Extrapyramidal Symptoms (EPS)

This podcast provides general information, not a substitute for professional medical advice. Please consult your physician for personalized guidance. Hello, hello, welcome back to PsychRounds, a resident-run educational psychiatry podcast. I'm Dr. Tanner Hewitt. Join us always with our co-hosts, Dr. Larry Wing and Dr. Bradley Miller. Now today we are covering some of the side effects of antipsychotics. Most notably today though, we'll be focusing in on the extra pyrimidinal symptoms commonly abbreviated as EPS. Now EPS represents one of the highest yield side effects of any psychiatric medication. Now we zero in on this not just for our board examination questions, but also in regards to the real world clinical practice and care of our patients. Now some of these side effects can be debilitating and early recognition and appropriate treatment can improve outcomes both from direct outcomes of the side effects but also improved adherence to medications and overall psychiatric care. So let's go ahead and get into it. So what does the term extra pyramidal mean anyway? Well the name is a reference to the descending motor tracks and so yes that means we're getting into some neuro. As a very quick summary, the corticospinal and cortical bulbor tracks run through the medullary pyramids, hence these being known as the pyramidal tracks. Both of these supply muscular control of the body that is consciously controlled. The extra pyramidal system on the other hand was first understood when Johann Pruss was investigating epileptic motor activity and realized that the above tracks do not account for this involuntary movement. So there must be tracks outside of the pyramidal ones. The extra pyramidal system is therefore the one that gives rise to involuntary motor control, contributing to things like postural to own corrective move for voluntary actions and especially inhibition of involuntary movements. The extra pyramidal track classically involves the basal nuclei for this issue. So etymology aside, extra pyramidal symptoms are essentially eye-atrogenic disorders of involuntary movement caused by dopamine blocking agents. These primarily include Parkinsonism, dystonia, dyskinesia, and acathesia. And like Dr. Miller said, the pathophysiology of all of these is related in some way to the dopamine, nitro stradal pathway in the basal nuclei. So first of all, there are a few risk factors that are worth covering as they apply to EPS as a whole, the first of which is high potency D2 blockate. So first generation and anti-psychotics have a high prevalence of EPS across the board. Anti-psychotic naive individuals are also at higher risk of developing EPS along with the elderly and those with intellectual disability as well. Parkinsonism and tardive dyskinesia are more associated with elderly females and dystonic reactions are more associated with young, ethnic males. Of course these are risk factors and these reactions can develop in anyone so keep an eye out for any patient who may develop EPS. In general, higher remember this is that EPS, more so dystonia is often higher in those with less body fat percentage. So for example, on average it's more common in young thin males rather than adult obese females, although like I just said it can happen to anyone. Additionally rates of EPS are generally higher with injectable anti-psychotics compared to oral anti-psychotics. Also just so we don't have to repeat this for every topic, one of the first line treatments for EPS is removal of the positive agent or at least reduction of the dose. This is generally going to be preferred to adding another medication to control the symptoms, but for obvious reasons this is not always possible. So an alternative would be to switch to a medication with a lower risk of causing EPS such as a second gen that has lower D2 binding affinity or more pronounced 5HG2A antagonism. And to just briefly add on to Dr. Miller's introduction with a bit more neuroscience, the motor output from the basal nuclei is thought to be controlled from a balance of colon orgic excitatory action and the inhibitory action of dopamine in the basal nuclei. Now this will help us understand the pathophysiology of most EPS symptoms. And for example in Parkinsonism the D2 blockade ends up dis-inhibiting the inhibitory indirect pathway. So that's a little confusing with a few double negatives, but it just ends up suppressing the output of the basal nuclei similar to what is seen in Parkinson's disease. Now this colonergic dopamine imbalance hypothesis will help us butter understand treatment, which spoiler alert tends to