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Headache ISSN 0017-8748
C
2006 by American Headache Society doi: 10.1111/j.1526-4610.2006.00386.x
Published by Blackwell Publishing
Correspondence and Clinical Notes
Clinical Notes
Migraine Triggered by Sucralose—A Case Report
Marcelo E. Bigal, MD, PhD; Abouch V. Krymchantowski, MD, PhD
Sucralose is the active compound of the most commonly sold sweetener in the United States. Different than
aspartame, sucralose is not considered to be a migraine trigger. Herein we report a patient with attacks of migraine
consistently triggered by sucralose. She also suffers from menstrually related migraine that had been well-controlled
for several months since she switched her contraceptive from fixed estrogen to triphasic contraceptive pills. Some
attacks triggered by sucralose were preceded by aura, and she had never experienced migraine with aura before.
Withdrawal of the compound was associated with complete resolution of the attacks. Single-blind exposure (vs.
sugar) triggered the attacks, after an attack-free period.
Key words: migraine, triggers, sucralose, migraine-induced
(Headache 2006;46:515-527)
Migraine attacks may be triggered by external or in-
ternal precipitants in many individuals.1A prospective
case–control matched survey, conducted in France, con-
trasted headache triggers in migraineurs and in those with
tension-type headache. The information was collected using
headache calendars over a 3-month period.2Fatigue, sleep
problems, stress, specific food and/or drinks, menstruation,
and hot or cold weather were identified as migraine trig-
gers. Other studies show that potential migraine triggers
include dietary components (monosodium glutamate, red
wine),3,4other exogenous factors (flickering lights, weather
changes),5,6as well as endogenous factors (stress, menstrua-
tion).7,8
From the Department of Neurology, The Albert Einstein Col-
lege of Medicine, Bronx, NY; The New England Center for
Headache, Stamford, CT; and The Montefiore Headache Unit,
Bronx, NY (Dr. Bigal); Headache Center of Rio, Rio de Janeiro,
RJ, Brazil (Dr. Krymchantowski); and Department of Neu-
rology, Universidade Federal Fluminense, Rio de Janeiro, RJ,
Brazil (Dr. Krymchantowski).
Address all correspondence to Dr. Marcelo E. Bigal, Depart-
ment of Neurology, Albert Einstein College of Medicine, 1165
Morris Park Avenue, Bronx, NY 10461.
Accepted for publication November 10, 2005.
Aspartame, commonly used as an artificial sweetener,
is a trigger for some migraineurs. In a survey of 190 consec-
utive patients seen in a headache unit, 8.2% of them iden-
tified aspartame as their most important trigger,9although
a negative relation between aspartame and headaches has
also been reported.10 More recently, two migraineurs with
attacks probably triggered by a triptan formulation contain-
ing aspartame were reported.11
Sucralose, another low-calorie sweetener, is the sweet-
ening ingredient used worldwide in more than 4,000 food,
beverage, and nutritional products (and is the sweetening
ingredient in SPLENDABrand Sweetener).12 Sucralose is
considered safe, and is not associated with side effects in
usual doses.12 Different from aspartame, sucralose was never
reported as a migraine trigger.
Herein we report the case of a migraineur with attacks
consistently triggered by a sweetener containing sucralose.
The trigger was identified using headache calendars and
trigger questionnaires, and confirmed by prospective single-
blinded challenge.
CASE REPORT
The subject is a 30-year-old woman, who suffers from
migraine without aura since menarche. The subject is
515
516 March 2006
married to one of the authors of this study. Until recently,
around 90% of her migraine attacks were related to men-
struation. She had no more than one nonmenstrually related
attack per month. Around 6 months ago, her contraceptive
pill was changed to a triphasic oral contraceptive, and the
menstruallyrelatedmigraineattacksdecreasedbymorethan
80%. However, around 4 months ago, she reported an impor-
tant increase in the frequency of her nonmenstrual attacks,
for more than 10 days per month. Attacks were also more
severe and disabling. She could not identify changes in her
lifestyle or in other medications.
She was given a headache calendar and daily trigger
questionnaires, asking about known migraine triggers. The
trigger questionnaires had also blank spaces for substances
not included on it. She was oriented to use the questionnaire
every day, even without a headache. Sucralose is not listed
in this questionnaire, but aspartame is.
Thesubjectexperienced10headacheattacksinlessthan
1 month. Migraine without aura was the diagnosis in 6 of
them, probable migraine happened in other three, and mi-
graine with typical visual aura (never experienced before)
in 1.
Analysis of the trigger questionnaire revealed that in
all but one attack (90% of the attacks), she had used sweet-
eners containing sucralose from 30 minutes to 3 hours be-
fore the headache (this was specifically written in the blank
space of the trigger questionnaire). The use of sucralose on
a non-headache day happened just once. All other triggers
(sleep changes, red wine, etc) were present on no more than
2 headache days, and happened no more frequently than
on non-headache days. When specifically asked she realized
that she had changed the sweetener (from aspartame to su-
cralose) by the time her headaches started to increase.
The subject discontinued sucralose use and started mag-
nesium (400 mg of the salt bid) and pyridoxine (200 mg bid).
She remained pain-free for 1 month. However, since we
were still not convinced that sucralose was the trigger, we
proposed to her to let us sweet her beverage with sugar or
sweetener, and use it for 6 consecutive times.She was blinded
to the product (orange juice with sucralose vs. sugar). On the
first 3 days we used sugar and she did not have a headache.
