Download Progressive Multifocal Leukoencephalopathy and MS

PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY AND
MULTIPLE SCLEROSIS
Elizabeth M R Dragan, MD
December 9, 2015
Background
 Progressive multifocal leukoencephalopathy (PML) was first described in 1958 by
Aström and colleagues as an unexplained progressive white matter disorder. The
authors reviewed the literature and found reports of a similar disease dating back to
1930.
 In years following this publication, it was discovered that the pathology was due to a
viral infection. This virus was later named the JC virus.
 In 1984, Brooks and Walker reported on 230 cases of PML from their own
experiences and through review of the literature. 95% of the patients they reported
had an underlying diseases that resulted in immunodeficiency (mainly hematologic
malignancies, some autoimmune disorders and granulomatous diseases).
 The advent of the acquired immune deficiency syndrome (AIDS) epidemic in 1981 led
to a remarkable increase in the reports of PML.
 In 1993, 87% of the reported cases of PML were due to an underlying AIDS
infection1
Medications and PML
 There have been reports of PML and immune suppressive medications. This had
largely been reported in the oncology, transplant, or rheumatology literature until
2005.1
 In fact, rituximab and mycophenolate mofetil have black box warnings about PML. Although the risk
of PML with rituximab is about 1/30,000 and unknown for mycohphenolate mofetil.
 In 2005, the first cases of PML were reported with use of natalizumab. There were
three reported cases (2 in patients with multiple sclerosis (MS) and 1 patient with
Chron’s disease). These were the first reports of PML in patients with either
demyelinating disease or inflammatory bowel disease.1,2,3
Why do certain therapies increase the risk of PML
 To answer this we must understand the proposed mechanism of PML development:
 1. Primary infection
 What the primary infection does is debatable. Due to the presence of latent JCV found in the GI tract, some
propose it causes a GI illness. However, it is also found in the lungs, tonsils, spleen, bone marrow, and
kidney.
 2. Development of latent infection
 3. Gene re-arrangement to lead to a neurotropic form of the virus.
 B cells are thought to play the primary role in this due to the association of PML with B-cell malignancies and
diseases associated with B-cell activation such as AIDS.




4.
5.
6.
7.
Re-expression of the virus
Viral entry into the brain
Infection of the astrocytes and oligodendrocytes
Failure of CNS immune system1
Natalizumab and PML
 It was initially thought that combination therapies with natalizumab increased the
risk of PML since both of the initial reported cases occurred in patients that were
enrolled in the SENTINEL trial (combination interferon beta 1-a IM and natalizumab
vs interferon beta 1-a IM alone).2,3
 Subsequently, further analysis showed increased risk with use of prior immune
suppressive therapies, i.e. mycophenolate, cyclophosphamide, azathioprine, etc.4
 So, why does natalizumab treatment increase the risk of PML over other immune
suppressive therapies?
 Natalizumab blocks the binding of lymphocytes to vascular-cell adhesion molecule-1
expressed on endothelial cells in the brain and spinal cord. Thus decreasing CNS
immune surveillance.5,6
 In addition, natalizumab increases CD 34+ B lymphocyte production from the bone
marrow. Potentially explaining a mechanism of gene re-arrangement7
Risk of natalizumab associated PML
 Three major risk factors for the development of natalizumab associated PML
 Prior immune suppression
 Longer duration of treatment with natalizumab (>2 years)
 Presence of JC virus antibody (JCV Ab)4
 If a patient is JCV Ab positive, overall risk is:4
Duration of treatment
No prior immune
suppression
Prior immune
suppression
1-24 months
<1/1000
1/1000 (0.1%)
25-48 months
3/1000 (0.3%)
12/1000 (1.2%)
49-72 months
6/1000 (0.6%)
13/1000 (1.3%)
Risk of natalizumab associated PML
 In 2013, a second generation assay was developed in 2013 which is able to now give
an index which has further stratified risk of natalizumab associated PML
Index value
1-24 doses
25-48 doses
49-72 doses
≤0.9
0.1/1000 (0.01%)
0.3/1000 (0.03%)
0.4/1000 (0.04%)
≤1.1
0.1/1000 (0.01%)
0.7/1000 (0.07%)
0.7/1000 (0.07%)
≤1.3
0.1/1000 (0.01%)
1.0/1000 (0.1%)
1.2/1000 (0.12%)
≤1.5
0.1/1000 (0.01%)
1.2/1000 (0.12%)
1.3/1000 (0.13%)
>1.5
1.0/1000 (0.1%)
8.1/1000 (0.81%)
8.5/1000 (0.85%)
 *In patients with no prior immune suppression.8,9
Natalizumab associated PML
 To date, there are approximately 570 patients worldwide who have developed PML.