be the anti-colonergic medications. Now diving more into drug induced Parkinsonism, it is going to present with our usual symptoms of Parkinson's disease. So what are those? Like of our things like rigidity, tremor, shuffling gait, the bradycanesia, but tremors in particular are considered a cardinal sign of anti-psychotic induced Parkinson's. And as opposed to a true idiopathic Parkinson's process, this is generally going to present bilaterally since the drug is theoretically affecting both basal nuclei equally. Keep in mind that the initiation of an anti-psychotic can also unmask an underlying idiopathic Parkinson's process as well. Now in regards to the neuroscience, there are a lot of other hypotheses, which include oxidative stress, adenosine, fast association, etc. But if you're more interested, you can read, quote, the pathophysiological mechanisms of anti-psychotic induced Parkinsonism if you're really interested. So, getting back to treatment, Bensterpina is often the anticholinergic of choice for treatment of drug-induced Parkinsonism. One to four milligrams per day, split either once or twice daily, is a recommended dose. Drug-induced Parkinsonism can be transient, so it can be ripped, trialing the patient off of the medication after a one to two week period to see if they still need it. That brings us to the next point, which is very important. Anti-colonergics are not benign medications in the long term, and long term use should be avoided if possible. It is definitely not recommended to initiate Bensterpine prophylactically if you're afraid of Parkinsonism or other EPS. Additionally, if an anti-psychotic is already anti-colonergic itself, then adding an anti-colonergic medication like Bensterpine on top can sometimes be redundant. I think our medications like chlorpromazine, olanzapine, clasapine, or quityapine. All right, so we have a good foundation with Parkinsonism that should let us cover the next one fairly quickly. So next will be dystonia. This is most commonly acute dystonia, occurring immediately or within days of starting an anti-psychotic. Acute dystonia manifests as sustained muscular contractions, often involving the neck, or oral facial regions, ocular muscles, your tongue, or postural muscles of the back. So prevalence estimates of acute dystonia vary widely based on risk factors, but one estimate puts it in the range of 3-10% occurrence with anti-psychotics. The pathophysiology here is pretty similar to Parkinsonism with a colonergic, dopaminergic and balance, just manifesting differently and much more acutely with a sudden drop. An endogenous dopamine signaling. Now acute dystonia can be a very severe condition. It can be life-threatening. Airway impairment can occur, laryngeous basm or diaphragmatic involvement can also occur, leading to dysnia, and generally bad outcomes in those cases. Now a few other manifestations of acute dystonia are worth noting. Bacchulogyoric crisis refers to an involuntary upward deviation of the eyes, which can also be permanently damaging. And torrid colis refers to the neck muscles contracting to one side, causing the patient to turn their head sideways. And opus tonos is when the back muscles are affected and this will cause the patient to have their back in a rigid, bridged or arched position. Now vocabulary lesseness side, acute dystonia is also treated with anticholinergic, with ventrypene, brand-in, kogeta and being the one that we most commonly see used today. Now this can typically be used anywhere from 1 to 2 milligrams IAM or IV. And the medication is continued orally after an event to prevent reoccurrence. F and hybrid remain, vene drill is also a reasonable alternative for treatment, and you may also see this listed on your board exams. Sometimes even tri-hexyl phenylmethyl or arten can also be used. Yeah, nice. Next up is. Akadisha, which is defined as an inability to set still. I also get the pleasure of the one I most commonly mispronounce so bear with me. Akadisha has generally a faster onset, not as quick as Acute Dastonia, but also faster than Parkinsonism and dyskinesis, typically within 10 days of initiation of the Antisecotic. The Barnes-Akadisha rating scale, or Barr's B-A-R-S, is a good screening tool and describes the symptoms well. It can include manifestations such as restless movements, pacing, intense compulsion to move, and rocking. It is important to note that Akadisha can be very distressing and can contribute to agitation, anxiety, and can even be a risk factor for suicide. The pathophysiology of Akadisha is much more mysterious than the other EPS at the moment. Anticolonurgics don't