Short Circuit

Want to know what toxin can cause the brain to lose its brakes? What happens when anti-epileptics don't work to stop a seizure? And why might the nurse have to give 50 vials of the antidote?

This is Pick Your Poison. I’m Dr JP. ER doctor. Toxicologist, and unapologetic lover of all things poison. Want to know what toxin can cause the brain loses its brakes? What happens when anti-epileptics don't work to stop a seizure? And why the nurse might have to give 50 vials of the antidote? Stay right here to find out.
This is an interactive story.
Survival isn't guaranteed.
Will our patient live or die?
It's up to you and the choices you make.
Come with me and let's step into the emergency department.
The charge nurse asks you to see The patient in room seven says she doesn't look great and is acting like she's drunk. You look at the computer and see that the patient’s age is 13. A drunk 13-year-old? Anything is possible in the emergency department, but this seems a little unusual.
In the room, The patient is lying on the stretcher. She opens her eyes when you say your name but doesn't do much else. Her mother is sitting on the stretcher holding her hand. Her dad is pacing around the room but stops when you enter. They speak Indonesian so you get an interpreter on the phone.
The parents say the patient was fine this morning. In fact she seemed completely fine until about four hours ago, when she started complaining of dizziness and vomited several times. She's having difficulty walking. She lay down to take a nap and when they checked on her a few hours later they could barely wake her up. She hasn't had a fever, no headache, no cough or cold symptoms. She wasn't complaining of abdominal pain or anything else.
The parents say she has a history of asthma. She has a history of asthma and takes medicine for her lungs, but is otherwise healthy. They say she doesn't use tobacco, no drugs, and are adamant she doesn't drink nor is there any alcohol in the house as they are strict Muslims. She is doing well in school, straight As, which they are especially proud of because they recently immigrated from Indonesia and she initially struggled with the language barrier. No one else is sick at home. She hasn't recently had any cold or flu symptoms. She wasn't complaining of headache or neck stiffness.
The patient has a temperature of 98.5 or 37°C, a heart rate 125 bpm. Her respiratory rate is 20 breaths per minute, with a blood pressure of 110/80 and an oxygen saturation of 100% on room air. She's a pediatric patient so what do we think about these vital signs? Well she's afebrile obviously and her blood pressure is on the low side but she's a thin teenager so This is probably normal for her. Her heart rate, however, is a little fast. Her breathing and oxygenation are good.
On examination, she is lethargic and minimally engaged. She follows simple commands inconsistently, answers only enough to state her name, and her speech is noticeably slurred. Her cranial nerves are normal, pupils equal, rounded, and reactive to light. Her neck is supple. Other than the mildly elevated heart rate, heart and lungs are clear, no Abdominal tenderness. She's moving all of her extremities with normal reflexes. There are no external signs of trauma.
Other than the slurred speech there's really nothing at all remarkable on the exam. Until you ask her to give a urine specimen. She sits up on the stretcher with her mother's assistance. You notice her torso moving back and forth. Like she's sitting on a boat, moving up and down in choppy water. Except of course the stretcher is not moving. This is called ataxia. Mom assists her to stand up and it gets even worse. Her whole body is swaying and she does look like a drunk person trying to walk on an unsteady boat. You grab her arm and assist her back to bed so she doesn't fall.
Question number one. This could be:
1. A. alcohol intoxication
2. B. low blood sugar
3. C. a brain tumor
4. D. all of the above
The answer is D. All of the above could cause these symptoms. Do you think she's drunk? She does look intoxicated with slurred speech, an altered mental status, and ataxia. I'd send an alcohol level for sure. That said, a 13 year-old straight-A student who's been at home all day in a house with no alcohol, while nothing is impossible in the emergency department but this doesn't seem like the most likely scenario. It would be a big mistake to assume this was alcohol intoxication and stop your work up there.
As we've mentioned before, alcohol intoxication is extremely super common in the emergency department but it is also unfortunately fraught with pitfalls, Given the number of things that can mimic it, like low blood glucose, head injuries, infection. And that's just to name a few common things off the top of my head.
