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Retinal nerve fibre layer thinning is associated

with drug resistance in epilepsy


Krishna Chinthapalli,Josemir W Sander,Sanjay M Sisodiya

Department of Clinical and Experimental


Epilepsy,
UCL Institute of Neurology, London, UK

The retinal nerve fibre layer (RNFL) contains glia


and the unmyelinated axons of retinal ganglion
cells
Retinal axons are devoid of myelin until they
penetrate the lamina cribrosa
The evaluation of RNFL thickness has been
suggested as a method of assessing axonal
integrity in the visual pathway.

Optical coherence tomography (OCT) is a noninvasive technique for cross-sectional imaging of


retinal microstructure and quantification of RNFL
thickness
Widespread white matter involvement in epilepsy
has already described
DTI and volumetric MRI have demonstrated
abnormalities in white matter integrity in people
with temporal lobe epilepsy

AIM
To study the clinical and neuroradiological
features of epilepsy associated with RNFL
thinning

METHODS
Participants
454 adult patients 18-60 years with epilepsy able
to undertake OCT were consecutively included in
this cross-sectional cohort study.

Ninety healthy control participants were


recruited.
People were recruited from tertiary care clinics at
the National Hospital for Neurology and
Neurosurgery from September 2008 to August
2013.
Demographic and clinical data were obtained.

Exclusion Crtieria

Previous exposure to vigabatrin


Diabetes
Glaucoma or other known ocular disease
Concurrent diagnosis of multiple sclerosis
History of trauma or surgery to the eye or orbit
Refractive error of >4.50 dioptres mean sphere/
>2.5 dioptres cylinder
Brain MRI evidence of visual pathway
involvement

Clinical data
The following variables were evaluated:
Age, sex, ethnicity
Epilepsy diagnosis, duration of epilepsy (from the
time of diagnosis to the date of OCT assessment)
Handedness, intellectual disability
Antiepileptic drug (AED) history
Epilepsy surgery
Presence of VNS

Intellectual disability was defined as an


IQ<70

Drug resistance was defined as previous


failure of adequate trials of two tolerated,
appropriately chosen and used AED schedules
(whether as monotherapies or in combination) to
achieve sustained (>12 months) seizure freedom
Anyone who had therapeutic neurosurgical
resection for the treatment of epilepsy was
considered drug-resistant .

Optical coherence tomography


All participants were assessed using spectraldomain OCT (Cirrus OCT; Carl Zeiss Meditec,
USA), by six experienced operators.
Average RNFL thickness in the peripapillary area
and the four 90 quadrants (temporal, nasal,
superior and inferior) was measured.
The automated report gave the percentile into
which the RNFL thickness fell, based on the
manufacturers internal database of age
corrected normal values

Normal 5th - 95th centiles,


Borderline 1st - 5th
Abnormal <1st centile).
Only data from the right eye were analysed

Brain MRIs performed within a 12-month interval


before or after OCT were evaluated.

Standard protocol approvals,


registrations and consent
This study was approved by the institutional
ethics committee.
All participants provided written informed
consent.

Statistics
Data were analysed using Stata/IC V.11.1 soft
ware
(Stata, Texas, USA).

RESULTS
Three hundred of the 454 people with epilepsy
attending specialist clinics were included in this
study.
Their scans were analysed and compared to results
from 90 healthy controls.
Most people had drug-resistant epilepsy (210
individuals 70 %) and long disease duration (mean
23.3 years, SD 15.1)
The average RNFL thickness and the thickness of
each 90 quadrant were significantly lower in people
with epilepsy than in healthy controls
No control had abnormal RNFL thinning (<1st centile)

Average RNFL thickness and


clinical characteristics
It was found that a correlation between smaller
average RNFL thickness and Increasing Age
(p<0.001) and Epilepsy Duration (p=0.015)
Age was not correlated with RNFL thickness in the
modest number of healthy controls (p=0.919)
Average RNFL thickness was greater in females
(88.8 mm14.0 SD) than males (85.5 mm13.3
SD;p=0.021).

