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Retroviral Infections of the Nervous System 

Retroviral Infections of the Nervous System
Chapter:
Retroviral Infections of the Nervous System
Author(s):

Michel Toledano

and Allen J. Aksamit Jr

DOI:
10.1093/med/9780190244927.003.0075
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date: 04 December 2020

Introduction

Retroviruses are a family of viruses that replicate by reverse transcription. This family includes human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV). This chapter reviews neurologic manifestations of these retroviruses.

Human Immunodeficiency Virus

Epidemiology

A retrovirus in the lentivirus family, HIV has 2 forms, HIV-1 and HIV-2. HIV-1 is associated with the global AIDS pandemic, whereas HIV-2 causes an AIDS-like illness primarily in West Africa, although pockets of infection exist globally.

HIV preferentially infects CD4+ cells, typically affecting monocytes, T lymphocytes, and microglia. The viral envelope glycoprotein gp120 binds to CD4 and to the CCR5 (macrophages) and CXCR4 (T cells) receptors, allowing the virus to enter the cell. Primary infection affects macrophages first, and patients homozygous for a deletion in CCR5 are relatively resistant to infection. Infected macrophages fuse with CD4 T cells, and the virus spreads to organs such as the brain, spleen, and lymph nodes. Replication in host cells leads to cell death and severe immunodeficiency.

The main routes of transmission are by blood and genital secretions, typically by sexual contact or intravenous drug use. Screening of blood products and organ donors is now routine. Mother-to-infant transmission can occur in utero, during birth, or through breast milk.

Primary Infection

Primary infection may be associated with a flulike illness, which can include fever, malaise, myalgias, a maculopapular rash, and rarely aseptic meningitis. During the clinical latent period that follows, the patient is asymptomatic but viral reproduction continues and the CD4 count decreases. This latent period lasts 10 years on average. Invariably, patients have symptoms suggestive of reduced cell-mediated immunity. As the CD4 counts continue to decrease, opportunistic infections and AIDS develop (Table 65.1). With the exception of aseptic meningitis, most neurologic complications occur during the later stages. Without treatment, neurologic symptoms develop in more than 50% of HIV patients during the course of their illness. Highly active antiretroviral therapy (HAART) has decreased the incidence of neurologic complications.

Table 65.1 Opportunistic Infections Encountered in HIV Infection According to CD4 Cell Count

CNS Disease

CD4 Cell Count/μ‎L

Syphilitic meningitis

>500

Tuberculous meningitis

200–500

Toxoplasmosis

<200

Cryptococcal meningitis

<200

CMV encephalitis, polyradiculopathy

<50

PML

<50

Abbreviations: CMV, cytomegalovirus; CNS, central nervous system; HIV, human immunodeficiency virus; PML, progressive multifocal leukoencephalopathy.

Other Clinical Manifestations and Associated Syndromes

Aseptic Meningitis

Aseptic meningitis is a monophasic illness that usually occurs within the first 6 weeks of seroconversion. Patients may have HIV antibodies in their blood, but they may test positive for p24 antigen only in the early course of infection. Typically, this is a self-limited disease.

HIV-Associated Dementia

HIV-associated dementia usually occurs late in an HIV infection, when the CD4 cell count is less than 200/μ‎L, and is thought to be related to the HIV infection itself. The incidence has decreased considerably since the introduction of HAART and is currently between 7% and 15%. The prevalence, however, may be increasing as patients with HIV live longer. Clinically, HIV-associated dementia is characterized by slowly progressive behavioral changes and subcortical dementia (poor attention, bradyphrenia, memory loss, and bradykinesia).

Magnetic resonance imaging (MRI) demonstrates diffuse T2-signal abnormalities in the periventricular white matter and generalized atrophy (Figure 65.1).

Figure 65.1 Human Immunodeficiency Virus–Associated Dementia.
Magnetic resonance imaging shows the characteristic feature: diffuse, confluent, ill-defined periventricular white matter hyperintense lesions on axial fluid-attenuated inversion recovery sequences.

Figure 65.1 Human Immunodeficiency Virus–Associated Dementia.

Magnetic resonance imaging shows the characteristic feature: diffuse, confluent, ill-defined periventricular white matter hyperintense lesions on axial fluid-attenuated inversion recovery sequences.

