Thank you for the opportunity to speak today. My name is Arianne Lewis. I'm the Director of Neurocritical Care at NYU Langone Medical Center in New York. I'm going to be speaking today about the evaluation of coma and encephalopathy. I have no disclosures. During this talk, we'll review the terminology associated with coma and encephalopathy, review the etiologies of coma and encephalopathy, review the workup for coma and encephalopathy, and review treatments for various etiologies of coma and encephalopathy. The terminology associated with coma and encephalopathy can be a bit confusing at times. As a result, in the past year, there was a publication put forth by 10 different critical care societies regarding how we should define these terms. They noted that the term coma refers to a clinical state of severely depressed responsiveness defined by diagnostic systems such as GCS or the four score, and that the term acute encephalopathy refers to a rapidly developing over less than four weeks, but usually within hours to a few days, pathobiological process in the brain. Both of these are preferred terms. Contrastingly, the terms altered mental status, acute confusional state, acute brain dysfunction, and acute brain failure were noted that they should not be used. Another term that is a preferred term is the term delirium, which refers to a clinical state characterized by a combination of features defined by the DSM-5. These features include disturbance in attention, such as reduced ability to direct, focus, sustain, and shift attention and awareness, reduced orientation to the environment. Delirium develops over a short period, usually hours to days, and represents an acute change from baseline attention and awareness. And delirium tends to fluctuate in severity over the course of the day. Patients who are delirious can also have a disturbance in cognition. Patients who are delirious have evidence from their history, their physical exam, or lab findings that the disturbance is a direct physiologic consequence of another medical condition, substance intoxication or withdrawal, exposure to a toxin, or could be due to multiple different etiologies. When thinking about encephalopathy, there are a number of different types of etiologies, including vascular pathology, infection, trauma, toxins, autoimmune processes like ADEM or steroid-responsive encephalopathy, metabolic abnormalities such as abnormalities and derangements of electrolytes, endocrinopathies, renal failure, liver failure, hypercarbia or hypoxemia. Additionally, there could be encephalopathy due to iatrogenic situations such as limited mobility, day-night dysregulation, sensory deprivation, and post-operative pain. Patients can also develop encephalopathy due to cancer for a wide range of different reasons, including primary or metastatic CNS tumors, carcinomatous meningitis, or perineoplastic limbic encephalitis. And encephalopathy can also be the result of neurodegenerative or epileptic processes. When thinking about toxic encephalopathy, there are a wide range of different agents that can lead to toxic encephalopathy. These include anticholinergic agents, which present in addition to encephalopathy with tachycardia, urinary retention, flushing, medriasis, dry skin, and this can be reversed using physostigmine. Sympathomimetic agents can lead to euphoria, agitation, medriasis, hypertension, tachycardia, and diaphoresis in addition to encephalopathy, and this can be reversed using benzodiazepines. Serotonin syndrome presents with hyperreflexia and clonus, as well as autonomic hyperactivity in addition to encephalopathy, and this can be reversed using ciproheptidine. Hallucinogens lead to euphoria and altered perceptions and hallucinations in addition to encephalopathy, and this can also be treated with benzodiazepines, as can withdrawal from GABA-A agonists. Wernicke's encephalopathy presents with ataxia, and it also includes ophthalmoparesis and ocular cranial nerve deficits, and patients present with confabulation, and this can be treated with thiamine. In terms of prevention and treatment of delirium in the ICU setting, there are both pharmacologic and non-pharmacologic means to do this. From a pharmacologic perspective, we can prevent and treat delirium using dexmedetomidine or dopamine antagonists like haloperidol, quetiapine, or ziprasidone. It's important to note that dopamine antagonists should be used sparingly for agitation, as there are a number of risks associated with them, including sedation, hypotension, or sudden death in the setting of arrhythmias. Melatonin can also be beneficial to correct the day-night dysregulation. From a non-pharmacologic perspective, early physical therapy, ensuring the use of hearing and visual aids and frequent reorientation can help to correct delirium, and additionally, reduction of the use of restraints and sleep hygiene is also beneficial. We now turn to our first case, which is a case of PRESS, posterior reversible encephalopathic syndrome. So in this case, a 45-year-old woman with a history of hypertension comes in with confusion, headache, and seizures. Her systolic blood pressure was in the 180s. As you can see on the MRI here, there are hyperintensities on this flare sequence bilaterally, and