Comment
guidance on modifiable risk factors—ie, actionable advice
to delay or prevent dementia. Even for patients facing a
high chance of eventually developing dementia, several
behavioural or social interventions may afford extra years
of independence and high quality of life. Identifying
resources that improve cognitive reserve should be a high
priority for public health and for clinical care for patients
at high genetic risk. Incorporating information on the
genetic factors should effectively improve statistical power
in many studies, because such data eliminates extraneous
variation in outcome measures. These improvements can
enable us to learn more from smaller samples; every step
towards strengthening statistical power accelerates the
progress of Alzheimer’s disease research. Many apparent
technical innovations inadvertently render research more
expensive, so it is notable when a technical advance
reduces the cost of research.
The evidence from van der Lee and colleagues2 might also
reveal better understanding of biological pathways. We
can start to unpack the biological and social mechanisms
linking these variants, including APOE, to Alzheimer’s
disease and dementia. We should also explore in detail how
the variants interact to influence risk. Careful evaluation of
synergistic effects of specific variants might illuminate how
successive steps in a lifelong biological process culminate
in Alzheimer’s disease and dementia. This research will be
especially valuable in genetically diverse populations.
Evidence-based care in Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a severely
progressive X-linked recessive neuromuscular disorder. It
is caused by mutations in the dystrophin gene that result
in absent or insufficient functional dystrophin protein,
and manifests as progressive muscle degeneration and
weakness with symptom onset between ages 3 and
5 years. The disease primarily affects boys and men, but
in rare cases it can affect girls and women. Prevalence of
DMD has been reported as one case per 5000–6000 live
male births.1–3
After the original care considerations for DMD were
published in 2010,4,5 the need for updated guidelines
across a patient’s lifespan was primarily driven by
the emerging use of more sensitive diagnostic
techniques, earlier therapeutic interventions in many
areas of care, and the expectation of longer survival
www.thelancet.com/neurology Vol 17 May 2018 389
We can now achieve impressive predictive power with
a handful of simple measures. The most important task
facing us next is moving from prediction to prevention.
The evidence offered by van der Lee and colleagues2 will
provide a valuable technical tool and points the way to
high priority research questions to evaluate preventive
strategies.
*Carole Dufouil, M Maria Glymour
Inserm U1219, Institut de Santé Publique, d’Epidémiologie et de
Développement, Bordeaux School of Public Health, Université de
Bordeaux, CHU de Bordeaux, Bordeaux, 33000 France (CD); and
University of California, San Francisco, Department of
Epidemiology and Biostatistics, San Francisco, CA, USA (MMG)
carole.dufouil@inserm.fr
We declare no competing interests.
1 Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention,
intervention, and care. Lancet 2017; 390: 2673–734.
2 van der Lee SJ, Wolters FJ, Ikram MK, et al. The effect of APOE and other
common genetic variants on the onset of Alzheimer’s disease and
dementia: a community-based cohort study. Lancet Neurol 2018; published
online Mar 16. http://dx.doi.org/10.1016/S1474-4422(18)30053-X.
3 Skoog I. Dementia: dementia incidence—the times, they are a-changing.
Nat Rev Neurol 2016; 12: 316.
4 Chapko D, McCormack R, Black C, Staff R, Murray A.Life-course
determinants of cognitive reserve (CR) in cognitive aging and dementia—a
systematic literature review. Aging Ment Health 2017; published online July
13. doi: 10.1080/13607863.2017.1348471.
5 Desikan RS, Fan CC, Wang Y, et al. Genetic assessment of age-associated
Alzheimer disease risk: Development and validation of a polygenic hazard
score. PLoS Med 2017; 14: e1002258.
well into adulthood. The authors of the revised DMD See Review page 445
care considerations6–8 are to be congratulated for a See Review Lancet Neurol
2018; 17: 251–67, and Review
thoughtful and extensive three-part review published Lancet Neurol 2018; 17: 347–61
in The Lancet Neurology. Three of the 11 topics are new
since the 2010 considerations:4,5 primary care and
emergency medicine, endocrinology (including growth,
adrenal insufficiency, and bone health management),
and transitions of care across the lifespan.
