Version May 2024
INTRODUCTION — Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system. The epidemiology, clinical features, and diagnosis of PML will be reviewed here. The treatment of PML is discussed separately. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis".)
ETIOLOGY — Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the polyomavirus JC (JCV) [1-3]. Asymptomatic primary infection with JCV occurs in childhood and antibodies can be found in 86 percent of adults [4]. In most individuals, JCV remains latent in kidneys and lymphoid organs, but, in the context of profound cellular immunosuppression, JCV can reactivate. Replication in this setting may lead to rearrangement of the viral genome, producing neurotropic variants that can replicate in glial cells [5]. The virus can then spread to the brain and induce a lytic infection of oligodendrocytes, which are the myelin-producing cells in the central nervous system. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections".)
The classification, virology, transmission, and pathogenesis of polyomavirus infections is discussed in detail separately. (See "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections", section on 'Pathogenesis'.)
NEUROPATHOLOGY — PML-associated demyelination affects both the subcortical white matter and the cortex. JCV causes infection of cortical neurons and demyelinating lesions of PML frequently involve gray matter [6,7].
One study examined autopsy brain tissue from 13 patients with PML and human immunodeficiency virus (HIV) infection found cortical demyelinating lesions in all 13 [6]. Two types of demyelinating lesions were detected in these patients:
●Leukocortical lesions, which extended to the cortex from underlying white matter and accounted for the highest percentage of demyelination in PML brains
●Intracortical lesions, which were located entirely within the cortex and were typically small (0.03 to 0.6 mm3) and numerous
In another report that looked at neuropathologic tissue from 49 patients with PML, demyelinating lesions were present in the white matter and gray-white junction in 96 percent and in the gray matter in 57 percent of patients [7]. While most of the cells infected with JCV were glial, JCV infection of neurons was found in approximately one-half of patients. In addition, JCV infection of gray matter neurons located outside of demyelinating lesions was present in 11 percent of patients.
The histopathologic features of PML (figure 1) are described below. (See 'Brain biopsy' below.)
EPIDEMIOLOGY — PML is a rare disease that occurs almost exclusively in immunocompromised individuals [5,8]. There are few population-based studies of PML epidemiology; most reports have looked at incidence in specific populations of patients at risk (eg, malignancy, HIV infection, organ transplantation, autoimmune disorders), as discussed in the sections that follow.
UNDERLYING CONDITIONS
Malignancy — PML was initially described in patients with lymphoproliferative and myeloproliferative diseases such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma [9-14]. Malignancy is the most common or second most common (after HIV) predisposing condition among PML cases, depending upon the population studied [5,8,15,16].
HIV infection — HIV infection is a common predisposing condition among patients with PML [5,8]. Most patients with HIV infection and PML are profoundly immunosuppressed, with CD4+ T cell counts <200 cells/microL [9,17]. However, PML can occur in patients with HIV who have normal CD4+ T cell counts [18].
Prior to the widespread use of effective antiretroviral therapy (ART) in the United States and Europe, PML was recognized as a major opportunistic infection associated with HIV infection in adults, with a prevalence of 1 to 5 percent [19-22]. PML has also been described in HIV-infected children [23-25], at an estimated rate of 0.06 per 100 person-years prior to effective ART [25].
Since the widespread use of effective ART, the incidence of PML in patients with HIV infection has decreased [26,27]. In a population-based study from Denmark involving a nationwide cohort of patients aged 16 and older with HIV infection, the incidence of PML declined over three observation periods as follows [27]:
●1995 to 1996 (pre-ART): 3.3 cases/1000 patient-years at risk (PYR); 95% CI 1.9-5.7)
●1997 to 1999 (early ART): 1.8 cases/1000 PYR (95% CI 1.0-3.2)
●2000 to 2006 (effective ART): 1.3 cases/1000 PYR (95% CI 0.8-1.9)
In contrast to the above findings from the United States and Europe, PML was rarely reported before 2010 in HIV-infected patients in India and Africa. The reason for this phenomenon is not clear, but nonrecognition, lack of simple diagnostic tests, underreporting, premature deaths due to other infections, potential interactions between JCV and different HIV clades, or host genetic differences may have been the cause [28]. However, there is accumulating evidence that the prevalence of PML in patients with HIV infection from Africa is probably similar to other regions. As examples, a 2014 study of 331 HIV-infected patients in Zambia who presented with central nervous system opportunistic infection found that JCV DNA by polymerase chain reaction (PCR) was present in 6 percent of cerebrospinal fluid samples [29]. A later study found that the seroprevalence of JCV is similar in Zambia and the United States [30].