People with epilepsy and intellectual disability


had thinner average RNFL (83 mm12.5 SD) than
those with normal intellectual function (86.1
mm14.8 SD; p=0.049)
There was no difference in the distribution of
RNFL thickness according to handedness
(p=0.523), epilepsy type (p=0.219, ANOVA) or
ethnicity (p=0.436).

The effect of different AED combinations on RNFL


thickness was not tested.
The presence of VNS was also associated with
thinner average RNFL thickness.
Operated patients had thinner average RNFL (82.5
mm15.7 SD) than healthy controls (95.3
mm8.8 SD; p<0.001).

There was no significant correlation between the


average RNFL thickness and the total number of
AEDs taken(p=0.154).
People with drug-resistant epilepsy had thinner
average RNFL (84.2 mm 13.9 SD) than people
with non-resistant epilepsy (88.1 mm 15.3 SD;
p=0.038, t test), who in turn had thinner average
RNFL than healthy controls (95.3 mm8.8 SD;
p=0.001).

Multivariate linear regression showed


significant association for RNFL thinning only
with epilepsy duration, intellectual disability,
drug resistance (p<0.001)
Multivariate logistic regression model-Only
Drug resistance

Correlation between average RNFL thickness


and MRI brain volumes
Of 300 people with epilepsy, 212 had an MRI
performed within12 months of OCT
172 MRIs were included (107 interpreted as
normal, 65 as abnormal)
A significant association between RNFL thickness
and brain parenchymal fraction was found
(p=0.010).

Discussion
People with drug-resistant epilepsy have a more
than twofold of RNFL thinning compared with
people with non-resistant epilepsy
The biological mechanisms leading to the
association between RNFL changes and
intellectual disability, lower brain parenchymal
fraction or drug resistance are unknown

Retina and brain share common embryonic


origin and patterns of gene expression.
Physical association between these two
structures of neuroectodermal origin also
manifest through trans-synaptic
degeneration
-A process occurring when damage spreads from
posterior to anterior visual pathway or vice versa,
described in several central nervous system diseases, with
neuronal damage caused by a focal brain lesion affecting
the function and morphology of remote, apparently intact,
regions following interruption of brain circuits

In people with temporal lobe epilepsy, transsynaptic degeneration of the limbic system or
extratemporal areas has been demonstrated
using MRI, PET and SPECT
Several previous studies have suggested that
correleation between RNFL thickness and brain
parenchymal fraction in MS independent of optic
neuritis
This is the first study in epilepsy, which showed a
significant association between RNFL thinning
and lower brain volume as assessed by brain MRI.

In the analysis, drug resistance is an independent


predictor of a borderline or abnormal RNFL
thickness.
One possible explanation is that ongoing seizures
cause cerebral damage that may manifest in
lower brain parenchymal fraction and secondary
thinning of RNFL.
There are alternative interpretations, such as the
concept of intrinsic epilepsy severity,
Developing this theory, thinner RNFL, smaller
brain parenchymal fraction and presence of
intellectual disability might all be part of a more
severe epilepsy condition from outset.

Limitations
Though excluded participants with known glaucoma,
glaucoma might be asymptomatic or undiagnosed.
Individuals with intraocular pressure in the normal
range might still have normal-tension glaucoma and
RNFL thinning.
A cross-sectional study may not yield the strongest
correlations.

This association need to be confirmed in future


prospective studies

OCT is a fast, reproducible, non-invasive, welltolerated and cost-efficient investigation.


OCT is is much cheaper to run and can be
undertaken and interpreted by easily trained
operators.
RNFL thickness might be considered as an
objective, complementary and repeatable
measure of the biology of drug resistance, and
possibly disease severity.

Comments
RNFL- Syndromic Epilepsy -need to be explored.
The study included fewer controls than cases.

Study of novel risk factors for


PRES in SLE
Javier Merayo-Chalico et al.

