisis.  What he had to say, and the very fact that he brought so many people from all over the country together for an indoor rally where masks were not required, and where people who had to sign a waver stating they would not hold him liable if they caught COVID-19, was dangerous, and sent a very bad message about public health and his lack of concern for the wellbeing of even his own supporters.  This came even after the deaths over 120,000 Americans during this pandemic, a number which is still growing.   

We need a lot more testing to understand the incidence of asymptomatic cases, for contact tracing, isolation, and public health.  We need leaders who, if they don’t understand what is going on, at least listen to experts, take their recommendations, and model the behavior in those recommendations. This comment is not about politics. It is about common sense and public health. 

Until we have a vaccine or some reasonable intervention comes along we need to wear masks, practice physical distancing, wash our hands, stop touching our faces (unless the hands and the face are clean).  Stay well, and follow the advice of the Maine CDC.

FOOTNOTE:  We should note of course that coughing and sneezing emit huge numbers compared with talking or simple breathing.  Still, the point is important, asymptomatic people can shed a lot of viral particles, and infect others.

Should you wear a mask or face cover in public?

As we have previously discussed here, the CDC in Atlanta has recommended that people wear a cloth face cover when out in public (see footnote). A face cover is not meant to substitute for social distancing, and the recommendation that people remain at least 6 feet apart remains.  Because so many people still don’t seem to understand the reason for wearing a face covering, I will go over that here. Specifically, I am trying to address people who believe they are not infected, don’t think there are sick people around them, and therefore think they don’t need to wear a mask in public.  

The point of wearing a face cover or mask in public or around others who are not close contacts in the home is to limit the spread of SARS-CoV-2, the virus that causes COVID-19.  To date this disease has claimed over 115,000 lives in the U.S., where there have been over 2 million cases (over a quarter of cases worldwide).   

How a face covering prevents the spread of COVID-19 is simple.  It is a barrier.  We need that because  even healthy people release moisture in the form of respiratory droplets when they breathe or talk. Some people release more droplets than others – loud talkers for example.  We usually can’t see these droplets because they are so small, from 0.1 to 1000 μm (a micrometer is a millionth of a meter).  These tiny droplets tend to fly a certain distance before falling to the ground or some other target – hence the 6 foot rule.   Droplets <5 μm can form aerosols and hang in the air. The droplets and aerosol may contain viral particles if a person is infected.

To be clear, although a mask or face covering is a barrier, it still does not stop all droplets. This should not lead one to think masks are useless (as I have also heard several times).   We are not likely to get an infection unless we inhale or otherwise become infected with a certain number of virus particles, (likely a number in the 1000s).  The point of the mask is to limit the number of particles released.  It also probably helps limit the number you might breathe in, or at least block a few droplets flying at you. 

Now, back to those who think they are healthy, and don’t see sick people around them.  I hope they are all healthy, but the truth is there are asymptomatic carriers of this infection who can spread disease and not know they are infected. As I previously discussed here, if someone is infected with the virus that causes COVID-19, it can be up to 14 days before they show symptoms (the average time to symptoms is 5 days).  However, they often start shedding virus in as little as 2 days.  Thus, they are “presymptomatic,” spreading disease, and don’t know they are ill anywhere from 3-12 days.  And, there are those who become infected, shed virus, and never develop symptoms. Wearing a mask would at least limit their ability to unknowingly make someone else sick.

Unless you have just been tested, you don’t know whether you are infected.  You can’t tell just by looking at someone if they are infected either. Thus, the only thing we can recommend for now is that you wear a mask or face covering to prevent the spread of disease.  It tells others that you care about their well-being. 

FOOTNOTE:  The CDC recommendation regarding wearing a cloth face covering in public was for everyone except children under age 2, anyone who has trouble breathing, or is unconscious, incapacitated or otherwise unable to remove the mask without assistance.

To put on a face covering, grip the cover by the draw strings or elastic material used over the ears. It is okay to adjust to tightness around the nose, but try not to touch the material through which you will breathe. In general, try to limit touching the mask while wearing, and if you do so, use clean hands. If you accidentally touch your mask while wearing, clean your hands. Keep in mind that any cloth face cover should be washed regularly, depending on use. It follows then that any material you select should be capable of being laundered and machine dried without damage or change to shape.