Organ transplantation — PML is a potential complication of solid organ transplantation and bone marrow transplantation. Immunosuppressive therapy to prevent graft rejection is a major risk factor for PML in this setting. A review of 427 cases of heart or lung transplant recipients identified 3 cases of PML, with a calculated incidence rate of 1.2 cases per 1000 post-transplantation years [31].
Immunomodulatory therapy — There is an increased risk of PML associated with the use of some monoclonal antibody therapies. The prototypical example is natalizumab (image 1), an immunomodulatory drug that prevents normal trafficking of leukocytes by binding to integrin receptors. Natalizumab is primarily used to treat patients with relapsing-remitting multiple sclerosis and select patients with Crohn disease. These associations are described in detail elsewhere. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab' and "Medical management of moderate to severe Crohn disease in adults", section on 'Anti-integrin antibody therapy'.)
PML has also been reported occasionally in patients treated with other monoclonal antibody therapies and immunomodulatory drugs, including but not limited to:
●Azathioprine [8]
●Belatacept [32,33]
●Carfilzomib [37]
●Eculizumab [38]
●Efalizumab [39,40]
●Fludarabine [10-14]
●Glucocorticoids [41]
●Idelalisib [42]
●Infliximab [44]
●Obinutuzumab [42]
●Ocrelizumab [48]
●Ofatumumab [42]
●Rituximab (image 2) [8,51-53]
●Ruxolitinib [54,55]
●Thalidomide [50]
In some cases, these drugs were used in combination with other immunosuppressive medications (eg, cyclophosphamide, leflunomide, methotrexate) [44,56]. Many of the patients had an underlying hematologic malignancy or collagen vascular disease.
A case-control study demonstrated that rare variants in specific genes associated with immunodeficiency disorders (C8B, LY9, FCN2, and STXBP2) are associated with increased susceptibility to PML in carriers who are exposed to immunosuppressant drugs [57]. This finding suggests that testing for these variants could be used to identify patients at risk for PML who are being considered for immunosuppressant therapy.
Autoimmune disorders — PML has been reported in numerous autoimmune disorders including [5,18]:
●Systemic lupus erythematosus
●Vasculitis, including granulomatosis with polyangiitis
●Dermatomyositis
●Polymyositis
●Scleroderma
●Rheumatoid arthritis
●Sjögren's disease
●Sarcoidosis
Autoimmune disorders are the underlying condition in up to 23 percent of PML cases [5,15,16]. Immunosuppressive drug treatment is the main risk factor for PML in these cases. The risk of PML among rheumatologic disorders may be highest for systemic lupus erythematosus [58].
In a retrospective population-based study that analyzed a health insurance database, the incidence rates of PML in patients with systemic lupus erythematosus and autoimmune vasculitis were 2.4 and 10.8 per 100,000 person-years [59].
Primary immunodeficiency disorders — Rare cases of PML have been reported in patients with primary immunodeficiency disorders [60], including idiopathic CD4+ T-cell lymphocytopenia [61-63], CD8+ T-cell lymphocytopenia [64], and GOF STAT1 deficiency (ie, gain-of-function signal transducer and activator of transcription 1 deficiency) [65]. (See "Idiopathic CD4+ lymphocytopenia" and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'Autosomal dominant GOF STAT1 deficiency'.)
Minimal or no immunosuppression — There are only isolated case reports of PML in patients without apparent immunosuppression [66-70]. There are, however, reports of PML affecting patients who have conditions associated with minimal or occult immunosuppression, such as hepatic cirrhosis or renal failure [71,72].
CLINICAL FORMS
Classic PML — PML usually manifests with subacute neurologic deficits including altered mental status, motor deficits (hemiparesis or monoparesis), limb ataxia, gait ataxia, and visual symptoms such as hemianopia and diplopia [17]. PML may be asymptomatic in the earliest stages [73].
Initial symptoms may vary greatly from patient to patient, depending on the location of their lesions in the central nervous system white matter. PML typically begins in the brain hemispheres and spreads into other regions. Isolated brainstem lesions at disease onset have been reported but are atypical [74]. PML typically spares the optic nerves and the spinal cord. However, PML limited to the spinal cord was detected postmortem in one patient [75], and incidental finding of PML lesions in the spinal cord was reported in the postmortem examination of another patient with HIV infection who died from hemispheric PML [76].