PRES is a clinicalradiological entity with main


clinical manifestations as seizures, altered
mental status and visual impairment.
Different entities have been associated with
PRES, including hypertension, preeclampsia/
eclampsia, renal dysfunction, cytotoxic drugs,
systemic infections and autoimmune diseases.
Systemic lupus erythematosus (SLE) is the
autoimmune disease that has more frequently
been associated with PRES when comapred with
others.

Up to 50% of patients with SLE may present


neurological signs or symptoms throughout their
disease
Various neuropsychiatric syndromes have been
described in SLE and PRES is not one of them.
The most relevant risk factors for the SLE/PRES
Lupus nephritis
Hypertension,
High activity scores according to Systemic Lupus
Erythematosus Activity Index (SLEDAI)
Recent use of immunosuppressive drugs.

Aim
To identify of the novel risk factors associated
with SLE/PRES

A retrospective, casecontrol study


PATIENTS AND METHODS
Data regarding patients were collected from
clinical records of four tertiary level hospitals in
Mexico from January 1999 to May 2014.
Cases :Patients with the SLE/PRES association
Control groups :
1)Patients with SLE without PRES (SLEwoPRES)
2)Patients with PRES without SLE (PRESwoSLE)
SLE diagnosis was considered when patients fulfilled
at least four American College of Rheumatology
classification criteria

Exclusion:
Patients with another rheumatological
disease were excluded.
Persistent lymphopenia :
At least two peripheral blood lymphocyte
counts <1000 cells/mm3, at least 3 months apart.
Dyslipidemia :
Hypercholesterolaemia 5.18 mmol/L
and/or hypertriglyceridaemia 1.69 mmol/L).

PRES -Neurological manifestations


seizures
visual impairment
altered mental status
intense occipital headache
MRI findings of vasogenic oedema

Isointensity or hypointensity in T1
Hyperintensity in T2 and FLAIR sequences
No restriction on DWI

Diagnosis was made by neurologist and neuroradiologist and


the same was documented in records

Serum markers:
Double-stranded DNA
ANA
Anticardiolipin
Anti-2-glycoprotein
C3 and C4 levels
PRES reversibility was defined on follow-up
clinical evaluation and in some cases was confirmed
by MRI.

ETHICS
The study was approved by the local ethics
committees.

STATISTICS
Data were analysed with SPSS V.21

RESULTS

168 patients were analysed


43 -SLE/PRES
96 - SLEwoPRES
29 -PRESwoSLE.

Most events of PRES in patients with SLE occurred


in women (43/48 events, 89.6%)
Patients with SLE/PRES association were younger
than those without PRES (29.91.05 vs 36.21.36
years, p<0.001).
Hypertension was more frequent in patients with
SLE/PRES compared to controls (68% vs 38%,
p=0.001).

The frequency of dyslipidemia was similar


between groups (p=0.25)

Patients with SLE/PRES had higher levels of


Total cholesterol- p=0.001
Non-high-density lipoprotein cholesterol -p=0.003
Triglycerides -p=0.001

History of diffuse alveolar haemorrhage was more


frequent in the SLE/PRES group than in patients
without PRES (10% vs1%, p=0.008)

Haemoglobin levels were significantly lower in


cases 3 months prior as well as at the PRES
episode (p<0.001 and p=0.016, respectively).
Total leucocyte count was not different between
cases and controls 3 months before (p=0.24) or
at the PRES episode (p=0.39)
Lymphocyte count was persistently lower in
patients with SLE/PRES ( p=0.005 in the previous
3 months,p=0.049 at the PRES episode).

Renal function was more affected in patients with SLE


with PRES, as serum creatinine (p=0.01) and blood
urea nitrogen (p=0.001) were both higher than in
patients without PRES.
Patients with SLE/PRES had
Higher anti-double-stranded DNA antibody levels (p=0.021)
Lower C3 levels (p=0.004).

SLEDAI score was also higher in the three previous


months ( p<0.001) and at the time of the event
(p<0.001).

Mean prednisone dose prior to the event and the


cumulative cyclophosphamide dose in the past 6
months were higher in the SLE/ PRES group.

