Intracranial Hemorrhage

Intracranial hemorrhage is categorized by the compartment where the bleeding occurs, including the brain parenchyma (e.g., intraparenchymal or intracerebral) and the subarachnoid, subdural, or epidural spaces. Encephalopathy can accompany acute hemorrhage into any of the intracranial compartments and is often associated with headache and/or focal neurologic deficits. This diagnosis is suspected clinically but made definitively by CT. An acute intracranial hemorrhage is a neurologic emergency given the potential for rapid elevations in intracranial pressure and cerebral herniation due to expansion of the blood, especially those under arterial pressure (e.g., aneurysmal subarachnoid hemorrhage and epidural hematoma).

Subarachnoid hemorrhage, particularly when caused by rupture of a cerebral artery aneurysm, is often associated with a sudden, severe headache and can be accompanied by signs of meningeal irritation (e.g., meningismus, photophobia, nausea), seizures, and encephalopathy characterized by a reduced level of arousal. Subarachnoid hemorrhages have many underlying causes, including cerebral aneurysm (e.g., idiopathic and mycotic), head trauma/traumatic brain injury (TBI), vascular malformation, reversible cerebral vasoconstriction syndrome, venous sinus thrombosis, cerebral amyloid angiopathy, and others.

Intraparenchymal hemorrhage typically presents with focal neurologic deficits that correspond to the location of hemorrhage and is often accompanied by headache, nausea, seizures, and hypertension. Encephalopathy can have different characteristics depending on the location and size of the hemorrhage. Wakefulness may be affected by large lesions causing elevations in intracranial pressure and/or smaller focal injuries to arousal centers (e.g., brainstem and thalamus). Cognitive, emotional, and motivational symptoms can develop with focal injury to the networks supporting these functions. The common causes of intraparenchymal hemorrhage include hypertension, cerebral amyloid angiopathy, head trauma, vascular malformation, coagulopathy, brain metastases, venous sinus thrombosis, and ischemic stroke with hemorrhagic transformation.

Epidural and subdural hematoma are almost always associated with head trauma. Epidural hematomas often cause encephalopathy with a depressed level of consciousness, although there may be a “lucid interval” prior to this change. Epidural hematoma usually occurs with damage to the middle meningeal artery, which allows arterial blood to collect in the epidural space, leading to rapidly increased intracranial pressure and the risk of herniation. Subdural hematomas are less apt to occur on hyperacute timescales, although they can cause seizures, which in turn can be hyperacute.

Ischemic Stroke

Ischemic stroke is caused by lack of blood flow to one or more regions of the brain leading to infarction. Most patients present with focal deficits, and the precise clinical syndrome depends on the functions supported by the ischemic tissue. Encephalopathic states with changes in arousal, cognition, and emotion can occur with lesions of the bilateral thalami (e.g., “top of the basilar” syndrome, artery of Percheron stroke), mesencephalic-diencephalic junction, and diffuse bilateral cortical-subcortical microemboli. A much broader set of focal cognitive, neuropsychiatric, and behavioral syndromes can also occur secondary to ischemic stroke depending on infarct location(s). Acute confusional states characterized by impaired orientation, inattention, and aberrant perception may occur as a result of right middle cerebral artery infarctions disrupting networks that subserve attention. Patients are alert but concentration is impaired, and memories are poorly formed. They may become agitated with awareness of irrelevant stimuli. The disorder may occur as a result of right parietal or right temporal lesions. The right temporal lesions may be more likely to produce a confusional state due to the proximity to the limbic system disrupting modulation of affective responses. Elderly patients with preexisting cognitive decline are more prone to develop a confusional state following a stroke.

Seizure

Seizures are caused by abnormal, excessive, rhythmic electrical discharges in the brain and usually occur as discrete events with a rapid onset. The clinical presentation of seizure (e.g., semiology) is highly variable and depends on where in the brain the aberrant electrical activity originates and whether it remains in one location (i.e., partial) or becomes more widespread (i.e., generalized). Generalized seizures lead to a loss of consciousness and are followed by a variable-length postictal period of encephalopathy with a return to baseline. Partial seizures often produce focal symptoms that reflect the function of the area where the aberrant electrical activity occurs (e.g., motor, sensory, and autonomic). Sudden changes in arousal, attention (e.g., absence), memory (e.g., focal dyscognitive), language (e.g., speech arrest), and/or emotion (e.g., ictal panic, gelastic) can occur and are important causes of encephalopathy. Nonconvulsive seizures (i.e., those without obvious motor manifestations) should also be considered in patients with sudden onset and/or fluctuating encephalopathy symptoms.

