Central Nervous System Diseases due to Opportunistic and Coinfections

Abstract

With the widespread use of combination antiretroviral therapy (cART), the incidence of central nervous system (CNS) opportunistic infections and coinfections has significantly decreased. This review focuses on the clinical presentation, diagnostic laboratory and radiologic findings, as well as the treatment of neurosyphilis, progressive multifocal leukoencephalopathy, primary CNS lymphoma, and toxoplasmosis, which are CNS opportunistic infections and coinfections that are most relevant to clinicians in North America.

In the era before combination antiretroviral therapy (cART), central nervous system (CNS) diseases due to opportunistic infections and coinfections were common in human immunodeficiency virus- (HIV-) infected patients. Many of these diseases, such as progressive multifocal leukoencephalopathy (PML), primary CNS lymphoma (PCNSL), and toxoplasmosis, are acquired immunodeficiency syndrome- (AIDS-) defining conditions and are associated with high mortality.^1,2 With the widespread use of cART, the incidence of CNS opportunistic infections has decreased significantly and overall survival has improved.^2,3 However, clinicians still need to be able to recognize these diseases because they continue to occur in those patients with significant HIV-associated immunosuppression, particularly in those not on cART. CNS opportunistic infections and coinfections such as neurosyphilis continue to perplex and challenge medical providers.

Neurosyphilis

Syphilis is caused by the bacterium Treponema pallidum subspecies pallidum, which can invade the central nervous system (CNS) to cause neurosyphilis. Although neurosyphilis has been traditionally considered a late or “tertiary” manifestation of syphilis, in reality, asymptomatic or symptomatic neurosyphilis can occur at any time after infection. Neurosyphilis is of particular concern in HIV-infected patients. Syphilis occurs commonly in this patient population and HIV-infected patients are at higher risk of failing therapy for early syphilis and developing early neurosyphilis (see discussion below on neurorelapse). Neurosyphilis may be more difficult to diagnose in the setting of concomitant HIV, and HIV-infected patients may be more likely to fail therapy for neurosyphilis. We address each of these issues in the following sections.

In the last decade, the number of cases of syphilis in the United States has increased, with a doubling in the rate of early syphilis cases.⁴ Syphilis has resurged in Europe and China as well.^5–8 In 2011, 72% of primary and secondary syphilis cases reported to the U.S. Centers for Disease Control and Prevention (CDC) occurred in men who have sex with men (MSM), many of whom were also infected with HIV.⁴

The clinical manifestations of syphilis involving the CNS are extremely variable and include asymptomatic neurosyphilis, symptomatic meningitis, meningovascular syphilis (affecting brain or spinal cord), ocular syphilis, otologic syphilis, general paresis, and tabes dorsalis. The forms of neurosyphilis that are characterized by meningeal inflammation (asymptomatic, meningeal, and meningovascular) are most common in the initial few years after infection, while parenchymal forms of neurosyphilis (general paresis and tabes dorsalis) occur years or decades after infection; general paresis and tabes dorsalis are rarely seen in the modern antibiotic era. Ocular and otological manifestations may occur in both early and late stages, often in combination with meningitis. Thus, neurosyphilis should be considered in the differential diagnosis of any HIV-infected patient with acute aseptic meningitis, chronic meningitis, stroke involving the brain or spinal cord, transverse myelitis, chronic myelopathy, and dementia.