What else should we do to investigate? A finger stick to check her blood glucose, Definitely basic labs. We'd asked for the urine to make sure she doesn't have a urinary tract infection. I would order a head CT though. I suspect it's likely low yield. When you see people with slurred speech and ataxia, it often indicates a problem in the cerebellum, which is the part of the brain on the bottom near the brain stem. Alcohol affects the cerebellum. The cerebellum is often not well visualized on a CAT scan but given that most emergency departments can get them relatively quickly and it's non-invasive, it's probably a good idea.
You leave the room, order the work up, and move on to the next patient, An elderly man with a fall, while waiting for her results. Walking past her room on the way to his, when you hear her parents shout for help. You detour into the room and see that she's having a generalized tonic-clonic seizure. She's completely unconscious and all of her limbs are shaking violently. The nurses come in to help and you order 2mg of lorazepam (i.e. Ativan), a benzodiazepine to treat the seizure. You get a finger stick to check our blood sugar, which is 100 mg/dL, which is normal.
Usually the first-line treatment for seizures in the emergency department is a benzo. We could have a long discussion about which one to use and which route to give it. Fortunately she has an IV. The seizure stops quickly, before the nurse administers the medicine. You ask the nurse to expedite the head CT and to Take the patient on a heart monitor down to radiology.
You ask about the finger stick. The nurse says it was normal at 100 mg/dL. What about the urine specimen you say? Negative, she says. No infection, pregnancy negative.
She motions to the patient's breathing and asks if you want a chest X-ray. She's making some snoring sounds And the nurse is worried she might have aspirated during the seizure. You say, "Sure."
The patient's labs come back. You take a quick look, noting that her bicarb is slightly low, meaning she's probably slightly acidotic but nothing otherwise worrisome. No evidence of infection, Or electrolyte disturbances.
The next thing we need to consider is whether or not to do a spinal tap. Could this be meningitis? Well she doesn't have a fever , headache, or a stiff neck, So no classic meningitis symptoms. Encephalitis is possible as you can have altered mental status and seizure without the other symptoms. Typically patients have several days of symptoms like viral symptoms before becoming critically ill but it's something to consider. Of course this could be new-onset epilepsy. That's always difficult for us to know in the emergency department with a new seizure. You decide to talk to neurology about it when after she comes back from CT.
You're in the room talking to To the man about his fall when you hear "Code Blue radiology, Code Blue radiology" overhead.
Question #2. What do you do next?
Finish examining this man to make sure he doesn't have any serious traumatic injuries. The radiologist will handle it.
Run down to Radiology.
The answer is B: run down to radiology as fast as possible. The radiologist will not handle the cardiac arrest and in most cases these days there are reading studies from home.
If there's any phrase that can make an ER doctor's blood run cold, I'll tell you this one is right up there at the top. Why? Because when anything happens in the radiology suite, it's usually complete chaos. They do have a code cart (i.e., a cart with all the medicines we use for cardiac arrest) but But they are definitely not used to cardiac arrests. The best thing to do is to get the patient back to the emergency Departure as soon as possible, where we're set up to handle this.
Every time I hear this I run down my mental list of patients to see who I recently sent down to CT, In case it's one of my patients. You run down the back hall towards radiology along with several of your colleagues and nurses and burst into the radiology suite. Your patient is having another seizure in the CT scanner. Not great, but she's also clearly alive and not in cardiac arrest. The CT tech panicked and called a code blue to get help. Fortunately they were able to Obtain the CT images before the seizure started.
You and the nurses grab the sheet Underneath her and yank Her back onto the ED stretcher. You ask one of the nurses to go back to the emergency department and get the lorazepam you'd ordered previously but didn't give since the seizure had stopped. You and the other nurses roll her Back to her room One nurse administers the lorazepam immediately, The others hook her up to the monitor and try to get accurate vital signs. It's very difficult to do during a seizure for obvious reasons, They're never completely accurate but nothing about her vital signs seems to have changed significantly. One of the nurses applies an oxygen mask, As a precaution.
You give the Lorazepam a minute to work? What happens? Nothing. Lorazepam, even IV, doesn't work immediately, so it's always a sort of a knuckle-biting situation where you try to give it long enough to work while battling your natural instinct to call for five other things at the same time. What happens if you give too much? Well the side effect of benzodiazepines, as we've discussed many times before, is sedation. What you don't want to do is stack up a whole bunch of doses before the effects kick in. Because if you do, you'll find yourself in a situation where you have to intubate the patient and put them on a ventilator until the benzodiazepines wear off. On the other hand, you don't want this seizure to go for any longer than necessary. You have to try to balance the two.
