INTRODUCTION:

Progressive Multifocal Leukoencephalopathy is a demyelinating disease of the Central Nervous System characterized by widespread lesions due to infection of oligodendrocytes by JC(John Cunningham) virus which is a polyoma virus (formerly known as papova virus). It is a small non- enveloped double-stranded DNA virus and was defined as an etiological agent in 1967. It was named after John Cunningham as he first isolated the JC virus in 1971¹.The JC virus is a popular polyoma virus and is widespread with a specific target of myelinating oligodendrocytes².

It occurs mostly in immunocompromised patients. Ex: Patients with advanced HIV infection, hematological malignancies, lymphoproliferative disorders, autoimmune rheumatological diseases or those have undergone organ transplantation¹. in the kidney, bone marrow, and lymphoid organs, the JC virus remains in latent stage². In course of immune suppression the virus gets reactivated from lymphoid tissues, kidney and thus causes targeted myelin destruction and corresponding neurological deficits³. JC viral infection have also been reported in patients receiving immune therapy with monoclonal antibodies(Ex: Natalizumab, Rituximab)¹. Primary infection occurs in childhood and it is asymptomatic in most patients³.

EPIDEMIOLOGY:

PML is an AIDS-defining classified illness and has an approximate incidence of 3-5%⁴.People who have been on treatment with corticosteroids and other immunosuppressive drugs are reported to have the highest incidence of PML from 1958 to 1980’s⁵.A United States study found that 82% of cases were associated with HIV infection out of 9,675 cases of PML from 1998-2005⁶.Due to diagnostic challenges and differences in JC virus isolates, The incidence of PML is low in India and Africa⁷.In hematologic malignant patients, the prevalence of PML was estimated to be 0.07%⁸and 0.8% in a retrospective autopsy study of liver transplant recipients⁹.WhenHAART was introduced, the mortality associated with PML has decreased significantly in the United States since 1996. The PML associated death rate decreased from 2.76 deaths per 1 million populations in 1992-1995 to 0.66 in 2002-2005, in large part because of fewer deaths among HIV-infected patients¹⁰.

In the Pre- HAART era, only 5% of HIV- infected individuals were diagnosed with PML and the median survival was only 6 months. Less than 10% were alive 1 year after the onset of symptoms¹¹. Worldwide, the one-year survival increased from 10% in the 1980-1990’s to around 50% nowadays¹².Also important is the fact that more than half of the long-term PML survivors have no or only mild disability¹³.

PATHOPHYSIOLOGY:

The Pathological infection of JC virus begins

Small demyelinating foci at the cortex- white matter junction

Convergence of these foci

Results in large irregular white matter lesions that involve cerebrum, cerebellum and brain stem.

Post Demyelination, Axons spread relatively.

The infected oligodendrocytes contain a nucleus packed with viral particles which look enlarged and give a ground glass appearance. PML is a lytic infection leading to oligodendrocyte destruction. There are variable cases accompanying PML. Immune reconstitution inflammatory syndrome (IRIS) has the general pathological features of PML but lack intranuclear inclusions. They show no JCV reactivity by immunohistochemistry. Polyomavirus can also become included into the host genome and cause neoplastic transformation. Inflammation is usually minimal, except when the immune system recovers with antiretrovirals. Such cases show brisk inflammation resembling encephalitis. There is no peripheral nerve demyelination or disease in any other organ system¹⁴.

PROGNOSIS:

Generally, the death rate of PML in the first few months varied between 30-50% after the diagnosis of the disease. The mortality rate depended highly on the severity of the disease¹⁵.During the pre- HAART era, the prognosis of PML is very poor. The maximum time gap between the First onset of symptoms and death was only 3-6 months. Usually after getting bedridden for several days, patients die due to secondary complications. The prognosis is slightly better at CD4 counts above 200/µl¹¹.Disease progression seems to be slower on treatment with ART. It even seems to make complete remission possible¹⁶.However, these effects are not as impressive as for others: in a Spanish study of 118 PML patients on ART, 64% were still alive 2.2 years after diagnosis¹⁷. Complete remissions are not much possible, even under sufficient ART. They mainly occur in the case of inflammatory PML, which occurs due to IRIS condition¹⁸.the number of CD4 T-cells and the JC-virus specific immune response seems to be relevant as prognostic markers, however, the JCV viral load does not seem relevant^{19, 20}.

