Hello, I'm Christy O'Fallon, Neurocritical Care at the University of Miami. Today we're going to talk about neurotoxicology and metabolic syndromes that you see in patients with acute encephalopathy. I have no relevant disclosures to this topic. Our learning objectives are as follows. We're going to look at clinical approaches to patients with acute encephalopathy, identify common metabolic derangements which are seen in this population, think about some common toxidromes and their treatment, and review specific clinical manifestations that might lead you in the right direction. Clinical exam is very important and the neurologic manifestations of these disturbances will help you determine their etiology. Physical exam starts with vital signs. Derangements of temperature, heart rate, and blood pressure are fairly common in many of these syndromes. They're important to look at when you're examining a patient. Looking for evidence of organ failure, specifically renal failure, hepatic failure is helpful when you're trying to look at a differential diagnosis. You may see changes in the skin, you may see ascites or icterus, and you may see patients with respiratory distress, which would lead you in a particular direction. The neurologic exam is important and noting whether there's focality to the exam can help you determine whether you're looking for a systemic syndrome such as organ failure, or something focal or structural such as a stroke or a tumor. Non-focal exams are usually more symmetrical and do not have one side of the body weak, for example, or cranial nerve abnormalities on one side, for example. You may see asterixis or other movement disorders in these patients, which will lead you to the diagnosis of an organ dysfunction such as hepatic encephalopathy. Eye exams are important. You may see nystagmus or pupillary changes with dilation or constriction. Again, asterixis, which is negative myoclonus or loss of muscle tone or contraction, which is associated with passive or active hand-wrist extension, can be seen with metabolic encephalopathy, hepatic encephalopathy, and uremia. Tremor and myoclonus are often also seen in patients with organ dysfunction. Reflexes may be increased or decreased depending on the syndrome. Skin exam is important. Rashes or skin abnormalities may point you in the right direction when looking for systemic problems or organ dysfunction. History is important but difficult to obtain as the patients often cannot tell you what happened to them. Finding friends, family, neighbors, or EMS evaluations is often quite helpful. Thinking about what part of the nervous system is most effective can also help you with a differential diagnosis. Is this mainly a central nervous problem or peripheral nervous or muscle or neuromuscular junction issue? This is a case of a young man that we took care of a couple of years ago, 25-year-old who was brought to the ED after cardiac arrest at home. They achieved raw skin 10 minutes and he was treated with therapeutic hypothermia. Initially, his Glasgow Coma Scale was three and he had mid-position sluggish pupils. No cough, no gag, no corneal reflexes were noted and there was no movement. He had flaccid tone throughout. An EEG done on admission showed essentially flat EEG and his reflexes were significantly diminished but still present. He was quite hypotensive, required resuscitation with fluids and vasopressors. Even after therapeutic hypothermia was completed, he remained quite hypothermic. An endocrine workup and toxicology were sent. Imaging, you can see here a CT scan on the right, showed essentially a normal brain CT without significant edema, midline shift, or structural abnormalities. Actually, the gray-white distinction is preserved throughout, which is something that you wouldn't expect for somebody who presented with a significant neurologic dysfunction, such as this young man. We obtained more history and found that he had overdosed on phenobarbital and he actually recovered over the following seven days, was extubated and discharged from the hospital. This is an example of how the disconnect between the imaging and the clinical presentation is super important to help guide you towards looking for an alternative explanation or etiology for the dysfunction. We will go through some common metabolic abnormalities that we see in the neuro-ICU. Sodium is one of the most common seen in patients with acute brain injury. It can precipitate cerebral edema, it can be associated with encephalopathy and seizures. You can see abnormalities with both high and low sodiums. Sodium does not move freely across cell membranes and it is a primary determinant of tonicity in the brain. It is a disorder of water balance and hyponatremia is typically symptomatic at levels below 120 millimoles per liter. When patients are suspected of having chronic hyponatremia, too rapid correction can precipitate osmotic demyelination syndrome, which can be very debilitating for patients and is not reversible. Typically, we target a goal of no more than 8-10 millimoles per liter in a 24-hour period if we feel that the hyponatremia is chronic. Hyponatremia is usually symptomatic over a level of 160 millimoles per liter and rapid correction can precipitate cerebral edema, so we typically try to do this slowly as well. Hepatic failure is a cause of encephalopathy and cerebral edema that we see in the ICU. Specifically, patients who are treated with TIPS procedure may be at risk for this. The shunt causes an increase in encephalopathy because of increased ammonia, which causes astrocytes to dysfunction in the brain and can be seen with cerebral edema. Wilson's disease is a rare disorder of copper, which accumulates in the liver and kidneys. You can diagnose it with a slit lamp examination of the eyes, which diagnose Kaiser Fleischer rings. It's treated with chelation therapy, oral depenicillamine, and paradoxine. Hepatic porphyrias are also rare but important to know about because their treatment is quite specific. Patients present with abdominal pain, encephalopathy, psychosis. The treatment is IV hematin, as well as avoidance of triggers, which are often medications that are given. This is an example of a triphasic wave, which is commonly seen on EEG in patients with hepatic encephalopathy. The typical pattern of triphasic waves is here in the A panel on the left. You see an upwards deflection, which is labeled 1, followed by a downwards deflection labeled 2, and then another upward deflection labeled 3. On the right side of the figure, the B panel, you see that these triphasic waves are generalized throughout the EEG, and they tend to follow an anterior to posterior temporal distribution. You can see that the abnormality shows up on the EEG in the frontal electrodes just slightly before the posterior or occipital electrodes. Several GI syndromes are associated with metabolic encephalopathies. Some of these are malabsorption