'Headache Research in Cumbria' - Dr Jitka Vanderpol (Consultant Neurologist for Cumbria Partnership NHS Foundation Trust) from the Cumbria Neuroscience Conference

1. Headache Research in Cumbria
Dr. Jitka Vanderpol MD FRCP
Cumbria Consultant Neurologist

2. Headache Research in Cumbria
1. Cool Head Trial
2. Botox Post license Observational Study

3. Cool Head Trial
• Nasal cannula is inserted into the patients nostrils, so that
coolant driven by either medical air or oxygen can be evaporated
within the nasopharynx cooling the brain vessels indirectly.

4. The cooling device and catheter

5. Pathophysiology

6. Pathophysiology of Migraine
1. Wolff’s original vascular concept: vascular constriction, focal hypo-
perfusion of the cortex, followed by a reactive vasodilatation, resulting in
throbbing headache.
2. Currently, migraine is considered a neurovascular disorder involving the
trigemino-vascular system
3. The genetic predisposition, multifactorial, autosomal dominant with
many different mutations
4. The paroxysmal nature of migraine suggests that it might be related to
mutations in the calcium channel gene, leading in neurons being
unstable, reacting to normal environmental stimuli abnormally.
5. The prodromal phase of the migraine is possibility related to
hypothalamic activation/dysfunction
6. Cortical spreading depression (CSD) accepted as possible major
underlying mechanism of migraine aura

7. Trigemino-vascular system
• The trigeminal system innervates the meninges, and provides
sensory innervation to the intracranial vessels.
• Upon stimulation impulses travel antidromally to dural tissue
causing dilatation of the meningeal blood vessels and
local release of neuropeptides – Substance P, nitric oxide,
vasoactive intestinal polypeptide, 5-HT, Neurokinin A and CGRP,
a potent vasodilator.
• This leads to plasma protein extravasation and initiation of sterile
neurogenic inflammation
• This causes reactive impulses to travel orthodromally back to the
brainstem to the trigeminal nucleus caudalis TNC, pain
modulation centres, (peri-aqueductal gray, locus ceruleus)
• TNC the information travels via the thalamus to cortex causing
central pain perception; central sensitization.

8. Pathophysiology of Migraine

9. Pathophysiology of Cluster Headache
• The cephalic pain is relayed to the central nervous system via
nociceptive ophthalmic branches of the trigeminal nerve,
which innervates pain-sensitive intracranial structures such as
the Dura mater and Dural blood vessels
• Substance P and calcitonin gene-related peptide (CGRP)
trigemino-vascular neuropeptides
• Neurogenic inflammation and dilation of dural blood vessels.
• Activation of the trigemino-vascular system
• Superior salivatory nucleus, the trigeminal nucleus
caudalis, the fibers travel with the VII nerve and synapse in the
pterygopalatine ganglia (lacrimal and nasal mucosal glands),
carotid sympathetic plexus (Horner’s sy).
• Circadian, and seasonal rhythmicity suggests a periodic
hypothalamic disorder.

10. Pathophysiology of Cluster Headache

11. The Hypothesis
• The hypothesis we suppose is that the cooling effect
from the device might cause vasoconstriction of the
dilated meningeal blood vessels and reverse the pain
in both Migraine and Cluster headache cases.

12. BOTOX® Post-license Observational
Study• Botox injections for the treatment of Chronic Migraine
• headache ≥15 days/month and prior or current diagnosis of
migraine, with or without medication overuse

13. The fixed-site fixed-dose injection paradigm
A total of 31 injections across seven specific head and neck
muscles, with a minimum dose of 155 U of BOTOX®
injected per
patient
1. Blumenfeld A et al. Lancet 2010. In press.
Frontalis
(4 x 5 U)
Procerus
(1 x 5 U)
Corrugator
(2 x 5 U)
Occipitalis
(6 x 5 U)
Temporalis
(8 x 5 U)
Cervical
paraspinal
group
(4 x 5 U)
Trapezius
(6 x 5 U)

14. Postulated mode of action of BOTOX® in
chronic migraine

15. PREEMPT pooled analysis: mean change from baseline
in frequency of headache days (primary)1–3
At Week 56, ~70% of patients achieved ≥50% reduction in headache
days (from baseline)
Mean ± standard error.
The double-blind phase included 688 subjects in the BOTOX®
group and 696 in the placebo group.
Headache days at baseline: 19.9 BOTOX®
group vs 19.8 placebo group, p=0.498.
Double-blind phase:
BOTOX®
vs placebo
Open-label phase:
all patients on BOTOX®
1. Allergan Data on File, 56-week responder data, 2010.
2. Dodick DW et al. Headache 2010;50:921–936.
3. Aurora SK et al. Presented at IHC 2009.
15
Study week
Meanchangeinfrequencyofheadachedays
frombaseline(days/28-dayperiod)
52484440363228241612840
0
20 56
-2
-4
-6
-8
-10
-12
-14
BOTOX®
(n=688)
Placebo (n=696)
p=0.019
p=0.047
p=0.007
p=0.01
p=0.008
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p=0.019 p=0.011

16. PREEMPT: treatment-related AEs reported in ≥2% of
patients Pooled data, double-blind phase (%)
No new treatment-related AEs were identified
Most AEs were mild or moderate in severity and resolved without sequelae.
Dodick DW et al. Headache 2010;50:921–936.
Most AEs were mild or moderate in severity and resolved without sequelae.
16

17. Summary
• BOTOX®
has been found to be effective and generally well-
tolerated for the prophylaxis of headache in adults with chronic
migraine at doses ranging from 155 U to 195 U administered
intramuscularly across seven head and neck muscles every 12
weeks for up to five treatment cycles
• Discontinuation rates due to adverse events are low, and most
reported are transient, mild‑to-moderate in severity, and localised
to the sites of injection
• BOTOX®
is the first and only licensed prophylactic treatment
option available for this patient population
1. Blumenfeld A et al. Lancet 2010. In press.