CLINICAL PRESENTATION:

Neurological manifestations of JCV induced tissue damage include the classic triad of presenting symptoms of PML. These are visual, motor, and cognitive impairments. Though the neuropathology is multifocal, the presenting symptoms seem to be unifocal, but the MRI shows multifocal pathology. Major opportunistic disorders that produce focal brain lesions like cerebral toxoplasmosis, primary CNS lymphomaprogress over the course of hours or a few days. But PML evolves over several weeks. In 40% of the initial symptoms, Hemianopsia or the loss of vision in the bisection of the visual field is the most common²¹.Cortical blindness is another common symptom present at the time of initial assessment. In greater than 50% of the cases, severe muscle weakness progressing into hemiparesis or hemiplegia is present. This lack of voluntary muscle coordination often presents itself in the form of gait disturbances or loss of balance. Many of the PML patients admitting with seizures are found to have demyelinating lesions immediately adjacent to the cortex. Seizures usually responded well to treatment and did not affect survival. Deterioration of cognitive functions may be rapid, leading to confusion, extreme emotional ability, and ultimately, dementia.

PHYSICAL EXAMINATION:

Focal neurologic signs include aphasia, hemiparesis, ataxia, cortical blindness, limb apraxia, brainstem symptoms and, less frequently, head tremor. Focal signs are mostly related to the posterior brain (e.g. occipital lobes). At the time of initial clinical presentation, 65% of people present with gait abnormalities whereas 30% of the people show cognitive impairment. Conjugate gaze abnormalities i.e., inability to move the eyes in a single direction are common in the initial clinical presentation (30%). Abnormalities may advance to quadriparesis and coma. Occasionally, neurologic signs are diffuse rather than focal²².

WORKUP:

Neuroimaging-The diagnosis of PML is most appropriately done by brain imaging technique. Hypodense lesions of the affected white matter can be found in CT of the brain in case of PML. On CT scan, the lesions of PML do not exhibit mass effect and infrequently contrast enhance. When the subcortical arcuate fibers are involved, a “scalloped” appearance beneath the cortex is noted. The presence of the white matter lesions of PML can be sensitively detected by cranial MRI rather than by CT scan. Hyperintense lesions on T2-weighted images and fluid-attenuated inversion recovery (FLAIR) images in the affected regions are revealed in MRI. These lesions are hypointense in T1- weighted images. In 5%–10% of cases faint, typically peripheral, contrast enhancement may be observed with CT scan. Gadolinium enhancement on MRI was detected in 15% of patients with HIV-associated PML and 40% of patients in Natalizumab-associated PML at the time of diagnosis. Although characteristically multifocal, the lesions of PML can occur virtually at any part of the brain and they need not be multifocal. For example, Natalizumab-associated PML is often monofocal, with mostly frontal lobe lesions. In every radiographic series of PML, mostly frontal and parietooccipital regions are affected, presumably as a consequence of their volume. However, the isolated or associated involvement of the basal ganglia, external capsule, and posterior fossa structures (cerebellum and brainstem) may be seen as well.

The role of other neuroimaging techniques, such as magnetization transfer MRI, magnetic resonance spectroscopy, SPECT (Single photon emission computerized tomography), and PET (Positron emission tomography), is limited. Monitoring the degree of demyelination in PML can be detected in Magnetization transfer MRI. Magnetic resonance spectroscopy reveals the levels of decreased N-acetyl aspartate and creatine and increased choline products, myoinositol, and lactate in the lesions of PML. These changes probably demonstrate neuronal loss and cell membrane and myelin breakdown. Cerebral angiography is not routinely performed, but when used it determined the arteriovenous shunting and a parenchymal blush in the absence of contrast enhancement on MRI in 4 of 6 patients in one study. These unexpected angiographic features can be explained by small-vessel proliferation and perivascular inflammation. A patient with contrast-enhancing MRI lesions and a positive Tl²⁰¹ SPECT and 2 patients with both positive Tl²⁰¹ and gallium SPECT mistakenly diagnosed as CNS lymphoma have been reported. PET imaging with ¹⁸F fluorodeoxyglucose typically demonstrates hypometabolic lesions. In one instance, ¹⁸F PET at conventional (60 minutes after injection) and delayed (300 minutes after injection) were unable to distinguish pathologically proven PML from a malignant brain lesion. So SPECT and PET studies are not usually helpful in diagnosing PML.

