Progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a disease of the white matter of the brain, caused by a virus infection that targets cells that make myelin--the material that insulates nerve cells (neurons). Polyomavirus JC (often called JC virus) is carried by a majority of people and is harmless except among those with lowered immune defenses. The disease is rare and occurs in patients undergoing chronic corticosteroid or immunosuppressive therapy for organ transplant, or individuals with cancer (such as Hodgkin’s disease or lymphoma). Individuals with autoimmune conditions such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus -- some of whom are treated with biological therapies that allow JC virus reactivation -- are at risk for PML as well. PML is most common among individuals with HIV-1 infection / acquired immune deficiency syndrome (AIDS). Currently, the best available therapy is reversal of the immune-deficient state, since there are no effective drugs that block virus infection without toxicity. Reversal may be achieved by using plasma exchange to accelerate the removal of the therapeutic agents that put patients at risk for PML. In the case of HIV-associated PML, immediately beginning anti-retroviral therapy will benefit most individuals. Several new drugs that laboratory tests found effective against infection are being used in PML patients with special permission of the U.S. Food and Drug Administration. Hexadecyloxypropyl-Cidofovir (CMX001) is currently being studied as a treatment option for JVC because of its ability to suppress JVC by inhibiting viral DNA replication.

In general, PML has a mortality rate of 30-50 percent in the first few months following diagnosis but depends on the severity of the underlying disease and treatment received. Those who survive PML can be left with severe neurological disabilities.

1. Amr Hassan, MD,FEBN
Professor of Neurology
Cairo University -Egypt
Progressive multifocal
leukoencephalopathy (PML)

2. ▪John Cunningham virus (JCV) is a
double-stranded DNA
polyomavirus.
▪Takesitsnamefromtheinitialsof
thepatientfromwhomitwas
firstisolated.
▪PMLwasinitiallydescribedin
patientswithunderlyingB-cell
lymphoproliferativedisorders[1]
JC virus

3. JC virus

4. Progressive Multifocal Leukoencephalopathy

5. JCPyVand the development of PML

6. JCPyVand the development of PML

7. JCPyVand the development of PML

15. ▪50-90% of adults have been exposed to this virus
▪19-27% of these people shedding JCV in their urine.
[5,7-10]
▪Acquisition of this virus is not associated with a clinical
syndrome.
[9]
▪Opportunistic infection, caused by the polyomavirus JC virus
▪Characterized by focal demyelination in the CNS
▪Worldwide distribution, seroprevalenceof 39-69% in adults
▪Primary infection usually in childhood
▪No recognized acute JC virus infection
▪Likely asymptomatic chronic carrier state
PML: epidemiology

16. In a large review spanning the 30 years from 1958 to
1984, only 230 cases were identified, with only 69 being
confirmed pathologically.
PML: epidemiology

17. PML: epidemiology

19. •B-cell malignancies
•Other myeloproliferativediseases,
•Carcinomas
•Congenital immune deficiencies
•Organ transplantation
•Granulomatous, inflammatory,orother immune-
mediated conditions.
•3-7% of persons with AIDS
Conditions associated with PML

20. –Adenosine deaminase deficiency
–CD40 ligand deficiency
–Comimmunedeficiency bined
–Common variable immune deficiency
–DOCK8 (dedicator of cytokinesis 8
protein) deficiency
–Gamma heavy chain disease
–Hyper-IgM syndrome
–Immunodeficiency-centromeric
instability-facial dysmorphismsyndrome
syndrome
–Purine nucleoside phosphorylase
deficiency
–Severe combined immune deficiency
–Signal transducer and activator of
transcription 1 gain-of-function immune
deficiency
–Wiskott-Aldrich syndrome
–X-linked agammaglobulinaemia
–Idiopathic CD4+ lymphopenia*
ZerbeCS, Marciano BE, KatialRK, Santos CB, AdamoN, Hsu AP, et al.ProgressiveMultifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of
Function and Review of the Literature. ClinInfect Dis. 2016;62(8):986–94.
Hereditary immune deficiencies linked to
PML