help, which means that there has to be more going on. It appears to arise from an imbalance between noradrenurgic and dopamidurgic transmission, with Gaba-Inter neuron, perhaps playing a role. It could be quite complex, and I got lost in this literature, honestly, but you can read pathophysiology and management of Akadisha. If you want to understand a bit more in depth, but the brief summary is we don't know. So as always, consider lowering the dose of the medication and/or switching to another medication. Otherwise, beta blockers such as Burpranolol are often first-lined. This can be started at 10 milligrams three times a day, and upper limits can be as high as 40 milligrams three times a day. My personal go-to is metasapine or remeron, which actually be Burpranol in the head-to-head trial. And I also prefer metasapine because it can be dosed once a day. It does not really affect the patient's heart rate or blood pressure, and can even help with sleep, which patients with Akadisha often struggle with. It's also important to note that metasapine is only effective for Akadisha at lower doses, so around 7.5 to 15 milligrams per day, and may actually worsen Akadisha at higher doses by modulating noripaneshion release. And in fact, there are case reports of high dose metasapine, so we're talking maybe 30, 45, 60 milligrams a day, actually causing Akadisha. So I personally started 7.5 and may titrate to 15 if necessary. This might take two to seven days to have an effect based on the literature, but when it does resolve, maintenance doses may be as low as 3.75 at night time. Second line options include medications like benzodiazepines and alpha acridrux like clonidine, but in general, I did advise against using anticholinergic as they do not appear to be effective in Akadisha. Now we get to one of my favorite things to rant about right now, at least, is I want to add vitamin B6 to that list. There was a 2018 pilot study by Shams Alizeta at all comparing vitamin B6 to proprenol, and the two had no significant difference, meaning B6 was equally effective. Now this was only 66 patients large, but does have more evidence supporting it since then. There was a recent meta-analysis that was just published in March of 2024, titled Drug Efficacy in the Treatment of Antisecotic Induced Akadisha, that is supporting much of what Dr. Wague just said. In particular, those medications that rose to the top include mortasopine, biparidin, myansarine, trasidone, and proprenol. This study also found that vitamin B6 was a number of their favorable options. And I quote, "Vitamin B6 has a moderate to large effect size that also extends to different subgroup analyses. Its major potency lies in its exxing-linked tolerability and acceptability profile. Vitamin B6 may play a role, notably as a corrector of dopamine imbalance and as a free radical scapager." Really, the entire discussion section of this paper is worth a read. It gives a good insight into each of the medications we just mentioned. Laspus certainly not least to cover in terms of these EPS domains is Tardiv Diskinesia. Now, this commonly presents as oral facial dyskinesias, which can include things like grimacing, lip smacking, and tongue riding. These movements can also include the trunk and extremities. And Tardiv Diskinesia, unfortunately, can be irreversible once it starts. So early recognition is crucial. Now, one of the tests we use is the abnormal involuntary movement scale, also known as Ames. Now, this is the test used to look for thearius dyskinetic symptoms, and it includes activation techniques to make the symptoms more prominent so that we can unmask them and make them easier to catch. Now, the pathophysiology of Tardiv Diskinesia is very interesting. Essentially, using antipsychotics is blocking the post-ineptic neuron from receiving its usual dopamine signaling. In response, the neuron upregulates dopamine receptors to increase its sensitivity as a compensatory mechanism. Eventually, the increased sensitivity in the neuron and these motor pathways causes aberrant activation and dysregulation of the extra-priminal control, resulting in what we see as Tardiv Diskinesia. Now, in terms of the medications we use, one interesting tidbit is that the estimated prevalence from exposure to antipsychotics is around 20 to 30% with first-generation medications, so knowing the treatment is high yield. And as always, altering dose, as well as switching or stopping the offending agent is the first consideration. But if the symptoms persist, there are currently two FDA-proof medications for Tardiv Diskinesia. Valbenazine, also known by its brand