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Deep brain stimulation to relieve drug-resistant SUNCT.

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Deep Brain Stimulation to
Relieve Drug-Resistant
SUNCT
Massimo Leone, MD,1 Angelo Franzini, MD,2
Giovanni D’Andrea, MD,3 Giovanni Broggi, MD,2
Gerardo Casucci, MD,4 and Gennaro Bussone, MD1
The rare primary headache short-lasting unilateral neuralgiform headache attacks with conjunctival injection and
tearing (SUNCT) is characterized by 3 to 200 attacks per
day of severe unilateral orbital pain. Functional magnetic
resonance imaging shows increased blood flow in the ipsilateral posterior inferior hypothalamus during attacks, indicating activation. We report the first patient with
SUNCT in whom severe intractable pain (70 per day) was
well controlled by electrode implant to and continuous
stimulation of the posterior inferior hypothalamus.
Ann Neurol 2005;57:924 –927
Short-lasting unilateral neuralgiform headache attacks
with conjunctival injection and tearing (SUNCT) is a
rare primary headache characterized by frequent
(3–200 per day) attacks of unilateral, orbital, supraorbital, or temporal stabbing or pulsating pain lasting 5
to 240 seconds.1,2 The pain is accompanied by red eye,
tearing, and blocked or runny nostril, all ipsilateral to
the pain. Attacks can be triggered by mechanical stimuli such as touching the face, washing, eating, talking,
and neck movements. Disease course and severity are
variable: some patients experience a severe chronic
course with no pain-free periods. SUNCT is notoriously refractory to medication,3,4 and severely affected
patients may consent to surgical ablation of the trigeminal nerve; however, outcomes are generally poor. Black
and Dodick5 report on two patients with SUNCT who
were treated surgically. One received glycerol rhizotomy, then gammaknife, and then suboccipital microvascular decompression as a last resort. No procedure
From the 1Department of Neurology and Headache Centre, and
2
Department of Neurosurgery, Istituto Nazionale Neurologico
Carlo Besta, Milano; 3Headache and Cerebrovascular Center, Villa
Margherita Neurological Clinic, Arcugnano, Vicenza; and 4Casa di
Cura San Francesco, Telese Terme, Benevento, Italy.
Received Feb 4, 2005, and in revised formMar 25. Accepted for
publication Mar 27, 2005.
Published online May 23, 2005 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20507
Address correspondence to Dr Leone, Department of Neurology
and Headache Centre, Istituto Nazionale Neurologico “Carlo
Besta,” via Celoria 11, 20133 Milano, Italy.
E-mail: leone@istituto-besta.it
924
Annals of Neurology
Vol 57
No 6
June 2005
produced benefit; sequelae were hypoesthesia in all trigeminal branches and anesthesia dolorosa. The second
patient received gammaknife and two microvascular
decompressions, all without benefit; sequelae were
deafness, balance disturbances, and vertigo.
During SUNCT attacks, increased blood flow in the
ipsilateral posterior inferior hypothalamus, compatible
with activation, has been demonstrated by functional
magnetic resonance imaging (MRI).6 – 8 Increased
blood flow in this area has also been shown in cluster
headache attacks.9,10 Cluster headache is a primary
headache with clinical characteristics closely resembling
those of SUNCT, the main differences being that
SUNCT attacks are shorter and more frequent.2 Stereotactic stimulation of the ipsilateral posterior inferior
hypothalamus resolves drug-resistant cluster headache
pain not responsive to repeated trigeminal surgery,11–14
strongly supporting the hypothesis that this brain area
is involved in the pathogenesis of the condition. We
hypothesized that stimulation to this area might also
relieve intractable SUNCT pain. We report on a patient with severe drug-resistant SUNCT who dramatically improved with continuous stimulation of the ipsilateral posterior hypothalamus after stereotactic
electrode implantation.
