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Trigeminal Autonomic Cephalgias – From Pathophysiology to Neurostimulation
characterised by very short (five- to 240-second) pain attacks occurring
Table 1: The International Classification of Headache Disorders –
about 60 (three to 200) times per day. Attacks are strictly unilateral
Trigeminal Autonomic Cephalgias
1
(peri-orbital) and often triggered by touching, speaking or chewing. There is
Cluster headache
no refractory period. Autonomic symptoms are mainly restricted to
A: At least five headache attacks fulfilling criteria B–D
lacrimation and conjunctival injection. Distinct episodic and chronic forms of
B: Severe or very severe unilateral orbital, supra-orbital and/or temporal headache
SUNCT are yet to be recognised by the formal classifications,
15
although
attacks, which last untreated for 15–180 minutes
both occur. Classic trigeminal neuralgia should always be considered in the
C: The headache is accompanied by at least one of the following symptoms ipsilateral to
differential diagnosis of SUNCT. The former is distinguished by less the pain:
prominent autonomic symptoms and a clear refractory period after
• conjunctival injection or lacrimation
triggered attacks. SUNCT is uncommon and its real frequency is unclear. The
• nasal congestion and/or rhinorrhea
male-to-female ratio is about one to four.
15
• eyelid oedema
• forehead and facial sweating
•miosis and/or ptosis
Pathophysiology of Trigeminal Autonomic Cephalgias
•a sense of restlessness and agitation
D: The attacks have a frequency from one every other day to eight per day
The Trigeminofacial Reflex E: History or physical and neurological examination do not suggest any other disorder,
During an attack of cluster headache or paroxysmal hemicrania, levels of and/or they are ruled out by appropriate investigations.
calcitonin gene-related peptide (CGRP) are increased in jugular vein blood
Paroxysmal hemicrania
on the pain side but not contralaterally, indicating activation of the
A. At least 20 attacks fulfilling criteria B–D
B. Attacks of severe unilateral orbital, supra-orbital or temporal pain lasting two to 30
trigeminal fibres.
16,17
Vasoactive intestinal polypeptide (VIP) is also increased
minutes
in homolateral jugular vein blood. VIP is released by parasympathetic
C. Headache is accompanied by at least one of the following:
terminals of cranial nerve VII and, again, indicates activation.
17
• ipsilateral conjunctival injection and/or lacrimation
Parasympathetic activation explains the presence of most of the ipsilateral
• ipsilateral nasal congestion and/or rhinorrhea
oculo–nasal autonomic manifestations accompanying the pain.
13
•ipsilateral eyelid oedema
Simultaneous activation of the trigeminal nerve and parasympathetic
• ipsilateral forehead and facial sweating
components of the facial nerve on the pain side led to the hypothesis that a
• ipsilateral miosis and/or ptosis
D. Attacks have a frequency above five per day for more than half the time, although
trigeminofacial reflex was responsible for the pain and the autonomic
periods with lower frequency may occur
manifestations of TACs.
13
Different extents of activation of this reflex may be
E. Attacks are prevented completely by therapeutic doses of indomethacin
able to explain some of the clinical differences between the various TAC
F. Not attributed to another disorder
forms.
18
However, trigeminofacial activation cannot explain the circadian
SUNCT
rhythm of the attacks in cluster headache, the circannual recurrence of the A. At least five attacks fulfilling criteria B–D
cluster periods,
2,3
the clear predominance in males
3
or the prophylactic
B. Attacks of unilateral orbital, supra-orbital or temporal stabbing or pulsating pain
efficacy of centrally acting lithium.
3
Furthermore, the cause of the
lasting five to 240 seconds
trigeminofacial activation has not been identified – does some peripheral
C. Pain is accompanied by ipsilateral conjunctival injection and lacrimation
D. Attacks occur with a frequency of three to 200 per day
mechanism trigger it, or is the primum movens within the brain itself?
E. Not attributed to another disorder
The striking circadian rhythmicity of cluster headache attacks and the
SUNCT = short-lasting unilateral neuralgiform headache attacks with conjunctival injection
circannual recurrence of the cluster periods, particularly in autumn and
and tearing.
spring when changes in light intensity are marked, suggests involvement of
an endogenous clock.
3
The hypothalamus is the principal regulator subsequent voxel-based morphometry study revealed a structural
of biological rhythms and its derangement would offer a ready explanation anomaly (increased neuronal density) in this area in remission-phase
for the periodicity of cluster headache attacks. Furthermore, neuro- cluster headache patients.
22
Proton magnetic resonance spectroscopy
endocrinological studies on patients with cluster headache have clearly (PMRS) to probe hypothalamic metabolism in cluster headache
documented alterations of the hypothalamus, lending support to the idea of revealed lowered N-acetylaspartate and creatine levels compared with
hypothalamic involvement in cluster headache pathophysiology.
4
controls both during and outside pain periods.
23,24
For the first time,
therefore, a putative lesion site responsible for a primary headache had
Neuroimaging of Trigenimal Autonomic Cephalgias been identified.
Over the last decade, neuroimaging studies during ongoing TAC headaches
have greatly increased understanding of attack-associated events, and Subsequently, functional MRI and PET studies showed that the
provided clues to the mechanisms underlying TAC pathophysiology.
19
posterior inferior hypothalamic grey matter was also activated during
SUNCT
25
and paroxysmal hemicrania.
26
Such activation seems specific
Positron emission tomography (PET) studies during spontaneous
20
or to TACs since PET studies in migraine
27,28
and subjects with
nitroglycerine-induced
21
cluster headache attacks show activation of experimentally induced trigeminal pain show no activation in this
brain areas known to be concerned with pain modulation and area.
29
A PET study on a cluster headache patient undergoing a
perception (anterior cingulate cortex, insulae and contralateral migraine (the patient had two primary headaches) also showed no
thalamus), but also reveal activation of the grey matter of the posterior hypothalamic activation.
30
Similarly, injection of capsaicin into the
inferior hypothalamus on the pain side. The posterior inferior frontal area in healthy subjects evokes intense pain through activation
hypothalamus was initially thought to be activated only during cluster of trigeminal endings and increased regional blood flow to
headache attacks and was proposed as the cluster generator.
21
A the anterior insulae (Brodmann area 13), contralateral thalamus,
EUROPEAN NEUROLOGICAL DISEASE 2007 29
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