Migraine

Typical migraine is characterized by unilateral and throbbing headaches lasting several hours that are often accompanied by nausea, photophobia, and phonophobia. These headaches tend to build over the course of several minutes and may be preceded by an aura that is often visual (e.g., “scintillating scotoma”) or somatosensory (e.g., spreading paresthesias). Migraine can occasionally produce symptoms of confusion (“confusional migraine”), which can rarely occur in the absence of headache (“acephalgic migraine”). Acute confusional migraine manifests with acute confusion, agitation, disorientation, altered mental status, and speech and memory difficulty and may be the first presentation of migraine in children or adolescents. Most patients develop a headache prior to the onset of the confusional state. The confusion may be a manifestation of cortical spreading depression and some patients may experience, visual, somatosensory, and/or speech difficulty prior to or during the period of confusion. The confusion resolves within 24 hours and acute confusional migraine is a diagnosis of exclusion. Infection, seizures, inflammatory, neoplastic, and vascular disorders, and metabolic abnormalities must be ruled out. In one adult study, acute confusional migraine was noted to be the initial presentation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Traumatic Brain Injury

Acute TBI is a common cause of hyperacute encephalopathy. Changes in both the level of arousal (e.g., lethargy and coma) as well as contents of consciousness (e.g., amnesia and disorientation) can occur, depending on the severity of injury.

The term concussion is used to describe the mildest form of traumatic brain injury associated with altered mental status and only occasionally loss of consciousness. Patients with concussion can experience a posttraumatic encephalopathy as part of a broader postconcussive syndrome (e.g., headaches, dizziness, mental fogginess, intolerance of loud noises or bright lights), and the onset of symptoms may be delayed by hours or days following impact. Neuropsychiatric symptoms may accompany the syndrome, including fatigue, excessive sleeping or insomnia, personality changes (e.g., irritability, labile affect), memory loss, poor concentration, and slow processing speed. Symptoms usually resolve within a few weeks but can persist for months or years.

Subdural Hematoma

Subdural hematoma is hemorrhage into the subdural space, often due to the injury of the bridging veins that connect the surface of the brain with the dura. Since the cause is generally venous bleeding, the slow accumulation of blood can take days or even weeks to cause a clinically significant mass effect. Common symptoms include headache, seizure, and encephalopathy with reduced arousal and cognitive impairment, sometimes with focal elemental deficits. Subdural hematoma may be caused by head trauma, coagulopathy, anticoagulant medications, and intracranial hypotension (often due to the lumbar puncture or shunt). In older adults, perhaps due to stretching of bridging veins due to aging-associated brain atrophy (i.e., larger space between the brain parenchyma and dura), subdural hematoma can develop after only mild TBI. Acute-to-subacute encephalopathy in this age group should prompt head CT to assess for subdural bleeding.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome is caused by breakdown of the neurovascular autoregulation of blood pressure, which leads to vasogenic edema in the brain parenchyma, which has a predilection for posterior regions (e.g., occipitoparietal areas). Common symptoms include headache, seizures (occipital > others), and encephalopathy characterized by reduced arousal, confusion, and occasionally cortical blindness. It is associated with conditions that predispose to endothelial dysfunction, including hypertension, preeclampsia, and drug toxicity (e.g., cyclosporine, tacrolimus, and bevacizumab).

Demyelinating Conditions (e.g., Multiple Sclerosis and Acute Disseminated Encephalomyelitis)

Demyelinating diseases of the central nervous system include MS and ADEM. Although MS is a chronic disease, the most common form has a relapsing-remitting course that is often punctuated by acute flares that cause focal elemental neurologic deficits (e.g., optic neuritis and transverse myelitis). Encephalopathy can occur with focal or multifocal demyelination, leading to fatigue, cognitive slowing, and apathy, when focal cognitive/behavioral networks are involved. ADEM is an acute, multifocal demyelinating disorder of the CNS that usually occurs after an infection, most commonly in children.

