Altered Mental Status in the Emergency Department

Austin T. Smith, MD; Jin H. Han, MD, MSc


Semin Neurol. 2019;39(1):5-19. 

In This Article

Differential Diagnosis

In the undifferentiated patient who presents with AMS, a broad differential diagnosis (Table 2) must be considered, as this will guide the evaluation. While a central nervous system etiology should strongly be considered, AMS is often precipitated by an underlying medical illness. In these cases, AMS represents end-organ damage of the brain. For this reason, it is important to also consider a patient's vulnerability to developing AMS (Table 3). Younger patients and those with little to no vulnerability require a highly noxious stimulus, such as severe sepsis, to develop AMS. Therefore, these patients should be considered to have a life-threatening illness until proven otherwise.[36–44]

Given the Broad Differential of Ams, We Recommend a Systemic Approach (Table 2) When Considering the Etiologies. It is Important to Note That Causes Often Coexist, Particularly in Older Patients.[45]

Given the Broad Differential of Ams, We Recommend a Systemic Approach (Table 2) When Considering the Etiologies. It is Important to Note That Causes Often Coexist, Particularly in Older Patients.[45]

Primary Neurologic

Trauma. Patients presenting with AMS after a trauma may have a subdural hemorrhage, epidural hemorrhage, subarachnoid hemorrhage, or other types of intracranial hemorrhage. Sheer injury or concussion can also present with AMS. Though rare, delayed presentations of intracranial hemorrhage can occur[46] and meningitis can present later as a result of facial or skull fractures.

Structural. Structural causes include stroke, ruptured aneurysms causing subarachnoid hemorrhage, seizures, locked-in syndrome, hydrocephalus, neoplasm, posterior reversible encephalopathy syndrome (PRES), and reversible cerebrovascular vasoconstriction syndrome (RCVS) among other causes. Seizures, though often easy to recognize, can present with subtle findings or as nonconvulsive status epilepticus (NCSE). The incidence of NCSE in patients with AMS is as high as 8 to 30%.[47]

Infectious. Central nervous system infections such as meningitis or encephalitis can present with the classic triad of fever, nuchal rigidity, and AMS or with unexplained neurologic deficits or AMS without focality.[48,49]

Autoimmune/Other. Other less common neurologic causes of AMS include neuropsychiatric lupus, Behçet's syndrome, vasculitis, acute disseminated encephalomyelitis, and autoimmune limbic encephalitis.[9]

Wernicke's encephalopathy is a clinical diagnosis that presents with ataxia, ophthalmoplegia, and confusion.[50] Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor, among several other functions, and is required by neurons and other supporting cells in the nervous system.[50] The heart and central nervous system are particularly sensitive to thiamine deficiency.[50] Thiamine deficiency can result in Wernicke–Korsakoff syndrome along with multiple other forms of brain injury.[50] Providers should have a high suspicion for thiamine deficiency in chronic alcoholics, malnourished patients (e.g., anorexia nervosa, hyperemesis gravidarum), and in those with malabsorption syndromes. An important population to consider for being thiamine deficient are those who have had bariatric surgery, particularly a vertical sleeve gastrectomy.[51]

Metabolic. Disruption of normal metabolism can result in end-organ damage to the brain. Given the breadth of this category, we have separated this into four major subcategories: toxic, electrolyte, endocrine, and hepatic.

Toxic. Exogenous toxins can cause AMS through a variety of mechanisms including introduction of exogenous neurotransmitters, release of endogenous neurotransmitters, metabolic derangements, or other physiologic alterations. Clinical presentations typically depend on the class of toxins, varying from coma (opioids, alcohol, benzodiazepines) to combativeness (sympathomimetics, anticholinergics). Some toxins, such as gamma-hydroxybutyric (GHB) acid, can vary drastically in their clinical presentation, making it difficult to determine the specific toxin on initial presentation. Medication reactions such as serotonin syndrome or neuroleptic malignant syndrome can also present as AMS. Unintentional and intentional overdose of over-the-counter medications such as salicylates can also cause deadly poisonings and can mimic other conditions such as sepsis, ultimately delaying the diagnosis and increasing mortality and morbidity.

Electrolyte. Several electrolyte derangements can result in AMS and require emergent treatment. We have included alterations in glucose and blood urea nitrogen in this section. Though not true electrolytes, they are reported with electrolytes and, for the sake of recall, have been included in this section.

