Approach
Diagnosis of acute mental status changes in HIV infection requires urgent identification of the underlying cause.
Viral etiologies
Herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV) encephalitis present acutely and are difficult to distinguish from one another.
Viral encephalitis
HSV is a common cause of sporadic encephalitis in the general population and can also be identified in patients with more advanced HIV infection. VZV is an uncommon cause of encephalitis, and neurologic involvement during disseminated disease is more likely in those with CD4 cell counts <200 cells/microliter. CMV tends to occur only in people with advanced HIV infection with CD4 cell counts <50 cells/microliter.
Most systemic signs are nonspecific and include fever, malaise, nausea, and vomiting. Central nervous system (CNS) symptoms include headache, confusion, speech difficulty, seizures, and behavioral changes. Focal neurologic deficits, such as hemiparesis or cranial nerve deficits, may be present. Patients may have ataxia, with brisk tendon reflexes and extensor plantar responses. They may also have involuntary movements (myoclonus and tremors), visual field defects, and sensory disturbances.
Epstein Barr virus-associated primary central nervous system (CNS) lymphoma
An acute presentation requiring urgent assessment may also be seen with a primary CNS lymphoma associated with Epstein-Barr virus in patients not receiving antiretroviral therapy (ART).
Symptoms and signs may be similar to those seen with encephalitis or meningitis, with unexplained headache, change in vision or motor function, poor coordination, ataxia, and seizures. Systemic features include nausea, vertigo, and sudden deafness. Exam findings also include varying focal neurologic deficits, such as hemiparesis, brisk tendon reflexes, cranial nerve deficits, involuntary movements, visual field defects, and sensory disturbances.
Bacterial etiologies
Bacterial etiologies of meningitis include Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes.
Tuberculous meningitis and/or encephalitis
Should be considered in HIV-infected patients with epidemiologic risk factors for tuberculosis (TB), especially in the presence of respiratory symptoms or signs. A further history and exam for evidence of pulmonary or extrapulmonary TB should be carried out. This would include a history of shortness of breath, cough, lymphadenopathy, abdominal pain, and dysuria. Fever, chills, weight loss, and night sweats may indicate systemic infection. Respiratory signs of tachypnea, decreased breath sounds, crackles, and dullness to percussion may be present. There may be signs of a pleural effusion.
Neurosyphilis
Can occur at any stage of syphilis infection. Meningismus, concomitant uveitis, or cranial neuropathy may be seen. Those with tertiary syphilis may present with hyporeflexia, ataxia, anisocoria, Argyll Robertson pupils, cranial neuropathy, and motor or sensory deficits. Patients may have associated dementia and paranoia.
Other infectious etiologies
Include cryptococcal meningitis and parasitis etiologies.
Cryptococcal meningitis
Has an acute or subacute onset with similar but progressive symptoms. There may be a history of meningismus and headache. Patients with cryptococcal meningitis may also have photophobia, drowsiness, reduced visual acuity, and papilledema.
Toxoplasmosis
Toxoplasmosis occurs in the setting of advanced immune suppression, with a CD4 cell count <100 cells/microliter. Confusion and fever are often present, and neurologic deficit or seizure is common. Imaging reveals the presence of ring-enhancing lesions (usually multiple).
Initial investigations
Investigations in patients with acute alterations in mental status may include:
Toxicology screen: to identify opiates, cocaine, amphetamines, or sedatives.
Complete blood count (CBC), chemistry panel, urinalysis: to rule out infection, metabolic disturbances, and hepatic encephalopathy.
Arterial blood gas: to evaluate for hypoxia and acidosis.
CD4 count: if an opportunistic infection is suspected. The count is typically <100 cells/microliter in the presence of more common infectious causes, such as Cryptococcus or toxoplasmosis, but is <50 cells/microliter in CMV infection and progressive multifocal leukoencephalopathy (PML).
Infectious workup: including blood cultures (two sets), screening Treponema pallidum enzyme immunoassay (EIA) or rapid plasma reagin (RPR) for syphilis, and serum cryptococcal antigen (determined by latex agglutination, enzyme immunoassay, or lateral flow assay).[16][41] Toxoplasma serology is usually positive in those with CNS disease, although a negative IgG does not preclude the possibility of toxoplasmosis infection.
Chest x-ray: to rule out pneumonia or other potential causes of hypoxia.
ECG: to rule out myocardial infarction.
Electroencephalogram (EEG): may ultimately be considered to rule out seizure activity and encephalopathy.
Neuroimaging
Should be considered for the majority of HIV-infected patients with altered mental status. Magnetic resonance imaging (MRI) is the study of choice. Computed tomography (CT) may be more readily available and faster than MRI, but the latter can provide more detail.
