Neurological infection in HIV and immunosuppression

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Neurological infection in immunosuppression is a pattern-recognition and parallel-testing problem. Host information is diagnostic data: current and nadir CD4 count, HIV viral load, adherence, opportunistic prophylaxis, transplant type, immunomodulators, neutrophil count and corticosteroid dose all shift probabilities. Presentation tempo also helps. Pyogenic infection and haemorrhage can evolve quickly; toxoplasmosis often evolves over days; cryptococcus and tuberculosis are commonly subacute; progressive multifocal leukoencephalopathy and lymphoma may unfold over weeks.

Imaging generally precedes lumbar puncture when a mass lesion is possible. Contrast MRI distinguishes focal ring-enhancing lesions, non-enhancing white-matter disease, basal meningitis, ventriculitis and infarction better than CT, while CT provides rapid emergency assessment. Cerebrospinal fluid then requires a deliberately selected panel: opening pressure, cell count, glucose, protein, bacterial culture, cryptococcal antigen and culture, viral PCR, mycobacterial tests, cytology or flow cytometry and JC or Epstein-Barr viral studies according to the imaging and host.

Treatment is organism- and pressure-specific. Cryptococcal disease needs fungicidal induction plus repeated therapeutic lumbar puncture for raised pressure when safe; cerebral toxoplasmosis usually receives empirical combination therapy with planned clinical and radiological reassessment; PML needs immune restoration; tuberculosis needs multidrug therapy and corticosteroids; lymphoma needs tissue-led oncological care. The timing of antiretroviral therapy differs across these syndromes. BHIVA and local specialist protocols should govern exact regimens because recommendations change with evidence, interactions and drug access.

Key points

The differential is shaped by the type and depth of immune impairment, antiretroviral or prophylaxis history, transplant medicines, neutropenia, corticosteroid exposure, geography and previous latent infections.
In advanced HIV, cerebral toxoplasmosis often causes headache, fever, focal deficit or seizure with multiple ring-enhancing lesions, frequently involving basal ganglia, although imaging is not diagnostic by itself.
Cryptococcal meningitis typically causes subacute headache, fever and cognitive slowing; neck stiffness may be absent and raised opening pressure is a major cause of visual loss and death.
Progressive multifocal leukoencephalopathy produces subacute progressive focal or cognitive deficits with white-matter lesions that usually have little mass effect; immune restoration is the central treatment.
Primary central nervous system lymphoma can resemble toxoplasmosis, often with fewer enhancing lesions, profound immunosuppression and cerebrospinal-fluid Epstein-Barr-virus signal, but tissue may be required.
Tuberculous meningitis tends to cause basal meningeal enhancement, cranial neuropathies, hydrocephalus, infarcts and low cerebrospinal-fluid glucose; obtain adequate volume for mycobacterial tests.
CMV ventriculoencephalitis or polyradiculopathy occurs mainly with very low CD4 counts and can produce confusion, cranial signs, urinary retention and rapidly progressive lower-limb weakness.
Always consider ordinary bacterial meningitis, HSV or VZV encephalitis, abscess and sepsis alongside opportunistic disease; immunosuppression may remove fever and cerebrospinal-fluid pleocytosis.
Antiretroviral therapy should not be started or restarted on an improvised timetable: early immune recovery helps many infections but increases lethal intracranial inflammatory risk in cryptococcal or tuberculous meningitis.
Coordinate HIV or transplant specialists, microbiology, neurology, neuroradiology and pharmacy because drug interactions, marrow toxicity, renal injury and immune-reconstitution syndromes commonly determine outcome.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Advanced HIV-related immune loss

Low cellular immunity permits reactivation or acquisition of toxoplasma, cryptococcus, JC virus, tuberculosis, CMV and other opportunistic pathogens.

Transplant and medicine immunosuppression

Corticosteroids, cytotoxic treatment, biological therapy and transplant medicines suppress different immune arms, changing both pathogen range and inflammatory presentation.

Neutropenia and malignancy

Marrow failure and cancer impair innate defence and barrier integrity, increasing fungal, bacterial and treatment-related central nervous-system infection.