However, she developed a headache in the first two episodes
of sucralose use, and stopped participation. Immediately af-
ter drinking the juice, we asked her to tell us, according to
the taste, if the juice had been sweetened with sucralose or
sugar. From the 5 exposures, she correctly identified sugar
in one, sucralose in another, and was wrong or unsure in the
other three attacks. She just had one nonmenstrually related
migraine attack since she discontinued the use of sucralose.
DISCUSSION
We are convinced that one of the compounds of the
sweetener was the trigger in the case reported herein. Since
sucralose is the active component, we postulate that it was
the trigger. However, inactive compounds present in the
sweetener, maltodextrin and dextrose, could also be the trig-
ger. Since these inactive compounds are present in a number
of processed foods, and the patient reported a clear onset of
her headaches associated with the use of the sweetener, we
suggest that sucralose was the trigger. Additionally it is pos-
sible that the magnesium and pyridoxine, known migraine
preventives, are responsible for the improvement. Although
this is plausible, we think it is not probable, since posterior
trigger exposition caused attacks of migraine with aura.
Sucraloseisa noncaloric sweetener.IntheUnitedStates
it is known by the trade name Splenda. In the European
Union it is also known under the E number (additive code)
E955. It is 500 to 600 times sweeter than sucrose, making it
roughly four times as sweet as aspartame. It is manufactured
by the selective chlorination of sucrose, by which three of su-
crose’s hydroxyl groups are substituted with chlorine atoms
to produce 1,6-dichloro-1,6-dideoxy-β-D-fructo-furanosyl
4-chloro-4-deoxy-α-D-galactopyranoside (Figure 1).13,14
Fig 1.—Chemical structure of sucralose.
Headache 517
The literature on sucralose is scarce. At the time of
this writing, a pubmed search using the single keyword “su-
cralose” revealed just 79 papers, most dealing with ani-
mal models,13 the pharmacological properties of the com-
pound,14 or reviewing the overall use of sweeteners in low
caloric diets.15 No reports dealt with side effects of su-
cralose in humans, or with headache induced by sucralose.
Meanwhile, the sales of products containing sucralose are
dramatically increasing worldwide, while the consumption
of aspartame is gradually decreasing.16
Aspartame is a known migraine trigger in a sizeable pro-
portionoftheindividuals.9Hereinwe identified a migraineur
with attacks most probably triggered by sucralose. This re-
lation was identified with the use of prospective question-
naires, headache calendars, and was further confirmed by
single-blind challenge. Since many migraineurs are exposed
to sucralose, and that triggers overall may render a headache
refractory, we suggest that providers consider sucralose as a
potential (although very likely infrequent) migraine trigger.
REFERENCES
1. Martin VT, Behbehani MM. Toward a rational under-
standing of migraine trigger factors. Med Clin North Am.
2001;85(4):911-941.
2. Chabriat H, Danchot J, Michel P, Joire JE, Henry P. Precipi-
tating factors of headache. A prospective study in a national
control-matched survey in migraineurs and nonmigraineurs.
Headache. 1999;39(5):335-338.
3. Sauber WJ. What is Chinese restaurant syndrome? Lancet.
1980;1(8170):721-722.
4. Peatfield RC. Relationships between food, wine, and
beer-precipitated migrainous headaches. Headache.
1995;35(6):355-357.
5. Kowacs PA, Piovesan EJ, Werneck LC, Fameli H, Pereira
da Silva H. Headache related to a specific screen flickering
frequency band. Cephalalgia. 2004;24(5):408-410.
6. Prince PB, Rapoport AM, Sheftell FD, Tepper SJ, Bi-
gal ME. The effect of weather on headache. Headache.
2004;44(6):596-602.
7. Rains JC, Penzien DB, McCrory DC, Gray RN. Behavioral
headache treatment: History, review of the empirical litera-
ture, and methodological critique. Headache. 2005;45(suppl
2):S92-S109.
8. MacGregor EA. Female sex hormones and migraine. Rev
Neurol (Paris). 2005;161(6-7):677-678.
9. Lipton RB, Newman LC, Cohen JS, Solomon S. Aspartame
as a dietary trigger of headache. Headache. 1989;29(2):90-
92.
10. Koehler SM, Glaros A. The effect of aspartame on migraine
headache. Headache. 1988;28(1):10-14.
11. Newman LC, Lipton RB. Migraine MLT-down: An un-
usual presentation of migraine in patients with aspartame-
triggered headaches. Headache. 2001;41(9):899-901.
12. Sucralose.org. The facts about sucralose. Available at
http://www.sucralose.org/. Accessed 10/05/2005.
13. Sclafani A, Clare RA. Female rats show a bimodal prefer-
ence response to the artificial sweetener sucralose. Chem
Senses. 2004;29(6):523-528.
14. McCourt J, Stroka J, Anklam E. Experimental design-based
development and single laboratory validation of a capillary
zone electrophoresis method for the determination of the
artificial sweetener sucralose in food matrices. Anal Bioanal
Chem. 2005;382(5):1269-1278.
15. American Dietetic Association. Position of the American
Dietetic Association: Use of nutritive and nonnutritive
sweeteners. J Am Diet Assoc. 2004;104(2):255-275.
16. Johnson and Johnson. SPLENDA(sucralose) No Calo-
rie Sweetener Earns #1 Spot In U.S. Retail Sales. Ava-
ilable at http://www.jnj.com/news/jnj news/20030611 1651
21.htm. Accessed 10/08/2005.