Case Report
A 66-year-old woman had a 14-year history of shortlasting (2–20 seconds), severe, “piercing and burning”
pain episodes located in the right orbit and upper right
corner of the mouth, and sometimes irradiating to the
jaw, ear, and occipital region. The attacks were strictly
unilateral with no side shift and were always accompanied by ipsilateral eyelid edema, eye reddening, nostril
obstruction, and massive tearing. Attacks could be triggered by chewing, talking, neck movements, face washing, teeth brushing, or face touching, and often occurred more than 100 (mean, 70; maximum, 300)
times a day with no refractory period to triggering. In
the 2 years preceding implant, the patient experienced
more than a thousand attacks per month.
The patient’s history was unremarkable, except for
mild hypertension and block of the right branch of the
atrioventricular bundle, indicated by electrocardiogram.
Physical and neurological examinations were unremarkable. Computed tomography (CT), MRI, and
MR angiography of the brain and orbits were all normal. None of the following drugs given with prophylactic intent controlled the pain: carbamazepine
(1,200mg/day; not tolerated because it produced vertigo); gabapentin (2,400mg/day); oral and intravenous
valproate (1,500mg/day); lamotrigine (300mg/day);
topiramate (200mg/day); indomethacin (oral 200mg/
day, 12 days; intramuscular up to 150mg/day) and ketorolac; methylprednisolone and prednisone; and tramadol. The right branch block and patient’s advanced
age contraindicated verapamil. The patient weighed
80kg.
Surgery and Follow-Up
We performed ipsilateral electrode implant in July
2003 after ethical committee approval and the patient’s
informed consent. Anatomically detailed cerebral MR
images, obtained before surgery, were transferred to the
operating room workstation (StealthStation; Medtronic
Sofamor Danek, Memphis, TN). After the stereotactic
frame had been positioned on the patient’s head, CT
scans were taken containing spatial information on the
frame and well-recognizable anatomic structures. The
MR and CT images were fused using the workstation
and Framelink 4.0 software (Medtronic Sofamor
Danek). From the resulting three-dimensional reconstruction, the exact position of the anterior commissure–posterior commissure line and the coordinates of
the target were derived. In this patient, the target coordinates were as follows: 3mm behind the midcommissural point, 5mm below the midcommissural point,
and 2mm lateral to the midline.9 After a burr hole had
been drilled and a rigid cannula inserted to within
10mm of the target, the electrode (DBS-3389;
Medtronic Sofamor Danek) was then inserted, so that
the tip reached the predetermined coordinates. The patient remained conscious. Intraoperative stimulation
followed (60 microseconds, 180Hz, up to 7V) to investigate tolerability and side effects. At amplitudes
greater than 4V, there was left (stimulation side) eye
lateroversion with consequent diplopia that disappeared
in monocular vision.9 The patient also reported the intensely disagreeable sensation that she was about to die,
without evident autonomic disturbances, and no mood
changes. Throughout the implantation procedure and
intraoperative stimulation, pupils, heart rate, blood
pressure, electrocardiogram, body temperature, and respiratory function all remained stable.
Cerebral CT was performed immediately after implant, and MRI 48 hours later to check electrode position (Fig 1). After implant, the SUNCT crises were
unchanged. Stimulation was therefore initiated. The
initial stimulation parameters were bipolar: 5 days at
30Hz, 60-microsecond pulse width, followed by 5
days at 180Hz, 60-microsecond pulse width. There
was no improvement. In our experience with patients
with cluster headache, bipolar stimulation has never
been effective. Because the clinical condition of this
patient was poor as a result of continuing crises, we
did not continue experimenting with stimulation setting but, 18 days after surgery, initiated unipolar
stimulation using the parameters generally effective in
cluster headache8 –10: continuous stimulation, frequency 180Hz, 60-microsecond pulse width, and
gradually increasing amplitude (Fig 2). The main limitation in increasing amplitude was the above-
Fig 1. Postoperative cerebral magnetic resonance imaging. Arrow indicates the position of the electrode tip.
mentioned eye movement disturbance manifesting after each such increase. The pain attacks subsided
slowly after 1 month of stimulation at 0.9V but reappeared after 2 months. The amplitude was gradually increased to 1.8V, and again the attacks subsided.
