Neurology JC026: Severe Headache: Headache And Neuralgia, Neuroimaging 1

Question 1

Primary headache disorders

Answer 1

International Classification of Headache Disorders (ICHD)
1. Migraine
- Without aura
- With aura
- Ophthalmoplegic

2. Tension-type headache
   - Episodic
   - Chronic
   - Not fulfilling above criteria
3. Trigeminal autonomic cephalgias (TACs)
   - Types: Cluster headache, Chronic paroxysmal hemicrania, Other TACs
   - TACs (e.g. paroxysmal hemicrania): Pathophysiology involving CN5 nucleus —> ***Autonomic manifestations e.g. Miosis, ↑ sweating
4. Miscellaneous headache unassociated with structural lesion

Question 2

Secondary headache disorders

Answer 2

1. Head trauma
2. Vascular disorders
   - SAH
   - Vascular malformation
   - Unruptured aneurysm
3. Non-vascular intracranial disorder
   - High / Low ICP
   - Intracranial infection e.g. Meningitis
   - Intracranial sarcoidosis and other non-infectious inflammatory diseases
4. Substances abuse / Withdrawal
   - Usually younger patients without obvious history
5. Non-cephalic infection
   - Viral / Bacterial URTI
6. Metabolic disorder
   - Hypoxia
   - Hypercapnia
   - Hypoglycaemia
7. Disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, other facial / cranial structures
   - Conjunctivitis
   - Periorbital cellulitis
   - Ear infection
   - Rhinitis
   - Sinusitis
   - Periodontal abscess
8. Cranial neuralgias, Nerve trunk pain, Deafferentation pain
   - Trigeminal neuralgia
   - Glossopharyngeal neuralgia
9. Headache not classifiable

Question 3

History taking for Headache

Answer 3

OPQRST
1. Onset
- Sudden / Chronic

2. Location
   - Bilateral / Unilateral
3. Duration
4. Frequency and timing (if episodic)
   - ***Circadian distribution (day / night / random)
5. Severity
   - Course + Progression (constant, paroxysmal-recurrent, slowly / rapidly progressive)
6. Nature / Quality
   - Sharp (stab pain)
   - Pinprick
   - Burning
7. Aggravating / Precipitating factors
8. Relieving factors
9. Associated S/S
   - ***Autonomic S/S
10. Past headache history
11. Impact of headache
12. Medical history
13. Drug history
    - Drug that cause headache
14. Family history
    - Familial hemiplegic migraine
15. Social history
    - Alcohol intake
    - Substance abuse

Question 4

Tension-type headache (TTH) diagnostic criteria

Answer 4

1. ***>=10 attacks for >=3 months + (B-D)
2. Attack lasting from ***30 mins - 7 days
3. > =2 following characteristics
   - **Bilateral location
   - **Pressing / Tightening (Non-pulsating / Non-throbbing quality)
   - **Mild / Moderate intensity
   - **Not aggravated by routine physical activity e.g. walking / climbing stairs
4. Both of following:
   - **No N+V
   - **No >=1 photophobia / phonophobia
5. Not attributed to another disorder
   - Intracranial structural lesions e.g. Brain metastasis by Lung / Breast / Colorectal cancer

Question 5

Pathophysiology of TTH

Answer 5

Not entirely understood

Afferent signals from pain receptors in PMT (**Pericranial myofascial tissue)
—> SH/THC (Spinal horn / Trigeminal nucleus caudalis)
—> **Abnormal sensitisation of nociceptive 2nd order neuron
—> Cortex / Limbic system (Pain perceived by brain)
—> Motor efferents
—> ***Contraction of muscles in PMT

Question 6

Treatment of TTH

Answer 6

Aim:
- Prevent TTH from becoming Chronic

1. Short term, abortive treatment of attacks (mainly Pharmacological)
   - NSAIDs (Ibuprofen, Naproxen, Aspirin 500mg / 1000mg) (Gastric irritation, Nephrotoxicity)
   - COX2 inhibitor (Lumiracoxib)
   - Paracetamol (500mg / 1000mg)
   - Combination (NSAID + Sedative (BDZ) + Caffeine + Tranquilliser (i.e. Anxiolytic))
   - Topical Tiger Balm / Peppermint oil
2. Long term prophylactic treatment (aim at ↓ sensitisation of nociceptor)
   - Pharmacological
   —> **Antidepressants (Amitriptyline, Mirtazapine, Maprotiline, slow release Venlafaxine) (also useful for Migraine)
   —> *Anti-epileptic (Topiramate) (also useful for Migraine)
   —> ***α2-agonist (Tizanidine + Amitriptyline)

• Non-pharmacological

Question 7

Putative pathophysiological targets of preventive therapies for TTH

Answer 7

CNS:
- Coping with stress
- Depressive mood
- Central dysnociception
- Central sensitisation
1. TCA (Amitriptyline)
2. Stress management
3. Relaxation therapy
4. Acupuncture?
5. New drugs?

PNS:
- Muscle strain
- Myofascial factors
- Peripheral sensitisation
1. Physical therapy
2. Relaxation therapy
3. New drugs?

Question 8

Migraine

Answer 8

• ***Neurovascular disorder of brain
• Common, chronic, incapacitating
• Attacks of:
  1. Severe headache
  2. **Autonomic nervous system dysfunction (e.g. Trigeminal autonomic cephalgias)
  3. **Aura involving neurologic symptoms (in some) (e.g. Visual symptoms)

2 Main types (up to 33% experience both types):
- **Migraine without Aura (75%)
- **Migraine with Aura (33%)

Definition:
- Individuals having **>= 5 attacks without Aura / **>=2 attacks with Aura

Prevalence:
- 15% global prevalence
- 10% general population active migraineurs
- **F>M (2-3 times more frequent from 16 yo)
- **10-19 yo sharp but transient rise in 1 year prevalence —> peak around F 14-16, M 10-12
- F: less abrupt second rise until 40 yo
- **F: ~40 yo highest prevalence (25%)
- **onset nearly always (90%) before 50 yo

Question 9

Migraine diagnostic criteria

Answer 9

同Tension headache剛好相反

Without Aura:
1. >=5 attacks fulfilling (B-D)

2. Lasting ***4-72 hours
3. > =2 following characteristics:
   - **Unilateral location
   - Pulsating / **Throbbing quality
   - **Moderate / Severe intensity
   - **Aggravation by routine physical activity e.g. walking / climbing stairs
4. > =1 of following:
   - **N+V
   - **Photophobia / Phonophobia
5. Not attributed to another disorder

Question 10

Migraine with Aura

Answer 10

Aura symptoms (>=1 Transient focal neurological Aura symptoms):
1. Visual (99%)
2. Sensory (31%)
3. Aphasic (18%)
4. Motor weakness (6%) (mimic stroke e.g. tetraplegia)

• ***Gradual development of Aura symptoms over >4 mins / Several symptoms in succession
  —> vs Stroke (Abrupt onset to maximum symptoms)
• ***Last 5-60 mins (Motor symptoms longer)
• Aura symptoms nearly always ***precede headache
• Headache follows / accompanies Aura within 60mins
• up to 42% may have migraine aura ***without headache (hard to diagnose from TIA)
  —> Timeline: Aura (develop over 4 min) —> Headache (within 60 mins)

Visual:
- **Fortification spectra: distorted images —> **Enlarging spectra along time

Question 11

Mimic Migraine headache

Answer 11

1. AV malformation
2. ***ICA dissection
3. ***Epilepsy
4. ***MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes)
   - Mitochondrial DNA disorders: mitochondrial DNA mutation —> mitochondrial cytopathy —> ↓ functioning mitochondria —> cells prone to ATP deficiency —> cell death esp. muscle cells, neurons —> muscle weakness, seizure, encephalopathy)
5. ***CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy)
   - abnormal pathology of arteries —> ischaemic infarction of brain —> encephalopathy

Question 12

Mechanisms of Migraine

Answer 12

Not fully understood

**Dysfunction of brainstem pathways that normally modulate sensory input:
Trigeminovascular input (sensory afferent fibres arising from meningeal blood vessels)
—> Trigemino-autonomic reflex (exaggerated in Trigemino-autonomic cephalgias)
—> **Modulation of Trigeminovascular nociceptive input from Dorsal raphe nucleus, Locus ceruleus, Magnus raphe nucleus
—>

1. **Autonomic output to meningeal blood vessels
   —> **Vasodilatation of meningeal blood vessels + ***↓ Cerebral blood flow (Oligemia) during migraine aura, preceded by a phase of Focal hyperaemia
   —> Headache
2. ***Thalamocortical projection
   —> Perception of pain

Another mechanism
1. Neuropeptide release (**Neurokinin A, **Substance P, **CGRP) from Trigeminal sensory afferents + Spinal trigeminal nucleus
—> **Vasodilatation + ***Neurogenic inflammation

2. Modulation of neurotransmission of ***5HT1b receptors
   —> Modulation of Pain signal transmission to cortex
   —> Abnormal perception of pain

Question 13

Mechanism of Aura

Answer 13

Time-dependent BOLD (Blood Oxygen Level Dependent) activity:
- Shows **blood flow ↓ during Aura development (i.e. Gradual oligemia) in Cortex
- Spreading **suppression of cortical activation (∵ blood flow ↓)

Question 14

Familial hemiplegic migraine

Answer 14

FHM type 1:
- mutations in different sites of voltage gated Ca channel α1 subunit

FHM type 2:
- mutations in Na, K-ATPase α2 subunit

FHM type 3:
- mutations in Na channel α1 subunit

FHM gene mutations:
- **Abnormal Ion transport —> ↑ synaptic [Glumate] + [K] —> ↑ susceptibility for **Cortical Spreading Depression (slowly propagated wave of depolarization followed by suppression of brain activity)
- ***↑ Neuronal excitability

Question 15

Treatment of Migraine Acute Attacks

Answer 15

1. Simple analgesics
   - NSAIDs: Aspirin, Ibuprofen, Naproxen, Diclofenac
2. Ergot derivatives (Ergotamines / Dihydroergotamines)
   - **5HT receptor agonist —> inhibit **neuropeptide release
   - sustained generalised vasoconstrictor effects —> adverse vascular events (e.g. MI)
   - high risk of overuse syndromes + rebound headache
3. ***Anti-emetics / Pro-kinetic drugs
   - Metoclopramide
4. Triptans (Drug of choice) (e.g. Sumatriptan)
   - Serotonin 5HT1b/d receptor agonists
   - selective pharmacology, simple, consistent pharmacokinetics
   - evidence-based
   - moderate SE (Vasoconstriction, CI in patients with vascular disorders)
   - well established safety record
   - 3 potential MOA:
5. ***Cranial vasoconstriction —> ↑ MAP —> ↑ Cerebral perfusion
6. ***Peripheral neuronal inhibition
7. ***Inhibition of transmission through 2nd order neurons of Trigeminocervical complex
   —> inhibit effects of activated nociceptive trigeminal afferents from meningeal vessels to Trigeminovascular complex

Use of Triptans:
- **limited to 2-3 days per week, avoid analgesic overuse —> **medication overuse headache (MOH)
- **keep headache diary: monitor for escalation in headache drug use
- **avoid opioids: mask pain without suppressing pathophysiologic mechanism of attack, can cause cognitive impairment / addiction

Question 16

Prophylactic treatment of Migraine

Answer 16

Indications:
- Attacks weekly / several times a month, >=8 headache days per month
- Attacks less often but very prolonged + debilitating
- **Hemiplegic migraine, Migraine with brainstem aura (e.g. Tetraparesis)
- Frequent, prolonged, uncomfortable aura symptoms
- **Migranous infarction (∵ ↓ CBF)

• Most effective prophylactic agent available
• ↓ Headache frequency by >=50% in 50% patients

Drug:
1. ***β blocker
- Propranolol
- Metoprolol
- SE: lethargy, tiredness, depression, postural symptoms
- CI: asthma

2. ***CCB
   - Flunarizine
   - Verapamil
   - SE: tiredness, weight gain, depression, Parkinsonism
3. ***Antidepressant
   - Amitriptyline / Other TCA
   - Venlafaxine (SNRI)
   - SE: drowsiness, anticholinergic SE, weight gain, serotonin syndrome
4. **Valproate
   - SE: drowsiness, weight gain, tremor, alopecia, **teratogenic (fetal abnormalities), thrombocytopenia, hepatotoxicity
5. ***Topiramate
   - SE: sedation, cognitive impairment (slow, gradual titration), paresthesia, weight loss, risk of renal stones
6. ***Gabapentin
   - SE: dizziness, sedation
7. Methysergide (serotonergic agent) (NOT used now)
   - SE: dizziness, leg cramps, alopecia, retroperitoneal fibrosis, mediastinal fibrosis, cardiac valve fibrosis

Recently accepted:
8. ***Onabotulinumtoxin A (IM, SC)
- MOA: inhibition of neuropeptide / neurotransmitter release
- SE: muscle weakness, atrophy

9. ***CGRP-receptor antagonist (SC, IV)
   - MOA: neutralise circulating neuropeptide / CGRP receptor blockade
10. Riboflavin (oral)
11. Mg citrate (oral)

Question 17

Non-pharmacological treatment of Migraine

Answer 17

Neurostimulation devices
1. ***Transcranial magnetic stimulation
- acute treatment of migraine with aura
- acute + prophylactic treatment of migraine

2. ***External trigeminal nerve stimulation
   - acute treatment of migraine +/- aura
   - preventive treatment of episodic migraine

Non-invasive:
- Transcranial magnetic stimulation
- Transcranial direct current stimulation
- Supraorbital transcutaneous stimulation
- Non-invasive vagal nerve stimulation

Invasive:
- Occipital nerve stimulation
- Implanted vagal nerve stimulation
- Peripheral nerve stimulator

Question 18

Cluster headache, Chronic paroxysmal hemicrania, Other trigeminal autonomic cephalgias (TACs)

Answer 18

• Rare form of TAC
• Severe attacks of episodic headache

2 types:
1. Episodic cluster headache
2. Chronic cluster headache

Epidemiology:
- ***M:F = 3:1
- Prevalence 0.9%
- Age of onset: 28-30

Pain:
- **Piercing, Stabbing, Throbbing
- **Extremely high intensity
- **Periorbital
- 15-120 mins
- Frequency: **1-8 per day
- **++ Autonomic symptoms: ∵ Activation of Hypothalamus
- **+ Circadian rhythmicity
- ++ Alcohol trigger

Cluster headache and other TACs (no need to know):
- Cluster headache
- Paroxysmal hemicrania
- Short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing (SUNCT)
- Probable TAC
- Refractory TAC

Question 19

Diagnostic criteria for Cluster headache

Answer 19

1. > =5 attacks fulfilling (B-D)
2. Severe / Very severe ***unilateral orbital / supraorbital / temporal pain lasting 15-180 mins if untreated
3. Headache accompanied by >=1 following **Autonomic manifestation:
   - Ipsilateral **conjunctival injection / lacrimation
   - Ipsilateral **nasal congestion / rhinorrhea
   - Ipsilateral **eyelid edema
   - Ipsilateral **forehead + facial sweating
   - Ipsilateral **miosis / ptosis
   - Sense of restlessness / agitation
4. Attacks having frequency from 1 every other day to 8 per day
5. Not attributed to another disorder

Question 20

Treatment of Cluster headache

Answer 20

Acute treatment:
- **100% O2, 15L / min
- **Lidocaine (Intranasal)
- ***Sumatriptan

Preventive treatment:
- **Verapamil
- **Lithium
- ***Topiramate
- Corticosteroid (short course)
- Methysergide

2nd line treatment:
- Valproate
- Ergotamine
- Melatonin
- Pizotifen (Serotonergic agent)
- Indomethacin

Question 21

Temporal arteritis (TA) / Giant cell arteritis (GCA)

Answer 21

• ***Secondary headache
• typically elderly
• new onset of headache in elderly
• ***Bitemporal
• ***multiple arteries affected causing ischaemia
• associated symptoms (Negative phenomenon (無左d野)):
  1. **Polymyalgia rheumatica (pain in shoulder, limb girdle etc.)
  2. Malaise
  3. Jaw pain during chewing (Jaw claudication, ∵ ischaemia of jaw muscle during prolonged chewing)
  4. Fever, Neuropathy, Cough, Sore throat, Dysphagia
  5. **Amaurosis fugax (risk of permanent vision loss ∵ Ophthalmic artery involved —> Ischaemic optic neuropathy —> Retinal ischaemia)
  6. **Limb claudication
  7. **TIA / Stroke (∵ Cerebral arteries involved)
  8. Autonomic dysfunction (e.g. ***Horner ∵ Brainstem ischaemia)

Question 22

Diagnostic criteria for Temporal arteritis

Answer 22

> =3 following (>90% sensitivity / specificity):
1. Age of onset >=50

2. New onset of headache
3. Abnormalities of temporal artery at clinical examination
   - **Temporal tenderness
   - **Long tortuous, tender temporal artery felt
4. ***↑ ESR (>=50 mm/hr) / ↑ CRP (>5 mg/L)
5. Abnormal findings on biopsy of Temporal artery
   - Inflammation / Thrombosis / Obliteration fo Temporal artery (***Endarteritis obliterans)
   - Inflammatory cells infiltration (Giant cells)

Question 23

Headache of sudden onset

Answer 23

Primary headache:
- **Crash migraine
- **Cluster headache
- ***Benign exertional headache
- Benign orgasmic cephalgia (Sexual headache)

Secondary headache:
Vascular disorders associated
- **SAH
- Unruptured saccular aneurysm (Impending rupture in dissected artery)
- **Internal carotid artery dissection / aneurysm
- ***Cerebral venous thrombosis
- Acute HT
—> Phaeochromocytoma
—> Pressor response

Non-vascular intracranial disorders associated
- Intermittent hydrocephalus
- Benign intracranial HT
- **Pituitary apoplexy (∵ Necrosis / Infarction of pituitary tumour)
- **Infection
—> Meningoencephalitis
—> Acute sinusitis
- Acute mountain sickness
- ***Eye disorders
—> Acute glaucoma
—> Acute optic neuritis

Question 24

Neuralgia

Answer 24

• Sudden, intense, sharp, aching, lancinating, ***burning, stabbing pain
• ***Short (seconds - 2 mins)
• ***Recurring repeatedly within short periods
• ***Triggered by sensory / mechanical stimuli (e.g. touching face in trigger spots)

Question 25

Trigeminal neuralgia

Answer 25

Epidemiology:
- most frequent facial neuralgia
- 3-6 / 100,000
- incidence ↑ with age
- ~70% ***>60yo onset

Clinical hallmarks:
- Paroxysms of pain
- Very intensive
- Almost exclusively ***unilateral in trigeminal distribution

Distribution:
- Typical: CNV2, CNV3 (both affected ~1/3)
- CNV1 (~5%)
- Bilateral pain rare (if bilateral: suggest ***secondary origin e.g. tumour in brainstem)

Pain:
- Spontaneous / precipitated by sensory stimulation of certain areas in face (i.e. Trigger spots)
- ***Trigger spots: cheek, chin, lip, tongue
- Typical triggers: touching / washing face, shaving, brushing teeth, chewing, wind blowing at face

Disease course:
- Stereotypic pain attacks usually many times / day for weeks / months —> suddenly stop (subsequent **pain-free periods for months / years)
- pain attacks tend to become **more frequent over years, remission periods shorter
- rarely become longer lasting / permanent dull background pain

Pretrigeminal neuralgia:
- Atypical, longer lasting facial pain (several hours)
- Triggered by jaw movements / drinking
- followed by typical neuralgia after latency of days / years

Form:
- **Idiopathic / Primary TN: normal neurological / MRI examination (i.e. no cause identifiable)
- Secondary (up to 15%):
—> **Compression of Trigeminal nerve root by an **aberrant loop of blood vessel (60-90%) in neurosurgical / neuroradiological series (most common identifiable cause)
—> Multiple sclerosis esp. young patients + when bilateral
—> Other structural lesions mainly in pontine region:
1. Vestibular / Trigeminal **schwannoma, meningiomas
2. Epidermoid / other cysts
3. Vascular brainstem lesions esp. Pontine infarctions, Angiomas, AVM

Investigations:
- MRI of brain (to identify aberrant loop of blood vessel)

Symptomatic TN:
- often associated with other ***motor / sensory deficits (e.g. weakness in masticatory muscles innervated by CN5)
- ↑ in:
1. Bilateral involvement
2. Abnormal trigeminal reflex
3. Trigeminal sensory deficits

Question 26

Treatment of Trigeminal neuralgia

Answer 26

• Primary TN: Medical / Surgical
• TN due to focal lesions compressing sensory root of CNV: ***Surgical decompression

Medical:
1. **Carbamazepine
- most effective drug, respond in ~75%, 1st line
- severe allergic reaction (SJS) —> check **HLA-B1502 before starting
- initiate with small doses (50-100mg) —> increase slowly as tolerated —> once pain controlled —> taper dose every few weeks to determine whether remission has developed
- SE (esp. in elderly): vertigo, drowsiness, ataxia
- monitor: ***regular blood counts (first few months) —> Agranulocytosis (yearly)

2. 2nd line drugs (trial / alone / in combination, when CPZ not helpful / tolerated)
   - Gabapentin (benign SE, beneficial in neuropathic pain)
   - Pregabalin
   - Phenytoin
   - Baclofen
   - Valproate
   - Clonazepam
   - Lamotrigine
   - Oxcarbazepine
   - Topiramate

Non-medical:
1. ***Alcohol block of peripheral branch of CNV (relapse common)

2. ***Microvascular decompression (separation of CNV compressing the vessel)
   - risk of damage to other CN
3. ***Percutaneous radiofrequency thermocoagulation of CNV sensory root
   - corneal sensory loss
   - anaesthesia dolorosa (painful sensation in numb area)
4. Section of CNV sensory root (surgical) (less often used now)