Mohan Kottapally, MD

A 64-year-old woman undergoes elective T10-S1 nerve decompression with fusion for chronic idiopathic scoliosis. Soon afterward, she develops acute urinary retention attributed to an Escherichia coli urinary tract infection and narcotic medications. She is treated with antibiotics, an indwelling catheter is inserted, and her symptoms resolve. She is transferred to the inpatient physical rehabilitation unit.

See related editorial

On postoperative day 9, she develops an acute change in mental status, suddenly becoming extremely anxious and falsely believing she has a “terminal illness.” A psychiatrist suggests that these symptoms are a manifestation of delirium, given the patient’s recent surgery and exposure to benzodiazepine and narcotic medications. On postoperative day 10, she is awake but is now mute and uncooperative. An internist is consulted for an evaluation for encephalopathy and delirium.

MEDICAL HISTORY

Her medical history, obtained by chart review and interviewing her husband, includes well-controlled bipolar disorder over the last 4 years, with no episodes of frank psychosis or mania. She had a “bout of delirium” 4 years earlier attributed to a catastrophic life event, but the symptoms resolved after adjustment of her anxiolytic and mood-stabilizing drugs. She also has well-controlled hypertension, hypothyroidism, and gastroesophageal reflux. Her only surgery was her recent elective procedure.

She has a family history of dementia (Pick disease in her mother).

She is married, lives with her husband, and has an adult son. She is employed as a media specialist and also teaches English as a second language. Before this hospital admission, she was described as happy and content, though her primary psychiatrist had noted intermittent anxiety. Her husband does not suspect illicit drug use and denies significant alcohol or tobacco abuse.

A thorough review of systems is not possible, given her encephalopathy. But before her acute decline, she had complained of “choking on blood” and a subjective inability to swallow.

Her home medications include dextroamphetamine extended-release, alprazolam as needed for sleep, venlafaxine extended-release, lamotrigine, lisinopril, propranolol, amlodipine, atorvastatin, levothyroxine, omep­razole, iron, and vitamin B₁₂. At the time of the evaluation, she is on her home medications with the addition of olanzapine, vitamin D, polyethylene glycol, and an intravenous infusion of dextrose 5% with 0.45% saline at a rate of 100 mL/hour. She has allergies to latex, penicillin, peanuts, and shellfish.

PHYSICAL EXAMINATION

On physical examination, the patient seems healthy and appears normal for her stated age. She is wearing a spinal brace and is in no apparent distress. She is afebrile, pulse 104 beats per minute, respirations 16 breaths per minute and unlabored, and oxygen saturation good on room air. The skin is normal. No thyromegaly, bruits, or lymphadenopathy is noted. Cardiovascular, respiratory, and abdominal examinations, though limited by the spinal brace, are unremarkable. She has no evidence of peripheral edema or vascular insufficiency. Muscle bulk and tone are adequate and symmetric.

She is awake and alert and able to follow simple commands with some prompting. She does not initiate movements spontaneously. She makes some eye contact but does not track or acknowledge the interviewer consistently and does not respond verbally to questions. Her sclera are nonicteric, the pupils are equally round and reactive to light, and the external ocular muscles are intact. There is no facial asymmetry, and the tongue protrudes at midline. She blinks appropriately to threat bilaterally. Strength is at least 3/5 in the upper extremities and 2/5 in the lower extremities, though the examination is limited by lack of patient cooperation. She shows minimal grimace on noxious stimulation but does not withdraw extremities. Reflexes are present and mildly depressed symmetrically. Plantar reflexes are downgoing bilaterally.

INITIAL LABORATORY EVALUATION

On initial laboratory testing, the serum sodium is 132 mmol/L (reference range 136–144), stable since admission. Point-of-care glucose is 98 mg/dL. Aspartate aminotransferase and alanine aminotransferase levels are mildly elevated at 59 U/L (13–35) and 51 U/L (7–38), respectively, but serum ammonia is undetectable. Vitamin B₁₂, folate, thyroid-stimulating hormone, and free thyroxine are within the normal ranges. Leukocytosis is noted, with 14 × 10⁹ cells/L (3.7–11.0), 86% neutrophils, and a mild left shift. Urinalysis is negative for leukocyte esterase, nitrites, and white blood cells.

1. Which of the following risk factors predisposes this patient to postoperative delirium?

• Hyponatremia
• Polypharmacy
• Family history of dementia
• Depression

Altered mental status, or encephalopathy, is one of the most common yet challenging conditions in medicine. When a consult is placed for altered mental status, it is important to determine the affected domain that has changed from the patient’s normal state. Changes can include alterations in consciousness, attention, behavior, cognition, language, speech, and praxis and can reflect varying degrees of cerebral dysfunction.

Electrolyte abnormalities

Disorders of sodium homeostasis are common in hospitalized patients and may contribute to the onset of delirium. Hyponatremia is especially frequent and often iatrogenic, with a prevalence significantly higher in women (2.1% vs 1.3%, P = .0044) and in the elderly.²

Neurologic manifestations are often the result of cerebral edema due to osmolar volume shifts.^3–6 Acute hyponatremic encephalopathy is most likely to occur when sodium shifts are rapid, usually within 24 hours, and is often seen in postoperative patients requiring significant volume resuscitation with hypotonic fluids.⁶ Young premenopausal women appear to be at especially high risk of permanent brain damage secondary to hyponatremic encephalopathy,⁷ a finding that may reflect the limited compliance within the intracranial vault and lack of significant involutional parenchymal changes that occur with aging.^8–11

Aging also has important effects on fluid balance, as restoration of body fluid homeostasis is slower in older patients.¹²

Hormonal effects of estrogen appear to play a synergistic role in the expression of arginine vasopressin in postmenopausal women, further contributing to hyponatremia.

Although our patient has mild hyponatremia, there has been no acute change in her sodium balance since admission to the hospital, and so it is unlikely to be the cause of her acute delirium. Her mild hyponatremia may in part be from hypo-osmolar maintenance fluids with dextrose 5% and 0.45% normal saline.

Mild chronic hyponatremia may affect balance and has been associated with increased mortality risk in certain chronic disease states, but this is unlikely to be the main cause of acute delirium.

Polypharmacy

Patients admitted to the hospital with polypharmacy are at high risk of drug-induced delirium. In approaching delirium, a patient’s medications should be evaluated for interactions, as well as for possible effects of newly prescribed drugs. New medications that affect cytochrome P450 enzymes warrant investigation, as do drugs with narrow therapeutic windows that the patient has been using long-term.

Consultation with a clinical pharmacist is often helpful. Macrolides, protease inhibitors, and nondihydropyridine calcium channel blockers are common P450 inhibitors, while many anticonvulsants are known inducers of the P450 system. Selective serotonin reuptake inhibitors and diuretics can lead to electrolyte imbalances such as hyponatremia, which may further predispose to bouts of delirium, as described above.

The patient’s extensive list of psychoactive medications makes polypharmacy a significant risk factor for delirium. Quetiapine and venlafaxine both cause sedation and increase the risk of serotonin syndrome. However, in this case, the patient does not have marked fever, rigidity, or hyperreflexia to corroborate that diagnosis.

Dementia

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), defines dementia as a disorder involving cognitive impairment in at least 1 cognitive domain, with a significant decline from a previous level of functioning.¹ These impairments need not necessarily occur separately from bouts of delirium, but the time course for most forms of dementia tends to be progressive over a subacute to chronic duration.

Dementia increases the risk for acute confusion and delirium in hospitalized patients.¹³ This is partly reflected by pathophysiologic changes that leave elderly patients susceptible to the effects of anticholinergic drugs.¹⁴ Structural changes due to small-vessel ischemia may also predispose patients to seizures in the setting of metabolic derangement or critical illness. Diagnosing dementia thus remains a challenge, as dementia must be clearly distinguished from other disorders such as delirium and depression.

The acute change in this patient’s case makes the isolated diagnosis of dementia much less likely than other causes of altered mental status. Also, her previous level of function does not suggest a clinically significant personal history of impairment.