Ordinary community infection

Bacterial meningitis, HSV, VZV and sepsis remain important despite immunosuppression and may present without expected fever or cerebrospinal-fluid inflammation.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Loss of immune surveillance
Impaired T-cell, antibody or neutrophil function allows latent organisms to reactivate or newly acquired pathogens to disseminate.
2
CNS invasion
Organisms reach meninges, brain, spinal cord or roots and produce focal masses, diffuse white-matter injury, meningitis or ventriculoencephalitis.
3
Direct and inflammatory injury
Pathogen replication damages neural tissue while a variable host response adds oedema, vasculitis, pressure and seizures.
4
Immune-restoration inflammation
Recovery of immune function can produce an exaggerated response around residual antigen, transiently worsening neurological disease despite microbial control.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Toxoplasma pattern

Advanced HIV with headache, fever, seizure or focal deficit and multiple enhancing lesions, especially around basal ganglia, is a classic empirical-treatment presentation.

Cryptococcal pressure syndrome

Subacute headache, visual blurring, diplopia or confusion with a positive cryptococcal antigen requires opening-pressure measurement and active pressure management when puncture is safe.

PML phenotype

Progressive weakness, visual-field loss, ataxia, aphasia or cognitive change with asymmetric white-matter lesions and little mass effect suggests JC-virus disease.

Basal meningitis

Cranial neuropathies, hydrocephalus, hyponatraemia and small deep infarcts with basal enhancement raise tuberculosis or fungal infection.

CMV polyradiculopathyRed flag

Rapid flaccid leg weakness, saddle sensory change, areflexia and sphincter dysfunction in profound immunosuppression is an urgent cauda-equina-like opportunistic syndrome.

Immune reconstitution

Paradoxical deterioration after starting antiretroviral or reducing immunosuppression may reflect inflammatory recovery, but treatment failure, resistance and a new infection must first be reassessed.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
HIV status, CD4 count and viral loadFirst step
Why
Quantify immune risk and establish whether virological failure or previously undiagnosed HIV is present.
Interpretation and limitations
Lower CD4 strata increase particular opportunistic risks, but no numerical threshold excludes ordinary infection; obtain resistance and adherence input when viraemia persists.
02
Contrast MRI brain
Why
Differentiate mass lesions, white-matter disease, meningitis, ventriculitis, infarction and malignancy.
Interpretation and limitations
Number, distribution, diffusion, haemorrhage and mass effect narrow the differential but rarely prove organism; compare with prior scans and immune trajectory.
03
Serum cryptococcal antigen
Why
Rapidly detect cryptococcal polysaccharide in a compatible advanced-HIV or transplant presentation.
Interpretation and limitations
A positive result with neurological symptoms requires urgent cerebrospinal-fluid evaluation if safe; titre does not replace opening pressure, culture and clinical severity.
04
Lumbar puncture with opening pressure
Why
Diagnose meningitis and measure a directly treatable pressure complication.
Interpretation and limitations
After imaging excludes unsafe mass effect, send pathogen-directed studies and record pressure accurately; minimal pleocytosis does not reassure in profound immune failure.
05
Toxoplasma IgG and treatment response
Why
Support previous exposure and the probability of cerebral reactivation.
Interpretation and limitations
Negative IgG makes reactivation less likely but does not universally exclude it; lack of clinical or imaging response by the specialist review point prompts biopsy or alternative diagnosis.
06
Cerebrospinal-fluid JC-virus PCR
Why
Support progressive multifocal leukoencephalopathy in the correct imaging phenotype.
Interpretation and limitations
A positive result is persuasive in context; sensitivity falls with immune restoration, so negative fluid may require repeat testing or biopsy when suspicion stays high.
07
Mycobacterial and fungal cultures or molecular assays
Why
Detect tuberculosis, cryptococcus and other opportunists using adequate sample volume.
Interpretation and limitations
Smear sensitivity can be low and cultures are slow; combine molecular results, antigen, imaging and repeated sampling with specialist interpretation.
08
Brain biopsy
Why
Establish infection, lymphoma or inflammatory disease when non-invasive evidence and empirical response are insufficient.
Interpretation and limitations
Choose target and timing through neuroradiology, neurosurgery, infection and haematology because prior treatment can reduce diagnostic yield.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Primary CNS lymphoma

Fewer enhancing lesions, profound immunosuppression and supportive viral markers suggest lymphoma, but tissue may be needed when imaging overlaps toxoplasmosis.