21. –Human immunodefiencyinfection or
acquired immune deficiency syndrome
–Haematopieticstem cell
transplantation
–Immunosuppressive therapy in organ
transplant recipients
–Haematologicalmalignancies
(e.g. lymphomas and leukaemias)
–Immunosuppression during
chemotherapy of solid cancers
–Systemic lupus erythematosus
–Sarcoidosis
–Immunosuppressive or -modulatory
therapy in autoimmune diseases (rheumatoid
arthritis, psoriatic arthritis, psoriasis, juvenile
idiopathic arthritis, inflammatory bowel
disease, ankylosing spondylitis, multiple
sclerosis)
Brew BJ, Davies NW, Cinque P, Clifford DB, NathA. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol. 2010;6(12):667–79.
Amend KL, Turnbull B, FoskettN, NapalkovP, KurthT, Seeger J. Incidence of progressive multifocal leukoencephalopathy in patients without HIV. Neurology. 2010;75(15):1326–32. doi
Acquired immune deficiencies linked to PML

22. Organ Transplant:
Heart, lung, kidney
1/1000
HIV
AIDS-defining
1/100 without HART
6/10.000 with HAART
Bone marrow
Transplant
3.5/10.000 per year
Hematologic
Malignancies
8.3/100.000 per year
In lymphoma
Immunomodulatory
Treatments
(e.g.in MS)
Rheumatologic
Conditions
1/100.000 per year
Conditions associated with PML

23. –Natalizumab
–Efalizumab
–Belimumab
–Rituximab
–Fingolimod
–Dimethylfumarate
–Alemtuzumab
–Tumournecrosis factor-alpha inhibitors (infliximab, adalimumab, etanercept)
–Ofatumumab
–Mycophenolatemofetil
–Betalacept
–Brentuximab
–Fludarabine
–Ruxolitinib
–Leflunomide
Major EO. Progressive multifocal leukoencephalopathyin patients on immunomodulatorytherapies. AnnuRev Med. 2010;61(1):35–47.
Brew BJ, Davies NW, Cinque P, Clifford DB, NathA. Progressive multifocal leukoencephalopathyand other forms of JC virus disease. Nat Rev Neurol. 2010;6(12):667–79.
ZaheerF, Berger JR. Treatment-related progressive multifocal leukoencephalopathy: current understanding and future steps. TherAdvDrug Saf. 2012;3(5):227–39.
Berger JR. Classifying PML risk with disease modifying therapies. MultSclerRelatDisord. 2017;12:59–63.
Immunomodulatorytreatments linked to
PML

24. –Natalizumab
–Efalizumab
–Belimumab
–Rituximab
–Fingolimod
–Dimethylfumarate
–Alemtuzumab
–Tumournecrosis factor-alpha inhibitors (infliximab, adalimumab, etanercept)
–Ofatumumab
–Mycophenolatemofetil
–Betalacept
–Brentuximab
–Fludarabine
–Ruxolitinib
–Leflunomide
Immunomodulatorytreatments linked to
PML
Major EO. Progressive multifocal leukoencephalopathyin patients on immunomodulatorytherapies. AnnuRev Med. 2010;61(1):35–47.
Brew BJ, Davies NW, Cinque P, Clifford DB, NathA. Progressive multifocal leukoencephalopathyand other forms of JC virus disease. Nat Rev Neurol. 2010;6(12):667–79.
ZaheerF, Berger JR. Treatment-related progressive multifocal leukoencephalopathy: current understanding and future steps. TherAdvDrug Saf. 2012;3(5):227–39.
Berger JR. Classifying PML risk with disease modifying therapies. MultSclerRelatDisord. 2017;12:59–63.

25. Least concern :
Interferon beta, glatirameracetate
Some concern:
Alemtuzumab(Lemtrada)
Teriflunamide(Aubagio)
Fingolimod(Gilenya)
Dimethyl fumarate(Tecfidera)
High concern:
Natalizumab(Tysabri)
Carson et al. 2009; Berger et al. 2013
Concern for PML

26. 26
•Focal neurologic deficits, usually with insidious onset,
steady progression over several weeks/months
•Demyelinating lesions may involve any region of the
brain
–Common: occipital lobes (hemianopsia), frontal and parietal
lobes (aphasia, hemiparesis, hemisensorydeficits), cerebellar
peduncles and deep white matter (dysmetria, ataxia)
–Spinal cord involvement is rare
PML: Clinical Manifestations