Mental illness

Several studies have examined the link between preoperative mental health disorders and postoperative delirium.^15–17 Depression appears to be a risk factor for postoperative delirium in patients undergoing elective orthopedic surgery,¹⁵ and this includes elderly patients.¹⁶ While a clear etiologic link has yet to be determined, disruption of circadian rhythm and abnormal cerebral response to stress may play a role. Studies have also suggested an association between schizophrenia and delirium, though this may be related to perioperative suspension of medications.¹⁷

Bipolar disorder has not been well studied with regard to postoperative complications. However, this patient has had a previous episode of decompensated mania, therefore making bipolar disorder a plausible condition in the differential diagnosis.

CASE CONTINUED: ACUTE DETERIORATION

Without a clearly identifiable cause for our patient’s acute confusional state, neurology and medical consultants recommend neuroimaging.

Computed tomography (CT) and magnetic resonance imaging (MRI) without contrast are ordered and performed on postoperative day 11 and demonstrate chronic small-vessel ischemic disease, consistent with our patient’s age, as well as frontotemporal atrophy. There is no evidence of mass effect, bleeding, or acute ischemia.

Overnight, she becomes obtunded, and the rapid response team is called. Her vital signs appear stable, and she is afebrile. Basic laboratory studies, imaging, and electrocardiography are repeated, and the results are unchanged from recent tests. She is transferred to the intensive care unit (ICU) for closer monitoring.

2. What is most likely cause of the patient’s declining mental status, and what is the next appropriate step?

• Acute stroke: repeat MRI with contrast
• Urinary tract infection: order blood and urine cultures, and start empiric antibiotics
• Neuroleptic malignant syndrome: start dantrolene
• Seizures: order electroencephalography (EEG)

Acute stroke

Acute stroke can affect mental status and consciousness through several pathways. Stroke syndromes can vary in presentation depending on the level of cortical and subcortical involvement, with clinical manifestations including confusion, aphasia, neglect, and inattention. Wakefulness and the ability to maintain consciousness is impaired, with disruption of the ascending reticular activating system, often seen in injuries to the brainstem. Large territorial or hemispheric infarcts, with subsequent cerebral edema, can also disrupt this system and lead to cerebral herniation and coma.

MRI without contrast is extremely sensitive for ischemia and can typically detect ischemia in acute stroke within 3 to 30 minutes.^18–20 Repeating the study with contrast is unlikely to provide additional benefit.

In our patient’s case, the lack of localizing neurologic symptoms, in addition to her recent negative neuroimaging workup, makes the diagnosis of acute stroke unlikely.

Infection

The role of severe infection in patients with altered mental status is well documented and likely relates to diffuse cerebral dysfunction caused by an inflammatory cascade. Less well understood is the role of occult infection, especially urinary tract infection, in otherwise immunocompetent patients. Urinary tract infection has long been thought to cause delirium in otherwise asymptomatic elderly patients, but few studies have examined this relationship, and those studies have been shown to have significant methodologic errors.²¹ In the absence of better data, urinary tract infection as the cause of frank delirium in an otherwise well patient should be viewed with skepticism, and alternative causes should be sought.

Although the patient has a nonspecific leukocytosis, her benign urinalysis and lack of corroborating evidence makes urinary tract infection an unlikely cause of her frank delirium.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is defined as fever, rigidity, mental status changes, and autonomic instability after exposure to antidopaminergic drugs. It is classically seen after administration of typical antipsychotics, though atypical antipsychotics and antiemetic drugs may be implicated as well.

Patients often exhibit agitation and confusion, which when severe may progress to mutism and catatonia. Likewise, psychotropic drugs such as quetiapine and venlafaxine, used in combination, have the additional risk of serotonin syndrome.

Additional symptoms include hyperreflexia, ataxia, and myoclonus. Withdrawal of the causative agent and supportive care are the mainstays of therapy. Targeted therapies with agents such as dantrolene, bromocriptine, and amantadine have also been reported anecdotally, but their efficacy is unclear, with variable results.²²

As noted earlier, the addition of quetiapine to the patient’s already lengthy medication list could conceivably cause neuroleptic malignant syndrome or serotonin syndrome and should be considered. However, additional neurologic findings to confirm this diagnosis are lacking.

Seizures

Nonconvulsive seizure, particularly nonconvulsive status epilepticus (NCSE), is not well recognized and is particularly challenging to diagnose without EEG. In several case series of patients presenting to the emergency room with altered mental status, NCSE was found in 16% to 28% of patients in whom EEG was performed after an initial evaluation failed to show an obvious cause for the delirium.^23,24 Historical features are unreliable for ruling out NCSE as a cause of delirium, as up to 41% of patients in whom the condition is ultimately diagnosed have only confusion as the presenting clinical symptom.²⁵

Likewise, alternating ictal and postictal periods may mimic the typical waxing and waning course classically associated with delirium of other causes. Physical findings such as nystagmus, anisocoria, and hippus may be helpful but are often overlooked or absent. EEG is thus an essential requirement for the diagnosis.²⁶

Given the lack of a clear diagnosis, a workup with EEG should be considered in this patient.

CASE CONTINUED: ADDITIONAL SIGNS

In the ICU, our patient is evaluated by the intensivist team. Her vital signs are stable, and while she is now awakening, she is unable to follow commands and remains mute. She does not initiate movement spontaneously but offers slight resistance to passive movements, holding and maintaining postures her extremities are placed in. She keeps her eyes closed, but when opened by the examining physician, dysconjugate gaze and anisocoria are noted.

3. What clinical entity is most consistent with these physical findings, and what is the next step in management?

• Catatonia secondary to bipolar disorder type I: challenge with intravenous lorazepam 2 mg
• Oculomotor nerve palsy due to enlarging intracranial aneurysm: aggressive blood pressure lowering, elevation of the head of the bed
• Toxic leukoencephalopathy: supportive care and withdrawal of the causative agent
• NCSE: challenge with intravenous lorazepam 2 mg and order EEG

Catatonia

The DSM-5 defines catatonia as a behavioral syndrome complicating an underlying psychiatric or medical condition, as opposed to a distinct diagnosis. It is most commonly encountered in psychiatric illnesses including bipolar disorder, major depression, and schizophrenia. Akinesis, stupor, mutism, and “waxy” flexibility often dominate the clinical picture.

The pathophysiology is poorly defined, but likely involves neurotransmitter imbalances particularly with an increase in N-methyl-d-aspartate (NMDA) activity and suppression of gamma-aminobutyric acid (GABA) activity. This hypothesis is supported by the finding that benzodiazepines, electroconvulsive therapy, and NMDA antagonists such as amantadine are all effective in treating catatonia.^27,28 Findings of focal neurologic abnormalities warrant further investigation. EEG may be necessary to differentiate catatonia from NCSE, as both may respond to a benzodiazepine challenge.

As pure catatonia is a diagnosis of exclusion, further workup, including EEG, is necessary to confirm the diagnosis.

Oculomotor nerve palsy

Anisocoria together with dysconjugate gaze should prompt consideration of a lesion involving the oculomotor nerve. Loss of tonic muscle activity from the lateral rectus and superior oblique cause a downward and outward gaze. Furthermore, loss of parasympathetic tone occurs with compressive palsies of the oculomotor nerve, clinically manifesting as a mydriatic and unreactive pupil with ptosis. Given its anatomic course and proximity to other vascular and parenchymal structures, the oculomotor nerve is vulnerable to compression from many sources, including aneurysmal dilation (especially of the posterior cerebral artery), uncal herniation, and inflammation of the cavernous sinus.

Noncontrast CT and lumbar puncture are very sensitive for making the diagnosis of sentinel bleeding within the first 24 hours,²⁹ whereas computed tomographic angiography and magnetic resonance angiography can reliably detect unruptured aneurysms as small as 3 mm.³⁰

Conditions that can lead to oculomotor palsy are unlikely to cause an acute gain in appendicular muscle tone, as noted by the catatonia this patient is demonstrating. Also, mass lesions or bleeding associated with oculomotor palsy is likely to cause acute loss of tone. Chronic upper-motor neuron lesions lead to spasticity rather than the waxy flexibility seen in this patient. In our patient, the findings of isolated anisocoria without further clinical evidence of oculomotor nerve compression make this diagnosis unlikely.