HIV-associated cognitive disease

Diffuse cognitive and motor slowing without a focal opportunistic pattern may reflect HIV-related brain dysfunction after infection and substance causes are assessed.

Medicine toxicity

Antivirals, immunosuppressants and interacting drugs can cause encephalopathy, neuropathy or seizures, often with renal, hepatic or concentration changes.

Stroke or inflammatory disease

Vascular-territory onset, dissection, vasculitis and immune complications can mimic infection and require parallel imaging and physiological assessment.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Immediate stratificationUse host, tempo and imaging togetherFirst stepAn immunosuppressed person develops new neurological symptoms.

1Stabilise airway and seizures, record antiretroviral and immunosuppressive medicines, CD4 or neutrophil history, prophylaxis, travel, exposures and symptom tempo.
2Obtain urgent contrast brain imaging before lumbar puncture when headache, focal signs, seizure or impaired consciousness makes a mass lesion plausible.
3Start syndrome-directed empirical treatment for bacterial meningitis, HSV encephalitis or a life-threatening opportunistic infection when delay is more dangerous than reduced microbiological yield.

02Ring lesionsDistinguish toxoplasmosis from competing massesMRI shows one or more enhancing intracranial lesions in advanced HIV or another immunocompromised state.

1Review lesion number and distribution, toxoplasma serology, prophylaxis and systemic cancer evidence while consulting HIV, infection and neuroradiology specialists.
2Start the current anti-toxoplasma regimen when probability is high and it is safe, defining in advance the date and measures for clinical and radiological response.
3AlternativePursue early biopsy or alternative studies when imaging is atypical, serology is unsupportive or expected improvement does not occur, particularly for lymphoma, fungal abscess or tuberculosis.

03Cryptococcal diseaseTreat fungus and intracranial pressureCryptococcal antigen or culture supports meningitis in a symptomatic patient.

1Begin specialist fungicidal induction with liposomal amphotericin B and flucytosine under the current BHIVA protocol, obtaining baseline kidney, electrolyte and blood-count measurements.
2EscalationMeasure opening pressure and use repeated therapeutic lumbar punctures when pressure is raised and anatomically safe, escalating resistant hydrocephalus to neurosurgical drainage.
3Delay antiretroviral initiation to the guideline-directed interval, then monitor closely for immune-reconstitution inflammation, relapse, visual loss and drug toxicity.

04Antiretroviral decisionRestore immunity on the disease-specific timetableAn opportunistic central nervous system infection is diagnosed in a person not on effective HIV treatment.

1Confirm HIV genotype, previous therapy, resistance, interactions, adherence barriers and the pathogen-specific risk of intracranial immune-reconstitution inflammation.
2Start or optimise antiretroviral therapy promptly for conditions such as PML when specialists recommend it, but defer appropriately for cryptococcal or tuberculous meningitis.
3Provide prophylaxis, interaction management and follow-up through the HIV multidisciplinary team, never allowing discharge to interrupt induction or immune-restoration care.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Established induction treatment for cerebral toxoplasmosis, followed by consolidation or suppressive therapy until immune recovery.

Pyrimethamine, sulfadiazine and folinic acid

Use the current BHIVA weight-based loading and maintenance regimen under specialist care; folinic acid accompanies pyrimethamine throughout marrow-toxic exposure.

Monitor blood count, liver and renal function, rash, crystalluria and sulfonamide allergy; major antiretroviral and prophylaxis decisions need HIV-pharmacy review.

Rapidly fungicidal combination treatment for cryptococcal central nervous system infection.

Liposomal amphotericin B plus flucytosine

Induction doses and duration follow current BHIVA cryptococcal-meningitis guidance, weight, kidney function and local antifungal access.