Imaging is essential when there is a strong possibility of a structural brain lesion or for diagnosing specific disorders. Where an intracranial infection is suspected, cranial imaging should be performed before lumbar puncture to exclude a mass lesion and a risk of iatrogenic brain herniation. All patients presenting with focal neurologic deficits and an abnormal motor system exam, cranial nerve deficits, involuntary movements, visual field defects, sensory disturbances, and seizures should undergo cranial imaging.
MRI or CT can help distinguish between CNS infections and tumors. Ring-enhancing lesions in the basal ganglia are seen in toxoplasmosis, whereas solid or ring-enhancing lesions in the gray matter are seen in primary CNS lymphoma. Diffuse white matter intensities are seen in CMV infection. Hydrocephalus may indicate cryptococcal meningitis or TB.
Cryptococcal meningitis is also associated with enhancement and parenchymal lesions, whereas TB produces edema, basilar meningeal thickening, or tuberculomas. Hypodense white matter lesions on T1-weighted imaging with T2-weighted hyperdensity are seen in PML. Gyral edema with high signal intensity in the temporal lobe or cingulate gyrus is seen in herpes. Imaging is usually normal in neurosyphilis, but possible changes include generalized cerebral atrophy with ventricular dilation, multiple small infarcts in the basal ganglia, and syphilitic cerebral gummas.
MRI or CT may be helpful in distinguishing HIV-associated neurocognitive disorders (HAND) from cognitive impairment of other etiology. The MRI is normal in asymptomatic neurocognitive impairment (ANI), but may show signs of progressive brain atrophy, cerebellar degeneration, basal ganglia atrophy, and diffuse periventricular white matter hyperintensities in HIV-associated dementia (HAD). By contrast, Alzheimer disease typically produces hippocampal volume loss, atrophy of the medial temporal lobe, and posterior cortical atrophy.
If the patient has had a recent stroke, CT reveals hypoattenuation (darkness) of the brain parenchyma, loss of gray matter-white matter differentiation, and sulcal effacement. An MRI reveals brightness on diffuse weighted imaging and increased signal in the ischemic territory on T2 images.
Lumbar puncture (LP)
LP is almost mandatory in patients presenting with signs and symptoms of an intracranial infection (e.g., encephalitis or meningitis) unless specific contraindications exist (such as a mass lesion or a coagulopathy). The opening pressure should be documented in all cases and is of vital importance in the management of cryptococcal meningitis.
Cerebrospinal fluid (CSF) analysis should include white blood cell (WBC) counts and protein/glucose levels. CSF bacterial, mycobacterial, and fungal cultures and cytology may also be performed.
A lymphocytic pleocytosis can be seen in toxoplasmosis, CMV, cryptococcal infection, neurosyphilis, TB, and primary CNS lymphoma. CSF glucose may be decreased in cryptococcal infection and primary CNS lymphoma, and can be markedly decreased in the setting of TB. CSF glucose is usually normal in neurosyphilis, and only rarely decreased in the setting of toxoplasmosis.
A normal CSF, or mildly elevated protein in an otherwise normal CSF, is seen in PML, while mild elevations in CSF protein can be seen with other viral etiologies. Cryptococcal meningitis and TB are both associated with moderate to high levels of CSF protein.
Specific tests:
CSF cryptococcal antigen: highly sensitive and specific for Cryptococcus.
Venereal Disease Research Laboratory CSF test: can be used to identify syphilis.
Polymerase chain reaction (PCR):
may be performed for HSV, VZV, and CMV (if CD4 cell count is low)
can be diagnostic for John Cunningham virus (JCV) as the agent responsible for PML
PCR (or nucleic acid amplification) may identify toxoplasmosis or TB, but not standardized in this setting.
A brain biopsy may be required to confirm an intracranial lymphoma or other cause of focal lesions, particularly if there has been no response to a trial of empiric toxoplasmosis therapy.
[Figure caption and citation for the preceding image starts]: Evaluation of HIV-related mental status changesAdapted from Tessier D, Dion H, Grossman DW, et al. HIV care: a primer and resource guide for family physicians. 2nd ed. Mississauga, Ont: College of Family Physicians of Canada; (c) 2001, 2002. All rights reserved. The College of Family Physicians of Canada; used with permission [Citation ends].
Insidious mental status change
An insidious onset and progression are features normally associated with HAND or psychiatric comorbidity. Typically, HIV-associated neurocognitive disorder (HAND) is diagnosed after excluding other potential etiologies to explain a decline in cognition. Patients do not have any focal neurologic signs or acute systemic disease. HANDs include asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). However, these can be difficult to identify in patients with a pre-existing psychiatric, developmental, or neurologic disorder.[6][32]
HIV-associated neurocognitive disorder (HAND)
Asymptomatic neurocognitive impairment (ANI): insidious and progressive cognitive decline without affecting activities of daily living suggests ANI. These patients typically have mild impairment on neuropsychological testing.