In addition to the clinical presentation, neurosyphilis is diagnosed by cerebrospinal fluid (CSF) abnormalities, including pleocytosis, elevated CSF protein, or reactive CSF-VDRL (Venereal Disease Research Laboratory; the gold standard diagnostic test). The diagnosis of asymptomatic neurosyphilis is based upon the presence of CSF abnormalities alone. CSF white blood cell (WBC) concentration in neurosyphilis is generally > 10/uL with a lymphocytic predominance. Because CSF-VDRL may be nonreactive in neurosyphilis (sensitivity ~ 30–70%^9–11), a reactive CSF-VDRL establishes the diagnosis of neurosyphilis, but a nonreactive test does not exclude the diagnosis. Thus, in an HIV-infected person, the diagnosis of neurosyphilis may need to be based solely on identification of CSF pleocytosis. Because HIV itself can cause mild CSF pleocytosis,¹² diagnosing neurosyphilis in HIV-infected patients can be particularly challenging. We have typically used a cutoff of > 20 WBC/uL as diagnostic of neurosyphilis in HIV-infected individuals.¹³ A lower cutoff has been used by others,¹⁴ and is most appropriate when the peripheral blood CD4+ T cell concentration is low, in patients who are taking cART, and in those with undetectable plasma HIV RNA, because these lower the risk of HIV-related CSF pleocytosis.¹² Other tests that may aid in the diagnosis of asymptomatic neurosyphilis, but are not currently used clinically include (1) the proportion of CSF lymphocytes that are B cells,¹⁵ and (2) the CSF concentration of the chemokine, C-X-C motif ligand 13 (CXCL-13), which is a B-cell chemoattractant. Both are elevated in patients with neurosyphilis compared with patients with uncomplicated syphilis.^16,17

Several studies have examined predictors of abnormal CSF in neurologically asymptomatic and symptomatic patients with syphilis. The odds of neurosyphilis are higher when serum rapid plasma reagin (RPR) titers are ≥ 1:32, and when peripheral blood CD4+ T cells are ≤ 350/uL.^13,18,19 Also, HIV-infected patients with syphilis who are taking cART may be at lower risk of neurosyphilis compared with those not taking cART.¹⁴ A small, retrospective study suggested that high plasma HIV RNA concentration increased the risk of neurosyphilis among individuals with peripheral blood CD4+ T cells > 350/uL.²⁰

The recommended first-line treatment for neurosyphilis by the Centers for Disease Control and Prevention (CDC) is high-dose intravenous (IV) penicillin G (Table 1). An alternative treatment is intramuscular (IM) procaine penicillin G with oral probenecid (Table 1–²¹). Case reports^22–25 and a small study of HIV-infected patients with early neurosyphilis²⁶ suggest that ceftriaxone may be an acceptable alternative to penicillin (Table 1). Treatment for ocular and otosyphilis is identical to neurosyphilis treatment, although steroids are sometimes recommended as an adjunctive therapy.^27–31 The European³² and UK³³ syphilis guidelines recommend doxycycline 200 mg orally twice daily for 28 days as an alternative neurosyphilis treatment regimen for those patients who are allergic to penicillin or who refuse parenteral therapy. Currently, the CDC guidelines do not recommend doxycycline as an alternative treatment for neurosyphilis, but recommend penicillin desensitization for penicillin allergic patients in whom ceftriaxone is not an option.²¹ Patients with resolution or stabilization of neurologic signs and symptoms and normalization of CSF abnormalities are thought to be successfully treated for neurosyphilis. Careful follow-up after neurosyphilis therapy with repeat CSF testing every 3 to 6 months is mandatory for all patients. The CDC guidelines state that CSF WBC count should decline at 6 months and all CSF abnormalities should resolve by 2 years after treatment.²¹ Patients who fail to meet these criteria should be retreated.

Table 1.

Treatment for neurosyphilis

Recommended therapy (10–14 d)
Penicillin G	24 million units IV every d (continuous infusion or divided into 6 doses)
Alternative therapies (10–14 d)
Procaine penicillin G plus Probenecid	2.4 million units IM 500 mg PO qid
or
Ceftriaxone	1–2 g IV every d

Abbreviations: IM, intramuscularly; PO, by mouth; qid, 4 times a day

Neurorelapse is defined as development of neurosyphilis (including ocular or otologic syphilis) after appropriate treatment for early syphilis. Neurorelapse was recognized in the preantibiotic era and was more likely in patients who had received inadequate treatment for uncomplicated syphilis.³⁴ Syphilologists at the time theorized that partial treatment downregulated the host immune response, which, in combination with treatment that did not eradicate bacteria from the CNS, eye, or inner ear, predisposed to symptomatic neurologic disease. Several case reports document neurorelapse occurring in HIV-infected patients.^29,35–37 Neurorelapse may be more common in HIV-infected patients with syphilis because benzathine penicillin G, the usual treatment for uncomplicated syphilis, does not clear T. pallidum from the CNS, the eye or the inner ear^38,39 and HIV-induced cell-mediated immunity impairs clearance of organisms that persist at these sites.³⁵