you can actually see that this is not just in the posterior distribution, but actually can be seen anteriorly as well. That P in PRESS is a bit of a misnomer, in that it's not necessary for these changes to appear in a posterior distribution. Also the R is a misnomer, because it's not necessary for these changes to be reversible. Some patients with PRESS can actually have infertentorial changes as well. In terms of etiologies for PRESS, this can develop in the setting of hypertension, renal failure, inflammatory disorders, or in the setting of a number of different drugs, such as immunosuppressives, antivirals, chemo, or stimulants. In terms of management of PRESS, it's necessary to control blood pressure, and of course to discontinue the inciting agents. Our second case is a case of Warnicki's encephalopathy. In this case, a 63-year-old woman with a history of depression comes in with disorientation, inattentiveness, and ophthalmoparesis. As you can see on the MRI here, this flare sequence shows that there's hyperintensities symmetrically bilaterally in the thalami. When thinking about Warnicki's encephalopathy, it's important to recognize there are a number of different etiologies for this. There can be low uptake, absorption, or utilization of thiamine, or there can be raised thiamine metabolism. And this can be the result of toxins, such as alcohol or chemotherapy, can be the result of GI abnormalities, hyperthyroidism, infectious or inflammatory disorders, or genetic inactivation of thiamine transport. In terms of management, it's important to start high-dose thiamine early. Our third case is a case of post-operative encephalopathy. In this case, a 50-year-old man had a bifrontal meningioma resected yesterday. He was doing well post-op, but now he's somnolent. We can see on his head CT here that he's got marked bifrontal pneumocephalus, and this can be certainly contributing to his encephalopathy. In terms of management, we lay the head of bed flat and can put him on 100% non-rebreather. This can help to displace the air that's in his brain, since 100% non-rebreather will give him all oxygen, whereas the air in his brain is mostly nitrogen. In the most extreme of circumstances, you could think about a needle decompression like you would for a pneumothorax, if there's any opening in the skull, and also could think about a bifrontal craniectomy if you think that the air is causing so much pressure that there's risk of herniation. Our fourth case is a case of hepatic encephalopathy. In this case, a 50-year-old man with a history of cirrhosis is found to be lethargic and disoriented to time and situation. He has asterixis and an ammonia level of 250. We can see on his head CT here that there's some sulcal effacement and loss of differentiation of the gray-white matter. In terms of workup for hepatic encephalopathy, imaging is very important to be able to assess for evidence of cerebral edema. This can be done with a head CT or an MRI. EEG is beneficial to be able to rule out seizures. Transcranial dopplers are used in some cases to be able to evaluate intracranial pressure. Similarly, evaluation of optic nerve sheath diameter can be used using ultrasound in order to evaluate ICP. In terms of management, lactulose can help to remove some of the ammonia. This is an osmotic laxative. Rifaximin helps to decrease ammonia production, and then when ammonia is quite high, as it is in this case, dialysis can help to get the ammonia out of a patient's system. And then, of course, in terms of management of cerebral edema, we have hypertonic saline and mannitol. We turn now to a discussion of coma. Coma develops in the setting of damage to the bilateral hemispheres or brain stem. Patients who are comatose only have reflexive motor responses. They have no sleep-wake cycle, no ability to communicate, and no vision. Patients who are comatose have no arousal or awareness for at least one hour. The Glasgow Coma Scale can be used to describe the depth of a patient's coma, ranging from 3 to 15, with 3 indicating that they have no eye opening to voice or pain, no response to tactile stimulation, and are nonverbal, and 15 meaning that they're following commands, they're alert and oriented, and have spontaneous eye opening. This number provides a gross assessment as to the patient's state, but doesn't really qualify the specifics associated with the exam. For example, a 10 on the GCS score could mean a variety of different things in terms of the level of alertness and in terms of the motor exam. As a result, when describing a patient's exam, it's best to describe each individual component of the exam in terms of how alert they are, what is their cranial nerve functionality, and what is their motor assessment, rather than just providing a simple number from the GCS score. Another rating score which can be used to evaluate the extent of coma is the 4 score. The 4 score evaluates eye response, motor response, brainstem reflex, and respiration pattern. A study published in 2009 by Iyer et al. found that there was similar inter-rater reliability between observers who completed the 4 score and completed the GCS for patients. In terms of the predictive power for poor neurologic outcome, which was defined as a modified rank and scale