(Adapted from Tracy JA, Mowzoon N. Neurology of infectious diseases. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated study guide. Rochester [MN]: Mayo Clinic Scientific Press and Florence [KY]: Informa Healthcare USA; c2007. p. 589–626. Used with permission of Mayo Foundation for Medical Education and Research.)

Histologically, there is periventricular and perivascular inflammation with multinucleated giant cells and reactive gliosis.

HIV-Associated Vacuolar Myelopathy

HIV-associated vacuolar myelopathy usually occurs late in the disease, which differentiates it from the far less common HIV transverse myelitis associated with acute infection. HIV-associated vacuolar myelopathy is characterized by the subacute progression of spastic paraparesis, bladder dysfunction and sensory loss (primarily proprioception). The disease is caused by degeneration of the posterior and lateral columns of the spine.

Histologic findings include spongiform change with vacuolization of myelin sheaths, lipid-laden macrophages and microglia, and multinucleated giant cells.

HIV-Associated Neuromuscular Disease

Neuromuscular conditions associated with HIV infection or its treatment are listed in Table 65.2.

Table 65.2 Neuromuscular Disease Associated With Human Immunodeficiency Virus (HIV) Infection

Condition

Description

Distal sensory polyneuropathy

  • Painful, symmetric, predominantly sensory (small fiber more than large fiber) axonal neuropathy that develops late in the disease

  • It is clinically apparent in up to 30% of patients with AIDS

Antiretroviral-associated neuropathy

  • Associated with nucleoside analogues such as didanosine, zalcitabine, and stavudine

  • Clinically and electrophysiologically, it resembles primary HIV neuropathy and can be distinguished only by empirical removal of the offending agent

Cranial mononeuropathies and mononeuritis multiplex

  • Mononeuropathies are an uncommon clinical manifestation of neurologic disease in HIV-positive patients and can involve either cranial or peripheral nerves

  • Facial nerve palsy is the most common cranial neuropathy

  • HIV-infected patients with mononeuropathy multiplex and CD4 cell counts <200/μ‎L should be evaluated for cytomegalovirus infection

  • Hepatitis B surface antigen and hepatitis C antibody should also be considered

Demyelinating polyradiculoneuropathy

  • The 2 major forms of acquired inflammatory demyelinating polyradiculoneuropathy are acute demyelinating polyradiculoneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy

  • Both have occurred in patients with underlying HIV infection

  • Treatment is with intravenous immunoglobulin or plasma exchange

Lumbosacral polyradiculopathy

  • Rapidly progressing lumbosacral polyradiculopathy (cauda equina syndrome) occurs mainly in HIV-infected patients with CD4 cell counts of <50/μ‎L

  • The most common cause is cytomegalovirus

  • Sacral radiculomyelitis can occur with primary HSV-2 infection at any stage of HIV disease

HIV-associated myopathy

  • Characterized by progressive muscle weakness (proximal muscles more than distal muscles), myalgias, and mild elevation of creatine kinase

  • Pathophysiology is unclear

Antiretroviral-associated neuromuscular weakness

  • Zidovudine and stavudine can cause progressive muscular weakness and myalgias

  • Mechanism is thought to be due to mitochondrial toxicity

Motor neuron disease

  • An amyotrophic lateral sclerosis–like illness can occur late in the course of HIV infection

  • Improves with antiretroviral therapy

Treatment

The mainstay of HIV therapy includes HAART, which generally refers to a cocktail of several antiretroviral medications (6 separate classes of medications). HAART decreases the viral load and has dramatically increased life expectancies and decreased opportunistic infections. General adverse effects of some of the medications include hepatotoxicity, lactic acidosis, rash, and dyslipidemia. Potential neurologic adverse effects of the medications are listed in Table 65.3).

Table 65.3 Neurologic Complications of Highly Active Antiretroviral Therapy (HAART)

Drug

Potential Neurologic Complication

Class

Example

Nucleoside analogue

Zidovudine

  • Myalgia

  • Myopathy (related to mitochondrial toxicity)

  • Neuropathy (related to mitochondrial toxicity; the combination of didanosine and stavudine carries the highest risk)

Non-nucleoside reverse transcriptase inhibitor

Nevirapine

  • Hepatotoxicity leads to hepatic encephalopathy

  • Headache

  • Nightmares

  • Confusion

  • Mood changes

Protease inhibitor

Ritonavir

  • Headache

  • Circumoral and limb paresthesia

CCR5 inhibitor

Maraviroc

Musculoskeletal symptoms

Integrase inhibitor

Raltegravir

  • Headache

  • Myositis

  • HIV preferentially infects CD4+ cells, typically affecting monocytes, T lymphocytes, and microglia.

