Headache is one of the most common neurological problems accounting for 4% of primary
care consultations and up to 30% of neurology appointments. Even though considerable
advances in the understanding of the pathogenesis of migraine, new pharmacologic
treatments and the emergence of new innovative interventions for difficult cases, in many
patients with migraine remain intractable to medical therapy.
The trigeminocervical complex (TCC) has a crucial role in the pathophysiology of
migraines. The TCC is a common convergent pathway by which both trigeminal (dural) and
cervical (mainly via the greater occipital nerve) afferent inputs project into higher
centres in the thalamus and cortex. This afferent pathway is further influenced by the
conditioned pain modulation (CPM) pathway originating from the brainstem structures
including periaqueductal grey matter, nucleus raphe magnus, and the rostroventral
medulla. There is some evidence to suggest that increased peripheral sensitization of the
afferent inputs of the TCC, generalized central sensitization of the trigemino-spinal or
the second order trigeminal neurons and impaired descending pain inhibitory pathway, may
all contribute to the development of the chronic intractable or treatment resistant
primary headache disorder Neurostimulation techniques for treating intractable headache
range from invasive deep brain stimulation to less invasive peripheral implantation and
stimulation. In 1999 Weiner and Reed described the beneficial effects of subcutaneous
Occipital nerve stimulation (ONS) in patients with medically intractable, highly
disabling chronic headache disorders Open-label studies have suggested that this
treatment modality is effective and safe (Lambru and Matharu 2012). Although the exact
mechanism of action is poorly understood, ONS is thought to act by stimulating the distal
branches of C1, C2 and C3 in turn influencing the TCC favourably by inhibiting the
nociceptive process, resulting in an improvement of symptoms. Previous work has
demonstrated a consistent and sustained improvement in conditioned pain modulation (CPM)
following ONS as confirmed with quantitative sensory testing (QST) (Wodehouse et al,
2014). QST has the particular advantage of being a functional test that provides a
quantitative pain stimulus and assesses the subject's individual response to the
stimulus. QST also provides a reliable assessment of changes in pain thresholds and the
benefit of ONS. However general anaesthetic has also been demonstrated to cause
changes/improvements in pain thresholds, peripheral and central sensitisation and this
effect can be long lasting and may account for changes/improvements as measured by QST in
subjects having ONS that the anaesthetic provides relief as opposed to the ONS
intervention.
Quantitative sensory testing (QST) QST is a term used to describe different forms of
psychophysical testing of skin, mucosa, or muscle tissue that assess sensory and pain
perception pathways. Nociception inputs can trigger a prolonged but reversible increase
in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the
phenomenon of central sensitisation in turn manifesting as pain hypersensitivity,
particularly dynamic tactile allodynia, and secondary punctate or pressure hyperalgesia
and enhanced temporal summation.
QST has been used for measuring thresholds for different sensations in neuropathic pain
reflecting the possible nerve fibres that may be implicated in the pathogenesis. Heat
sensation threshold reflects the unmyelinated C-fiber function, cold sensation threshold
reflects the thinly myelinated A-fiber function and vibration threshold reflects the
thickly myelinated AB- fiber function.
QST tests can be classified into the following:
Measurement of pressure pain thresholds (PPT) (Static measure): This test measures
sensitivity of peripheral pain pathways to increasing mechanical pressure. A
computer-controlled pressure algometer (available as a bed side instrument) is used to
measure PPTs at a standardized point and compared with the affected area. A standardized
speed of pressure increase of 0.3kg/s is kept constant during pressure application to the
point when perception changes from pressure to pain (pressure pain threshold). This is
useful for confirming small fibres neuropathic lesion.
Temperature thresholds: Thermal QST evaluates small nerve fibres, using thresholds for
warm, cold, heat-induced pain and cold-induced pain. It involves altering a thermal
stimulus until a sensation is perceived. Four sensory sub-modalities will be measured; C
fibre mediated warm sensation (WS), A-delta fibre mediated cold sensation (CS), heat
induced pain (HP) (mostly C fibre mediated sensation with some involvement of A-delta
fibres) and C- and A-delta fibre mediated cold induced pain (CP).