Many substantive changes are in the updated care
considerations, but several important modifications
should be highlighted: recommendations to manage
and mitigate the multiple toxicities of steroids have
been improved, with specific protocols for clinicians
to follow; new recommendations have been added
for assessment of disease-induced and steroid-
induced bone fragility, which represent a paradigm
 Comment
shift now emphasised by the preference for lateral
spine radiographs over dual x-ray absorptiometry-
measured bone mineral density; the respiratory
criterion for initiation of mechanical cough assistance
and non-invasive ventilation has been adjusted, to
be more proactive from a preventive point of view
and encourage initiation of these management
strategies earlier and always before transition to
adult care providers; cardiovascular MRI rather than
echocardiography is now recommended as the non-
invasive imaging modality of choice for DMD to assess
for cardiomyopathy after age 6–7 years; in addition to
early afterload reduction with angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers
(which should now always be started by age 10 years);
β-adrenergic blockade is recommended in patients with
evidence of ventricular dysfunction on cardiac MRI or
echocardiogram; and the importance of behavioural
and emotional difficulties in teenagers and adults with
DMD are now recognised with new recommendations
for mental health and quality of life screening at each
visit, and specific recommendations for consideration
of pharmacological management of depression, anxiety,
obsessive-compulsive disorder, anger, emotional dys­
regulation, and attention-deficit hyperactivity disorder.
Controversies remain in these care considerations that
will require future study. For example, treatment of young
children with glucocorticoids improves muscle strength
and function in the short term, but it is unclear whether
children younger than 3–4 years should be started on an
intermittent regimen to preserve their growth or given
daily doses, which are effective but known to stunt
growth. Another problem is that DMD patients who
have long-term treatment with glucocorticoids might
have emotionally troubling height restriction that might
also confer relative functional advantages because of
shortened limb segments in the setting of dystrophy-
related weakness, and no consensus has been reached
as to whether these patients should also be treated with
growth hormone. Additionally, the timing of initiation of
a mineralocorticoid receptor antagonist (eg, eplerenone)
for treatment of cardiomyopathy is unknown. Finally,
like many of the updated DMD care considerations, the
new criteria for initiation of mechanical cough assistance
(including thresholds of forced vital capacity [FVC]
<50% of predicted, peak cough flow <270 L/min, or
maximal expiratory pressure <60 cm H2O) and initiation
390 www.thelancet.com/neurology Vol 17 May 2018
of non-invasive assisted ventilation (new thresholds of
FVC <50% of predicted, maximal inspiratory pressure
<60 cm H2O) are not evidence based. Rather, these new
criteria are intended to result in more anticipatory use
of these interventions, with the possibility that therapy
will be initiated in slightly younger patients than in
current practice.
Notably, as is typical for a rare disease, the care
considerations were mainly obtained using the RAND
Corporation–University of California Los Angeles
Appropriateness Method and are not conventionally
evidence based. This method was used because of the
absence of large-scale randomised controlled trials
involving the care of individuals with DMD, with the
possible exception of evidence favouring the use of
glucocorticoids and new therapeutics to ameliorate
disease progression.
In The Lancet,9 a prospective cohort study, which
was published after the submission of the DMD care
considerations, analyses 10 years of natural history
data of patients with DMD collected by the Cooperative
International Neuromuscular Research Group. The
analyses confirmed the benefit of glucocorticoids across
the lifespan, with delayed loss of clinically meaningful
functional milestones and improved survival reported.
Furthermore, these new data validate the concept that
early treatment benefits in DMD extrapolate to later
benefits in upper limb and pulmonary function. Similar
prospective studies are needed to assess whether these
revised care considerations will lead to better outcomes
based on strong evidence.
Future studies will also need to identify biomarkers
that indicate short-term attenuation of disease-related
progression. Development of DMD-specific growth
charts as well as accurate techniques for establishing body
composition are needed. Additional work is also needed
to assess the potential of growth-promoting therapies to
prevent bone fragility and treat osteoporosis. Adults with
DMD, who have not been the subject of studies thus far,
should be included in future research.
These updated care considerations are important
goals for clinicians and care givers to aim for and they
will likely have a far-reaching international impact.
However, full implementation will be expensive,
time consuming, and not achievable in all settings.
Better funding models for the proposed expanded
multidisciplinary care are needed.

Finally, we are entering an era in which access to
novel therapies for DMD, including novel dystrophin
restoration therapies and other innovative treatments,
will increasingly drive patient outcomes in DMD
incrementally beyond optimised standard care. New
data will need to be obtained to describe the evolving
disease course that will undoubtedly be affected by
combinatorial novel therapeutics, which will continue to
improve function and slow disease progression.
