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Natalizumab-associated JCV reactivation can cause both PML and possibly JCV granule cell neuronopathy.
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Natalizumab acts in several ways to increases PML risk.
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There are limitations in our understanding of PML risk, particularly in the JCV seronegative population.
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Imaging features can help distinguish MS PML and PML-IRIS.
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The goal of therapy in PML is reinstatement of immunocompetence.
Abstract
The natural history and clinical import of Progressive Multifocal Leukoencephalopathy has changed enormously in the last thirty years. After a resurgence of PML during the HIV/AIDS epidemic, advances in the treatment of multiple sclerosis created another group of ‘at risk’ patients. With a focus on issues pertaining to the multiple sclerosis patient population, this review covers pathophysiology of the JC virus, causes of PML, mechanisms by which natalizumab increases the risk of PML, determinants of PML risk in natalizumab-treated patients, risks of natalizumab discontinuation, PML prevention and surveillance, PML imaging features, PML diagnosis and stumbling blocks to making the diagnosis, PML and PML-Immune Reconstitution Inflammatory Syndrome (IRIS) treatment.
Progressive Multifocal Leukoencephalopathy (PML) is a potentially fatal or disabling infection of the brain by the JC virus that almost always occurs in the setting of immunosuppression. In the past three decades, PML has taken on new importance in the era of HIV/AIDS and monoclonal antibodies used in the treatment of multiple sclerosis (MS) and autoimmune conditions, such as rheumatoid arthritis.
PML has particularly impacted the field of multiple sclerosis where 418 cases have been observed among 120,500 patients treated with natalizumab through November 2013 (
). This humanized monoclonal antibody is effective in MS due to its ability to inhibit alpha-4 beta-1 integrin, preventing transmigration of lymphocytes across the blood brain barrier. Balancing the therapeutic efficacy of natalizumab with the risk of PML has become an issue of great importance for patients and clinicians alike.
As the nature of immunosuppression causing PML has changed, so too has the diagnosis and management of PML. Furthermore, the nature of immunosuppression underlying PML determines prognosis, treatment and emergence of PML-related immune reconstitution inflammatory syndrome (PML-IRIS). As there is no established anti-viral treatment, PML-related care is directed at re-institution of immunocompetence.
This review will cover the biology of the JC Virus, etiologies of PML, PML diagnosis, PML-IRIS, PML management with a focus on issues pertaining to the multiple sclerosis patient population.
2. Pathophysiology
The etiologic agent, the John Cunningham virus (JCV) is a ubiquitous polyoma virus that exclusively infects humans (
). The enclosed circular genome is comprised of coding (90% of genome) and regulatory regions (10% of genome) that are encoded counterclockwise and clockwise, respectively. Tissue tropism of the virus is determined largely by the hypervariable non-coding control region (regulatory region) while the genomic regions coding for regulatory and structural proteins are largely conserved (
). JCV found in the brain of patients with PML is referred to as the “prototype” virus and differs from the ubiquitous “archetype” virus due to insertions, deletions, re-arrangements, and importantly, tandem repeats in the regulatory region of the virus. PML occurs when JCV is unchecked by cellular immunity, reactivates, and migrates to the CNS where it infects glial cells. Neurotropism of JCV is not limited to glial cells as JCV can cause a fulminant JCV encephalopathy of cortical pyramidal neurons (
), which if confirmed by other groups could represent a second natalizumb-related JCV syndrome in the MS patient population.
Primary exposure to the JC virus occurs asymptomatically in childhood or adolescence, but serological studies indicate that it may also occur in adulthood (
). Thereafter, JCV can be found latent in the kidneys, bone marrow, lymphoid tissue, and other tissues. In a case series of bone marrow specimens, JCV DNA and proteins were more commonly detected in HIV-seropositive than seronegative patients (
Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation.