Primary Central Nervous System Infections (Meningitis/Encephalitis/Abscess)

Central nervous system infections such as meningitis and encephalitis can present with acute encephalopathy, usually accompanied by headache and fever (as well as neck stiffness in the former). Acute bacterial, fungal, and parasitic meningitis may be fatal if untreated. Infectious encephalitis can cause encephalopathy via the disruption of arousal, cognitive, and limbic-affective networks. Herpes simplex virus can cause an acute change in personality, emotion, and cognition that rapidly progresses to coma if untreated.

Transient Global Amnesia

The syndrome of TGA is characterized by a temporary inability to form new episodic memories and presents with disorientation, repeated questioning, and a subsequent amnesia for the symptomatic period. Arousal and other aspects of cognitive and emotional functioning are typically normal. The condition always resolves within 24 hours and typically lasts only a few hours. TGA may be triggered by intense physiological or emotional stimuli (e.g., sexual intercourse, argument) or exposure to extreme environmental conditions (e.g., cold water). Although the condition is typically idiopathic, the syndrome may rarely be caused by posterior cerebral artery infarction or temporal lobe seizure.

Intensive Care Unit Delirium

Delirium is the most common clinical manifestation of acute brain dysfunction in the intensive care unit (ICU) and always warrants a full evaluation. ICU delirium is characterized by the sudden onset of confusion, inattention, and altered consciousness. Certain factors increase the risk including older age, preexisting cognitive impairment, prolonged mechanical ventilation, severe illness, use of sedative medication, and history of alcohol or substance abuse. There is a broad differential, and the leading causes include infection, metabolic abnormalities, medications, Wernicke disease due to thiamine deficiency, seizures, stroke, hypoxia, vitamin deficiencies, trauma, endocrinopathies, and alcohol/substance withdrawal or intoxication. Patients with ICU delirium will require a longer stay in the ICU and often a longer duration of mechanical ventilation. There is also an increased risk of mortality and patients may continue to have cognitive impairment with a decline in their ability to perform activities of daily living after discharge from the hospital. Many patients, however, who experience ICU delirium will fully recover and the underlying medical illness and quality of care in the ICU play a role in determining the outcome. Treating ICU delirium involves treating the underlying causes and providing optimal supportive care. Maintaining a normal sleep-wake cycle, minimizing the use of sedative medication, involving family members in the care, and early mobilization with physical therapy are essential in preventing and managing ICU delirium.

Subdural Hematoma

Subdural hematoma (discussed earlier) can produce cognitive symptoms that emerge slowly, sometimes weeks after onset.

Brain Tumors and Complications of Chemotherapy/Radiation

Primary brain tumors (e.g., glioblastoma, meningioma, primary CNS lymphoma) can cause encephalopathy. Symptoms may result from direct infiltrative damage to local tissue, edema, mass effect and intracranial shifts, effects on intracranial pressure, seizures, or hemorrhages. Headache is common during the course of the disease but rarely the sole presenting symptom.

Solitary parenchymal brain metastases commonly present with focal deficits that can affect arousal, cognition, emotion, and behavior depending on the involved brain region(s) affected. Widespread metastatic disease can mimic diffuse, systemic symptoms of encephalopathy. Headaches, seizures, and hemorrhages are common.

Subacute to chronic changes in cognition can occur as a side effect of treatments used for intracranial tumors, including tissue resection, radiation, and chemotherapy. Radiation is associated with tissue necrosis and vasculopathy. Leukoencephalopathy is reported with some chemotherapy agents (e.g., methotrexate). Episodic headaches, seizures, and other focal deficits, including those affecting cognition, can occur as part of the syndrome of stroke-like migraine attacks after radiation therapy (SMART syndrome).

Antibody-Mediated Autoimmune/Paraneoplastic Conditions

A growing number of recently described antibody-mediated autoimmune conditions can affect the central nervous system, causing subacute changes in cognition, emotion, and behavior due to the antibodies’ affinity for limbic brain regions (i.e., autoimmune limbic encephalitis). Additional focal neurologic deficits are common and depend on the antibody’s tropism for different parts of the neuraxis. These antibody-mediated encephalopathies can be isolated or occur as a paraneoplastic phenomenon. A well-described entity is the limbic encephalitis associated with autoantibodies against the glutamate N -methyl- d -aspartate receptor. Initial presentation with memory loss and personality/mood changes may be mistaken for primary psychiatric disease, though seizures and/or movement disorders often develop, revealing a neurologic rather than a primary psychiatric cause of the alterations in mental status.