Toxic leukoencephalopathy

Toxic leukoencephalopathy—widespread destruction of myelin, particularly in the white matter tracts that support higher cortical functions—can be caused by antineoplastic agents, immunosuppressant agents, and industrial solvents, as well as by abuse of vaporized drugs such as heroin (“chasing the dragon”). In its mild forms it may cause behavioral disturbances or inattention. In severe forms, a neurobehavioral syndrome of akinetic mutism may be present and can mimic catatonia.³¹

The diagnosis is often based on the clinical history and neuroimaging, particularly MRI, which demonstrates hyperintensity of the white matter tracts in T2-weighted images.³²

This patient does not have a clear history of exposure to an agent typically associated with toxic leukoencephalopathy and does not have the corroborating MRI findings to support this diagnosis.

Because recent neuroimaging revealed no structural brain lesions and no cause for brain herniation, the patient receives a challenge of 2 mg of intravenous lorazepam to treat potential NCSE. Subsequent improvement is noted in her anisocoria, gaze deviation, and encephalopathy. EEG reveals frequent focal seizures arising from mesial frontal regions with bilateral hemisphere propagation, consistent with bifrontal focal NCSE.

As our patient is being transferred to a room for continuous EEG monitoring, her condition begins to deteriorate, and she again becomes more encephalopathic, with anisocoria and dysconjugate gaze. Additional doses of lorazepam are given (to complete a 0.1-mg/kg load), and additional therapy with intravenous fos­phenytoin (20-mg/kg load) is given. Intubation is done for airway protection.

Continuous EEG monitoring reveals multiple frequent electrographic seizures arising from the bifrontal territories, concerning for persistent focal NCSE. A midazolam drip is initiated for EEG burst suppression of cerebral activity. Over 24 hours, EEG shows resolution of seizure activity. As the patient is weaned from sedation, she awakens and follows commands consistently, tolerating extubation without complications. Her neurologic status remains stable over the next 48 hours, having returned to her neurologic baseline level of functioning. She is able to be transferred out of the ICU in stable condition while continuing on scheduled antiepileptic therapy with phenytoin.

ALTERED MENTAL STATUS IN INPATIENTS

Altered mental status is one of the most frequently encountered reasons for medical consultation from nonmedical services. The workup and management of metabolic, toxic, psychiatric, and neurologic causes requires a deep appreciation for the broad differential diagnosis and a multidisciplinary approach. Physicians caring for these patients should avoid prematurely drawing conclusions when the patient’s clinical condition fails to respond to typical measures.

Delirium is a challenging adverse event in older patients during hospitalization, with a significant national financial burden of $164 billion per year.³³ The prevalence of delirium in adults on hospital admission is estimated as 14% to 24%, with an inpatient hospitalization incidence ranging from 6% to 56% in general hospital patients.³⁴ In addition, postoperative delirium has been reported in 15% to 53% of older patients.³⁵

While delirium is preventable in 30% to 40% of cases,^36,37 it remains an important independent prognostic determinant of hospital outcomes.^38–40

Delirium in hospitalized patients requires a thorough, individualized workup. In our patient’s case, the clinical findings of hypoactive delirium were found to be manifestations of NCSE, a rare life-threatening and potentially reversible neurologic disease.

While establishing seizures as a diagnosis, careful attention must first be directed towards investigating environmental or metabolic triggers that may be inciting the disease. This often involves a similar workup for metabolic derangements, as seen in the approach to delirium.

The diagnosis of NCSE, while made in this patient’s case, remains challenging. Careful physical examination should assess for automatisms, “negative” symptoms (staring, aphasia, weakness), and “positive” symptoms (hallucinations, psychosis). Cataplexy, mutism, and other acute psychiatric features have been associated with NCSE,⁴⁴ highlighting the importance of EEG. A trial of a benzodiazepine in conjunction with clinical and EEG monitoring may help guide clinical decision- making.

As there is no current universally accepted definition for NCSE nor an accepted agreement on required EEG diagnostic features at this time,⁴¹ accurate diagnosis is most likely to be obtained in facilities with both subspecialty neurologic consultation and EEG capabilities.

Our patient’s family history of Pick disease is interesting, as this is a progressive form of frontotemporal dementia with both sporadic and genetically linked cases. Recent studies have shown evidence that patients with neurodegenerative disease have increased seizure frequency early in the disease course,³¹ and efforts are under way to establish the incidence of first unprovoked seizure in patients with frontotemporal dementia. In our patient’s case, resolution of seizure activity yielded a return to her baseline level of neurologic function.

Early use of selective serotonin reuptake inhibitors has been shown to help with the behavioral symptoms of frontotemporal dementia,⁴⁵ but increasing requirements over time may indicate progression of neurodegeneration and should warrant further appropriate investigation.

In our patient’s case, escalating dose requirements may have reflected worsening frontotemporal atrophy. However, the diagnosis of a neurodegenerative disease such as frontotemporal dementia in a patient such as ours is not definitively established at this time and is being investigated on an outpatient basis.

Given the frequency of delirium and its many risk factors in the inpatient setting, verifying a causative diagnosis can be difficult. Detailed consideration of the patient’s individual clinical circumstances, often in concert with appropriate subspecialty consultations, is essential to the evaluation. Although it is time-intensive, multidisciplinary intervention can lead to safer outcomes and shorter hospital stays.

A 64-year-old woman undergoes elective T10-S1 nerve decompression with fusion for chronic idiopathic scoliosis. Soon afterward, she develops acute urinary retention attributed to an Escherichia coli urinary tract infection and narcotic medications. She is treated with antibiotics, an indwelling catheter is inserted, and her symptoms resolve. She is transferred to the inpatient physical rehabilitation unit.

See related editorial

On postoperative day 9, she develops an acute change in mental status, suddenly becoming extremely anxious and falsely believing she has a “terminal illness.” A psychiatrist suggests that these symptoms are a manifestation of delirium, given the patient’s recent surgery and exposure to benzodiazepine and narcotic medications. On postoperative day 10, she is awake but is now mute and uncooperative. An internist is consulted for an evaluation for encephalopathy and delirium.

MEDICAL HISTORY

Her medical history, obtained by chart review and interviewing her husband, includes well-controlled bipolar disorder over the last 4 years, with no episodes of frank psychosis or mania. She had a “bout of delirium” 4 years earlier attributed to a catastrophic life event, but the symptoms resolved after adjustment of her anxiolytic and mood-stabilizing drugs. She also has well-controlled hypertension, hypothyroidism, and gastroesophageal reflux. Her only surgery was her recent elective procedure.

She has a family history of dementia (Pick disease in her mother).

She is married, lives with her husband, and has an adult son. She is employed as a media specialist and also teaches English as a second language. Before this hospital admission, she was described as happy and content, though her primary psychiatrist had noted intermittent anxiety. Her husband does not suspect illicit drug use and denies significant alcohol or tobacco abuse.

A thorough review of systems is not possible, given her encephalopathy. But before her acute decline, she had complained of “choking on blood” and a subjective inability to swallow.

Her home medications include dextroamphetamine extended-release, alprazolam as needed for sleep, venlafaxine extended-release, lamotrigine, lisinopril, propranolol, amlodipine, atorvastatin, levothyroxine, omep­razole, iron, and vitamin B₁₂. At the time of the evaluation, she is on her home medications with the addition of olanzapine, vitamin D, polyethylene glycol, and an intravenous infusion of dextrose 5% with 0.45% saline at a rate of 100 mL/hour. She has allergies to latex, penicillin, peanuts, and shellfish.

PHYSICAL EXAMINATION

On physical examination, the patient seems healthy and appears normal for her stated age. She is wearing a spinal brace and is in no apparent distress. She is afebrile, pulse 104 beats per minute, respirations 16 breaths per minute and unlabored, and oxygen saturation good on room air. The skin is normal. No thyromegaly, bruits, or lymphadenopathy is noted. Cardiovascular, respiratory, and abdominal examinations, though limited by the spinal brace, are unremarkable. She has no evidence of peripheral edema or vascular insufficiency. Muscle bulk and tone are adequate and symmetric.