). Whether JCV is latent in brain tissue of healthy controls remains controversial, but one study of brain banked tissue from healthy controls showed that 5/19 brains harbored JCV DNA (
). JCV seropositivity increased with age: 49.5% seropositive if younger than 30 years old and 66% if 60 years or older. There was regional variation in JCV seropositivity ranging from 47.4% in Norway to 67.7% in Turkey. JC viremia is infrequently demonstrated, but occasional studies have observed a high prevalence in both healthy controls and untreated MS patients (
). In the same study, JC viremia was detected in plasma of 17% of patients with PML and 12% of disease matched controls. After primary exposure, the virus can be intermittently excreted in the urine. JC viruria has been demonstrated in 10–40% of adults (
). The rarity of PML despite the widespread prevalence of JCV infection in the world׳s population implies that there are multiple barriers to the development of the disease. The most common observation is that altered cell-mediated immune dysfunction is a significant predisposing factor for the development of PML.
Insights into immune clearance of PML can be gained from neuropathologic studies of PML-IRIS of both HIV-AIDS associated PML-IRIS (
). Typically, there is an intensely inflammatory cellular infiltrate with a preponderance of CD8+ T cells aggregating around infected oligodendrocytes accompanied by CD 20+ B Cells and CD138+ plasma cells. JCV-specific CD8+ T cells are known to play a critical role in JCV suppression and prevention of PML (
). In contrast, antibody-mediated immunity seems not to protect against PML as patients with high JCV index are not protected from PML, in fact, the opposite seems to be the case (
)) commonly include cognitive and behavioral abnormalities, motor weakness, gait abnormalities and incoordination, sensory loss, visual deficits, headache and seizures.
3. Causes of PML and prognosis
Immunosuppression is a requisite antecedent for PML. In some patients with no immediate risk factor for PML, idiopathic CD4 T-cell lymphopenia has been described (
). In one study of the US Nationwide Inpatient Sample database, 9113 patients with PML had a clear risk factor (HIV – 82%, hematologic malignancy – 8.4%, solid malignancy – 2.83%, SLE – 0.44%, rheumatoid arthritis – 0.25%) (
). There were 4 cases of PML per 100,000 SLE patients as compared with 0.4 cases of PML per 100,000 RA patients. Interestingly, 28% of SLE patients with PML had received minimal or no immunosuppressive therapy. PML is a known complication of solid organ and bone marrow transplantation. In one series combining 54 published case reports and 15PML cases from a multicenter retrospective cohort, the risk of PML at one institution was 1.24 per 1,000 post-transplantation person-years (95% CI, 0.25–3.61) (
PML is an AIDS-defining illness that has become less common in the era of antiretroviral therapy. In the EuroSIDA cohort, before antiretroviral therapy, the incidence of PML was 0.7/100 person year of follow up, whereas, it fell afterward to 0.07/100 person year of follow up (
), though not all studies have demonstrated a significant reduction in PML incidence with the advent of effective antiretroviral therapy. Prognosis in the pre-antiretroviral era was abysmal with 10% 1 year survival (
Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA).
). In HIV-associated PML, patients whose CD4 count was <100 cells/microL had an odds ratio of death of 2.71 (95% confidence interval, 1.19–6.15) when compared to patients with CD4 counts >100 cells/microL (
In multiple sclerosis, PML has been observed in association with natalizumab, an alpha-4 beta-1 integrin blocking human IgG monoclonal antibody. The first case reports of PML with MS (
) were unanticipated as patients had demonstrated no other evidence of immunsuppression. The PML cases prompted a voluntary suspension of natalizumab in February 2005, months after it was made available to patients. Natalizumab was re-approved by the FDA in June 2006 and is administered under the TOUCH program, a centralized registry of all patients treated with natalizumab that tracks adverse events. Natalizumab remains the most effective MS agent for relapse reduction but its use is limited by concerns of PML.
