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Another complication of natalizumab treatment Taking the challenge.

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Another Complication of
Natalizumab Treatment?
Taking the Challenge
The monoclonal antibody natalizumab (Tysabri) is
the paradigm of a multiple sclerosis (MS) treatment
designed on the basis of an immunological rationale
and successfully taken from “bench to bedside” or
“from mouse to man.”1,2 By interacting with the
VLA4 receptor, natalizumab blocks lymphocyte extravasation, thus inhibiting the invasion of activated
and potentially autoaggressive cells into the central
nervous system (CNS). As this effect is not selective,
it was also expected that it would necessarily reduce
immunosurveillance within the CNS, leading to increased susceptibility to infections and neoplastic diseases. Contrasting these expectations, 2 pivotal large
scale clinical trials and their follow-up studies in relapsing MS did not show an increased overall incidence of either infections or cancers as compared to
placebo.2,3 Observations in now ⬎50,000 MS patients treated with marketed natalizumab apparently
confirm this reassuring finding.4 Yet a small fraction
of an estimated 0.1% (or less) seem to be prone to
develop the rare but potentially lethal JC-virus–induced progressive multifocal leukoencephalopathy
(PML).5 Although PML is usually observed together
with other opportunistic infections in patients severely immunocompromised by human immunodeficiency virus (HIV) or immunosuppressive drugs, its
apparently selective occurrence in some natalizumabtreated patients suggested a link to the compound’s
mode of action and a specific predisposition based on
interaction with other immunomodulating or immunosuppressive treatments, or genetic variations.6,7 In
this issue of the Annals of Neurology, Schweikert and
colleagues8 describe the first case of another expected
complication of natalizumab treatment: a patient
who, after 21 treatment cycles, developed a histologically verified primary CNS B-cell lymphoma. Is there
an interrelationship between MS, natalizumab treatment, and primary CNS lymphoma (PCNSL)? Coincidence of MS and PCNSL has been described before,9 as have cases of PCNSL mimicking MS.10
Based on the description provided by the authors, especially the clinical course with longer-lasting remissions and the magnetic resonance imaging features including asynchronous growth and regression of
lesions and early manifestations in the spinal cord, we
do not doubt that this patient had active inflammatory relapsing-remitting CNS disease that fulfils cur-
Annals of Neurology
Vol 66
No 3
September 2009
rent diagnostic criteria for MS.11 However, this case
did display atypical features from the beginning (not
ruling out MS diagnosis), such as epileptic seizures as
initial clinical presentation12 or lesions in the cortical
gray matter, thalamus, and basal ganglia.13 Interestingly, at the first biopsy, which is described as disclosing “mild inflammation with T-cell infiltrates
compatible with MS,” no demyelinating features are
From a purely statistical point of view, a single case
observation will never be seen as evidence for more
than coincidence. But is a purely statistical approach
adequate in this situation? Certainly not! The type of
malignancy reveals obvious parallels to PML. PCNSL
is not a common cancer, but a similarly rare condition almost exclusively found in patients severely immunocompromised by HIV or certain immunosuppressive drugs.14,15 Its rare occurrence is again
compatible with the assumption of a very distinct and
specific interaction of natalizumab and the host’s immune system.
Do we have clues about this interaction? In view of
a growing body of literature suggesting an association
between Epstein-Barr virus (EBV) infection and
MS16 –20 and the widely accepted role of EBV in
(HIV-associated) PCNSL,21,22 it is tempting to speculate about EBV as a possible link between MS and
PCNSL pathogenesis. A reduced steady state immunosurveillance of the CNS by virus-specific T cells
might particularly augment the consequences of
chronic infections with viruses known to latently persist in the host’s body, such as JC virus, EBV, and
possibly others. Whether they may be simply “winning an edge” because of the specific mode of drug
action or even be related to the cause of the underlying disease remains to be determined.23 Although
the data presented by Schweikert and colleagues do
not provide evidence for this PCNSL tie to EBV infection, recent controversy about studies investigating
the presence of EBV-infected B cells in MS brain tissue24,25 indicates that technical issues affecting the
sensitivity and specificity of detection of EBVinfected cells have not been fully resolved.26
Although these questions cannot be answered with
sufficient certainty at this time, it is obvious that intermediate and long-term side effects of natalizumab
treatment will only be uncovered gradually, possibly
displaying an array of rare conditions by themselves,
each with hopefully only slightly raised frequency under treatment. This is and will be true for any new
and potent MS therapy, and underlines the necessity
for vigilance and expertise when treating MS patients
with new immunomodulatory agents. However, based
on current evidence, it seems unwise to abandon the
positive chances for many to avoid the negative risks
for a few. The case report by Schweikert and col-
leagues further illustrates that although there is no
such thing as a free lunch in MS treatment, the thorough analysis of these challenging complications is not
only a necessary defense measure allowing for their early
detection and optimized management, but may also enhance our knowledge of the new drug’s specific modes of
action and even help shed more light on MS pathogenesis. Let us take the challenge!