She is awake and alert and able to follow simple commands with some prompting. She does not initiate movements spontaneously. She makes some eye contact but does not track or acknowledge the interviewer consistently and does not respond verbally to questions. Her sclera are nonicteric, the pupils are equally round and reactive to light, and the external ocular muscles are intact. There is no facial asymmetry, and the tongue protrudes at midline. She blinks appropriately to threat bilaterally. Strength is at least 3/5 in the upper extremities and 2/5 in the lower extremities, though the examination is limited by lack of patient cooperation. She shows minimal grimace on noxious stimulation but does not withdraw extremities. Reflexes are present and mildly depressed symmetrically. Plantar reflexes are downgoing bilaterally.

INITIAL LABORATORY EVALUATION

On initial laboratory testing, the serum sodium is 132 mmol/L (reference range 136–144), stable since admission. Point-of-care glucose is 98 mg/dL. Aspartate aminotransferase and alanine aminotransferase levels are mildly elevated at 59 U/L (13–35) and 51 U/L (7–38), respectively, but serum ammonia is undetectable. Vitamin B₁₂, folate, thyroid-stimulating hormone, and free thyroxine are within the normal ranges. Leukocytosis is noted, with 14 × 10⁹ cells/L (3.7–11.0), 86% neutrophils, and a mild left shift. Urinalysis is negative for leukocyte esterase, nitrites, and white blood cells.

1. Which of the following risk factors predisposes this patient to postoperative delirium?

• Hyponatremia
• Polypharmacy
• Family history of dementia
• Depression

Altered mental status, or encephalopathy, is one of the most common yet challenging conditions in medicine. When a consult is placed for altered mental status, it is important to determine the affected domain that has changed from the patient’s normal state. Changes can include alterations in consciousness, attention, behavior, cognition, language, speech, and praxis and can reflect varying degrees of cerebral dysfunction.

Electrolyte abnormalities

Disorders of sodium homeostasis are common in hospitalized patients and may contribute to the onset of delirium. Hyponatremia is especially frequent and often iatrogenic, with a prevalence significantly higher in women (2.1% vs 1.3%, P = .0044) and in the elderly.²

Neurologic manifestations are often the result of cerebral edema due to osmolar volume shifts.^3–6 Acute hyponatremic encephalopathy is most likely to occur when sodium shifts are rapid, usually within 24 hours, and is often seen in postoperative patients requiring significant volume resuscitation with hypotonic fluids.⁶ Young premenopausal women appear to be at especially high risk of permanent brain damage secondary to hyponatremic encephalopathy,⁷ a finding that may reflect the limited compliance within the intracranial vault and lack of significant involutional parenchymal changes that occur with aging.^8–11

Aging also has important effects on fluid balance, as restoration of body fluid homeostasis is slower in older patients.¹²

Hormonal effects of estrogen appear to play a synergistic role in the expression of arginine vasopressin in postmenopausal women, further contributing to hyponatremia.

Although our patient has mild hyponatremia, there has been no acute change in her sodium balance since admission to the hospital, and so it is unlikely to be the cause of her acute delirium. Her mild hyponatremia may in part be from hypo-osmolar maintenance fluids with dextrose 5% and 0.45% normal saline.

Mild chronic hyponatremia may affect balance and has been associated with increased mortality risk in certain chronic disease states, but this is unlikely to be the main cause of acute delirium.

Polypharmacy

Patients admitted to the hospital with polypharmacy are at high risk of drug-induced delirium. In approaching delirium, a patient’s medications should be evaluated for interactions, as well as for possible effects of newly prescribed drugs. New medications that affect cytochrome P450 enzymes warrant investigation, as do drugs with narrow therapeutic windows that the patient has been using long-term.

Consultation with a clinical pharmacist is often helpful. Macrolides, protease inhibitors, and nondihydropyridine calcium channel blockers are common P450 inhibitors, while many anticonvulsants are known inducers of the P450 system. Selective serotonin reuptake inhibitors and diuretics can lead to electrolyte imbalances such as hyponatremia, which may further predispose to bouts of delirium, as described above.

The patient’s extensive list of psychoactive medications makes polypharmacy a significant risk factor for delirium. Quetiapine and venlafaxine both cause sedation and increase the risk of serotonin syndrome. However, in this case, the patient does not have marked fever, rigidity, or hyperreflexia to corroborate that diagnosis.

Dementia

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), defines dementia as a disorder involving cognitive impairment in at least 1 cognitive domain, with a significant decline from a previous level of functioning.¹ These impairments need not necessarily occur separately from bouts of delirium, but the time course for most forms of dementia tends to be progressive over a subacute to chronic duration.

Dementia increases the risk for acute confusion and delirium in hospitalized patients.¹³ This is partly reflected by pathophysiologic changes that leave elderly patients susceptible to the effects of anticholinergic drugs.¹⁴ Structural changes due to small-vessel ischemia may also predispose patients to seizures in the setting of metabolic derangement or critical illness. Diagnosing dementia thus remains a challenge, as dementia must be clearly distinguished from other disorders such as delirium and depression.

The acute change in this patient’s case makes the isolated diagnosis of dementia much less likely than other causes of altered mental status. Also, her previous level of function does not suggest a clinically significant personal history of impairment.

Mental illness

Several studies have examined the link between preoperative mental health disorders and postoperative delirium.^15–17 Depression appears to be a risk factor for postoperative delirium in patients undergoing elective orthopedic surgery,¹⁵ and this includes elderly patients.¹⁶ While a clear etiologic link has yet to be determined, disruption of circadian rhythm and abnormal cerebral response to stress may play a role. Studies have also suggested an association between schizophrenia and delirium, though this may be related to perioperative suspension of medications.¹⁷

Bipolar disorder has not been well studied with regard to postoperative complications. However, this patient has had a previous episode of decompensated mania, therefore making bipolar disorder a plausible condition in the differential diagnosis.

CASE CONTINUED: ACUTE DETERIORATION

Without a clearly identifiable cause for our patient’s acute confusional state, neurology and medical consultants recommend neuroimaging.

Computed tomography (CT) and magnetic resonance imaging (MRI) without contrast are ordered and performed on postoperative day 11 and demonstrate chronic small-vessel ischemic disease, consistent with our patient’s age, as well as frontotemporal atrophy. There is no evidence of mass effect, bleeding, or acute ischemia.

Overnight, she becomes obtunded, and the rapid response team is called. Her vital signs appear stable, and she is afebrile. Basic laboratory studies, imaging, and electrocardiography are repeated, and the results are unchanged from recent tests. She is transferred to the intensive care unit (ICU) for closer monitoring.

2. What is most likely cause of the patient’s declining mental status, and what is the next appropriate step?

• Acute stroke: repeat MRI with contrast
• Urinary tract infection: order blood and urine cultures, and start empiric antibiotics
• Neuroleptic malignant syndrome: start dantrolene
• Seizures: order electroencephalography (EEG)

Acute stroke

Acute stroke can affect mental status and consciousness through several pathways. Stroke syndromes can vary in presentation depending on the level of cortical and subcortical involvement, with clinical manifestations including confusion, aphasia, neglect, and inattention. Wakefulness and the ability to maintain consciousness is impaired, with disruption of the ascending reticular activating system, often seen in injuries to the brainstem. Large territorial or hemispheric infarcts, with subsequent cerebral edema, can also disrupt this system and lead to cerebral herniation and coma.

MRI without contrast is extremely sensitive for ischemia and can typically detect ischemia in acute stroke within 3 to 30 minutes.^18–20 Repeating the study with contrast is unlikely to provide additional benefit.

In our patient’s case, the lack of localizing neurologic symptoms, in addition to her recent negative neuroimaging workup, makes the diagnosis of acute stroke unlikely.

