Residency · Residency · Neurology
HIV-Associated Neurological Disorders
Introduction
Neurological complications affect 40-70% of individuals with HIV infection over the course of their disease. The spectrum of HIV-associated neurological disorders spans direct viral effects on the nervous system, opportunistic infections, neoplasms, and immune reconstitution inflammatory syndrome. Despite the success of combination antiretroviral therapy (cART), milder forms of HIV-associated neurocognitive disorder remain prevalent, and neurologists must be familiar with the full range of CNS and PNS manifestations.
HIV-Associated Neurocognitive Disorders (HAND)
Classification (Frascati Criteria)
HAND is classified into three categories. Asymptomatic neurocognitive impairment (ANI) involves impairment on neuropsychological testing in 2 or more cognitive domains (1 SD below mean) without functional impairment. Mild neurocognitive disorder (MND) involves cognitive impairment with mild functional impact. HIV-associated dementia (HAD) represents severe cognitive impairment with marked functional disability.
Pathophysiology
HIV enters the CNS early after primary infection via infected monocytes through the Trojan horse mechanism. Viral proteins including gp120 and Tat cause direct neuronal toxicity and synaptic dysfunction. Chronic microglial activation and neuroinflammation persist even with suppressed plasma viral load. The subcortical white matter and basal ganglia are preferentially affected.
Clinical Features
The cognitive profile follows a subcortical pattern with psychomotor slowing, impaired attention and concentration, executive dysfunction, and memory retrieval deficits. Motor features include gait instability, clumsiness, and tremor. Behavioral changes manifest as apathy, social withdrawal, and irritability. In the cART era, HAD is less common, but ANI and MND remain prevalent in 30-50% of treated patients.
Diagnosis and Management
Diagnosis requires neuropsychological testing covering at least 5 cognitive domains. MRI shows cerebral atrophy and white matter T2/FLAIR hyperintensities. CSF may show mild pleocytosis, elevated protein, and detectable HIV RNA. Treatment consists of initiation or optimization of cART with CNS-penetrating regimens, though no proven adjunctive neuroprotective therapy exists.
Opportunistic Infections
| Condition | CD4 Threshold | Key Imaging | Diagnosis | Treatment |
|---|---|---|---|---|
| Toxoplasma encephalitis | <100 | Multiple ring-enhancing lesions (basal ganglia, gray-white junction) | Toxoplasma IgG + imaging + clinical response | Pyrimethamine + sulfadiazine + leucovorin |
| Cryptococcal meningitis | <100 | Normal or hydrocephalus | CSF CrAg (>95% sensitive); India ink | Amphotericin B + flucytosine; serial LPs for ICP |
| PML (JC virus) | <200 | Asymmetric white matter lesions; no mass effect; no enhancement | CSF JC virus PCR (70-90%) | cART (immune reconstitution); no antiviral |
| CMV ventriculoencephalitis | <50 | Periventricular enhancement | CSF CMV PCR | Ganciclovir + foscarnet |
| Primary CNS lymphoma | <50 | Solitary periventricular enhancing lesion | CSF EBV PCR; biopsy | cART + radiation or MTX-based chemo |
Toxoplasma Encephalitis
Toxoplasma encephalitis is the most common CNS opportunistic infection in AIDS, occurring when CD4 falls below 100 cells/mcL. It results from reactivation of latent Toxoplasma gondii infection. Patients present with headache, fever, focal neurological deficits, seizures, and altered mental status. MRI characteristically shows multiple ring-enhancing lesions with surrounding edema, typically in the basal ganglia and at the corticomedullary junction. Diagnosis rests on positive Toxoplasma IgG serology (present in 95% of cases), characteristic imaging, and clinical response to empiric therapy. Treatment is pyrimethamine plus sulfadiazine plus leucovorin for at least 6 weeks, followed by lifelong secondary prophylaxis until immune reconstitution.
Cryptococcal Meningitis
Cryptococcal meningitis is caused by Cryptococcus neoformans and typically occurs at CD4 less than 100 cells/mcL. It presents subacutely with headache, fever, and altered mental status. Elevated ICP is common and a major cause of morbidity and mortality. CSF shows elevated opening pressure (often greater than 25 cm H2O), lymphocytic pleocytosis (which may be minimal), elevated protein, and low glucose. CSF cryptococcal antigen (CrAg) has sensitivity greater than 95%, while India ink preparation is positive in 60-80%. Treatment involves induction with amphotericin B desoxycolate or liposomal amphotericin plus flucytosine for 2 weeks, consolidation with fluconazole, and serial therapeutic LPs to manage elevated ICP.