name and Graza and due tetrabenazine, also known by its brand name Austito, which are both V-MAT2 inhibitors. So we might cover these two in more detail in the near future, but for now, I'll keep it brief. V-MAT2 is the enzyme that packages dopamine into the pre-synaptic vesicles. So, inhibiting this reduces dopamine release into the synaptic cleft. This helps restore the dopamine signaling balance with those hypersensitive postsynaptic neurons. So essentially, the theory behind TD, like we kind of already talked about, is kind of super sensitivity of dopamine. Anyway, these drugs are derived from tetrabenazine, which is used to treat career from huntins disease. But unfortunately, both are pretty expensive at this time. Usually hospital formularies will not even have them, so the patient has to bring this medication from home as a home medication if they do go inpatient. If this is not possible, what we often do as a backup is use something like a manzody, which has also shown to have some efficacy in TD. And a study actually below tested this medication against placebo at 100 milligrams with positive results. Vitamin E, as well, has been considered to have some mild benefit for TD. We kind of mentioned before how anti-colonurgics are not effective for ectathesia, and they're not effective for tarteif dyskinesia as well. In fact, they can actually potentially worsen TD. All right, we covered a lot of ground with EPS today. So I want to summarize the take-home points with a few one-liners for each one. So this is a good summary of what we talked about. For all EPS, first consider removal of the offending agent, dose decrease, or switch to an agent less likely to cause EPS. These include anti-psychotics like olansapine, quattitipine, clasapine, and even acenapine, although this depends on the EPS in question. Parkinsonism is the emergence of Parkinsonian rigidity, tremor, and bradykinesia. Treat this with anti-colonurgics daily like benstropine, but do not use these anti-colonurgics prophylactically and consider trialing the patient off of them in a couple of weeks as this often results. Acute dystonia is the rapid onset of muscle contractions. Treat this with intramuscular or intravenous anti-colonurgics and consider it an emergency. Consider continuing PEO anti-colonurgics for a few days to prevent recurrence. Acuteia is the emergence of rustlessness and an inability to sit still. It could be manifesting as anxiety or agitation in your patients, so have a low threshold for considering this. Consider use of the Barnes Acuteia rating scale, and consider options like vitamin B6, mertazapine, and propryanolol as agents to treat it early on. Tardiv dyskinesia is the often irreversible amormal movements often of the face, tongue, and mouth. Use the Ames test regularly to screen and monitor. Treat with V-matte, two inhibitors, like valve benzene and due tetrabenazine. And that's my summary of all of it. I I do want to mention one more thing. And I was picky about the language here of calling this generally dyskinesias and dystonias because we don't talk about part of dystonia very much, which is dystonia, like a cute dystonia that onset's quite later. And this is something that isn't as well illustrated often and we're not gonna go into a ton of detail here, but I just wanna mention it and put it on your radar. That sometimes in our cases dystonia it hand manifests in a much later time period. - And I also wanna add something so just like Tarte of dyskidysdonia, there's something called Tarte of Acathesia, which is Acathesia, so often restlessness, movement of the lower extremities, long after the medication was started or even taken off. So I had seen a case of this on my consult rotation. Doing a history, the patient was on a billify years and years ago, it was withdrawn years prior but he continued to have an internal sense of restlessness, lower extremity movements, but no oral facial or tongue movements, nothing like that. Looking at the literature, there's nothing really well studied for treatment of Tarte of Acathesia. We're looking at the case report level, but I just wanted to throw that in as well. - All right, so I think that just about brings this episode to a close. Now today we talked about the extraperminal symptoms, including Parkinsonism, Acute Distonia, Acathesia, and Tarte of dyskinesia. As always, feel free to contact us at [email protected]. If you're a fan of the podcast, please drop us a follow, comment, rating, or review as this helps us recharge our audiences. Thank you for listening. As always, we will see you next time and have a great rest of the week.