Thunderclap Headache From Complicated Sinusitis
Brian E. McGeeney, MD, MPH; Glenn Barest MD; Gregory Grillone, MD
We report a case of complicated pansinusitis presenting with thunderclap headache. The patient quickly devel-
oped left ophthalmoplegia and imaging demonstrated extension of inflammation from the sphenoid sinus into the
sellar region. Thunderclap headache is well known to occur from a variety of intracranial events, but complicated
sinusitis presenting this way is seldom described. The patient recovered completely with appropriate treatment.
Key words: thunderclap, headache, sinusitis
518 March 2006
Thunderclap headache often heralds an intracranial
vascular catastrophe such as hemorrhage from an intracra-
nial aneurysm and may also be a manifestation of primary
headache.1,2Othersecondarycausesincludecerebralvenous
thrombosis, intracranial hypotension, pituitary apoplexy,
and carotid artery dissection. Sinusitis is well known to cause
headache and facial pain, especially the acute variety, but a
thunderclap presentation is very unusual and may be the
presentation of sinusitis-related intracranial complications.
Intracranial complications are particularly associated with
sphenoid involvement and the case presentation involves
extension of inflammation beyond the limits of the sphe-
noid and into the sella turcica with involvement of adjacent
cranial nerves also.3
CASE REPORT
A 34-year-old Hispanic man developed a sudden se-
vere headache with immediate peak intensity, at about 2 a.m.
one night while preparing for bed after playing video games.
The pain was predominantly located in both temples and a
sense of flowing or movement of the pain was described.
Headache was followed by nausea and vomiting. The next
morning he presented to the Emergency Department. He
was well prior to the headache although there were symp-
toms of a viral upper respiratoryinfection 1 to 2 weeks be-
forehand. His background medical history is notable for re-
current sinus infections for years including recent months.
On examination he was afebrile and there were no signs of
meningeal irritation. Cranial computed tomography (CT)
of the brain was remarkable only for pansinusitis (Figure 1).
Laboratory testing included a white blood count of 17,500
permm3,90%neutrophils.Cerebrospinalfluid(CSF)exami-
nation was clear to inspection with 27 red blood cells per high
power field and 22 white blood cells per high power field of
which 94% were lymphocytes and 6% mononuclear histio-
cytes.CSF protein level was elevated at 69 mg/dL and glucose
level was 77 mg/dL. A diagnosis of sinusitis was made and he
was discharged home on amoxicillin/clavulanate, ibuprofen,
From the Department of Neurology, Boston University School
of Medicine, Boston, MA (Dr. McGeeney); Department of Ra-
diology, Boston University School of Medicine, Boston, MA
(Dr. Barest); and Department of Otolaryngology, Boston Uni-
versity School of Medicine, Boston, MA (Dr. Grillone).
Address all correspondence to Dr. Brian E. McGeeney, 715
Albany Street, Dept of Neurology, Boston University School
of Medicine, C329, Boston, MA 02118.
Accepted for publication November 16, 2005.
Fig 1.—CT brain on initial presentation. Opacified right sphe-
noid sinus (arrow). Fluid-filled ethmoid sinuses are also seen.
oxycodone, and pseudoephedrine.The next day diplopia and
left ptosis developed. The patient continued to feel unwell
and presented again in the Emergency Department 2 days af-
ter initial evaluation. By this time the headache was bifrontal
and worst in the left periorbital region. A white blood count
was 18,800 per mm3, 69% neutrophils. He was febrile (103◦F)
and without meningismus, but a left ptosis and partial ocu-
lomotor and abducent palsies were present. Pupils were re-
active and visual acuity was 20/20 bilaterally. Therapy was
instituted with intravenous ceftriaxone and vancomycin, and
later metronidazole was added. Streptococcus mitis was cul-
tured from the CSF, which was of uncertain pathological
significance. Over next 24 hours he developed complete left
ophthalmoplegia, with retention of visual acuity. Magnetic
resonance imaging of the brain revealed abnormalities of the
sphenoid sinus, sella, and cavernous sinuses with enhance-
ment. Pituitary signal was abnormal (Figure 2). A CT of the
sinuses noted dehiscence of the sellar floor/roof of sphenoid
sinus (Figure 3). Although consistent with sinusitis, the dif-
ferential included other inflammatory processes and tumor.
Therewasnocavernoussinusthrombosis. Laboratory results
suggested pituitary insufficiency.
The headache improved markedly within a few days and
the ophthalmoplegia began to resolve. Maxillary washouts
and endoscopic sphenoidotomies were performed and
Headache 519
Fig 2.—MR brain. Sagittal T1 pre- and postgadolinium images 2 days after initial presentation. Note similar signal intensity of
material filling sphenoid sinus and sella (long arrow). Pituitary gland not well discriminated with abnormal pattern of enhancement.
Abnormal enhancement of subfrontal dura and hypothalamus (short arrows). Abnormality of cavernous sinuses was demonstrated
on coronal images (not shown).
cultures grew Pseudomonas aeruginosa and Enterococcus of
unclear significance. There was no evidence of tumor. Two
weeks after initial presentation the left ophthalmoplegia was
practically gone and eventually the patient returned to nor-
mal. A repeat MRI of brain demonstrated that the pitu-
itary contour returned to normal although mucosal thicken-
Fig 3.—CT sinuses. Thin-section sagittal (left) and coronal (right) reconstructions show dehiscence of floor of sella/roof of sphenoid
sinus.
ing and inflammatory changes of the sphenoid sinus remain
(Figure 4).