Progressive Multifocal Leukoencephalopathy (PML)
PML is caused by JC virus reactivation in severely immunosuppressed patients with CD4 less than 200 cells/mcL. It presents with subacute progressive focal neurological deficits including hemiparesis, visual field cuts, ataxia, and cognitive decline. MRI shows asymmetric, confluent white matter lesions without mass effect or contrast enhancement, though enhancement may occur with IRIS. CSF JC virus PCR has sensitivity of 70-90% and specificity greater than 95%. There is no specific antiviral therapy, and treatment is immune reconstitution with cART. One-year mortality is 50% in HIV, with better outcomes achieved with early cART and immune recovery.
CMV Encephalitis and Other CNS Infections
CMV ventriculoencephalitis shows periventricular enhancement on MRI with concurrent retinitis common, and is treated with ganciclovir plus foscarnet. Tuberculous meningitis presents with basal meningeal enhancement and hydrocephalus. Neurosyphilis remains an important consideration in HIV-positive patients.
CNS Lymphoma
Primary CNS lymphoma (PCNSL) is an EBV-driven B-cell lymphoma occurring when CD4 falls below 50 cells/mcL. It presents as solitary or few enhancing periventricular lesions that may be difficult to distinguish from toxoplasmosis. CSF EBV PCR is positive in most cases, and stereotactic brain biopsy may be required. Key features distinguishing it from toxoplasmosis include a solitary lesion, periventricular location, negative Toxoplasma serology, and failure to respond to empiric anti-Toxoplasma therapy. Treatment is cART plus whole-brain radiation or methotrexate-based chemotherapy.
HIV-Associated Peripheral Nervous System Disorders
Distal Sensory Polyneuropathy (DSP)
DSP is the most common neuropathy in HIV, affecting up to 50% of patients. It presents as a symmetric, length-dependent, painful neuropathy affecting the feet and legs with burning pain, paresthesias, allodynia, reduced ankle reflexes, and diminished vibration sense. It is caused by HIV viral proteins and antiretroviral toxicity, especially older NRTIs such as didanosine, stavudine, and zalcitabine. Treatment involves optimizing cART, discontinuing neurotoxic agents, and symptomatic management with gabapentin, pregabalin, duloxetine, or topical capsaicin.
Other Neuropathies
Inflammatory demyelinating polyneuropathy (AIDP/CIDP) can occur at any CD4 count with presentation and treatment similar to non-HIV GBS/CIDP. Progressive polyradiculopathy from CMV presents as rapidly ascending flaccid paraparesis with areflexia and sphincter dysfunction, with CSF showing neutrophilic pleocytosis, and is treated with ganciclovir. Mononeuropathy multiplex is vasculitis-related, occurs at low CD4 counts, and requires treatment of the underlying infection.
HIV-Associated Myelopathy (Vacuolar Myelopathy)
Vacuolar myelopathy presents as progressive spastic paraparesis with sensory ataxia and bladder dysfunction. Pathology shows vacuolation of the posterior and lateral columns of the thoracic spinal cord, resembling subacute combined degeneration. It occurs in advanced AIDS with no specific treatment beyond cART. Other causes must be excluded including HTLV-1 myelopathy, vitamin B12 deficiency, compressive myelopathy, and neurosyphilis.
Immune Reconstitution Inflammatory Syndrome (IRIS)
IRIS is a paradoxical worsening of known or subclinical opportunistic infection after cART initiation, typically occurring within 4-8 weeks of starting cART when the CD4 count begins rising. CNS IRIS is most commonly associated with PML, cryptococcal meningitis, and tuberculosis. It may present with worsening neurological deficits, new contrast enhancement on MRI, and increased inflammation in CSF. Treatment involves continuing cART, administering corticosteroids for severe cases, and treating the underlying opportunistic infection.
Clinical Pearls
Multiple ring-enhancing lesions in an AIDS patient are toxoplasmosis until proven otherwise; empiric treatment should be initiated and response assessed at 10-14 days. CSF opening pressure must always be measured in cryptococcal meningitis, with serial therapeutic LPs performed to maintain pressure below 20 cm H2O to reduce mortality. PML lesions characteristically lack mass effect and do not enhance; contrast enhancement in PML should raise concern for immune reconstitution. HIV-associated neurocognitive disorder remains prevalent even in virally suppressed patients, and neuropsychological testing can identify subtle deficits. When starting cART in patients with known or suspected CNS opportunistic infections, close monitoring for IRIS is essential, as it can cause rapid neurological deterioration.
References
- Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013;13(11):976-986.
- Bowen LN, Smith B, Reich D, Quezado M, Nath A. HIV-associated opportunistic CNS infections. J Neuroimmunol. 2016;15(1):164-178.
- Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799.
- Manji H, Jager HR, Winston A. HIV, dementia, and antiretroviral drugs: 30 years of an epidemic. J Neurol Neurosurg Psychiatry. 2013;84(10):1126-1137.