4. Mechanisms by which natalizumab potentiates PML
Natalizumab treatment has been shown to foster conditions that would promote PML. First, natalizumab precludes effective CNS immunosurveillance by JCV-specific T cells by blocking alpha 4 beta 1 integrin. The administration of natalizumab leads to changes in CSF CD4/8 ratios that parallel those seen in HIV infection for up to 6 months (
). A recent study demonstrated that RRMS patients treated with natalizumab had not only reduced CSF T cell numbers, but also reduced T-cell receptor heterogeneity compared to other RRMS patients not treated with natalizumab (
). In a series of brain biopsied patients, samples associated with PML were accompanied by a reduction in CD209+ dendritic cells which express MHC class II and contribute to activation and retention of T cells in peripheral tissues (
Secondly, natalizumab may increase the peripheral expression of JCV and increase the likelihood of the emergence of the neurotropic prototype virus. In one study of 19 MS patients treated with natalizumab, JC viruria increased significantly from 19% of samples to 63% after 12 months and then JCV DNA was detectable in 3/15 plasma samples, and 9/15 peripheral-blood mononuclear cells (60%) (
). This was accompanied by a drop in JCV-specific immunity over 6–12 months as measured by JCV-specific IFN-gamma producing peripheral blood mononuclear cells. Interestingly, the regulatory region sequences found in patient serum samples was similar to those found in PML lesions. Another cross-sectional study of natalizumab-treated MS patients demonstrated that JCV-specific effector T memory cell responses increased with duration of therapy (
), which might suggest ongoing JCV replication in a subset of patients. In another 30 month longitudinal study of 50 RRMS patients treated with natalizumab (
), blood samples demonstrated increased marginal zone B cells. These cells are typically found in the spleen and are susceptible to JCV infection. Natalizumab-related redistribution of marginal zone premature B cells to the circulation harboring JCV could contribute to the development of PML. During the maturation process of these cells, transcriptional factors may transactivate JCV, increasing replication and enhancing the probability that the prototype virus will appear.
5. Determinants of PML risk in natalizumab-treated MS patients
Industry-sponsored data support a model of PML risk that is impacted by duration of treatment, history of previous immunosuppression, and JCV serology (see Fig. 1) (
). When combining safety data from clinical trials and post-marketing studies, the incidence of PML in the first year is low enough (4/99,571 or 0.04/1000) that some practitioners will treat patients for a year even without checking a JCV serology if warranted. From first year to the second year, the incidence rises to 37/65,981, or 0.56/1000. Afterward, PML risk plateaus, which suggests that there may be a vulnerable population. The PML risk is also determined by the history of prior immunosuppressive therapy, such as mitoxantrone, methotrexate, cyclophosphamide and mycophenolate mofetil. It is unclear whether this data applies to patients treated with other agents such as fingolimod and rituximab. This uncertainty should be taken into account when offering natalizumab to patients previously treated with these agents, particularly if the patient is JCV seropositive (Fig. 2).
Fig. 1PML risk by JCV serologic status, treatment duration and history of prior immunosuppression. Reproduced with permission from “PML Incidence in Patients Receiving TYSABRI” available at medinfo.biogenidec.com from October 2013 update.
Fig. 2Multiple sclerosis patient MRI showing extensive and confluent T2 FLAIR lesions (A) with an acute lesion in the left frontal periventricular white matter demonstrating restricted diffusion (B), absence of T1 hypointensity and well-circumscribed gadolinium enhancement (D).
), rather than detect for primary exposure. The ELISA test detects antibodies responding to the JCV׳s Viral-Like Peptides (VLP) in a first step. For patients with an indeterminate result, a confirmatory test using JCV VLPs to pre-adsorb JCV-specific antibodies demonstrates specificity. The false negative rate of the test was determined in patients with positive urinary JCV DNA PCR and was thought to be 2.5%. While there were no reported cases of JCV sero-negative patients developing PML at the time of publication of Bloomgren׳s data (
), there have been two subsequent cases of PML in patients with negative JCV serology eight and nine months prior to PML diagnosis. This important event prompted a label change of natalizumab requiring JCV serologic testing every six months.
The false negative rate of the JCV serologic test has come into question when two separate case series suggested that the false negative rate of JCV serology could be as high as 37% (
). Theoretically, even a handful of additional occurrences of PML in JCV seronegative natalizumab-associated patients could prompt the MS community to re-think this risk paradigm (
). For the time being, one must remember that JCV seropositive patients accounted for 186 of 188 cases of natalizumab-associated PML where JCV serologic data was available (
). Additional evidence that JCV serology functions to predict PML risk is that among JCV seropositive patients, a low JCV index (<0.9) was associated with a substantially reduced risk of PML (
). This data has not yet been published in a peer reviewed journal, but does suggest that there is a continuum of PML risk that is predicted by JCV index, at least in the JCV seropositive range.
These uncertainties reflect a major limitation of JCV serologic testing which is that there is no gold-standard of JCV primary exposure against which to determine the test׳s sensitivity and specificity. While the current methodology of JCV serology may not capture all individuals harboring latent or persistent JCV, the 2 step ELISA does appear to be a very good study for predicting the risk of developing PML.