Length of hospital stay was similar in patients


with SLE/PRES and SLEwoPRES (17.32.07 vs
14.61.11 days, p=0.20).
There were no deaths directly associated with
PRES, but three patients in the SLE/PRES group
and one in the control group died in the year
following the event

PRESS/SLE Vs PRESS wo SLE


PRESwoSLE

PRES/SLE

P value

Serum
creatinine

304.0943.3

180.354.04
mmol/L,

0.079

Hypertension

34%,

68%

0.003

Dyslipidemia

3%

37%

0.001

Lymphocyte
count

2422398.9

77690.7

0.001

Symptom
reversibility in
less than 72 h
Mean hospital
stay
Mortality at 12
months

0.44

13.12.66

17.32.07

0.21
0.51

DISCUSSION
SLE is the most frequently associated
rheumatological disease.
The prevalence of PRES in patients with SLE
has been reported to be less than 1%
Aggressive immunosuppressive treatments
High SLEDAI scores,
Renal dysfunction
Uncontrolled hypertension
previously described as factors related to
PRES development in patients with SLE.

This study, the largest to date evaluating SLEassociated PRES, and also described two novelrisk factors:
Lymphopenia
Dyslipidemia.

The physiopathology of PRES is not completely understood.


Dysfunction in the autoregulatory cerebral perfusion
These are generally associated with changes in systemic
arterial pressure, as well as BBB disorders.
Additional possibilities, in which blood pressure does not
play such a fundamental role, were also have been
proposed
The endothelial dysfunction theory
lays emphasis on the role of pro-inflammatory cytokines
(mainly TNF-, IL-1,IL-6), which would induce a high
expression of adhesion molecules (ICAM,VCAM) and VEGF
High levels of serum VEGF have been found in patients
with SLE with internal organ involvement and high
disease activity indexes.

The results of the study regarding lymphopenia


and dyslipidemia in patients with SLE/PRES may
be partially explained by the endothelial
dysfunction theory.
Dyslipidemia is strongly related to endothelial
disruption and increased oxidative stress, which
have a linear correlation with increased
antiendothelium antibodies in patients with SLE

There is evidence of the presence of


autoantibodies in various CNS disorders like
NMDA and antiaquaporin 4, antiendothelial
antibodies
Therefore, it is possible that there is a relevant
autoimmune component underlying PRES.

Lymphopenia, which is a common manifestation in


patients with SLE may also be related to
endothelial abnormalities.
Recently, it has been described that lymphopenia
per se is associated with carotid intima-media
thickness.
In fact, the relationship between lymphopenia an
endothelial damage has also been reported in HIVinfected patients and transplant recipients.
IFN I could be of special relevance in the
lymphopeniaendothelial dysfunction interplay in
patients with SLE

In agreement with other studies, it was found that


patients with SLE who develop PRES are younger,
have high activity indexes and present with
seizures as the main clinical manifestation.
Attaining the proper diagnosis of a potentially
benign entity, such as PRES, would help to limit
unnecessary tests and more aggressive
treatments.

limitations
Retrospective
PRES events were found by searching the
electronic clinical record systems of each
hospital, which could be associated with a lack of
complete clinical data in some of the included
subjects.

Conclusions
Aside from corroborating the conventional risk
factors for the PRES/SLE association (high SLEDAI,
renal dysfunction and hypertension), this study
also described lymphopenia as a novel risk factor
and dyslipidemia as a metabolic feature that is
strongly associated with SLE-associated PRES.

Comments
Prospective studies will be needed to confirm
these findings
Confounding factors on dyslipidemia needs to be
take into account

Neuroflaments in the diagnosis of


motor neuron diseases: a
prospective study
Petra Steinacker, Emily Feneberg et al.

Introduction
Motorneuron diseases are a group of
neurodegenerative disorders, the most common form
of which is ALS.
It is characterised by degeneration of the upper and
lower motor neurons.
ALS has a median survival of 3 years from symptom
onset.
Around 7% of those initially diagnosed as ALS
ultimately turned out to have a different disease.