After 1 pain-free month (January 2004), the stimulator was turned off without the patient’s knowledge
and she remained pain free for a further 3 months. In
May 2004, the attacks gradually reappeared and persisted. The stimulator was turned on again without
the patient’s knowledge and the amplitude gradually
increased to 0.9V. At this amplitude, crisis frequency
was much less than before surgery (see Fig 2) and
remained low from June through August, after which
the amplitude was increased to 1.8V at which point
the patient said she felt the stimulation (mild and
transient diplopia), and we confirmed that the stimulator was on; the crises disappeared. In October
2004, the patient started experiencing sporadic attacks, and lamotrigine was given at 100mg/day; the
attacks subsided (see Fig 2). From the surgery (July
2003) to October 2004 the stimulator was adjusted
on 12 occasions. The patient remained blind to stimulation status from January to August 2004.
Stimulation was always well tolerated. However, when
the amplitude was increased, difficulties in conjugated
eye movements appeared, then subsided spontaneously a
few minutes to a few hours later. No other side effects
have occurred. Blood pressure, heart rate, electrocardio-
Leone et al: Hypothalamic Stimulation in SUNCT
925
Fig 2. Number of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing per months before
and after hypothalamic implant performed on July 28, 2003. Without the patient’s knowledge, stimulation was switched off at the
end of January 2004 and turned on again in May 2004.
gram, electrolyte balance, hormone levels, temperature,
sleep–waking cycle, body weight, and behavior have remained normal from implant to latest checkup.
Discussion
This article reports the first patient to receive electrode
implant for intractable SUNCT. The target (posterior
inferior hypothalamus) was chosen based on functional
MRI observations that this area is activated during crises6 and the fact that stimulation at the same site reliably produces pain relief in cluster headache.11–14 Prolonged stimulation in our patient has resulted in longlasting pain relief without the continuous drug
administration and with virtually no side effects. Before
the surgery, all pertinent drugs had been tried extensively and had failed to ameliorate the pain, which produced severe disability. When the stimulator was
turned off without the patient’s knowledge, the crises
reappeared but gradually disappeared after it was
turned back on. These observations, together with the
long-lasting relief, exclude a placebo effect, which
could not be investigated systematically because of the
patient’s poor condition when experiencing attacks.
Notably, before the surgery, lamotrigine (300mg/day)
produced no benefit, whereas after the surgery it eliminated sporadic attacks at a lower dosage. This observation suggests that long-term hypothalamic stimulation
926
Annals of Neurology
Vol 57
No 6
June 2005
has modified circuits involving the hypothalamus that
are implicated both in the pathophysiology of SUNCT
and the mechanism of action of lamotrigine.15–17 We
conclude that hypothalamic stimulation appears a promising treatment for intractable SUNCT, just as it is for
chronic intractable cluster headache.
We thank D. Ward for help with the language and editing.
References
1. Sjaastad O, Saunte C, Salvesen R, et al. Shortlasting unilateral
neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Cephalalgia 1989;9:147–156.
2. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders (second edition). Cephalalgia 2004;24:1–195.
3. Matharu MS, Cohen AS, Boes CJ, Goadsby PJ. Short-lasting
unilateral neuralgiform headache with conjunctival injection
and tearing syndrome: a review. Curr Pain Headache Rep
2003;7:308 –318.
4. Pareja JA, Kruszewski P, Sjaastad O. SUNCT syndrome: trials
of drugs and anesthetic blockades. Headache 1995;35:
138 –142.
5. Black DF, Dodick DW. Two cases of medically and surgically
intractable SUNCT: a reason for caution and an argument for
a central mechanism. Cephalalgia 2002;22:201–214.
6. May A, Bahra A, Buchel C, et al. Functional MRI in spontaneous attacks of SUNCT: short-lasting neuralgiform headache
with conjunctival injection and tearing. Ann Neurol 1999;46:
791–793.
7. Sprenger T, Valet M, Hammes M, et al. Hypothalamic activation in trigeminal autonomic cephalgia: functional imaging of
an atypical case. Cephalalgia 2004;24:753–757.