Hashimoto Encephalopathy

Hashimoto encephalopathy (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis, occurs in association with autoantibodies against thyroglobulin or thyroid peroxidase, although neither the antibodies nor the thyroid state itself have been clearly established to mechanistically underlie the symptomatology. HE can present with global or focal symptomatology, at times as a rapidly progressive dementia syndrome. Patients typically experience a robust improvement with intravenous corticosteroids.

Infectious Meningitis/Encephalitis

Subacute infectious meningoencephalitis can occur with fungal, tuberculous, viral (human immunodeficiency virus [HIV]), or syphilis infection. Typical meningeal symptoms may be present but often emerge more subacutely than in bacterial or viral meningitis. Seizures and strokes can occur. Immunocompromised patients are at higher risk for developing fungal meningitis.

Prion Disease/Jakob-Creutzfeldt Disease

Prion disease (e.g., Jakob-Creutzfeldt disease [CJD]) is a rare but important cause of rapidly progressive dementia in adults. Patients may present initially with cognitive impairment and behavioral changes (e.g., psychosis, paranoia, personality change), and movement disorders (e.g., myoclonus, parkinsonism), sensory changes, and altered sleep-wake cycles are common with disease progression. The Heidenhain variant of CJD is characterized by visual disturbances at onset due to prions targeting the occipital lobes early in the disease and may persist for weeks before there is cognitive involvement.

Central Nervous System Vasculitis

CNS vasculitis can present with subacute progressive cognitive decline. Nearly all patients have headaches, and neuroimaging generally shows subcortical infarctions of different ages. CNS vasculitis may be isolated to the CNS (i.e., primary) or secondary to systemic vasculitis (e.g., granulomatosis with polyangiitis or infection [e.g., varicella zoster]).

Neurosarcoidosis

Sarcoidosis is a granulomatous inflammatory condition that can affect multiple organ systems, including the brain. Neurosarcoidosis most commonly causes cranial nerve palsies, although subacute meningitis and/or direct parenchymal involvement may also occur, leading to cognitive and behavioral changes with encephalopathy. The observed neurologic deficits can be widespread or focal, depending on the location and extent of the pathology. Seizures may also occur.

Degenerative Disease

In older adults, the most common causes of chronic symptoms with features of encephalopathy are the neurodegenerative diseases associated with cognitive decline. There is considerable syndromic variability across the spectrum of degenerative disease, and it can impact aspects of cognitive, perceptual, limbic-emotional, motor, sensory, autonomic, and arousal/sleep functions. Precise characterization of deficits can help predict the underlying pathology, prognosis, and treatment options. By their nature, all degenerative diseases tend to progress gradually over the course of years. Many degenerative diseases are associated with the accumulation and network-based spread of toxic proteins within the brain. Patients with neurodegenerative cognitive impairment are more susceptible to acute and subacute encephalopathy in the setting of systemic and/or other neurologic conditions, perhaps reflecting vulnerabilities (i.e., reduced resiliency) of the neuroanatomical networks supporting these disrupted functions.

Alzheimer disease is the most common degenerative disease and is associated with the excessive deposition of amyloid plaques and tau neurofibrillary tangles in brain tissues. Typical presentations of Alzheimer disease include early and disproportionate episodic memory loss, often accompanied to a lesser extent by deficits in visuospatial skills, aspects of language (e.g., lexical retrieval), and executive functions. Less common presentations of Alzheimer disease include those with relative sparing of episodic memory with disproportionate involvement of other domains, including language (e.g., logopenic variant of primary progressive aphasia), visuospatial functioning (e.g., posterior cortical atrophy), and a frontal-behavioral or dysexecutive variant. These “atypical” variants are more common in patients with an early age of onset. “Sundowning,” a type of encephalopathy characterized by changes in cognition, arousal, limbic-emotional functioning at the end of the day, is common in later stages of AD even in the absence of a superimposed condition.

New disease-modifying antiamyloid therapies (e.g., lecanemab, donanemab) can slow cognitive and functional decline in patients with mild cognitive impairment or early dementia due to biomarker-positive Alzheimer disease (e.g., cerebrospinal fluid, amyloid-positron emission tomography). The benefits of this therapy need to be balanced against the risk of cerebral edema and brain hemorrhage. Diagnosing Alzheimer disease at an early stage is more urgent than previously, given the limited window for accessing this novel therapy.

