Good morning. My name is Dr. Ed Conway. I'm the Chief of Pediatric Critical Care at Jacobi Medical Center in the Bronx, and I thank the Society of Critical Care Medicine for the opportunity to deliver Part 2 of my presentation for the Pediatric Critical Care Board Review. As I had mentioned on my prior talk, I have no financial disclosures. However, I am a former question writer for the ABP for both the general PEDS exam as well as the critical care exam, and I had written questions for eight years for PICU Prep as an editorial board member. As I had mentioned in the prior talk, I'm recording this on April 1st, 2022, and the exam is not until November 3rd, giving you over 200 days to prepare. However, time flies by quickly, so here's just a little mnemonic. Once again, you forgot about another big test, and here we are at the last minute helping you cram. And again, we've sort of got the big brain and the little brain, but we'll bring everybody to an equal point in time over the next 45 minutes. And just to mention prometrics, for those of you that have not had the pleasure of taking an exam at one of these computer centers, get there early. It takes time to get checked in. Sleep well the night before. When I was taking my last exam at prometrics, the kid next to me was typing her essay for her SAT, and it was quite distracting. All right, so without further ado, let's get this lecture rolling. Here's one of several embedded questions. Question one, you're examining a patient who sustained a lower mode of neuron injury. Which of the following findings would be present? Hyperreflexia, spasticity, primitive reflexes, muscle atrophy. I'll give you a few seconds to think about it. So basically what they're asking you here is a finding on a lower motor neuron lesion in comparison to an upper motor neuron lesion. The prior talk dealt with the upper motor system in the CNS, and I'll have a slide contrasting the two coming up. So the correct answer here is muscle atrophy, lower motor neuron lesion. This diagram represents a lower motor neuron. We talk about the lower motor neuron, we think of a unit with several components. Unfortunately, I don't believe the arrow has been showing up on these recorded sessions, but we're going to start looking at the spinal cord itself with the butterfly looking inside of it. And so just to remember that you have gray matter internally and surrounded by white matter. So the anterior horn cell and the motor neuron cell body is sort of the happening place. And then we see the ventral and dorsal root ganglion go out. And if we track it down along the peripheral nerve, remember that the peripheral nerve is in sheath with myelin. We'll come back to that with some entities a little bit later. Continues down to the neuromuscular junction, you've got the synaptic cleft, and it ends up in the muscle tissue itself. And we'll talk about entities that affect the lower motor neuron, starting within the spinal cord and work our way out and down ultimately to various muscle diseases. So the question was, what would the physical finding be if you had a lower motor neuron injury? So let's start with the upper motor neuron injury. So we talk about upper motor neuron injuries. We're usually talking about the cerebral cortex and the upper spinal cord, the upper C-spine spinal cord. And those patients would have increased tone and spasticity, hyperreflexia, reemergence of primitive reflexes. Whereas the lower motor neuron that was depicted in the preceding slide that consists of the anterior horn cell going out to the peripheral nerve, down to the neuromuscular junction, and then the muscle itself, an injury anywhere along that unit would lead to plasticity, depressed or absent reflexes, fasciculations, and atrophy. And so we're going to start our study of the lower motor neuron with diseases that affect the anterior horn cell. We'll then look at diseases that affect peripheral nerve, neuromuscular junction, both pre- and post-synaptic. And finally, we'll look at some major muscle diseases that one should be familiar with. The next two slides is going to be a review of the autonomic nervous system, both the sympathetic and the parasympathetic nervous systems. These are key concepts that are tested frequently on the exam. One should be familiar with it. This first slide demonstrates the pre-ganglionic and the post-ganglionic neurotransmitters. And if we see in the sympathetic nervous system, the pre-ganglionic neurotransmitter is acetylcholine, and the post-ganglionic is norepinephrine, which affects the adrenergic receptors. The CNS sympathetic system, pre-ganglionic and pre-adrenal gland, is also acetylcholine and nicotinic receptor stimulants. And epinephrine is released directly into the blood from the adrenal gland, and also post-ganglionic adrenergic receptors. The parasympathetic nervous system, the pre-ganglionic and the post-ganglionic receptors, are all acetylcholine that can affect nicotinic, which are receptors located on smooth muscle, demonstrated on the next slide, or muscarinic, which is involving the muscles, muscle contracture and movement. And lastly, the somatic nervous system, where large neurons that go directly from the central nervous system and synapse at various skeletal muscles, again, acetylcholine is the receptor post-ganglionic. Although this slide looks daunting at first, I like it because I think it summarizes all the key concepts. And what you'll see on the left is the sympathetic nervous system, sympathetic chain, sympathetic ganglia, and again, the primary neurotransmitter will be norepinephrine. And you can see what it does to each of the organs. It causes medriasis or dilated pupils, it reduces salivary flow, it increases heart rate and stroke volume, causes vasoconstriction, thereby elevating blood pressure, reduced parasalsis and secretion, glycogen releases glucose and inhibits bladder emptying. So this is the fight or flight hormonal path here, the sympathetic. And yesterday, I gave you about a dozen extra teaching slides at the end of the talk, review Horner syndrome, guaranteed you'll see a question on the Horner syndrome and how the sympathetic chain plays a role. And on the right portion of the slide, we've got the parasympathetic nervous system. Again, the primary neurotransmitter is acetylcholine. And here you've got both nicotinic and muscarinic receptors. It stimulates salivary flow, decreases heart rate, can cause bronchoconstriction, stimulates parasalsis and secretion, and empties the bladder. So basically, the way I remember the parasympathetic is everything you want to dump out of the body that you don't need. And in a time of an emergency is another way to think of it. And again, we will go over questions and examples of different disease states that affect either the sympathetic or the parasympathetic nervous system. Since I previously mentioned that acetylcholine appears to be a very predominant neurotransmitter in both the sympathetic and parasympathetic nervous system, it's essential to understand the metabolism of acetylcholine. And basically, it's sort of made in the neuron and stored in synaptic vesicles, which are then released. There are a myriad of disease states and entities that block the release of acetylcholine. Acetylcholine is released into the synaptic junction here, and then binds to the muscle receptor, leading to muscle contraction at the nicotinic receptors. Acetylcholine, there's an enzyme in here, acetylcholinesterase, that breaks down acetylcholine, releases from the muscle, decreases the contraction, and the muscle relaxes. There are a myriad of drugs and disease states that can interfere with the enzyme and the metabolism of acetylcholine. So when the cholinesterase is in effect, acetylcholinesterase breaks it down. Acetylcholine gets reabsorbed into the neuron and gets synthesized again, stored in the synaptic cleft, and ready to be released again. Here again, I'm sharing a drawing from my hospital artist that we'll review again later in this talk. However, it's just to reemphasize that we have the preganglionic neuron, the synaptic vesicle with the neurotransmitter, predominantly acetylcholine, stored. Electric impulse releases the acetylcholine. It goes through the synaptic cleft, binds to the receptors, causes the muscle to contract, and then the acetylcholinesterase, and there's plasma cholinesterase, will break down the acetylcholine, release it from these receptors, and the muscle will relax. So now what I'd like to do is to apply the physiology that was discussed in the previous several slides. And one has to think about neuromuscular disease mostly comes to the intensivist's attention due to respiratory failure. And it can either be from respiratory muscle weakness, respiratory muscle fatigue, alterations in respiratory mechanics, you can have impairment of central nervous system control of breathing, or weakness of muscles of the airway. So to understand neuromuscular physiology, one has to be familiar with the muscles of respiration. The primary muscle of respiration for inspiration is the diaphragm. And for exhalation, we use the lateral intercostals and abdominal muscles, also important in generating a cough. And then there's the upper airway muscles, which can cause bulbar weakness where patients have trouble swallowing and handling their secretions. So again, this is one of the slides I call a bonus slide or to read on your own. It's not an eye exam that I'm prepping you for now. And it just lists the level of the lesion, where it's located, what would actually be affected, where the anomaly would have its major effect, and then it lists the respiratory abnormalities. So if you're challenged with a patient with a description of X, Y, and Z, you should be able to figure out if you think it's a spinal cord lesion, is it a brain stem or peripheral nerve? And this is just a study guide to sort of help you do that and just become familiar with this on your own time. So neuromuscular disease, the presentation of respiratory failure can occur in one of three ways. One, it can be an acute event. Examples will be Guillain-Barre, myasthenia gravis, and botulism, which we'll discuss each individually. It can be an acute decompensation superimposed on a chronically ill child. So an example would be RSV virus in a child with pre-existing neuromuscular disease, such as SMA, spinal muscle atrophy, which again, we'll discuss later in the talk. Or is it a chronic slow progressive disease with something such as Duchenne's muscular dystrophy, which will affect the respiratory system over time? The next two slides are specific for discussing respiratory muscle weakness and what all of these diseases share together to make it easier for you to understand the particular entities and help you study for the exam. So they can have a poor cough and that gives less airway clearing, and that can lead to secretion retention and atelectasis. They can have a lower vital capacity, which I'll discuss further on the next slide, but they take less sighs. A sigh is sort of what you're doing now, taking a deep breath, and going, oh my God, is this ever going to end? And that can lead to atelectasis. Atelectasis leads to pulmonary AV shunting, ultimately can lead to hypoxia. The respiratory muscle weakness can lead to lower tidal volumes and fatigue and increased work of breathing. And you put all of this together and it's a setup for the patient to suffer hypoxic respiratory arrest. I like this slide, although it's more geared for adult patients where it's easier for us to do some of these pulmonary function tests and measure, but the concepts are important to understand. So if we look at vital capacity and an ideal vital capacity being 70 cc's per kilo, what you see on the left is respiratory pathophysiology and on the right suggested ventilatory management. And what you can see is not until you get down, if 70 is the ideal cc's per kilo, not until you get down to less than half, about 30 cc's per kilo, patients start to have trouble with weak coughs and start to retain secretions. And the vent management, respiratory support would be perhaps physical therapy. As it starts to decrease below half, we get down to 25, sign mechanisms compromise, you get atelectasis. And as I showed you on the preceding slide, we'll predispose the patient to hypoxemia. This is where we try and encourage incentive spirometry. And as it goes lower, this day and age, we would probably use non-invasive attempts at non-invasive ventilation, perhaps with high flow nasal cannula, which probably won't do very much for these patients, may help with the secretions. However, the use of BiPAP can be helpful. But once you get down to 20, 15 cc's per kilo, we usually electively intubate these patients because they're going to have VQ mismatch, they're going to hypoventilate, they're going to have hypercapnia. Blood gases are not very predictive of impending respiratory failure, because if this is an acute event going on with the patient, who's kind of going down the tubes rapidly, we all know how difficult it can be on occasion to get a blood gas, we stick the patient a few times, they hyperventilate. So the gas may not be as predictive. So what we actually look for is to see what their vital capacity or their negative inspiratory force. If it's below a minus 20, we would electively intubate the patient again. And those are fair game for Pediatric Critical Care Board questions. When would you intubate the patient at what point in time? So here's a second of our embedded questions. Which area is the primary site affected by the West Nile virus? Is it area A, B, C, or D? And I'll give you a few seconds to think this out. Okay, so the correct answer here, you're quite familiar with the lower motor neuron pathway at this point in time, is the West Nile virus is area B, affects the anterior horn cell. Again, area A is the posterior horn cell, C is the peripheral myelinated nerve, and D here is muscle tissue. So West Nile virus, as well as several other entities, will affect the anterior horn cell, and we'll review those now. So the most common disease that one would have seen decades ago would be poliomyelitis. Polio virus has a predilection for the anterior horn cell, and thus leading to all the problems that can occur that we talked early on with lower motor neuron lesions with weakness, vesiculations, and atrophy. And so although this is more of a historical disease for practicing intensivists currently, it is sort of an oldie but goodie to teach pathophysiology. So as we all know, it's quite rare in the United States. The viral predilection I mentioned for the anterior horn cells, as well as cranionuclei of the brainstem, one to five week incubation, 90% of infections, however, asymptomatic or mild. Only 2% of patients have the paralytic polio. Again, and although more a historic disease, it does cause respiratory failure by directly infiltrating the breathing center, causes bulbar palsy, and increases oropharyngeal secretions. Also can get into costal paralysis. In infants, this leads to chest wall instability and retractions with diaphragmatic inspiratory motion. So again, increases the work of breathing if you think back to the triangle of respiratory failure I shared with you several slides ago. And so the question asked, where does West Nile virus cause the pathology? And again, it's at the anterior horn cell. This is just the schematic of the West Nile virus that's transmitted by mosquitoes and can be transmitted to humans and leading to the neurologic and the asymmetric weakness that these patients present with. A more recent disease that's reportable to the CDC is acute flaccid paralysis or AFP. And we know that it's caused by an enterovirus, which is a ubiquitous pathogen. It was seen in 2014 with enterovirus outbreaks of D68. And it appears for some unexplained reason in only even years. So we saw more in 2016, 2018. 2020, we didn't see as much as we're all aware we're dealing with coronavirus and COVID-19. And perhaps with everyone being indoors or for some other reason, unbeknownst to me or anyone else at this current time, we just didn't see as much of it. But we know AFP can cause respiratory infections, caused by respiratory infections, hand, foot, mouth disease, aseptic meningitis. There is a predilection again for the anterior horn cell for whatever reason that is. And these patients present with a brief febrile illness with limb weakness and cranial nerve dysfunction with a rather rapid onset. And here is the title of this brief article. One dead nine hospitalized with a rare polio-like illness at Seattle Children's. So although we may not see polio currently, there's this new one of the many, many enteroviruses that causes a polio-like illness. And it's been well described. Now that we've covered several infectious diseases that can cause problems at the anterior horn cell, now we'll talk about spinal muscle atrophy, which is the most commonly inherited neuromuscular disease in hypotonic infants. It occurs as an autosomal recessive in about 10 to 15 patients per 100,000. And it's an abnormality on chromosome five. It's caused by a homozygous deletion or mutation in the survival motor neuron, SMN1 in the gene leads to a decrease in SMN protein production. The decrease in this protein production is this protein is needed to stop the ongoing apoptosis. It allows the pathologic continuation of programmed cell death that should be turned off at some point during embryonic development. And the decrease in this protein leads to ultimate degeneration of motor neurons in the spinal cord. There are several types of spinal muscle atrophy. The most common being Werdig-Hoffmann that occurs usually in children under