Many groups are working to enhance PML risk prediction. Adding serum and urinary JCV DNA PCR to JCV serology did not enhance prediction of PML in one study of natalizumab-treated MS patients (
), but this has yet to be validated independently. One group did not find statistically significant enrichment of PML by blood type, although there was a trend for greater risk of PML with Type O blood, whereas type A appeared to be slightly protective of PML (
While there is a great deal of concern about PML risk with natalizumab, this review would be incomplete without reviewing the potential risk of MS re-activation following natalizumab withdrawal. The mean natalizumab half-life in MS patients is 11 days and pharmacokinetics vary with age, gender, weight and presence of anti-natalizumab antibodies (
. Natalizumab discontinuation data from pivotal clinical trials and safety extension studies demonstrate a return of disease activity between 2 and 6 months with a substantial number of patients developing new gadolinium-enhancing lesions by 6 months (
), 65% of patients suffered a relapse during the washout period. In the analysis, the single factor that correlated with suffering an attack was length of the washout period. After natalizumab discontinuation, some groups offer three doses of intravenous methylprednisolone 1 g monthly to bridge a patient to the subsequent therapy.
7. PML risk with other MS treatments
Other treatments for multiple sclerosis, such as fingolimod and rituximab, do not carry the same risk of PML. In approximately 71,000 fingolimod-treated patients, there are two reported cases of PML. One occurred in a patient previously treated with natalizumab. The second case was recently reported by Novartis and is under investigation (
). While data of PML risk in rituximab-treated MS patients is sparse, but there are six reported cases in 147,862 exposed rheumatoid arthritis patients (
), although it is unclear whether this risk would apply to the MS patient population. Furthermore, these patients had Sjogren׳s and PML risk factors, such as lymphopenia and exposure to immunosuppression (
One new multiple sclerosis agent, dimethyl fumarate (Tecfidera), is a component of Fumaderm, an oral medication used for psoriasis in Europe. Fumaderm or similar compounded agents have been associated with a few reported cases of PML in patients with a history of other immunsuppressant use (
); however, it has also been observed in a patient treated for MS who developed lymphopenia while on the drug and whose only other medication was intravenous methylprednisolone (
). A wealth of post-marketing safety data will be available in the coming years as many patients have started dimethyl fumarate since its approval.
8. PML prevention and surveillance
The optimal PML mitigation strategy is prevention and appropriate surveillance. Many clinicians would not recommend natalizumab treatment in patients who have been JCV seropositive at any point; however, as previously stated, the risk of developing PML within the first 12 months of natalizumab initiation is rather low (
). Natalizumab-treated patients must have JCV serology at least every six months and in the event of seroconversion, one must strongly consider a change in therapy.
In clinical practice, JCV seropositivity does not lead inexorably to natalizumab discontinuation. In an observational study, JCV seropositivity did not consistently result in natalizumab discontinuation (
). Patients in another observational study who were JCV seropositive had increased anxiety as measured by the Hospital Anxiety and Depression Scale, but only 3% of these patients had changed therapy (
). Thus, some patients with demonstrable concern about their predicament elect to remain on natalizumab despite an increased risk of PML.
For patients who elect to receive natalizumab while JCV seropositive, we recommend frequent MRIs especially when accompanied by another PML risk factor (treatment duration greater than two years or prior immunosuppression). Semiannual MRI is one strategy, although some centers are trying to establish a yearly standard MRI supplemented by a limited MRI every 4 months (Axial T2, Axial and Sagital T2 Flair, DWI/ADC, Sagital T1) without contrast. Neuroradiology must be specifically asked to entertain the diagnosis of PML in high-risk natalizumab-treated patients.