 The last update from Biogen in September 2015, reported a mortality of 23%.
Survivors have a varying level of disability.
 PML can occur up to 6 months after discontinuation of natalizumab.22
 Favorable prognostic factors include:




Younger age at diagnosis
Less functional disability prior to diagnosis
Lower JC viral load at diagnosis.
More localized brain involvement at diagnosis.4
Other Disease modifying therapies or agents and PML
 To date there have been 4 patients treated with dimethyl fumarate (Tecfidera) who
have developed PML (out of 170,000 patients treated worldwide).
 Dimethyl fumarate acts on the nuclear 1 factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which
transcribes multiple genes involved in antioxidative response.
 6% of patients experience grade 3 lymphopenia (<500 cells/mm3)10, 11
 The first three patients had lymphocytes less than 500 for long periods of time – i.e greater than 6
months. The fourth patient had lymphocytes around 600 cells/mm3)
 There have also been 4 reports of PML in patients treated with fingolimod (Gilenya)
without prior use of Tysabri (out of about 125,000 patients treated worldwide).
 Fingolimod acts to suppress lymphocyte egress from the lymph nodes.
 Lymphocyte counts drop to abut 75% of baseline.12, 13
 However, there is an increase in naïve B cell lymphocytes, memory and regulatory T cells, increased
CD80 and CD 86+ B cells and programmed death expression of follicular T cells.
Signs and Symptoms of PML
 Because PML can affect any area of the brain, the variability of the clinical
presentation is large.
 The most frequent presentation involves cognitive or behavioral changes (1/3 to
1/2 of patients). These seem to be more frequent in patients with MS than in
patients with AIDS who develop PML. This is followed by motor weakness and
language or speech abnormalities. Visual field defects and gait abnormalities have
also been reported. Headaches, seizures, diplopia, and sensory loss can occur, but
appear to be less frequent.
 Distinguishing between symptoms related to a MS relapse from PML can be
difficult.14
Radiographic/Laboratory features of PML
 Larger (> 3mm) T2 hyperintense lesions extending to the gray-white junction with
less periventricular involvement.
 T1 hypointense
 Enhancement is usually minimal (exception being with PML-IRIS).
 In natalizumab associated PML, lesions are predominantly frontal with some
involving the parieto-occipital regions.14, 15
 JCV PCR is only about 75% sensitive. Newer ultra sensitive, is about 95%
sensitive.14
MRI in PML
Honce JM, Nagae L, Nyberg E. Neuroimaging of Natalizumab Complications in Multiple Sclerosis: PML and
Other Associated Entities, 2015.
Current consensus for PML diagnosis (2013)14
Certainty of PML
diagnosis
Compatible
clinical features
Compatible
imaging findings
CSF PCR for JC
virus
Definite
+
+
+
Probable
+
-
+
-
+
+
+
+
-/not done
-
-
+
-
-
-
+
-
-
-
+
-
Possible
Not PML
PML-IRIS
 Immune Reconstitution Inflammatory Syndrome (IRIS) has been described in patients
with AIDS after starting highly active anti-retroviral therapy (HAART). This
phenomenon also occurs in patients with MS after stopping natalizumab.
 The initial course of action in a patient on natalizumab deemed to have PML is to
initiate plasma exchange to remove the drug. This can lead to IRIS.
 Mortality with PML-IRIS is reported as high as 30%.4, 15
PML-IRIS
Honce JM, Nagae L, Nyberg E.
Neuroimaging of Natalizumab
Complications in Multiple Sclerosis: PML
and Other Associated Entities, 2015.
MS rebound
 To further complicate things, interruption of natalizumab therapy is known to lead to
“rebound” or return of MS activity.
 The RESTORE study was designed to look at MS disease activity, pharmacokinetics,
pharmacodynamics and immune parameters in patients undergoing a 24 week
interruption in natalizumab dose. The purpose was to evaluate whether
natalizumab interruption was possible to use as a way to decrease total exposure
and therefore, potentially decrease PML risk.
 Patients were all previously treated with natalizumab for at least 12 months and then
randomized in a 1:1:2 fashion of natalizumab, placebo infusion, or other therapies
for 24 weeks. After 24 weeks all patients were placed back on natalizumab.