syndromes, such as Wernicke's encephalopathy with thiamine deficiency, celiac disease, which can present with 10 percent of patients having neurologic manifestations. The cerebellar dysfunction in celiac disease is caused by chronic fat malabsorption. B12 malabsorption can lead to subacute combined degeneration, peripheral neuropathy, delirium, and psychosis. Things I left out in this part of the review are endocrine, specific endocrine disorders, chemotherapy, antibiotic-related encephalopathy, stem cell transplantations, and CAR T therapy. These are covered elsewhere in the course. We're going to go over some acute toxidromes that it's important to know about. The most important thing to consider when trying to diagnose these disorders is that you must be open to the possibility of their existence, so you have to look for it in order to find it. In general, you should be thinking about this when you're examining patients with an altered sensorium, altered level of consciousness, which are many of our patients in the neuro ICU. Specific symptoms such as acidosis, GI distress, seizures may point you in the correct direction. And it's helpful to evaluate the disconnect between the labs or the imaging that you have and the clinical manifestations, such as in our case that we discussed a minute ago. These are some listed typical signs and symptoms suggesting poisonings with different drug classes. So cholinergics, anticholinergics, sedative hypnotics, and pathomimetics. These are common causes of poisonings and listed here are examples of medications that may cause this and the clinical manifestations. Some antidotes that are important to think about are listed here. Tylenol, anticholinergics, beta blockers. These are not infrequently seen and it's important to know the antidote or to be able to find the correct approach. Other common syndromes that we may see in the neuro ICU include neuroleptics, which would be treated with bromocryptin or dantrolene. Opioid overdoses treated with naloxone. Tricyclic antidepressants are not seen as commonly now as previously, but are treated with sodium bicarbonate and valproic acid treated with L-carnitine. So manifestations of anticholinergics include changes in memory, attention, executive function. These medications are lipophilic, so they impact the CNS more than other organs. And they occur frequently in medications which end in zine, pene, or amine, and also can be seen in some botanicals that might be taken recreationally, which are listed here. These are treatable with neostigmine, but important to remember that this has significant cardiac side effects, so telemetry monitoring is important during treatment. Cholinergics are less common, and organophosphate or pesticide exposure is probably what we see the most. An overdose of cholinesterase inhibitor or abrupt cessation of an anticholinergic medication can cause these syndromes that are typical with salivation, lacrimation, urination, defecation, GI cramping, and emesis. The treatment is with atropine if severe, glycopyrrolate if CNS manifestations are minor. Again, there will be some cardiac side effects to this, so important to have the patients in a monitored setting. Sedative hypnotics are used frequently in the ICU, and they also may be a cause for abnormalities when patients present with encephalopathy. Pure benzodiazepine toxicity rarely causes severe respiratory depression, so if people present with this, you should look for some other concomitant drug ingestion. Paradoxical agitation may present with delirium after benzodiazepine use. Barbiturates can produce shock, apnea, and changes in pupillary function. Routine use of flumazenil is discouraged in patients with suspected benzo overdose due to potential for arrhythmias and seizures, and so typically the support is symptomatic acutely until the patient has time to clear their medication. Opioids are CNS depressants that can cause respiratory depression, coma, and death, also meiosis. Naloxone is probably the most commonly used medication. One of the downsides of naloxone is its short half-life, and so often these patients have recurrent abnormalities in their mental status after the first dose of naloxone wears off. Nalmophene has a longer half-life, so it can be used to avoid this problem. Critical care support is important for the accompanying hypotension and organ failure, risk of rhabdo, acute renal failure, and ARDS. Sympathomimetics such as cocaine, amphetamine, decongestants, ketamine bath salts are not infrequently seen. Patients present with hypertension, tachycardic, severe cases may have intracranial hemorrhage or seizures, cardiomyopathy, and shock. The treatment is sodium bicarbonate. It mediates the effect on the neuronal and the cardiac sodium channels, and symptomatic support, blood pressure with direct vasodilators is helpful. Beta-blockers should be used with caution as it may lead alpha-adrenergic stimulation unopposed. Typical antipsychotics or the first-generation antipsychotics may be associated with neuroleptic malignant syndrome. Drugs with dopamine receptor antagonism such as Haldol, phenothiazines, this can cause dystonias and extrapyramidal symptoms. The dystonias are treated with anticholinergics, benzotropine, diphenhydramine, and seizures, tardive dyskinesia, and neuroleptic malignant syndrome can also be seen with these medications. So here's another case, a 45-year-old African-American man presented to the emergency department with fever, encephalopathy, tachypnea, tachycardia, hypotension, and significant clonus on exam. He was admitted for meningitis given his altered mental status and fever. Eventually, he was treated with cooling fluids, benzodiazepines, and bromocriptine after his CSF was found to be after his CSF was found to be negative with no cells and negative cultures, and his family brought in a bottle of risperidone which was found empty at his bedside. So neuroleptics may cause significant arrhythmias as well as serotonin syndrome and neuroleptic malignant syndrome. This is a figure showing the typical sequence for torsades de pointe which starts with QT prolongation on the left side of the figure followed by ventricular ectopy and then into torsades de pointe in the section labeled D. Tachycardia is common and anticholinergic effects are seen in this patient group as well as hypotension because of alpha-1 adrenergic blockade. So in summary, you start with your physical exam to try to point you in the correct direction when dealing with patients that present with encephalopathy. Vital signs will help elucidate the pathophysiology and remember to keep your differential diagnosis broad. Look for metabolic derangements or intoxication if symptoms are out of proportion to the imaging or lab abnormalities. Thank you for your attention.

neurotoxicology

metabolic syndromes

acute encephalopathy

clinical approach

manifestations

physical exam findings