Although PML lesions are located mainly in the white matter, PML symptoms are frequently indicative of a cortical disorder. These cortical symptoms have been attributed to lesions of white matter tracts that subserve relevant cortical areas. As examples, aphasia may result from lesions underlying the language areas in the left frontal and temporal lobes, and lesions in the occipital lobe white matter can mimic symptoms of cortical blindness. However, neuropathologic study has revealed that cortical demyelination is a frequent finding with PML, suggesting that cortical symptoms in PML may arise from cortical demyelinating lesions. (See 'Neuropathology' above.)
Seizures are usually thought to be a manifestation of cortical injury rather than white matter disease. Nonetheless, seizures occur in up to 44 percent of patients who survive PML, mainly when PML lesions are located immediately adjacent to the cortex [77,78].
The disease course of PML is usually progressive and is often fatal. This is discussed separately. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'Prognosis'.)
Inflammatory PML (PML-IRIS) — Some patients with a reversible cause of immunosuppression may develop an inflammatory reaction in PML lesions known as the immune reconstitution inflammatory syndrome (IRIS), which is associated with new onset or clinical worsening of PML and with contrast enhancement of PML lesions on brain magnetic resonance imaging (MRI).
PML-IRIS occurs mainly in patients with HIV undergoing antiretroviral therapy (ART) who display a marked increase in CD4+ T-cell counts and a decrease in HIV plasma viral load, indicating a recovery of the immune system. (See "Immune reconstitution inflammatory syndrome".)
Patients with multiple sclerosis who are treated with natalizumab may develop PML, followed by PML-IRIS after withdrawal of natalizumab and restoration of immune response [79-82]. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'Natalizumab-associated PML' and "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)
Other conditions caused by JCV infection — As the name implies, classic PML is progressive, multifocal, and involves the white matter. However, other presentations of JCV infection are increasingly recognized. These include JCV granule cell neuronopathy, JCV encephalopathy, and JCV meningitis. Thus, JCV can also present as a single lesion, may not always be progressive, and may involve the gray matter [9].
JCV cerebellar granule cell neuronopathy — JCV may cause a productive and lytic infection of cerebellar granule cell neurons, leading to ataxia, incoordination, dysarthria, and cerebellar atrophy [83-85]. This syndrome is named JCV granule cell neuronopathy (GCN). It causes cerebellar atrophy but does not result in white matter lesions of cerebellar PML. In some cases, JCV GCN may be the first manifestation of AIDS in HIV infection [86].
The data indicate that JCV, at least in certain individuals, is capable of infecting cerebellar granule cell neurons, and not only glial cells [83,84]. In a study examining brain tissue (nearly all derived from autopsy) from patients with PML, infection of granule cell neurons by JCV was detected in 15 of 19 tested samples (79 percent), including some cases without PML lesions in the nearby cerebellar white mater (figure 2) [87]. Pathogenic variants in the structure of the JCV VP1 capsid protein have been identified in a few patients with JCV GCN, suggesting that VP1 protein alterations are important to the pathogenesis of GCN [88,89].
JCV GCN should be differentiated from the PML cerebellar syndrome when lesions occur in the cerebellar white matter.
JCV encephalopathy — JCV infection can result in a gray matter syndrome characterized by encephalopathy [55,90-92]. A case report describes a patient who developed aphasia and progressive cognitive decline in the absence of focal neurologic deficits after chemotherapy for non-small cell lung cancer [90]. The course was rapidly fatal. Polymerase chain reaction detected JCV in cerebrospinal fluid and brain biopsy tissue. Neuropathologic examination showed focal areas of cell loss in the cortex and limited demyelination. JCV infection of enlarged cortical pyramidal neurons was confirmed by immunostaining and electron microscopy.
JCV meningitis — JCV may cause meningitis [93-95]. As an example, one case report described a woman, age 67 years and seronegative for HIV, who presented with a two-month course characterized by headache, urinary incontinence, leg weakness, and lethargy [93]. Brain imaging showed ventricular dilation but no parenchymal lesion and no meningeal enhancement. Cerebrospinal fluid analyses revealed a peak white blood cell count of 10 per mm3, elevated protein, and a very high JCV load. She developed pancytopenia and died five and a half months after symptom onset. Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement.