HIV-infected individuals may be more likely than HIV-uninfected patients to fail neurosyphilis therapy based on clinical and serological criteria as well as on failure to normalize CSF abnormalities.^14,40–45 In a prospective analysis of 13 HIV-uninfected and 46 HIV-infected patients with neurosyphilis, those who were HIV-infected were 2.5 times less likely to normalize CSF-VDRL after therapy.⁴⁴ Among the HIV-infected subjects, those with peripheral blood CD4+ T cells ≤ 200/uL were 3.3 times less likely to normalize CSF-VDRL.⁴⁴ These data emphasize the need for diligent follow-up after treatment for neurosyphilis in HIV-infected individuals.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is caused by a polyoma virus, JC virus. The virus is very prevalent, with 70 to 90% of people acquiring it in childhood or adolescence.^46,47 Afterwards, the virus remains latent in the kidney and perhaps the brain, reactivating during immunosuppression, such as in HIV-infection.^48,49 Infection of oligodendrocytes results in demyelination and clinical disease.

The typical clinical presentation of PML is subacute onset of progressive focal neurological deficits (e.g., cognitive dysfunction, limb weakness, gait disturbance, incoordination and vision loss); one-third of patients have headache.⁵⁰ Less common manifestations of CNS JC infection include neuronopathy⁵¹ and JC infection of cortical pyramidal neurons causing an acute encephalopathy.⁵² Typically, HIV-infected patients with PML have peripheral blood CD4+ T cells < 200/uL.⁵⁰ In the cART era, individuals with PML and much higher or even near-normal peripheral blood CD4+ T cell concentrations have been reported.^53,54

With respect to neuroimaging, brain computed tomography (CT) in patients with PML may be normal. More often, it shows multiple, often confluent, white matter hypodense lesions that are most commonly located in the parietooccipital regions with little, if any, mass effect⁵⁰ (Fig. 1). Enhancement may be seen in 10% of CT scans and is usually faint and peripheral.⁵⁰ Brain magnetic resonance imaging (MRI) is more sensitive than CT in revealing PML lesions.⁵⁵ In contrast to white matter lesions seen in HIV-associated dementia, which are visible only on T2-weighted images, PML lesions are low intensity on T1-weighted and high intensity on T2-weighted images; restricted diffusion is observed⁵⁶ and ~ 15% of patients show faint contrast enhancement,⁵⁰ particularly in the setting of immune reconstitution (see section on immune reconstitution inflammatory syndrome).

Fig. 1.

Progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome in an human immunodeficiency virus-infected man. (A) Fluid attenuation inversion recovery images show focal increased signal in the right posterior frontal lobe. The area of abnormality did not enhance with contrast (not shown). (B) T1-weighted contrast enhanced images after antiretroviral therapy for 11 weeks shows new contrast enhancement. Courtesy of Christina M. Marra, MD.

Other diseases that should be considered in a patient suspected of having PML include varicella zoster encephalitis, which may also cause demyelination⁵⁷; substance abuse, particularly a form of heroin use called “chasing the dragon,” which can cause clinical and radiographic abnormalities similar to PML⁵⁸; and a severe form of HIV-associated leukoencephalopathy with patchy or confluent white matter high signal intensity seen on brain MRI that occurs in patients failing cART who have high levels of brain and CSF HIV RNA.⁵⁹ Leukoencephalopathy has also been described in individuals with CNS immune reconstitution^60–62 or CNS escape, in which patients have detectable CSF HIV RNA in the setting of controlled peripheral viremia⁶³; in these patients, CSF pleocytosis is observed, making PML less likely.