*Craig M McDonald, Eugenio Mercuri
Department of Physical Medicine and Rehabilitation, University of
California Davis Medical Center, Sacramento, CA 95817, USA
(CMM); Pediatric Neurology Unit and Nemo Center, Policlinico
Gemelli, Catholic University, Rome, Italy (EM)
cmmcdonald@ucdavis.edu
CMM has received research support from Sarepta Therapeutics, PTC
Therapeutics, Pfizer, Santhera Pharmaceuticals, Italfarmaco, Reveragen, Eli Lilly,
and Capricor Therapeutics, and has served on advisory boards for PTC
Therapeutics, Sarepta Therapeutics, Santhera Pharmaceuticals, Eli Lilly,
Catabasis, and Astellas/Mitobridge. EM received research support from Biogen,
and has served on the advisory boards for Sarepta Therapeutics, Santhera
Pharmaceuticals, PTC Therapeutics, Roche, Biogen, and AveXis.
Understanding risk of PML through multiple sclerosis
Progressive multifocal leukoencephalopathy (PML),
first described in 1959, is an often-fatal disease caused
by an opportunistic infection by JC virus (JCV), which
most human beings carry throughout life without
consequences.1,2 PML was a major cause of death in
patients with AIDS, but its prevalence decreased sharply
with the introduction of retroviral therapy. PML is
now mostly seen in patients during chemotherapy or
immunosuppression. The first PML cases in patients with
multiple sclerosis who were treated with natalizumab
came as a surprise in 20053,4 because PML had not
been observed with other drugs for multiple sclerosis
(interferon β and glatiramer acetate) and because, except
for an autoimmune reaction against CNS tissue, patients
with multiple sclerosis are immunologically healthy,
cope well with infections, and show no increased risk of
malignancies. These cases therefore led the regulatory
authorities to suspend approval of natalizumab, although
the drug was allowed back on the market in 2006 after
risk factors for PML were identified6 and the manufacturer
provided a reasonable risk management path through
the introduction of a sensitive assay to measure antibody
responsiveness against JCV. In their Review, Eugene Major
www.thelancet.com/neurology Vol 17 May 2018 391
Comment
1 Centers for Disease Control and Prevention. Prevalence of Duchenne/
Becker muscular dystrophy among males aged 5–24 years—four states,
2007. MMWR Morb Mortal Wkly Rep 2009; 58: 1119–22.
2 Romitti PA, Zhu Y, Puzhankara S, et al. Prevalence of Duchenne and Becker
muscular dystrophies in the United States. Pediatrics 2015; 135: 513–21.
3 Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot
screening for Duchenne muscular dystrophy: 21 years experience in Wales
(UK). Eur J Hum Genet 2013; 21: 1049–53.
4 Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of
Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and
psychosocial management. Lancet Neurol 2010; 9: 77–93.
5 Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of
Duchenne muscular dystrophy, part 2: implementation of multidisciplinary
care. Lancet Neurol 2010; 9: 177–89.
6 Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of
Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular,
rehabilitation, endocrine, and gastrointestinal and nutritional
management. Lancet Neurol 2018; 17: 251–67.
7 Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of
Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health,
and orthopaedic management. Lancet Neurol 2018; 17: 347–61.
8 Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of
Duchenne muscular dystrophy, part 3: primary care, emergency
management, psychosocial care, and transitions of care across the lifespan.
Lancet Neurol 2018; 17: 445–55.
9 McDonald CM, Henricson EK, Abresch RT, et al. Long-term effects of
glucocorticoids on function, quality of life, and survival in patients with
Duchenne muscular dystrophy: a prospective cohort study. Lancet 2018;
391: 451–61.
and colleagues5 discuss how instructive a serious adverse See Review page 467
event of natalizumab treatment in patients with multiple
sclerosis has been both with respect to improving
understanding of PML pathogenesis and, importantly,
patient management.
A puzzling observation is that patients with high anti-
JCV antibody indices who are treated with natalizumab
have a high risk of developing PML (one in 70 chance
or higher). The risk is much lower in patients with low
antibody titres and is negligible in individuals who are
negative for anti-JCV antibody, which runs counter
to what one might expect.6 Besides regular antibody
testing, the routine use of MRI to identify early signs of
incipient PML before clinical manifestations is another
important step in reducing the risk of serious brain
damage. Major and colleagues5 provide guidance on how
often patients should be scanned, which MRI findings
hint at the beginning of PML, how to identify PML
immune reconstitution inflammatory syndrome as a sign
of an immune response against the infected brain cells
versus expanding PML lesions, and which steps should
be taken to manage the patient once MRI lesions that
indicate PML are identified. The authors discuss how to