headache

1. Headache in Pediatrics
Presented by Dr M V Basle
Pediatric Neuro fellow
TNMC & BYL NAIR Hospital

2. Approach to a child with headache

3. Introduction

4. The International Classification of Headache disorders
ICDH 3b

6. ● Improved characterisation of its clinical features,
● Viewed now as a complex, variable disorder of nervous
system function rather than simply a vascular headache.
● New insights into its genetic causes, anatomical and
physiological features, and pharmacological mechanisms.
Migraine – What is new?

7. ● Two genetic mutations encoding the enzyme casein kinase 1δ (CK1δ).
● 38 genomic loci associated with migraine have been validated in
population studies
● Loci associated with migraine were found to be enriched in genes that
are expressed in vascular and gastrointestinal tissue
● Familial Hemiplegic migraine
● FHM 1:CACNA 1A gene
● FHM 2:ATP 1A2
● FHM 3:SCN 1A
● Potential genetic mechanisms lead to migraine raises the possibility
that gene therapy could eventually be tailored to specific genetic
mechanisms
.
Genetics

9. Pain carrying structures in head

10. Difference between primary and secondary headache

11. Etiology of acute headache in children

13. Peculiarities in children

14. ● Phases of migraine attack
 Premonitory
 Aura
 Headache
 Postdrome
Pathophysiology

15. ● Initially thought to be vascular
● Functional MRI shows phase of hyperemia precedes phase of oligemia during
migraine aura
● Oligemia spreads across cerebral cortex @ 2-4 mm/min
● Atypical activity or atypical interactions between functional networks that process
pain, visual/auditory/olfactory stimuli, regulating sleep /awareness.
Vascular vs Neuronal

16. ● Region responsible for trigerring the attack
● fMRI demonstrated brain stem or hypothalamus
● PET study of Nitroglycerine trigerred migraine – posterolateral hypothalamus
● Brain stem – Midbrain tegmentum, Periaqueductal grey mater, Dorsal Pons
● Hypothalamic dysfunction – symptoms of premonitory phase
● Not a single generator – shared by all people/within individuals from attack to
attack
Migraine Generator

17. ● Electrophysiological substrate for Aura
● Starts in the occipital pole- spreads forward over cerebral
hemisphere @ 2-4 mm/min – causes disruption in ionic
gradients/depolarization followed by hyperpolarization
● Corresponds to pattern of Positive symptoms followed by
negative symptoms
● f MRI – strongly support this mechanism for Aura
● CSD leads to activation of TCS & trigger headache phase
CSD

18. Consist
 Trigeminal nucleus caudalis (TNC) – extends upto C2
 Trigeminal ganglion
 Trigeminal nerve – V1,V2,V3
 Ascending branch from TNC to higher cortical regions
TCS innervate intracranial & extracranial blood vessels
TCS activation – release of vasoactive neuropeptides
1.CGRP( calcitonin gene related peptide)
2. Substance P
3. VIP
4. NO
5.PACAP (pituitary adenylate cyclase activating peptide)
NP results in vasadilation,plasma protein extravasation,inflammation- causing headache
Trigemino cervical system(TCS)

19. ● Exuberant response to sensitive stimuli
Probable due to
● hypoactivation of primary pain inhibiting regions in brain stem,
● Intrinsic cortical excitability
Recurrent /prolonged activation of TCS leads to
Peripheral and central sensitization causing
Lower thresholds for activation
Increased spontaneous activity
Receptive field expansion
A therapeutic target for pharmacological and neuromodulatory approach such as
transcranial magnetic stimulation
Hyperexcitable Migraine Brain

22. Migraine with aura

23. Episodic syndromes that may be associated with migraine

25. Patterns of headache

26. Headache: Location and quality

27. Migraine triggers in children

28. Examination

29. Clues on examination

30. Role of routine refractive error testing

31. Red flags

32. Clinical evaluation summary

33. Indication of neuroimaging in headache

37. Yield of MRI in childhood headache

38. What imaging to perform

39. Investigations

40. Principles of management: Primary headache

41. Lifestyle SMART plan

42. Diet in Migraine

43. Preventive therapy:When to start?

47. ACUTE MIGRAINE TREATMENT

48. Acute treatment:start at the onset headache

49. Preventive therapy:how to choose?

50. ● Accumulating evidence indicates a primary role for
calcitonin gene-related peptide (CGRP) as an important
therapeutic target
● CGRP is released into the circulation during a migraine or
cluster headache attack, normalises with triptan therapy
● Infusion of CGRP triggers delayed migraine in susceptible
individuals
● Efficacy of monoclonal antibodies against CGRP or its
receptors for migraine prevention confirms the primary
role of CGRP in migraine
Neuropeptides – Mediators of Migraine

51. ● Promising advance in acute migraine management
● IV Olcagepant – First developed – Effective, but very low oral bioavailability
● Telcagepant – First oral formulation – As effective as Triptans – Stopped due to liver
toxicity
● Recently two other drugs BI 44370 TA & BMS – 927711 have shown promise in the
management of migraine
CGRP Antagonists

