Brainstem Testing

Pupillary reflexes in themselves can point to the etiology of coma. Bilateral miotic pupils are most commonly the result of a pontine lesion or intoxication with drugs of abuse such as opiates or cocaine. On the other hand, bilateral mydriasis can be due to opiate withdrawal or intoxication with anticholinergics or drugs of sedating properties. Pupillary asymmetry can be the result of pathology to either the larger pupil in the setting of herniation causing blown pupil, or pathology to the smaller pupil in Horner syndrome. An acute Horner syndrome in the ICU is typically the result of damage to the third-order sympathetic chain fibers from internal jugular vein central line placement or to the second-order sympathetic fibers during thoracic surgery. Unilateral pupillary dilation in the setting of aerosolized anticholinergics for respiratory conditions or a scopolamine patch for nausea can commonly raise alarms and lead to unnecessary brain imaging. A unilateral blown pupil in an individual who is neurologically otherwise intact and able to converse normally should raise suspicion for topical drug-related mydriasis.

An acute oval pupil implies either midbrain disease or increased ICP with impending herniation. Chronic oval or irregular pupils reflect intrinsic eye disease or previous ocular surgery (2). Hippus is an intriguing, but normal, cyclic pupillary constriction and dilation to ongoing illumination which can catch the eye of the astute observer.

Forced gaze deviation can be seen in a multitude of etiologies and do not necessarily point toward a structural focus. Gaze preference on the other hand implies injury to the ipsilateral hemisphere in either frontal, parietal, or occipital gaze centers. Intermittent gaze preference would point toward an epileptic etiology. Downward gaze can occur in a lesion to the thalamus or dorsal midbrain as a result of either hypoxic/ischemic injury, increased ICP, or acute hydrocephalus. Upward gaze on the other hand is poorly localized, indicative of bihemispheric damage and seen especially in the setting of considerable anoxic injury. Skew deviation is the vertical malalignment of the eyes and indicates damage to either the brainstem or the cerebellum. Roving eye movements are constant spontaneous horizontal back and forth eye movements which are frequently seen in severe encephalopathy of any cause. Ping pong gaze is also spontaneous horizontal gaze that alternates every few seconds and has been seen in toxometabolic encephalopathy, strokes, and hemorrhages (3). Ocular bobbing is spontaneous rapid downward nystagmus with slow upward correction whereas ocular dipping is rapid upward nystagmus with slow downward correction, both indicating pontine damage. Finally, convergence nystagmus occurs with ocular divergence followed by rapid convergence. Most of the gaze findings with the exception of roving eye movements and forced gaze deviation are indicative of structural brain lesions.

Corneal reflexes test the integrity of ipsilateral cranial nerve (CN) V to bilateral CN VII. The examiner can squirt a small amount (about 2–3 mL) of normal saline into the eye and test for a blink response. This is advised in order to avoid corneal trauma via repeated scratch testing. Please take care in wiping tears of patients with infections transmissible via mucous membranes such as hepatitis C. If saline does not trigger a blink, one should proceed with a cotton wisp or the edge of a tissue and slightly touch the side of the cornea. Please keep in mind that corneal reflexes might not be consistent when patients develop corneal edema frequently seen in prolonged ICU admissions.

The facial nerve can be assessed grossly in the intubated patient by examining the symmetry of grimacing to painful stimuli. Vestibuloocular or oculocephalic reflexes test the reflex arc between CN VIII and CN III and VI. This test should be substituted with cold calorics if the patient is in a neck collar. Frequent missteps while performing the cold calorics testing include neglecting to examine the tympanic membrane for perforation and insufficient coldness to the water used.