CSF examination is very helpful in excluding other diagnoses. Cell counts are usually less than 20 cells/mm³. In one large study, the central cell count was 2 cells/mm³ and the average was 7.7 cells/mm³. In that same study, 55% had an atypically raised CSF protein with the highest recorded value being 208 mg/dL (2.08 g/L); however, the mean value was 66.5 mg/dL. Hypoglycorrhachia was observed in less than 15%. These abnormalities are not erratic with those previously reported to arise with HIV infection alone and may not certainly be imputable to PML²³.

DIAGNOSIS:

The approach to the diagnosis of PML has progressed considerably since its initial elucidation in 1958. Initially, the diagnosis of PML was established on brain histopathology as there were no clinical, laboratories, or radiographic features that would unequivocally establish the diagnosis²⁴.A classic triad of demyelination, bizarre astrocytes, and oligodendroglial nuclear inclusions include the histopathology of PML. The histological and virological examination of brain material obtained by brain biopsy or at postmortem is the basis of clinical diagnosis of PML. Both serum and CSF should be examined for antibodies against JCV before going for a Brain biopsy. A positive result will not confirm PML, but a negative result makes the diagnosis of PML implausible. It is rare to detect antibodies against JC in the Cerebro Spinal Fluid. When it is detected, it suggests the presence of active multiplication of JCV within the CNS. The brain biopsy or autopsy material can be examined by Electron Microscopy or Immune Electron Microscopy. The specimen of the biopsy can also be examined directly for JCV antigen by immunofluorescence or immunoperoxidase staining. Virus isolation is very difficult for JCV but, when made an effort, primary human fetal glial cells are used. The presence of the virus in culture is confirmed by Electron Microscopy, Immunofluorescence or haemagglutination. JC is rarely excreted in the urine of patients suffering from PML²⁵.

TREATMENT:

All treatments are exploratory in progressive multifocal Leukoencephalopathy (PML). The principal approach is antiretroviral therapy. Treatment guidelines for PML recommend

1. Initiation of antiretroviral therapy immediately in patients with PML who are not on therapy

2. Optimizing the antiretroviral regimen for virologic suppression in patients who are receiving antiretroviral therapy but who remain HIV-viremic because of antiretroviral resistance i.e., treatment with HAART.

In PML patients with undetectable plasma HIV, Intensive treatment with 4 classes of antiretroviral drugs, including enfuvirtide, has been reported as delivering a possible survival benefit. In AIDS patients, antiretroviral therapy (ART) has improved outcome in PML, escalating the one-year survival rate from 10 to 50%²⁶. Experimental use of drugs such as cidofovir and other antivirals has failed to furnish a benefit to the patient. However, patients treated with aggressive antiretroviral therapy may develop immune reconstitution inflammatory syndrome (IRIS). In IRIS the recovering immune system produces an intense inflammatory response against the JC virus, thus worsening the disease in the patient.

Mefloquine is one of the options to fight PML based on an in-vitro study. But recent trials have shown that Mefloquine lacked efficacy in treating PML. In some patients with very low CD4⁺ count, Worsening of disease occurs on initiation of HAART. This occurs as secondarily to immune reconstitution inflammatory syndrome (IRIS).

Unreliable case reports have reported that use of pulsed methylprednisolonehas improved the condition of a patient with PML. Treatment guidelines consider the use of corticosteroids justified in this setting. However, if patients stop taking corticosteroids, they fall under the risk of developing IRIS. If PML develops in patients taking Natalizumab, another immunomodulatory drug, the drug should be stopped, and plasma exchange should be done to remove residual circulating drug²⁷.

A report suggested the use of drugs that block the serotonergic 5HT2a receptor (e.g. olanzapine, ziprasidone, mirtazapine, cyproheptadine, risperidone) as the supportive treatment of PML on the basis of a fact that this receptor acts as a surface receptor for JC virus . However, its routine use is not considered justified. Passive and active immunization against JCV infection and PML is a potential approach that is being considered for future evaluation²⁸.

