Progressive Multifocal Leukoencephalopathy

Etiology

JC virus is a DNA virus of the polyomaviridae family. The virus remains latent in most immunocompetent hosts and rarely presents pathologically. In immunosuppressed hosts, however, a combination of poor cellular response of the host along with reactivation of the virus secondary to recombination of genes results in active disease. 

Progressive multifocal leukoencephalopathy can occur in the context of immune reconstitution syndrome. In AIDS patients on antiretroviral therapy who present with focal neurological deficits or altered mental status along with non-contrast enhancing lesions, a diagnosis of PML IRIS ought to be considered. This condition can present from 1 week to 26 months after the initiation of HAART.[3]

PML has been known to occur following treatment with monoclonal antibodies, specifically natalizumab, rituximab, efalizumab, and eculizumab.[4][5][6] These drugs are used to treat autoimmune conditions such as multiple sclerosis, Crohn's disease, psoriasis, and lupus. Clinicians should be keen to notice new-onset neurological dysfunction in patients on these drugs. Natalizumab, in particular, is recommended as monotherapy for MS as combined immunosuppressive therapy is associated with an increased risk of PML in these patients. Furthermore, the increased frequency of natalizumab infusions increases the likelihood of PML occurrence.

Epidemiology

Most cases of progressive multifocal leukoencephalopathy occur as a reactivation of latent JC virus infection. PML is symptomatic in patients who are severely immunocompromised, such as HIV-AIDS patients, particularly those with a CD4 count of less than 200, organ transplant recipients, those with hematological malignancies, and of late those who undergo treatment with monoclonal antibodies such as natalizumab. After the initiation of antiretroviral therapy, in contrast to the expected decline in the incidence of PML, a rise and a deterioration in existing cases have been noticed secondary to immune reconstitution after antiretroviral treatment.[7]

Pathophysiology

Rearrangement of gene sequences in the DNA of JC viruses is essential for the reactivation of these latent forms, particularly in immunocompromised states.[8] Host response plays a crucial role in the clearance of the virus.[9] There is intense perivascular infiltration of immune cells, HIV antigens, and viral proteins resulting in demyelination. The cellular immune response is a key component in the defense mechanism, particularly the cytotoxic T lymphocytes. Cytotoxic T lymphocytes have been found to be elevated in CSF samples of patients who cleared the virus resulting in inactive disease.[10] 

Due to a failing cellular response in conditions such as AIDS, such patients are more prone to this demyelinating disease. The focus of latent infection begins in the oligodendrocytes of the CNS and results in a lytic infection upon reactivation that destroys the myelin it produces. This severe demyelinating leukoencephalopathy commonly presents as white matter lesions in the CNS.

History and Physical

The evaluation of new-onset neurological symptoms in a patient with suspected or confirmed immunosuppression should include progressive multifocal leukoencephalopathy as part of the differential diagnosis.[11] These patients may present with altered mental status or an abnormal neurological examination and need to be evaluated. 

In AIDS patients, the degree of immunosuppression, as evidenced by the CD4 count, is an indicator of the possible etiology underlying the abnormal neurological presentation. PML enters the differential when the CD4 count is less than 200. However, it may present even at levels above 200.[12]

The neurologic deficits that manifest correlate with the area of white matter demyelination. The presentation of PML includes progressive, multifocal, subacute focal neurological deficits that vary depending on the site of the lesion and include a spectrum of presentations including cognitive impairment, limb ataxia, gait ataxia, hemiparesis, hemianopia, and aphasia. Areas commonly involved include the subcortical white matter, periventricular areas, and cerebellar peduncles. In most cases, the optic nerve and the spinal cord are unaffected.

Evaluation

Routine blood counts and HIV PCR testing are indicated to identify the cause of the immunosuppressed state that led to the reactivation of the JC virus. The evaluation of abnormal neurological findings in immunosuppressed patients, such as those with AIDS, begins with radiological imaging. Contrast-enhanced imaging with either CT or MRI aids the clinician in determining the presence of inflammatory change and mass effect. These findings are absent in PML, and their presence would point towards an alternative diagnosis such as toxoplasma encephalitis or primary CNS lymphoma.[13]

PML appears as hypodense confluent lesions on a CT without mass effect, contrast enhancement, or risks of herniation. On an MRI, they appear as areas of a decreased signal on T1 weighted images. MRI with contrast reveals hyperintense lesions on T2 weighted images, particularly in the subcortical lesions, periventricular areas, and lesions limited to the cerebellum.

In PML-IRIS, patients present with worsening neurological status after initiating ART, or after reducing immunosuppressive therapy, inflammatory changes follow and would reveal contrast enhancement, edema, and mass effect on MRI imaging.[3] Similiar MRI findings are noticed in patients who develop PML following natalizumab therapy.[14] 

CSF JCV DNA isolation with PCR confirms the diagnosis of PML.[11] In PML-IRIS, CSF DNA for JCV may be negative due to competent immune system defenses with the ability to counter viral replication such that it becomes undetectable on a viral assay.