two years of age. And they present in the first weeks to months of life with severe hypotonia, generalized weakness, thin muscle mass, involvement of the tongue, face and jaw muscles. They tend to lie flaccid and be unable to overcome gravity. And two thirds of those patients die by age two and many prior to that in infancy. The heart is usually not involved and their diagnosis is made by a blood assay for the SMN gene. One of the fascinating things I find with spinal muscle atrophy is the application of translational medicine. When I started my career over 35 years ago, this was considered a lethal disease. I remember two painful conversations sitting with families with our neurologist, a very prominent pediatric neuromuscular expert telling the family there's nothing to do. They shouldn't shrink these patients or G2 them because they're going to pass away. And here we are 35 years later where we have gene replacement therapy showing that these patients can live longer and do much better. The question always comes up, what is it that this protein does? And intracellular, it's found to do a bunch of things involving mRNA transport, different functions inside the neuron itself, as well as being released synaptically, playing a role in actin. And we all know actin myosin is sort of important for muscle contraction. So now we actually have therapeutic options that include gene replacement. Initially, the earlier studies were via spinal taps directly into the CNS, followed by infusions. And now there are some oral therapies that are being trialed. And again, you probably won't be tested this on the boards, but I think it's worth knowing that this entity is out there. So if we look at a healthy individual and we look at the two genes that we have, SM1 and SM2 to make the proteins, the SMN1 makes the majority of that important protein. The SN2 gene makes very little of the protein. However, by translational medicine and developing and delivering through gene therapy, altering the function of the SMN2, we can produce more of the appropriate protein. And as we increase more copies of it, the SMA severity will decrease. And again, I share this slide. This is one of my favorite little patients. And he would go on BiPAP for several hours during the day and sleep on it at night. He would call it his elephant mask. And we had a whole ritual. You'll also notice that he's got a game console at his fingers because the weakness is usually the proximal musculature. So he couldn't on occasion tap it until he got tired. But this just represents where we're going in critical care, multi-center caring for these patients. And again, now that we have some therapeutic options, it's quite exciting for the families of these children. And for those of us that care for them. As we continue to work our way down the lower motor neuron grouping, the specific question here is, which of the following entities exerts its predominant pathologic effect at the site marked with the arrow? So is it Guillain-Barre, aminoglycosides, botulism, or tick paralysis? And again, I'll give you 10 or 15 seconds to think about it. ♪♪ ♪♪ Okay, so now we had tines pointing at the peripheral nerve. And if the choice is there, Guillain-Barre causes a demyelination of the myelin along the peripheral nerve going down to the musculature. Aminoglycosides exert their effect more at the neuromuscular junction. Botulism and tick paralysis, we'll talk in a little bit, actually prevent the release of acetylcholine at the vesicle, at the synaptic cleft. And we'll come back to that in a bit. What this cartoon depicts is an action potential traveling down a normal myelinated nerve above and below the demyelination that occurs in Guillain-Barre, slowing that action potential down. And we'll discuss the pathophysiology in correlation with EMG findings as well. So Guillain-Barre syndrome is a diffuse peripheral nerve demyelination and leads to ultimate motor dysfunction. The onset is usually preceded by a viral type illness, upper respiratory, or a GI bug. Particular organisms that are well studied are mycoplasma and campylobacter. However, almost any entity can sort of lead to Guillain-Barre. It's a autoimmune pathology. It usually occurs two to four weeks after the initial exposure. And the earliest sign is weakness of the lower extremities. And this is an ascending paralysis. A lot of times you'll be given a clinical scenario and asked which is most likely. Remember, Guillain-Barre starts at the legs and ascends, many of the others descend. And I'll point that out as we get to each specific entity. So again, as I mentioned, Guillain-Barre is a demyelinating disease. And what this slide depicts is what's described as molecular mimicry. And again, I don't know if the cursor is showing or not, but on the left side, we see a ganglia side, okay, which is a nerve cell membrane. And we can see one of the proteins associated with it. Below is campylobacter and the outer wall of a gram negative. We can see here that there are markers, molecular markers, on the membrane of the campylobacter. The human body immune system response to that makes antibodies to clear the campylobacter. Those antibodies are still circulating two to four weeks later, and they recognize the ganglia side because of the similarity in structure and thus becomes an autoimmune process. And the slide on the right basically depicts a monocyte and there's sort of a foot. And you can see the foot is peeling the myelin off the nerve I'm pointing to it here. Hopefully you can see it. It's under the dark black curve, which is the myelin being lifted and thus the demyelination is occurring. Other findings seen in Guillain-Barré is areflexia, a stocking glove numbness. You can see cranial nerve palsies, ataxia, urinary retention, and you'll see respiratory muscle paresis in approximately one in three patients of whom about 20% require mechanical ventilation. Guillain-Barré is diagnosed by history and physical, but usually clinical signs and symptoms. And when one does a spinal tap, you'll find an albuminocytologic disassociation, which means you'll see a very elevated CSF protein in an absence of pleocytosis. And if one does an EMG, you'll find delayed motor conduction. I refer you back to the cartoon where the orange axon potential was slowed down. And basically that's what you would see in an EMG is a slowing, and that is a content spec for us to be familiar with. One of the questions you may be asked is a disposition of a patient with Guillain-Barré, where should they be admitted? Reason for PICU admission, respiratory failure, marginal muscle reserve. If they have atelectasis and pneumonia, loss of protective reflexes, and again, they can have autonomic instability with arrhythmias and hypotension, they'd be best monitored in a PICU. So these are indications for intubation and mechanical ventilation, not just of Guillain-Barré patients, but any patient with a neuromuscular disease. So I had mentioned earlier in the talk about the forced vital capacity. Once it gets down to 15 to 20 cc's per kilo, a maximum negative inspiratory pressure of minus 20 to minus 30 would be an indication. If you have them on N-title CO2 and they're demonstrating alveolar hypoventilation with a rise in PA CO2 of 450 or above, consider intubating. If they're retaining secretions and they can't protect their airway, and when you do intubate these patients, you should avoid the polarizing neuromuscular blockers, of which the only one available in the United States is succinylcholine. Therapeutic options for patients with Guillain-Barré include gamma globulin and or plasmapheresis. They appear to be equivalent with a lot less complication seen in patients that have received gamma globulin. And on rare occasions, patients with Guillain-Barré may require a second administration of gamma globulin. Also, the therapeutic options lend themselves to be good questions because you'll get a patient with Guillain-Barré who got one or the other of these therapies and then develop a complication. So again, I refer you back to yesterday's introductory slide when you're thinking and studying about a particular entity, how to address it. Although a bit challenging, I can try and describe the EMG findings in the patient. If you look at the top two curves is acute Guillain-Barré syndrome, you'll see the top peak, the first line, crosshair line, is when the muscle, the nerve is stimulated. And you can see in the line below how much longer it takes for the action potential to reach the muscle, thus explaining the weakness. And if you look at the recovery picture below, you can see the actual height or amplitude of the recovery and the shortened latency period where stimulation leads to a rather rapid muscle contraction. Here's another sample question. And again, the best way to study is questions, questions, questions. Which of the following exerts its toxic effect postsynaptically? Is it the black widow spider? Botulism, toxic nerve agents, or tick paralysis? And again, I'll give you 10 or 15 seconds to think about it. ♪ Wouldn't it be nice if we were older ♪ ♪ And we wouldn't have to wait so long ♪ ♪ And wouldn't it be nice to live together ♪ ♪ Be in the kind of world where we belong ♪ ♪ You know it's gonna make you happy ♪ So postsynaptically, so that's after the acetylcholine has been released to the neuromuscular junction and binding to the muscle to cause a contraction. So of the choices here, and we'll discuss each of them going forward, the black widow spider, botulism, and tick paralysis all prevent release of acetylcholine to effectively bind with the muscle. Toxic nerve agents bind directly at the neuromuscular junction and cause their problems, as seen several outbreaks of sarin gas in Japan. So again, I show this slide just for clarification. So presynaptic is anything here. Postsynaptic is after the synaptic junction where they would bind to the muscle. And we'll talk about all these different entities because a lot of things can happen in these few microns here. So let's start, we'll talk with botulism. And here I show you the typical infant with the ptosis and just sort of very weak looking. We'll talk about where the toxin actually comes from. I'm sure we all have cans like this stored in our pantries in the basement, at least I know I do at my house. And it's been reported with folks who are getting Botox injection, which is always why the warnings, if you have difficulty swallowing, et cetera, after you received it, because it can accidentally be released into the vasculature. This slide just depicts that infant botulism is unusual, but it can occur in flurries. And here's the number of cases per year. And you can see in 27, 28, we had a peak. And another peak in 2013. And these sort of come and go. In New York, we saw a large increase in botulism following 9-11, when all the destroyed building materials were taken to Staten Island, as they begin to sift through them. And the spores, everything got released in the air, depending on which way the wind was blowing. We saw a market increase during that time as well. So this slide is to depict the mechanism of botulism. And here's the sort of guilty bacterium seen over here, Clostridium botulism. And what you see is the motor nerve normally releases acetylcholine, causes the muscle to contract. Here, botulism binds to the vesicles, doesn't allow the release of acetylcholine. Therefore, the muscles can't contract. And thus you see the weakness. Botulism usually spreads from the head down, which is why the droopy eyes and the slow non-responsive pupils are some of the earlier findings that we see in these patients. Here are several of the fun facts of botulism. Again, as I mentioned, it's an ocular bulbar muscle weakness, again, starting at the head and working its way down. Early findings, ptosis, blurring