Neuroimaging features — The typical appearance of PML on neuroimaging studies consists of discrete unilateral or bilateral foci of demyelination that do not conform to cerebrovascular territories and exhibit neither mass effect nor contrast enhancement. PML lesions usually begin in the subcortical white matter of the parieto-occipital or frontal lobes but may also involve the corpus callosum, brainstem, pyramidal tracts, and cerebellum [18,96-98]. Involvement of the deep gray structures, including basal ganglia and thalamus, can be found in up to 17 percent of cases, but this is always in conjunction with white matter disease (image 3) [99]. Of note, cortical demyelination in PML is not discernible with conventional MRI [100]. (See 'Neuropathology' above.)
On cranial CT, PML lesions can appear as patchy or confluent hypodense white matter lesions (image 4) [96]. On MRI, the lesions of PML are seen as areas of decreased signal on T1-weighted images and increased signal on T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences (image 5 and image 4 and image 6) [96-98]. Contiguous enlargement of infectious demyelination is typical for the progression of PML over time (image 7). Unlike vasogenic edema, there is relatively little mass effect on adjacent, uninvolved tissues (image 8) [99]. On trace diffusion-weighted MRI sequences, PML lesions may show a hyperintense rim along the periphery or advancing edge of the lesion but there this is not attributed to reduced water diffusivity on corresponding apparent diffusion coefficient (ADC) images (image 3 and image 6) [101,102].
The lesions of PML generally do not contrast-enhance (image 4 and image 6 and image 8) [99]. However, enhancing PML may occur in patients with PML-IRIS. These radiologic findings have been observed most often in patients with HIV infection who initiated combined antiretroviral therapy (ART) and then became neurologically symptomatic from PML disease (image 9) [103-105]. They also have been reported in rare patients without HIV infection, including some with natalizumab-associated PML [106,107]. (See 'Inflammatory PML (PML-IRIS)' above.)
DIAGNOSIS
When to suspect PML — The diagnosis of PML should be suspected in patients who present with subacute neurologic deficits in the setting of immunosuppression or immunomodulatory therapy if brain magnetic resonance imaging (MRI) reveals focal or multifocal white matter lesions, generally without mass effect, that do not conform to vascular territories.
Diagnostic approach — patients with suspected PML should have a brain MRI with and without gadolinium, if not already done as part of the initial evaluation.
Routine blood studies include a complete blood count and differential, and HIV serology and viral load if HIV status is unknown (algorithm 1). (See "Screening and diagnostic testing for HIV infection".)
For patients with clinical and neuroimaging features of PML, a lumbar puncture is indicated for cerebrospinal fluid analysis, including polymerase chain reaction (PCR) for JCV.
For patients with who have a negative initial PCR for JCV in the cerebrospinal fluid, our suggested approach is to evaluate for other neurologic disorders (see 'Differential diagnosis' below) and repeat the lumbar puncture and PCR of the cerebrospinal fluid for JCV (algorithm 2). Brain biopsy may be pursued if this evaluation and the repeat PCR are unrevealing, and if there is concern for another cause such as tumor.
Of note, retrospective data suggest that diagnostic delay is common for patients with PML [108]. This may be due, at least in part, to the rarity of PML and the nonspecific and heterogeneous symptoms and signs.
Lumbar puncture and PCR — In patients with compatible clinical and neuroimaging features, the diagnosis of PML is established by demonstrating the presence of JCV DNA in the cerebrospinal fluid using PCR [17]. Therefore, PCR is the preferred approach to confirm the diagnosis.
In addition to PCR for JCV, cerebrospinal fluid should be analyzed for routine studies (white count and differential, protein concentration, glucose concentration, and Gram stain); we also obtain cerebrospinal fluid cytology, flow cytometry (to rule out lymphoma), HIV viral load, cryptococcal antigen (if seropositive for HIV), and PCR for Epstein-Barr virus, varicella-zoster virus, cytomegalovirus, herpes simplex virus-1, and herpes simplex virus-2.