By the time the patients fulfil the criteria for


clinically definite ALS they are usually in the
advanced stage of disease
Validated neurochemical biomarkers that
distinguish early between ALS and its differential
diagnoses are lacking.
Early disease diagnosis through the use of
biomarkers may aid in correct clinical management
of patients and possibly delay time to ventilator.

Aim
To determine the CSF biomarkers to differentiate
MND from its mimics.

Neuroflaments (NF) are the 10 nm intermediate


filaments found in neurons.
They are a major component of the neuronal
cytoskeleton
Disorganized neurofilaments can provoke
degeneration and death of neurons(Apoptosis)
An interference of axonal transport by disorganized
neurofilaments has been proposed as one possible
mechanism of neurofilament-induced pathology

It is a monocentric prospective study


Study Place: Department of Neurology, University
of Ulm,Germany
Study Period: May 2010 to June 2014

MATERIAL/METHODS
Participants and clinical characterisation
Ethical Clearance:
Patients provided written informed consent for
the study
The study was approved by the ethics committee
of the University of Ulm

A total of 455 participating patients were seen in a


prospective manner.
All patients who consulted the Department of
Neurology (inpatients and outpatients) were asked to
participate in this study.

Patients were then followed up every 6


months.

Neuromuscular

Laboratory markers
CSF was obtained by lumbar puncture,
centrifuged and stored within 2 h at 80C until
analysis.
Commercially available ELISA kits were used for
NfL and pNfH and for Tau and pTau.

Calculations and statistics


JMP-SAS-software.

RESULTS
There was no age difference between the MND
group and the control groups.
The concentrations of NfL and pNfH were
significantly higher in the CSF obtained from
patients with MND (p<0.0001)
The concentrations of Tau and pTau in the CSF
were significantly higher in AD patients than in all
patients with non-AD diagnoses taken together.
(p<0.0001).

There was no significant difference between ALS,


PLS and genetically defined ALS for all biomarkers
(NfL: p=0.095, pNfH: p=0.059; Tau: p=0.829, pTau:
p=0.769).
False positive cases: 11 patients

Application of cut-offs for NfL


and pNfH
An NfL concentration above 2200 pg/mL yielded
the optimal discrimination between MND and MND
mimics sensitivity - 77% (CI 71% to 82%)
Specificity- 88% (CI 79% to 94%)
PPV - 95% (CI 91% to 98%),
NPV- 56% (CI 48% to 65%).

For pNfH, the best diagnostic performance was


achieved at a cut-off of 560 pg/mL.
Sensitivity- 83% (CI 78% to 88%)
Specificity - 80% (CI 70% to 88%)
PPV of 93% (CI 88% to 95%)
NPV of 62% (CI 52% to 71%).

Higher progression rates were associated with


higher Nf concentrations in MND
No correlation could be found between biomarker
levels and FA-CST values of MRI

False positive cases


11 patients had high values for NfL (>2200 pg/mL) and pNfH
(>560 pg/mL)

Myopathy (n=2)
CIDP
PNP
Benign fasciculation
Encephalitis
Radiculopathy
Myositis
Endocrine myopathy
Chronic pain
Spinocerebellar ataxia

DISCUSSION
CSF levels of NfL and pNfH are elevated in MND,
thus enabling a sensitive and specific
discrimination of MND vs MND Mimics
In particular, a high positive predictive value
could be found for these biomarkers qualifying
them as confirmation markers for suspected MND.
Negative results for these markers do not rule
out MND diagnosis.

Nf levels were associated with MND disease


progression and disease duration, and potentially
qualify as prognostic markers
In contrast to recent observations on a much
smaller cohort of patients with ALS (n=51), pTau
and Tau concentrations did not show a specific
profile in this large cohort and were only
elevated in patients with AD.
The highest concentrations of Nf are found in CSF
following neuroaxonal damage.