9. Imaging features of PML
While both MS and PML cause white matter lesions, some imaging features suggest PML or PML-IRIS rather than multiple sclerosis (Table 1). PML lesions tend to be greater than 3 cm, T2 bright, peripheral, subcortical, confluent with distinct borders next to gray matter and indistinct borders next to white matter (Fig. 3), and exhibit no mass effect (
). Some reports indicate that these lesions are much more prominent on DWI imaging due to T2 “shine through.” There is commonly T1 hypointensity and sometimes some microcystic changes. At clinical presentation, 41% of natalizumab-PML lesions have some hazy peripheral and sometimes punctate or nodular enhancement. When mass effect and enhancement are more prominent, one should be suspicious for PML-IRIS, particularly when accompanied by a clinical deterioration. These features should be contrasted with classic features of MS lesions, which are rounded well circumscribed periventricularT2 lesions, frequently associated with open-ring enhancement with minimal mass effect.
Table 1Imaging features of MS, PML and PML-IRIS.
MS
PML
PML-IRIS
Size (T2 FLAIR)
<3 cm
Size <3 cm does not exclude PML
Depends on extent of PML
Location (T2 FLAIR)
Periventricular, juxtacortical, infratentorial
Subcortical at gray-white junction, peripheral, occasionally infratentorial
Similar to PML, can involve deep gray structures
Shape (T2 FLAIR and T2)
Rounded
Amorphous, following white matter tracts
Mass effect
Mild
None
Significant
Borders (T2 Flair and T2)
Well circumscribed (see Figure)
Ill-demarcated in white matter but well-defined next to gray matter (see Figure)
T1 Sequence
May be T1 hypointense, usually well-demarcated
Patchy T1 hypointensity
Rim of intrinsic T1 hyperintensity sometimes present
Contrast Enhancement
Well-defined borders, open ring enhancement
Variable within lesions, speckled or nodular patterns
More pronounced than with PML
Diffusion Sequences
Sometimes ADC hypointense with DWI hyperintensity
DWI bright due to T2 “shine through” – can help PML lesions stand out when surrounded by chronic MS lesions
Evolution
Variable
Rapid enlargement and extension along white matter tracts
Fig. 3PML patient scan with bifrontal but left greater than right T2 FLAIR lesions (A) that are more prominent on DWI due to T2 “shine through” (B) with T1 hypointensity (C) and no appreciable gadolinium enhancement (D). The smaller lesion in the right frontal white matter is an excellent example of an early PML lesion with ill-defined borders (A) and T2 “shine through” on DWI (B).
In natalizumab-associated PML, imaging features can be associated with prognosis. Widespread disease at diagnosis is present in 71% of fatal cases, whereas unilobar and multilobar lesions are present in 85% of survivors (
). The average age of survivors was 40, as compared to non-survivors whose mean age was 50. Asymptomatic cases of PML found on screening MRI have been associated with good clinical outcomes (
Presymptomatic diagnosis with MRI and adequate treatment ameliorate the outcome after natalizumab-associated progressive multifocal leukoencephalopathy.
) and in one abstract comparing 21 clinically asymptomatic PML cases to 298 symptomatic PML cases, asymptomatic patients had better survival and disability outcomes than symptomatic individuals (
Natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients: survival and functional outcome when asymptomatic at diagnosis.
Common features of reported cases of natalizumab-associated PML underscore the need for a systematic approach in pursuing a diagnosis of PML. PML diagnosis can be delayed due to misattribution of new neurologic symptoms or new MRI lesions to MS (
). These cases show that prospectively distinguishing PML from new MS lesions is particularly challenging especially when PML is early and lesions are less than 3 cm. Judicious evaluation of new T2 lesions is warranted.
Atypical presentations of PML represent another impediment to PML diagnosis, such as, clinically silent PML (
). PML of the spinal cord has been observed pathologically, but is exceedingly rare and has never been reported with recognized myelopathic clinical features, and have only been seen in the setting of AIDS (
) on diagnostic criteria for PML utilized clinical features, imaging features and CSF PCR for JC Virus as different criteria to make a determination of “definite, probable, possible” PML or “not PML.” The authors propose an algorithm (Fig. 4) for diagnosing PML that starts with an MRI, which if suggestive of PML should prompt a lumbar puncture and CSF JCV PCR using an ultrasensitive assay. If positive, definite PML can be diagnosed. With negative CSF JCV PCR, workup for other disorders (vasculitis, posterior reversible encephalopathy syndrome (PRES), varicella zoster virus (VZV) vasculitis, leukoencephalopathy, malignancy, etc.) should be accompanied by a repeat CSF JCV PCR as in reported cases, two or more CSF JCV PCR tests were falsely negative (Kuhle, Gosert, 2011,
). If workup is unrevealing, brain biopsy with immunohistochemistry or in situ hybridization for the virus is recommended. Bearing in mind important caveats such as sampling error, PML diagnosis can be made or excluded using neuropathologic features such as the classic histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with immunohistochemistry or electron microscopy and tissue PCR for JCV. Making a diagnosis of natalizumab-related PML in MS patients is confounded by presence of inflammation and demyelination in both conditions. Even in the absence of CNS demyelinating disease, white matter lesions of PML can be attributed to another entity. One of the two cases of natalizumab-associated PML in the setting of inflammatory bowel disease was first diagnosed as an astrocytoma after a brain biopsy showed atypical nuclei, microglial proliferation (
Fig. 4This T2 image from a patient with left frontoparietal PML is an excellent example of how PML lesions have poorly-defined borders toward white matter, in contrast to the well-delineated border to gray matter.