Recently published diagnostic criteria⁶⁴ indicate that patients with characteristic clinical and neuroimaging findings, characteristic histological examination or identification of JC virus DNA by polymerase chain reaction (PCR) in CSF have a confirmed diagnosis of PML. However, a negative CSF PCR does not exclude the diagnosis. A negative JC virus PCR is more likely to occur in patients receiving cART as well as those with higher peripheral blood CD4+ T cell concentrations.⁶⁵

There is no specific treatment for PML; however, treatment with cART has resulted in significantly improved survival.^66–68 All HIV-infected patients with PML should be treated with cART aimed at complete suppression of plasma HIV viremia. Whether certain types of antiretroviral regimens are more effective than others is not known. Two retrospective analyses suggest that a regimen that includes a protease inhibitor may be more effective than one that does not.^69,70 One multicenter, prospective, open-label trial of an individualized regimen of five antiretrovirals, including enfuvirtide for the first 6 months, in 28 HIV-infected patients with PML showed that the 1-year survival was 75%,⁷¹ significantly higher than expected.^71,72 Poorer outcome is associated with mass effect on MRI⁷³ and brainstem and cerebellar involvement,^74,75 while better outcome is associated with higher peripheral blood CD4+ T cell count at diagnosis,^{55,67,71,76–78} PML as the AIDS-defining illness,⁷⁷ lower concentration and decline in CSF JC virus DNA concentration during antiretroviral therapy,^{71,72,78–81} and the presence of JC virus-specific cytotoxic T cells in blood.^82–84 HIV-infected patients with PML who survive generally have persistent neurologic deficits, but may regain independence.^67,68,71,74

As a consequence of an immune reconstitution inflammatory syndrome (IRIS), PML may develop or worsen after beginning cART. In an observational study of 61 PML patients, 14 (23%) developed PML-IRIS.⁶⁶ Another case review reported that PML-IRIS developed 1 week to 26 months (median 7 months) after beginning cART, with a shorter latency, greater number of MRI-defined brain lesions and poorer outcome in those with known PML who worsened after beginning cART compared with those who developed PML after beginning cART.⁸⁵ Very low peripheral blood CD4+ T cells (< 50/uL) at the time of initiating cART significantly increases the risk of PML IRIS.⁸⁶ Histopathologic studies of 11 patients with PML-IRIS who underwent brain biopsy showed that PML-IRIS brain lesions are enriched in cytotoxic CD8+ T cells that engage JC virus-infected oligodendrocytes.⁸⁷ Despite differences in the outcome of patients with different manifestations of PML-IRIS described above, the prognosis of patients with PML IRIS may be similar to that of PML patients without IRIS.⁸⁶

While PML-IRIS that develops after beginning cART can be difficult to distinguish from progressive disease, the onset of clinical worsening in IRIS may be more acute. PML-IRIS can be benign or fatal,^85,88–90 and mayor may not respond to steroids, although these are commonly used.^85,91 The National Institutes of Health Guidelines for Prevention and Treatment of Opportunistic Infections⁹² recommend that empiric steroids may be used with clinical benefit: They suggest a 3- to 5-day course of IV methylprednisolone 1 g per day, followed by an oral prednisone taper (60 mg/d, tapered over 1–6 wk), although they note that the dosage and duration of steroids have not been established. Follow-up imaging with contrast-enhanced MRI at 2 to 6 weeks may be helpful in documenting resolution of inflammation and edema and to obtain a new baseline, but the clinical status of the patient is likely the best indicator of treatment efficacy. A single case of rapid improvement in PML-IRIS after treatment with the CCR5 inhibitor, maraviroc, but not with methylprednisolone, has been reported.⁹³ The authors speculated that blocking of CCR5+ leukocyte recruitment to the CNS might have been the underlying mechanism of improvement.