27. 27
•Headache and fever not characteristic (except in severe IRIS)
•Seizures in 20%
•Cognitive dysfunction may occur but diffuse encephalopathy or
dementia is rare
PML: Clinical Manifestations

28. PML: Radiological diagnosis
An early progressive
multifocal
leukoencephalopathy (PML)
patient within 6 days of PML
diagnosis with a large (A)
T2-hyperintense and (B) fluid-
attenuated inversion
recovery–hyperintense lesion
in the right frontal lobe. The
lesion was (C) T1
hypointense and (D)
diffusion-weighted imaging
hyperintense, with sharp
scalloped borders toward the
gray matter and illdefined
borders toward the white
matter.

29. PML: Radiological diagnosis

30. 30
PML, CT scan PML, MRI scan
PML: Radiological diagnosis
CT scan: single or multiple hypodense, nonenhancingwhite matter lesions

31. PML: Radiological diagnosis
Progressive multifocal leukoencephalopathy (PML) radiographically.
(a) Typical lesion of PML as a T2 hyperintensity
involving large portion of 1 hemisphere. (b) T2 fluid-attenuated
inversion recovery image demonstrating hyperintensity in the bilateral
cerebellum consistent with PML

32. PML: Radiological diagnosis
Contrast enhancement in 10-15% but usually sparse, IRIS PMN may have different appearance
An early progressive multifocal leukoencephalopathy (PML) patient who developed PML-immune reconstitution
inflammatory syndrome (IRIS). At the time of PML diagnosis, this patient had (A) a diffuse T2-hyperintense lesion in the right
frontal lobe and (B, arrows) multiple punctate T2 lesions in the vicinity of the main lesion. The lesion was (C) T1 hypointense
and (D) DWI hyperintense. (E) The lesion had increased in size by the IRIS phase, which was 37 days after the first scan, and (F)
exhibited contrast enhancement on T1-weighted (T1W) imaging. (G) Ten days later, there was a T1-hyperintense rim around
the lesion on precontrastT1W imaging, which (H) did not enhance postcontrast, although punctate enhancement was seen in
the contralateral hemisphere.

33. PML: Radiological diagnosis
Diffusion-weighted imaging and MR
spectroscopy may give additional
diagnositicinformation
FIGURE 3: (A) In this early
progressive multifocal
leukoencephalopathy (PML)
patient, PML was difficult to
distinguish from
the confluent lesion burden on the
fluid-attenuated inversion recovery
(FLAIR) image. (B) However, the
hyperintensity in diffusion-
weighted imaging identified new
areas of abnormality. A further
magnetic resonance examination 6
days later showed (C)
an increase in size of the right
frontal lesion on FLAIR with (D) T1
hypointensity.

34. PML: Radiological diagnosis
FIGURE 4: A patient with an early
progressive multifocal
leukoencephalopathy lesion filling a
segment of the precentral gyrus.
The lesion was (A) T2 hyperintense,
(B) hyperintense on diffusion-
weighted imaging, and (C–E) more
readily seen on fluid-attenuated
inversion recovery (FLAIR). (A, C)
Punctate T2-/FLAIR-hyperintense
lesions were seen in the vicinity of
the main lesion.
(D) The lesion increased in size
during the IRIS phase (D; 51 days
after the first scan) and (E) the post-
IRIS phase (85 days after
the first scan). No enhancement was
noted at any stage.

35. PML: Radiological diagnosis
FIGURE 5: An early progressive
multifocal leukoencephalopathy
(PML) patient, 9 days prior to
PML diagnosis, shows (A) an
unusual cluster of punctate T2-
hyperintense lesions, many of
which (B) were enhanced with
contrast on T1-weighted (T1W)
imaging and were diffusion-
weighted imaging (DWI)
hyperintense. (D) The lesions
became confluent on a T2-
weighted followup
scan 30 days later. (E) There was
no contrast enhancement on
T1W imaging, but (F) the cluster
remained hyperintense on
DWI.