There are different types of masks and facial coverings. The CDC recommends a cloth face covering for non-medical people. This should be made of cloth such as old T-shirt or a bandana. Paper surgical masks are worn by health care workers. Typically, the colored side goes out (somewhat waterproof to stop droplets from the outside), and the light side to your face (absorbent to to trap your own droplets), and the piece over the nose bends to conform to the bridge of the nose. Doctors wear these to prevent getting respiratory droplets on patients, but also to protect against droplets or other fluids. N95 masks are specialized respirators that filter particulates (95% of small particles). Wearers must be fitted, and the respirator does not work well (if at all) over a beard. Masks with one-way valves that make it easier for the wearer to exhale do not filter and do not prevent the wearer from spreading the virus-defeating the purpose of the CDC recommendation.

Wash your hands!

R.E.M. Behavior Disorder

R.E.M. Behavior Disorder (RBD) is a common issue in Parkinson disease (PD), affecting at least 40% of patients (1), and may occur at any time in disease, though most commonly seen years before motor signs of tremor, stiffness (rigidity), or slowness (bradykinesia). A part of the three highly prognostic non-motor symptoms of PD – symptoms that might indicate a person is going to develop the disease, RBD is often experienced with a loss of sense of smell (hyposmia), and/or constipation (2). If one has all three of these issues without a clear explanation, the likelihood that PD will develop is high.

RBD symptoms can range from mild to severe, with behaviors characterized by sometimes aggressive or violent activity during dreams, usually in the second half of the night. People with RBD may act out dreams, writhe, twist, shout, appear to be awake or hallucinating. Sleeping bed partners may be punched, kicked, even choked by an affected person. Bed partners who try to wake an affected person may sometimes become incorporated in the dream, though my anecdotal understanding is that most patients can actually be awakened or redirected. And, usually the affected person has no recollection of the dream the next day, though those that do describe very vivid dreams. Obviously, RBD is disruptive for sleep and normal rest. RBD should not be confused with the nightmares seen in people with post-traumatic stress disorder (PTSD), night terrors, other spells seen in narcolepsy, or other parasomnias (abnormal behavior during sleep).

Though common to PD, RBD is not exclusive to this condition alone. In other words, having RBD does not guarantee a diagnosis of PD. In the general population the incidence of RBD is probably about 0.5% (3), though it is difficult to know because not everyone reports abnormal sleep behaviors, and many people who have RBD are unaware of their own symptoms. It does seem in the literature that most cases of RBD occur in people who either have, or will develop neurologic diseases. However, in some cases isolate RBD simply runs in a family, and in others it appears to be sporadic, affecting only one person. RBD can be seen in people with Lewy body dementia (LBD) or multiple system atrophy (MSA), and seems to occur in all synucleinopathies (diseases with abnormal accumulation of alpha-synuclein). RBD may rarely be seen in other neurodegenerative diseases.

In the case of PD, RBD corresponds with Braak stage II (4). This means that Lewy bodies, the pathologic hallmark of PD, have spread to a part of the brainstem called the pons, and have begun to affect control of sleep (footnote).