 MRI activity began at 12 weeks with relapses occurring as early as 4 to 8 weeks.16
MS rebound
 Fingolimod has also been reported to be associated with rebound. Most report
rebound occurring between 6 to 9 months after stopping therapy, but it has been
reported within 3 months of stopping.17, 18, 19, 20
 There has also been one report of rebound with dimethyl fumarate.20
MRI 3 months after stopping fingolimod
MRI 3 months after stopping fingolimod
MRI 3 months after stopping fingolimod
Treatment of natalizumab-associated PML
 Again, initial management is PLEX.
 Then you have to monitor for PML-IRIS.
 PML-IRIS is typically treated with IVMP. Some will initiate IVMP during PLEX or just
after in the hopes of preventing PML-IRIS.
 Other medications such as mirtazapine, cidofovir, cytarabine, and mefloquine are
used but studies have not shown a statistically significant benefit.21
Challenges in patients with MS
 1. Symptoms of PML can be the same as symptoms of a MS relapse.
 The exception being acute/relatively subacute cognitive or behavioral changes.
 2. MRI findings can overlap
 3. MS disease rebound after therapy is withdrawn.
 This typically happens 4 to 6 months after the last dose, but can occur as early as 8 weeks after the
last infusion.
 Rebound can lead to numerous enhancing lesions and rapid deterioration and even cognitive
changes.
 4. PML can develop after therapy is withdrawn
MRI in MS
MRIs of patients with advanced MS
PML is a MS patient
“. . . involving the subcortical U-fibers which also extent centrally to the
periventricular surface. (b) T2-weighted image on the same patient demonstrates
“granular” or “microcystic” foci (arrows).”
“. . . sharply demarcated peripheral border
along the subcortical U-fibers (arrow) and a
hazy, ill-defined central border (dashed arrow)”
Diffusion weighted images in PML
Diffusion weighted images in a patient with large PML lesions demonstrate
peripheral restricted diffusion where the lesion is active (arrows) and central
facilitated diffusion where the lesion is more quiescent (dotted arrows).
Case presentation
 35 yo W with history of relapsing-remitting MS since 2003 previously treated with
interferon beta 1-a IM (Avonex), on natalizumab (Tysabri) since approximately 2007.
JCV repeatedly negative.
 JCV returns positive and patient brought into clinic to discuss results and risks. At
that time, JCV index was unknown (later found to be 1.35). She has no known prior
immune suppression and had received 76 doses of natalizumab. Risk at that time
was approximately 5/1000. Due to having young children, she elected to stop
natalizumab and start fingolimod.
 At that time, our practice was to have a wash-out period of 12 weeks prior to
starting a new therapy. Her last dose of natalizumab was 6/26/13.
 She presented on September 17, 2013 with unsteady gait and blurry vision. She
was offered steroids, but declined. The confusion and unsteady gait progressed
(requiring use of cane) and she started PO steroids, but then lost the prescription.
Case
 She continued to worsen and ended up falling. She was started on IV steroids after
calling the clinic.
 During her second infusion, I was called by the infusion center to evaluate her.
 She had fallen the night before and had a cut across her forehead requiring sutures
at an outside hospital. She was now very confused (does not recognize me and I
saw her in July) and ataxic to the point of requiring a wheelchair.
 She was admitted to the hospital on 9/24/15 for IV steroids and further evaluation
for possible PML.
Admission Exam:
 Cranial Nerve Examination: VA 20/200 both eyes without glasses. Pupils poorly
reactive to light bilaterally, Right lower motor neuron facial droop. Tongue and
palate midline. 5/5 SCM strength.
 Motor Examination: 5/5 strength in the upper and lower extremities.
 Reflexes: 3+ biceps, triceps brachioradialis, patellar and ankle jerks.
 Sensation: Pinprick, and light touch intact throughout except decreased pinprick on
LLE
 Coordination: Bilateral dysmetria finger to nose.
 Gait, Balance and Posture: Pt very unsteady could only take a few small wide based
steps with support
MRI 9/25/13
MRI 9/25/13
MRI 9/25/13
Case
 Ultra sensitive JCV PCR from CSF was negative. Remainder of CSF studies: protein 53, glucose 86,
WBC 125, 94%L, RBC 5
 She was treated with IVMP for 7 days and transferred to inpatient rehab on 10/1 with the following
exam:
 Mental Status: Awake, oriented to person and place, not date but knows year. Speech fluent. Serial
'7s to 93. Can spell "world" backwards
 Cranial Nerve Examination: Fundi: Pupils equal, round, and reactive to light. Visual fields are full. Pt
has decreased upward gaze today with improvement and L upper quadrantopia.. No nystagmus.
