THE NEW YORK TIMES, TUESDAY, OCTOBER 8, 2019 N D5MY GRANDSON STEFANwas about 8 years
old when he began to get migraines. As soon
as he could after getting home from school,
he would lie down and go to sleep, awak-
ening an hour or two later, usually with the
headache gone. But before the pain abated,
he sometimes vomited, prompting him and
his relatives to keep barf bags handy at all
times.
Then as Stefan approached puberty,
these debilitating headaches stopped as
mysteriously as they had begun.
Though Stefan’s headaches were disrup-
tive and disabling, he was luckier than his
grandma. My migraine attacks (misdiag-
nosed as sinus headaches) began around
puberty, usually occurred three times a
month, each lasting for three days, and did-
n’t end until menopause. Even though sleep
can often terminate a migraine attack, noth-
ing I tried brought relief, and there were no
prescription medications at the time to treat
or prevent them.
Attention parents, teachers, coaches,
doctors and anyone else who interacts with
children and teens: Too often, adults tell
them to “suck it up, it’s just a headache.” A
migraine is not “just a headache,” nor is it
something they can ignore. A migraine
makes you feel sick all over, often acutely
sensitive to light and noise, nauseated and
unable to concentrate on anything but the
desire for relief. Very young children with
migraine may be spared the head pain and
instead get only gastrointestinal symptoms
like vomiting and stomach pain.
Migraine is a disease with a genetic com-
ponent and often runs in families. The
pounding, nauseating headache is a symp-
tom of that disease. Before puberty, the dis-
order affects boys and girls equally, but af-
ter puberty, when testosterone kicks in to
suppress migraine attacks in boys, the inci-
dence among girls becomes very much
higher.
Happily, for the more than six million chil-
dren who suffer frequently from migraines,
the prospects for relief are now very much
better than when I was a teen and pre-
menopausal adult. In August, the American
Academy of Neurology and the American
Headache Society issued new guidelines for
therapies for children and adolescents that
can both reduce, if not eliminate, attacks of
migraine and greatly shorten their dura-
tion.
Since 2004, when the organizations pub-
lished the first guidelines, “a lot more stud-
ies have been done of acute and preventive
therapies that have been approved for chil-
dren and adolescents by the Food and Drug
Administration,” said Dr. Andrew Hershey,
professor of pediatrics and neurology and
director of the Headache Center at Cincin-
nati Children’s Hospital Medical Center.
For youngsters with chronic migraine
who have headaches for about 15 or more
days a month, there is now at least one ef-
fective preventive: a combination of cogni-
tive behavioral therapy and an antidepress-
ant called amitriptyline (Elavil), Dr. Her-
shey said. Treatment options for an acute
headache run the gamut from an over-the-
counter NSAID (nonsteroidal anti-inflam-
matory drug like ibuprofen) to a prescribed
triptan like Imitrex, Maxalt or Zomig that
are safe and effective for young sufferers,
he said.
Interestingly, with respect to preven-
tives, the main randomized study of 361
young patients, called CHAMP, found that areduction of 50 percent or more in the num-
ber of headache days occurred in both
groups taking either the drug amitriptyline
or topiramate (Topamax, an anti-seizure
drug), as well as those in the placebo group,
and the active drugs caused more side ef-
fects.
The findings suggest to Dr. Hershey that
“it’s not so much what we do but how we do
it. We offer options: ‘Do headaches bother
you enough to take a preventive medication
every day?’ We give patients the choice,
and the expectation of a response drives a
clinically positive result.
“We can use that expectation clinically,
telling patients they don’t have to be on
medication very long. When the frequency
of headaches declines to two or three times
a month and the headaches go away in an
hour, they can stop preventive medication
and use an acute therapy to treat the head-
ache when it occurs.”
Based on the results of the CHAMP trial,
Dr. Christina L. Szperka, pediatric neurolo-
gist and director of the pediatric headache
program at Children’s Hospital of Philadel-phia, suggests that clinicians first try a nu-
traceutical like magnesium or riboflavin
(vitamin B2) to reduce headache frequency,
along with lifestyle measures like staying
well hydrated, eating regular meals, not
skipping breakfast, getting enough sleep
and getting some exercise.