CONCLUSION:

PML is a continuing deadly complication of HIV. Clinical presentation of progressive symptoms of PML plays an important role in the diagnosis of the disease. Initial presentation of neurological manifestations in HIV setting should suggest the diagnosis of PML. Recognition of atypical form of PML may be clinically important. Initiation of HAART is the only available option for treating PML. But the incidence of IRIS on initiation of HAART worsens the disease and this acts as a limitation to HAART. Corticosteroids prove to be another unreliable treatment option of PML. Further approaches to the isolation of virus and the immunization against the virus may arrest the progression of PML and its deadly complications.

REFERENCES:

1. Bartt RE. Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy. CurrOpin Neurol. 2006 Aug. 19(4):341-9.

2. Friedman H, Klein T, Madden J. Neuroimmune circuits, drugs of abuse, and infectious diseases. New York: Kluwer Academic; 2002.

3. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010;9:425-437.

4. Ferenczy M, Marshall L, Nelson C, Atwood W, Nath A, Khalili K et al. Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain. Clinical Microbiology Reviews. 2012;25(3):471-506.

5. Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy.NeurolClin 1984;2:299-313.

6. Molloy E Calabrese L. Progressive multifocal leukoencephalopathy: A national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum. 2009;60(12):3761-3765.

7. Sharma Sk, Soneja M, Ranjan S, Mighani S et al. PML in HIV/AIDS: Observational study from the tertiary care center in northern India. Indian J Med Res.2013.138:72-7

8. Power C, Gladden JG, Halliday W et al. AIDS and NonAIDS related PML association with distinct P₅₃ Polymorphism. Neurology 2000; 54: 743

9. Martinez AJ, Ahdab-barmada M. The neuropathology of liver transplantation: comparison of main complications in children and adults. Mod Pathol 1993;6:25.

10. Christensen KL, Holman RC, Hammett TA, Belay ED, Schoberger LB. PML deaths in USA, 1979-2005. Neuroepidemiology. 2010. 35 (3): 178-84.

11. Berger JR, Pall L, Lanska D, Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol 1998; 4:59-68.

12. Tan CKoralnik I. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. The Lancet Neurology. 2010;9(4):425-437.

13. Lima MA, Bernal- Cana F, Clifford DB et al. Clinical Outcome of long-term survivors of PML. J Neurol Neurosurg Psych. 2010: 81;1288-1291

14. Dimitri Agamanolis M. Progressive multifocal leukoencephalopathy -PML [Internet]. Neuropathology-web.org. 2016.

15. Progressive Multifocal Leukoencephalopathy Information Page: National Institute of Neurological Disorders and Stroke (NINDS) [Internet]. Ninds.nih.gov. 2016.

16. Albrecht H, Hoffmann C, Degen O, et al. HAART significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. AIDS 1998, 12:1149-1154.

17. Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003, 36: 1047-52.

18. Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003; 9 Suppl 1:25-31.

19. Khanna N, Elzi L, Mueller NJ, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis 2009, 48:1459-66.

20. Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009, 73:1551-8.

21. Berger J Major E. Progressive Multifocal Leukoencephalopathy. Seminars in Neurology. 1999;19(02):193-200.

22. [Guideline] Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE, et al. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 May. 58 (9):1308-11.

23. A.K. Bag,J.K. Cure, P.R. Chapman, G.H. Roberson, and R. Shah. JC Virus Infection of the Brain. Neurology. 2013; 81: 964-970.

24. Progressive Multifocal Leukoencephalopathy - NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2016.

25. Berger J, Aksamit A, Clifford D, Davis L, Koralnik I, Sejvar J et al. PML diagnostic criteria: Consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80(15):1430-1438.

26. Progressive Multifocal Leukoencephalopathy in HIV: Overview, Pathophysiology, Epidemiology [Internet]. Emedicine.medscape.com. 2016.

27. Wenning W, Haghikia A, Laubenberger J, Clifford D, Behrens P, Chan A et al. Treatment of Progressive Multifocal Leukoencephalopathy Associated with Natalizumab. New England Journal of Medicine. 2009; 361(11):1075-1080.

28. Progressive Multifocal Leukoencephalopathy (PML) [Internet]. Merck Manuals Professional Edition. 2016.

Received on 07.09.2016 Modified on 28.09.2016

Research J. Pharm. and Tech 2016; 9(12):2349-2353.

DOI: 10.5958/0974-360X.2016.00469.8