In conclusion, it suggested that Nf


measurements are included in the diagnostic
work-up of patients with ALS
Nfs correlate with MND progression and the
applicability of Nf as prognostic marker in clinical
routine should be investigated further.

Comments
The correlation between CSF and serun NF levels
need to be studied.

Oral Ponesimod in RRMS: a


randomised phase II trial
Aaron Boster, scar Fernndez, Mark S Freedman
Department of Clinical Neurosciences, Karolinska Institute,
Neuroimmunology Unit,
Stockholm ,Sweden

INTRODUCTION
Multiple sclerosis (MS) is a chronic inflammatory disease
of the CNS affecting an estimated 2.5 million people
worldwide

o
o
o
o
o
o
o
o

Disease-modifying drugs for its treatment include


Interferon ,
Glatiramer acetate,
Mitoxantrone,
Fingolimod
Teriflunomide,
Dimethyl fumarate,
Alemtuzumab
Natalizumab.

Fingolimod, which modulates sphingosine 1-phosphate


(S1P) receptors, including S1P1, S1P3, S1P4 and S1P5

A drug which selectively acts on S1P1 receptor may


have similar immunomodulatory effect with less
undisered side effects

Ponesimod an iminothiazolidinone derivative, is a


reversible, orally active, selective S1P1 receptor
modulator
Lymphocyte exit from lymph nodes and their
migration into the blood and target tissues is
mediated by S1P binding to S1P1 receptors
Binding of ponesimod to the S1P1 receptor
lymphocyte sequestration in the lymph nodes.

Phase I studies demonstrated that ponesimod


Pharmacokinetics are dose-proportional
Characterised by low variability
Circulating lymphocyte counts are reduced in a dose
dependent manner.

Ponesimod has a rapid onset of action, with maximal


plasma concentrations observed 2.54 h after dosing
Maximum lymphocyte count reduction achieved 6 h
after dosing.
Ponesimod has a terminal half-life of approximately
32 h
After treatment discontinuation, mean lymphocyte
count returns to normal range within 7 days

Objective
This is a double-blind, placebo-controlled, phase II
study evaluated the efficacy and safety of
ponesimod, an oral selective S1P1 receptor
modulator for the treatment of patients with
RRMS.

Eligible patients were men and women aged 18


55 years with RRMS and an Expanded Disability
Status Scale (EDSS) score of 05.5, with at least
one of the following characteristics:

1 documented relapse(s) within the 12 months


before screening
at least one T1-weighted gadolinium-enhanced (Gd+)
lesion detected on brain MRI at screening.

Study exclusion criteria


Use of systemic corticosteroids within 30 days of
randomisation
Use of immunomodulators (interferon , glatiramer
acetate) and some immunosuppressants
(cyclosporine, sirolimus and mycophenolic acid)
lymphocyte-depleting biological agents (alemtuzumab
and rituximab) were excluded from the study.

Study design and procedures


This was a prospective, multicentre and multinational
(94 centres in 23 countries, including Europe, Australia,
Canada and USA), randomised, double-blind, placebocontrolled, four-arm, parallel group, phase II study
Within each investigation site, patients were
randomised in a 1:1:1:1 ratio to once-daily treatment
with placebo or ponesimod 10, 20 or 40 mg for 24
weeks
The primary investigator/treating neurologist, physician
evaluating cardiac safety assessments, care providers,
patients and sponsor were blinded to the treatment.

The dose range selected for this study was based


on phase I data.
Ponesimod 10 mg was selected as the lowest
dose as it was associated with an approximate
50% reduction in peripheral lymphocyte counts,
which was considered as the minimum reduction
required for an immunomodulatory effect.
Ponesimod 40 mg was selected as the highest
dose as it was associated with an approximate
70% reduction in peripheral lymphocyte counts

Study visits took place at screening, baseline, on day 1


(randomisation), days 8 and 15 (up-titration), at week 4
and then every 4 weeks until the end of the 24-week
treatment period or study drug discontinuation.
Patients who completed treatment at week 24 were
offered enrolment into an ongoing, long-term, doseblinded extension study where all patients would
receive ponesimod
For those patients who prematurely discontinued study
treatment or who completed 24 weeks of treatment but
chose not to enter the extension study, two safety
follow-up visits were performed 7 and 30 days after the
last dose of study drug.