Gag testing should be completed with a gloved hand physically gagging the comatose patient with the other hand over the diaphragm to assess for minimal responses. Reflex arcs for gag include CN V to CN X when stimulated on the soft palate and CN IX to CN X when assessed posteriorly by the pharynx. Cough reflex is stimulated by introducing a suction catheter into the endotracheal tube. One should note the depth of catheter advancement required to stimulate a cough reflex. The examiner should also note the ability of the patient to take independent breaths above the ventilator setting, so-called “breathing over the vent.” This assessment can be tricky for several reasons. When patients are hyperventilated with a ventilator rate set at or above 18 breaths/min, there is usually no physiologic drive to breathe over the set rate. These patients would commonly be labeled as not breathing over the vent. On the other hand, the sensitivity of the ventilator in picking up an initial breath might be set so low that random movements can be misconstrued by the machine as an attempt to breath. These patients will falsely be labeled as breathing over the ventilator. There are several ways to assess for independent breathing including switching ventilation to spontaneous mode, disconnecting the ventilator transiently, or setting the respiratory rate low and the sensitivity high. In conclusion, a good coma brainstem examination can assess for CN II, III, V, VI, VII, VIII, IX, and X.

Motor Testing

Motor testing in an uncooperative patient can be difficult. Much of the testing is done by observation of spontaneous movements. Restraints on a patient can offer a good starting point of motor assessment. If a patient does not require restraints on his right arm, one would suspect paresis. Tone is a valuable component of the coma examination which is unfortunately frequently overlooked. Asymmetric tone is suspicious for hemiparesis whereas diffuse hypertonia raises suspicion for tetany or neuroleptic malignant syndrome (NMS). Tone predominantly increased in the lower extremities is a common presentation of serotonin syndrome (SS). Meningeal signs should also be tested with nuchal rigidity and Kernig and Brudzinski signs. Marked acute flaccidity might point to poisoning or drug intoxication whereas flaccidity in the setting of a prolonged ICU admission implies critical illness myopathy.

Miscellaneous Testing

Adventitious movements should be noted, especially fine rhythmic movements such as flickering of eyelids, continuous low amplitude jerking of any limb, or continued nystagmus which should raise alarm for nonconvulsive status epilepticus (NCSE). Asterixis or negative myoclonus, if noted, can point toward a hepatic or renal encephalopathy. Asterixis is seen not only in the failure to maintain extension of the hand at the wrist but also with the inability to sustain lip puckering or a flexion–abduction position at the hip.

General Care Principles

The following subsections discuss the most common causes of altered awareness within each subset of patients. There is a plethora of causes for mental status changes and any of these etiologies can be found in any patient. Tables 120.2 and 120.3 review common items in a differential diagnosis of encephalopathy, separated by history, location, general examination findings, neurologic examination findings, laboratory results, and electrophysiologic testing and imaging.

Coma in the Infected Patient

Meningoencephalitis can undoubtedly result in mental status changes. With any suspicion for a meningeal infection, blood cultures should be drawn before antibiotics are administered, as long as doing so does not delay the dosing. Acyclovir should be added to the meningeal antimicrobial regimen until herpes simplex virus has been ruled out by cerebrospinal fluid (CSF) analysis.

Systemic infections resulting sepsis or septic shock commonly give rise to mental status changes largely as a result of hypoxic–ischemic conditions (4). One should be cautious in attributing altered mental status to a urinary tract infection unless in the setting of overt pyuria or urosepsis.

Altered consciousness can be triggered by not only systemic infections, but also by antibiotics or other drugs prescribed by medical practitioners (Table 120.4). The main culprits for antibiotic-induced encephalopathy are cefepime and metronidazole. Cefepime-related encephalopathy can be quite severe and has even been noted to present almost like brain death (5). Withdrawal of these antimicrobials should result in gradual mental status improvement.

Coma in the Risk-Taking Patient

Patients in this cohort are those who partake in substance abuse, either alcohol, illicit medications, or prescription medication. Performing toxicology screens are absolutely essential in the workup of patient with altered mental status; one needs be familiar with the various toxicology screens available in their institution between urine and serum analysis. Alcohol intoxication and withdrawal are obvious causes of mental status changes and will not be discussed further. Please see Definitions section on delirium tremens. With any suspicion for alcohol history, administer thiamine prior to glucose in order to avoid depletion of thiamine stores and precipitation of Wernicke encephalopathy.

