428082

2011
MSJ18610.1177/1352458511428082Kwiatkowski et al.Multiple Sclerosis Journal

MULTIPLE
SCLEROSIS MSJ
Case Study JOURNAL

Multiple Sclerosis Journal

Herpes encephalitis during natalizumab 18(6) 909­–911

© The Author(s) 2012
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DOI: 10.1177/1352458511428082
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A Kwiatkowski, J Gallois, N Bilbault, G Calais, A Mackowiak

and P Hautecoeur

Abstract
In this case report we describe the first non-fatal herpes simplex virus encephalitis (HSE) case with natalizumab for
multiple sclerosis (MS). A 36-year-old woman, previously treated with immunomodulatory and immunosuppressive drugs
for MS, developed acute encephalitis after 6 monthly natalizumab perfusions. Brain imaging demonstrated suggestive
bi-temporal lesions. Herpes simplex virus type-1 DNA was detected in cerebrospinal fluid. The patient improved gradually
after a 21-day course of intravenous acyclovir, but neuropsychiatric changes remained 5 months later. Our non-fatal case
of HSE and other reported cases of herpes infections provide evidence of an increased risk with natalizumab and point
to the need for clinicians to maintain awareness.

Keywords
acyclovir, encephalitis, herpes simplex, monoclonal antibody, multiple sclerosis, natalizumab
Date recieved: 11th August 2011; revised: 5th October 2011; accepted: 6th October 2011

Introduction IV immunoglobulins were administrated for a 5-day course

We report a non-fatal case of herpes simplex virus type-1
encephalitis (HSE) in a woman with relapsing–remitting
multiple sclerosis (RRMS) during natalizumab therapy.
Only one other fatal HSE case with natalizumab is known
in the postmarketing experience.
Level of evidence
The report provides class IV evidence and is a single obser-
vational study without controls.
Case report
A 36-year-old woman began monthly intravenous (IV) per-
fusions with natalizumab in June 2010 and was recruited in
an observational TOP survey study. The patient had been
diagnosed with RRMS 7 years earlier. She had no other
relevant medical history. Before initiating natalizumab, she
received immunomodulatory drugs with weekly intra-mus-
cular interferon beta-1-a injections between October 2003
and July 2005, glatiramer acetate between August 2005 and
April 2008, and mycophenolate mophetil in October 2009.
A relapse, with ocular neuritis and sensory–motor symp-
toms, occurred in March 2010 and was treated with high
doses of IV methylprednisolone for two 3-day courses in
March and in April 2010. Owing to insufficient recovery,
in May 2010.
Nine days after the 6th perfusion of natalizumab in
December 2010, she was admitted to the emergency depart-
ment for a secondary generalized seizure. Two days after,
she developed hyperthermia, confusion and a second gen-
eralized seizure. Neurological examination confirmed
aphasia and acute memory impairment. Brain CT scan
showed a vast hypodensity in the right temporal lobe.
Examination of the cerebrospinal fluid (CSF) revealed 14
leukocytes/mm3 with lymphocytic predominance, normal
protein and glucose levels. Gram staining was negative for
organisms. Empirical antiviral treatment (acyclovir 15 mg/
kg every 8 hours) and levetiracetam were started. First
brain MRI scans demonstrated left temporal and insular,
cortico-subcortical and white matter hypo-intensity on T1,
with correspondent hyper-intensity on T2-weighted, diffu-
sion and proton density images and smaller but similar
abnormalities in the right temporal lobe. A contrast
PRES Lille Nord de France, Université Catholique de Lille, Groupe
Hospitalier de l’Institut Catholique de Lille / Faculté Libre de Médecine,
Clinique de Neurologie, Lille, France
Corresponding author:
Dr Arnaud Kwiatkowski, Service de Neurologie, Hôpital Saint Vincent
de Paul, GHICL, Boulevard de Belfort BP 387, F-59020 LILLE cedex,
France.
Email: kwiatkowski.arnaud@ghicl.net

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910 Multiple Sclerosis Journal 18(6)

Figure 1. (A, C) T2 fluid attenuated inversion recovery (FLAIR) transverse and T2-weighted coronal MRI sequences: hyper-
intensities in the left temporal cortico-subcortical and white matter. (B) T1 sequences with gadolinium injection: note contrast
enhancement in the left hippocampic region. (D) T2 FLAIR MRI sequences: multiple hyper-intensities in periventricular white matter,
consistent with multiple sclerosis.