Mild neurocognitive disorder (MND): progressive cognitive decline and impaired ability affecting work performance, homemaking, or social functioning is more indicative of HIV-associated MND. On neuropsychological testing, impairment is of the same severity as found in ANI, but it does impact functioning.
HIV-associated dementia (HAD): patients with severe impairment in cognitive functioning that produces marked interference with day-to-day functioning are diagnosed with HAD. They tend to have a delayed speech output, with long pauses between words, and a poor thought process. They may also appear depressed, with a flat or labile affect, apathy, and social withdrawal, but sadness is usually not present, which helps to distinguish this state from depression. There may be associated gait abnormalities and a reduction in motor movements, frontal release signs, spasticity, and brisk deep tendon reflexes.
As psychiatric comorbidity may coexist with HAND, it may be difficult to distinguish between them. Patients with pre-existing depression may report persistent long-standing dysphoric mood, anxiety, irritability, feelings of hopelessness, loss of self-esteem, and anhedonia (loss of interest in usual activities). Depressed patients may also have cognitive difficulties such as impaired episodic memory, executive function, and processing speed, as well as psychomotor slowing, agitation, poor concentration, sleep and appetite disturbances, fatigue, and recurrent thoughts of death.[42]
Progressive multifocal leukoencephalopathy (PML)
PML occurs as a consequence of infection with JCV. Patients may not be receiving ART or may have had a poor immunologic response to it, making them susceptible to opportunistic infections. The impairment in cognition is insidious, with behavioral changes, motor and visual impairment, and focal neurologic deficits (e.g., hemiparesis, ataxia, pyramidal signs, cranial nerve deficits, involuntary movements, sensory disturbances, and seizures).
Organic disease
Change in mental status could also be due to an organic disease such as a stroke, vitamin B12 deficiency, hypothyroidism, hypogonadism, or hepatic encephalopathy. The patient is more likely to have systemic involvement.
Stroke: a history of cardiac disease or syphilis may suggest stroke. The changes in mental status are acute and associated with neurologic symptoms: for example, unilateral weakness or numbness; change in vision (unilateral or bilateral); difficulty with speech and comprehension; loss of coordination; difficulty walking. Preceding symptoms prior to the stroke may include severe headache and confusion. Exam reveals focal neurologic signs such as unilateral hemiparesis, hemianopia, aphasia, and ataxia. Cardiac failure may be present.
Vitamin B12 deficiency: cognitive impairment in the presence of paresthesias, memory loss, gait disturbances, lower extremity numbness with hyporeflexia but a positive Babinski sign suggesting a peripheral neuropathy, and atrophic glossitis, suggest vitamin B12 deficiency.
Hepatic encephalopathy: hepatic encephalopathy due to hepatitis B or C infection, or other causes of liver failure (e.g., alcoholic). Stigmata of liver disease, such as spider angiomata, gynecomastia, hepatomegaly, ascites, and jaundice, may be present.
Investigations to identify the etiology
Initial laboratory tests should be guided by medical history (obtained from patient and, if possible, an informant who knows the patient well) and physical exam findings. It should be noted that patients with HAD may not be aware of their cognitive deficits (anosognosia) and therefore may be unreliable informants. When cognition is severely impaired, history needs to be complemented by interview with an informant and, when possible, neuropsychological testing and/or an evaluation by an occupational therapist.
CBC: may be normal or show macrocytic anemia (in vitamin B12 deficiency or chronic alcoholism) or an abnormal WBC count.
Liver function tests: abnormal in hepatitis co-infection or chronic alcoholism.
Serum vitamin B12, homocysteine, and methylmalonic acid: measured if vitamin B12 deficiency is suspected. A serum vitamin B12 <200 picograms/mL with elevated serum homocysteine and methylmalonic acid levels are diagnostic.
Thyroid-stimulating hormone, testosterone, and cortisol levels: measured if hypothyroidism, hypogonadism, or adrenal insufficiency, respectively, are suspected.
Serum T pallidum EIA or RPR to rule out neurosyphilis.
Berlin Questionnaire: can be used to screen for the presence of OSA.[43] Obstructive sleep apnea (OSA) can contribute to cognitive difficulties and is increased in people living with HIV.[44] A positive screen should be followed by a referral for investigation.