Hypoglycemia can present with AMS ranging from delirium to coma; focal neurological symptoms may not be present. Similarly, hyperglycemia can present with AMS. Changes in mentation are a diagnostic criterion for hyperosmolar hyperglycemic state (HHS).[52] Diabetic ketoacidosis can also present with changes in mental status, though usually to less of a degree than with HHS.[52]

Hyponatremia can also result in alterations in mental status. It is the most common electrolyte disorder,[53] and the most common cause of such in the outpatient setting is thiazide diuretic use.[54] Hyponatremia can occur in euvolemic states (SIADH), hypervolemic states (heart failure, cirrhosis), or hypovolemic states (dehydration with poor intake). Hypotonic hyponatremia is the most common and relevant form of the disorder.[55] Clinical manifestations are dependent on the severity and acuteness of the state, but levels less than 120 mEq/L are considered severe.[55–59] At these levels, AMS can occur secondary to brain swelling and intracranial hypertension.[55] It can progress rapidly to life-threatening neurologic conditions including seizures, coma, and cerebral edema leading to brainstem herniation. Herniation can cause respiratory arrest leading to permanent brain damage or death.[55] These complications typically occur in euvolemic hyponatremia, such as with psychogenic polydipsia, the postoperative state, intracranial pathology, endurance exercise, or from recent use of medications including thiazides or oxytocin use, as these conditions typically cause acute (described arbitrarily as < 48 hours) rather than chronic changes. With acute changes, no intracranial adaptation occurs, making the brain more susceptible to edema.[55] Though adaptation is beneficial in this sense, the risk of osmotic demyelination in these patients markedly increases.[56,57,60] For this reason, extreme caution should be taken when raising a patient's serum sodium concentration.

Hypernatremia, though not as common, can also cause AMS typically from diabetes insipidus or severe dehydration.

Severe acidosis or alkalemia can result in AMS, especially in patients with acute respiratory acidosis from respiratory failure and subsequent hypercarbia.

Disorders in calcium can result in AMS. Hypercalcemia is classically thought as presenting with "stones, bones, groans, and psychiatric overtones." The last one refers to changes in mentation from hypercalcemia. The most common cause of hypercalcemia in outpatients is hyperparathyroidism; in inpatients, it is malignancy.[61] Hypocalcemia can result in hypotension, cardiac dysrhythmias, or heart failure which can also precipitate AMS.[62,63]

Uremia usually does not cause changes in mental status until levels reach 100 mg/dL or higher.[64] At these levels, emergent dialysis is indicated if the patient is suffering from AMS.[65,66]

Endocrine. Thyroid dysfunction can cause a wide array of symptoms. Hypothyroidism can present with vague symptoms or as myxedema coma in its most severe form. It is important to consider hypothyroidism in elderly patients as their symptoms are often attributed to normal aging or another cause, resulting in missed or delays in diagnosis.[67] Similarly, hyperthyroidism can result in mild symptoms or as severe as thyroid storm, an endocrinologic emergency.

Adrenal insufficiency is unlikely to present as isolated AMS, but can present with AMS from hypotension that may be refractory to treatment. Other clues to this diagnosis may include dark skin pigmentation, hyponatremia with hyperkalemia, hypoglycemia, or profound refractory shock. A corticosteroid-producing (i.e., Cushing's syndrome) condition may present with changes in mood and headaches with AMS.

Hepatic. Acute liver failure can result in hepatic encephalopathy. Hepatic encephalopathy is not completely understood, but ammonia and several other toxins are believed to play a role. Acute liver failure can also result in cerebral edema, hypoglycemia, coagulopathy, infection, and acute renal failure, all of which can contribute directly or indirectly to AMS.


Both systemic (e.g., pneumonia, pyelonephritis) and central nervous system infections (e.g., infections described earlier) can result in AMS. In the former case, AMS should be considered end-organ dysfunction of the brain as a result of the insult and may be indicative of severe disease. Certain risk factors make patients more vulnerable to this. Risk factors include older age, dementia, functional impairment, medical comorbidities, malnutrition, and substance abuse[68,69] (Table 3). Patients who have acute changes in mental status from a systemic infection and have little or no vulnerability factors should be assumed to have a life-threatening condition such as severe sepsis. It is important to note that AMS in the setting of a systemic infection is component of the Sequential Organ Failure Assessment (SOFA) score, which has been shown to be a predictor of prolonged intensive care unit stay and hospital mortality.[70,71]


A psychiatric cause of AMS is a diagnosis of exclusion. Psychiatric patients suffer from a high rate of comorbid illnesses which are largely undiagnosed and untreated.[72] Several studies have shown increased mortality for psychiatric patients from both natural and unnatural causes.[72] In one study, 20% of psychiatric patients had a medical problem causing or exacerbating their condition.[72] Changes in vision appear to be the most predictive of a medical illness causing, or at least contributing to, their symptoms.[72] Patients with an abnormal neurologic exam, vital sign abnormalities, no history of a psychiatric disorder (particularly if older than 40 years) need a thorough medical evaluation before attributing symptoms to a psychiatric cause. It is also important to note that in the elderly, "altered mental status" is strongly indicative of delirium.[6]