HIV Neurology

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HIV Neurology

Neurological complications affect more than 50% of patients with HIV infection and remain a major source of morbidity even in the era of effective antiretroviral therapy (ART). The nervous system is involved at all levels — brain, spinal cord, peripheral nerves, and muscle — through both direct viral effects and opportunistic processes that emerge as immune surveillance fails. For the neurologist, understanding the relationship between CD4 count and specific neurological complications is essential for constructing an accurate differential diagnosis. While the incidence of opportunistic infections has declined dramatically with widespread ART access, HIV-associated neurocognitive disorders persist and new challenges such as immune reconstitution inflammatory syndrome (IRIS) have emerged. This topic provides a comprehensive, clinically oriented framework for evaluating and managing neurological disease in the HIV-positive patient.

Bottom Line

CD4 count guides the differential: Toxoplasmosis and PML at CD4 <200; CNS lymphoma, CMV, and cryptococcal meningitis at CD4 <100; the CD4 count is the single most important piece of clinical data
HAND persists despite ART: HIV-associated neurocognitive disorders affect up to 50% of treated patients; the subcortical pattern (psychomotor slowing, executive dysfunction, retrieval deficits) is characteristic
Ring-enhancing lesion → treat for toxoplasma first: Empiric pyrimethamine + sulfadiazine for 2 weeks; if no improvement, biopsy for CNS lymphoma
Cryptococcal meningitis: High opening pressure is the key management issue; serial therapeutic LPs are essential; screen with serum CrAg when CD4 <100
Distal sensory polyneuropathy: The most common neurological complication of HIV; distinguish from antiretroviral toxic neuropathy (d-drugs)
IRIS: Paradoxical worsening after ART initiation; particularly dangerous in PML and cryptococcal meningitis; delay ART 2–4 weeks for crypto, 2–8 weeks for TB meningitis
PML: JC virus demyelination with no proven treatment beyond ART-mediated immune reconstitution; mortality remains ~50% at 1 year

Direct HIV Neurological Complications

HIV itself is neurotropic, entering the CNS within days of primary infection via infected monocytes and CD4+ T cells ("Trojan horse" mechanism). The virus establishes a persistent reservoir in perivascular macrophages and microglia. Direct viral neurotoxicity is mediated through release of viral proteins (gp120, Tat), inflammatory cytokines, and excitotoxic mechanisms.

HIV-Associated Neurocognitive Disorders (HAND)

HAND represents a spectrum of cognitive impairment directly attributable to HIV infection of the CNS. Despite effective viral suppression with ART, HAND remains prevalent, affecting 30–50% of HIV-positive individuals in the current era. The nomenclature was standardized by the Frascati criteria (Antinori et al., 2007).

HAND Category	Cognitive Impairment	Functional Impact	Prevalence (ART era)
Asymptomatic Neurocognitive Impairment (ANI)	≥1 SD below mean in ≥2 cognitive domains on neuropsychological testing	No functional impairment in daily activities	20–30%
Mild Neurocognitive Disorder (MND)	≥1 SD below mean in ≥2 cognitive domains	Mild interference with daily functioning (work, home management)	10–20%
HIV-Associated Dementia (HAD)	≥2 SD below mean in ≥2 cognitive domains	Marked functional impairment; unable to work; needs assistance	2–5% (down from 15–20% pre-ART)

Clinical Features of HAND

Subcortical pattern: The cognitive profile of HAND is characteristically subcortical, distinguishing it from cortical dementias such as Alzheimer disease
Psychomotor slowing: The hallmark feature; patients are slow in thinking, processing, and motor responses
Executive dysfunction: Impaired planning, mental flexibility, and decision-making
Memory retrieval deficit: Recognition memory is relatively preserved (unlike Alzheimer disease where encoding is impaired); patients benefit from cues and prompts
Attention and concentration deficits: Impaired sustained and divided attention
Motor features (in HAD): Gait ataxia, tremor, bradykinesia, hyperreflexia, frontal release signs
Behavioral changes: Apathy (more common than depression), social withdrawal, irritability
MRI findings: Cerebral atrophy (especially caudate), periventricular white matter T2/FLAIR hyperintensities; no enhancement or mass effect