DISCUSSION
This case highlights a rare headache presentation of
complicated sinusitis, namely thunderclap headache. The
520 March 2006
Fig 4.—MR Brain 6 weeks later. Sagittal T1 pre- and postgadolinium images. Pituitary contour has returned to normal (long arrow),
but still shows heterogeneous pattern of enhancement. Pituitary stalk and hypothalamus are now normal (short arrow).
patient had involvement of the sphenoid (in addition to other
sinuses) which is known to result in major complications.4
The sphenoid walls can be very thin, bounded by the sella
and pituitary above, and laterally from cranial nerves and
vascular contents of the cavernous sinus region. It is pos-
sible that (continued) extension of the inflammatory mate-
rial outside the confines of the sphenoid sinuses resulted in
thunderclap headache. The patient had an aseptic menin-
gitis picture of the CSF suggesting that the parameningeal
infection was contained, as has been described before.5Bac-
terial meningitis may ensue.6Thrombosis of the cavernous
sinus which did not occur here can also present with thunder-
clap headache in the setting of sphenoid sinusitis.7Pain from
sphenoid infection and its complications has a varied loca-
tion and has been associated with occipital, vertex, frontal,
and bitemporal pain.3Periorbital pain is common. Sinusi-
tis should be considered when evaluating new onset severe
headache, and thunderclap headache is a rare presentation
of complicated sinusitis with sphenoidal involvement. Physi-
cians should ensure that CT brain scans performed for the
indication of thunderclap headache include adequate sinus
views, especially of the sphenoid sinuses.
REFERENCES
1. Dodick DW. Thunderclap headache. J Neurol Neurosurg Psy-
chiatry. 2002;72:6-11.
2. Cumurciuc R, Crassard I, Sarov M, Valade D, Bousser MG.
Headache as the only neurological sign of cerebral venous
thrombosis: A series of 17 cases. J Neurol Neurosurg Psychi-
atry. 2005;76:1084-1087.
3. Silberstein SD. Headaches due to nasal and paranasal sinus
disease. Neurol Clin. 2004;22(1):1-19, v. Review.
4. Ruoppi P, Seppa J, Pukkila M, Ruoppi P, Seppa J, Pukkila M,
Nuutinen J. Isolated sphenoid sinus diseases. Arch Otolaryn-
gol Head Neck Surg. 2000;126:777-781.
5. Brook I, Overturf GD, Steinberg EA, Brook I, Over-
turf GD, Steinberg EA, Hawkins DB. Acute sphenoid si-
nusitis presenting as aseptic meningitis: A pachymenin-
gitis syndrome. Int J Pediatr Otorhinolaryngol. 1982;4:77-
81.
6. Lew D, Southwick FS, Montgomery WW, Weber AL, Baker
AS. Sphenoid sinusitis. A review of 30 cases. N Engl J Med.
1983;309(19):1149-1154.
7. Kibblewhite DJ, Cleland J, Mintz DR. Acute sphenoid sinusi-
tis: Management strategies. J Otolaryngol. 1998;17(4):159-
163.
Thunderclap Stroke: Embolic Cerebellar Infarcts Presenting
as Thunderclap Headache
Todd J. Schwedt, MD; David W. Dodick, MD
Thunderclap headache is known to be a presenting feature of subarachnoid hemorrhage,unrupturedintracranial
aneurysm, cerebral venous thrombosis, cervical artery dissection, spontaneous intracranial hypotension, pituitary
Headache 521
apoplexy, retroclival hematoma, and hypertensive reversible posterior leukoencephalopathy. We describe a case
of thunderclap headache in the absence of focal, long-tract, or lateralizing neurological findings, as the primary
clinical feature of embolic cerebellar infarcts. This case expands the differential diagnosis of thunderclap headache
and reinforces the need for magnetic resonance imaging in the evaluation of such patients, even when neurologic
examination, brain computed tomography, and cerebrospinal fluid analysis are normal.
Key words: headache disorders, cerebrovascular accident, vascular headaches, intracranial aneurysm, subarachnoid
hemorrhage
CASE REPORT
A 66-year-old right-handed woman presented after
acute onset of a sudden and severe headache. That morn-
ing, while at work, she stood up from a chair and suddenly
experienced an explosive headache in the occipital region.
This was accompanied by binocular visual disturbance de-
scribed as “waves of water” traveling from her peripheral
to central vision. With eyes closed, she saw vertical white
beams of light with superimposed colored dots. Additional
symptoms included transient lightheadedness and nausea.
She took 325 mg of aspirin and presented to our institu-
tion. At the time of arrival to our institution, her symp-
toms had resolved except for a mild frontal and occipital
headache.
The patient’s past medical history was significant for hy-
pertension, hyperlipidemia, and obesity. There was no his-
tory of headache, transient ischemic attack or stroke,tobacco
use, atrial fibrillation, or ischemic heart disease. Her medi-
cations at admission included aspirin, lisinopril, pravastatin,
and estrogen.
Vital signs and physical examination were normal.
Neurological examination disclosed no focal, long-tract,
or lateralizing neurological findings. Laboratory testing of
blood counts, basic chemistries, prothrombin time, par-
tial thromboplastin time, homocysteine, sedimentation rate,
anti-nuclear antibodies, anticardiolipin antibodies, and car-
diac enzymes was normal. Electrocardiogram showed nor-
mal sinus rhythm with normal axis and a rate of 76 beats
per minute. Computed tomography (CT) scan of the head
without contrast was normal. Magnetic resonance imaging
From the Department of Neurology, Mayo Clinic, Scottsdale,
AZ.
Address all correspondence to Dr. Todd J. Schwedt, MD, De-
partment of Neurology, Mayo Clinic, 13400 East Shea Blvd.,
Scottsdale, AZ 85259.
Accepted for publication January 11, 2005.