In the era before the advent of effective antiretroviral therapy (ART), JCV PCR of cerebrospinal fluid for the diagnosis of PML had a sensitivity of 72 to 92 percent and specificity of 92 to 100 percent [109]. Modern ultrasensitive PCR techniques have a sensitivity of >95 percent or higher [17]. However, a negative PCR test does not rule out PML, and it is possible to find negative JCV cerebrospinal fluid PCR results in patients with HIV infection who have a clinical presentation indistinguishable from PML [110]. A plausible explanation for this discrepancy is that ART-induced recovery of the immune system leads to decreased viral replication and clearance of JCV DNA from the cerebrospinal fluid [111].
Based upon a consensus for PML diagnostic certainty [17,112], these patients should be considered as "possible PML" cases and managed accordingly, after appropriate exclusion of other neurologic conditions such as primary central nervous system lymphoma and HIV encephalopathy. (See 'Differential diagnosis' below.)
Other cerebrospinal fluid findings in PML are nonspecific; the white blood cell count usually reveals a mild pleocytosis with <20 cells/microL and a moderate protein elevation of <100 mg/dL [18]. A white blood cell count >20 cells/microL can be seen with inflammatory PML in the setting of restored host immunity (ie, PML-IRIS) but otherwise suggests a different infectious cause [18].
Brain biopsy — As noted above, PCR is the preferred approach to the diagnosis of PML. However, brain biopsy remains the gold standard in circumstances where another condition such as CNS lymphoma is part of the differential diagnosis. Histologic examination of PML lesions reveals single or multiple areas of demyelination with the following features (figure 1):
●JCV-infected oligodendrocytes with enlarged amphophilic nuclei located at the periphery of the lesions
●Reactive gliosis with enlarged, bizarre astrocytes, some sustaining a restrictive, nonlytic JCV infection
●Macrophages containing phagocytosed myelin and cellular debris
The typical histopathologic triad of PML (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) is not observed in other neurologic disorders [17]. The presence of JCV-infected glial cells should be confirmed by immunohistochemistry for polyomavirus proteins, or in situ hybridization for JCV DNA. Antibodies used for immunohistochemistry are generally raised against the simian virus 40, a polyomavirus endemic in monkeys that cross-reacts with JCV.
PML lesions are usually devoid of inflammatory infiltrates. In the context of an IRIS, active inflammatory changes may be present, including intraparenchymal and perivascular CD8+ T-lymphocyte infiltration associated with the presence of abundant JCV as well as areas of perivenous leukoencephalitis devoid of JCV [113].
Brain biopsy has a sensitivity of 64 to 96 percent and a specificity of 100 percent for the diagnosis of PML [114]. However, the risk of morbidity and mortality associated with brain biopsy in patients with HIV infection is estimated to be approximately 8 and 3 percent, respectively [115]. Furthermore, some patients may not be able to tolerate brain biopsy, or lesions may be inaccessible.
DIFFERENTIAL DIAGNOSIS
Radiologic differential — The differential diagnoses for the imaging signs of PML include posterior reversible encephalopathy syndrome, white matter injury from chemoradiation, acute disseminated encephalomyelitis, and diffuse low-grade glioma [116,117].
Clinical differential
●With HIV infection – In patients with HIV infection, the differential diagnosis of PML includes HIV encephalopathy and primary central nervous system lymphoma. Whereas PML lesions are usually asymmetric, distributed throughout the white matter, well demarcated, and associated with focal neurologic deficits, the lesions of HIV are more likely to be symmetrical, poorly demarcated, and located in the periventricular areas; they may be associated with cognitive problems and an elevated HIV viral load in the cerebrospinal fluid, but not with focal sensory, motor, or visual deficits.
Primary central nervous system (CNS) lymphoma may also mimic PML lesions. However, cortical involvement, moderate edema, diffuse postcontrast enhancement, and positive cerebrospinal fluid cytology or polymerase chain reaction for Epstein-Barr virus should help differentiate these entities. The radiological presentation of these disorders in patients with HIV infection is covered in greater detail elsewhere. (See "Approach to the patient with HIV and central nervous system lesions".)
●Without HIV infection – In immunosuppressed patients without HIV infection, PML may be initially mistaken for a stroke or brain tumor [118,119]. However, clinical suspicion for PML should be heightened if the neuroimaging features are those of a multifocal process limited to the white matter that does not conform to vascular territories and exhibits neither mass effect nor contrast enhancement.
Other disorders to consider in the differential of PML include the following [17]:
•Primary central nervous system lymphoma, as with HIV infection.