52. ● Pituitary adenylate cyclase-activating polypeptide
(PACAP) – Mediator of migraine
● Systemic administration of PACAP triggers migraine in
susceptible individuals
● PAC 1 receptor antagonists represents a promising
therapeutic treatment in migraine- Under trial

53. ● Another encouraging new acute treatment for migraine is
represented by the drug class of 5-HT1F receptor agonist
called Ditans
● Ditans inhibit activation of cells in the trigeminal nucleus
caudalis
● Lasmiditan has been studied in two randomized, placebo
controlled double-blind trials which showed significant
improvement, measured in terms of headache freedom at
2 hours
● Lack of cardiovascular side effectrs – major advantage
Serotonin Receptor Agonists

54. ● Botox – FDA approved for chronic migraine
● Onabotulinum toxin A injected
● 150U
● Forehead,temporalis,occipitals,splenius capitis,trapezius
● Benefits starts after 7-10 days ,lasts upto three months,
● Therapeutic effect- Due to blockade of glutamate,
substance P and CGRP release peripherally
● By inhibiting peripheral sensitisation /decrease central
sensitisation
● Comparable efficacy to Topiramate in chronic migraine
Neurotoxin Therapy

57. ● Occipital nerve stimulation
Low frequency stimulation of Greater occipital nerve -
Modulates the activity of Trigeminocervical complex
 Optimistic results in 3 randomised trials
 Useful treatment strategy in refractory migraine
 Research ongoing
● Supraorbital stimulation
Combined with ONS - Effective & superior pain relief
Neuromodulation
schoenen et all 2013b

58. Vagal nerve stimulation – not much useful
Sphenopalatine ganglion stimulation
 Two studies - found useful in acute atacks of cluster
headache
 In drug resistant migraine, acute SPG stimulation -
effective in 5 out of 10 patients
● Deep Brain Stimulation
 Not yet explored for Migraine
 Studied in cluster headaches
Acute Treatment of intractable migraine with
SPG electrical stimulation
Headache 2009;49:983-9

59. ● Transcranial Magnetic Stimulation
 Non invasive method using a weak electric current to induce a magnetic field &
modulate brain activity
 Single pulse/Repititive
● Hypothesized to disrupt CSD

61. ● Nitric oxide antagonism
 Current interest focuses on inhibition of endothelial NO
synthase and neuronal NO synthase
 Pure NOS inhibitors have not reached clinical trials
 NXN 188 – Serotonin receptor agonist with nNOS
antagonism- phase II trial- statistically significant response
for pain freedom
Emerging Therapies

62. ● Aura - attributed to CSD- a wave of eletrophysiological hyperactivity in cortex
followed by inhibition
● CSD - moves from cell to cell through gap junctions
● TONABERSAT - gap junction modulator- inhibits CSD in animal models
● Useful in migraine with aura
Gap Junction Modulators
#Focal hyperemia followed by
spreading oligemia and impaired

63. ● Glutamate - Excitatory neurotransmitter - activates two
different receptor types
1)Ionotropic Receptor Antagonists
● NMDA antagonist- Ketamine, Memantine
● AMPA antagonist - BGG492 - Clinical development
● Kainate antagonist- LY466195 - effective- limited
therapeutic potential due to visual disturbances
● Tezampanel - AMPA/Kainate antagonist - effective in
migraine
Glutamate Receptor Antagonists

64. 2)Metabotropic Receptor Antagonist
 ADX10059 - mGLUR5 negative allostric modulator
 Early studies - useful in migraine- but limited by side effects ( visual disturbances,
impaired concentration)
 Randomised double blind study ongoing - for its usefulness in migaine prophylaxis

65. ● Peptides - integral to sleep - alter function of key components of trigeminovascular
system
● MK- 6096 - Antagonist of orexin receptor - currently being developed for insomnia
● Phase I trial is underway evaluating its efficacy in migraine
Orexin Receptor antagonist

66. ● TPRV1 - detection & regulation of body temperature
 Activation - release of CGRP
 TPRV1 agonist - Civamide- useful in Cluster headache
 Not effetive in migraine
 TPRV1 antagonist - SB 705498 - Phase II trial completed
● Prostanoid Receptor antagonist
 BGC20-1531 - currently undergoing phase II trial for
migraine
Transient Receptor Potential Vanilloid 1
Receptor Modulators

67. ● Cluster headache is a trigeminal autonomic cephalalgia
characterised by extremely painful, strictly unilateral,
short-lasting headache attacks accompanied by ipsilateral
autonomic symptoms or the sense of restlessness and
agitation, or both.
● One of the most painful medical conditions known to
humans
Cluster Headache

68. ● Genetics
 A genome-wide analysis study has suggested that a variant
of the pituitary adenylate cyclase-activating polypeptide
(PACAP) receptor gene ADCYAP1R1 could be relevant to
cluster headache.
 This finding is particularly interesting because PACAP
concentration in plasma has been shown to increase
during cluster attacks.
Advances in Cluster headache

69. ● Pathophysiology
 Significant progress has been made in the understanding of
the pathophysiology of cluster headache.
 The posterior hypothalamus is implicated in pain
processing and pain modulation and several lines of
research support the role of the posterior hypothalamus
in cluster headache.
 Hypothalamic derangement seen in cluster headache -
likely to create a permissive state.
 Allows abnormal firing of the neuronal loop responsible for
relaying pain signals to the brain in cluster headache - the
trigemino-autonomic reflex.