(MRI) of the brain revealed two small areas of restricted
diffusion in the inferior right cerebellar hemisphere and a
punctate area of restricted diffusion in the left side of the
cerebellar vermis (Figure). Magnetic resonance angiography
of the circle of Willis was normal. Transesophageal echocar-
diography and duplex ultrasound of the lower extremities
were normal.
DISCUSSION
Thunderclap headache refers to a sudden and se-
vere headache that comes unexpectedly, reminding one
of a “clap of thunder.” The initial description of this
headache type was related to an unruptured intracra-
nial aneurysm.1Since that time, there have been an ex-
panding number of conditions associated with thunderclap
headache. These include cerebral venous sinus thrombosis,
cervical artery dissection, spontaneous intracranial hypoten-
sion, pituitary apoplexy, retroclival hematoma, and hyper-
tensive reversible posterior leukoencephalopathy.2-4In ad-
dition, the International Headache Society has recognized
primary thunderclap headache as an idiopathic headache
disorder that may occur in the absence of intracranial
catastrophe.
Although headaches occurring in the context of an is-
chemic stroke are not uncommon, this is the first report
of a thunderclap headache as the presenting and primary
clinical feature, in the absence of neurological findings. Ap-
proximately 25% of patients with stroke develop an asso-
ciated headache, but is often overshadowed by the abrupt
neurological deficits.5Headaches may resemble a patient’s
usual headache, or may be a new headache that is most com-
monly throbbing, and if unilateral, ipsilateral to the side of
the stroke. Pain in the frontal region of the head is more com-
mon with anterior circulation strokes while diffuse or occip-
ital pain is more common with posterior circulation strokes.6
Headaches more frequently occur with strokes that are large,
522 March 2006
Figure.—MRI Brain: Right cerebellar and left vermian areas of restricted diffusion correlating with apparent diffusion coefficient
(ADC) changes. These findings are consistent with acute ischemic infarction.
intheposteriorcirculation,hemorrhagic,andinpatientswith
a primary headache disorder.6
The underlying pathophysiology for headache with
stroke is multifactorial. Likely, there is direct activation of
sensory afferents that innervate the intracranial vasculature.
Headaches are twice as common with strokes in the pos-
terior circulation, which is more densely innervated by no-
ciceptive sensory afferents from upper cervical ganglia and
superior vagal ganglia. In addition, a pattern of neurogenic
inflammation is created during ischemic stroke with release
of vasoactive neuropeptides from sensory afferents, inflam-
matory cytokines, nitrogen oxide from damaged tissue, and
bradykinins.7This reaction results in increased nociceptive
input into the nervous system and head pain.
The addition of ischemic stroke expands the differential
diagnosis of thunderclap headache and reinforces the need
for MR imaging, even when the initial neurological examina-
tion, brain CT, and cerebrospinal fluid exam are unrevealing.
In some cases, imaging of the cranial and cervical arteries and
intracranial venous system is also necessary.
REFERENCES
1. Day JW, Raskin NH. Thunderclap headache: A symp-
tom of unruptured cerebral aneurysm. Lancet. 1986;2:1247-
1248.
2. Dodick DW. Thunderclap headache. Curr Pain Headache
Rep. 2002;6:226-232.
3. Dodick DW, Eross EJ, Drazkowski JF, et al. Thun-
derclap headache associated with reversible vasospasm
and posterior leukoencephalopathy syndrome. Cephalalgia.
2003;23:994-997.
4. de Bruijn SFTM, Stam J, Kappelle LJ, for the CVST
Study Group. Thunderclap headache as first symptom of
cerebral venous sinus thrombosis. Lancet. 1996;348:1623-
1625.
5. Vestergaard K, Andersen G, Nielsen MI, et al. Headache in
stroke. Stroke. 1993;24:1621-1624.
6. Kumral E, Bogousslavsky J, Van Melle G, et al. Headache
at stroke onset: The Lausanne Stroke Registry. J Neurol
Neurosurg Psychiatry. 1995;58:490-492.
7. Dray A. Inflammatory mediators of pain. Br Anaesth.
1995;75:125-131.
Headache 523
Chronic Long-Standing Headache due to Neurocysticercosis
Josef Finsterer, MD, PhD; Mei Li, MD; Kartrin Rasmkogeler, MD; Herbert Auer, PhD
A 35-year-old Chinese woman presented with a 26-year history of persistent headache, relieved only by diuret-
ics. Characteristic CT findings, peripheral eosinophilia, lymphocytic CSF pleocytosis, elevated CSF IgG, positive
oligoclonal bands, antibody-positive ELISA, and Western blot results with Taenia solium antigen, and a favorable
response to albendazole led to the diagnosis of neurocysticercosis.
Key words: parasitological infection, parasitosis, aseptic meningitis, chronic headache, eosinophilia, Taenia solium
Neurocysticercosis (NCC) is the most frequent parasitic
infection of the central nervous system and is protean in its
clinical presentations (Table).1,2Cysts are predominantly lo-
cated in the parenchyma (91%), but also occur in the ven-
tricles, subarachnoidal space, and spinal cord.2We present
an unusual case of NCC manifesting as recurrent headache
over a period of 26 years.
CASE REPORT
A 35-year-old Chinese woman reported episodes of
holocranial headache since age 9. She described her
headaches as pulsatile, originating in the neck and extend-
ing over the entire head. Her headache often was accom-
panied by blurred or double vision, vertigo, and fever; for
the previous 5 years, she also reported nausea and emesis.