•Central nervous system vasculitis demonstrates multiple infarctions of different ages involving gray and white matter, distinguishing it from PML. (See "Primary angiitis of the central nervous system in adults".)
•Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy. Unlike PRES, PML tends to occur in the setting of immunosuppression and the lesions do not revert, though there have been reports of cases that overlap. PRES also tends to have more gray matter involvement, and does not cause hypointense lesions on T1-weighted magnetic resonance imaging (MRI). (See "Reversible posterior leukoencephalopathy syndrome".)
•Varicella-zoster virus encephalopathy. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Encephalitis'.)
●With disease-modifying therapy for multiple sclerosis – In patients with multiple sclerosis (MS), particularly those being treated with natalizumab, who are therefore at increased risk for PML, it may be difficult to distinguish recurrent attacks of MS from PML based upon clinical and radiologic findings. However, certain neuroimaging features may be useful in this regard:
•PML lesions after natalizumab therapy are usually unifocal if detected early on MRI, located at the gray-white junction of the frontal and parieto-occipital lobes, and are larger than typical foci of demyelination in MS. By contrast, MS lesions are more often small, multifocal, and predominate in the periventricular white matter.
•MS lesions usually have an ovoid shape and are oriented perpendicular to the corpus callosum (the abutting calloso-septal margin) or long axis on the lateral ventricles (Dawson finger pattern); PML lesions do not follow this pattern.
•PML lesions may be hyperintense on trace diffusion-weighted MRI (image 3), whereas MS lesions are usually not.
SUMMARY AND RECOMMENDATIONS
●Progressive multifocal leukoencephalopathy (PML) is a potentially fatal demyelinating disease of the central nervous system caused by a reactivation of the JC polyomavirus (JCV) that occurs almost exclusively in immunosuppressed individuals. (See 'Etiology' above.)
●PML is a rare disease that is seen primarily in immunocompromised patients with lymphoproliferative and myeloproliferative diseases, HIV infection, immunomodulatory therapy after organ transplantation, or primary immunodeficiency disorders. (See 'Epidemiology' above and 'Underlying conditions' above.)
●PML typically presents with subacute neurologic deficits, including altered mental status, visual symptoms such as hemianopia and diplopia, hemiparesis or monoparesis, and appendicular or gait ataxia. Seizures occur in up to 18 percent of patients. PML with the immune reconstitution inflammatory syndrome (PML-IRIS) is associated with new onset or clinical worsening of PML and with contrast enhancement of PML lesions on brain magnetic resonance imaging (MRI). (See 'Classic PML' above and 'Inflammatory PML (PML-IRIS)' above.)
●Other conditions caused by JCV infection include a pure cerebellar syndrome (JCV granule cell neuronopathy), a cortical syndrome with encephalopathy (JCV encephalopathy), and meningitis (JCV meningitis). (See 'Other conditions caused by JCV infection' above.)
●Clinical suspicion for PML should be heightened if neuroimaging reveals discrete unilateral or bilateral foci of demyelination in the white matter that do not conform to vascular territories and exhibit neither mass effect nor contrast enhancement. An exception is that lesions of PML-IRIS may show contrast enhancement. (See 'Neuroimaging features' above.)
●For patients with clinical and neuroimaging features of PML, a lumbar puncture is indicated for cerebrospinal fluid analysis, including polymerase chain reaction (PCR) for JCV. (See 'Diagnosis' above.)
●In patients with appropriate neurologic and neuroradiologic features, the diagnosis of PML can usually be established by PCR detection of JCV DNA in the cerebrospinal fluid. Patients with who have a negative initial PCR for JCV should be evaluated for other neurologic disorders and have a repeat the lumbar puncture and PCR for JCV (algorithm 2). Brain biopsy may be pursued if this evaluation and the repeat PCR are unrevealing, and another condition such as central nervous system lymphoma is part of the differential diagnosis. (See 'Diagnosis' above.)
●The differential diagnosis of PML varies according to the clinical setting. For patients with HIV infection, the differential includes primarily HIV encephalopathy and primary central nervous system lymphoma. For patients without HIV infection who have underlying immunosuppression, the differential includes primarily central nervous system lymphoma, central nervous system vasculitis, posterior reversible encephalopathy syndrome, and varicella-zoster virus encephalopathy. For patients treated with disease-modifying therapy for multiple sclerosis, the differential includes new or recurrent attacks of multiple sclerosis. (See 'Differential diagnosis' above.)
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