Mom looks horrified and dad is crying. You ask if she's ever had a seizure before. They say no. You ask if there's any family history of seizures. Again no. You check the clock. It's been a few minutes. The seizure still hasn't stopped so you order another dose of lorazepam. Generally we wait about five minutes though I can tell you when you're standing there with someone having a seizure, this feels more like five hours.
Another four minutes slowly tick by. The seizure still hasn't stopped. Now you're starting to get worried. Seizures are common. Epilepsy is common. Febrile seizures in kids are exceedingly common. These are all typically short and self-limited seizures. Sometimes they need a dose of medicine. Most times they stop on their own. It's extremely upsetting for family members to see seizures for obvious reasons, but Giving a dose or two of anti-epileptics in the emergency department is a fairly common occurrence. But if I give two doses and the patient hasn't stopped seizing, now I do start to get worried about status epilepticus, which is a true emergency.
It's a sudden uncontrolled surge of electricity in the brain. Basically your neurons start firing. Status epilepticus is when they won't stop. Most seizures, as I said are self-limited because your brain turns off the abnormal activity, But when it can't, That's a serious emergency.
There are two main definitions of status epilepticus. The first is a seizure that lasts for longer than five minutes. The second is having two seizures in a row without returning to your baseline mental status in between. It's common for patients after seizures, as we've said before, to have a postictal phase where they may be confused, agitated, or lethargic. This can last for minutes or hours and they usually gradually wake up. But if you have a second seizure while still in the postictal phase, this can be considered status epilepticus as well Because the brain hasn't really recovered before another seizure happens.
What next? The main goal here is to make the seizure stop. Different hospitals have different protocols for status epilepticus. There may be some differences between adult and pediatric protocols but the general idea is Simple. Keep treating until the seizure stops and try to make it stop as quickly as possible.
If two doses of benzodiazepines don't work, you could give a third dose or you could move on to an anti-epileptic drug, which is probably what I would do at this point. Again you'll see a lot of variability, And there aren't strictly right or wrong answers here. I'd give a loading dose of levetiracetam, ie Keppra in the US. It's very effective for seizures and the other benefit is it doesn't have sedation as a side effect. The nurses give the Keppra.
She's still seizing.
This is getting really worrisome and is without a doubt a true emergency at this point.
What next?
It's time to get some help from neurology. You call and ask for further recommendations. They lay out a strategy of additional antiepileptics,Which you order?
Question #3. She Needs to be intubated.
A: true
B: false
Answer: Honestly A or B in this case.
We're at a point where things start to get really difficult because you have to make a decision about intubating her and putting her on a ventilator. Every single time I have to make this decision about a patient in status epilepticus, it's really difficult. I personally always feel like I failed to stop the seizures if I have to intubate them though of course I've gone down. the status epilepticus protocol, And treated the patient appropriately, it’s obviously not my fault.
Why is this difficult? Because there are several competing concerns. I don't want to intubate and ventilate a patient if the seizure is going to stop shortly, Because they'll be on the ventilator for at least a day or so, that opens them up to infections and other risks. The other problem is if we intubate a person we lose the ability to know if they are still seizing or not. In almost all cases and definitely in the case where the patient is actively seizing, we have to give a paralytic to be able to actually put the tube down into their airway. After you give the paralytic the tonic-clonic movements will stop.
But that doesn't mean the seizure has stopped.
It just means you can't see the seizure anymore. The over-excitation and excessive neural impulses from the brain, which is really what the seizure is, haven't stopped. We just can't see its effects. And if we don't treat status epilepticus, we dramatically worsen the patient's outcome. EEG monitoring will tell you if the patient is still seizing but in most places this is difficult to get in a timely fashion.
If we don't intubate?
Then they might aspirate and choke on their own secretions.
You tell the intern and the respiratory therapist to get things set up. You ask the nurse for intubation medicines but drag your feet on intubating her, Hoping the seizures will stop if you give it a few more minutes.
There are a lot of things that can cause status epilepticus including epilepsy itself, underlying brain lesions, infections, endocrine disturbance. But as you know this is a toxicology podcast so let's Not waste any more time and get right to toxins. I've mentioned before that many, many, many toxins can cause seizures and the end point of many poisonings is often seizure, coma, and death. Status epilepticus, however, is a much shorter list of toxins.