Infection

The role of severe infection in patients with altered mental status is well documented and likely relates to diffuse cerebral dysfunction caused by an inflammatory cascade. Less well understood is the role of occult infection, especially urinary tract infection, in otherwise immunocompetent patients. Urinary tract infection has long been thought to cause delirium in otherwise asymptomatic elderly patients, but few studies have examined this relationship, and those studies have been shown to have significant methodologic errors.²¹ In the absence of better data, urinary tract infection as the cause of frank delirium in an otherwise well patient should be viewed with skepticism, and alternative causes should be sought.

Although the patient has a nonspecific leukocytosis, her benign urinalysis and lack of corroborating evidence makes urinary tract infection an unlikely cause of her frank delirium.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is defined as fever, rigidity, mental status changes, and autonomic instability after exposure to antidopaminergic drugs. It is classically seen after administration of typical antipsychotics, though atypical antipsychotics and antiemetic drugs may be implicated as well.

Patients often exhibit agitation and confusion, which when severe may progress to mutism and catatonia. Likewise, psychotropic drugs such as quetiapine and venlafaxine, used in combination, have the additional risk of serotonin syndrome.

Additional symptoms include hyperreflexia, ataxia, and myoclonus. Withdrawal of the causative agent and supportive care are the mainstays of therapy. Targeted therapies with agents such as dantrolene, bromocriptine, and amantadine have also been reported anecdotally, but their efficacy is unclear, with variable results.²²

As noted earlier, the addition of quetiapine to the patient’s already lengthy medication list could conceivably cause neuroleptic malignant syndrome or serotonin syndrome and should be considered. However, additional neurologic findings to confirm this diagnosis are lacking.

Seizures

Nonconvulsive seizure, particularly nonconvulsive status epilepticus (NCSE), is not well recognized and is particularly challenging to diagnose without EEG. In several case series of patients presenting to the emergency room with altered mental status, NCSE was found in 16% to 28% of patients in whom EEG was performed after an initial evaluation failed to show an obvious cause for the delirium.^23,24 Historical features are unreliable for ruling out NCSE as a cause of delirium, as up to 41% of patients in whom the condition is ultimately diagnosed have only confusion as the presenting clinical symptom.²⁵

Likewise, alternating ictal and postictal periods may mimic the typical waxing and waning course classically associated with delirium of other causes. Physical findings such as nystagmus, anisocoria, and hippus may be helpful but are often overlooked or absent. EEG is thus an essential requirement for the diagnosis.²⁶

Given the lack of a clear diagnosis, a workup with EEG should be considered in this patient.

CASE CONTINUED: ADDITIONAL SIGNS

In the ICU, our patient is evaluated by the intensivist team. Her vital signs are stable, and while she is now awakening, she is unable to follow commands and remains mute. She does not initiate movement spontaneously but offers slight resistance to passive movements, holding and maintaining postures her extremities are placed in. She keeps her eyes closed, but when opened by the examining physician, dysconjugate gaze and anisocoria are noted.

3. What clinical entity is most consistent with these physical findings, and what is the next step in management?

• Catatonia secondary to bipolar disorder type I: challenge with intravenous lorazepam 2 mg
• Oculomotor nerve palsy due to enlarging intracranial aneurysm: aggressive blood pressure lowering, elevation of the head of the bed
• Toxic leukoencephalopathy: supportive care and withdrawal of the causative agent
• NCSE: challenge with intravenous lorazepam 2 mg and order EEG

Catatonia

The DSM-5 defines catatonia as a behavioral syndrome complicating an underlying psychiatric or medical condition, as opposed to a distinct diagnosis. It is most commonly encountered in psychiatric illnesses including bipolar disorder, major depression, and schizophrenia. Akinesis, stupor, mutism, and “waxy” flexibility often dominate the clinical picture.

The pathophysiology is poorly defined, but likely involves neurotransmitter imbalances particularly with an increase in N-methyl-d-aspartate (NMDA) activity and suppression of gamma-aminobutyric acid (GABA) activity. This hypothesis is supported by the finding that benzodiazepines, electroconvulsive therapy, and NMDA antagonists such as amantadine are all effective in treating catatonia.^27,28 Findings of focal neurologic abnormalities warrant further investigation. EEG may be necessary to differentiate catatonia from NCSE, as both may respond to a benzodiazepine challenge.

As pure catatonia is a diagnosis of exclusion, further workup, including EEG, is necessary to confirm the diagnosis.

Oculomotor nerve palsy

Anisocoria together with dysconjugate gaze should prompt consideration of a lesion involving the oculomotor nerve. Loss of tonic muscle activity from the lateral rectus and superior oblique cause a downward and outward gaze. Furthermore, loss of parasympathetic tone occurs with compressive palsies of the oculomotor nerve, clinically manifesting as a mydriatic and unreactive pupil with ptosis. Given its anatomic course and proximity to other vascular and parenchymal structures, the oculomotor nerve is vulnerable to compression from many sources, including aneurysmal dilation (especially of the posterior cerebral artery), uncal herniation, and inflammation of the cavernous sinus.

Noncontrast CT and lumbar puncture are very sensitive for making the diagnosis of sentinel bleeding within the first 24 hours,²⁹ whereas computed tomographic angiography and magnetic resonance angiography can reliably detect unruptured aneurysms as small as 3 mm.³⁰

Conditions that can lead to oculomotor palsy are unlikely to cause an acute gain in appendicular muscle tone, as noted by the catatonia this patient is demonstrating. Also, mass lesions or bleeding associated with oculomotor palsy is likely to cause acute loss of tone. Chronic upper-motor neuron lesions lead to spasticity rather than the waxy flexibility seen in this patient. In our patient, the findings of isolated anisocoria without further clinical evidence of oculomotor nerve compression make this diagnosis unlikely.

Toxic leukoencephalopathy

Toxic leukoencephalopathy—widespread destruction of myelin, particularly in the white matter tracts that support higher cortical functions—can be caused by antineoplastic agents, immunosuppressant agents, and industrial solvents, as well as by abuse of vaporized drugs such as heroin (“chasing the dragon”). In its mild forms it may cause behavioral disturbances or inattention. In severe forms, a neurobehavioral syndrome of akinetic mutism may be present and can mimic catatonia.³¹

The diagnosis is often based on the clinical history and neuroimaging, particularly MRI, which demonstrates hyperintensity of the white matter tracts in T2-weighted images.³²

This patient does not have a clear history of exposure to an agent typically associated with toxic leukoencephalopathy and does not have the corroborating MRI findings to support this diagnosis.

Because recent neuroimaging revealed no structural brain lesions and no cause for brain herniation, the patient receives a challenge of 2 mg of intravenous lorazepam to treat potential NCSE. Subsequent improvement is noted in her anisocoria, gaze deviation, and encephalopathy. EEG reveals frequent focal seizures arising from mesial frontal regions with bilateral hemisphere propagation, consistent with bifrontal focal NCSE.

As our patient is being transferred to a room for continuous EEG monitoring, her condition begins to deteriorate, and she again becomes more encephalopathic, with anisocoria and dysconjugate gaze. Additional doses of lorazepam are given (to complete a 0.1-mg/kg load), and additional therapy with intravenous fos­phenytoin (20-mg/kg load) is given. Intubation is done for airway protection.

Continuous EEG monitoring reveals multiple frequent electrographic seizures arising from the bifrontal territories, concerning for persistent focal NCSE. A midazolam drip is initiated for EEG burst suppression of cerebral activity. Over 24 hours, EEG shows resolution of seizure activity. As the patient is weaned from sedation, she awakens and follows commands consistently, tolerating extubation without complications. Her neurologic status remains stable over the next 48 hours, having returned to her neurologic baseline level of functioning. She is able to be transferred out of the ICU in stable condition while continuing on scheduled antiepileptic therapy with phenytoin.

ALTERED MENTAL STATUS IN INPATIENTS

Altered mental status is one of the most frequently encountered reasons for medical consultation from nonmedical services. The workup and management of metabolic, toxic, psychiatric, and neurologic causes requires a deep appreciation for the broad differential diagnosis and a multidisciplinary approach. Physicians caring for these patients should avoid prematurely drawing conclusions when the patient’s clinical condition fails to respond to typical measures.