HAND in the ART Era: Persistent Challenges

Shifting spectrum: HAD has become rare with ART, but milder forms (ANI, MND) persist; the overall prevalence of HAND has not significantly decreased
Contributing factors: Aging HIV-positive population with vascular risk factors, hepatitis C co-infection, substance use, chronic inflammation despite viral suppression
CNS penetration-effectiveness (CPE) score: A ranking of ART agents by CNS penetration; higher CPE regimens may improve neurocognitive outcomes in some studies, but evidence remains mixed and CPE-based switching is not routinely recommended
Diagnosis of exclusion: Always rule out opportunistic infections, metabolic causes, depression, substance use, and medication side effects before attributing cognitive impairment to HAND

HIV Myelopathy (Vacuolar Myelopathy)

HIV-associated vacuolar myelopathy is a progressive myelopathy occurring in advanced HIV disease (typically CD4 <200). It is pathologically characterized by vacuolization of the posterior and lateral columns of the thoracic spinal cord, resembling the myelopathy of vitamin B12 deficiency (subacute combined degeneration).

Clinical Features of HIV Myelopathy

Progressive spastic paraparesis: Gradual onset over weeks to months; bilateral leg weakness and stiffness
Posterior column dysfunction: Impaired vibration and proprioception in the lower extremities; sensory ataxia
Sphincter dysfunction: Urinary urgency and incontinence; erectile dysfunction
Often coexists with DSP: The combination of upper motor neuron signs (spasticity, hyperreflexia) and peripheral neuropathy (absent ankle reflexes) is characteristic
Differential diagnosis: B12 deficiency (check levels — can coexist), copper deficiency, HTLV-1 myelopathy, compressive myelopathy, CMV myeloradiculopathy
MRI: May show T2 hyperintensity in the posterior columns; often normal
Treatment: ART initiation or optimization; no specific treatment; supportive care with physical therapy, spasticity management

HIV-Associated Peripheral Neuropathy

Neuropathy Type	Stage of HIV	Clinical Features	Key Points
Distal sensory polyneuropathy (DSP)	Any CD4 (most common at <200)	Burning feet, numbness, allodynia; stocking distribution; reduced/absent ankle reflexes	Most common neurological complication of HIV; affects 30–60% of patients; length-dependent, symmetric
Antiretroviral toxic neuropathy (ATN)	Any CD4 (drug-related)	Clinically identical to DSP; onset weeks to months after starting offending agent	Caused by "d-drugs": didanosine (ddI), stavudine (d4T), zalcitabine (ddC); mitochondrial toxicity; reversible if drug discontinued early
Acute inflammatory demyelinating polyneuropathy (AIDP)	Seroconversion or early HIV	Classic GBS presentation: ascending weakness, areflexia, albuminocytologic dissociation	May occur at time of seroconversion; CSF may show mild pleocytosis (unlike typical GBS); treatment same as for HIV-negative patients (IVIG, PLEX)
Chronic inflammatory demyelinating polyneuropathy (CIDP)	Any CD4	Progressive or relapsing proximal and distal weakness; areflexia; elevated CSF protein	More common at higher CD4 counts; responds to IVIG or corticosteroids; steroids generally safe if CD4 adequately preserved
CMV polyradiculopathy	CD4 <50	Rapidly progressive cauda equina syndrome: flaccid paraparesis, urinary retention, saddle anesthesia	CSF shows neutrophilic pleocytosis (unusual for viral); CMV PCR positive; treat urgently with ganciclovir/foscarnet
Mononeuritis multiplex	Any CD4; worse at <200	Asymmetric involvement of individual nerves; painful; may be vasculitic	At higher CD4: self-limited; at low CD4: may be due to CMV vasculitis — treat underlying cause
Progressive polyradiculopathy (non-CMV)	CD4 <200	Cauda equina syndrome	Consider lymphomatous or syphilitic infiltration

Acute HIV Neurological Manifestations

Neurological Features of Acute HIV Seroconversion

Aseptic meningitis: The most common neurological manifestation of acute HIV; fever, headache, meningismus; CSF lymphocytic pleocytosis with normal glucose; self-limited
Acute inflammatory demyelinating polyneuropathy (AIDP): Clinically identical to Guillain-Barré syndrome; may occur weeks to months after seroconversion
Facial nerve palsy: May be bilateral; similar to Bell palsy; occurs during seroconversion
Acute transverse myelitis: Rare; inflammatory myelopathy during seroconversion
Key point: Any young patient with aseptic meningitis, unexplained GBS, or bilateral facial palsy should be tested for HIV, including acute HIV RNA testing (antibody tests may be negative during the window period)

Opportunistic Infections by CD4 Count

The CD4 count is the single most important laboratory value for constructing the neurological differential diagnosis in an HIV-positive patient. The following table summarizes the major opportunistic infections and their typical CD4 thresholds.