  • Clinically, HIV-associated dementia is characterized by slowly progressive behavioral changes and subcortical dementia (poor attention, bradyphrenia, memory loss, and bradykinesia).

  • HIV-associated vacuolar myelopathy usually occurs late in the disease, which differentiates it from the far less common HIV transverse myelitis associated with acute infection.

  • The mainstay of HIV therapy includes HAART.

Opportunistic Infections Common With HIV Infection

Toxoplasmosis

Toxoplasmosis usually occurs in patients with CD4 cell counts less than 100/μ‎L. The infection is caused by reactivation of latent Toxoplasma gondii, an obligate intracellular protozoa. (See also Chapter 68, “Parasitic Infections of the Central Nervous System.”) About one-third of the population is seropositive for T gondii by adulthood. The primary mode of transmission is the fecal-oral route through the ingestion of oocytes or cysts in feline feces, contaminated food, or uncooked meat.

Neurologic symptoms are secondary to the development of focal parenchymal abscess or abscesses and consist of headache, seizures, hemiparesis, hemianopia, aphasia, or ataxia. Subacute encephalitis can also ensue.

Neuroimaging of a patient with toxoplasmosis shows 1 or more ring-enhancing lesions with a predilection for the basal ganglia. About two-thirds of patients have multiple lesions at presentation, unlike patients with HIV-associated central nervous system (CNS) lymphoma, who usually present with a solitary lesion. Imaging findings help distinguish between neurotoxoplasmosis and lymphoma: Lymphoma has greater thallium uptake on thallium single-photon emission computed tomography and greater glucose and methionine metabolism on positron emission tomography than neurotoxoplasmosis. Polymerase chain reaction for T gondii in the cerebrospinal fluid (CSF) has a specificity of more than 95%, but sensitivity is variable. Lumbar puncture may be contraindicated if a focal mass lesion is present.

Treatment is with pyrimethamine, sulfadiazine, and folinic acid. HAART should be initiated and maintenance therapy continued until the CD4 cell count is more than 200/μ‎L. Patients should then receive lifelong prophylaxis with trimethoprim-sulfamethoxazole.

Cryptococcal Meningitis

Cryptococcal meningitis is caused by Cryptococcus neoformans, an encapsulated yeast. It was a frequent cause of meningitis in AIDS before HAART. (See also Chapter 67, “Fungal Infections of the Central Nervous System.”) Cryptococcal meningitis rarely occurs in patients with CD4 cell counts greater than 100/μ‎L.

Cryptococcosis is characterized by chronic basilar meningitis with slow onset of altered mentation, cranial neuropathies, behavioral changes, and seizures leading to coma. Headache and nuchal rigidity are absent because of the mild inflammatory reaction.

MRI may be normal or may show sulcal or basilar leptomeningeal enhancement or nonspecific T2 hyperintensities.

CSF analysis shows a mild mononuclear pleocytosis with slightly increased protein and decreased glucose concentration. CSF fungal cultures have high sensitivity and specificity but take several weeks to grow. Increased serum and CSF cryptococcal capsular polysaccharide antigen titer is faster and can be diagnostic. India ink stain is no longer used routinely.

Histologic examination shows leptomeningeal inflammatory infiltrates and enlarged perivascular cystic spaces (cryptococcal cysts) filled with encapsulated cryptococci or budding yeast (Figure 65.2).