Delirium is a challenging adverse event in older patients during hospitalization, with a significant national financial burden of $164 billion per year.³³ The prevalence of delirium in adults on hospital admission is estimated as 14% to 24%, with an inpatient hospitalization incidence ranging from 6% to 56% in general hospital patients.³⁴ In addition, postoperative delirium has been reported in 15% to 53% of older patients.³⁵

While delirium is preventable in 30% to 40% of cases,^36,37 it remains an important independent prognostic determinant of hospital outcomes.^38–40

Delirium in hospitalized patients requires a thorough, individualized workup. In our patient’s case, the clinical findings of hypoactive delirium were found to be manifestations of NCSE, a rare life-threatening and potentially reversible neurologic disease.

While establishing seizures as a diagnosis, careful attention must first be directed towards investigating environmental or metabolic triggers that may be inciting the disease. This often involves a similar workup for metabolic derangements, as seen in the approach to delirium.

The diagnosis of NCSE, while made in this patient’s case, remains challenging. Careful physical examination should assess for automatisms, “negative” symptoms (staring, aphasia, weakness), and “positive” symptoms (hallucinations, psychosis). Cataplexy, mutism, and other acute psychiatric features have been associated with NCSE,⁴⁴ highlighting the importance of EEG. A trial of a benzodiazepine in conjunction with clinical and EEG monitoring may help guide clinical decision- making.

As there is no current universally accepted definition for NCSE nor an accepted agreement on required EEG diagnostic features at this time,⁴¹ accurate diagnosis is most likely to be obtained in facilities with both subspecialty neurologic consultation and EEG capabilities.

Our patient’s family history of Pick disease is interesting, as this is a progressive form of frontotemporal dementia with both sporadic and genetically linked cases. Recent studies have shown evidence that patients with neurodegenerative disease have increased seizure frequency early in the disease course,³¹ and efforts are under way to establish the incidence of first unprovoked seizure in patients with frontotemporal dementia. In our patient’s case, resolution of seizure activity yielded a return to her baseline level of neurologic function.

Early use of selective serotonin reuptake inhibitors has been shown to help with the behavioral symptoms of frontotemporal dementia,⁴⁵ but increasing requirements over time may indicate progression of neurodegeneration and should warrant further appropriate investigation.

In our patient’s case, escalating dose requirements may have reflected worsening frontotemporal atrophy. However, the diagnosis of a neurodegenerative disease such as frontotemporal dementia in a patient such as ours is not definitively established at this time and is being investigated on an outpatient basis.

Given the frequency of delirium and its many risk factors in the inpatient setting, verifying a causative diagnosis can be difficult. Detailed consideration of the patient’s individual clinical circumstances, often in concert with appropriate subspecialty consultations, is essential to the evaluation. Although it is time-intensive, multidisciplinary intervention can lead to safer outcomes and shorter hospital stays.

A 64-year-old woman undergoes elective T10-S1 nerve decompression with fusion for chronic idiopathic scoliosis. Soon afterward, she develops acute urinary retention attributed to an Escherichia coli urinary tract infection and narcotic medications. She is treated with antibiotics, an indwelling catheter is inserted, and her symptoms resolve. She is transferred to the inpatient physical rehabilitation unit.

See related editorial

On postoperative day 9, she develops an acute change in mental status, suddenly becoming extremely anxious and falsely believing she has a “terminal illness.” A psychiatrist suggests that these symptoms are a manifestation of delirium, given the patient’s recent surgery and exposure to benzodiazepine and narcotic medications. On postoperative day 10, she is awake but is now mute and uncooperative. An internist is consulted for an evaluation for encephalopathy and delirium.

MEDICAL HISTORY

Her medical history, obtained by chart review and interviewing her husband, includes well-controlled bipolar disorder over the last 4 years, with no episodes of frank psychosis or mania. She had a “bout of delirium” 4 years earlier attributed to a catastrophic life event, but the symptoms resolved after adjustment of her anxiolytic and mood-stabilizing drugs. She also has well-controlled hypertension, hypothyroidism, and gastroesophageal reflux. Her only surgery was her recent elective procedure.

She has a family history of dementia (Pick disease in her mother).

She is married, lives with her husband, and has an adult son. She is employed as a media specialist and also teaches English as a second language. Before this hospital admission, she was described as happy and content, though her primary psychiatrist had noted intermittent anxiety. Her husband does not suspect illicit drug use and denies significant alcohol or tobacco abuse.

A thorough review of systems is not possible, given her encephalopathy. But before her acute decline, she had complained of “choking on blood” and a subjective inability to swallow.

Her home medications include dextroamphetamine extended-release, alprazolam as needed for sleep, venlafaxine extended-release, lamotrigine, lisinopril, propranolol, amlodipine, atorvastatin, levothyroxine, omep­razole, iron, and vitamin B₁₂. At the time of the evaluation, she is on her home medications with the addition of olanzapine, vitamin D, polyethylene glycol, and an intravenous infusion of dextrose 5% with 0.45% saline at a rate of 100 mL/hour. She has allergies to latex, penicillin, peanuts, and shellfish.

PHYSICAL EXAMINATION

On physical examination, the patient seems healthy and appears normal for her stated age. She is wearing a spinal brace and is in no apparent distress. She is afebrile, pulse 104 beats per minute, respirations 16 breaths per minute and unlabored, and oxygen saturation good on room air. The skin is normal. No thyromegaly, bruits, or lymphadenopathy is noted. Cardiovascular, respiratory, and abdominal examinations, though limited by the spinal brace, are unremarkable. She has no evidence of peripheral edema or vascular insufficiency. Muscle bulk and tone are adequate and symmetric.

She is awake and alert and able to follow simple commands with some prompting. She does not initiate movements spontaneously. She makes some eye contact but does not track or acknowledge the interviewer consistently and does not respond verbally to questions. Her sclera are nonicteric, the pupils are equally round and reactive to light, and the external ocular muscles are intact. There is no facial asymmetry, and the tongue protrudes at midline. She blinks appropriately to threat bilaterally. Strength is at least 3/5 in the upper extremities and 2/5 in the lower extremities, though the examination is limited by lack of patient cooperation. She shows minimal grimace on noxious stimulation but does not withdraw extremities. Reflexes are present and mildly depressed symmetrically. Plantar reflexes are downgoing bilaterally.

INITIAL LABORATORY EVALUATION

On initial laboratory testing, the serum sodium is 132 mmol/L (reference range 136–144), stable since admission. Point-of-care glucose is 98 mg/dL. Aspartate aminotransferase and alanine aminotransferase levels are mildly elevated at 59 U/L (13–35) and 51 U/L (7–38), respectively, but serum ammonia is undetectable. Vitamin B₁₂, folate, thyroid-stimulating hormone, and free thyroxine are within the normal ranges. Leukocytosis is noted, with 14 × 10⁹ cells/L (3.7–11.0), 86% neutrophils, and a mild left shift. Urinalysis is negative for leukocyte esterase, nitrites, and white blood cells.

1. Which of the following risk factors predisposes this patient to postoperative delirium?

• Hyponatremia
• Polypharmacy
• Family history of dementia
• Depression

Altered mental status, or encephalopathy, is one of the most common yet challenging conditions in medicine. When a consult is placed for altered mental status, it is important to determine the affected domain that has changed from the patient’s normal state. Changes can include alterations in consciousness, attention, behavior, cognition, language, speech, and praxis and can reflect varying degrees of cerebral dysfunction.

Electrolyte abnormalities

Disorders of sodium homeostasis are common in hospitalized patients and may contribute to the onset of delirium. Hyponatremia is especially frequent and often iatrogenic, with a prevalence significantly higher in women (2.1% vs 1.3%, P = .0044) and in the elderly.²

Neurologic manifestations are often the result of cerebral edema due to osmolar volume shifts.^3–6 Acute hyponatremic encephalopathy is most likely to occur when sodium shifts are rapid, usually within 24 hours, and is often seen in postoperative patients requiring significant volume resuscitation with hypotonic fluids.⁶ Young premenopausal women appear to be at especially high risk of permanent brain damage secondary to hyponatremic encephalopathy,⁷ a finding that may reflect the limited compliance within the intracranial vault and lack of significant involutional parenchymal changes that occur with aging.^8–11

Aging also has important effects on fluid balance, as restoration of body fluid homeostasis is slower in older patients.¹²

Hormonal effects of estrogen appear to play a synergistic role in the expression of arginine vasopressin in postmenopausal women, further contributing to hyponatremia.