of vision. You also see pupillary abnormalities, slow non-responsive pupils. They can have dysarthria and dysphagia. It's a descending pattern of weakness. And then after the head, you'll see the upper limbs, lower limbs, and eventually respiratory muscles. Autonomic findings include constipation, urinary retention, pupillary abnormalities. There is an antidote for botulism that can be administered to the patient. The sooner it's administered, the better. Once the botulism toxin has bound, there's nothing we can do. You do not treat these patients with antibiotics. It will cause lysis of the organism and release of more toxin. And number two, we aggressively try and feed them. The administration of the antitoxin has shown a marked decrease in length of time, both on ventilator and admitted into the ICU in general. So again, do not treat them with antibiotics. And enteral feeds are excellent. The earlier, the better. Another challenging diagnosis to be made in pediatric patients is tick paralysis. The way the tick toxin works, it causes a problem with ACH release from the external terminals, secondary to the neurotoxin blocking depolarization and thus release of the acetylcholine from the vesicles. Usually the culprit is a wood or a dog tick, pregnant female. And in feeding, they engorge and they actually increase almost 100 fold in size when you see a fed tick versus a primary attachment tick before they started feeding. And you get weakness, loss of coordination, sometimes an ascending paralysis. It can look similar to Guillain-Barre syndrome. So these can be difficult to tell one from the other. So tick paralysis, fun facts, they can have absent deep tendon reflexes diagnosed by EMG. When you remove the tick, one has to be sure that we get the head out. And we're all taught medical school. And once you actually see this, it's so where arguments ensue. Do we turn it clockwise or counterclockwise? And they have these devices that are available ticked off that can help you safely remove the tick. Once the tick is removed, these patients regain motor movement within hours. And there was an association noted with tick paralysis in girls with long black hair. Well, it's pretty obvious if you've got long black hair, it's gonna be very hard to see a black tick buried in there. However, I guess in light of the Academy Awards and alopecia jokes, if we look at this, my daughter claimed that this could be a picture of my head and it would be easy to find a tick on me should I be afflicted in such a way. Other critters that actually cause presynaptic problems are the black widow spider and scorpion bites. Their toxins can actually cause problems with the release presynaptically, again, of acetylcholine. And I show these particular critters from Texas because allegedly everything is bigger in Texas. Another challenging neuromuscular disease is to consider is tetanus and here is the epistatonic position of someone of a rendering in the 1800s of a painting demonstrating someone with the contortion of their body exceedingly painful as one can imagine. This picture depicts a child who demonstrates the extreme pain and contraction noted in patients suffering from tetanus. And here's a picture of the organism Clostridium and here's a picture of the organism Clostridium tetani that's responsible for this and the release. This is another toxin-mediated disease. One of the findings that's most notable in tetanus is this finding of the facial grimacing of the patient's rhesus sardonicus. And this reminds me back in the day when I would take care of post-op hearts. It would be demonstrated by the cardiothoracic attending asking why the patient was still on some dopamine. And God forbid we had asked why was there a four-hour pump run. So rhesus sardonicus can be seen in various subspecialty attendings. So here are tetanus fun facts. It causes a severe painful muscle rigidity and spasm from a toxin called tetanus spasm. Risk factors include wounds, IV drug abuse, diabetes, lack of immunizations. You may get a history of a child born in a poor country where the umbilical cord was cut in the field or with something that wasn't deemed sterile, etc. So then the bacteria enter via the wound. They produce this toxin and the toxin enters the peripheral nerves and travels to the CNS via retrograde axonal transport. It then enters presynaptic neurons and inhibits the release of GABA and thus explains the signs and symptoms of disinhibition that's clinically seen in these patients. So trismus, I showed you a picture of the sardonicus, occurs in 50 to 75 percent of the patients. You can see nuchal rigidity, irritability, apistotonus, dysphagia, and facial muscle dysfunction. There's something called a bedside spatula test where if you stick a tongue blade in these patients mouth they bite down and it's near impossible to get it back. There are no serologic tests for tetanus and bacterial cultures are frequently negative. Treatment is usually administration of a benzodiazepine working as a GABA agonist, hyperpolarizing the cells so that they don't release the neurotransmitters to decrease muscle contractions. Magnesium has been used as well as baclofen and these patients at times may have to be intubated and have neuromuscular blockers. We also administer humans tetanus immune globulin which neutralizes again only circulating tetanus spasm. Penicillin is sort of a pediatric drug of choice that will prevent ongoing toxic production, toxin production in these patients. We'll now move forward and talk with diseases of the postsynaptic junction. So the acetylcholine was able to be released and the question is whether it can effectively bind, effectively be released, etc. So we'll start with myasthenia gravis. You notice in the upper right hand corner of the slide I have a picture of one of the seven dwarfs, Sleepy. Rumor has it that each of the seven dwarfs were based on friends of