36. From: Natalizumab-Associated Progressive Multifocal Leukoencephalopathyin a Patient With Multiple Sclerosis: A Postmortem Study
J NeuropatholExpNeurol. 2013;72(11):1043-1051. doi:10.1097/NEN.0000000000000005
J NeuropatholExpNeurol| © 2013, by the American Association of Neuropathologists, Inc.
PML: Radiological diagnosis

37. PML: Radiological diagnosis
Magnetic resonance imaging evaluation of multiple sclerosis (MS) and progressive
multifocal leukoencephalopathy (PML). After receiving 55 infusions of Natalizumab
(May 2013). Axial FLAIR (A) and corresponding contrast enhanced T1W images (B)
show MS lesions in the periventricular white matter and a new area of hyperintense
FLAIR signal (white arrow) and faint enhancement (black arrow) in the left parietal
subcortical white matter.

38. PML: Radiological diagnosis

39. PML: Radiological diagnosis
Figure 3:Evolution of progressive multifocal leukoencephalopathy –Immune reconstitution
inflammatory syndrome (PML-IRIS). Axial FLAIR and corresponding contrast enhanced T1W
images through the parietal lobe. (A) Ten weeks after Natalizumab discontinuation and
before steroid treatment (October 21, 2013), there is further extension of the parietal lobe
white matter lesion (white arrows) with associated enhancement (black arrowheads). (B)
Eleven weeks after Natalizumab discontinuation and after IV steroid therapy (October 29,
2013), there is decreased enhancement without change in FLAIR signal abnormality. (C) 6-
month follow up after steroid treatment, there is further improvement with complete
resolution of the enhancement.

40. Elizabeth C. Neil, and Lisa M. DeAngelisBlood Adv2017;1:2041-2045© 2017 by The American Society of Hematology
PML: Radiological diagnosis

41. Features Characteristics
Location SubcorticalLocation is the prime site,therebyinvolving U-fibers cortex and basal ganglia are
often involved; often bilatcral
Size Usually> 3cm
Borders Sharptoward the gray matter, ill defined toward the white matter
Modeof extension Lesionsincrease in size and new lesions appear
Mass effect No mass effect in small or large lesions
T2W images Always hyperintense
T1Wimages Typically hypointense;no reversion of signal intenstiy; hyperintensityis suggestive of PML-
IRIS
FLALR Alwayshyperintense; better appreciated than om T2W images
DW images Always hyperintense; in larger lesions thereis a hyperintenserim at the lesion’s edge
Perilesional Small,punctate T2-hyperintense lesions in the immediate vicinity of the main lesion are
often present
Enhancement Frequentenhancement, punctate and/or rimlike
Atrophy Noatrophy in the early phase
Ann Neurol.2012 Nov;72(5):779-87. doi: 10.1002/ana.23676.
PML: Radiological diagnosis

42. •CSF evaluation for JC virus DNA (BY PCR): helpful
positive; 70-90% sensitive in patients who are not on
ART(lower in those on ART)
•Specificity 92-100%
•Sensitivity 72-93%
•Serologic testing generally not useful,butnewer
approaches under investigation
PML: diagnosis

43. PML: Brain biopsy
•Identification of JC virus;
•Oligodendrocytes
with intranuclearinclusions
•Bizarre astrocytes,
•Lipid-laden macrophages

44. Berger et al. 2013

45. Featuresindicative of
MS PML
Onset Acute Sub-acute
Evolution •Overhours to days
•Normally stabilise
•Resolve spontaneously
even without therapy
•Over weeks
•progressive
Clinical
Presentation
•Diplopia
•Paraesthesia
•Paraparesis
•Optic neuritis
•myelopathy
•Aphasia
•Behaviouralor cognitive
changesand neuropsychological
alteration
•Retrochiasmalvisual deficits
•Hemiparesis
•Seizures
•Ataxia (for GCN)
PML VsAn attack

46. Fernándezet al Neurologia2012;27:432-41
PML VsAn attack

47. Pei-Ran Hoet al., Risk of natalizumab-associated progressive multifocal eukoencephalopathyin patients with multiple sclerosis: a retrospective analysis of data from four clinical
studies.Lancet,2017.S1474-4422(17)30335-6
PML and Natalizumab