8. Sánchez del Rio M. Functional neuroimaging in primary headaches. Cephalalgia 2003;23:567–569.
9. May A, Bahra A, Buchel C, et al. Hypothalamic activation in
cluster headache attacks. Lancet 1998;352:275–278.
10. Sprenger T, Boecker H, Toelle TR, et al. Specific hypothalamic
activation during a spontaneous cluster headache attack. Neurology 2004;3:516 –517.
11. Leone M, Franzini A, Bussone G. Stereotactic stimulation of
posterior hypothalamic gray matter for intractable cluster headache. N Engl J Med 2001;345:1428 –1429.
12. Franzini A, Ferroli P, Leone M, Broggi G. Stimulation of the
posterior hypothalamus for treatment of chronic intractable
cluster headaches: first reported series. Neurosurgery 2003;52:
1095–1099.
13. Leone M, Franzini A, Broggi G, et al. Long-term follow up of
bilateral hypothalamic stimulation for intractable cluster headache. Brain 2004;127:2259 –2264.
14. Schoenen J, Di Clemente L, Vandenheede M, et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of
efficacy and mode of action. Brain 2005;128:940 –947.
15. D’Andrea G, Granella F, Ghiotto N, Nappi G. Lamotrigine in
the treatment of SUNCT syndrome. Neurology 2001;57:
1723–1725.
16. Leone M, Rigamonti A, Usai S, et al. Two new SUNCT cases
responsive to lamotrigine. Cephalalgia 2001;20;845– 847.
17. Belousov AB. Glutamate-dependent regulation of cholinergic
phenotype in hypothalamic neurons. Neuroreport 2003;14:
2445–2449.
Methylenetetrahydrofolate
Reductase C677T Genotype
and PD
Lonneke M. L. de Lau, MD,1,2
Peter J. Koudstaal, MD, PhD,2
Joyce B. J. van Meurs, PhD,3
André G. Uitterlinden, PhD,1,3
Albert Hofman, MD, PhD,1
and Monique M. B. Breteler, MD, PhD1
In a prospective, population-based cohort study among
5,920 participants aged 55 years or older, we observed
that the TT variant of the methylenetetrahydrofolate reductase C677T polymorphism is associated with an increased risk for Parkinson’s disease in smokers. Both
smoking and the TT genotype are known to induce hyperhomocystinemia, and synergistic effects on homocysteine levels have been reported. Increased plasma levels of
homocysteine through direct neurotoxic effects might accelerate the selective dopaminergic cell death underlying
Parkinson’s disease. Our findings support the hypothesis
that homocysteine plays a role in the pathogenesis of Parkinson’s disease.
Ann Neurol 2005;57:927–930
Oxidative stress and mitochondrial dysfunction are
thought to be involved in the selective dopaminergic
cell death in Parkinson’s disease (PD).1,2 Increasing evidence suggests that high plasma levels of homocysteine
might contribute to these processes through direct neurotoxic effects. In animal models of PD, brain injections of homocysteine exacerbated 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine–induced motor dysfunction
and loss of dopaminergic neurons. Homocysteine has
also been observed to cause DNA strand breaks and to
enhance oxidative stress, mitochondrial dysfunction,
and apoptosis induced by rotenone and iron in cultured human dopaminergic cells.2,3
Increased plasma levels of homocysteine have been
found in patients with PD, although mainly in those
receiving L-dopa therapy.4 – 6 Therefore, it is unclear
From the Departments of 1Epidemiology and Biostatistics, 2Neurology, and 3Internal Medicine, Erasmus Medical Center Rotterdam,
Rotterdam, the Netherlands.
Received Feb 7, 2005, and in revised form Mar 28. Accepted for
publication Mar 28, 2005.
Published online May 23, 2005 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20509
Address correspondence to Dr Breteler, Department of Epidemiology and Biostatistics, Erasmus Medical Center, P.O. Box 1738,
3000 DR Rotterdam, the Netherlands.
E-mail: m.breteler@erasmusmc.nl
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
927
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