Walt Disney himself and one of his friends was noted to have myasthenia and was always tired with the droopy eyes and thus sleepy. So that may be an easy way to help you remember a very unusual entity, myasthenia gravis. And what happens here for whatever reason, acetylcholine is made, stored in the vesicles, released normally. However, there's a problem with the number of acetylcholine receptors on the skeletal muscle itself and these patients make antibodies to the ACH receptors. So although I have the right amount of neurotransmitter, they don't have enough of receptors to get an effective contraction of the muscle. And again, this is sort of immune mediating. Again, as I mentioned, the release of acetylcholine is normal. However, there are decreased number of receptors available. Infants born to mothers with myasthenia gravis may have a transient migraine due to placentally transferred anti-receptor antibodies. This is distinct from a very rare congenital form of myasthenia. So earlier presentation of myasthenia may be, again, with the eyes noting ptosis. And again, just think of sleepy as one of the seven dwarfs and extraocular muscle weakness. They can have dysphagia and facial weakness is very common in infancy. Reflexes may be decreased, but they're not lost. And they actually suffer rapid fatigue of muscles. So if you ask patients that are old enough to sustain an upward gaze for 30 to 90 seconds, they may struggle. Have them lie down and hold their head up. They can't do it. Have them open and close their fists repetitively or to raise their arms over their head. And eventually, their deltoids get weak, and they tend to get more symptomatic later in the day. And again, don't shoot the presenter, but this is a content spec for us to be familiar with, is an EMG. And basically, if you think about it, and you look at the picture on the left is normal. And on the right, you can see a weakness as they go through doing something. So just imagine, if you're lifting your hands over your head here, and you're normal, you just keep doing it. Myasthenia, you keep doing it, you get tired, more tired, more tired, and you do it less. So I think this is an easier EMG to recall than perhaps the one I showed you with Guillain-Barre. So I show this slide, and again, to make it easy to remember. So here's Sleepy after he got a dose of Tensylon. So what is that? So the Tensylon test is something that can be done to challenge a child. It used to be done to challenge a child and see if we could make the diagnosis of myasthenia. And we used to, kids over two years of age, we would give them edrophodium, which is an anti-cholinesterase. So if you think about this, these patients make acetylcholine, they release it, but there's no receptors. So the acetylcholinesterase is sort of breaking it down. So by blocking the enzyme, the normally released acetylcholine sticks around longer. So even though there's fewer receptors, more of them, because the enzyme that breaks it down is being inactivated, perhaps can potentiate. And these patients wake up, they get stronger. And this is a short-acting test that we used to do. I just put it in so to help you think about nicotinic, muscarinic, parasympathetic nervous system. And this is a good point to review here, because they could hypothetically ask you to do a tensilon test. And again, because of the nicotinic and the muscarinic, so the muscarinic receptors, if you give too much acetylcholine, you can get bradycardic and all kinds of issues. So you want to have atropine at the bedside. And again, when we used to do this test, you'd see the effect in 10 seconds, and it would end in two minutes. So again, fun facts of myasthenia. Mild may not require any medication. However, the way that the older patients are treated is they're given different types of cholinesterase inhibitors. So again, stopping the enzyme, preventing the breakdown from the normal acetylcholine, just to potentiate it to stick around longer with less receptors to keep them sort of saturated. There is some question whether steroid therapy is appropriate. These patients have been treated with IVIG, as well as with plasmapheresis. A life-threatening entity is called myasthenic crisis. It's defined as respiratory failure, usually requiring mechanical ventilation. Most often, it's precipitated by infection. However, change in medication, such as the adding or withdrawing of steroids, can precipitate it, or withdrawal of the anticholinesterase. So you take away the enzyme that allows the acetylcholine to stay in the space. So the key to help differentiate between a myasthenic rabies crisis and a cholinergic overdose is pupil size. The pupil should be smaller pinpoint in a cholinergic crisis. And we'll speak a little bit more about cholinergic crisis in an upcoming slide. Read the question carefully. I put this in as a helpful list of drugs that can exacerbate weakness in myasthenic rabies. For the sake of time, I'm not going to read it to you. Just on your own, take a look at it and understand why these drugs can cause these problems. In an earlier slide, I alluded to differentiating between myasthenic crisis and cholinergic overdose and toxicity. Cholinergic toxicity is caused by substances that may stimulate, enhance, or mimic the neurotransmitter acetylcholine. It's the primary neurotransmitter of the parasympathetic nervous system. Thus, recall it can stimulate both miscarinic and nicotinic receptors, which may cause muscle contraction and glandular secretions. This is another FYI chart that I think will be helpful as you think about nicotinic muscarinic effects of cholinesterase inhibitors. This can be a confusing topic, and I assure you, you'll see several questions on the board. I'm going to go through an example. We're going to use organophosphates as one of these particular drugs and how it works and causes problems. Organophosphates. Most commonly used insecticides are either organophosphates or carbamates. Also, nerve agents and bioterrorism that can be used. A mechanism is the bind to cholinesterase enzyme prevents the breakdown of ACH and just massive outpouring of ACH on the nicotinic and the muscarinic receptors. They bind irreversibly, and it's called aging, and it occurs within two or three days following exposure. So if we can identify these patients earlier, we do have therapeutic options that we can intervene with. So concerning organophosphates, significant symptoms don't appear until the acetylcholinesterase enzymes fall below 25%. So treatment includes two antidotes, and we usually start with 2-PAM followed by atropine. 