Fig. 5Diagnostic Schema for PML and JCV Granule Cell Neuronopathy, used with permission and adapted to inculde JCV Granule Cell Neuronopathy. ⁎Ultrasensitive CSF JCV PCR techniques should be used.
While these diagnostic criteria make it possible to make a definite diagnosis of PML without brain biopsy, one must bear in mind that a negative CSF JCV PCR result does not rule out PML as sensitivity is imperfect even with new ultrasensitive techniques capable of detecting 10 copies/mL of JCV (
), positive CSF results in the absence of clinical and radiographic features suggesting PML must weighed cautiously. Last, there is insufficient data to comment on whether this approach also applies in natalizumab-related JC Virus granule cell neuronopathy.
11. Incidence and prognosis of PML-IRIS by cause
In patients with a reversible cause of immunosuppression, re-establishment of immunocompetence can be associated with PML-IRIS, an often exuberant inflammatory response directed at the JC virus. Patients typically present with a clinical worsening associated with new gadolinium-enhancement and, on rare occasion, exhibit mass effect on MRI. PML-IRIS is potentially disabling and fatal.
The likelihood of developing PML-IRIS depends on the underlying predisposing factor for PML. In the HIV literature, 23% of HIV-infected patients with PML develop PML-IRIS (
). In one case series of natalizumab-associated PML in MS patients mostly treated with plasma exchange and immunoadsorption, all 42 patients developed IRIS (
) and it seemed that plasma exchange/immunadsorption (PLEX/IA) accelerated IRIS. All patients had worsened disability as measured by EDSS, but patients with early-onset IRIS had significantly worse disability compared to late-onset IRIS. Mortality was approximately 25%.
12. PML and PML-IRIS management
Data determining optimal treatment of PML and PML-IRIS is unavailable, but in general: (1) in patients with PML, the cause of underlying immunosuppression must be addressed and (2) PML-IRIS can be destructive if unchecked. In patients with HIV, HAART is employed and IRIS is not inevitable.
In multiple sclerosis patients with natalizumab-associated PML, plasma exchange and immunoadsorption does remove natalizumab, restore leukocyte transmigratory capacity and when natalizumab concentration falls below 1 μg/mL, desaturation of alpha4-integrin is observed (
). While offering plasma exchange and immunoadsorption to patients with natalizumab associated PML is standard of care, it is conceivable that it is not mandatory. Given that natalizumab׳s half-life is 11 days, in a patient diagnosed with PML 55 days or 5 half-lives from last natalizumab infusion, it might be reasonable to hold plasma exchange. Furthermore, patients with clinical deterioration in the setting of MR findings suggestive of PML-IRIS might be made worse by plasma exchange.
Optimal steroid treatment for PML-IRIS is unknown. In the HIV literature, a case series of 54 patients with AIDS associated PML-IRIS developing with antiretroviral therapy had mixed results with corticosteroid therapy (
). Of patients treated with steroids, five died, but seven had good neurologic recovery. The authors felt that early treatment of IRIS with steroids was responsible for improved outcomes; however, the absence of contrast enhancement on MRI in five patients raised the question about the diagnostic accuracy of PML-IRIS in these patients (
In one case series of 42 natalizumab-related PML cases in which natalizumab was removed with plasma exchange and immunoadsorption, steroid use was associated with an improved outcome (
). Given that PML-IRIS can be fatal, many clinicians would offer high-dose steroids to blunt inflammation, but this strategy might come at the expense of JCV clearance. In a study of JCV-specific cellular immunity of RRMS patients receiving steroids for relapses, JCV-specific immunity was diminished (
), but this has not been studied in larger groups.