Saccades normal. Normal light touch within distribution of fifth cranial nerve. No dysarthria. Lower
motor neuron facial droop in R chronic Hearing normal bilaterally to finger rub. Tongue and palate
midline. 5/5 SCM strength.
 Motor Examination: Normal bulk. 5/5 strength in the upper and lower extremities.
 Reflexes: 3+ biceps, triceps brachioradialis, patellar and ankle jerks.
 Sensation: Temperature, joint position, and light touch intact throughout.
 Coordination:mild dysmetria on FTN bilaterally
 Gait, Balance and Posture: Did not test
Case
 Inpatient team was called on 10/4/13 due to increased confusion and BLE
weakness, however, she was found to have an UTI. Recommendations were to treat
the UTI and monitor.
 We were called again on 10/7 because no improvement. She is alert, oriented to
person, time, and place. Speech fluent, but sometimes responds tangentially.
Comprehension and naming intact. Unable to perform serial sevens or recall three
items. No apraxia or neglect. Visual fields uta due do patient not cooperating, but
BTT bilaterally. Patient would not follow finger, unclear if not participating. 5/5 in
upper extremities, 2/5 in lower extremities bilaterally
 However, she was just started on antibiotics. So, recommendations remained the
same.
Case
 Inpatient team was again called on 10/9 because she was not improving.
transferred back to inpatient neurology.
She was
 Exam:
 Mental Status: Interval change in mentation and cooperativity. Alert but confused. Able
to name hospital as St. Luke’s, the city as Houston. But reported that she is 28 years
old, birthday in August and states the month is September. Speech fluent, but
sometimes responds tangentially. Comprehension and naming intact. Unable to perform
serial sevens or recall three items. No apraxia or neglect.
 Cranial Nerve Examination: Visual fields uta due do patient not cooperating, but BTT
bilaterally. APD on right. Mild right ptosis. EOMI appears grossly intact but was
inconsistent in track and follow. No nystagmus. Saccades normal.
 Motor Examination: At least 4/5 RUE, refused to voluntarily move LUE. At least 2/5 in
lower extremities bilaterally
 Sensation: Light touch grossly intact throughout.
 Coordination: Would not try FTN or RAM. No truncal or appendicular ataxia noted.
MRI 10/14/13
MRI 10/14/13
MRI 10/14/13
Case
 She was started on PLEX plus IVMP. However, she only received 5 doses due to
intermittent tachycardia between 130-140 and IVMP 3/5 days.
 10/14/13 Minimally responsive to voice, largely nonverbal, no purposeful
movements of extremities, minimal spontaneous movements. Left sided eyebrow
and left sided mouth twitching was noted on 10/14/13 and EEG was negative.
Repeat MRI brain on 10/14/13 showed diffuse worsening of supratentorial
enhancing leukoencephalopathy. MRI C-spine showed C2/3 level myelopathy
changes with enhancement. Patient was sent to ICU on 10/14/13.
 10/15/13 Repeat LP in ICU with unchanged results. At that time no JC Virus PCR
was sent. Patient became increasingly somnolent and continued to be treated with
levofloxacin and unasyn for UTI and remained with tachycardia with Cardiology
following. On 10/17 was transferred to floor and became increasingly less
responsive and it was decided to hold PLEX therapy (after 5 days) as reports of
transient clinical deterioration were present. IVMP 10/10 days were completed.
Case
 10/19/13 Febrile again, tachycardia worsened and R IJ was removed and culture sent. DVT screen
was negative at that time. Patient developed fever of 104F the following
 night and was found to be positive for CONS in IJ line. Due to sepsis, was transferred to ICU on
10/20/13 and placed on vancomycin and meropenem. At that time patient was no longer
grimacing to sternal rub, pupils were sluggish bilaterally, and eyes maintained downward gaze.
Extensor posturing was also observed to tactile stimuli. CTH showed no acute change and was
negative for hemorrhage, shift, or herniation. Patient became hypotensive in ICU and completed 7
day course of vancomycin. Was transferred to floor on 10/24/13 after stabilization.