CD4 Count	Opportunistic Process	Key Features	Diagnosis
<200 cells/μL	Cerebral toxoplasmosis	Multiple ring-enhancing lesions; basal ganglia predilection; edema and mass effect	Serum Toxoplasma IgG (95% seropositive); MRI pattern; empiric treatment response
	Progressive multifocal leukoencephalopathy (PML)	Multifocal white matter lesions; NO enhancement, NO mass effect; progressive cognitive/motor decline	CSF JC virus PCR (sensitivity 70–90%); MRI pattern; brain biopsy if PCR negative
	Cryptococcal meningitis	Subacute headache; elevated ICP; minimal CSF pleocytosis; high opening pressure	CSF CrAg (>95% sensitive); India ink (75%); serum CrAg screening
<100 cells/μL	Primary CNS lymphoma (PCNSL)	Solitary or few enhancing lesions; periventricular; often EBV-associated	CSF EBV PCR; Thallium SPECT or FDG-PET (hot lesion); stereotactic biopsy
	CMV encephalitis/ventriculitis	Rapidly progressive encephalopathy; periventricular enhancement (ventriculitis pattern)	CSF CMV PCR; retinal exam (CMV retinitis in 30–40%)
	CMV polyradiculopathy	Rapidly progressive cauda equina; neutrophilic CSF pleocytosis	CSF CMV PCR; EMG shows axonal polyradiculopathy
<50 cells/μL	Mycobacterium avium complex (MAC)	Disseminated disease; rarely isolated CNS involvement; fever, weight loss, hepatosplenomegaly	Blood cultures; tissue biopsy

Cerebral Toxoplasmosis

Approach to Cerebral Toxoplasmosis

Most common CNS mass lesion in AIDS: Caused by reactivation of latent Toxoplasma gondii infection in the setting of CD4 <200
Imaging: Multiple ring-enhancing lesions with surrounding edema; basal ganglia, corticomedullary junction, and thalamus are preferred sites; "eccentric target sign" on MRI is suggestive
Serology: Toxoplasma IgG positive in ~95% of cases; a negative IgG makes toxoplasmosis unlikely (but does not exclude it)
Empiric treatment: Pyrimethamine (200 mg loading dose, then 50–75 mg/day) + sulfadiazine (1–1.5 g QID) + leucovorin (folinic acid 10–25 mg/day); alternative: TMP-SMX
Response assessment: Clinical improvement expected within 7–14 days; repeat MRI at 2 weeks should show reduction in lesion size
No response at 2 weeks → brain biopsy: If no improvement with empiric therapy, stereotactic biopsy is required to evaluate for CNS lymphoma or other diagnoses
Prophylaxis: TMP-SMX (also covers PCP) when CD4 <100 and Toxoplasma IgG positive; continue until CD4 >200 for ≥3 months on ART

Toxoplasmosis vs. Primary CNS Lymphoma

Feature	Toxoplasmosis	Primary CNS Lymphoma
Number of lesions	Usually multiple (>3)	Usually solitary or few (1–3)
Enhancement pattern	Ring-enhancing	Homogeneous or ring-enhancing; may be irregular
Location	Basal ganglia, corticomedullary junction	Periventricular, corpus callosum, deep white matter
Toxoplasma IgG	Positive in ~95%	May be positive or negative
CSF EBV PCR	Negative	Positive in 80–90%
Thallium SPECT	Cold (no uptake)	Hot (increased uptake)
FDG-PET	Hypometabolic	Hypermetabolic
Response to empiric treatment	Improvement in 1–2 weeks	No response
Typical CD4	<200	<100 (usually <50)