score of 3 to 6, the area under their operating curve was similar for both the 4 score and the GCS score, 0.75 for the 4 score and 0.76 for GCS. Mortality for patients with the lowest 4 score, a score of 0, was 89% and was higher than that of the lowest GCS score of 3, which was 71%. The 4 score, like the GCS score, has a low score for patients who are completely unresponsive and have no reflexes, have a poor breathing pattern, and are not moving, and a high score for patients who are awake and alert and interactive and following commands. The potential etiologies for coma are the same as the etiologies for encephalopathy. There can be problems both in the brain and systemic issues that lead to coma. In terms of brain injury, TBI, including subdural hematoma, epidural hematoma, or intraparenchymal hemorrhage, could lead to brain compression and herniation. Both ischemic and hemorrhagic strokes could also lead to coma, such as in the setting of a posterior circulation infarct or bleed or a subarachnoid hemorrhage. Infections of the brain and meninges, like encephalitis and meningitis, could also cause coma. Neoplasms could cause brain edema and subsequent compression, leading to coma. Hydrocephalus, PRESS, seizures, and anoxic brain injury are other causes for coma. From the systemic perspective, a wide array of different processes could lead to coma. Cardiac arrest could cause coma. Hypoxic or hypercarbic respiratory failure could lead to coma. Uremia or severe hypo- or hypernatremia could cause coma. From a GI perspective, as we spoke about earlier in this presentation, hepatic encephalopathy and severe vitamin deficiencies, particularly thiamine deficiency, could lead to coma. Sepsis and TTP are other causes of coma. Endocrinopathy, such as severe hypo- or hyperthyroidism or hypo- or hyperglycemia, could also cause coma. A wide range of toxins, as we mentioned earlier in this talk, could also lead to coma, including alcohol, benzodiazepines, opiates, and other drugs. As a result, the workup for coma needs to be broad. Of course, the workup should be directed based upon the clinical history. Workup should include electrolytes, LFTs, CBC, coags, alcohol level, serum and eutox, and ABG, troponin, blood cultures, UA and urine culture, ammonia, B12, folate, and TSH. If none of these labs are revealing for an etiology for coma, it's appropriate to proceed with getting a head CT. This is also particularly important if a patient has been found down or if there's any concern for primary pathology in the brain. If all of these tests do not provide the answer in terms of why a patient is comatose, then getting an EEG to rule out seizures or an LP to rule out CNS infection or an MRI to do a better study of the brain is warranted. In the best case scenario, when a patient is comatose, they subsequently recover. However, this does not always happen. Plum and Posner described the various states of disorders of consciousness which can emerge after coma, including a minimally conscious state, a vegetative state, and brain death. Brain death was first described in detail in the United States in a publication in the Journal of the American Medical Association in 1968. The article was written by an ad hoc group at Harvard, which had convened to address the definition of brain death, which was also known as an irreversible coma. The criteria for brain death included coma, absence of brainstem reflexes, and inability to breathe spontaneously. This will be discussed further in a talk later today. The vegetative state was described by the American Academy of Neurology in a statement in 1995. Patients who are vegetative have transitioned from coma to a vegetative state after about 10 days when they've reacquired the ability to open their eyes. As with comatose patients, these patients lack awareness of themselves or their environment, but they do have preserved sleep-wake cycles. There can be variable preservation of cranial nerve function and only non-purposeful or reflexive movements. The vegetative state may be temporary or may be permanent. A persistent vegetative state is described as a vegetative state that lasts more than 30 days, whereas a permanent vegetative state is described as a persistent vegetative state that is believed, with a high degree of clinical certainty, to be irreversible. Minimally conscious state was described by Joe Giacino. In this state, patients have partial preservation of consciousness. There can also be fluctuation of their partial preservation of consciousness. In order to be declared as being in a minimally conscious state, the patient must be able to reproducibly follow commands, gesture or provide yes-no responses, vocalize intelligibly, and exhibit purposeful behavior. They may localize to sound or noxious stimuli and may be able to reach for objects. Patients can be in a minimally conscious state in a temporary basis or on a permanent basis. It's important to recognize that the minimally conscious state can sometimes be confused for a vegetative state. This is particularly problematic in terms of considerations related to rehab and therapy and prognosis on account of the fact that patients who are minimally conscious have some degree of interactability and ability to participate in