Amphotericin causes renal potassium and magnesium loss, while flucytosine causes marrow and hepatic toxicity; therapeutic monitoring does not replace active intracranial-pressure management.

Restores pathogen-specific immunity and is the principal effective intervention for HIV-associated PML.

Antiretroviral therapy

Select a complete combination regimen from current BHIVA guidance using genotype, previous exposure, organ function, interactions and the opportunistic infection timetable.

Starting too early in cryptococcal or tuberculous meningitis may worsen intracranial inflammation; interaction checks are crucial with rifamycins, anticonvulsants, azoles and corticosteroids.

An alternative effective anti-toxoplasma regimen where first-choice combinations are unsuitable or unavailable.

High-dose co-trimoxazole

Some UK pathways use weight-based intravenous or oral trimethoprim-sulfamethoxazole for toxoplasmosis; prescribe only to the current specialist protocol with renal adjustment.

Monitor rash, cytopenias, potassium, creatinine and interactions; severe sulfonamide reaction, pregnancy considerations and glucose-6-phosphate dehydrogenase context require specialist review.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Raised pressure and herniation

Cryptococcal disease, abscess, tumour-like lesions and hydrocephalus can dangerously increase intracranial pressure and impair vision or consciousness.

Seizures and permanent focal disability

Cortical infection and infarction can cause status epilepticus, weakness, language loss and later epilepsy after recovery.

Immune-reconstitution syndrome

Poorly timed immune recovery may intensify intracranial inflammation, worsening pressure, neurological deficit and mortality in selected infections.

Treatment interaction and organ injury

Combined antimicrobial, antiretroviral and immunosuppressive regimens can cause marrow, liver, kidney, electrical and concentration-related toxicity during combined treatment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Repeat neurological and visual assessment frequently, using lesion-specific measures such as power, language, field deficit and seizure burden to judge response.
Track CD4 count and HIV viral load over the appropriate timescale while recognising that early neurological response may precede or lag laboratory immune recovery.
Monitor full blood count, renal function, potassium, magnesium and liver tests at the frequency required by amphotericin, flucytosine, pyrimethamine and interacting therapy.
For cryptococcosis, record every opening pressure, volume removed, post-procedure symptoms and indication for repeat drainage rather than treating pressure with analgesia alone.
Repeat MRI at the disease-specific review point for toxoplasma lesions or uncertain masses, escalating non-response rather than extending empirical therapy indefinitely.
After starting antiretrovirals, investigate deterioration for immune-reconstitution syndrome, antimicrobial failure, resistance, toxicity and a second opportunistic process in parallel.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Inflammation may be absent

Profound immune failure can produce severe infection with little fever, modest CRP and few cerebrospinal-fluid white cells, so weak host response is not reassurance.

Pressure is a treatment target

In cryptococcal meningitis, repeated therapeutic lumbar puncture can be life saving; antifungals alone do not rapidly correct dangerous intracranial pressure.

Response can diagnose

Improvement after anti-toxoplasma therapy supports the diagnosis, but only when an explicit reassessment deadline prevents delayed lymphoma biopsy.

PML lacks a direct antiviral

Effective immune restoration is central, and early inflammatory worsening may reflect PML immune-reconstitution syndrome rather than simple virological progression.

ART timing is pathogen specific

A maxim that antiretrovirals are always immediate is unsafe for cryptococcal and tuberculous meningitis, where intracranial inflammation changes the balance.

11Common pitfallsFrequent interpretation and management errors.

01
Using a CD4 threshold to exclude common bacterial or herpetic infection.
02
Performing lumbar puncture before imaging a possible mass lesion.
03
Diagnosing toxoplasmosis from ring enhancement without a response deadline.
04
Treating cryptococcal headache without measuring and managing opening pressure.
05
Starting antiretroviral therapy on the same timetable for every opportunistic infection.
06
Forgetting marrow, renal, electrolyte and interaction toxicity from combination therapy.
07
Calling neurological worsening immune reconstitution without excluding treatment failure.