Let's start with what we know the patient had access to. Her parents said she had asthma and took lung medicine. That might be albuterol, what we use in inhalers and breathing treatments. Occasionally in a large overdose albuterol can cause a seizure but not status epilepticus. As we go through the rest of these toxins again I'm going to focus on status rather than just a single seizure. You asked the parents what other medicines they have in the house. They say acetaminophen (i.e. Tylenol) and ibuprofen (i.e. Motrin). What about those? No, neither can cause status. Dad says he has high blood pressure, But forgot the name of his medicine.
What about a high blood pressure medicine? We use a lot of different classes of drugs to treat hypertension, obviously. She doesn't have a low blood pressure or heart rate to suggest a calcium channel or a beta blocker. Running through the list of common blood pressure medicines in your mind nothing Jumps Out is causing status epilepticus.
You've given the second anti-epileptic as recommended by the neurologist and she's still seizing. Why do ER doctors and toxicologists worry about status so much? First the longer the seizure goes on, the harder it is to treat, leading to a vicious cycle. Morbidity and mortality rise sharply with the longer the seizure lasts. We know prolonged seizures result in brain damage, with some estimates that about 10% of survivors will have a new neurological disability as a result. Also, Status can actually trigger multi-system organ failure, including cardiac arrhythmias and hemodynamic collapse. We talked already about aspiration. It can cause respiratory failure, Hyperthermia because of the muscle activity resulting in rhabdomyolysis or muscle breakdown, which in turn causes kidney failure. Even DIC disseminated intravascular coagulation resulting in both blood clotting and bleeding. The estimated mortality rate of status epilepticus is about 16%, a number which hasn't improved since the 1990s.
The list of the medicines the parents have given in the house is a dead end. As I said the list of toxins causing status epilepticus is relatively small so Let's try that angle. Sympathomimetics are at the top of the list: cocaine, methamphetamine. Narcotics, including heroin. Tramadol, pain medicine, specifically has a side effect of causing seizures. Another big cause is alcohol withdrawal, Similarly benzodiazepine and baclofen withdrawal .
Medications include: Bupropion. This one causes a lot of seizures, so much so that after it was initially FDA-approved in the U.S., it had to be withdrawn due to seizures. It was eventually re-released with a lower therapeutic dose. An older class of antidepressants, tricyclic antidepressants or TCAs, which are not that commonly used now, can cause it. Theophylline, a drug like caffeine, occasionally used for asthma. Local anesthetics, we've talked about before. Antihistamines, like diphenhydramine (i.e. Benadryl). Occasionally antipsychotics.
Pesticides like organic phosphates. We previously talked about strychnine and tetanus, also water hemlock. Drug use and substance withdrawal doesn't seem that likely. The parents deny having any of these medicines in the house. They say there are no pesticides in the house. They live in a city so she hasn't been foraging.
You asked the nurse recording in the computer to check to see if the radiologist read the head CT. He pulls it up and says negative. Which is good news but doesn't help us get to the bottom of this case. He reads the chest X-ray report. Upper lobe lesion In the right lung, Possible calcified granuloma.
An upper lobe lesion on X-ray is classic for which of the following diseases? Question # 4.
A. Asthma
B. tuberculosis
C. silicosis
D. lung cancer
The answer is B. Upper lobe lesions are a classic finding in tuberculosis. A calcified granuloma could represent a previous, active TB infection. In asthma you don't expect to find significant changes on X-ray. Silicosis, as we've talked about before, causes significant lung disease across the lungs, not localized to one area. Lung cancer can cause a lesion anywhere but the upper lobe lesion is classically associated with tuberculosis. Especially in a thirteen-year-old girl who's not likely to have cancer. Also she's from Indonesia and while you can certainly get tuberculosis anywhere, including the US, Indonesia has a high incidence of disease.
This has given us a very important clue about what might be causing status epilepticus. You ask the parent if she's being treated for tuberculosis. They say yes. They say yes that's the medicine she's taking for her lungs. Medicine for tuberculosis, not medicine for asthma. As with the blood pressure medicine they don't know the name. You ask if anyone's at home to text a picture of the bottle. Unfortunately no one else is there.