MRI scans were performed at baseline, every 4


weeks from week 4 to 24 (end of treatment (EOT))
and at the second safety follow-up visit for patients
not entering the extension study.
MRI scans were centrally evaluated in a fully
blinded manner
(Medical Image Analysis Centre, Basel, Switzerland).
EDSS assessments were performed at screening,
baseline, week 24, at follow-up visit and at
unscheduled visits in case of MS relapse by an
independent neurologist.

The main pharmacodynamic variable was total lymphocyte


count, which was centrally analysed at screening,
baseline, on days 8 and 15, every 4 weeks thereafter until
EOT and at the two safety follow-up visits.
On treatment initiation and dose up-titration days, cardiac
monitoring was performed by an independent cardiologist.
This included 12-lead ECG, blood pressure measurements
over 6 h and Holter ECG monitoring over 24 h
Pulmonary function tests (PFTs) were performed at all
study visits

Study endpoints
The primary efficacy endpoint was the cumulative
number of new Gd+ lesions per patient detected
on T1-weighted MRI scans from weeks 12 to 24.
Cumulative number of new or enlarging nonenhancing T2 lesions at weeks 12, 16, 20 and 24
Cumulative number of combined unique active
lesions (CUALs; sum of all new T1 Gd+ lesions
and new or enlarging T2 lesions since previous
MRI scan) at weeks 12, 16, 20 and 24

Secondary efficacy endpoints is the annualised


confirmed relapse rate (ARR) within 24 weeks of
ponesimod initiation.

Relapse - the occurrence of an acute episode of one or


more new symptoms or a worsening of existing
symptoms of MS, not associated with fever or infection,
and lasting for 24 h after a stable period of 30 days.

A confirmed relapse -a relapse with an increase of 0.5


points from baseline in the EDSS score or an increase of
1 point in at least 1 functional system score (excluding
bowel, bladder and mental functional systems)
assessed within 7 days of onset by the independent
neurologist.

Statistical analyses
The global null hypothesis was that none of the
three ponesimod groups differed from the placebo
group in the mean cumulative number of new T1
Gd+ lesions at weeks 12 to 24.
The alternate hypothesis was that at least one of
the ponesimod treatment groups differed from
the placebo group.

RESULTS
Patients
Of the 621 patients screened, 464 were
randomised between October 2009 and
November 2010 to receive ponesimod 10, 20 or
40 mg, or placebo.
Demographic and baseline disease characteristics
were similar across treatment groups

End Points
Mean
cumulative
number of new
T1 Gd+ lesions

The mean
reduction in new
or enlarging T2
lesions

10 Mg

3.5

31% (p=0.2194)

20 mg

1.1

56% (p=0.0208)

40 mg

1.4

34% (p=0.2194

ARR reduction
The ARR was numerically lower in each
ponesimod group
ARR was reduced by
37% - ponesimod 10 mg (p=0.1619)
21%-ponesimod 20 mg (p=0.4420)
52%- ponesimod 40 mg (p=0.0363)

K-M

Pharmacodynamics analysis
Lymphocyte counts were rapidly reduced with
ponesimod treatment in a dose-dependent
manner
Mean reductions from baseline to week 24 were
50%, 65% and 69% for ponesimod 10, 20 and 40
mg, respectively, and 3% in the placebo group.

In the subgroup of patients who discontinued treatment


prematurely or did not enter the extension study at
week 24 (n=122), mean lymphocyte count returned to
baseline range within 1 week of treatment
discontinuation
The proportion of patients with a lymphocyte count
0.8109/L at the first safety follow-up visit

100% (19/19 patients)- 10 mg


100% (24/24 patients)-20 mg
97% (31/32 patients) -40 mg groups, respectively,
and
96% (27/28) -placebo group.