2-PAM chemically breaks the bond between the organophosphate and the enzyme, liberating the enzyme and degradating the organophosphate, which will be excreted renally. And the atropine is to counteract only the muscarinic effects. Again, it will do nothing for the nicotinic and the muscle effects. So these two have to be given in tandem. Clinical presentation of cholinergic crisis can be recalled by the mnemonic sludge for salivation, lacrimation, urinary retention, defecation, GI cramps, and emesis and edema. So again, read the vignette carefully. And just for completeness sake, we'll cover one other than SMA, Duchenne muscular dystrophy. All muscular dystrophies are distinguished from other neuromuscular diseases by meeting the following four criteria. It's a primary myopathy. It's inherited. It's a genetic basis. It's got a slow, progressive, predictable course. And usually, degeneration and death of muscle fibers must occur at some point in the disease. Muscular dystrophy, fun facts to be known for the exam. It's the most common hereditary neuromuscular disease. It occurs one in 3,600 live-born infant boys. It's an X-linked recessive. The abnormal gene is the XP21 loci. And they don't produce a protein called dystrophin. And there's another protein, dystroglycan, that can also be decreased. And that's important for normal brain development. And again, this is just to demonstrate that Duchenne muscular dystrophy meets the criteria for MD. Here's a muscle biopsy of a normal 3-year-old. Here's a 3-year-old boy in the middle with Duchenne muscular dystrophy presenting early, and a 9-year-old with DMD. And you can just see the loss of muscle mass and the infiltration by fatty infiltrates. So along with the loss of mass, there's also a simultaneous loss of function. And what ultimately gets these children into trouble is without the normal tension of sort of muscle and nerve growth being torn and the muscle weakness, they develop severe scoliosis and a lordosis. And this begins about age 10. And what happens is they then begin to lose vital capacity over time. And the respiratory failure develops quickly once the child becomes wheelchair dependent. They, in effect, develop a restrictive lung disease, and they lose between 4% to 10% of their functional vital capacity per year. So again, if something's going to be done, it has to be done early in these particular children. And lastly, we have to remember that muscular dystrophy also affects the heart. So they do develop a cardiomyopathy as they get into the second and third decade of life and can be seen with associated ventricular dysrhythmias as well. Another topic that which we're all familiar is the utilization of neuromuscular blockers. The only depolarizing available in the U.S. is succinylcholine. The majority of the ones we use are termed non-depolarizing, and many of them have a steroid-like nucleus. They act by competitively inhibiting the interaction of acetylcholine with this receptor on the motor end plate. Approximately 99% or 95% of receptors have to be blocked for total inhibition. And just remember, the diaphragm is more densely populated with acetylcholine receptors, so it may continue to function after the hands, the eyelids, and the upper airway are effectively paralyzed. The next two slides are just summaries of medications that will either potentiate or decrease the functionality of neuromuscular blockers. You should take time and read this, again, content spec that's frequently tested on the boards. And again, these are just drugs that may antagonize the effect of neuromuscular blockers, which may not work, they may not work effectively, they may just take longer to kick in. All right, we're almost done. Be familiar with train of four. Know how it works. Know what one twitch versus four twitch implicates. You should take a few minutes and just read up on your PNS. I see I've gone over approximately 10 minutes longer than I should have, so I'm just going to leave you with two last slides, and then about a dozen more you can take a peek at on your own time. This slide, the pathophysiological mechanisms of ICU-acquired weakness, sort of a very hot topic. This is an excellent review article in the New England Journal, and I suggest everyone download it and take a look at it. Again, we always look at associated things that cause one thing leading to another. If there's a question on ICU-acquired weakness, this sort of demonstrates everything we do. The more particular culprits are neuromuscular blockade and sepsis, but prolonged immobility, prolonged ventilation, use of steroids, neuromuscular blockers, malnutrition can all contribute, and they're well-discussed in that New England Journal article. Well, my question is, have you had enough? Thank you for hanging in there for the review of the neuromuscular, and I wish everybody good luck and have a healthy and happy career in PCCF. Good luck with the boards, and then 10 years later, you get to sign up for MOC. All right, take care.

Pediatric Critical Care Board Review

Neuromuscular Diseases

Lower Motor Neuron Lesions

Autonomic Nervous System

Acetylcholine Metabolism

Respiratory Function

Neuromuscular Weakness

Polio

Guillain-Barré Syndrome

Muscular Dystrophy