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A rare, opportunistic disease in a patient with AIDS

PML is a demyelinating disease that affects immunosuppressed patients. PML associated with AIDS is difficult to treat, and the prognosis for those afflicted is generally poor.

Meredith Cadorette, MMSc, PA-C

Meredith Cadorette practices in the emergency department at Piedmont Hospital, Atlanta, Georgia. She has indicated no relationships to disclose relating to the content of this article.

CASE

A 41-year-old African-American man presented to the hospital with slurred speech, left facial droop, and ataxia of 3 weeks’ duration. Serologic test results were positive for HIV-1 infection with a CD4⁺ cell count of 31 cells/mm³. The viral load was not determined at that time. Initial CT showed ill-defined, nonspecific lesions in the brain. MRI with fluid-attenuated inversion recovery and T2-weighted techniques demonstrated multiple areas of ill-defined, focal hyperintensities in the subcortical white matter of the right frontoparietal lobe, parasagittal left frontal region, right pons, and right middle cerebellar peduncle (see Figure 1). CSF examination with DNA amplification by polymerase chain reaction (PCR) for detection of JC virus was positive. A diagnosis of progressive multifocal leukoencephalopathy (PML) was established based on the radiographic and CSF findings. A highly active antiretroviral treatment (HAART) regimen with emtricitabine (200 mg daily), tenofovir (300 mg daily), and efavirenz (600 mg at bedtime) was initiated.

Three weeks after starting HAART, the patient’s condition deteriorated. He was readmitted to the hospital with worsening dysarthria and ataxia, as well as new-onset dysphagia, left upper and lower extremity weakness, and episodes of confusion. The patient denied any visual disturbances or seizures and said he had taken the antiretroviral medications as prescribed.

Vital signs were as follows: temperature, 97.2˚F heart rate, 84 beats per minute; respirations, 20 breaths per minute; and supine BP, 104/66 mm Hg. The patient was somnolent and dysarthric. Recent and remote memories were appropriate. Gross vision and extraocular movements were intact, and pupils were equal, round, and reactive. A left-sided facial droop was present. The uvula was midline, and the tongue deviated to the left with protrusion. Examination of the extremities revealed normal tone with 0/5 strength in the left upper extremity, 3/5 strength in the proximal left lower extremity, and 4/5 strength in the distal left lower extremity. Strength in the right upper and lower extremities was normal. The left bicep and brachioradialis reflexes were hyperreflexive. Evaluation of cerebellar function revealed right finger-to-nose dysmetria and poor heel-to-shin coordination in both lower extremities.

Repeat laboratory studies showed a CD4⁺ cell count of 43 cells/mm³ and a viral load of 3,551 copies/mL. HIV-1 genotypic resistance testing identified no resistance patterns. Compared to previous imaging studies, an additional MRI of the head showed interval worsening as demonstrated by more conspicuous white matter lesions that had increased in size. Minimal mass effect and cortical enhancement were noted. Stereotactic biopsies of the lesions were not performed.

The patient was evaluated and treated by specialists in infectious disease, neurology, speech therapy, and physical therapy. His condition stabilized, and he was discharged home on the same HAART regimen with close follow-up. His CD4⁺ cell count increased to 230 cells/mm³, and the viral load decreased to 826 copies/mL. Despite therapeutic efforts and evidence of partial recovery of his immune system, however, the patient died 14 weeks after the diagnoses of AIDS and PML were established. CT performed 1 week before death demonstrated extensive leukoencephalopathic changes without significant enhancement or mass effect (see Figure 2).

DISCUSSION

PML is a CNS disease that causes demyelination of white matter in the brain due to reactivation of the JC polyomavirus in the setting of immunosuppression. About 85% of PML cases are associated with HIV infection.¹ The disease is rapidly progressive, usually resulting in death within 6 months from the onset of symptoms. Although no consistently effective treatment is yet available, evidence is accumulating that patients with HIV-associated PML may derive some benefit from HAART.^2,3 Clinical improvement with such treatment is neither certain, nor predictable, however, and the immune system reconstitution seen after starting HAART may in fact be detrimental, as occurred with this patient.^4,5

Epidemiology and pathogenesis More than 80% of the adult population is estimated to have antibodies to JC virus.⁶ Seropositive conversion usually takes place during the first 14 years of life, and primary infection is thought to be minimally symptomatic.⁷ Despite this high prevalence, JC virus-induced disease is quite rare. PML was first identified in 1958 in patients with chronic lymphocytic leukemia and Hodgkin’s disease;⁸ not until 1971 was JC virus named as the causative agent.⁹ PML is considered an AIDS-defining disease and occurs in 1% to 4% of patients with AIDS.³ Activation of latent virus in the brain and other CNS tissues occurs in the setting of impaired immune response.