Figure 65.2 Cryptococcosis.
A, Typical macroscopic appearance of multiple small intraparenchymal gelatinous cysts involving the cerebral cortex. B, Parenchymal lesions are cystic spaces, often appearing as enlarged perivascular spaces, filled with colonies of cryptococci. C, Higher magnification shows encapsulated organisms, which appear as round basophilic structures.
Figure 65.2 Cryptococcosis.
A, Typical macroscopic appearance of multiple small intraparenchymal gelatinous cysts involving the cerebral cortex. B, Parenchymal lesions are cystic spaces, often appearing as enlarged perivascular spaces, filled with colonies of cryptococci. C, Higher magnification shows encapsulated organisms, which appear as round basophilic structures.
Figure 65.2 Cryptococcosis.
A, Typical macroscopic appearance of multiple small intraparenchymal gelatinous cysts involving the cerebral cortex. B, Parenchymal lesions are cystic spaces, often appearing as enlarged perivascular spaces, filled with colonies of cryptococci. C, Higher magnification shows encapsulated organisms, which appear as round basophilic structures.

Figure 65.2 Cryptococcosis.

A, Typical macroscopic appearance of multiple small intraparenchymal gelatinous cysts involving the cerebral cortex. B, Parenchymal lesions are cystic spaces, often appearing as enlarged perivascular spaces, filled with colonies of cryptococci. C, Higher magnification shows encapsulated organisms, which appear as round basophilic structures.

(Adapted from Tracy JA, Mowzoon N. Neurology of infectious diseases. In: Mowzoon N, Flemming KD, editors. Neurology board review: an illustrated study guide. Rochester [MN]: Mayo Clinic Scientific Press and Florence [KY]: Informa Healthcare USA; c2007. p. 589–626. Used with permission of Mayo Foundation for Medical Education and Research.)

Treatment is with amphotericin B followed by fluconazole.

Other Viral Infections

Patients with HIV infection may be more susceptible to progressive multifocal leukoencephalopathy (PML) and cytomegalovirus (CMV) infection. In addition, patients with HIV infection may have primary CNS lymphoma related to Epstein-Barr virus infection. For additional details, see Chapter 64, “DNA and RNA Viral Infections of the Nervous System.”

  • Neuroimaging of a patient with toxoplasmosis shows 1 or more ring-enhancing lesions with a predilection for the basal ganglia.

  • Imaging findings help distinguish between neurotoxoplasmosis and lymphoma: Lymphoma has greater thallium uptake on thallium single-photon emission computed tomography and greater glucose and methionine metabolism on positron emission tomography than neurotoxoplasmosis.

Approach to Patients With HIV Infection and CNS Disease

When evaluating a patient with known HIV infection, it is helpful to consider the clinical syndromes directly related to HIV in addition to opportunistic infections and complications of HIV therapy. The most common diseases associated with advanced HIV infection include toxoplasmosis, CMV encephalitis, primary CNS lymphoma, PML, and HIV dementia.

If a patient has a known HIV infection and a CNS mass lesion with mass effect, considerations generally include toxoplasmosis, primary CNS lymphoma, and other infections (bacterial or fungal) common in the immunosuppressed. For a patient with known HIV infection and a CNS mass without mass effect, considerations may include PML, HIV dementia or encephalopathy, or CMV encephalitis. MRI with a contrast agent is important for the differential diagnosis. A common approach to the diagnosis and treatment of these entities is shown in Figure 65.3.

Figure 65.3 Approach to Patients With HIV Infection and a CNS Mass Lesion.
CNS indicates central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; LP, lumbar puncture; MRI, magnetic resonance imaging; Rx, treatment; SPECT, single-photon emission computed tomography.

Figure 65.3 Approach to Patients With HIV Infection and a CNS Mass Lesion.

CNS indicates central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; LP, lumbar puncture; MRI, magnetic resonance imaging; Rx, treatment; SPECT, single-photon emission computed tomography.

  • When evaluating a patient with known HIV infection, it is helpful to consider the clinical syndromes directly related to HIV in addition to opportunistic infections and complications of HIV therapy.

HTLV-1 Infection

Tropical spastic paraparesis results from the HTLV-1 infection. Transmission of this virus, similar to transmission of HIV, may be vertical (mother to child), sexual, or parenteral. Intravenous drug users are at increased risk for this condition. Myelopathy develops in only 1 in 250 patients infected with HTLV-1.

Patients typically present with a slowly progressive myelopathy primarily affecting the thoracic segments. The bladder is often affected. HTLV-1 may also be associated with a demyelinating polyneuropathy and ataxia.

Notes:

Abbreviations: CMV, cytomegalovirus; CNS, central nervous system; CSF, cerebrospinal fluid; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HTLV, human T-lymphotropic virus; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy