HEADACHE & FACIAL PAIN

Panayiotis Mitsias, MD, PhD

Professor and Chairman, Department of Neurology
School of Medicine & University Hospital
University of Crete
Introduction
■ Headache occurs in all age groups
■ Headache accounts for 1-2% if emergency department evaluations and 4% of
medical office visits
■ The causes are myriad
■ Headache of new onset may be the principal manifestation of serious systemic or
intracranial disease and requires thorough and systematic evaluation
■ An etiologic diagnosis is based on understanding the pathophysiology of head pain
– Obtaining a history, with characterization of the pain as acute, subacute, or
chronic
– Performing a careful physical examination
– Formulating a differential diagnosis
 Causes of Headache and Facial Pain
Acute Onset
■ Common Causes
– Subarachnoid hemorrhage
– Other cerebrovascular diseases
– Meningitis or encephalitis
– Ophthalmic disorders
■ Less Common Causes
– Seizures
– Lumbar puncture
– Hypertensive encephalopathy
– Coitus
Subacute onset
■ Giant-cell arteritis
■ Intracranial mass
■ Idiopathic intracranial
hypertension
■ Trigeminal neuralgia
■ Glossopharyngeal neuralgia
■ Postherpetic neuralgia
■ Persistent idiopathic facial
pain
Chronic
■ Migraine
■ Medication overuse
■ Cluster headache
■ Tension headache
■ Icepick-like headache
■ Cervicogenic headache
■ Sinusitis
■ Dental disease
Approach to Diagnosis
■ PAIN SENSITIVE STRUCTURES
– Traction, displacement, inflammation, distention of pain-sensitive
structures in the head of neck
– Intracranial pain sensitive structures
• Venous sinuses
• Anterior and middle meningeal arteries
• Dura
• Trigeminal, glossopharyngeal and vagus nerves
• Proximal portions of ICA, MCA, ACA, PCA, Basilar, Vertebral
arteries
– Extracranial pain sensitive structures
• Periosteum of the skull
• Subcutaneous tissues, muscles, arteries
• C2 and C3 roots
• Eyes, ears, teeth, sinuses, oropharynx
• Mucous membranes of the nasal cavity
PAIN SENSITIVE STRUCTURES
■ RADIATION OF PAIN
– Trigeminal nerve
– Glossopharyngeal nerve
– Upper cervical roots (C2-C3)
 History
■ Acute Headache & Facial Pain
■ Subacute Headache & Facial Pain
■ Chronic Headache & Facial Pain
■ Precipitating factors
■ Prodromal Symptoms (auras)
■ Characteristics of Pain
■ Location of Pain
■ Associated Symptoms
■ Temporal Pattern of Headache
■ Exacerbating Factors
■ Relieving Factors
 Physical Examination
■ Temperature
■ Pulse, Blood Pressure, Respiration
■ Weight loss
■ Skin examination
■ Scalp, Face & Headache
■ Neck, Neck stiffness
■ Heart and Lung
■ Fundoscopic Exam
■ Ophthalmoscopy
Headache classification

■ Primary headaches
■ Secondary headaches
Secondary Headaches
■ Meningitis
■ Subarachnoid hemorrhage
■ Brain tumor
■ Temporal arteritis
■ Glaucoma
■ Paranasal sinus infections
■ Systemic infections
■ Endocrine headaches
Subarachnoid Hemorrhage

■ Clinical
– Abrupt onset headache (‘thunderclap headache’)
– Photophobia, Vomiting
– Cranial nerve palsies (IIIn), focal signs
– Depressed level of consciousness
– Meningeal signs
■ Diagnosis
– CT scan (sensitivity 95%-100%
– Lumbar puncture
■ Management
– CTA, catheter angiography
– Aneurysm obliteration
– ICU management
– Vasospasm
Meningitis

■ Headache
– Acute onset, but not thunderclap-like
– Fever, Vomiting, Somnolence
■ Depressed LOC
■ Blood cultures
■ IV Antibiotics + IV dexamethasone
■ CT scan
■ CSF analysis
Giant Cell Arteritis (Temporal Arteritis)
■ Systemic vasculitis affecting medium-sized and large arteries, especially branches of the
external carotid artery
– Subacute granulomatous inflammation of arterial wall
■ GCA affects caucasians most often, women more than men, uncommon < 60 years
■ Frequently associated with systemic symptoms
– malaise, myalgias, weight loss, fever, arthralgias
– new, continuous, non-specific headache, unilateral or bilateral
■ Scalp tenderness, jaw claudication
■ Visual loss (arteritic anterior ischemic optic neuropathy)
■ Diagnosis:
– ESR: 100 mm/h, CRP>2.45, Thrombocytosis >400,000
– Biopsy of affected temporal artery
■ Management:
– Prompt evaluation, Prednisone 60 mg daily
– Maintain ESR within normal limits, taper dose of prednisone
Red flags for Secondary Headache Disorders
(SNOOP10)
■ First or worst headache
■ Abrupt-onset headache
■ Progression or fundamental change in pattern of headache
■ New headache in those <5 years or >50 years
■ New headache with cancer, immunosuppression, or pregnancy
■ Headache with syncope or seizure
■ Headache triggered by exertion, Valsalva, sex
■ Neurological symptoms lasting longer than 1 hour
■ Abnormal general or neurological exam
 Primary Headaches
■ Migraine
– Migraine with aura
– Migraine without aura
■ Trigeminal Autonomic Cephalalgias (TAC)
– Cluster headache
– Paroxysmal hemicranias
– SUNCT
■ Tension Headache
– Episodic
– Chronic
Migraine
Epidemiology
• Attacks of migraine may start at any age
• 1% at 6 years, 5% at 11 years, 9% at 15 years
• Incidence peaks in early to mid-adolescence
• In US and WE, one year prevalence is 11%:
• 6% among men
• 15-18% among women
• Cumulative lifetime prevalence:
• 43% among women
• 18% among men
• Median frequency of attacks: 1.5/month
• Median duration of attacks: 24 hours
• 10% of patients have weekly attacks
• 20% have attacks lasting 2-3 days
Migraine: A very common disorder

■ Usually hereditary, Polygenic inheritance

■ Trauma precipitates headache with migrainous features
■ Migraine has many triggers
₋ Interaction of environmental triggers and a susceptible host
₋ Exertion, Dietary, Sleep, Trauma, Hormones, Meds, Nitrous Oxide
₋ Hypertension
Co-morbid conditions
■ Mitral Valve Prolapse
■ Patent Foramen Ovale (PFO)
■ Raynaud’s phenomenon
■ Stroke
÷ Migrainous stroke
÷ Risk factor for stroke
■ Epilepsy
■ Psychiatric Disorders
÷ Depression
÷ Bipolar disorder
÷ Social phobias
Clinical Manifestations
▪ Any severe and recurrent headache is likely to be a form of migraine
▪ In 15-18% of patients migraine attacks are preceded or accompanied by
transient focal neurological symptoms
▪ Recent large study:
… 18% only migraine with aura
… 64% only migraine without aura
… 13% have aura on some occasions only
Headache Classification (IHS)
Improving & simplifying the diagnosis of headache syndromes

■ Diagnostic criteria of the International Headache Society

– 1988 & 2004 & 2013
■ Migraine was defined by the component clinical parts of an attack
■ The most important tool for the clinician is a good history
Migraine Without Aura
Migraine With Aura
Notes

1. When, for example, three symptoms occur during an aura,

the acceptable maximal duration is 360 minutes. Motor
symptoms may last up to 72 hours.
2. Aphasia is always regarded as a unilateral symptom;
dysarthria may or may not be.
 Types of aura symptoms

■ Visual aura
■ Sensory aura
■ Motor aura
■ Speech aura
■ Less typical aura symptoms
Chronic migraine
A migraine attack

Goadsby & Holland, 2019

 Pathophysiology of migraine

■ Primary disorder of the brain

■ A form of neurovascular headache
■ Brainstem aminergic neurons (locus ceruleus)
■ Trigeminovascular system
■ Cortical hyperexcitability
Cephalalgia 2013
Hyperexcitability of the occipital cortex
Genetics of migraine
■ Logical to suppose that all migraine sufferers have a genetic predisposition
activated by physiological or other life events.
■ First concrete example of inherited migraine is FHM
– Missense mutations in the Cav2.1 subunit of the gene for the P/Q type,
voltage-gated calcium channel on chromosome 19 (CACNA1A).
– Mutations in the ATP1A2 gene (a2 subunit of Na+/K+ pump)
– Mutations in the SCN1A gene (neuronal voltage gated sodium channel).
■ Abnormal ion channels whose strategic function and anatomical distribution in
the brain determine the clinical phenotype.
Premonitory Phase “Prodrome”

■ From a clinical perspective, the hypothalamus might be involved in the

premonitory symptoms prior to the experience of head pain.
■ Such symptoms involve:
– tiredness, concentration problems, yawning, appetite alterations,
and frequent urination
■ Activation in the midbrain and PAG likely reflects a mechanism
through which nociceptive head pain symptoms may be generated.
 Premonitory phase
H215O-PET: posterior hypothalamic region, periaqueductal grey, and dorsal pons

Maniyar et al, Brain 2014

 Migraine Aura & Cortical Spreading Depression

■ Migraine probably results from dysfunction of

brainstem or diencephalic nuclei involved in
sensory modulation of craniovascular
afferents
■ Aura of migraine related to spreading
neuronal depression
Cortical Spreading Depression
 Headache Phase
The Trigeminovascular System

Goadsby PJ, Lipton RB, Ferrari MD. N Eng J Med 2002

Pain Mechanisms
■ We do not completely understand the pathogenesis of pain in migraine
■ Three key factors merit consideration:
– Cranial blood vessels
– Trigeminal innervation of the vessels
– Reflex connections of the trigeminal system with the cranial
parasympathetic outflow
■ Bain substance is insensitive to pain
■ Pain can be generated by:
– Large cranial vessels
– Proximal intracranial vessels
– Dura matter
 Vascular Theory of Migraine?

Dilatation was seen in: MCA 10.5%, cerebral ICA 14.4%, and cavernous ICA
No dilatation was seen in the extracranial arteries
Amin et al, Lancet Neurol 2013
The migrainous brain during migraine head pain

DOI: (10.1152/physrev.00034.2015)
fMRI during the
Headache Phase
■ Activation of rostral brainstem
■ Implications of these studies for
clinicians
… We are confident that the disorder
is localized in the brain = a
disorder of brain function
… We can assure patients who feel
odd during attacks, perhaps have
trouble concentrating or simply
feel a little befuddled, that this is
expected of a brain disorder of
this type
Matharu et al, Brain 2006
 Craniovascular nerve fibers and their
vasoactive neuropeptides involved in migraine
CGRP plays a pivotal role in migraine

Russell FA et al. Physiol Rev 2014;94:1099.

 Summary - Migraine Pathophysiology

❖ Interictal Phase
▪ Hyperexcitability of the occipital cortex
▪ Hypoexcitability of the spinal trigeminal nucleus
❖ Premonitory symptoms
■ Suggest hypothalamic involvement
❖ Aura-Cortical Spreading Depression
■ Occurs in the cortex, cerebellum and hippocampus
❖ Activation of Trigeminovascular Reflex
■ Brainstem activation
■ Sterile neurogenic inflammation
■ CGRP, substance P, Neurokinin A release by trigeminal neurons supplying dural vessels
❖ Peripheral sensitization
■ Trigeminoparasympathetic reflex (miosis, ptosis, red eye, lacrimation, nasal stuffiness)
❖ Central sensitization (2nd and 3rd order neurons)
■ Wind-up phenomenon
■ Glutamergic and NO transmission
■ Cutaneous allodynia
 Pharmacological strategies for
migraine treatment
Acute treatment Preventive treatment

▪ Abortive or symptomatic ▪ Prophylactic therapy

▪ First choice for initial treatment ▪ May reduce frequency, severity,

and can provide symptom relief and duration of attacks, disability,
and cost of care
▪ Acute therapies are limited to a
narrow therapeutic window, due ▪ Very few effective, available
to: preventative treatments
• moderate or inconsistent • most of them are associated
benefits with issues of patient
• tolerability issues adherence
• medication-overuse headache

Giamberardino MA, et al. Expert Opin Emerging Drugs 2015;20:137–147

 Acute Phase Treatment

■ Regular analgesics
■ NSAIDs Goal for Acute treatment :

■ Triptans • To abort migraine attacks

■ Antiemetics-Prokinetics
■ Ergot alkaloids
■ Combinations
• Pain relief and improvement after 2 hours
• Sustained pain relief within 24 hours and
consistent efficacy in 2-3 attacks

50
Triptans (5-HT1B-D-F Agonists)
Triptans (5-HT1B-D-F Agonists)

Ferrari et al, NEJM 2002

Triptans (5-HT1B-D-F Agonists)

Ferrari et al, NEJM 2002

Preventive treatment

■ Preventive therapy is a crucial component of the management strategy to reduce

migraine disability
… Indicated in about a third of patients with migraine.
■ The mechanisms of action of current preventive treatments are not well understood.
… One potential mechanism could be the suppression of CSD
■ Consensus guidelines differ substantially with regard to recommendations about when
to start pharmacological migraine prophylaxis.
… In the US guidelines, treatment is recommended when attacks regularly > 2
times per week
… European guidelines suggest migraine prophylaxis for > 2 attacks per month.
■ Most treatments have been repurposed from other indications
 Commonly used drugs
CATEGORY DRUG DOSE SIDE-EFFECTS
BETA-BLOCKERS

Propranolol 40-120 mg twice daily Reduced energy, tiredness, postural symptoms

Contra-indicated in asthma, heart block

Metoprolol 25-75 mg twice daily Reduced energy, tiredness, postural symptoms

Contra-indicated in asthma, heart block

ANTICONVULSANTS

Valproate 250-500 mg twice daily Weight gain, Tremor, Hair loss, Liver abnormalities, Fetal
malformations
Topiramate 25-100 mg twice daily Paresthesias, Weight loss, Renal stones, Cognitive
dysfunction, Glaucoma
CALCIUM CHANNEL
BLOCKERS

Flunarazine 5-10 mg daily Weight gain, Pedal edema, Parkinsonism

ACEI-ARB
Lisinopril 5-20 mg daily Hypotension, Angioedema
Candesartan 4-32 mg daily Hypotension, Low back pain, Flu
 Other Commonly Used Drugs Nutraceuticals

SSRI No effect Riboflavin

SNRI Duloxetine
Butterbur
Tricyclic Antidepressants Amitryptiline
Nortiptyline Feverfew
Doxepin
Melatonin ??? Co-Enzyme Q-10
Greater Occipital Nerve Blocks & Stimulation
 External Trigeminal Stimulator (Cephaly)

PREMICE Trial
■ Prospective, multicenter, double-blinded, randomized
and sham-controlled trial
■ 67 patients with at least 2 migraine attacks per month.
■ Active vs sham stimulation for a 3-month treatment
period.
■ Significant reduction in migraine days (P = 0.023) and
in headache days (P = 0.011) between baseline and
the third month of treatment
■ Patients in the active stim group had a reduction of
29.7% in migraine days and 32.3% in headaches days
Botox treatment
• No evidence that it works in episodic migraine
▫ AAN guidelines (2009) recommended to not use Botox for
episodic migraine
• Several clinical studies suggested that it works for patients with high
headache frequency (> 12 headache days per month)
▫ FDA approval (2010)
• A reasonable treatment option for patients failing to respond or
unable to tolerate pharmacological treatments for chronic migraine
prophylaxis
 CGRP therapeutic monoclonal antibodies
for migraine prophylaxis
Erenumab Eptinezumab Galcanezumab Fremanezumab
(AMG 334) (ALD403) (LY2951742) (TEV-48125)

Target CGRP receptor CGRP CGRP CGRP

Episodic
Episodic Episodic Episodic
Migraine types studied Chronic
Chronic Chronic Chronic
Cluster headache

SC IV SC SC
Route of administration
(monthly) (monthly) (biweekly/monthly) (monthly)