What do we use to treat tuberculosis? Antibiotics. If you have active tuberculosis, you often need a multi-drug regimen given that there is a lot of resistance to tuberculosis, Usually a four-drug regimen. Latent tuberculosis is when your body has fought off the active infection. The bacteria, while contained by the immune system, tho still remains within the body. So the person isn’t sick or infectious but there's a risk of reactivation if in the future you become immunocompromised or ill from something else, HIV, cancer another infection. Your immune system might not be able to keep it contained and would become essentially active TB again. The treatment to get rid of the latent tuberculosis is 1-2 Antibiotics, which have to be taken for several months. Different places have different treatment recommendations based on what's available and resistance patterns, etc.
All right so it's time to pick your poison. This is a tough one, really more for the medical professionals. No shame if you guess wrong. Is the antibiotic responsible for status epilepticus in our patient? Question #5.
1. A. ethambutol
2. B. rifampin
3. C Pyrazinamide or
D-Isoniazid.
The answer is D. Isoniazid or INH for short. All of the drugs, including isoniazid, can cause hepatotoxicity, including in therapeutic doses, so patients have to be closely monitored. Depending on where you live, INH is a pretty common cause of status epilepticus.
Could this be INH toxicity? Her liver function tests came back normal. Does that change your mind? This absolutely could be INH toxicity. It does cause hepatotoxicity, More with chronic use and less commonly in children.
Does it feel like this seizure has been going on forever? Me too. And every time I have a case of status epilepticus I feel the same. Usually the family members are looking at me like, "Why aren't you making it stop?" I'm wondering the same thing, why the drugs aren't working, what I could possibly be missing.
What's the treatment for INH-induced status epilepticus? Bad news, anti-epileptics Don't work for INH-induced seizures.
Good news, we have an antidote.
The antidote is actually a vitamin. Can you guess which one? That's question number 6,.
Vitamin B6.
Folate
Vitamin A
Vitamin C.
The answer is actually vitamin B6, pyridoxine. It works great. As soon as you hear the chest X-ray results and think about tuberculosis as the patient's lung disease rather than her asthma, you order it immediately. The dose is 80 mg/kg, Our patient weighs 50 kg, so 4 grams.
The patient is still seizing and rather than giving the medicine there's a lot of discussion amongst the nurses and several calls to the pharmacy, which seems to be causing a delay.
Finally one of the nurses wheels over a metal mayo stand and says, "Are you sure about this dose?"
She points to the mayo stand, filled with pyridoxine vials. “4 g means 40 vials. Is that right?”
As a toxicologist I love when the nurses double-check orders and doses with me for patient safety. Normally if the nurse has to give 40 vials of something, you've ordered the wrong dose. Most medicines come in a vial Within range of a normal standard dose. 4 mg of morphine is a common dose, so it comes in a 4 mg vial. Using pyridoxine as an antidote is a rare exception when many vials may be required Because it's usually given in the main hospital as a vitamin rather than the very large dose required for its use as an antidote. For example a common size in pyridoxine is 100 mg vials And we need 4,000 mg or 4 g.
You confirm with the nurse, And make sure everyone’s on the same page and then several nurses help to pull the medicine up to several syringes to give as quickly as possible.
You hold your breath, hoping this works because nothing else has been helping so far. What if we're wrong and this isn't an INH overdose? What will happen? Nothing. There's no harm in giving a big dose of B6 once, even if it's unnecessary. In some cases pyridoxine is unofficially on the status epilepticus protocols in places withis a high incidence of tuberculosis because this is not an uncommon cause.
One minute ticks past. The patient is still seizing. Finally after a minute and a half she stops. You and the entire team breathe a huge sigh of relief. Additionally we managed to avoid intubation. The seizures have stopped. She is Barely conscious but is moving a little bit. This is most likely a postdictal phase, which will probably last for a long time, given the duration of the seizure . But you'll have to watch her closely to make sure.
She gets admitted to the hospital for ongoing observation to make sure she wakes up appropriately and to make sure the seizures don't reoccur. Later that day dad goes home and brings back the lung medicine. The pediatrician texts you a picture confirming It is isoniazid that she was prescribed.
What happened You ask? Still post-ictal, the pediatrician texts back. Meaning she's not awake enough to tell us.
There are several fairly common routes of exposure. The first is unfortunately Suicidal overdose, which is well documented in the medical literature. The family denies that she has been depressed. The pediatrician notes that when he counted the pills, the exact number from the date of prescription was missing.