Under normal circumstances sleep occurs in five stages. Light sleep, or stage I, is when one first drifts into sleep and can easily be awakened because they are almost conscious. Most people do this when they doze on the couch watching a mid afternoon movie or a weekend ballgame for example. People awakened from this stage of sleep are generally very clear and quick to reorient to the world around them, easily able to say, “I guess I was asleep.” They can quickly wake and interact with others. Stage II sleep is a little bit deeper, and these people are a little harder to wake, and a little slower getting started if awakened. Stage III sleep is deeper and characterized by slowing of some of the background brain waves, which neurologists can see on an electroencephalogram (EEG, one of the tools a neurologist or sleep medicine expert might use to diagnose RBD). If awakened, these people might have trouble orienting for a few seconds. Stage IV sleep is when greater than half of the brain waves have slowed significantly, and the person is very deeply asleep, and very difficult to awaken. The classic example is illustrated by the teenager. Because teens frequently spend more time in stage IV sleep around the time we expect them to get up and get ready for school, they are sometimes very hard to wake, and very slow to get started, (and very grumpy, sorry mom). Finally, the deepest is stage V, when R.E.M. sleep occurs, (rapid eye movement sleep). During dreams the eyes dart back and forth beneath closed lids. However, under normal conditions, during this stage arms and legs are flaccid: no muscle tone, and unable to move. This is a unique time in the 24-hour cycle, because at all other times there is a baseline tone in “skeletal” muscles akin to the idle speed of an engine. During R.E.M. sleep the flaccid, non-moving limb has some advantages. Think for example, of the benefit of not making a lot of noisy movement in sleep, and how that might have protected our ancestors from the very good ears of a hungry saber-tooth tiger.

When one has RBD, sleep architecture is abnormal. A person may be in light stage I sleep and simultaneously begin to dream (stage V). One problem with this is that they may have normal muscle tone, and be quite capable of acting out dreams. As above, the dreams are often quite vivid, meaning that they seem real and feel like wakefulness. The content of the dreams is often nightmarish, or terrifying. There are frequent themes of being attacked or pursued.

There is only one FDA approved drug for RBD: clonazepam (Klonopin). The drug does help reduce some of the activity of dreams but may not have any effect on the vivid dreaming itself. In low doses that is generally helpful and tolerated. The problem with this drug is that it is a benzodiazepine, a sedative/hypnotic drug which is potentially habit-forming (addictive). The drug can also be dangerous, or even deadly if taken in high doses. There are many possible side effects of clonazepam, such as sedation, confusion, respiratory depression (trouble breathing). Further, in recent years federal government agencies including the FDA have issued many warnings about controlled substances. The state of Maine requires doctors to check the prescription monitoring program for prescription history of a patient prior to writing a prescription for the drugs. Patients are also required to sign a controlled substance agreement with the prescribing physician.

Limited studies have shown benefit with the over-the-counter supplement melatonin. It is yet to be definitively established whether or not melatonin supplementation is a good treatment for RBD-though anecdotally I have often heard of good results. Melatonin is often considered by patients to be a much safer intervention than clonazepam. This is probably true. Melatonin is a neurotransmitter produced by a part of the brain called the pineal gland. It helps to regulate the sleep-wake cycle, the circadian rhythm. Melatonin does not by itself make one drowsy but causes a sort of chain reaction which leads to sleepiness, and hopefully progression into the normal stages of sleep. Another issue with melatonin is that in spite of the fact that it is a neurotransmitter, it is considered a supplement. Supplements are not regulated by the FDA, and there have been many cases of supplements containing impurities, some even toxic. There have also been cases of supplements containing concentrations very different from what is listed on the bottle. If one is to use a supplement it is important to make sure that the company has verified through an independent testing lab that what is written on the label reflects what is contained in the bottle.

Finally, sometimes RBD is fairly benign and manifested only by disruption of a bed partner’s sleep. A simple solution is to sleep in different rooms if possible. In some cases padded bed rails to prevent falls or injury are a good idea. Some patients will move the mattress to the floor. It is also generally a good idea to avoid stimulants late in the evening. Alcohol and high doses of dopaminergic drugs used to treat the motor symptoms of PD should generally be avoided late in the evening; discuss with your doctor. In fact, one should review all meds with a doctor, as some, including antidepressants, may worsen or trigger RBD.

Footnote: The issues Lewy bodies and misfolded alpha-synuclein are addressed in multiple other articles in MPDN. For more, use the search bar for these terms.

References

  1. Zhang, et al. Prevalence of rapid eye movement sleep behavior disorder (RBD) in Parkinson’s disease: a meta and meta-regression analysis. Neurol Sci. 2017 Jan;38(1):163-170.
  2. Reichman, H. Premotor Diagnosis of Parkinson’s Disease. Neurosci. Bull. 2017, 33(5):526–534.
  3. Ohayon MM, Caulet M, Priest RG. Violent behavior during sleep. J Clin Psychiatry 1997; 58: 369–76.
  4. Braak H. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 2003;24:197.

