Approach
Mental status change in people living with HIV may be acute or insidious. Screening tools may be of some benefit in the identification of insidious changes.
Diagnosis of acute mental status changes in HIV infection requires urgent identification of the underlying cause.
Acute mental status change: viral etiology
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 be identified in patients with more advanced HIV infection.[62] 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.[63] CMV encephalitis tends to occur only in people with advanced HIV infection with CD4 cell counts <50 cells/microliter.[64]
Most systemic signs are nonspecific and include fever, malaise, nausea, and vomiting. Central nervous system (CNS) symptoms include headache, confusion, speech difficulty, seizures, and/or 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. Involuntary movements (myoclonus, tremors, and hemiballismus), visual field defects, and sensory disturbances may be evident.
Epstein Barr virus (EBV)-associated primary CNS lymphoma
An acute presentation requiring urgent assessment. People with HIV-related EBV-positive primary CNS lymphoma may be less likely to be receiving ART, and have a CD4 cell count <50 cells/mm³.[55] Usually a sole mass lesion is identified, which may be confused with CNS toxoplasmosis. The diagnosis of primary CNS lymphoma often requires a brain biopsy.
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.
Acute mental status change: bacterial etiology
Bacterial etiologies of meningitis include Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes.
Tuberculous meningitis and/or encephalitis
Should be considered in people living with HIV with epidemiologic risk factors for tuberculosis (TB), especially in the presence of respiratory symptoms or signs. History and exam for evidence of pulmonary or extrapulmonary TB includes 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 pupil, cranial neuropathy, and motor or sensory deficits. Patients may have associated dementia and/or paranoia.
Acute mental status change: other infectious etiology
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. The CD4 cell count is typically <100 cells/microliter.[65]
Toxoplasmosis
Occurs in the setting of advanced immune suppression, with a CD4 cell count <100 cells/microliter.[66] Confusion and fever are often present, and neurologic deficit or seizure is common. Imaging reveals the presence of ring-enhancing lesions (usually multiple).
Acute mental status change: initial investigations
Consider the following investigations in patients with acute alterations in mental status:
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. Risk for toxoplasmosis or cryptococcal disease is greatest among people with CD4 counts <50 cells/mm³.[22]
Infectious workup: including blood cultures (two sets), screening Treponema pallidum enzyme immunoassay (EIA) plus rapid plasma reagin (RPR) for syphilis, and serum cryptococcal antigen (determined by latex agglutination, enzyme immunoassay, or lateral flow assay)[22][48]
Toxoplasma serology: indicated for those with a clinical presentation suggestive of toxoplasmosis; negative IgG does not preclude the possibility of toxoplasmosis infection[23]
Chest x-ray: to rule out pneumonia or other potential causes of hypoxia
Computed tomography: may be warranted when tuberculous meningitis is suspected
ECG: to rule out myocardial infarction
Electroencephalogram (EEG): may ultimately be considered to rule out seizure activity and encephalopathy
Nucleic acid amplification tests (NAAT): should be performed on at least one respiratory specimen when TB is suspected; assay for the detection of latent M tuberculosis infection may be considered.[23][67] World Health Organization (WHO) recommends concurrent testing with lateral flow urine lipoarabinomannan (LF-LAM) assay to assist in the diagnosis of active TB in adults living with HIV, adolescents, and children with signs and symptoms of TB, or who screen positive for TB.[67] WHO also recommends concurrent testing with LF-LAM in adults and adolescents living with HIV who are seriously ill or have advanced HIV.[67]
Insidious mental status change
An insidious onset and progression are features normally associated with HIV-associated neurocognitive disorder (HAND) or psychiatric comorbidity, regardless of CD4 cell count.
HIV-associated neurocognitive disorder
Typically, HAND is diagnosed after excluding other potential etiologies. Patients do not have any focal neurologic signs or acute systemic disease. Cognitive decline may range from asymptomatic neurocognitive impairment (ANI) to HIV-associated dementia (HAD).[23] However, these can be difficult to identify in patients with a preexisting psychiatric, developmental, or neurologic disorder.[14][40]
ANI: insidious and progressive cognitive decline involving at least two ability cognitive domains, documented by performance of at least one standard deviation (SD) below demographically corrected means for age-sex-education-appropriate norms, but with no impairment in the ability to perform everyday activities. These patients typically have mild impairment on neuropsychologic 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 neuropsychologic testing, impairment is of the same severity as found in ANI, but it does impact functioning.