rehab, whereas those who are in a vegetative state do not. There can be challenges, as I mentioned, in describing and identifying the difference between patients who are in a minimally conscious state and patients who are in a vegetative state. The rate of misinterpretation can be as high as 40%. In some cases, advanced techniques such as the use of an fMRI has been used to be able to assess for consciousness in patients who appear to be vegetative, and actually it's been found that some of these patients are able to communicate. And using the fMRI, patients are able to demonstrate that they can activate their supplementary motor area when asked to imagine playing tennis or be able to activate their parahippocampal gyrus when asked to imagine walking around their house. One study on this topic was published in New England Journal back in 2010. There's been a wide range of research pertaining to this in recent years, evaluating patients for covert consciousness. Like the fMRI studies, EEG has been utilized to evaluate for covert consciousness in patients who appear to be unconscious. Some studies have demonstrated that 15% of acutely brain injured patients who appear to be unconscious are actually able to demonstrate changes on their EEG when instructed to complete certain movements. This confirms that some of these patients actually have some degree of awareness, similar to what was found on the fMRI. A number of ethical questions are raised related to these findings. Our first case pertaining to coma is about a patient in a postoperative coma. This is an 84-year-old woman who remains unresponsive postoperatively after hip surgery. In this case, the differential diagnosis is that she's got residual effects of anesthesia still influencing her alertness, such that this is more of a toxic process. This could be an ischemic stroke that's leading her to remain unresponsive. It's possible that she has a big intracranial hemorrhage or that she's having ongoing seizures in this case. However, when she got an MRI, you can see here on the DWI sequence that there are small to medium-sized infarcts scattered throughout the brain bilaterally. Unfortunately, in the setting of hip surgery, this patient had a shower of fat emboli, which caused a devastating degree of infarcts in her brain. Our second case addresses anoxic coma with subsequent progression to anoxic encephalopathy. In this case, a 64-year-old man presented after a cardiac arrest with returned spontaneous circulation after 23 minutes. He was cooled and then subsequently rewarmed. His EEG initially showed generalized periodic epileptiform discharges, but after initiation of levotiracetam, it just showed slowing. His MRI, which is shown here, showed subtle posterior cortical riveting. You can see that around the rim of the cortex in this DWI sequence, there's a little bit of hyperintensity consistent with mild anoxic injury. On post-arrest day 7, he opened his eyes minimally to pain. He had reactive pupils, a sluggish corneal reflex bilaterally, no gag reflex, and didn't move his extremities to painful stimulation. At this time, his GCS score was 4. On post-arrest day 24, he had improved substantially and was opening his eyes spontaneously, attended, followed commands, was still nonverbal, but moved his arms more than his legs in the plane of the bed spontaneously. This demonstrates the progression of recovery from anoxic injury. Anoxic injury, which is discussed in a different talk in this series, can progress by beginning with a hypoxic event and then leading to decreased cerebral blood flow, loss of consciousness, intracellular acidosis, subsequent depletion of ATP stores, a release of cytokines and inflammatory mediators, then subsequent depolarization of neuronal membranes, intracellular influx of sodium chloride, water, and calcium, and then subsequent cellular swelling, metabolic dysfunction, and death. This process is attempted to be aborted by early CPR and then subsequently secondary injury is attempted to be prevented through the use of TTM. In this case, for this patient, who was indeed cooled, TTM allowed his brain to have gradual recovery and he obviously, even in this few-week period, showed significant improvement. Here's a few key takeaways regarding coma and encephalopathy. First, there are numerous etiologies for coma encephalopathy, including both primary neurological and systemic disorders. Second, identification of the etiology for coma and encephalopathy is dependent on obtaining a detailed history and, in some cases, can require a broad workup. Third, early empiric therapy for Wernicke's encephalopathy with high-dose thiamine should always be considered when evaluating patients who are comatose or encephalopathic that have a history that could be compatible with this diagnosis. It's important to recognize that coma and encephalopathy can improve over time, but sometimes prognostication can be challenging. Additional research about coma is needed. As a result, the Neurocritical Care Society has initiated the Curing Coma Campaign to address a wider range of research pertaining to care for patients with coma and recovery from coma. Thank you very much for your attention.

coma

encephalopathy

evaluation

etiologies

workup

consciousness