enhancement (CE) in the left hippocampic region was
noted (Figure 1). Electroencephalogram (EEG) showed
theta and delta activities located on the left temporal region
(no pseudo-periodic complex). The occurrence of electrical
seizure without clinical manifestation in the left temporal
lobe was noted during second EEG hyperventilation. CSF
polymerase chain reaction (PCR) for Herpes simplex virus
(HSV) type-1 was positive. Bacterial culture and PCR for
JC virus were negative. MRI scans, repeated 7 days after,
showed no change except a decrease in CE. Control CSF
samples were still positive for HSV-1 DNA after 5 days
with acyclovir treatment, and then became negative after
13 days. IV acyclovir was continued for a 21-day course.
Aphasia and confusion improved gradually. However, she
kept neuropsychiatric changes over the following 5 months.
The final cognitive evaluation confirmed persistent and
severe episodic memory defect with anosognosia and mild
aphasia. Executive functions were significantly improved.
It was decided to resume subcutaneous interferon beta-1-a
injection.
Discussion
Natalizumab is approved for the treatment of patients with
RRMS who have failed other disease-modifying therapies
or who have aggressive disease. This agent contains human-
ized neutralizing IgG4κ monoclonal antibodies against leu-
kocytes α4 integrins found on lymphocytes and monocytes.

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Kwiatkowski et al.
It exerts its biologic effect by abrogating movements of
mononuclear leucocytes to the CNS. Natalizumab offers
targeted and localized immunosuppression and was shown
to be dramatically effective in two phase III clinical trials. 1
Progressive multiple leukoencephalopathy (PML) caused
by reactivation of a clinically latent JC polyomavirus is
known to occur after 1 year of natalizumab treatment with
a frequency of 1–2 per 1000 treated patients.2 Consequently,
clinical vigilance and rapid evaluation with MRI scans and
CSF analysis are recommended for new neurological com-
plaints that might be early signs of PML. Natalizumab is
less clearly linked to an increased risk of other viral infec-
tion, although it is suggested that viral reactivation would
not be limited to JC virus. Human herpes virus type-6 may
be reactivated in patients with MS receiving natalizumab.3
In the MS clinical trials, infectious complications others
than PML were infrequent, but there was a small excess
of herpes infections in patients on natalizumab. Post-
marketing reports disclosed one case of fatal HSE, and one
non-fatal case of HSV meningitis,1 but no clinical details
are publicly available. Recently, a first case of HSV-2 men-
ingitis was described in a MS patient on monthly natali-
zumab.4 Finally, cutaneous HSV reactivations seem three
times more prevalent in MS patients on natalizumab.5
HSE is a rare disease in the general population, with an
annual incidence of 1–2 cases per 1,000,000 habitants and
has not been traditionally associated with immunodefi-
ciency. However, recent studies suggest that some paediat-
ric cases of HSE may be linked to defects in interferon
pathways.6,7 How natalizumab therapy affects the patho-
genesis and prognosis of HSE in humans has not been stud-
ied, but the lack of immune response in CNS related to
natalizumab might be responsible for a more aggressive
form of HSE. However, the positive response to acyclovir
in our patient is encouraging. This could emphasize the
critical need for early diagnosis. HSV infection has been
associated with other monoclonal antibodies. Drugs induc-
ing T-cell depletion such as OKT-3 and alemtuzumab are
associated with an increased risk of viral encephalitis after
allogeneic stem cell transplantation.8 Cutaneous HSV
infections (8%) and one case of viral meningitis were
reported in a recent study of alemtuzumab for early MS.9
An association between HSE and anti-TNF-α drugs (inf-
liximab and adalimumab) has been described in three
patients with rheumatologic disorders. However, metho-
trexate and corticosteroids were given in association to two
of these three patients.10
We identified the first case (to the best of the authors’
knowledge) of an adult who developed HSE during treat-
ment with natalizumab and significantly improved after
receiving acyclovir therapy. These reported cases of severe
HSV infections suggest that patients receiving natalizumab
may have an increased risk of HSE or HSV meningitis.
Additional clinical studies are required to document the
strength and mechanisms of this association. As early diag-
nosis and treatment are the keys to a better prognosis,
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911
neurologists should be aware that severe herpes infections
may occur during natalizumab treatment. PML should be
suspected in a patient on natalizumab presenting a first sei-
zure, but also HSE. Each new case should be reported to
local survey administration.
Acknowledgements
The authors thank the patient and her family for allowing us to
report these data. The authors thank Delphine Brière for advice on
the manuscript’s English.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The reported patient was included in the TOP observational sur-
vey study sponsored by Biogen Idec. The authors declare that
there are no other conflicts of interest.
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