At times, the pain reached such intensity that she would hy-
perventilate, exhibit tetany, and lose consciousness. At age
9, a diagnostic work-up (including a lumbar puncture CCP
and cerebral angiography) reportedly was normal. During
a severe attack at age 17, she was treated with mannitol,
four times daily for 3 days and experienced a significant
reduction in headaches. At age 21, a CSF analysis report-
edly demonstrated granulocytic pleocytosis of 770/3 with
slight eosinophilia. Tuberculous meningitis was suspected,
and treatment with antibiotics was initiated. Noting no im-
provement, the patient stopped all medications after 10
weeks. At age 22, she experienced a possible seizure. Mul-
tiple EEGs were normal, and no anti-epileptic medication
FromtheKrankenanstaltRudolfstiftung, Vienna, Austria(Drs.
Finsterer and Rasmkogeler); Otolaryngological Department,
Krankenanstalt Rudolfstiftung, Vienna, Austria (Dr. Li); and
InstituteofHygiene,UniversityofVienna, Vienna, Austria(Dr.
Auer).
Address all correspondence to Dr. J. Finsterer, Postach 20, 1180
Vienna, Austria.
Accepted for publication November 8, 2005.
was begun. Diagnostic work-up at age 31 disclosed a pseudo-
tumor cerebri and a cystic chiasmatic lesion. She refused a
spinal tap after her headache promptly improved following
a treatment with acetazolamide. Her relatives subsequently
observed her to exhibit slowly progressive cognitive decline
over the ensuing years.
At age 35, she again sought medical evaluation be-
cause of intensifying headache. Her examination revealed
only lymphadenopathy-reduced Achilles tendon reflexes,
and specifically the ophthalmologic exam was normal. Blood
studies revealed eosinophilia (6%; normal: 1% to 5%). Brain
CT demonstrated several calcified cysts in the Sylvian fis-
suresbilaterally. Cerebrospinal fluid analysis demonstrateda
lymphocytic pleocytosis (359/mm3), peripheral eosinophilia,
and the presence of oligoclonal bands; the lumbar puncture’s
opening pressure was normal. ELISA and Western blot tests
were positive for Taenia solium in the serum and CSF.
Albendazole, 800 mg daily, was administered for
3 weeks. After 2 days on albendazole therapy, the patient
reported increased headache along with vertigo, nausea,
and vomiting. The CSF white cell pleocytosis had increased
to 638/mm3; her headache improved significantly following
treatment with corticosteroids. Three months following dis-
continuation of albendazole, her headache had not recurred.
COMMENTS
Though headache is a common clinical feature of NCC,
it has not been described as a dominant symptom persist-
ing for years.2-5Patients with NCC most often present with
seizures (66%), symptomatic hydrocephalus (16%), menin-
gitis or encephalitis (12%), focal neurological deficits (11%),
or altered mental state (6%); headache occurs in about
15%.2In children with NCC, headache with associated vom-
iting reportedly is more common, occurring in one-third.5
The chronic headache reported by our patient presum-
ably reflected chronic meningitis or meningoencephalitis.
Except for the chiasmatic lesion noted when she was 31,
524 March 2006
Table.—CNS Manifestations of NCC
Epilepsy
Headache
Pseudotumor cerebri
Bilateral disc edema
Hydrocephalus
Intracranial hypertension
Stroke
Sinus thrombosis
Parkinson syndrome
Meningitis
Ependymitis
Ventriculitis
Arachnoiditis
Inflammatory aneurysm
Leptomeningeosis
Subarachnoid scarring
Cerebral edema
Cysternal cysts
Dementia
Global mental deterioration
Extrapyramidal signs
Syringomyelia
Third cranial nerve palsy
Calcifications
Diplopia
no intracranial cysts were evident on repeated MRIs. That
her NCC was so clinically indolent over a period of years, is
consistent with previous reports.2That NCC was diagnosed
in a Chinese woman living in Europe emphasizes both that
NCC has become more widely distributed due to immigra-
tion also in the Western world and the fact that NCC is one
of the major causes of neurological disease in China.6
Though there is no direct proof for a causal relation-
ship between the patient’s chronic headache and NCC, her
headache at last did resolve following treatment with alben-
dazole; and the CSF eosinophilia present at age 21 suggests
that she already was infected at that time. Her prognosis is
likely to be favorable as only a few calcified cysts were de-
tected via brain imaging, and death is rare in patients with
low cyst burden.7
This case confirms that NCC assumes an indolent course
over a period of years and may manifest only as chronic
headache. Such a relatively mild course may delay correct
diagnosis and appropriate treatment.
REFERENCES
1. Aditya GS, Mahadevan A, Santosh V, Chickabasaviah YT,
Ashwathnarayanarao CB, Krishna SS. Cysticercal chronic
basal arachnoiditis with infarcts, mimicking tuberculous pat-
hology in endemic areas. Neuropathology. 2004;24:320-325.
2. Wallin MT, Kurtzke JF. Neurocysticercosis in the United
States: Review of an important emerging infection. Neurol-
ogy. 2004;63:1559-1564.
3. Llompart Pou JA, Gene A, Ayestaran JI, Saus C. Neurocys-
ticercosis presenting as sudden death. Acta Neurochir (Wien).
2005;147:785-786.
4. Mahajan SK, Machhan PC, Sood BR, Kumar S, Sharma DD,
Mokta J, et al. Neurocysticercosis presenting with psychosis.
Assoc Physicians India. 2004;52:663-665.
5. SinghiP,SinghiS.Neurocysticercosisinchildren.J Child Neu-
rol. 2004;19:482-492.
6. Ikejima T, Piao ZX, Sako Y, Sato MO, Bao S, Si R, et al.
Evaluation of clinical and serological data from Taenia solium
cysticercosis patients in eastern Inner Mongolia Autonomous
Region, China. Trans R Soc Trop Med Hyg. 2005;99:625-630.