We thank Dr JD Lünemann, Zürich for helpful
Norbert Goebels, MD
Ludwig Kappos, MD
Departments of Neurology and Biomedicine
University Hospital Basel
Basel, Switzerland
Potential conflict: N.G. has received honoraria for
lectures from, served as principal investigator,
member of steering committees, or member of
advisory boards in clinical trials sponsored by, or
has had consulting agreements over the past 5 years
with Bayer-Schering, Biogen-Idec, Merck-Serono,
Novartis, Sanofi-Aventis, and other companies
involved in the development of MS therapeutics.
N.G. has received research support by the Swiss
National Research Foundation, the National Center
for Competence in Research Neural Plasticity and
Repair, Biogen-Idec, Merck-Serono SA Geneva, the
Swiss Multiple Sclerosis Society, the 3R Research
Foundation Switzerland, and the Koetser
Foundation for Brain Research.
L.K. has served as principal investigator, member, or
chair of planning and steering committees or advisory
boards in clinical trials sponsored by or has had
consulting agreements over the past 5 years with
Acorda, Actelion, AstraZeneca, Barofold, Bayer
Schering Pharma, Bayhill, Biogen Idec, Boehringer
Ingelheim, Centocor, Eisai, EMD Merck Serono,
Genentech, Genmab, Genzyme, GSK, Medicinova,
Neurocrine, Novartis, Peptimmune, Roche, SanofiAventis, Santhera, Shire, Teva, UCB, Wyeth, and
other companies involved in the development of MS
therapeutics. Honoraria and other payments have been
exclusively used for funding of research and clinical
activities at L.K.’s department. L.K. has received
research support from the Swiss National Research
Foundation, the Swiss MS Society, the European
Community, and the Gianni Rubatto Foundation.
1. Yednock TA, Cannon C, Fritz LC, et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63– 66.
2. Polman CH, O’Connor PW, Havrdova E, et al. A randomized,
placebo-controlled trial of natalizumab for relapsing multiple
sclerosis. N Engl J Med 2006;354:899 –910.
3. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus
interferon beta-1a for relapsing multiple sclerosis. N Engl
J Med 2006;354:911–923.
4. Bozic C, Belcher G, Kim R, et al. Natalizumab in patients with
relapsing multiple sclerosis: updated utilization and safety results including TOUCH (TM) and TYGRIS. Neurology 2009;
72(suppl 3):A113.
5. Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment
for multiple sclerosis: recommendations for patient selection
and monitoring. Lancet Neurol 2007;6:431– 441.
6. Lindberg RL, Achtnichts L, Hoffmann F, et al. Natalizumab
alters transcriptional expression profiles of blood cell subpopulations of multiple sclerosis patients. J Neuroimmunol 2008;
7. Houff SA, Berger J, Major EO. Response to Lindberg et al.
Natalizumab alters transcriptional expression profiles of blood
cell subpopulations of multiple sclerosis patients. J Neuroimmunol 2008;204:155–156.
8. Schweikert A, Kremer M, Ringel F, et al. Primary central nervous system lymphoma in a patient treated with natalizumab.
Ann Neurol 2009;66:403– 407.
9. Burgetova A, Seidl Z, Vaneckova M, Jakoubkova M. Concurrent
occurrence of multiple sclerosis and primary CNS lymphoma: a
case report. Neuro Endocrinol Lett 2008;29:867– 870.
10. DeAngelis LM. Primary central nervous system lymphoma imitates multiple sclerosis. J Neurooncol 1990;9:177–181.
11. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria
for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840 – 846.
12. Koch M, Uyttenboogaart M, Polman S, De Keyser J. Seizures
in multiple sclerosis. Epilepsia 2008;49:948 –953.
13. Küker W, Nägele T, Korfel A, et al. Primary central nervous
system lymphomas (PCNSL): MRI features at presentation in
100 patients. J Neurooncol 2005;72:169 –177.
14. Finelli PF, Naik K, DiGiuseppe JA, Prasad A. Primary lymphoma of CNS, mycophenolate mofetil and lupus. Lupus
2006;15:886 – 888.
15. Algazi AP, Kadoch C, Rubenstein JL. Biology and treatment of
primary central nervous system lymphoma. Neurotherapeutics
16. Jilek S, Schluep M, Meylan P, et al. Strong EBV-specific
CD8⫹ T-cell response in patients with early multiple sclerosis.
Brain 2008;131:1712–1721.
17. Farrell RA, Antony D, Wall GR, et al. Humoral immune response to EBV in multiple sclerosis is associated with disease
activity on MRI. Neurology 2009;73:32–38.
18. Lünemann JD, Jelcić I, Roberts S, et al. EBNA1-specific T cells
from patients with multiple sclerosis cross react with myelin
antigens and co-produce IFN-gamma and IL-2. J Exp Med
19. Salvetti M, Giovannoni G, Aloisi F. Epstein-Barr virus and
multiple sclerosis. Curr Opin Neurol 2009;22:201–206.