Primary CNS Lymphoma

The primary CNS lymphomas (PCNSL) that occur in HIV-infected patients are of B cell origin (diffuse large cell or immunoblastic⁹⁴); Epstein Barr virus (EBV) is detectable in virtually all of these tumors⁹⁴ and it is thought that immunosuppression as well as EBV-induced B cell stimulation leads to tumor development.⁹⁵ Historically, PCNSL occurred in 1 to 4% of HIV-infected patients, but with the widespread use of cART, the incidence of PCNSL has declined,^96,97 and survival has improved.^98,99

HIV-associated PCNSL occurs in patients with very low peripheral blood CD4+ T cell counts (< 50 cells/uL).¹⁰⁰ Patients present with confusion, lethargy, memory loss, hemiparesis, speech and language disorders, seizures, and cranial nerve palsies.^101,102 On brain imaging, PCNSL presents as ring or homogeneously enhancing lesion(s), often located periventricularly or in the frontal lobes, making it similar in appearance to toxoplasmosis and tuberculoma. PCNSL lesions may cross the midline in the corpus callosum and may be associated with patchy nodular ventricular enhancement.¹⁰³ Thallium (Tl)-201 SPECT may be helpful in distinguishing between CNS infections and PCNSL in HIV-infected individuals. Focal areas of increased Tl-201 uptake are seen in patients with lymphoma, while no brain uptake is seen in patients with CNS infections.^104,105 Delayed imaging and calculation of a retention index increase the specificity of the test.¹⁰⁵

Although the diagnosis of PCNSL can only be proven by histopathology, detection of EBV DNA by PCR in the CSF is sensitive and specific when it is used in the appropriate clinical setting¹⁰⁶ — an HIV-infected patient with a focal brain lesion with mass effect and enhancement. The positive predictive value of the test is highest in patients with a low likelihood of CNS toxoplasmosis, such as those who are Toxoplasma-seronegative or who have been taking trimethoprim-sulfamethoxazole for prophylaxis against toxoplasmosis.¹⁰⁶ When the test is used more broadly in clinical settings, the positive predictive value of detection of EBV DNA in CSF for diagnosis of PCNSL is lower.^107,108

HIV-associated PCNSL responds to steroids and to radiation therapy. In a retrospective analysis conducted before the availability of cART, median survival was 3 to 4 months with combination dexamethasone and radiation treatment, while untreated survival was only 3 to 4 weeks.¹⁰⁹ Most deaths were due to opportunistic infection.^101,102 More recent studies show that whole brain radiation therapy (at least 30 Gy)^98,110,111 and cART^98,111,112 improve survival, with the best survival seen in those who receive both modalities. Prolonged survival has also been reported in HIV-infected patients with PCNSL who received only cART.^113–115 Some clinicians have suggested that whole brain radiation should be reserved for patients who do not respond to cART because of the toxic side effects of radiation, including leukoencephalopathy. Other investigators have advocated for addition of anti-viral agents such as ganciclovir or foscarnet, because of the association of PCNSL with EBV.^116–121 Overall, the best treatment for HIV-associated primary CNS lymphoma is not known because no randomized trial has been thus far been conducted.

Toxoplasmosis

CNS toxoplasmosis in HIV-infected patients results from reactivation of latent infection by Toxoplasma gondii. It usually presents as one or more brain abscesses, and rarely, as meningoencephalitis. Toxoplasma gondii is an intracellular parasite that exists in three forms: (1) tachyzoites, replicating organisms that cause active disease; (2) bradyzooites, non-replicating organisms that are responsible for latent disease; and (3) oocysts, an infectious form that is shed in cat feces. Humans acquire infection by ingesting oocysts or by ingesting bradyzooites in undercooked meat. In 90% of immunocompetent individuals, the primary infection is asymptomatic; a minority of patients have a mononucleosis-like illness or regional lymphadenopathy.