JC virus directly infects and destroys oligodendrocytes (which are myelin-producing cells), whereas axons and other tissues are generally spared. This loss of myelin usually results in multiple discrete foci that become patchy or confluent with the natural progression of disease. Involvement tends to be bilateral, asymmetric, and free of perivascular inflammation.¹⁰ Lesions preferentially occur in cerebral white matter, although cerebellar and brain stem involvement is not uncommon. Involvement of the gray matter and deeper structures of the brain may be seen in up to 17% of cases.¹¹ Rarely, PML affects the spinal cord.

Diagnosis Classic neurologic findings associated with PML include ataxia, hemiparesis, and altered mental status. A list of common symptoms can be found in Table 1. These symptoms may be the initial manifestation of PML and herald a diagnosis of AIDS, or they may occur after AIDS has already been diagnosed. Patients with advanced disease may exhibit profound neurologic deficits, including cortical blindness, quadriparesis, severe dementia, seizure, and coma.

Neuroimaging in patients with PML characteristically demonstrates multiple hypodense foci on CT and increased signal intensity on T2-weighted MR images. Typically, lesions are nonenhancing and do not exhibit mass effect or midline shift. Several cases of atypical, contrast-enhancing lesions associated with PML have been described in the literature. These unusual findings occur in patients after the initiation of HAART and are thought to be due to an inflammatory response accompanying immune restoration.^10,12,13 Enhancing lesions in this setting may signify a more benign course and favorable prognosis.

Definitive diagnosis of PML is obtained by stereotactic brain biopsy or histologic examination of brain tissue during autopsy. Cytopathic changes are observed in the myelin-producing oligodendrocytes. These changes include nuclear enlargement, the presence of intranuclear inclusions, and loss of normal chromatin patterns.¹⁴ Giant astrocytes with pleomorphic and hyperchromatic nuclei are also commonly seen. Lymphoplasmacytic infiltrates are often present in those patients receiving HAART who show evidence of immune reconstitution and have contrast-enhancing lesions seen on imaging studies.^12,13

PCR used to detect JC virus DNA in CSF is reported to have sensitivities ranging from 70% to 80% and a specificity greater than 99%.² Diagnosis is commonly made based on the presence of JC virus in CSF, a clinical picture and neuroimages consistent with the disease, and the elimination of other neurologic diagnoses. Disorders that may imitate PML are listed in Table 2. Note that the presence of atypical lesions on imaging or the absence of detectable JC virus DNA does not exclude a diagnosis of PML. Furthermore, these findings may necessitate a need for brain tissue sampling if a clear diagnosis cannot be made.

Treatment No known effective treatment or prevention exists for JC virus or AIDS-associated PML. Many studies have looked at HAART to determine if potent regimens of antiretroviral medications can affect patient survival or disease status. Since the introduction of HAART, the overall outcome in patients with AIDS-associated PML has improved; however, its incidence remains unchanged.¹⁰

Multiple studies demonstrate increased survival among patients on HAART regimens that include a protease inhibitor.^2,3,15 Patients receiving such treatment experienced improvement of clinical symptoms or an unusually slow progression of their disease. Case reports of prolonged survival beyond 2.5 years have been documented.¹⁰ Clearance of JC virus DNA and improvement in other viral markers in CSF can occur after 4 months of treatment with HAART and correspond to an improvement in neurologic symptoms.² The exact mechanism by which patients with PML improve clinically on HAART is not known. It is also not clear as to the type and extent of immune restoration necessary to achieve immunocompetence.¹²

Although clinical status often improves with immune recovery, a paradoxical worsening of PML characterized by uncontrolled immune-inflammatory responses may develop after the initiation of HAART. This type of inflammatory PML typically begins 4 weeks, and peaks 12 weeks, after the start of treatment and can lead to rapidly worsening disease and death.^5,12 This reaction is often accompanied by enhancing lesions on imaging, which are suggestive of perivascular inflammation, along with evidence of inflammatory changes on brain biopsy. Reports of PML that developed only after HAART was started are rare.¹³

The general prognosis for patients with AIDS-associated PML is grave and unpredictable. Possible indicators of a more favorable outcome include younger age, the presence of enhancing lesions, and a higher CD4⁺ cell count at the time PML is diagnosed.^2,12 Only those patients that exhibited mass effect on MRI had an increased risk of death.¹¹

CONCLUSION

PML is a fatal opportunistic infection that occurs in the setting of severe immunosuppression. Although outcomes are variable and often unpredictable, the goal of treatment is restoring immune function. This case demonstrates, however, that even when immune recovery with HAART occurs, unfavorable clinical outcomes and death may still ensue. The timing of this patient’s deterioration and the improvement in virologic markers are consistent with paradoxical worsening associated with immune reconstitution, but the absence of inflammatory changes on CT may point to the natural progression of the disease.

REFERENCES

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