She told NeurologyLive: “If the act of tak-
ing something like a pill every day and be-
lieving it is likely to help you and is part of
what triggers the body’s response to heal it-
self, then we feel like it makes sense to think
about using something that’s pretty harm-
less to start the process. If they don’t re-
spond to those nutraceuticals, then that’s
when we bring in the other prescription
medications.”
Dr. Amy Gelfand, director of the child and
adolescent headache program at the Uni-
versity of California, San Francisco, has
found that taking melatonin along with ribo-
flavin can also help to reduce the frequency
of migraine attacks. Melatonin is the body’s
natural sleep-inducing hormone and is
available in pharmacies without a prescrip-
tion. “Too often kids and families are told
nothing can be done about migraine,” Dr.
Gelfand said. “That’s the wrong message.
The kids who are being treated are doing re-
ally well.”
An often-overlooked contributor to mi-
graines is stress. Dr. Szperka told me:
“Stress is a huge factor in migraine. Kids
have told us, ‘If I’m worried about some-
thing, that’s when I have my headache.’
Kids today are under so much pressure to
do well in school and in sports if they want
to get into a good college. They push them-
selves and suffer. Sometimes the best sug-
gestion to them is to ease up academically.”
Although it has long been thought that
certain foods — like chocolate, aged cheese,
processed meats, citrus fruits and artificial
sweeteners — can act as triggers for a mi-
graine, experts say this has yet to be prov-
en. The chocolate myth may have arisen,
Dr. Gelfand suggested, because the pre-
monitory phase before a migraine attack of-
ten induces a craving for sweets.
Still, for those who suspect a particular
substance or circumstance may be acting
as a migraine trigger, it can help to keep a
diary, recording under what conditions the
headaches seem to occur. A woman I know
used a food diary to discover that her head-
aches followed consumption of corn in any
form, even cornstarch as an ingredient.
If a child’s primary care doctor is unable
to deal successfully with migraine, the ex-
perts urged parents to consult a pediatric
neurologist or headache specialist.Pursuing Relief for Children’s Migraines
New guidelines for therapies
can reduce or eliminate attacks
and shorten their duration.
GRACIA LAM‘Stress is a huge
factor in migraine.’
DR. CHRISTINA L. SZPERKA
CHILDREN’S HOSPITAL OF
PHILADELPHIAPERSONAL HEALTH JANE E. BRODYWe l l
THE CATERPILLAR OFthe monarch butterfly
eats only milkweed, a poisonous plant that
should kill it. The caterpillars thrive on the
plant, even storing its toxins in their bodies
as a defense against hungry birds.
For decades, scientists have marveled at
this adaptation. Last Thursday, a team of re-
searchers announced they had pinpointed
the key evolutionary steps that led to it.
Only three genetic mutations were neces-
sary to turn the butterflies from vulnerable
to resistant, the researchers reported in the
journal Nature. They were able to introduce
these mutations into fruit flies, and sud-
denly they were able to eat milkweed, too.
Biologists hailed it as a tour de force that
harnessed gene-editing technology to un-
scramble a series of mutations evolving in
some species and then test them in yet an-
other.
“The gold standard is to directly test mu-
tations in the organism,” said Joseph W.
Thornton, an evolutionary biologist at the
University of Chicago. The new study “fi-
nally elevates our standards.”
Insects began dining on plants over 400
million years ago, spurring the evolution of
many botanical defenses, including harsh
chemicals. Certain plants, including milk-
weed, make particularly nasty toxins
known as cardiac glycosides.
The right dose can stop a beating heart or
disrupt the nervous system. For thousands
of years, African hunters have put these poi-
sons on the tips of arrows. Agatha Christie
wrote a murder mystery featuring fox-
glove, which produces cardiac glycosides.
The toxins gum up so-called sodium
pumps, an essential component of all ani-
mal cells. “It’s a very vulnerable point, and
plants have targeted it,” said Susanne
Dobler, a molecular biologist at the Univer-
sity of Hamburg in Germany.
These pumps move positively charged
sodium atoms out of cells, giving their inte-
riors a negative charge. Heart cells need so-
dium pumps to build enough electrical
charge to deliver a heartbeat. Nerves use
the pumps to produce signals to the brain. If
the pumps fail, then those functions come to
a halt.
