HIV-1 is known to have a strong tropism for the neurological tissues right from the initial stages of infection. The CNS microglial cells form one of the early and most important reservoirs for the virus, where it lies dormant until activated. With early immunodeficiency there is a polyclonal hypergammaglobulinemia resulting in number demyelinating and inflammatory disorders. With advanced immunosuppression the direct toxic effects of the virus come into play, predominantly due to excessive and inappropriate elaboration of cytokines.
Neurological complications occur from HIV itself, opportunistic infections, tumors or drug related complications. HIV enters the central nervous system (CNS) via microglial cells, the monocytes of the CNS, during the high-level viremia of primary infection. As a result a neurotoxic process is set in train, leading over time to cell death with loss of both white and grey matter. Vasculitis due to inflammatory changes in brain endothelium can result in endothelial calcification.
HIV encephalopathy
Up to 10% of infants presenting with HIV have severe developmental delay and encephalopathy.
HIV encephalopathy can be static or progressive. The subtle neurological manifestations include spasticity, hyperreflexia, and abnormal plantar reflex suggestive of pyramidal tract involvement. Common symptomatic manifestation include delayed developmental milestones in static type of encephalopathy and loss of achieved motor, fine motor and language milestones in progressive type of encephalopathy. Imaging of the CNS in infancy often demonstrates calcific-vasculopathy of the basal ganglia, and generalized atrophy is a later finding. Effective treatment of the HIV infection, although it may prevent further deterioration, cannot restore permanently damaged CNS tissue. With the advent of HAART, the prevalence of progressive encephalopathy is reduced.
Progressive Multifocal LeukoEncephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of central nervous system seen in immunocompromised patients. It is caused by primary infection or reactivation of the group B Human Papovaviruses (Jacob-Creutzfeldt virus, simian virus 40), also called as JC virus. It results in destruction of oligodendroglia leading to extensive demyelination. The majority of the population is believed to have been exposed to this virus leading to asymptomatic carriage in the kidneys, lymphoid tissue, bone marrow and lymphocytes. In a patient with weakened immune system, the virus may reactivate and spread to brain by lymphocytes causing neurologic dysfunction and serious and life threatening disease.
PML can cause a variety of symptoms such as confusion, disorientation, lack of energy, loss of balance, motor system abnormalities, blurred or double vision, speech difficulties, loss of vision in one eye, dementia and ultimately death. Mean survival after the onset of symptoms is 6-9 months whereas patients with AIDS on HAART may survive up to 2 years. Brain biopsy remains the definitive way to confirm a diagnosis of PML. DNA PCR tests to determine presence of JC virus in CSF specimen are also used, however, the PCR test does not produce a definitive diagnosis because some patients are JC-negative when diagnosed with PML. However MRI may help to identify and distinguish PML from other CNS lesions due to its characteristic imaging abnormalities. The typical distribution of PML is bilateral, asymmetrical with a predilection for the white matter of the posterior centrum semiovale. These lesions are patchy, poorly defined areas of hyperintensity in the white matter on T2 weighted images, and hypointense, non-enhancing on T1 weighted images which later become confluent and large.
There is no proven treatment specifically for PML although several drugs have been tested. Highly active antiretroviral therapy (HAART) is currently used to treat HIV positive patients who develop PML. Protease inhibitors are the most likely agents to improve survival after diagnosis of PML. There have been anecdotal reports of use of Cidofovir, cytarabine and interferon alpha as possible treatment for PML but their benefit seems minimal.
Other common neurological manifestations include meningitis (viral, bacterial, tuberculosis, cryptococcal), thrombosis and space occupying lesions (toxoplasma, tuberculosis, brain abscess, lymphoma).
References
- Shah Ira, Chudgar P. Progressive Multifocal Leukoencephalopathy (PML) Presenting As Intractable Dystonia In An HIV Infected Child. Journal of Tropical Pediatrics. 2005 Dec;51(6):380-2
- Gupta S, Shah DM, Shah Ira. Neurological disorders in HIV-infected children in India. Ann Trop Paediatr. 2009; 29: 177-181.
- Lyall H. Diagnosis, staging & clinical presentation of HIV in children. Clinical and laboratory diagnosis. Available from Tr@inforPedHIV 2011
- Berenguer J, Miralles P, Arrizabalaga J, Ribera E, Dronda F, Baraia-Etxaburu J et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis. 2003;36:1047-1052.