Cryptococcal Meningitis

Diagnosis and Management of Cryptococcal Meningitis

Clinical presentation: Subacute headache (often the predominant symptom), fever, altered mental status; meningismus may be absent; cranial neuropathies (especially CN VI and VIII) from elevated intracranial pressure
CSF profile: Variable; may show minimal pleocytosis (especially at very low CD4 counts — "acellular" meningitis); mildly elevated protein; low glucose in 50%; high opening pressure (>25 cm H₂O in >60%)
Diagnostic tests:
- CSF cryptococcal antigen (CrAg): Sensitivity >95%, specificity >98% — the best diagnostic test
- India ink preparation: Sensitivity ~75%; visualizes encapsulated yeast; less reliable at low organism burden
- Serum CrAg: >99% sensitivity for meningitis; use for screening when CD4 <100 (WHO recommendation)
- CSF culture: Gold standard; slower than antigen testing
Treatment protocol:
- Induction (2 weeks): Amphotericin B deoxycholate (0.7–1 mg/kg/day) + flucytosine (100 mg/kg/day in 4 divided doses)
- Consolidation (8 weeks): Fluconazole 400 mg/day
- Maintenance (secondary prophylaxis): Fluconazole 200 mg/day until CD4 >200 for ≥12 months on ART and undetectable CSF cultures
Elevated intracranial pressure management: Serial therapeutic lumbar punctures are critical — remove CSF to achieve closing pressure <20 cm H₂O; daily LPs may be needed initially; temporary lumbar drain or VP shunt for refractory cases

Critical Points in Cryptococcal Meningitis

Elevated ICP is the primary cause of death: Aggressive pressure management with serial LPs is more important than any pharmacologic intervention; do not rely on mannitol or acetazolamide
Delay ART initiation: Starting ART too early (within 1–2 weeks) increases mortality due to IRIS; current guidelines recommend delaying ART for 2–4 weeks after starting antifungal therapy (COAT trial, NEJM 2014)
Serum CrAg screening: WHO recommends screening all HIV-positive individuals with CD4 <100 for serum CrAg; pre-emptive fluconazole for those who are antigen-positive prevents progression to meningitis
Flucytosine availability: In resource-limited settings where flucytosine is unavailable, amphotericin B + fluconazole (1200 mg/day) is an alternative induction regimen (ACTA trial)

Progressive Multifocal Leukoencephalopathy (PML)

Feature	Details
Pathogen	JC virus (JCPyV); a polyomavirus that infects oligodendrocytes, causing progressive demyelination
Risk setting	CD4 <200 (usually <100); also seen with natalizumab, rituximab, and other immunosuppressive agents
Clinical presentation	Progressive focal deficits over weeks: hemiparesis, visual field cuts, cognitive decline, ataxia; no fever, no headache (distinguishes from infections)
MRI	Multifocal, asymmetric white matter T2/FLAIR hyperintensities; NO enhancement, NO mass effect; subcortical U-fibers involved; posterior fossa common
Diagnosis	CSF JC virus PCR: sensitivity 70–90%, specificity >95%; may be negative in early or low-burden disease; brain biopsy if PCR negative and suspicion high
Treatment	No specific antiviral therapy; ART-mediated immune reconstitution is the only proven strategy; survival improved from ~10% to ~50–60% with ART
PML-IRIS	Paradoxical worsening after ART initiation; new enhancement and edema on MRI; may be fatal; treated with corticosteroids (dexamethasone); continue ART
Prognosis	~50% survival at 1 year with ART; survivors often have significant residual deficits; better outcomes with higher CD4 nadir and earlier ART

Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS is a paradoxical clinical deterioration that occurs after initiation or intensification of ART, driven by a recovering immune system mounting an exaggerated inflammatory response against previously tolerated opportunistic pathogens (or their antigens). IRIS occurs in 10–30% of patients starting ART and is a major cause of morbidity in the first months of therapy.

IRIS Type	Definition	Timing	Examples
Paradoxical IRIS	Worsening of a known, previously treated OI after ART initiation	1–12 weeks after ART start	TB-IRIS (expanding tuberculomas, worsening meningitis); Crypto-IRIS (rising ICP); PML-IRIS (new enhancement, worsening deficits)
Unmasking IRIS	New presentation of a previously undiagnosed OI after ART initiation	1–12 weeks after ART start	Unmasked PML, tuberculosis, or cryptococcal meningitis presenting for the first time after ART

IRIS Management Principles

Do NOT stop ART: Continuation of ART is essential; stopping ART leads to further immunosuppression and worsened outcomes
Corticosteroids: The mainstay of treatment for moderate-to-severe IRIS; prednisone 1–1.5 mg/kg/day with taper over 4–8 weeks
Treat the underlying OI: Ensure optimal antimicrobial therapy for the OI that triggered IRIS
PML-IRIS is particularly dangerous: Can cause massive inflammatory demyelination with rapid deterioration; high-dose corticosteroids may be required; mortality 10–40%
Cryptococcal IRIS: Rising intracranial pressure is the main manifestation; aggressive serial LPs remain essential; do not rely solely on corticosteroids
Risk factors for IRIS: Low baseline CD4 (<50), high baseline viral load, short interval between OI treatment and ART initiation, rapid CD4 recovery

When to Start ART: Timing Considerations

The timing of ART initiation in the context of active neurological OIs is a critical clinical decision. Starting ART too early increases the risk of IRIS, while delaying too long prolongs immunosuppression and the risk of additional OIs.