Safety and tolerability


The proportions of patients who had 1 AE were similar across
all ponesimod groups (73.977.2%) and placebo (74.4%)
Frequently reported AEs with a higher incidence in the three
ponesimod groups compared with placebo
anxiety,
dizziness,
dyspnoea,
increased alanine aminotransferase,
influenza,
Insomnia
Cardiac side effects
peripheral oedema.

Incidences of dyspnoea and peripheral oedema


appeared to be dose-related
During the treatment period, a total of 27 SAEs
occurred
Two malignancies were reported: one case of
breast cancer in the ponesimod 10 mg group and
one case of cervix carcinoma in the placebo
group.
There were no deaths during the study.

Cardiac AEs associated with ponesimod treatment


initiation included first-degree (1.2%) and seconddegree (0.9%; no cases of Mobitz type II) AV block
and bradycardia (2%).
All AEs relating to heart rate and rhythm occurred
on day 1 when all patients randomised to
ponesimod received a dose of 10 mg
There was no need for intervention and no
recurrence of these AEs later during treatment.

The proportion of patients with 1 infectionassociated AEs was similar across the four groups
(placebo 45.5%; ponesimod 10 mg, 37.0%; 20
mg, 32.5%; 40 mg, 36.1%).
There were no treatment discontinuations due to
lymphopenia, nor was there a correlation
between the incidence of infections and
lymphocyte count reduction during the study.

The proportion of patients with 1 respiratory AE


was higher in the ponesimod than in the placebo
group (placebo, 6.6%; ponesimod 10 mg, 9.3%;
ponesimod 20 mg, 16.7%; ponesimod 40 mg,
31.9%).

In total, seven patients prematurely discontinued


ponesimod because of dyspnoea (six in the 40
mg group).

liver transaminase increases >3 ULN

ponesimod 10 mg, 2.8%;


Ponesimod 20 mg, 4.5%
ponesimod 40 mg, 4.2%
placebo group-No cases

4 macular oedema cases were reported, all starting


within 3 months of treatment initiation
3 cases were reported as SAEs in the ponesimod 20
mg group
The fourth case (AE) of macular oedema was reported
in the placebo group

DISCUSSION
Once-daily treatment with ponesimod 10, 20 or 40
mg for 24 weeks significantly and dose-dependently
achieved primary and secondary end points
Ponesimod was generally well tolerated at doses of
10 and 20 mg
The 40 mg dose showed signs of reduced
tolerability with no additional benefit with respect to
MRI or pharmacodynamic efficacy compared with
the 20 mg dose.
The reason for the lack of additional benefit with
ponesimod 40 mg compared with ponesimod 20 mg
is not entirely clear

Ponesimod was also associated with first-dose


cardiac effects
Lymphocyte counts were rapidly reduced upon
treatment initiation, with the maximum effect
established within 714 days for each dose level.
Importantly, no patients discontinued treatment
due to lymphopenia, and the decrease in
lymphocyte count was not associated with an
increased risk of infections.

As shown in preclinical and phase I studies,


ponesimod-associated lymphocyte sequestration
was rapidly reversed upon treatment
discontinuation, reaching levels close to baseline
within 1 week.
By comparison, lymphocyte counts return to
normal range within 12 months of stopping
therapy with fingolimod
ponesimod has a terminal half-life of 32 h, and of
fingolimod is 8 days.

Additionally, ponesimod is highly selective for the


S1P1 receptor, while fingolimod is active on the
S1P1 and S1P35 receptors.
At least three S1P receptors are present in the
heart and vasculature, and the predominantly
expressed receptor subtype varies with cell type.
Notably, activation of the S1P3 receptor results in
bradycardia in both mice and humans.
Fingolimod may have pro-fibrotic effects due to
the stimulation of the S1P3 receptor, an effect
that is not replicated with ponesimod.

Comments
The long-term safety and clinical efficacy needs
to be followed
Extension study is ongoing

Macular Hole