Treatment / Management

Currently, effective treatment for the complete cure for progressive multifocal leukoencephalopathy has not been found. Although drugs such as cidofovir, cytarabine, and mefloquine have been investigated, they have not shown to be clinically beneficial in the treatment of PML.[15][16][17](A1)

At present, treatment is guided by efforts made to boost the adaptive immune response, and the methods to achieve this goal varies depending on the clinical setting.

In HIV patients, prompt initiation of HAART is advised. In transplant patients, the use of multiple immunosuppressive therapies may be limited while weighing the risks of graft rejection. In PML induced by natalizumab use, cessation of therapy and resorting to plasma exchange therapy as a means of treatment have been advised.[14](B2)

Certain studies have explored the benefits of bolstering the adaptive immune response using dendritic cell vaccines.[18] Dendritic cells mounted with JC antigens can generate a significant CD8 response, which has demonstrated prolonged survival in PML patients. These studies were done on three PML patients, and hence there remains a need for further studies with a larger group to warrant the use of these agents. 

With regard to the treatment of PML IRIS, improvement in neurological status has been observed with the cessation of ART therapy. Certain studies have shown favorable outcomes with steroid treatment.[3] However, cessation of antiretroviral therapy may increase the viral load and lead to antiretroviral resistance. PML IRIS carries a significant risk for mass effect and herniation, and hence glucocorticoids can be utilized in the event of such complications to counter the damage caused by immune reconstitution.(B3)

Differential Diagnosis

While considering the differentials for an abnormal neurological evaluation in an immunosuppressed patient, the possibilities include toxoplasma encephalitis, primary CNS lymphoma, PML, HIV encephalopathy, and CMV encephalitis. From a clinical perspective, PML can present as focal neurological deficits in sensory, motor, or visual parameters. Hence this presentation is similar to that of Toxoplasma and primary CNS lymphoma and requires differentiation by radiological means.[12] Although the presentation mimics that of PML, radiologically PML is asymmetric, well-demarcated, and non-contrast-enhancing without a mass effect, whereas both Toxoplasma and PCNL present as contrast-enhancing lesions. Furthermore, the CSF examination in the case of PCNL could show positive results for the Epstein Barr virus.

Noncontrast-enhancing lesions are seen in PML, CMV encephalitis, and HIV encephalopathy. Therefore, these conditions need to be differentiated from one another.

HIV encephalopathy commonly presents as cognitive deficits and does not show signs of focal neurological deficits. Furthermore, the radiological assessment would reveal symmetric, poorly demarcated lesions. HIV encephalopathy would also show evidence of positive HIV viral load on the CSF examination.

CMV encephalitis is a differential to be considered. Its presentation mimics that of PML, and non-contrast enhancing lesions are noted on the MRI. However, the radiological appearance differs from PML. MRI imaging reveals multifocal diffuse micronodules in the cortex, basal ganglia, brainstem, and cerebellum.[19]

Recurrence of multiple sclerosis in patients on natalizumab therapy for MS requires differentiation from PML. As both diseases are demyelinating processes, clinical signs and symptoms can overlap, and it may prove to be difficult to distinguish between the two disease entities. However, radio imaging is distinctly different and can be useful in identifying natalizumab-induced PML. PML lesions are larger, hyperintense, and unifocal as compared to the multifocal, hypointense nature of typical MS lesions.

Prognosis

PML is a progressive and fatal disease. At present, the primary goal of treatment is to improve the chances of survival. Factors that improve survival rates include a low viral load of JC virus in PCR CSF samples, high CD4 count, and contrast enhancement on radiological imaging. Furthermore, in patients with AIDS, initiation of antiretroviral therapy has been known to improve survival rates. A robust adaptive cellular immune response is a good indicator of prolonged survival as evidenced by the presence of PML specific CTL lymphocytes in the serum of patients who have recovered from PML. Among transplant recipients who develop PML, it was found that those that underwent hematopoietic stem cell transplantation fared better with lower mortality rates and higher survival rates over patients who had undergone solid organ transplantation.

With respect to patients who develop natalizumab-induced PML, improved survival rates were noticed in patients with certain prognostic factors, which include younger age, low JC viral load, reduced neurological dysfunction prior to initiation of therapy, and an enhanced mass on contrast imaging.

In patients who develop PML-IRIS following antiretroviral therapy, administration of steroids and contrast-enhancing MRI imaging were good prognostic indicators for survival.[3]

Complications

PML is a severe, progressive, multifocal, demyelinating disease, and it is fatal in most cases. Present therapy is directed at prolonging survival rates. Remyelination does not occur, and patients can develop complications in the long term. These are primarily neurological and include cognitive impairment, sensory deficits, motor deficits, and disturbances in coordination.[1]