 10/28/13 MRI showed confluent white matter lesions with possible U fiber involvement, bright on
DWI with scattered enhancement, which could be from MS, IRIS or PML given the recent
seroconversion status. Given initial improvement with steroids (1st admission) possibility of initial
MS exacerbation/IRIS followed by second event was considered.
 10/30/13 Patient received PEG by IR, also found to have ulcer on initial attempt by GI in OR.
 10/31/13 Plan was to start IVIG therapy 10/31 however patient had low grade fever, elevated
WBC, and U/A with mod leukocytes. Foley changed. Urine Cx Negative. Blood Cx Negative.
Case
 11/02/13 CONS bacteremia, VRE in urine. Treated with abx (recurs 11/12 - PICC
removed, 11/27)
 11/05/13 LP done, sample tested negative for JCV (9/25 negative also)
 11/06/13 Patient screened for DVT and found to have left calf DVT, IVC filter placed
same day.
 11/08/13 Hb trending down , 2 unit of PRBCs transfused. DIC panel, peripheral
smear and 3 FOB's sent were negative. Hematology felt it was anemia of chronic
disease.
 11/14/13 Brain biopsy done; showed findings consistent with MS. No JCV identified.
 11/20/13 Two Cyclophosphamide cycles administered on consecutive days.
Neurologically, did not show significant improvement afterwards. Planned to repeat
28 years later. Decision was made for placement in LTAC.
Case
 By 10/21, she was not following any commands and had tonic posturing vs tonic
spasms. She was opening her eyes to voice and intermittently tracking
 By 11/7, she was not tracking and not appearing to attend to any stimuli. She has
significant upper extremity rigidity and continued to have intermittent fevers.
 During this time, she completed another course of IVMP and started on IVIG.
 Repeat LP on 11/4/13, again had negative ultra sensitive JCV PCR. WBC 2, RBC 3,
protein 43, glucose 75.
MRI 11/8/13
MRI 11/8/13
MRI 11/8/13
MRI 11/8/13
MRI 11/8/13
Case
 She continued to decline and finally had a bran biopsy on 11/14/13 which revealed
demyelination, gliosis, marcophage influx and mild perivascular chronic inflammation
with focal axonal dilatation. There were no atypical or bizarre nuclei to suggest PML. It
was “most suggestive of primary demyelinating lesion of acute multiple sclerosis”.
 While waiting for biopsy results, she was treated with IVIG.
 She received cyclophosphamide 750mg/m2 daily for 2 days on 11/19 and 11/20.
 She finally stabilized neurologically.
But continued to have medical complications.
 She had some fluctuation in alertness, eye tracking, spontaneous 2/5 movement in LUE
and spasticity however. Infection with CONS and VRE recurred and was managed by
the ID service with daptomycin and ertapenem. Tachycardia persisted but improved to a
baseline of 100 with fluids, infection control and increased beta blockade using
metoprolol. She suffered hyponatremia in the setting of SIADH that was corrected with
salt tabs and demeclocycline. She received a 3rd infusion of cyclophosphamide on
December 18th
MRI 12/20/13
MRI 12/20/13
MRI 12/20/13
MRI 12/20/13
Discharge Exam
 Mental: spontaneous eye opening, no eye tracking, intermittently follows command
by squeezing fingers in left hand.
 Cranial Nerve Examination: PERRL, Blink to threat intermittently; symmetric grimace.
 Motor Examination: B/L LE tone variable and greater than upper extremities. UE
tone L>R. Continues with spasticity LUE > RUE, fluctuating since admission.
Intermittently moves LUE spontaneously 2/5 briefly.
 Sensation: Grimace to pain on all extremities.
 Coordination, Gait, Balance and Posture: unable to assess
Summary
 Natalizumab, fingolimod, and dimethyl fumarate all have an increased risk of PML.
 Natalizumab carries the highest risk of PML of all MS therapies to date.
 Risk factors for natalizumab associated PML include: prior immune suppression,
longer duration of treatment with natalizumab (>2 years), presence of JC virus
antibody (JCV Ab).
 Diagnosis of PML is based off of clinical findings, MRI findings, and JCV PCR status in
the CSF.
 Treatment of natalizumab associated PML is primarily PLEX and supportive therapy
 PML-IRIS can occur and carries a risk of mortality up to 30%. Treatment is IVMP.
Summary
 PML can develop up to 6 months after natalizumab discontinuation.
 Rebound of MS activity after treatment withdraw further complicates diagnosis of
PML.
 Early recognition and intervention is importance and helps with a better prognosis.
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