Clinical Reasoning: Rapidly Progressive Dementia in a Man With HIV Infection and Undetectable Plasma Viral Load

Discussion

We present a case of RPD in an ART-treated man with HIV and peripheral viral suppression. Cognition improved with steroid treatment of empirically diagnosed PML-IRIS. However, recurrent symptoms prompted further workup, which led to the diagnosis of CSF discordance.

CSF HIV VL is a proxy for independent replication of HIV in brain parenchyma where HIV directly infects neurons, astrocytes, and oligodendrocytes but preferentially infects microglia and perivascular macrophages. HIV persists in these cells because they are not susceptible to the cytotoxic mechanisms of T-lymphocytes and, hence, can become reservoirs for persistent HIV replication.⁵ Although HIV enters the brain within 2 weeks of primary infection, plasma HIV suppression is generally accompanied by CNS viral suppression in ART-treated individuals.⁶

CSF discordance is defined as CSF HIV VL greater than 0.5 or 1Log₁₀ of plasma HIV VL. CSF escape is defined as any detectable CSF HIV VL when plasma HIV VL is undetectable.⁷ The exact incidence of CSF escape/discordance is unknown, especially outside high-income countries, and challenging to determine because it is often asymptomatic, transient, and of unclear significance. However, a pooled estimate from high-income countries estimated its prevalence at 7.1% of ART-treated individuals.⁸ Risk factors of CSF escape/discordance include low-level plasma viremia, maintenance of the same ART regimen for many years, and, in particular, taking a ritonavir-boosted protease inhibitor (PI) for many years.⁸ For example, atazanavir, a PI, and tenofovir, a nucleoside reverse transcriptase inhibitor, have been associated with CSF escape/discordance likely because of their low concentrations in CSF.^9,-,11 All of these factors were present in our patient.

Clinical manifestations of CSF escape/discordance vary from asymptomatic to death and its course from acute to subacute. Symptomatic manifestations include meningoencephalitis, psychosis, and personality changes, but progressive cognitive decline is most common. CSF escape/discordance should be suspected when new neurologic symptoms arise in ART-treated patients with well-controlled HIV infection. CSF may have high protein, lymphocytic pleocytosis, or abnormal glucose in the absence of an identified infection while brain MRI may reveal diffuse white matter hyperintensities on T2 and T2-FLAIR sequences.^12,13 Of note, CSF discordance/escape can co-occur with CD8⁺ encephalitis, an inflammatory brain disease characterized by marked infiltration of the cerebrum by CD8⁺ T cells that presents with acute or subacute deterioration of cerebral function characterized by headache, confusion, and progressive cognitive decline, among other features.^9,14

Treatment of CSF escape/discordance includes optimization of the ART regimen with special attention to the possibility of CNS compartmentalization. CNS compartmentalization occurs when CNS viral reservoirs develop mutations unique from circulating plasma HIV strains.⁵ If these mutations are ART-resistant, then CNS viral reservoirs become resistant to ART that may still be effectively suppressing plasma virus. In these situations, ART regimens should be optimized based on both CSF and plasma ART resistance profiles to ensure adequate peripheral and CNS viral suppression. Optimization can also be achieved by using ART agents with effective CNS penetration.⁷ However, no randomized controlled trials exist to support these practices, and treatment does not always result in immediate symptom resolution as demonstrated in this case.

Our patient improved transiently after steroids, although steroids are not a standard treatment of CSF discordance.^7,15 Although our patient did not have neuropathologic confirmation of CD8⁺ encephalitis (diagnostic gold standard) because of resource limitations, his MRI showed T2 white matter hyperintensities as are reported in CD8⁺ encephalitis.⁹ Steroids often improve CD8 encephalitis, so it is possible that our patient had an overlap of CSF discordance and CD8 encephalitis that improved with both steroids and optimization of his ART regimen. Repeat neuroimaging was not performed because the patient improved such that repeat imaging was unlikely to change management and would incur significant costs for the patient.

It is important to note that this case report highlights challenges of evaluating RPD in settings where resource limitations often preclude a comprehensive initial evaluation. Instead, a stepwise approach based on prevailing local epidemiology is undertaken and empiric treatment often initiated. However, close clinical follow-up and re-evaluation of empiric diagnoses is essential. For example, in retrospect, our patient likely never had PML-IRIS. Close follow-up and critical evaluation of prior presumptive diagnoses, however, enabled correct diagnosis and initiation of appropriate treatment.

Finally, this case report highlights the need to evaluate for CSF escape/discordance in people with HIV presenting with cognitive decline, especially in those with well-controlled systemic HIV and in whom CNS opportunistic infections have been excluded. This is especially important because CSF escape/discordance syndromes are treatable but can lead to marked impairment if not promptly diagnosed and treated.