CNS toxoplasmosis typically occurs in HIV-infected patients with CD4+ T cells < 200/uL. Patients who are not receiving trimethoprim-sulfamethoxazole prophylaxis, have detectable serum anti-Toxoplasma antibody (particularly if the titer is high), or are not receiving cART are at highest risk of developing CNS toxoplasmosis.^122–124 Approximately 80% of patients respond to therapy, but patients commonly have residual deficits and they are at increased risk for subsequent dementia.^125,126

Clinical manifestations of patients with CNS toxoplasmosis include headache, fever, hemiparesis, ataxia, change in level of consciousness and psychomotor retardation; ~ 30% of patients have seizures.¹²⁷ Almost all of HIV-infected patients with Toxoplasma encephalitis will have detectable serum anti-Toxoplasma IgG, but IgM is rarely detectable because the disease represents reactivation of a chronic infection.¹²⁸ Often, CSF examination is not helpful in establishing the diagnosis. On CT, there are round, isodense or hyperdense lesion(s) in the hemispheric gray–white junction, deep white matter, or basal ganglia. More than 90% of these lesions enhance with contrast in a ring, nodular, or homogenous pattern. MRI is more sensitive than CT and often identifies multiple lesions (Fig. 2).

Fig. 2.

Biopsy proven cerebral toxoplasmosis in an human immunodeficiency virus-infected patient. (A) Contrast enhanced T1-weighted image (left) and fluid attenuation inversion recovery image (right) at presentation. (B) Corresponding images 5 months after beginning treatment for toxoplasmosis. Courtesy of Christina M. Marra, MD.

For patients at high risk for CNS toxoplasmosis (see above), a presumptive diagnosis is made by response to a treatment trial. Diagnosis is established if clinical improvement occurs within 1 to 2 weeks and radiographic improvement within 2 to 3 weeks. Clinical providers should consider brain biopsy if there is no response to a treatment trial or for patients at low risk for CNS toxoplasmosis because, for example, they are Toxoplasma seronegative or have been taking trimethoprim-sulfamethoxazole or cART.

Treatment for cerebral toxoplasmosis occurs in two stages: primary therapy (≥ 6 wk) and chronic suppressive therapy (secondary prophylaxis continued until immune recovery occurs).⁹² Primary therapy consists of a combination of pyrimethamine, sulfadiazine and folinic acid (Table 2); chronic suppressive therapy consists of lower doses of these medications (Table 3). Clindamycin may be used in place of sulfadiazine in patients with a sulfa allergy (Tables 2, 3). For patients not already on cART, potent antiretroviral therapy is an important component of maintenance therapy. Immune reconstitution inflammatory syndrome is uncommon in HIV-infected patients treated for Toxoplasma encephalitis.¹²⁸ Secondary prophylaxis for Toxoplasma encephalitis can be discontinued in patients treated with cART who have a sustained increase in peripheral blood CD4+ T cells to > 200/uL for 3 to 6 months after completion of primary therapy. Some experts recommend repeat brain imaging before stopping secondary prophylaxis to confirm that Toxoplasma encephalitis is quiescent; in patients whose radiologic response to treatment is incomplete, a longer duration of primary therapy may be required.

Table 2.

Treatment for CNS toxoplasmosis in HIV

Primary Therapy (≥ 6wk)
Pyrimethamine plus	200 mg PO load, then 75 PO every d
Sulfadiazine or Clindamycin plus	1.5 g PO qid 600 mg PO or IV qid
Folinic acid (leucovorin)	10–50 mg PO per day

Abbreviations: CNS, central nervous system; HIV, human immunodeficiency virus; IV, intravenous; PO, by mouth; qid, 4 times a day.

Source: Table data from⁹².

Table 3.

Treatment for CNS toxoplasmosis in HIV

Chronic suppressive therapy or secondary prophylaxis (duration determined by response to cART)
Pyrimethamine plus	25–50 mg PO every d
Sulfadiazine or Clindamycin plus	1 g PO bid–qid 600 mg PO tid
Folinic acid (leucovorin)	10 – 50 mg PO every d

Abbreviations: bid, twice daily; cART, combination antiretroviral therapy; CNS, central nervous system; HIV, human immunodeficiency virus; IV, intravenous; PO, by mouth; qid, 4 times a day; tid, three times a day.

Source: Table data from⁹².