TABLE 120.2 Common Considerations in a Differential Diagnosis of Encephalopathy

Drug intoxication, be it illicit or prescription overdose, can be difficult to confirm at times. The metabolic rate to clear massive overdoses might be unpredictable and daily toxicology screens might be required to assure clearance of the offending agent. Of note, several of the newer synthetic illicit substances do not surface in conventional drug screens.

Coma in the Neurologic Patient

In addition to the etiologies listed in these subcategories, neurologic patients can present with abrupt mental status changes in the setting of certain infarcts, acute hydrocephalus, postictal periods, and herniation syndromes. Strokes causing altered awareness without focal findings include diffuse embolic shower commonly seen in patients with atrial fibrillation, a temporal lobe infarct, or a thalamic infarct. Keep in mind that not all strokes result in a focal finding; among infarcts, a strategic infarct of the pons can result in a locked in state in which patients have movement limited only to eyes. These patients appear to be comatose but are locked in with intact awareness as the RAS arc is spared. They have an intact ability to communicate via eye blinking and should not be classified as comatose.

Acute hydrocephalus in the setting of SAH can present as a brain dead patient. With confirmation via computerized tomography (CT) of the head, prompt CSF drainage can result in rapid improvement of mental status.

TABLE 120.3 Altered Mental Status with Normal CT/MRI of the Head

Patients with a history of seizures presenting with altered awareness should point to a postictal state. Look for clues of seizure such as Todd paresis or tongue trauma. Prolactin is released when a seizure focus runs through the thalamus. Levels are elevated only in cases of status epilepticus, generalized and complex partial seizures, not in focal or non convulsive seizures. Utility of prolactin levels is limited to distinguishing an epileptic convulsion from a pseudoseizure. An electroencephalogram (EEG) can be useful to rule out NCSE in patients with a prolonged postictal state with occasional adventitious movements described above.

TABLE 120.4 Causes of Drug-Induced Encephalopathy

Any of the herniation syndromes can result in altered awareness, if not coma. These patients exhibit Cushing reflex—bradycardia and hypertension—prior to having respiratory compromise, which completes the triad of Cushing. Interventions to lower intracerebral pressure such as hyperosmolar or hypertonic therapy, transient hyperventilation, and head of bed elevation to 30 degrees should be rapidly instituted. Treatment specifics for increased ICP are discussed in Chapter 118.

Coma in the Psychiatric Patient

Altered awareness in the psychiatric patient can result from NMS, SS, akinetic mutism, or benzodiazepine withdrawal, to name but a few of the causes.

NMS and SS should be at the top of the physician’s differential diagnostic list for psychiatric patients. There are numerous medications that can precipitate either of the syndromes and it is imperative to abort the offending agent as soon as it is discovered. NMS can present with many of the same signs and symptoms as SS. Both syndromes can cause altered awareness to varying degrees, fever, hypertonicity, and autonomic dysfunction. The onset of NMS is generally slower taking days to weeks whereas SS can occur abruptly. SS can also be differentiated by the presence of shivering and marked hypertonicity of the lower extremities compared to NMS which presents with symmetric hypertonicity. Hyporeflexia can be seen with NMS as opposed to hyperreflexia with SS. In either syndrome, the offending agent should be discontinued and benzodiazepine started, making the point that differentiating between the two syndromes is nowhere as important as implementing medication changes.

Patients with advanced psychiatric conditions can also present with akinetic mutism when falling ill with another medical condition. In this syndrome, patients appear locked in, only capable of moving their eyes, but have an unremarkable neurologic examination. Yet another issue is that scheduled benzodiazepines are frequently in a psychiatric patient’s outpatient medication regimen. Many of these medications are not continued for various reasons during an admission, which may result in benzodiazepine withdrawal gradually occurring.

Malingering patients can present with psychogenic coma, a diagnosis of exclusion. In addition to appearing to be in a coma, these patients resist and avoid various stimuli ranging from mildly irritating to noxious. The classic test of dropping the arm over the face will result in the patient swinging it down to avoid the face. Performing a cold caloric vestibuloocular test in a nonorganic coma patient might be the ultimate noxious stimuli resulting in emesis and rapid reversal of coma.