Half-life (days) 21 31 28 45

Current development phase Approved Approved Approved Approved

Tension-type Headache
 Treatment
■ Psychological and behavioral techniques
■ Physiotherapy
– Non-pharmacological pain control,
– Relaxation techniques,
– Home exercises,
– Ergonomy
– Psychosocial functioning
■ Oromandibular treatment
■ Acupuncture
■ Pharmacotherapy
– Tricyclic antidepressants (amitriptyline, nortriptyline, etc)
– SNRIs (duloxetine)
– Muscle relaxants (baclofen, tizanidine)
Trigeminal autonomic cephalalgias
Cluster headache (Aθροιστική Κεφαλαλγία)

■ Male:female = 4:1
■ Increased family risk
■ Mean age at onset: 28 years
■ Marked correlation between CH and prior head trauma
■ Increased tissue volume in posterior hypothalamic region
■ Hypofunction of sympathetic nerves during attacks
■ Hyperactivity of parasympathetic nerves
■ Circannual and circadian periodicity of CH
Pathophysiology
■ Findings favor a central cause
■ A locus within hypothalamus may disturb rhythm regulation of
importance for pain regulation and autonomic and vascular control
■ Peripheral mechanisms in CH pathogenesis
■ Recurrent activation of trigeminovascular system with secondary
parasympathetic recruitment
Important points
■ Lateralization of symptoms and signs
■ Photo-/phono-phobia ipsilateral to the pain
■ Role of pituitary gland
■ Propensity of pituitary and peripituitary gland pathology to
present as phenotypic TAC
■ 10% of 84 pts with pituitary tumors had TAC-like headache
■ Activity in region of hypothalamus
Diagnostic Criteria
 Differential Diagnosis

■ Pituitary – hypothalamic lesions

■ Internal carotid artery aneurysm-dissection
■ Cavernous sinus thrombosis – inflammation – tumors
■ Acute angle-closure glaucoma
Treatment of acute attack of CH

■ Oxygen, 12-15 L/min x 10-15 minutes via mask

■ Sumatriptan Subcutaneously
■ Dihydroergotamine Subcutaneously
Shortening of the CH bout

■ Oral and IV Corticosteroids

■ GON steroid blocks (+/- oral triptan daily)
Chronic prophylactic treatment
• Verapamil
• Lithium
• Topiramate, Valproate
• Galcanezumab (CGRP antagonist)
• Hypothalamic stimulation
Trigeminal Autonomic Cephalalgias
& Hypothalamic Dysfunction
Trigeminal Neuralgia
■ Unilateral disorder characterized by electric-shock-like pains, abrupt in
onset and termination, limited to the distribution of one or more divisions
of the trigeminal nerve
■ Pain is commonly evoked by trivial stimuli including washing, shaving,
smoking, talking or brushing the teeth, and frequently occurs
spontaneously.
■ Small areas of the nasolabial fold or chin may be particularly susceptible
to the precipitation of pain.
■ The pains usually remit for variable periods
Diagnostic criteria
D.D. of trigeminal neuralgia
■ Classical TN, purely paroxysmal
■ Painful trigeminal neuropathy
■ Painful trigeminal neuropathy attributed to acute Herpes Zoster
■ Post-herpetic trigeminal neuropathy
■ Painful post-traumatic trigeminal neuropathy
■ Painful trigeminal neuropathy attributed to space-occupying lesion
■ Painful trigeminal neuropathy attributed to other disorder (MS)
 Pharmacotherapy
■ Carbamazepine: 400-1200 mg/day
■ Oxcarbazepine: 600-1200 mg/day

■ Gabapentin: 600-2400 mg/day

■ Phenytoin: 200-400 mg/day
■ Lamotrigine: 200-400 mg/day
■ Baclofen: 30-80 mg/day
 Procedures
Neuroablative procedures
– Baloon compression-foramen ovale
– Glycerol gangliolysis
– Radiofrequency
– Stereotactic radiosurgery
– Temporary relief
– 40-50% recurrence at 36 months
– Post-treatment dysesthesias

Microvascular decompression
– Identify offending blood vessel (SCA)
– Immediate pain relief
– Mortality: 0-0.6%