Although our patient has mild hyponatremia, there has been no acute change in her sodium balance since admission to the hospital, and so it is unlikely to be the cause of her acute delirium. Her mild hyponatremia may in part be from hypo-osmolar maintenance fluids with dextrose 5% and 0.45% normal saline.

Mild chronic hyponatremia may affect balance and has been associated with increased mortality risk in certain chronic disease states, but this is unlikely to be the main cause of acute delirium.

Polypharmacy

Patients admitted to the hospital with polypharmacy are at high risk of drug-induced delirium. In approaching delirium, a patient’s medications should be evaluated for interactions, as well as for possible effects of newly prescribed drugs. New medications that affect cytochrome P450 enzymes warrant investigation, as do drugs with narrow therapeutic windows that the patient has been using long-term.

Consultation with a clinical pharmacist is often helpful. Macrolides, protease inhibitors, and nondihydropyridine calcium channel blockers are common P450 inhibitors, while many anticonvulsants are known inducers of the P450 system. Selective serotonin reuptake inhibitors and diuretics can lead to electrolyte imbalances such as hyponatremia, which may further predispose to bouts of delirium, as described above.

The patient’s extensive list of psychoactive medications makes polypharmacy a significant risk factor for delirium. Quetiapine and venlafaxine both cause sedation and increase the risk of serotonin syndrome. However, in this case, the patient does not have marked fever, rigidity, or hyperreflexia to corroborate that diagnosis.

Dementia

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), defines dementia as a disorder involving cognitive impairment in at least 1 cognitive domain, with a significant decline from a previous level of functioning.¹ These impairments need not necessarily occur separately from bouts of delirium, but the time course for most forms of dementia tends to be progressive over a subacute to chronic duration.

Dementia increases the risk for acute confusion and delirium in hospitalized patients.¹³ This is partly reflected by pathophysiologic changes that leave elderly patients susceptible to the effects of anticholinergic drugs.¹⁴ Structural changes due to small-vessel ischemia may also predispose patients to seizures in the setting of metabolic derangement or critical illness. Diagnosing dementia thus remains a challenge, as dementia must be clearly distinguished from other disorders such as delirium and depression.

The acute change in this patient’s case makes the isolated diagnosis of dementia much less likely than other causes of altered mental status. Also, her previous level of function does not suggest a clinically significant personal history of impairment.

Mental illness

Several studies have examined the link between preoperative mental health disorders and postoperative delirium.^15–17 Depression appears to be a risk factor for postoperative delirium in patients undergoing elective orthopedic surgery,¹⁵ and this includes elderly patients.¹⁶ While a clear etiologic link has yet to be determined, disruption of circadian rhythm and abnormal cerebral response to stress may play a role. Studies have also suggested an association between schizophrenia and delirium, though this may be related to perioperative suspension of medications.¹⁷

Bipolar disorder has not been well studied with regard to postoperative complications. However, this patient has had a previous episode of decompensated mania, therefore making bipolar disorder a plausible condition in the differential diagnosis.

CASE CONTINUED: ACUTE DETERIORATION

Without a clearly identifiable cause for our patient’s acute confusional state, neurology and medical consultants recommend neuroimaging.

Computed tomography (CT) and magnetic resonance imaging (MRI) without contrast are ordered and performed on postoperative day 11 and demonstrate chronic small-vessel ischemic disease, consistent with our patient’s age, as well as frontotemporal atrophy. There is no evidence of mass effect, bleeding, or acute ischemia.

Overnight, she becomes obtunded, and the rapid response team is called. Her vital signs appear stable, and she is afebrile. Basic laboratory studies, imaging, and electrocardiography are repeated, and the results are unchanged from recent tests. She is transferred to the intensive care unit (ICU) for closer monitoring.

2. What is most likely cause of the patient’s declining mental status, and what is the next appropriate step?

• Acute stroke: repeat MRI with contrast
• Urinary tract infection: order blood and urine cultures, and start empiric antibiotics
• Neuroleptic malignant syndrome: start dantrolene
• Seizures: order electroencephalography (EEG)

Acute stroke

Acute stroke can affect mental status and consciousness through several pathways. Stroke syndromes can vary in presentation depending on the level of cortical and subcortical involvement, with clinical manifestations including confusion, aphasia, neglect, and inattention. Wakefulness and the ability to maintain consciousness is impaired, with disruption of the ascending reticular activating system, often seen in injuries to the brainstem. Large territorial or hemispheric infarcts, with subsequent cerebral edema, can also disrupt this system and lead to cerebral herniation and coma.

MRI without contrast is extremely sensitive for ischemia and can typically detect ischemia in acute stroke within 3 to 30 minutes.^18–20 Repeating the study with contrast is unlikely to provide additional benefit.

In our patient’s case, the lack of localizing neurologic symptoms, in addition to her recent negative neuroimaging workup, makes the diagnosis of acute stroke unlikely.

Infection

The role of severe infection in patients with altered mental status is well documented and likely relates to diffuse cerebral dysfunction caused by an inflammatory cascade. Less well understood is the role of occult infection, especially urinary tract infection, in otherwise immunocompetent patients. Urinary tract infection has long been thought to cause delirium in otherwise asymptomatic elderly patients, but few studies have examined this relationship, and those studies have been shown to have significant methodologic errors.²¹ In the absence of better data, urinary tract infection as the cause of frank delirium in an otherwise well patient should be viewed with skepticism, and alternative causes should be sought.

Although the patient has a nonspecific leukocytosis, her benign urinalysis and lack of corroborating evidence makes urinary tract infection an unlikely cause of her frank delirium.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is defined as fever, rigidity, mental status changes, and autonomic instability after exposure to antidopaminergic drugs. It is classically seen after administration of typical antipsychotics, though atypical antipsychotics and antiemetic drugs may be implicated as well.

Patients often exhibit agitation and confusion, which when severe may progress to mutism and catatonia. Likewise, psychotropic drugs such as quetiapine and venlafaxine, used in combination, have the additional risk of serotonin syndrome.

Additional symptoms include hyperreflexia, ataxia, and myoclonus. Withdrawal of the causative agent and supportive care are the mainstays of therapy. Targeted therapies with agents such as dantrolene, bromocriptine, and amantadine have also been reported anecdotally, but their efficacy is unclear, with variable results.²²

As noted earlier, the addition of quetiapine to the patient’s already lengthy medication list could conceivably cause neuroleptic malignant syndrome or serotonin syndrome and should be considered. However, additional neurologic findings to confirm this diagnosis are lacking.

Seizures

Nonconvulsive seizure, particularly nonconvulsive status epilepticus (NCSE), is not well recognized and is particularly challenging to diagnose without EEG. In several case series of patients presenting to the emergency room with altered mental status, NCSE was found in 16% to 28% of patients in whom EEG was performed after an initial evaluation failed to show an obvious cause for the delirium.^23,24 Historical features are unreliable for ruling out NCSE as a cause of delirium, as up to 41% of patients in whom the condition is ultimately diagnosed have only confusion as the presenting clinical symptom.²⁵

Likewise, alternating ictal and postictal periods may mimic the typical waxing and waning course classically associated with delirium of other causes. Physical findings such as nystagmus, anisocoria, and hippus may be helpful but are often overlooked or absent. EEG is thus an essential requirement for the diagnosis.²⁶

Given the lack of a clear diagnosis, a workup with EEG should be considered in this patient.

CASE CONTINUED: ADDITIONAL SIGNS

In the ICU, our patient is evaluated by the intensivist team. Her vital signs are stable, and while she is now awakening, she is unable to follow commands and remains mute. She does not initiate movement spontaneously but offers slight resistance to passive movements, holding and maintaining postures her extremities are placed in. She keeps her eyes closed, but when opened by the examining physician, dysconjugate gaze and anisocoria are noted.