7. DeGiorgio CM, Houston I, Oviedo S, Sorvillo F. Deaths as-
sociated with cysticercosis. Report of three cases and review
of the literature. Neurosurg Focus. 2002;12:e2.
Hemicrania Continua: A Case in Which A Patient Experienced
Complete Relief on Melatonin
Roderick C. Spears, MD
This paper reports a case of hemicrania continua in which attacks were successfully eliminated while taking
melatonin 7 mg at bedtime after the patient was no longer able to tolerate indomethacin due to gastrointestinal
side effects.
Key words: hemicrania continua, melatonin
Headache 525
Hemicrania continua (HC) is an uncommon primary
headache disorder characterized by a continuous, mild-to-
moderate intensity, unilateral headache.1-4
Most patients will experience superimposed exacerba-
tions of more severe pain, often associated with ipsilateral
autonomic symptoms. Response to indomethacin is a neces-
sary criterion mandated by the International Headache So-
ciety guidelines.2,3,5Treatment with indomethacin, in doses
ranging from 25 to 300 mg per day, successfully eliminates
attacks. Some patients are unable to tolerate indomethacin
due to moderate-to-severe gastrointestinal (GI) side effects.
I now report a case of HC in which attacks were suc-
cessfully eliminated while taking melatonin 7 mg at bedtime
after the patient was no longer able to tolerate indomethacin.
This is the second such case in the literature.
CASE HISTORY
A 42-year-old, left-handed, Caucasian man initially
presented with a 12-year history of unilateral headaches
diagnosed as migraine and a 4-month history of unilat-
eral headache on the ipsilateral side that acutely became
a chronic daily headache. The patient reported prior to
4 months ago, he would have 1 headache attack per month as-
sociated with photophobia, phonophobia, osmophobia, and
nausea. He described the pain as throbbing and pressure-
like pain and rated it as 6 to 8 out of 10 in severity. He
reported this headache would last for 24 to 36 hours and
then resolve completely. The patient also reported that the
above described headaches could be triggered by weather
changes.
Within the 4 months prior to presentation to this author,
the patient reported acute onset of unilateral headache on
the left side, the same side as his previous headaches, which
had not resolved. He described a mild-to-moderate steady
ache,2to4outof10ontheseverity scale,affectingtheipsilat-
eral eye and radiating into the ipsilateral hemicranium. Su-
perimposed exacerbations of severe pain, described as “pok-
ing in my left eye,” would occur at varying intervals lasting
several minutes to hours. He reported ptosis, erythema, and
lacrimation involving the ipsilateral eye. The patient also re-
ported a “foreign body” sensation in the ipsilateral eye. He
FromtheUniversityofRochester/Rochester General Hospital,
Neurology, Rochester, NY, USA.
Address all correspondence to Dr. Roderick C. Spears, Uni-
versity of Rochester/Rochester General Hospital, Neurology,
Rochester, NY, USA.
Accepted for publication September 23, 2005.
reports that he is never pain free on the left side and that the
severe pain is associated with photophobia and nausea.
Past medical history was significant for migraine, ir-
ritable bowel syndrome, asthma, mitral valve prolaspe,
and gastric enteritis. The patient was taking escitalo-
pram oxalate, protriptyline, eletriptan, naratriptan, mon-
telukast, esomeprazole, mometasone, prochlorperazine, and
hydrocodone. The patient reports no relief from his new
headache when taking eletriptan, naratriptan, and hy-
drocodone. He also reported no relief taking prednisone.
Therewasafamilyhistoryofmigraineinthepatient’smother
and son. The general medical examination was normal. The
neurological examination was remarkable for decreased sen-
sation to vibration and temperature on the left side in his arm
and leg and decreased deep tendon reflexes at the patellar
and Achilles on the right side, it was otherwise normal. A
magnetic resonance imaging of the brain was normal.
The patient was treated with indomethacin 25 mg TID
and reported being headache free 36 hours later. The patient
remained headache free for 1 week but had to discontinue
the indomethacin due to GI irritation, and his headache re-
turned to pretreatment levels. The patient was started on
melatonin 5 mg QHS and had improvement in headache
pain. He became completely headache free on melatonin 7
mg QHS. The patient has been followed for 5 months and
has remained headache free on melatonin 7 mg QHS. At-
tempts to lower the dosage of melatonin have resulted in a
return of the headache within 24 hours.
COMMENTS
HC was first described in 1981 and officially named by
Sjaastad and Spierings in 1984.6,7There are now more than
100 reports of HC in the literature. HC was originally be-
lieved to be a rare primary headache disorder but more
recent evidence may suggest that HC is not rare, just un-
derrecognized.2In the clinical setting, HC is characterized
by a unilateral headache that is continuous and of mild-
to-moderate severity. The pain is usually reported as dull,
aching, or pressure-like pain without associated symptoms.
Exacerbations of more severe pain, lasting anywhere from
20 minutes to several days, are experienced in the major-
ity of those with HC, and when present are associated with
1 or more autonomic symptoms on the ipsilateral side. Mi-
grainous features, such as photophobia, phonophobia, nau-
sea, and vomiting commonly occur during exacerbations of
pain. Many patients will experience a sensation of a foreign
body in their eye similar to sand or an eyelash on the affected
side.
526 March 2006
HC presents as 2 temporal profiles: an episodic form
with distinct headache phases separated by periods of pain-
free remissions, and a chronic form in which the headache
persists without remission for years.3HC is chronic from
onset in 53% of patients; the disorder began in the episodic
form and evolved into the chronic form in 35%, and it begins
and remains episodic in 12% of patients.2
HC may be incorrectly diagnosed as cluster headache.