20. Lünemann JD, Münz C. EBV in MS: guilty by association?
Trends Immunol 2009;30:243–248.
21. MacMahon EM, Glass JD, Hayward SD, et al. Epstein-Barr
virus in AIDS-related primary central nervous system lymphoma. Lancet 1991;338:969 –973.
22. Kleinschmidt-DeMasters BK, Damek DM, Lillehei KO, et al.
Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropathol Exp Neurol 2008;67:1103–1111.
23. Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral
infection. Cell 2009;138:30 –50.
Goebels and Kappos: Natalizumab Treatment Complication
24. Serafini B, Rosicarelli B, Franciotta D, et al. Dysregulated
Epstein-Barr virus infection in the multiple sclerosis brain. J
Exp Med 2007;204:2899 –2912.
25. Willis SN, Stadelmann C, Rodig SJ, et al. Epstein-Barr virus
infection is not a characteristic feature of multiple sclerosis
brain. Brain advance access, doi:10.1093/brain/awp200.
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DOI: 10.1002/ana.21842
Environmental Factors,
Brain Development, and
Intelligence in Adulthood
Cognitive abilities in adulthood are highly dependent
on normal brain development during gestation. Disorders of the highly complex processes of brain development are associated with various degrees of cognitive
deficiency and autistic spectrum disorder. These conditions have a prevalence close to 1 or 2% of the population, with mild mental retardation 10 times more
common than severe retardation. Identification of the
causes of these problems is of prime importance for
both the family and society, because some etiologies
may be preventable. An underlying cause can be identified in 65 to 75% of patients. Identified causes are
genetic in 30 to 40% of diagnosed cases, structural
malformations (some genetic) in 15 to 20% of cases,
and complications of prematurity and perinatal conditions in 15 to 25% of cases. Other etiologies are related to environmental, behavioral, or socioeconomic
factors.1,2 The negative impact of exposure to alcohol
on future cognitive ability has been clearly demonstrated, and malnutrition, and maternal exposure to
cigarette smoking and street drugs are also suspected to
be detrimental.3 X-rays have a negative impact, whereas
the role of industrial toxins and of pharmaceutical molecules remains uncertain.4 Finally, early viral infections
of the fetus may induce abortion or changes to the
brain parenchyma, leading to severe cognitive deficits,
whereas cytomegalovirus (CMV) infection later in gestation may lead to isolated hearing loss or to moderate
cognitive disability (a direct causal link being difficult
to demonstrate epidemiologically). Despite careful evaluations, the cause remains elusive in 25 to 35% of
cases, particularly in those with mild mental defects.
Some of these cases are undoubtedly due to genetic
Annals of Neurology
Vol 66
No 3
September 2009
changes, which are now easier to detect with new techniques, such as comparative genomic hybridization arrays, but others may be related to environmental factors, which would require large epidemiological studies
to be identified.
In this issue of Annals of Neurology, Eriksen et al ask a
very provocative question: could a flu pandemic that occurred 20 years ago have decreased the ultimate cognitive ability of individuals who were in the early phase of
gestation during the epidemic?5 The authors did not aim
to identify major mental deficiencies in this study. Instead, they looked for a moderate reduction of cognitive
abilities in apparently normal young men who were undergoing medical and cognitive evaluation for compulsory military service. The main outbreak of Hong Kong
flu in Norway occurred between November 1969 and
January 1970, and the overall clinical attack rate was estimated at between 15 and 40% of the population.
However, no information was available about the specific rate for pregnant women or the intensity of symptoms in pregnant women, although flu is generally
thought to be clinically more severe during pregnancy.6
The sample consisted of ⬎200,000 men born between
1967 and 1973. After adjustment for parental educational level, paternal age, and percentage of premature
and small for gestational age children, the young men
who were born between July and October 1970 were
found to have a significantly lower score on the cognitive test battery than young men born during any other
period, including the same months in previous and subsequent years. These findings suggest that a bout of flu
early in pregnancy may affect the cognitive ability of the
mature subject evaluated 20 years later. This finding will
no doubt engender considerable controversy. Let us assume that the intelligence test data used in this study are
sufficiently robust and reliable in terms of both their reproducibility and their comparability with well-validated
measures of intelligence. The authors carefully justify
their findings. The most important question concerns
the extent of the reduction of performance on a standard
intelligence quotient (IQ) scale. This is difficult to evaluate, because individual results cannot be linked with
individual information about exposure to flu during gestation. The authors of this paper assume an exposure
rate of 20% in pregnant women and their fetuses. Consequently, they suggest that flu during pregnancy may
decrease the IQ of the offspring by 3 to 7 points as measured on a standard IQ scale. However, during the periods considered, almost 10% of the population did not
undergo military service because they had already died,
or for other reasons such as psychiatric illness or cognitive impairment. The authors could not control for this
potential bias. In this regard, it would be most interesting to determine whether severe brain malformations
leading to early death, severe mental retardation, psychiatric illness, or milder cognitive impairment were more
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