Dementia with Lewy bodies, a synucleinopathy, often presents with fluctuations in arousal, cognitive impairment (especially executive and visuospatial impairment), parkinsonism (usually minimally responsive to dopamine replacement), dysautonomia, REM sleep behavior disorder, and psychosis with visual hallucinations.

Frontotemporal lobar degeneration (FTLD) is a set of neuropathological proteinopathies (e.g., Pick disease, corticobasal degeneration, progressive supranuclear palsy, and TDP-43) that are often associated with frontotemporal dementia syndromes. The most common syndromic presentation is the behavioral variant of frontotemporal dementia, which is characterized by early behavioral, personality, and social changes including apathy, disinhibition, loss of empathy, repetitive or stereotyped movements, hyperorality (e.g., increased appetite, new food preferences, putting things in one’s mouth), and changes in executive functioning. FTLD pathologies also cause primary progressive aphasia syndromes (e.g., nonfluent/agrammatic and semantic variants), corticobasal syndrome, Richardson syndrome, and others, each reflecting tropism for other parts of the brain.

Cerebrovascular Disease

Vascular cognitive impairment is a common cause of chronic encephalopathy among older adults. Cerebrovascular disease can produce cognitive decline in several ways, including progressive accumulation of precisely located symptomatic strokes that leads to a stepwise reduction in function with each episode (e.g., multiinfarct dementia), or a slowly progressive accumulation of silent microinfarcts (often within the white matter), microhemorrhages, and other damage. When chronic and slowly progressive, vascular dementia often presents with deficits in executive functioning and visuospatial skill.

A rare but important cause of vascular cognitive impairment is CADASIL arising from Notch3 gene mutations and characterized by recurrent ischemic strokes accompanied by diffuse white matter lesions and subcortical infarcts. Patients with CADASIL often present with dementia at a younger age than those with atherosclerotic disease and may experience neuropsychiatric symptoms such as depression.

Normal Pressure Hydrocephalus

Normal pressure hydrocephalus is characterized by the excessive accumulation of cerebrospinal fluid without an accompanying elevation in intracranial pressure. The typical triad of symptoms includes gait unsteadiness with falls, urinary incontinence, and cognitive impairment. Cognitive involvement usually develops after the onset and progression of gait dysfunction. Cognitive and behavioral deficits reflect frontal-subcortical dysfunction and may include inattention, executive dysfunction (e.g., processing speed), apathy/abulia, impulsivity, and a tendency to perseverate.

Multiple Sclerosis

MS (as discussed earlier) is associated with chronic symptoms of cognitive impairment and fatigue. The cognitive syndrome typically affects attention, processing speed, executive functions, and episodic memory.

Infection

Chronic, smoldering infections can present with cognitive symptoms. Longstanding HIV infection is associated with progressive cognitive decline with motor slowing (i.e., HIV-associated neurocognitive disorder). Syphilis is a well-known cause of chronic cognitive impairment and behavioral changes. The neurologic phenotypes of syphilis are diverse, which may be due to the spirochete’s tropism for several CNS compartments, including the meninges, cerebral vessels, and parenchyma.

Progressive multifocal leukoencephalopathy is an infectious disease associated with JC virus infections that is seen in patients with chronic immunosuppression, often due to HIV infection or immunomodulatory medication (e.g., natalizumab).

Chronic Traumatic Encephalopathy

Recent evidence suggests that repetitive head trauma, as occurs with contact sports such as football, boxing, and soccer, is associated with a delayed-onset neurodegenerative disease. The symptoms include cognitive impairment, neurobehavioral changes (e.g., personality changes, impulsivity, depression, suicide), and parkinsonism.

Adult-Onset Leukodystrophies

Leukodystrophies are diseases that affect metabolic pathways important for myelin development, maintenance, and destruction. The clinical manifestations are diverse and often include cognitive and behavioral changes, motor dysfunction (e.g., spasticity), and seizures.

Mitochondrial Disorders

Mitochondrial diseases often affect multiple neurologic (and systemic) systems and are associated with leukoencephalopathy. MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multiorgan disease with broad manifestations including stroke-like episodes, lactic acidemia, epilepsy, dementia, and myopathy. Most patients suffer migrainous headaches and peripheral neuropathy is common. The encephalopathy manifests as a wide range of neurologic symptoms including seizures, headaches, muscle weakness, and cognitive decline. These symptoms can occur episodically, hence the term “stroke-like episodes.” Patients may develop cardiomyopathy, diabetes, gastrointestinal, renal, and pulmonary disease.