When assessing patients with acute or chronic changes in cognition, two interrelated questions should be pursued during the history and examination:
Is the presentation focal or global?
Is the problem arising from primary brain pathology or a systemic process that is affecting the brain?
Focal deficits suggest focal brain pathology (e.g., stroke, tumor, abscess), although focal findings can occur with systemic disease in the absence of focal central nervous system pathology (e.g., focal seizures or hemichorea caused by hyperglycemia or aphasia caused by cefepime toxicity). Global dysfunction is generally due to systemic pathology affecting the brain, although diffuse intrinsic brain pathology can also cause a global encephalopathy (e.g., multiple strokes, multiple metastases, a diffuse infiltrating malignant lesion, acute disseminated encephalomyelitis).
Focal cognitive deficits may give the initial misleading impression that there is a global encephalopathy. Examples of focal deficits that can initially appear to be global encephalopathic states unless examined in detail include Wernicke’s aphasia producing lack of comprehension and abnormal speech, and transient global amnesia causing isolated short-term memory impairment. On the other hand, global cognitive dysfunction may make it challenging to elicit coexisting focal deficits on examination since a core feature of global cognitive dysfunction is inattention, which can make it difficult to examine cognitive functions that rely on attention such as language, memory, and ability to follow commands.
Delirium refers to acute altered mental status (developing over hours to days), and dementia refers to chronic development of cognitive dysfunction (over years). Rapidly progressive dementia describes subacute development of cognitive dysfunction (over weeks to months).
Delirium is characterized by acute onset of altered mental status with fluctuations in both symptoms and level of arousal. Delirium causes a global encephalopathy, with inattention as the core feature. The differential diagnosis for acutely altered mental status is as broad as the differential diagnosis for any condition in medicine. Delirium can be caused by intrinsic brain pathology (see “Neurologic Causes of Acutely Altered Mental Status” below), systemic disease affecting the brain (e.g., renal or hepatic failure, systemic infections, electrolyte disturbances, hypoglycemia or hyperglycemia, hyperammonemia, hypothyroidism or hyperthyroidism), medications, toxins, drugs, or drug withdrawal. Primary psychiatric etiologies may also be causative or contributory. Although new changes in cognition or personality in patients with psychiatric disease may be due to the underlying psychiatric disease, potential reversible medical causes should be sought.
Patients who are elderly or have baseline neurologic dysfunction (e.g., dementia) are at increased risk of delirium due to any of the above etiologies (as well as due to the disorienting environment of the hospital if the patient is hospitalized).
Neurologic etiologies of acute-onset altered mental status include seizures, stroke and cerebrovascular disease, CNS infections, and transient global amnesia.
Nonconvulsive seizures can cause alterations in cognition and level of consciousness ranging from encephalopathy to coma. Diagnosis of nonconvulsive seizures may require continuous EEG monitoring (see “Nonconvulsive Status Epilepticus” in Ch. 18). A postictal state following a seizure can also lead to changes in mental status ranging from confusion to coma. An unwitnessed seizure with subsequent postictal state should be considered as a potential etiology of altered mental status, especially in patients who improve spontaneously from their altered state without any specific medical intervention.
Although stroke as a cause of acute alteration in mental status is generally easily recognized when focal features are present, certain regions of infarction may lead to global cognitive dysfunction without obvious focal signs. Additionally, focal signs such as subtle visual field deficits or neglect may be hard to elicit in confused patients. Sites of infarction that can lead to changes in mental status without obvious focal features include the thalamus (especially bilateral thalamic strokes due to artery of Percheron territory infarct; see “Posterior Cerebral Artery Territory Infarction” in Ch. 7), inferior division of the right middle cerebral artery (MCA), anterior cerebral artery (ACA) territory (if motor fibers to the leg are spared), anterior or complete posterior cerebral artery (PCA) territory (affecting the hippocampus/medial temporal lobe), and diffuse emboli.
Subacute development of a subdural hematoma can lead to subacute development of altered mental status (see “Subdural Hematoma” in Ch. 19).
Fever and altered mental status should raise concern for meningitis, encephalitis, or intracranial abscess (see Ch. 20). Although a systemic infection can cause alteration in mental status without direct CNS involvement, lumbar puncture should be considered in patients with fever and altered mental status if there is no obvious systemic source of infection.
Transient global amnesia (TGA) is a discrete episode (usually lasting 12 hours or less) during which the ability to form new memories is lost (anterograde amnesia). This inability to form new memories leads to repetitive questioning (“Where am I?”, “How did I get here?”) since the short-term memory buffer is essentially erased every few minutes. Patients with TGA may be disoriented with respect to time and place and forget events of the preceding day(s) but do not forget their name or other personal information. If personal information is forgotten, this is highly suggestive of a psychogenic etiology of amnesia (e.g., fugue state) rather than a neurologic etiology.