3. What clinical entity is most consistent with these physical findings, and what is the next step in management?

• Catatonia secondary to bipolar disorder type I: challenge with intravenous lorazepam 2 mg
• Oculomotor nerve palsy due to enlarging intracranial aneurysm: aggressive blood pressure lowering, elevation of the head of the bed
• Toxic leukoencephalopathy: supportive care and withdrawal of the causative agent
• NCSE: challenge with intravenous lorazepam 2 mg and order EEG

Catatonia

The DSM-5 defines catatonia as a behavioral syndrome complicating an underlying psychiatric or medical condition, as opposed to a distinct diagnosis. It is most commonly encountered in psychiatric illnesses including bipolar disorder, major depression, and schizophrenia. Akinesis, stupor, mutism, and “waxy” flexibility often dominate the clinical picture.

The pathophysiology is poorly defined, but likely involves neurotransmitter imbalances particularly with an increase in N-methyl-d-aspartate (NMDA) activity and suppression of gamma-aminobutyric acid (GABA) activity. This hypothesis is supported by the finding that benzodiazepines, electroconvulsive therapy, and NMDA antagonists such as amantadine are all effective in treating catatonia.^27,28 Findings of focal neurologic abnormalities warrant further investigation. EEG may be necessary to differentiate catatonia from NCSE, as both may respond to a benzodiazepine challenge.

As pure catatonia is a diagnosis of exclusion, further workup, including EEG, is necessary to confirm the diagnosis.

Oculomotor nerve palsy

Anisocoria together with dysconjugate gaze should prompt consideration of a lesion involving the oculomotor nerve. Loss of tonic muscle activity from the lateral rectus and superior oblique cause a downward and outward gaze. Furthermore, loss of parasympathetic tone occurs with compressive palsies of the oculomotor nerve, clinically manifesting as a mydriatic and unreactive pupil with ptosis. Given its anatomic course and proximity to other vascular and parenchymal structures, the oculomotor nerve is vulnerable to compression from many sources, including aneurysmal dilation (especially of the posterior cerebral artery), uncal herniation, and inflammation of the cavernous sinus.

Noncontrast CT and lumbar puncture are very sensitive for making the diagnosis of sentinel bleeding within the first 24 hours,²⁹ whereas computed tomographic angiography and magnetic resonance angiography can reliably detect unruptured aneurysms as small as 3 mm.³⁰

Conditions that can lead to oculomotor palsy are unlikely to cause an acute gain in appendicular muscle tone, as noted by the catatonia this patient is demonstrating. Also, mass lesions or bleeding associated with oculomotor palsy is likely to cause acute loss of tone. Chronic upper-motor neuron lesions lead to spasticity rather than the waxy flexibility seen in this patient. In our patient, the findings of isolated anisocoria without further clinical evidence of oculomotor nerve compression make this diagnosis unlikely.

Toxic leukoencephalopathy

Toxic leukoencephalopathy—widespread destruction of myelin, particularly in the white matter tracts that support higher cortical functions—can be caused by antineoplastic agents, immunosuppressant agents, and industrial solvents, as well as by abuse of vaporized drugs such as heroin (“chasing the dragon”). In its mild forms it may cause behavioral disturbances or inattention. In severe forms, a neurobehavioral syndrome of akinetic mutism may be present and can mimic catatonia.³¹

The diagnosis is often based on the clinical history and neuroimaging, particularly MRI, which demonstrates hyperintensity of the white matter tracts in T2-weighted images.³²

This patient does not have a clear history of exposure to an agent typically associated with toxic leukoencephalopathy and does not have the corroborating MRI findings to support this diagnosis.

Because recent neuroimaging revealed no structural brain lesions and no cause for brain herniation, the patient receives a challenge of 2 mg of intravenous lorazepam to treat potential NCSE. Subsequent improvement is noted in her anisocoria, gaze deviation, and encephalopathy. EEG reveals frequent focal seizures arising from mesial frontal regions with bilateral hemisphere propagation, consistent with bifrontal focal NCSE.

As our patient is being transferred to a room for continuous EEG monitoring, her condition begins to deteriorate, and she again becomes more encephalopathic, with anisocoria and dysconjugate gaze. Additional doses of lorazepam are given (to complete a 0.1-mg/kg load), and additional therapy with intravenous fos­phenytoin (20-mg/kg load) is given. Intubation is done for airway protection.

Continuous EEG monitoring reveals multiple frequent electrographic seizures arising from the bifrontal territories, concerning for persistent focal NCSE. A midazolam drip is initiated for EEG burst suppression of cerebral activity. Over 24 hours, EEG shows resolution of seizure activity. As the patient is weaned from sedation, she awakens and follows commands consistently, tolerating extubation without complications. Her neurologic status remains stable over the next 48 hours, having returned to her neurologic baseline level of functioning. She is able to be transferred out of the ICU in stable condition while continuing on scheduled antiepileptic therapy with phenytoin.

ALTERED MENTAL STATUS IN INPATIENTS

Altered mental status is one of the most frequently encountered reasons for medical consultation from nonmedical services. The workup and management of metabolic, toxic, psychiatric, and neurologic causes requires a deep appreciation for the broad differential diagnosis and a multidisciplinary approach. Physicians caring for these patients should avoid prematurely drawing conclusions when the patient’s clinical condition fails to respond to typical measures.

Delirium is a challenging adverse event in older patients during hospitalization, with a significant national financial burden of $164 billion per year.³³ The prevalence of delirium in adults on hospital admission is estimated as 14% to 24%, with an inpatient hospitalization incidence ranging from 6% to 56% in general hospital patients.³⁴ In addition, postoperative delirium has been reported in 15% to 53% of older patients.³⁵

While delirium is preventable in 30% to 40% of cases,^36,37 it remains an important independent prognostic determinant of hospital outcomes.^38–40

Delirium in hospitalized patients requires a thorough, individualized workup. In our patient’s case, the clinical findings of hypoactive delirium were found to be manifestations of NCSE, a rare life-threatening and potentially reversible neurologic disease.

While establishing seizures as a diagnosis, careful attention must first be directed towards investigating environmental or metabolic triggers that may be inciting the disease. This often involves a similar workup for metabolic derangements, as seen in the approach to delirium.

The diagnosis of NCSE, while made in this patient’s case, remains challenging. Careful physical examination should assess for automatisms, “negative” symptoms (staring, aphasia, weakness), and “positive” symptoms (hallucinations, psychosis). Cataplexy, mutism, and other acute psychiatric features have been associated with NCSE,⁴⁴ highlighting the importance of EEG. A trial of a benzodiazepine in conjunction with clinical and EEG monitoring may help guide clinical decision- making.

As there is no current universally accepted definition for NCSE nor an accepted agreement on required EEG diagnostic features at this time,⁴¹ accurate diagnosis is most likely to be obtained in facilities with both subspecialty neurologic consultation and EEG capabilities.

Our patient’s family history of Pick disease is interesting, as this is a progressive form of frontotemporal dementia with both sporadic and genetically linked cases. Recent studies have shown evidence that patients with neurodegenerative disease have increased seizure frequency early in the disease course,³¹ and efforts are under way to establish the incidence of first unprovoked seizure in patients with frontotemporal dementia. In our patient’s case, resolution of seizure activity yielded a return to her baseline level of neurologic function.

Early use of selective serotonin reuptake inhibitors has been shown to help with the behavioral symptoms of frontotemporal dementia,⁴⁵ but increasing requirements over time may indicate progression of neurodegeneration and should warrant further appropriate investigation.

In our patient’s case, escalating dose requirements may have reflected worsening frontotemporal atrophy. However, the diagnosis of a neurodegenerative disease such as frontotemporal dementia in a patient such as ours is not definitively established at this time and is being investigated on an outpatient basis.

Given the frequency of delirium and its many risk factors in the inpatient setting, verifying a causative diagnosis can be difficult. Detailed consideration of the patient’s individual clinical circumstances, often in concert with appropriate subspecialty consultations, is essential to the evaluation. Although it is time-intensive, multidisciplinary intervention can lead to safer outcomes and shorter hospital stays.

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