Coma in the Medical Care Unit

The medical intensive care unit (MICU) encounters its fair share of patients with altered mental status. In addition to the several etiologies discussed earlier in this chapter, the most common causes of encephalopathy in the MICU includes metabolic causes such as electrolyte imbalances, acid–base disturbances, blood sugar derangements, hypoxia, and drug-induced encephalopathy; Table 120.4 lists medications frequently resulting in encephalopathy.

Patients with renal, hepatic, or gastrointestinal comorbidities affecting absorption frequently have electrolyte imbalances. The main electrolytes at play for encephalopathy include sodium, magnesium, and calcium. Hepatic failure can result in hyperammonemia, which improves with lactulose. Renal failure, when severe, can cause mental status changes due to acidemia, further electrolyte changes, or uremic encephalopathy; the initial dialysis session can also trigger encephalopathy due to osmotic shifts with the initial dialysis, a condition known as dialysis disequilibrium syndrome.

Endocrine-related etiologies of mental status changes include severe hypothyroidism known as Hashimoto encephalopathy, as well as severe hypo- or hyperglycemia from poor insulin management. Acute adrenal insufficiency, Addison disease, can present due to either insufficient steroid supplementation at times of physical stress—such as surgery—or sepsis. As the adrenal crisis progress, patients can become profoundly encephalopathic, although, if treated appropriately, prognosis is good. Acidosis and hypoxia are very common in the MICU from various respiratory causes. Mental status changes resulting from severe hypoxia have a grim prognosis with respect to recovery; further details are discussed in the cardiac patient subcategory. The clinical spectrum of acidosis can range from neurologically intact to seizures and coma.

Patients with uncontrolled hypertension can develop posterior reversible encephalopathy syndrome (PRES). MRI of the brain shows white matter changes in posterior lobes, but these changes can also be found in the rest of the brain. When the high blood pressure is addressed, patients generally return to their baseline unless the PRES lesions resulted in ischemic or hemorrhagic complications.

Coma in the Pregnant Patient

Pregnant patients with preeclampsia are routinely subject to PRES, described above. One frequently overlooked detail is the patient’s baseline blood pressure. Pregnant women usually have low blood pressures and a sudden rise of systolic pressures to 160 or 170 might be high enough to trigger PRES. Seizures can result with eclampsia and should be treated immediately with magnesium. Seizures and altered mental status may also be the result of HELLP syndrome which is composed of hemolysis, elevated liver enzymes, and low platelets. With thrombocytopenia, widespread bleeding can occur including SAH. Treatment includes antihypertensives, platelet transfusions, and prompt delivery of the baby. Peripartum abrupt mental status changes are alarming, and usually due to either pituitary apoplexy or amniotic fluid embolism, both of which can have grim prognoses.

Coma in the Cardiac Care Unit

Consultations from the cardiac ICU for encephalopathy are mostly resultant to either cardioembolic infarcts or postresuscitative mental status changes; see the subsection on coma in neurologic patients for details on stroke-related encephalopathy.

With layperson CPR becoming commonplace, the survival of patients who suffer cardiac arrest has increased. Prognosis after cardiac arrest has become increasingly difficult in the era of hypothermia. Several of the previously known factors pointing toward poor prognosis are now noted to have higher false-positive rates (FPRs). Absence of pupillary reactivity, myoclonic jerks on the first day of arrest, absent somatosensory responses, and serum neuron–specific enolase (NSE) value more than 33 ng/mL previously had very low individual FPRs. Several case series have been published in regard to each of these prognostication markers with higher FPRs (6–9). It is important to consider these factors together for accurate prognostication after cardiac arrest in order to avoid the self-fulfilling prophecy that results from withdrawal of care.