A trigger commonly precedes TGA such as an emotionally intense situation (e.g., stressful event, sexual intercourse), vigorous exercise, or exposure to cold water. TGA is often idiopathic, but may be the presentation of a medial temporal lobe infarct (PCA territory), and so neuroimaging should be performed. In some patients with TGA, a punctate region of diffusion restriction can be seen in the hippocampus (Fig. 22–1), leading some to hypothesize that all TGA is a vascular phenomenon, although the pathophysiology of the condition is unknown. Although seizures can produce ictal or postictal amnesia, the period of amnesia with seizures is generally shorter than that in TGA, and seizures are often recurrent, whereas TGA usually lasts for hours and only very rarely recurs.
“Toxic-metabolic” encephalopathy refers to altered mental status due to medications, toxins, and/or metabolic abnormalities (e.g., uremia, hepatic failure). When faced with a case of potential toxic-metabolic encephalopathy, the consultant neurologist should try to determine which “toxic” and/or “metabolic” factor(s) may account for the patient’s altered state: Does the degree of renal or hepatic failure differ significantly from the patient’s baseline? Has a potentially deliriogenic medication been recently added? Has an old medication changed in dose or could it be reaching toxic levels at its previously tolerated dose due to new renal or hepatic dysfunction? Applying the catch-all “toxic-metabolic” term to encephalopathies without careful consideration can lead to premature closure and missed diagnoses. By thinking critically through any and all potential neurologic and systemic etiologies of altered mental status, reversible etiologies may be uncovered.
An important example of this is the case of medications. Nearly any medication can cause altered mental status. Neurologists are in the unique position of having seen and diagnosed cases of medication-induced neurotoxicity from medications that only rarely cause neurotoxicity. Other practitioners may have used a medication countless times without seeing neurologic side effects, and thus may not associate a particular drug with the potential to cause delirium. For example, many commonly used antibiotics can rarely cause encephalopathy, including cephalosporins (in particular cefepime and ceftazidime), fluoroquinolones, macrolides, metronidazole, and isoniazid (Bhattacharyya et al., 2016). Cephalosporin-associated encephalopathy is often associated with nonconvulsive seizures, fluoroquinolone- and macrolide-associated encephalopathy with hallucinations and psychotic symptoms, and metronidazole-associated encephalopathy with ataxia and characteristic MRI findings in the cerebellar white matter. Patients who develop alterations in mental status of unclear etiology on any of these medications should generally have these medications replaced with alternative antibiotics given the possibility of antibiotic-associated encephalopathy.
Wernicke’s encephalopathy is characterized by the triad of encephalopathy, ataxia, and eye movement abnormalities (nystagmus and/or gaze palsies), and is caused by thiamine (vitamin B1) deficiency that occurs in the setting of malnutrition (e.g., in patients with alcoholism, anorexia, gastric bypass surgery, or hyperemesis gravidarum). In many cases of Wernicke’s encephalopathy, the complete triad is not present, requiring a high index of suspicion for the condition. Wernicke’s encephalopathy can be precipitated acutely by giving glucose to a thiamine-deficient patient without giving thiamine simultaneously. Therefore, thiamine should always be given with glucose infusions in the setting of acutely altered mental status to prevent this complication in patients whose history may be unknown. Serum thiamine levels take a long time to return and may be unreliable, so empiric treatment with intravenous thiamine should be provided if there is any concern for Wernicke’s encephalopathy. MRI in Wernicke’s encephalopathy can demonstrate signal abnormalities in the mammillary bodies, thalamus, and around the third and fourth ventricles (Fig. 22–2).
Not treating Wernicke’s encephalopathy can result in Korsakoff’s syndrome, characterized by anterograde amnesia and confabulation.
If the cause of acute altered mental status is unclear after careful review of the patient’s medications and active medical issues, EEG should be considered to look for non-convulsive seizures, brain imaging should be considered to look for a causative lesion, and lumbar puncture should be considered (if there is concern for CNS infection or inflammation).
Dementia is defined as cognitive decline in one or more domains (e.g., memory, language, attention, visuospatial processing, social behavior) sufficient to impair independent daily function.
Insidious onset and gradual progression of cognitive impairment over months to years may be secondary to neurodegenerative diseases (Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia being the most common), chronic cerebrovascular disease (vascular dementia), or due to potentially treatable causes such as:
Systemic diseases:
Metabolic deficiency: vitamin B12 deficiency
Endocrine disease: Hypothyroidism
Chronic infection: AIDS, syphilis
Obstructive sleep apnea
Medications, such as psychotropic medications in older adults
Toxins, such as alcohol or drug abuse, heavy metal poisoning
Intracranial pathology, such as tumor, chronic subdural hematoma, normal pressure hydrocephalus
Psychiatric disease, such as depression
Neurodegenerative disease is progressive with no disease-modifying medications, and treatment is limited to symptomatic management and supportive care. Therefore, part of the initial evaluation of patients with dementia is to assess for potentially treatable causes. The history should evaluate for depression, medication history, and sleep apnea. Examination should assess for focal findings that might suggest focal underlying pathology. Mental status testing should be performed to assess for the type and extent of impairment(s), for example with the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MOCA).
Frontal release signs may be present on physical examination in patients with dementia, but are not universally present and some of these signs can be seen in non-demented elderly patients (and occur normally in infants as does Babinski’s sign). Frontal release signs include:
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