HAD: marked acquired impairment in cognitive functioning involving at least two ability cognitive domains, documented by performance of at least two SD below demographically corrected means and associated with a marked impairment in performing daily activities. Patients 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.
Psychiatric comorbidities
May coexist with HAND, making it difficult to distinguish between the two entities. Patients with preexisting 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.[68]
Neuropsychologic testing may be required to distinguish between psychiatric comorbidities and HAND.
Progressive multifocal leukoencephalopathy (PML)
PML occurs as a consequence of infection with human polyomavirus 2 (also known as JCV). Patients may not be receiving ART, may be nonadherent with ART, or may have had a poor immunologic response to ART, making them susceptible to opportunistic infections. The CD4 cell count is typically <100 cells/microliter.[69][70]
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 may 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 increase the risk of stroke. Changes in mental status are associated with neurologic symptoms, including: unilateral weakness or sensory changes/paresthesias; change in vision (unilateral or bilateral); difficulty with speech and/or 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 or hyperreflexia and a positive Babinski sign (suggesting a peripheral neuropathy), myelopathy and/or 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, upper gastrointestinal bleeding, and/or jaundice, may be present.
Insidious mental status change: initial investigations
Investigations in patients with insidious changes in mental status should be guided by medical history (obtained from the 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, neuropsychologic 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: measured if hypothyroidism is suspected.
Total serum testosterone: to check for hypogonadism; testosterone levels should be taken from morning, fasting blood samples when the patient is not acutely ill.[71]
Morning cortisol levels: measured if adrenal insufficiency is suspected.
Serum T pallidum EIA or RPR to rule out neurosyphilis.
Berlin Questionnaire: can be used to screen for the presence of obstructive sleep apnea (OSA).[72] People living with HIV are at increased risk of OSA, which can contribute to cognitive difficulties.[73] A positive screen should be followed by a referral for polysomnography for investigation.
Cerebrospinal fluid (CSF) analysis: role in noninfectious neurocognitive disorders is controversial. Early studies found that cognitive impairment was correlated to the HIV viral load in the CSF.[74] 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 (referred to as CSF viral escape).[75][76] 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; it may require modification of ART to include agents with superior penetration and effectiveness in the CNS.[40][77][78][79][80][81] 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).[82]
Additional investigations
ECG and echocardiogram should be ordered if a cardioembolic origin for stroke is suspected.
EEG: helpful for grading the severity of the encephalopathy associated with intracranial infection or evaluating for seizures. Note that a negative EEG may not rule out seizure if the EEG is not completed at the time of the seizure.
Neuroimaging
Imaging should be considered for the majority of people with HIV with altered mental status, and is essential when there is a strong possibility of a structural brain lesion. This includes 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.
MRI of the brain is the study of choice. CT brain may be more readily available, but MRI can provide more detail. MRI or CT can distinguish between CNS infections and tumors.
Where an intracranial infection is suspected, cranial imaging should be performed before lumbar puncture (LP) to exclude a mass lesion and risk of iatrogenic brain herniation.
Ring-enhancing lesions in the basal ganglia, frontal lobe, or parietal lobe, with surrounding edema: typical of toxoplasmosis. The occipital lobe, temporal lobe, and brain stem/cerebellum can be affected.[20][83]
Diffuse white matter intensities: seen in CMV infection and progressive multifocal leukoencephalopathy (human polyomavirus 2, also known as JCV). Hypodense white matter lesions on T1-weighted imaging with T2-weighted hyperdensity may also be revealed, with lesions in the area of the brain corresponding to the neurologic deficit.[20]
Hydrocephalus: may indicate cryptococcal meningitis or TB meningitis. Cryptococcal meningitis is associated with enhancement and parenchymal lesions (cryptococcomas); TB produces edema, basilar meningeal thickening, or tuberculomas, and may be indicated by multifocal cranial nerve deficits. Cryptococcal or tuberculosis testing should be obtained in patients with neuroimaging findings of ring-enhancing lesions.