48. Global NatalizumabPML Risk Estimates by
Treatment Epoch :March 2017

49. As of November 30, 2017, the global overall incidence of
PML in natalizumab-treated patients is: 4.19per 1000
patients (95% CI 3.89 to 4.49 per 1000 patients).
As of December 7, 2017 there have been 756confirmed
PML cases (753 MS, 3 CD), (205 US, 480 EEA, 71 ROW)
76.5% of patients were alive with varying levels of disability*
As of December 7, 2017, the duration of natalizumab
dosing prior to PML diagnosis ranged from 8 to 136 doses
Biogen, data on file.2017
PML and Natalizumab

50. PML and MS therapeutics

51. PML and Fingolimod

52. PML Cases in Patients Switching From
Natalizumabto Fingolimod
•Cases reported at ECTRIMS 2014
•Background: Now >135,800 patient-years of experience with fingolimod
accumulated; about 15–20% of patients were pre-exposed to natalizumab
1
•Objective: To investigate characteristics of the PML cases under fingolimod (post
natalizumab)1
•Data from Novartis pharmacovigilance database
1
•11 reports of PML to date; most had fairly long exposure to natalizumab (2.5–6.0
years, mean 4 years, median 5 years)
1,2
•10/11 cases had PML before fingolimod start or PML occurred within 6 months
after switch to fingolimod (washout (n=4) 1–5 months, information around JCV
status not always known)
•1 additional case; no previous exposure to natalizumab was reported as PML after 7
months of fingolimod treatment; clinical features and MRI evolution consistent with
neuromyelitis optica. Diagnosis made based on the results of CSF showing low copy
number of JCV
1
•The presenter argued for vigilance for PML following natalizumab discontinuation
1
1. Putzki N et al. ECTRIMS 2014. FC3.1; 2. Medscape Pharmacists.September 25, 2014.
52

53. PML and Fingolimod

54. PML and Fingolimod

55. PML cases with Gilenya in patient not
pre-treated with Tysabri
•1
st
case reported in Feb 2015
1,2
•49 year old male diagnosed with RRMS in 2009. Received prior treatment with Rebif which was
discontinued without initiating any other treatment, switched to Gilenya in October 2010.
Diagnosed with PML in January 2015
•No co-existing conditions reported, no concurrent treatment along with Gilenya, never received
Tysabi
•2
nd
case reported in July 2015
3,4
•54 year old female, developed PML after taking fingolimod for ~ 2.5 years. The patient had a
13-14 year history of MS and was previously treated with Betaferon for ~ 11 years. She also
received mesalazine for ulcerative colitis for the last 4 years
•FDA issued a warning regarding the 2 PML cases on Gilenya
3
•3
rd
case reported on August 17, 2015
4
•Patient had a history of colorectal cancer treated with chemotherapy and radiation treatment,
as well as Crohn’s disease. The role of various risk factors are currently evaluated
55
1. Novartis PressRelease on Feb16, 2015, availableon http://www.novartis.com/newsroom/product-related-info-center/gilenya-safety-update.shtml 2.
https://beta.mssociety.ca/research-news/article/case-of-pml-reported-in-patient-treated-with-gilenya(accessedAug24, 2015). 3.
www.fda.gov/Drugs/DrugSafety/ucm456919.htm(accessedAug24, 2015) 4. www.medscape.com/viewarticle/849015.

56. PML and DMF

57. 5 cases were associated with DMF use for multiple sclerosis
14 cases for psoriasis.
PML and DMF