Measurement of central sensitisation (Dynamic measure):
This will be done using 2 different techniques as outlined below.
Conditional Pain Modulation: Activity within the spinal dorsal horn arising from
peripheral nociceptive inputs can be modulated by powerful descending inhibitory and
facilitatory mechanisms. An example is provided by the phenomenon of conditioned
pain modulation (CPM), also known as diffuse noxious inhibitory control (DNIC) or
heterotrophic noxious conditioning stimulation. This refers to an altered response
to a painful stimulus following the administration of a second conditioning
stimulus.
CPM provides one of the main supraspinal pain inhibitory pathways and are impaired
in neuropathic pain. Diffuse noxious inhibitory controls refers to the observation
that the activity of multi-receptive neurons of the spinal cord can be strongly
suppressed by an intensive pain stimulus outside their peripheral receptive field.
Induction of CPM can be done by immersion in ice water (so-called cold-pressor
test), or hot water on a different/distant body part than the one on which the pain
perception testing is being performed. This effect represents a well-established
model of endogenous pain modulation.
Measurement of Temporal summation- Repetitive delivery of a painful stimulus leads
to an increased perception of pain which can be used as a marker for central
sensitization. Seventeen, progressively rigid, monofilament, von Frey fibers
(filaments represent stimuli from 0.039 - 4386mN) will be used on a standardised
position on the back decided by the physician. A baseline NRS score will be obtained
from the patient. The von Frey Fibre will first ascertain the least force that
measures a sensation of touch or pain (pressure pain threshold). The exact threshold
is found by repetitive testing using the ascending fibre sizes. The repetitive
stimulation consists of 10 repetitions of a pressure stimulus applied for 1 second
duration for 60 seconds. The magnitude of the stimulus is set at the level of the
subjects' pressure pain threshold. Patients rate the pain intensity on a NRS for
each pressure stimulus, and then for 15 sec after cessation of 10 stimulations.
Clinical Data for QST QST measurements have been used world-wide in the assessment of
altered pain experience and have been demonstrated to be safe and well tolerated. There
exists published evidence of QST measurements in chronic pain conditions like
osteoarthritis, fibromyalgia, migraine and other neuropathic pain conditions.
QST measurements have been used worldwide in the assessment of altered pain experience
and have been demonstrated to be safe and well tolerated. We do not expect any risks
associated with the QST. Any discomfort experienced is transient and patients at all
times are in control with the experience and can stop at any-time.
In addition, there is evidence to suggest that cytokines induce headache and headache
pain. Furthermore a higher level of cytokines can stimulate the activation of trigeminal
nerves, trigeminal nerve fibre sensitisation, the release vasoactive peptides or other
biochemical mediators like nitric oxide, which results in inflammation. Many studies have
investigated the role of different cytokines in the pathogenesis of migraine but the
results remain controversial. One reason for this may be the differing times of measured
cytokines in some cases ictally in others interictally. For this study we propose to
takes samples at baseline and at the follow up visits and investigate whether there is
any alteration in levels of cytokines with the ONS. We will be focusing on transforming
growth factor-beta 1 (TGF-1), which is a multifunctional proinflammatory cytokine
involved in the modulation of cell growth, differentiation and repairs following injury
and immune modulation. Ishizaki et al., 2005 demonstrated that serum levels of TGF-1 were
higher in migraine than in controls. TGF-1 has been described as a platelet-derived
cytokine as human platelets contain quantities of dormant TGF-1 and reports have
suggested that platelets play an important role in migraine and therefore maybe in
involved in headache pathogenesis and development of migraines.
Glutamate is a prominent neurotransmitter and has been implicated in migraine
pathogenesis. Migraine pain-relay centers, including the trigeminal ganglion, trigeminal
nucleus caudalis, and thalamus, contain glutamate-positive neurons, and glutamate
activates the trigeminal nucleus caudalis. Glutamate is implicated in cortical spreading
depression, trigeminovascular activation, and central sensitization. Glutamate in blood
(plasma) and urine will be measured prior to and after ONS.