Urgent considerations
See Differentials for more details
Delirium and acute mental status changes
Delirium is characterised by disturbance of attention and awareness, and a fairly rapid change in cognition.[46] Acute change in mental status demands immediate consideration from the healthcare provider.
The most frequent causes of delirium among people with HIV are: infection (including systemic bacterial or local central nervous system [CNS] infections); adverse effects from prescription or non-prescription drugs; intoxication (attributable to substance misuse); and, withdrawal from illicit drugs or alcohol or substances.
Fever, if present, suggests an infectious or inflammatory aetiology. An acute or subacute onset also suggests an infectious, inflammatory, or more widespread systemic aetiology.
Given the vast differential of delirium, investigations should be guided by history (including detailed drug history with a focus on recent initiation or changes in antiretroviral therapy [ART]) and physical examination findings. A careful history, physical and neurological examination, in addition to investigations, laboratory and radiographic studies, are required to identify the underlying cause(s).
Initial treatment should include emergency supportive care, which may include circulatory and electrolyte support. Subsequent management is dependent on underlying aetiology.
Systemic bacterial infection
In people with advanced HIV infection, systemic opportunistic infections such as Pneumocystis jirovecii pneumonia and mycobacterial infections must be considered.
HIV-related encephalitis
An acute or subacute onset of a febrile illness, altered mental status, and/or seizures raises suspicion for encephalitis. Altered mental state, ranging from subtle alterations in level of arousal and behavioural abnormalities through to coma, is typical. Focal neurological findings are unusual but possible and may include hemiparesis, ataxia, pyramidal signs (brisk tendon reflexes, extensor plantar responses), cranial nerve deficits, involuntary movements (myoclonus and tremors), and seizures.[47]
Bacterial infections, tuberculosis, syphilis, toxoplasmosis, cryptococcal disease, and other opportunistic infectious causes of encephalitis/meningitis or intracranial abscess should be excluded. Investigations include blood cultures, neuroimaging (preferably magnetic resonance imaging [MRI]), and cerebrospinal fluid (CSF) analysis (for cell count and differential, glucose/protein, bacterial or fungal culture). Organism-specific diagnostic PCR-based tests or acid fast bacilli culture could be considered if there is suspicion of tuberculosis infection. Additional diagnostic work-up (including polymerase chain reaction) may be considered for detection of viral aetiologies of encephalitis.
Treatment should include standard emergency supportive care, which may include circulatory and electrolyte support, and, potentially, endotracheal intubation and mechanical ventilation, with consideration for deep venous thrombosis and gastrointestinal (ulcer) prophylaxis.
HIV-related meningitis and intracranial abscess
Adults with meningitis classically present with features of fever, headache, and nuchal rigidity. In the setting of advanced HIV disease, the presentation may be varied and include focal neurological deficits or seizures. In non-bacterial cases, such as with CNS fungal infections, the presentation may be subacute in nature.
Diagnosis in many patients begins with the evaluation of clinical evidence for increased intracranial pressure, a focal neurological deficit, or papilloedema, which in virtually all cases should prompt neuroimaging with either contrast-enhanced computed tomography (CT) or, preferably, MRI of the brain. A decreased level of consciousness should prompt urgent neuroimaging studies to rule out a focal intracranial lesion or increased intracranial pressure.
Standard laboratory tests are helpful but never definitive, and should include, at a minimum, a full blood count with differential, which may suggest an infectious process. Urea and electrolyte may reveal an elevated lactate, or hepatic or renal impairment which may also contribute to acute altered mental status. Blood cultures (two sets) should be drawn prior to initiation of antimicrobial therapy in order to maximise the likelihood of identifying an underlying aetiology. Specific diagnostic blood tests can include serum cryptococcal antigen (determined by latex agglutination, enzyme immunoassay, or lateral flow assay), and screening Treponema pallidum enzyme immunoassay plus rapid plasma reagin for syphilis.[22][48] If blood tests for neurosyphilis are positive, and there are neurological changes, Venereal Disease Research Laboratory (VDRL) CSF test should be performed with a lumbar puncture (LP).
LP with CSF analysis is important in confirming CNS infection and in identifying the aetiological organism. Imaging should always precede the LP in immunocompromised patients to exclude a mass lesion. If a mass lesion is identified, the LP should not be performed, especially if there is evidence of mid-line shift on imaging.
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.
The typical radiological finding in patients with a brain abscess (on either CT or MRI) is of one or more ring-enhancing lesions. The finding of one or more contrast-enhancing lesions in such a patient should be investigated with consideration to the broad spectrum of possible aetiologies, and will be influenced by the degree of immunosuppression. Common CNS aetiologies include toxoplasmosis, tuberculosis, cryptococcosis, bacterial brain abscess, and lymphoma. In the setting of multiple ring-enhancing CNS lesions, empirical coverage for toxoplasmosis should be considered, while early brain biopsy may be required for single lesions to rule out CNS lymphoma and for patients not responding to empirical toxoplasmosis therapies.
HIV-related Epstein-Barr virus (EBV)-positive primary CNS lymphoma
An acute presentation requiring urgent assessment. EBV-positive primary CNS lymphoma is a rare, aggressive non-Hodgkin’s lymphoma. Symptoms and signs may be similar to those seen with encephalitis or meningitis. Usually a sole mass lesion is identified, which may be confused with CNS toxoplasmosis.
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] Treatment may comprise ART, rituximab, and high-dose methotrexate.[56]
Therapy-related toxicity
An acute presentation of psychiatric symptoms in patients who recently started ART could suggest therapy-related toxicities. This may not manifest with neurological deficits. Patients who are physically well may have experienced acute adverse effects of therapy.
Depression, anxiety, insomnia, and cognitive dysfunction have been reported most frequently in patients receiving efavirenz and, less frequently, in those receiving raltegravir or dolutegravir.[24][25][31][32][33][34][35][36] Patients may develop a persistent dysphoric mood, distress, anxiety, and irritability. Concentration may be poor, with sleep and appetite disturbances, fatigue, and psychomotor impairment.
Patients receiving ART may develop immune reconstitution inflammatory syndrome (IRIS) as a consequence of the reaction of a restored immune system to infectious agents. Commonly implicated infectious agents include Mycobacterium tuberculosis or M avium complex, although other causes (e.g., herpes simplex virus, varicella zoster virus, progressive multifocal leukoencephalopathy [human polyomavirus 2, also known as John Cunningham virus [JCV]], cytomegalovirus, cryptococcal infection and Toxoplasmosis gondii) are also recognised triggers.[37][38][39]
Adrenal insufficiency, with mood changes and fatigue, may be caused by antiviral drugs that inhibit cortisol production, particularly when co-administered with ritonavir or cobicistat.[45][57]
Substance misuse
An acute precipitation of mental status change may occur in people with HIV following recent alcohol or substance misuse. Neurocognitively active drugs and alcohol misuse increase risk for delirium in people living with HIV.[58] Opioid misuse is associated with increased frequency of neuropsychiatric symptoms.[59]
Substance withdrawal delirium may be more prevalent in people with HIV.[60]
Comorbid illness
Change in mental status could be due to organic disease, such as a stroke. HIV infection is associated with an increased risk for ischaemic stroke, which may be subsequent to HIV-associated vasculopathy (and/or ART).[41][61]
Additionally, comorbid systemic illnesses (such as hypothyroidism), leading to cognitive deficits, should be excluded.
Use of this content is subject to our disclaimer