Since the advent of cART CNS opportunistic infections have significantly declined, however they continue to cause significant morbidity and mortality in PLWH especially in those unaware of their HIV status (54). A recent multicentre retrospective analysis of patients presenting with encephalitis demonstrated a one-year mortality of 31.3% in PLWH compared to 16.0% in HIV negative counterparts (55). The following table summarises the clinical features, investigation and management of some common HIV-associated CNS pathogens pertinent to the Australian population (54).
| HIV-associated CNS infection
|
Toxoplasmosis | Cryptococcal meningitis | Varicella zoster virus encephalitis | Herpes simplex virus encephalitis | Cytomegalovirus
encephalitis |
Invasive aspergillus | Progressive multifocal leukoencephalopathy | Tuberculous meningitis | Neurosyphilis |
| Pathogen | Toxoplasma gondii | Cryptococcus neoformans or gattii (less common) | Varicella zoster virusv (VZV) | Herpes simplex virus (HSV) | Cytomegalovirus | Aspergillus spp. | JC virus | Mycobacterium tuberculosis | Treponema pallidum |
| Clinical features | cerebral abscess (subacute onset: visual field deficits, focal seizures, aphasia, hemiparesis / hemisensory deficits, confusion, movement disorders) diffuse encephalitis, chorioretinitis | Sub-acute onset, headaches, lethargy, fever, malaise, meningism (25% of cases), altered mental state | Encephalitis – lethargy, confusion, gait disturbance, headaches, cranial nerve palsy, ataxia, seizures, vesicular rash (frequently absent) | Encephalitis – lethargy, confusion, gait disturbance, headaches, cranial nerve palsy, ataxia, seizures, vesicular rash (frequently absent) | Encephalitis – lethargy, confusion, gait disturbance, headaches, cranial nerve palsy, ataxia, seizures, Retinitis – floaters, visual impairment, retinal detachment | Cranial nerve palsies, paraparesis, parathesis, altered mental status, seizures | Ataxia, hemiparesis, movement disorders, behavioural and cognitive abnormalities, cortical blindness, seizures (late)
Rarely, there may be pure cerebellar involvement by JC without white matter disease – JCV neuronopathy |
Fever, headache, impaired consciousness, meningism, lower cranial nerve palsies, hemiplegia, bulbar signs, sensory deficits | Hearing loss, acute hydrocephalus, seizures, hemiplegia, aphasia, cranial nerves palsies, argyl-robinson pupil, stroke syndromes, neuropsychiatric disturbance |
| Common CD4 count (cell/mm3) | < 100 | < 50 – 100 | < 300 | All stages | < 50 | < 200 | < 150 | All stages; increased risk < 200 | All stages |
| MRI | Ring-enchaining, brain lesions, often in basal ganglia, thalamus or dentate nucleus | Normal (2 – 8%), intracerebral masses, cortical and lacunar infarcts, pseudocyst, cerebritis, meningeal uptake | T2 hyperintensity and areas of restriction diffusion in cerebellum, thalami, cerebral cortex and basal ganglia | bilateral, asymmetric T2 hyperintensity and diffusion restriction of limbic and medial temporal lobes, more diffuse in advanced immunosuppression, T1 contrast enhancement in later disease | Linear periventricular hyperintensity with gadolinium enhancement, can be normal | Polylobulated mass with peripheral contrast enhancement, associated oedema adjacent structures and parenchyma | White matter hyperintensities of T2 and T1 FLAIR that are asymmetrical with particular involvement of the subcortical regions leading to a “scalloped” appearance.
In the rare instance of JCV cerebellar neuronopathy there is only atrophy |
Basilar exudates, arachnoiditis, tuberculomas of T2 | Cerebral infarct (typically lacunar middle cerebral artery), nonspecific white matter lesions, cerebral gummas, or arteritis |
| CSF | Toxoplasma PCR positive but insensitive and CSF analysis is often not possible because of raised intracranial pressure | Cryptococcal antigen (92 – 100% sensitive, 84 – 98% specific), positive India ink staining, pleocytosis, high CSF protein, increased elevated CSF opening pressure (poor prognosis) | Lymphocytic pleocytosis, elevated protein, positive VZV PCR (can be negative), antiVZV IgM/IgG | Lymphocytic pleocytosis, elevated protein, positive HSV-1 PCR, HSV-2 PCR | CMV PCR (95% sensitive, 85% specific), neutrophilic pleocytosis, elevated protein | Non-specific, often negative cultures | CSF JC virus PCR (98% specific, 76% sensitive), pleocytosis, elevated protein. Some individuals may have low levels of JCV therefore need to ensure PCR can detect 50-200 cpml | Can be normal (especially if CD4 <50), lymphocytic or neutrophilic pleocytosis < 100 cells/mm3 (in contrast to lymphocytic in immunocompetent cases), highly elevated protein, low glucose, AFB smear, culture, GeneXpert PCR (79.5% sensitive), serial high volume sampling often required | CSF VDRL, elevated protein, lymphocytic pleocytosis. However, a significant proportion have a negative CSF VDRL |
| Serum Investigations
(these may not be helpful if there is significant immune deficiency) |
Toxoplasma IgM, IgG | Serum cryptococcal Antigen, mycolytic blood culture | VZV IgM + IgG | HSV 2 IgM + IgG | Quantitative CMV PCR, CMV serology | Serum aspergillus galactomannan and aspergillus PCR | JC Virus PCR blood | Nil specific | Serum TPPA,FTA, RPR, VDRL (can be negative) |
| Management | Pyrimethamine + (sulfadiazine or trimethoprim/ sulfamethoxazole) for 6 weeks followed by secondary prophylaxis | Induction (2 weeks): Liposomal amphotericin 3 – 4mg*kg daily + Flucytosine 25mg*kg QID for 2 weeks*; Consolidation (10 weeks): Fluconazole 400mg daily; Maintenance 200mg daily for at least 12 months; serial therapeutic lumbar puncture for intracranial hypertension
*Single high dose liposomal amphotericin 10mg*kg + Flucytosine 100mg daily + Fluconazole 1200mg found to be non-inferior |
IV Aciclovir 14 – 21 days | IV Aciclovir 14 – 21 days | Encephalitis -Ganciclovir 5mg*kg BD + / – Foscarnet 90mg*kg BD for 3 – 6 weeks (nil clinical trial data for combination therapy however considered in context of poor outcomes (Ref), role of valganciclovir unclear
Retinitis – Valgaciclovir 900mg BD for 3 weeks then 900mg daily |
Voriconazole 6mg*kg BD loading for 2 doses then 4mg*kg BD; TDM monitoring aiming 1.0 – 5.0; poorly defined treatment duration | cART commencement/optimisation but beware of IRIS requiring corticosteroids
Whilst there is no specific therapy, T cell therapy is being trialled and limited data support pembrolizumab. |
Four drug therapy induction phase for two months then maintenance two drug regimen for at least nine – twelve months. cART initiation delayed up to 8 weeks. Nil mortality benefit of adjunctive corticosteroids excluding for IRIS | Benzylpenicillin 10.8g q24hourly for 15 days |
| Table 3: Clinical features, diagnosis and management of common CNS opportunistic pathogens in PLWH (54–58) | |||||||||