Coma in the Postoperative Patient

The most common reasons for coma or altered awareness in a postoperative patient include delayed anesthesia clearance, hypoxic or ischemic injury suffered during surgery, or fentanyl-related SS. A patient’s baseline cognitive status can help predict the rate of recovery from anesthesia. A patient that is demented will take longer to recover than a cognitively healthy individual. If a cognitive baseline is not available, a CT of the head showing considerable atrophy can be of help in determining the cause for slow emergence. Delayed clearance of anesthetics can also occur in patients with pre-existing hepatic or renal failure. To add to this, complicated surgeries can require patients to be placed under sedation for days to recover purely from a surgical standpoint. It is near impossible to predict when prolonged and continuous sedation will be completely metabolized. Finally, as surgical procedures are being performed in an increasingly aging population, it is not uncommon for patients to emerge from anesthesia after surgery with a stroke. Hypoxic/anoxic injury after surgery, resultant from prolonged esophageal intubation, is thankfully rare given the monitoring changes implemented in modern operating suites and driven by anesthesiology, such as pulse oximetry and capnography, among others.

Fentanyl is commonly used in the operating room, and patients on concomitant psychotropic medications with renal failure can be prone to SS. When patients are in the recovery room, altered mental status may not be recognized, and shivering from SS sets in; meperidine is frequently given for postoperative shivering which turns out to be another precipitant of SS. Unfortunately, SS is often not recognized, and patients can decline secondary to this failure to recognize. It requires an astute observer to note hypertonicity in the legs greater than arms to introduce SS into the differential diagnosis.

Coma in the Posttransplant Patient

Much related to coma in the posttransplant patients is shared with postoperative patients. However, in addition to the previously mentioned causes, the posttransplant patients also suffer from electrolyte derangements, hyperammonemia, neurotoxicity from potent immunosuppressive agents, and opportunistic infections.

Among opportunistic agents, cytomegalovirus, Cryptococcus neoformans, or Aspergillus fumigatus are common players. Cytomegalovirus, although the most common systemic posttransplant opportunistic infection, rarely triggers encephalitis. Fungi, on the other hand, can result in numerous brain abscesses which are both generators of seizures and may also result in intracranial hemorrhage. Aspergillosis should be considered in a posttransplant patient with multiple simultaneous intracranial hemorrhages.

Toxicity from either chemotherapeutic or immunosuppressant agents usually results in a gradual alteration of consciousness. MRI generally reveals diffuse white matter lesions, which are fully reversible with discontinuation of the medication. Tacrolimus and cyclosporine commonly cause neurotoxicity, whereas sirolimus is generally well tolerated from a neurologic standpoint (9). Seizures occur in up to 39% of cardiac transplant patients, most frequently due to immunosuppressive medications.

Coma in the Cancer Patient

Cancer patients are unfortunately subject to neurotoxicity from chemotherapeutics, seizures from cerebral metastasis, and intracerebral hemorrhage of metastases or carcinomatous meningitis.

Methotrexate is an agent notorious for causing encephalopathy. MRI usually demonstrates widespread white matter changes, not necessarily reversible if the agent is not discontinued promptly. Cerebral metastasis or primary neoplasms frequently bleeding include glioblastoma multiforme, renal cell carcinoma, small cell cancer of the lung, melanoma, and choriocarcinoma. These tumors have a higher incidence of bleeding as they are highly vascular or tend to erode into vasculature, as in the case of choriocarcinoma (10). Tumors that trigger seizures are usually slow growing primary brain tumors such as gliomas or a metastasis to the cortical surface. Typical cerebral metastasis that induce seizures include melanoma and lung and breast cancers (11). Lamotrigine, valproic acid, and topiramate are first-line antiepileptic treatments of choice (12).

Carcinomatous meningitis can be a difficult entity to diagnose, often requiring a high-quality MRI and several spinal fluid samples. The sensitivity for CSF cytology can be as low as 50% (13), with modest gains on repeat taps. Patients usually present with subacute signs very similar to meningoencephalitis, but may also acutely decompensate if hydrocephalus develops.