58. PML cases with dimethyl fumarate
1. Rosenkranz et al New Engl. J Med 2015; 372: 1476-1478. 2.http://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RI/2015/RI-dimethylfumarat.html Accessed July
21, 2015. 3. http://www.medpagetoday.com/Neurology/MultipleSclerosis/52622?isalert=1&uun=g274661d4296R5269425u&xid=NL_breakingnews_2015-07-16, accessed July 21, 2015 4.
Nieuwkamp, e al New Engl. J Med 2015; 372: 1474-1476, 5. Philipp et al 2013 et al, Eur. J Dermatol 2013; 23(3): 339-43 6. Spencer et al, Neurol Neuroimmunol Neuroinflamm 2015;2:e76
•Case 1
1
: Female, 4.5 years on DMF (participated in the DEFINE trial)
•3.5 years having severe lymphopenia (start 12 month after tx initiation, lymphocyte count, 290 to 580 cells per mm
3
).
Died from complications of pneumonia.
•On April 7, 2015, the German authorities mentioned 2 PML cases with Tecfidera (+ 9 with Fumaderm) but no
details provided
2
•On July 17, 2015, also Biogen confirmed a 2
nd
PML case with Tecfidera, (likewise no details provided)
3
•Role of lymphopenia
•About 2% of patients treated with DMF
develop lymphopenia < 500 cells per mm
3
)
1
•Monitoring of lymphocyte recommended
to prevent severe opportunistic infections
4
*
•In April 2015, Nieuwkamp et al published
a PML case with (compounded) DMF
for the tx of psoriasis. This patients had no
major lymphopenia (nadir 792 cells per mm
3
)
and no other immunosuppressive
therapies
4
*Researchers increasingly recommend to determine
besides the commonly-used differential blood counts
also lymphocyte subsets (mainly CD4+ and CD8+
Tcells)
5,6
Depletion of CD8+ T cells seems to be
more pronounced than that of CD4+T cells.
6
58

59. The PML case with
dimethyl fumarate led to
label change in the US
59
Description of the fatal PML case with Tecfidera
and initial signs/symptoms of PML
Recommendation to obtain complete blood
count (CBC) at baseline, after month 6 and in
due course every 6-12 months. Interrupt
treatment if lymphocyte counts are < 0.5 x 10
9
/L
persisting for more than 6 monthsNote: According to the European label, CBC should
be obtained at baseline, after 6 months and thereafter
every 6-12 months. No mention of PML in the label
Tecfidera US prescribing information, European Tecfidera prescribing information

60. PML and Teriflunomide

61. •A single fatal case
•Reported in a patient who switched from natalizumab
to alemtuzumab.
•however, retrospective analysis of the MRI data
showed that the onset of PML predated alemtuzumab
treatment and, therefore, was attributed to
natalizumabtreatment
Thomas Berger et al.,AlemtuzumabUse in Clinical Practice: Recommendations from European Multiple Sclerosis Experts.CNSDrugs. 2017; 31(1): 33–50.
PML and Alemtuzumab

62. PML and Ocrelizumab

64. •No specific treatment
•Restoring the immune system:
•Antiretroviralsin HIV
•Plasma exchange to remove natalizumab
•No proven benefit: Ara C, IFN gamma, IL-2, cidofovir,
mefloquine, mirtazapine
•Case report: 2 patients with CD4 lymphopeniaIL-7 and
vaccination with JCV VP1 protein
Sospedraet al. 2014
Treatment of PML

65. •Plasma exchange x3 (over 5-8 days)
•Accelerates clearance of free natalizumab
•(but still alpha-4 integrin receptor binding)
•Side effects: clearance of other medications,
hypotension, pulmonary edema (volume shift)
Khatriet al. 2009
Treatment of PML

66. ▪Younger age at PML
diagnosis
▪Lower pre-PML EDSS
▪Lower JC viral load at
diagnosis
▪More localisedbrain
involvement by MRI at the
time of diagnosis
▪Asymptomatic at diagnosis
Factors that appear to be
associated with improved
survival
Factors that do not appear to
affect survival
▪Gender
▪Prior immunosuppressant
therapy
▪MS duration
▪Natalizumabexposure at PML
diagnosis
▪Gdenhancement on MRI at
diagnosis
Survival in PML

67. •Clinical worsening due to improvement of immune
function rapid worsening.
•Neurological symptoms, fever, seizure.
•In most patients with natalizumab(up to 90%).
•3-6 weeks after antiretroviralsor plasma exchange.
Immune Reconstitution Syndrome (IRIS)

68. Enlarged lesions
Contrast enhancement
Mass effect
Immune Reconstitution Syndrome (IRIS)

69. Copyright © 2007 American Medical
Association. All rights reserved.
From: Potential Risk of Progressive Multifocal Leukoencephalopathy With Natalizumab TherapyPossible
Interventions
Arch Neurol. 2007;64(2):169-176. doi:10.1001/archneur.64.2.169

70. THANK YOU
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