This can occur by focusing exclusively on the ipsilateral au-
tonomic features that accompany the painful exacerbations
of HC. Similarly, focusing on the associated photophobia,
phonophobia, nausea, and vomiting that may occur during
exacerbations of HC may lead to misdiagnosing HC as mi-
graine. Autonomic features on the ipsilateral side, which are
present during exacerbations of HC, are at times also present
during acute attacks of migraine. HC is distinguished from
cluster headache and migraine by the presence of a contin-
uous baseline headache that is usually unilateral and mild
to moderate in severity. The associated features of photo-
phobia, phonophobia, nausea, and vomiting, as well as the
ipsilateral autonomic features of cluster are absent with the
continuous baseline pain of HC.
My patient suffers from the chronic form of HC
and therefore requires continuous therapy, typically in-
domethacin, for headache relief. Some patients are unable
to tolerate indomethacin due to GI distress, renal disease, or
concurrent anticoagulation therapy, and alternative types of
therapy must be considered. Peres and Silbertstein demon-
strated in a study using cyclooxygenase-2 inhibitors (COX-
2), efficacy of celecoxib and rofecoxib. They found 60% of
patients who received celecoxib and 33% who received ro-
fecoxib experienced a complete response.8There is also one
case in the literature similar to HC that did not respond to
indomethacin, and many other standard headache agents,
but was responsive to 1200 mg of gabapentin per day. That
patient had complete pain relief after 17 years of continu-
ous headache.9The most recent case report in the literature
involves a patient who initially responded to indomethacin.
When that no longer worked for her, she responded to ve-
rapamil with some relief at 40 mg, but complete relief at
120 mg per day.10 Finally, Rozen reported 3 cases of idio-
pathic stabbing headache, also an indomethacin responsive
headache that responded to melatonin, and 1 case of HC that
responded to melatonin.11,12 My patient was unable to tol-
erate indomethacin due to GI distress, but his headache has
been effectively controlled with melatonin through 5 months
of follow-up.
Melatonin may play a role in headache pathophysiology
via several mechanisms. It directly scavenges toxic-free rad-
icals, and inhibits the activity of nitric oxide synthase. Mela-
tonin has been shown to possess anti-inflammatory effects.
Its action in membrane stabilization, inhibition of dopamine
release, modulation of the GABAergic system, neuroprotec-
tion from glutamate induced toxicity, potentiation of opiod
analgesia, all suggest melatonin may play an important pro-
tective role in headache occurrence.13,14 Melatonin has also
been found to modulate serotonin. It is believed that mela-
tonin may interfere in cortical spreading depression, com-
monly found in the migraine spectrum, via its effect on the
nitric oxide, GABAergic, and glutamatergic systems. It is
also known that depression and migraine may be linked to
the serotoninergic and dopaminergic systems.15 I propose
that melatonin is a good alternative for patients with HC
who are not able to tolerate indomethacin. This becomes
more important in patients suffering from the chronic form
of HC.
REFERENCES
1. Bordini C, Antonaci F, Stover LJ, Schrader H, Sjaastad
O. ”Hemicrania continua”: A clinical review. Headache.
1991;31:20-26.
2. Peres MFP, Silberstein SD, Nahmias S, Shechter AL, Rozen
TD, Young WB. Hemicrania continua is not that rare. Neu-
rology. 2001;57:948-951.
3. Newman LC, Lipton RB, Solomon S. Hemicrania continua:
Ten new cases and a review of the literature. Neurology.
1994;44:2111-2114.
4. Goadsby PJ, Lipton RB. A review of paroxysmal hemicra-
nias, SUNCT syndrome and other short-lasting headaches
with autonomic features, including new cases. Brain.
1977;120:193-209.
5. Headache Classification Committee of the International
Headache Society. The international classification of
headache disorders, 2nd ed. Cephalalgia. 2004;24(suppl 1):
1-160.
6. Medina JL, Diamond S. Cluster headache variant: Spectrum
of a new headache syndrome. Arch Neurol. 1981;38:705-709.
7. Sjaastad O, Spierings EL. Hemicrania continua: Another
headache absolutely responsive to indomethacin. Cephalal-
gia. 1984;4:65-70.
8. Peres MF, Silberstein SD. Hemicrania continua responds to
cyclooxygenase-2 inhibitors. Headache. 2002;42:530-531.
9. Mariano da Silva H, Alcantara MC, Bordini CA, Speciali
JG. Strictly unilateral headache reminiscent of hemicra-
nia continua resistant to indomethacin but responsive to
gabapentin. Cephalalgia. 2002;22:409-410.
10. Rajabally YA, Jacob S. Hemicrania continua responsive to
verapamil. Headache. 2005;45:1082.
11. Rozen TD. Melatonin as treatment of idiopathic stabbing
headache. Neurology. 2003;61:865-866.
Headache 527
12. Rozen TD. Melatonin as treatment of indomethacin respon-
sive headache syndromes. Cephalalgia. 2003;23:734-735.
13. Peres MFP, Stiles MA, Oshinsky M, et al.. Remitting form
of hemicrania continua with a seasonal pattern. Headache.
2001;41:592-594.
14. Peres MFP, Zukerman E, Porto PP, Brandt RA. Headaches
and pineal cyst: A (more than) coincidental relationship?
Headache. 2004;44:929-930.
15. Peres MF. Melatonin, the pineal gland and their implications
for headache disorders. Cephalalgia. 2005;25:403-411.