Inhaled levodopa (Inbrija) approved by the FDA.

The FDA has approved inhaled levodopa (Inbrija), indicated for the intermittent treatment of OFF episodes in patients with Parkinson’s disease who are treated with carbidopa/levodopa. Inbrija is therefore a “rescue drug,” not meant to replace oral levodopa, but to be given when it is failing. Acorda Therapeutics, who owns the patent to this drug, projects Inbrija will be on pharmacy shelves in the first quarter of 2019. As yet, the cost of Inbrija is not being disclosed. For a summary of the study data leading to approval, see the Spring MPDN article “Pipeline drugs, part I: levodopa.”

Per the prescribing information of Inbrija, dosing will allow a patient to inhale the contents of two 42 mg capsules as needed for OFF symptoms, up to 5 times daily. Inbrija capsules are not meant to be swallowed. The maximum dose per OFF period is 84 mg, and the maximum recommended daily dosage of is 420 mg.

In summary of potential side effects seen in studies: in the phase II safety trial, among the 43 people who used the drug, the most frequently reported adverse events were dizziness, cough, and nausea, (each seen in 3 patients). In the phase III clinical/efficacy trial 339 participants were randomized to 84 mg, 60 mg, or placebo, and were allowed to self-administer treatment up to five times daily for 12 weeks. In the 84 mg dose group nausea was reported in 5.3% (2.7% with placebo), cough in 15% (1.8% with placebo), upper respiratory tract infection in 6% (2.7% with placebo).   When cough was reported, it was “typically mild and reported once per participant during the course of treatment.” Three people discontinued the study due to cough.

The manufacturer recommends doctors monitor patients on MAO-B inhibitors for orthostatic hypotension, and dopamine D2 antagonists, isoniazid, and iron salts, which may reduce the effectiveness of Inbrija.

Inbrija is contraindicated in patients currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine) or who have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently.

Some serious warnings are listed with the drug prescribing information, and these represent potential problems with using the drug:

sleep attack: falling asleep during activities of daily living, a rare side effect which can be seen in patients taking dopaminergic drugs

withdrawal-emergent hyperpyrexia and confusion: a very rare condition which may occcur with sudden discontinuation or rapid dose reduction of dopaminergic medications

hallucinations/ exacerbation of psychosis: patients with a
major psychotic disorder should not be treated with this drug

impulse control disorders:   see the article in MPDN last winter on ICD in PD

dyskinesia: may be triggered or exacerbated

asthma, COPD, or other chronic underlying lung disease: not recommended in patients with these conditions

Portland Area Atypical Parkinson’s Support Group

by Janet Edmunson

Occasionally, someone originally diagnosed with Parkinson’s may later have the diagnosis changed to one of the atypical Parkinsonian disorders.  These include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA) and Lewy Body Dementia (LBD).  While each of these have some movement and non-movement symptoms similar to Parkinson’s disease (PD), they also have other distinctive symptoms that are difficult to manage and deal with for the person affected and the caregiver.  In addition, PSP, CBD and MSA progress much more quickly than PD and LBD. 

Since their needs are unique, Barby Johnson and I started an atypical Parkinson’s support group here in Maine over 10 years ago.  Barby’s husband died of PSP and mine of CBD. 

Our group meets four times a year in Falmouth on Sundays from 1 p.m. to 3 p.m.  During the meeting we usually go around the room and allow every family to discuss what’s been happening since the last meeting and bring up any issues and concerns they are facing.  The group has a positive attitude and addresses issues in a supportive, uplifting way. 

If you are dealing with one of these diseases, we’d love to have you join us.  You can email or call us to get information on the dates of our upcoming meetings as well as directions to our meeting location in the MaineHealth Learning Center at 5 Bucknam Road in Falmouth. 

–Janet Edmunson (207) 799-4963 or janet@janetedmunson.com

–Barby Johnson (207) 633-0881