70. ● The orexinergic system is one of the most fascinating
potential targets.
● The Orexin system is implicated in a variety of functions
including sleep-wake cycle, autonomic function and
nociceptive processing.
● With their projections to the trigeminal nuclei and the
spinal cord they seem to modulate trigeminal pain
processing.
● Other neuropeptides - Calcitonin gene-related peptide
(CGRP) and the pituitary adenylate cyclase-activating
peptide (PACAP) are increased during cluster headache
attacks
● Potential target for new treatment

71. ● Four clinical trials are being conducted at this moment to
investigate whether the administration of monoclonal
antibodies targeting CGRP is effective in preventing cluster
headache attacks
● Two, phase III studies are evaluating the efficacy and safety of
the anti-CGRP monoclonal antibody Fremanezumab for the
prevention of both episodic and chronic cluster headache.
● Efficacy and safety of the monoclonal anti-CGRP antibody
Galcanezumab are being investigated for use in patients with
episodic and chronic cluster headache in two phase III,
randomized, double-blind, placebo-controlled trials
Advances in Treatment

72. ● Several ways of neuromodulation, both invasive and non-
invasive, have been investigated recently.
● Based on the findings of PET & voxel-based morphometry
- deep brain stimulation has been tried in patients -
abandoned now in view of several adverse effects
● Less invasive techniques are under research
 occipital nerve stimulation (ONS)
 SPG stimulation
 Non-invasive vagal nerve stimulation (nVNS).
Neuromodulatory Treatment

73. ● Greater Occipital nerve blocks
● Several open-label studies with invasive ONS have been
performed in patients with medically intractable chronic
cluster headache
 In addition, two randomized controlled trials showed a
significant reduction in cluster headache attacks in both
episodic and chronic cluster headache patients after
receiving a GON injection
Greater occipital nerve blocks in chronic cluster headache: a
prospective open-label study. Eur J Neurol. 2014;21(2):338–43.
Efficacy and safety of a single occipital nerve blockade in episodic
and chronic cluster headache: A prospective observational study.
Cephalalgia. 2017;37(9):873–80.
Occipital nerve stimulation in medically intractable, chronic
cluster headache. The ICON study: rationale and protocol of a
randomised trial. Cephalalgia. 2013;33(15):1238–47.

75. Vagal nerve stimulation
Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache
(PREVA): A randomised controlled study. Cephalalgia. 2016;36(6):534–
46.
Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster
Headache: Findings From the Randomized, Double-Blind, Sham-
Controlled ACT1 Study. Headache. 2016;56(8):1317–32
gammaCore®, the First Non-Invasive Vagus Nerve Stimulator Applied at the Neck, Now Available for Adult Patients in the U.S.2017
 Gammacore ,a device for nVNS, has
been investigated in several studies
in both acute and preventive
treatment for cluster headache
 The trials conducted so far have not
been able to prove the efficacy of
nVNS as an alternative to acute or
prophylactic treatment in chronic
cluster headache

76. ● Sphenopalatine ganglion-targeted therapies
 Stimulation of the SPG is a new acute treatment under
investigation at present.
 To apply stimulation to the SPG, a miniature device with
leads is placed in the pterygopalatine fossa.
 In a recent open-label study in 97 cluster headache patients
receiving SPG stimulation, 43 out of 78 patients (55%) with
chronic cluster headache experienced a more than 50%
reduction in attack frequency after 12 months of stimulation
 At present, a randomized controlled trial is investigating both
the safety and the efficacy of SPG stimulation in chronic
cluster headache
Sphenopalatine ganglion stimulation for
cluster headache, results from a large,
open-label European registry.

78. ● Botulinum toxin
 Local injection of onabotulinumtoxin into the spheno
palatine ganglion could effectively reduce the frequency of
cluster headache attacks
 Significant improvement in the number of attacks in
patients in a open labelled uncontrolled study
 However, these data need to be confirmed in placebo-
controlled studies
Pilot study of sphenopalatine
injection of onabotulinumtoxinA for
the treatment of intractable chronic
cluster headache. Cephalalgia 2016;
36: 503–09.

80. ● Further research is warranted to elucidate the exact role of the trigeminal nerve and
the trigemino cervical complex in cluster headache
● Mechanisms responsible for the abortion of attacks and the prevention of a cluster
bout remain unknown and deserve more attention in future studies.
Future Directions

82. Take home points

84. Case evaluation

85. Case study

86. THANK YOU