Despite the dangers, monarch butterflies
are completely dependent on toxic milk-
weed. Females lay their eggs on the plants,
and the caterpillars eat as much as they can
before forming a chrysalis.
As they develop into adults, the pupae
shuttle milkweed toxin from their guts to
their new wings. After emerging from the
chrysalis, the monarchs become flying poi-
son. Birds that try to eat the insects vomit
them back up.
To understand how monarchs evolved
this adaptation, Dr. Dobler and her col-
leagues took advantage of the fact that
other insect species have also evolved a re-
sistance to cardiac glycosides. A few even
eat milkweed.
The researchers compared the genes that
serve as blueprints for the sodium pump in
poison-resistant species, like the milkweed
beetle and the milkweed bug. Most of these
species, it turned out, had gained the same
three mutations.
But the mutations did not pop up all at
once. Instead, they arose one after another.
Monarchs share one of the mutations
with a related butterfly that doesn’t eat
milkweed, and a second mutation with a
closer relative that eats milkweed but does-
n’t store cardiac glycosides in its wings. The
third mutation arose in an even more recent
ancestor.
Gaining these mutations gradually al-
tered the sodium pumps in the monarchs’
cells, Dr. Dobler suspected, so that the car-
diac glycosides couldn’t disrupt them. As
the butterflies became more resistant, they
were able to enjoy a new supply of food un-
touched by most other insects.Noah Whiteman, an evolutionary biolo-
gist at the University of California, Berke-
ley, led the effort to test this hypothesis.
“These three mutations may be the thing
that unlocked the door” for the butterflies,
he said.
He and his colleagues figured out how touse Crispr, the gene-editing technology, to
introduce the mutations into fruit flies. The
flies survive on rotting fruit, and even a
small dose of cardiac glycosides can be
deadly to them.
The researchers began by giving the flies
the first mutation to arise the ancestors of
monarchs. The larvae that carried this mu-
tation were able to survive on a diet of yeast
laced with low levels of cardiac glycosides.
The second mutation let the flies with-
stand even more toxins, and the third made
them entirely resistant. With all three muta-
tions, the flies even ate dried milkweed
powder.
The third mutation had another striking
effect. When the flies with the gene devel-
oped into adults, their bodies carried low
levels of cardiac glycoside, useful as a de-
fense against predation.
Dr. Whiteman and his colleagues also
found a remarkable pattern. One of the
three mutations, called 122, provided the
biggest boost in resistance. But in all of the
insects resistant to cardiac glycosides, that
mutation always evolved after the other
two.
As it turned out, 122 on its own has a nasty
side effect.
The researchers put the mutant flies in a
centrifuge and spun them for 10 seconds.
Afterward, the flies were overwhelmed by
seizures for several minutes.
Ordinary flies, by contrast, immediately
walked away from the laboratory carnival
ride. Flies with the other two resistance mu-
tations were also unharmed by the pro-
cedure.
Dr. Whiteman and his colleagues suspect
that the 122 mutation is beneficial to insects
only if it is preceded by another mutation.
On its own, 122 may bend the pump into a
deformed shape that makes the insect
prone to seizures. Perhaps other mutations
compensate in some way.
Other studies have suggested that the or-
der of mutations can make a big difference
in how a creature evolves. Bacteria, for ex-
ample, can gain antibiotic resistance from
certain genetic mutations. But some of
those mutations are only beneficial if they
evolve after others.
The new study now shows how the order
affects animals, too.
“They really are reconstructing evolu-
tionary history,” Hopi Hoekstra, an evolu-
tionary biologist at Harvard, said of the new
research. “You can piece together what
happened over time.”MATTER CARL ZIMMERHow Monarch Butterflies Evolved to Eat Poison
Recently discovered genetic
mutations enabled these
insects to thrive on milkweed.
Top, a monarch butterfly eating
nectar from a toxic swamp
milkweed. Above, a fruit fly,
genetically modified with the
three poison-resistant
mutations found in monarchs,
resting on a monarch’s wing.ANN HEISENFELT/ASSOCIATED PRESSJULIANE PELAEZ‘They really are
reconstructing
evolutionary history.’
HOPI HOEKSTRA
HARVARD UNIVERSITY