Gyral edema with high signal intensity in the temporal lobe or cingulate gyrus: seen in HSV encephalitis.
Generalized cerebral atrophy with ventricular dilation, multiple small infarcts in the basal ganglia, and syphilitic cerebral gummas: may be seen, but imaging is usually normal in neurosyphilis.[84][85]
Neuroimaging of HIV-associated neurocognitive disorders
MRI or CT may be helpful in distinguishing HAND from cognitive impairment of another etiology.
The MRI is normal in ANI, but may show signs of progressive brain atrophy, cerebellar degeneration, basal ganglia atrophy, and diffuse periventricular white matter hyperintensities in HAD. By contrast, Alzheimer disease typically produces hippocampal volume loss, atrophy of the medial temporal lobe, and posterior cortical atrophy while motor regions are affected later.[86]
Patient with 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 in an acute stroke and increased signal in the ischemic territory on T2 images in a subacute stroke (>24 hours after symptom onset).
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 while the patient is in lateral decubitus position (an opening pressure in sitting position may be falsely elevated) should be documented in all cases and is of vital importance in the management of cryptococcal meningitis.
How to perform a diagnostic lumbar puncture in adults. Includes a discussion of patient positioning, choice of needle, and measurement of opening and closing pressure.
Tests to consider
Cerebrospinal fluid (CSF) analysis should include white blood cell (WBC) counts and protein/glucose levels. CSF bacterial, mycobacterial, and fungal cultures, and cytology and flow cytometry, may be performed.
CSF testing may also include the following specific tests.
Cryptococcal antigen: highly sensitive and specific for Cryptococcus.
Venereal Disease Research Laboratory (VDRL) test: can be used to identify neurosyphilis. CSF nucleic acid amplification testing (NAAT) may be considered.[87]
Polymerase chain reaction (PCR):
for HSV, VZV, and CMV (if CD4 cell count is low)
can be diagnostic for human polyomavirus 2 (also known as JCV), the agent responsible for PML
performed if toxoplasma encephalitis is suspected; a negative result does not rule out the presence of toxoplasma encephalitis.
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.
CSF findings that suggest etiology
Lymphocytic pleocytosis: can be seen in toxoplasmosis, CMV, cryptococcal infection, neurosyphilis, TB, and primary CNS lymphoma.
CSF glucose decreased: seen in bacterial or fungal infections, cryptococcal infection, and primary CNS lymphoma; can be markedly decreased in the setting of tuberculous meningitis. CSF glucose is usually normal in neurosyphilis, and only rarely decreased in the setting of toxoplasmosis.
Normal, or mildly elevated protein, in otherwise normal CSF: seen in PML, mild elevations in CSF protein can be seen with other viral etiologies.
Moderate to high levels of CSF protein: reported in cryptococcal meningitis and tuberculous meningitis.
[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].
Cognitive screens, neuropsychologic 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:[88]
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.[88]
Screening tools such as the HIV Dementia Scale (HDS) and the Montreal Cognitive Assessment (MoCA) can be useful. However, they are not specific to impairment found in HAND, and often lack sensitivity for the common milder forms of HAND. Results must be interpreted in the context of the medical history, clinical exam, and investigations.[40]
Referral for neuropsychologic testing completed by a neuropsychologist or psychometrist may be indicated.[14][23]
HIV Dementia Scale
Measures antisaccadic errors (voluntary eye movement made in the direction opposite to the side where a stimulus is presented), the recall of four items after five minutes, and timed alphabet writing and cube copying.[89] 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.[90]
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 HAND.[91] 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.[92] 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 neuropsychologic testing, including mild forms, is 90%, but this is associated with a very low specificity of 43%. Sensitivity and specificity for different cutoff values are available.[93] Overall accuracy can be further increased by application of modern psychometric methods to scoring of the individual items.[94]
Brief batteries of neuropsychologic 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.[95][96] These tests are administered by a neuropsychologist or a trained psychometrist under the supervision of 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 cutoff 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 Screening for anxiety should also be considered, using validated screening tools such as the generalized anxiety disorder scale 7-item (GAD-7) or the shortened GAD-2.[23][97]
Substance use screening
The CAGE alcohol screening test-Adapted to Include Drugs (CAGE-AID) is a 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.[98]
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