Coma in the Trauma Patient

Altered consciousness in the trauma patient is self-evidently due to damage to the structural integrity of the brain. The etiologies are most commonly contusion, concussion, and/or hemorrhage, be it subarachnoid, epidural, subdural, or intraparenchymal and, in severe cases, diffuse axonal injury (DAI) or herniation. If the patient has a poor coma scale score, demonstrated by either GCS or FOUR systems, an ICP monitor should be placed. Patients should be examined for periorbital or mastoid ecchymosis known as raccoon and Battle signs, respectively, both indicating skull fractures; CSF otorrhea and rhinorrhea can be noted in these cases.

Depending on the severity of injury, patients can have either concussions or contusions. Any of the different types of hemorrhage can present with coma depending on the degree of mass effect, brain shift, and subsequent swelling. Neurosurgery’s timely drainage or decompression of the lesion determines the best outcome. If this drainage does not occur, and if patients undergo uncal herniation, the mesial temporal lobe can cause mass effect and push the brainstem over to the contralateral side. As the contralateral cerebral peduncle is pushed against the tentorium, the patient develops paresis of the ipsilateral side to the primary brain injury. Hence, a patient with injury to the left temple can have left hemiparesis. This is known as the Kernohan notch phenomenon or the “uncal herniation false localizing sign” and is a frequent cause of misdiagnosis.

Fat embolus is a rare etiology for altered awareness in the setting of long bone injury after trauma. The fat emboli can cause pulmonary edema, marked hypoxia, and subconjunctival or axillary petechiae. These patients have a star-speckled pattern of diffusion changes on MRI of the brain, which slowly resolves over 3 to 4 weeks; these patients generally have an excellent recovery. Unfortunately, after the trauma patient is stabilized, some do not awaken. These patients should be considered to have, and worked up for severe DAI. DAI is known to occur mostly in younger patients, in whom trauma may disrupt nerve fiber integrity in a global fashion. Recovery from DAI is grim; follow-up scans will demonstrate widespread atrophy of injured regions.

Case 1

A middle-aged patient with a history of seizures and hypertension presents in a comatose state. There is no additional history or witnesses available. Vital signs demonstrate a normotensive and afebrile individual with slow breaths, bradycardia, and desaturations while on supplemental oxygen, which leads to endotracheal intubation (ETI). The differential diagnosis is broad at this point with a high suspicion for seizures. General and neurologic examinations are unrevealing apart from roving eye movements, which are nonlocalizing. Laboratory studies, including toxicology screen, are unremarkable except for an arterial blood gas analysis, performed prior to ETI, consistent with respiratory acidosis. An EEG is obtained and the report states “excessive beta activity without seizures”; a CT of the head is unremarkable. In keeping with Table 120.2, the differential diagnosis in this case leads to either benzodiazepine or barbiturate overdose; diligent review of the patient’s medication regimen reveals phenobarbital and a laboratory study confirms overdose.

Case 2

An elderly, anxious, individual is evaluated for, cleared for, and undergoes a liver transplant. The surgery is a success and the patient does well, about to be discharged on postoperative day 4. On the morning of discharge, the nurse pulls you aside to state that the patient has become quite agitated. Examination reveals a restless and tremulous individual with tachycardia, tachypnea, elevated blood pressure, and diaphoresis. Halfway through the examination, the patient suffers a generalized tonic–clonic seizure, without localizing signs. Laboratory studies and CT imaging of the head are unrevealing, and EEG demonstrates mild diffuse slowing, commonly seen after seizure. Careful review of the patient’s medications reveal that he takes 2 mg of lorazepam orally three times daily for anxiety, which had not been continued during his admission. This presentation is of benzodiazepine withdrawal, unfortunately a common scenario. The importance of scrutinizing medications cannot be overstated.

Case 3

A middle aged patient with no known medical history presents in a confused state with bloody emesis. Examination reveals tachycardia, the odor of alcohol on patient’s breath, ascites, and caput medusa. Neurologic examination shows roving eye movements, decreased muscle tone, and asterixis. Laboratory studies of hepatic function and ammonia confirm a suspicion for hepatic encephalopathy and the patient was treated with lactulose.