CSF analysis: role in noninfectious neurocognitive disorders is more controversial. Early studies found that cognitive impairment was correlated to the HIV viral load in the CSF.[45] Subsequent studies focused on autonomous viral replication within the CNS, as revealed by a high CSF/plasma viral load ratio, as a correlate of neurologic and cognitive disorders.[46][47] There can be discordance between CSF and plasma viral load, with viral load being undetectable in plasma while being detectable in the CSF. This viral presence in the CSF has clinical implications as it may require a change in antiretroviral agents in favor of those that have better penetration and effectiveness in the CNS.[32][48][49][50][51][52] However, it should be noted that CNS-targeted ART failed to demonstrate a significant benefit on neurocognitive performance among patients with HAND in a randomized controlled trial (that was terminated early on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome).[53]
Additional investigations
An ECG and echocardiogram should be ordered if a cardioembolic origin for stroke is suspected.
An EEG is helpful for grading the severity of the encephalopathy associated with intracranial infection.
Cognitive screens, neuropsychological testing, and other screening tools
The European AIDS Clinical Society guidelines recommend screening for the presence of neurocognitive impairment in people without any obvious confounding conditions by posing these questions:[54]
Do you experience frequent memory loss (e.g., forgetting the occurrence of special events - even the more recent ones - or appointments, etc.)?
Do you feel that you are slower when reasoning, planning activities, or solving problems?
Do you have major difficulties paying attention (e.g., to a conversation, a book, or a movie)?
Answering “yes” to one or more of these questions may indicate a cognitive disorder, although it may not necessarily be linked to HIV.[54]
Screening tools such as the HIV Dementia Scale (HDS) and the Montreal Cognitive Assessment (MoCA) can be somewhat useful in the identification of cognitive difficulties. However, they often lack sensitivity to the milder forms of HAND that are the most common, with relatively high sensitivity coming only at the expense of low specificity. They are also not specific to the type of impairment found in HAND; results must be interpreted in the context of the medical history, clinical examination, and investigations.[32]
HIV Dementia Scale (HDS)
The HDS measures antisaccadic errors (voluntary eye movement made in the direction opposite to the side where a stimulus is presented), the recall of 4 items after 5 minutes, and timed alphabet writing and cube copying.[55] Maximum HDS score is 16, with a score of 10 or less generally considered abnormal. It takes a few minutes to administer, but non-neurologists often have difficulty with the antisaccadic error task. Demographically adjusted normative standards are available.[56]
One study found a cutoff score of 14 points or less was associated with a good sensitivity and a good predictive value for the recognition of patients with HANDs.[57] Details of the HDS are available from the HIV Clinical Resource website of the New York State Department of Health AIDS Institute. HIV Clinical Resource: mental health screening tools - HDS (HIV Dementia Scale) Opens in new window
Montreal Cognitive Assessment (MoCA)
The MoCA is a brief cognitive test originally developed to screen for mild cognitive impairment in geriatric populations.[58] It takes approximately 10 minutes to administer and is available in several languages. The Montreal Cognitive Assessment Opens in new window When the threshold for classifying impairment is set very high (≤27/30), the sensitivity to impairment as determined by neuropsychological testing, including mild forms, is 90%, but this is associated with a very low specificity of 43%. Sensitivity and specificity for different cut-off values are available.[59] Overall accuracy can be further increased by application of modern psychometric methods to scoring of the individual items.[60]
Brief batteries of neuropsychological tests
Include the Brief Neurocognitive Screen, the Hopkins Verbal Learning Test-Revised (HVLT-R; Total Recall) with the Grooved Pegboard Test nondominant hand (PND) pair; and the HVLT-R with the Wechsler Adult Intelligence Scale-III (WAIS-III) Digit Symbol (DS) subtest.[61][62] These tests are administered by a neuropsychologist.
Screening tools useful for the evaluation of psychiatric comorbidity
The Patient Health Questionnaire-2 inquires about the frequency of depressed mood and anhedonia over the previous 2 weeks. The score ranges from 0 to 6, with a score of 3 indicating the optimal cut-off for screening purposes. Patient Health Questionnaire-2 (PHQ-2) Opens in new window A positive screen should be followed with the administration of the Patient Health Questionnaire-9. Patient Health Questionnaire-9 (PHQ-9) Opens in new window
The CAGE alcohol screening test-Adapted to Include Drugs (CAGE-AID) is a brief screening tool for the identification of alcohol or drug misuse, in which the patient is asked the following 4 questions:
Have you ever felt the need to Cut down on your use of alcohol or drugs?
Has anyone ever Annoyed you by criticizing your use of alcohol or drugs?
Have you ever felt Guilty because of something you have done while drinking or using drugs?
Have you ever taken a drink or used drugs to steady your nerves or get over a hangover (i.e., as an Eye-opener)?
A score of 2 or more may suggest a drug or alcohol problem.[63]
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