Condition	ART Timing	Rationale
Most OIs (toxoplasmosis, PML, general)	Within 2 weeks of OI treatment	Early ART improves survival in most OIs (ACTG A5164 trial)
Cryptococcal meningitis	Delay 2–4 weeks after starting antifungal therapy	Early ART increased mortality (COAT trial, NEJM 2014); allow CSF sterilization first
Tuberculous meningitis	Delay 2–8 weeks after starting anti-TB therapy	TB-IRIS in the CNS is particularly dangerous; WHO recommends 2–8 weeks depending on CD4
CMV encephalitis/retinitis	Within 2 weeks	Immune reconstitution is essential for CMV control; CMV-IRIS (immune recovery uveitis) is manageable
No active OI	Immediately	START and TEMPRANO trials: early ART reduces morbidity and mortality at any CD4 count

CNS Penetration of Antiretrovirals

The concept of CNS penetration-effectiveness (CPE) was developed to rank antiretroviral agents by their ability to penetrate the blood-brain barrier and achieve therapeutic concentrations in the CSF. The CPE score ranges from 1 (low penetration) to 4 (high penetration) for each drug, and a regimen's total CPE is the sum of its component scores.

CPE Score	Drug Class	Examples
4 (Best penetration)	NRTIs, NNRTIs	Zidovudine (AZT), nevirapine
3 (Good)	NRTIs, INSTIs, NNRTIs	Abacavir, emtricitabine, dolutegravir, efavirenz, darunavir/r
2 (Moderate)	Various	Tenofovir (TAF), lamivudine, atazanavir/r, raltegravir
1 (Low)	PIs, INSTIs	Tenofovir (TDF), elvitegravir, bictegravir (limited data)

Clinical Relevance of CPE Score

Higher CPE regimens may improve CSF viral suppression: Some studies show better CSF HIV RNA control with higher CPE scores
Neurocognitive benefit is debated: The CHARTER study found association between higher CPE and better cognition, but subsequent randomized trials have been inconclusive
Current recommendation: CPE score should not be the primary determinant of ART selection; systemic viral suppression, tolerability, resistance profile, and drug interactions take priority
Dolutegravir: Widely used first-line INSTI with good CNS penetration (CPE 3); achieves CSF levels well above the IC90 for wild-type HIV

Approach to the HIV-Positive Patient with Neurological Symptoms

Presentation	Primary Differential (by CD4)	Key Initial Workup
Ring-enhancing brain lesion(s)	Toxoplasmosis (CD4 <200), CNS lymphoma (CD4 <100), brain abscess	MRI with contrast; Toxoplasma IgG; CSF EBV PCR; empiric toxoplasma Rx → biopsy if no response at 2 weeks
Non-enhancing white matter lesions	PML (CD4 <200), HAND, HIV leukoencephalopathy	MRI; CSF JC virus PCR; neuropsychological testing; brain biopsy if uncertain
Subacute meningitis	Cryptococcal meningitis, TB meningitis, syphilitic meningitis, HIV meningitis	LP with opening pressure; CrAg; AFB/Xpert; VDRL; CSF cell count and chemistry
Rapidly progressive encephalopathy	CMV encephalitis (CD4 <100), HAND/HAD, HSV encephalitis, metabolic	MRI; CSF CMV and HSV PCR; retinal exam; metabolic panel; EEG
Progressive myelopathy	Vacuolar myelopathy, B12 deficiency, HTLV-1, CMV, compressive lesion	Spinal MRI; B12, methylmalonic acid, homocysteine; HTLV-1 serology; CSF CMV PCR
Painful feet/neuropathy	HIV DSP, antiretroviral toxic neuropathy, CMV (if CD4 <50), B12 deficiency, diabetes	EMG/NCS; review ART regimen for neurotoxic agents; B12; glucose; CMV PCR if severe
Acute cauda equina syndrome	CMV polyradiculopathy (CD4 <50), lymphomatous meningitis	Spinal MRI; LP with cytology, CMV PCR; CSF cell count (neutrophilic in CMV)

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