When the patient wakes up she explains what happened. She says that she missed her doses for a number of days and in order to make up for lost time took a whole handful of pills at once. This is another common way people are exposed and I've had a number of cases where this happened.
This is a fictional case, as are all our cases, to protect the innocent. But it is based on real poisonings. It highlights the dangers of taking missing pills and taking them all to "catch up". If you miss doses of your medicine, please get in touch with your physician for advice on what to do. If you take a handful of your blood pressure medicine, you might end up with a Dangerously low heart rate and low blood pressure. On the other hand drugs like anti-epileptics might require a higher loading dose to get your blood levels back to therapeutic. Don't try to guess and do this on your own. Talk to your doctor to do it safely.
How does isoniazid cause seizures? Isoniazid interferes with B6, pyridoxine metabolism, Inhibiting and enzyme called pyridine phosphokinase. Without enough B6 GABA, one of the inhibitory neurotransmitters in your brain, can't be made. If you run out of GABA, it means your brain becomes overstimulated with too many electrical impulses (i.e. status epilepticus).
Wait a minute did I hear you say? Don't benzodiazepines also work on GABA? Why weren't they helping? Benzodiazepines do stimulate GABA receptors to open, causing sedation. However they require GABA to go through the channel to cause these effects. If they open the channel and but there's no GABA, nothing happens.
Paradoxine's action as an antidote is pretty simple. If you give pyridoxine back, you can restore GABA synthesis and normal GABA levels, stopping the seizure.
We gave our patient a weight-based dose of pyridoxine and the seizures stopped. There is one potential pitfall with this approach. What is it? That's question number 7.
In patients an enzyme Deficiency
In pediatrics
In patients who also have epilepsy
The answer is actually B. You can run into some difficulty with the weight-based dosing of pyridoxine in very, very small patients. The actual ideal dose of the antidote is milligram per milligram for the amount of INH that the patient actually took. Now this is easy to do if you knew how much the patient ingested but the reality is in the emergency department we usually have no idea. Therefore we do the weight-based approach to give the patient a high dose, Which is usually a good guess.
There's a case report of a 10-month-old who stopped seizing after a weight-based dosing of 650mg of pyridoxine but 5 hours later developed seizures again. In this case they gave more pyridoxine and the seizures stopped. The 650 mg of pyridoxine helped but it was too low a dose because he was such a little guy in comparison to what was ingested. Just something to keep in mind when you're taking care of very small patients.
The other issue you can run into is that the hospital may not have enough pyridoxine. A one-month supply of INH for an adult could be 10 g so you may need to give 10 g and many hospital pharmacies don't stock 50 vials, for example.
Epilepsy as a disease has a long and very fascinating history. In ancient civilizations, it was seen as a sacred or spiritual condition. Ancient Egyptians, however noted that in the patient with an open head wound, when stimulation was applied to the exposed brain, the patient would “Shutter exceedingly. ”. In ancient Greece seizures were associated with men of high status and came to be called the disease of geniuses. In contrast, in the Middle Ages in Europe people with epilepsy were often accused of witchcraft. I had wondered before I did this episode how pyridoxine was discovered as an antidote for INH. When isoniazid was first discovered as an anti-tuberculosis agent, patients were treated with high doses, causing peripheral neuropathy. Clinical studies showed that pyridoxine prevented the nerve damage without affecting its potency against tuberculosis.
There's a book called "The Black Angels" about black women working as nurses in 1929 at a large tuberculosis sanitarium in Staten Island, undertaking a difficult and dangerous job that no one else wanted at a time when one in seven people died of tuberculosis. They played an important role in The clinical trials for isoniazid. I haven't read this book. If you have, let me know if it's worth a read.
And that brings us to the last question in today's podcast, a historical/pop culture question. Which of the following famous people died of tuberculosis?
Eleanor Roosevelt
George Orwell
Anton Chekhov
Frida Kahlo
Follow the X and Instagram feeds both @pickpoison1 for the answer. Remember, never try anything on this podcast at home or anywhere else.
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While I’m a real doctor this podcast is fictional, meant for entertainment and educational purposes, not medical advice. If you have a medical problem, please see your primary care practitioner. Until next time, take care and stay safe.