There are no established clinically effective JCV-specific antiviral treatments. A study of mefloquine 250 mg orally every day for 3 days, followed by 250 mg orally once per week in mostly HIV-associated PML was terminated early because of lack of benefit in pre-planned analyses in CSF JCV viral load and clinical/radiographic outcomes (
). This does not absolutely preclude benefit in the MS patient population. One case series of four patients with HIV-associated PML suggested benefit of mirtazipine 15 mg orally daily (
). Most of the reports of the value of this and other therapies, either alone or in combination, for PML is purely anecdotal, e.g, the report of a patient with PML in the context of sarcoidosis who did well with cidofovir and mirtazipine (
In the absence of plentiful high quality data, physicians can offer medicines such as mefloquine and mirtazapine in consultation with pharmacists and while being mindful of the patient׳s comorbidities. It is not clear whether this data would apply in JCV granule cell neuronopathy.
13. Conclusions
JCV is a common indolent viral infection of humans that causes the opportunistic infection PML in the setting of inadequate adaptive immune surveillance. With the HIV epidemic and development of new biologic therapies for autoimmune disease, PML has emerged as both an AIDS-defining illness and calamitous consequence of efficacious therapies for autoimmune disease. JCV granule cell neuronopathy and other rare forms of JCV infection have been described in association with both HIV infection and natalizumab treatment for MS. Despite the absence of confirmatory cases, the concept of JCV granule cell neuronopathy is mentioned due to obvious treatment implications in natalizumab-treated MS patients.
With PML, prognosis and therapy is largely driven by underlying cause. In the HIV+ patient population, CD4+ T cell counts can be associated with survival. Furthermore, institution of antiretrovirals offers a survival benefit. In the multiple sclerosis patient population, outcomes are determined by age, extent of disease at diagnosis, early versus late onset of IRIS and use of corticosteroids. PML risk can be minimized with judicious use of biologics and JCV serology testing. While the risk of PML in JCV sero-negative patients is unclear, serial JCV testing is necessary. For high-risk patients, a well-planned and executed MRI monitoring program can diagnose PML prior to clinical symptoms, leading to improved outcomes. Imaging features can specifically suggest PML versus other entities such as multiple sclerosis attacks. Neuroradiologists should comment specifically on changes concerning for PML.
A diagnosis of PML should be pursued according to the AAN Neuroinfectious Disease section consensus statement. This approach allows two opportunities for CSF JCV PCR to return positive and offers a clear path to a well-indicated brain biopsy.
When there is legitimate concern for PML in natalizumab-treated patients, plasma exchange and immunoadsorption is generally indicated. While not every patient should undergo plasma exchange for natalizumab-associated PML, it does clear the drug and enable the immune system to detect and clear JCV.
While interventions aimed at bolstering the immune system in both HIV-associated PML and natalizumab-associated PML can help clear JCV, they also promote IRIS, which can be fatal or disabling. When present, one can consider corticosteroid therapy. Unfortunately, there is insufficient data to guide JCV-specific treatments such as mefloquine, mirtazipine and cidofovir, although they can be used when the likelihood of harm to the patient is low.
The susceptible population for PML has changed enormously in the era of HIV/AIDS and widespread use of monoclonal antibodies for autoimmune disease. Given the interventions available for these two patient populations, the natural history of PML is changing with the genuine possibility of good outcomes.
Conflict of interest statement
Funding source: Dr. Carruthers reports consulting fees from Genzyme and received a Clinical Fellowship Training grant from the National Multiple Sclerosis Society. Dr. Berger reports grants from PML Consortium, BiogenIdec, personal fees from Millennium, Genentech, Amgen, Genzyme, Eisai, Novartis, outside the submitted work.
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Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA).
Presymptomatic diagnosis with MRI and adequate treatment ameliorate the outcome after natalizumab-associated progressive multifocal leukoencephalopathy.
Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation.
Natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients: survival and functional outcome when asymptomatic at diagnosis.
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