INTRODUCTION

• Headache is among the most common reasons patients seek medical attention.

• Semantically, the term headache encompasses all aches and pains located in the head, but in
practice, its application is restricted to discomfort in the region of the cranial vault.

• It is responsible for more disability than any other neurologic problem.

• Primary headaches are those in which headache and its associated features are the disorder
itself.

• Secondary headaches are those caused by exogenous disorders.

CLASSIFICATION
 ANATOMY AND PHYSIOLOGY OF
HEADACHE
• Pain usually occurs when peripheral nociceptors are stimulated in response to tissue injury,
visceral distension, or other factors.

• Pain can also result when pain-producing pathways of the peripheral or central nervous system
(CNS) are damaged or activated inappropriately.

• Headache may originate from either or both mechanisms.

• Pain producing cranial structures include the scalp, meningeal arteries, dural sinuses, falx
cerebri, and proximal segments of the large pial arteries whereas the ventricular
ependyma, choroid plexus, pial veins, and much of the brain parenchyma are not pain-
producing.
• The key structures involved in primary headache appear to be the following:

The large intracranial vessels and dura mater and the peripheral terminals of the trigeminal
nerve that innervate these structures

The caudal portion of the trigeminal nucleus, which extends into the dorsal horns of the
upper cervical spinal cord and receives input from the first and second cervical nerve roots
(the trigeminocervical complex)

Rostral pain-processing regions, such as the ventroposteromedial thalamus and the cortex

The pain-modulatory systems in the brain that modulate input from trigeminal nociceptors
at all levels of the pain-processing pathways and influence vegetative functions, such as
hypothalamus and brainstem structures
• The innervation of the large intracranial vessels and dura mater by the trigeminal nerve is
known as the trigeminovascular system.

• Cranial autonomic symptoms, such as lacrimation, conjunctival injection, nasal congestion,

rhinorrhea, periorbital swelling, aural fullness, and ptosis, are prominent in the trigeminal
autonomic cephalalgias (TACs), including cluster headache and paroxysmal hemicrania, and
may also be seen in migraine, even in children.

• They can often be mistaken for symptoms or signs of cranial sinus inflammation, which is thus
overdiagnosed and inappropriately managed.
• Migraine is commonly mistaken for sinus headache (over 40%) because─

Pain is often located over the sinuses.

Migraine is also often triggered by weather changes.

Tearing and nasal congestion are common autonomic symptoms during migraine.

Sinus medications may help abort migraine episode as well.

 PRIMARY HEADACHE DISORDERS

Tension Type Headache (TTH)

• Most common type of primary headache.

• Chronic head-pain syndrome characterized by bilateral tight, band-like discomfort.

• Pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for
many days.

• May be episodic or chronic (present >15 days per month).

• Headaches are completely without accompanying features such as nausea, vomiting,

photophobia, phonophobia, osmophobia, throbbing, and aggravation with movement.
• Middle aged females of 30-45 years are affected.

• 33% is associated with depression.

• Does not affect activities of daily living and sleep is never disturbed by TTH.

• It seems likely that TTH is due to a primary disorder of central nervous system pain modulation
alone, unlike migraine, which involves a more generalized disturbance of sensory modulation.

• The name tension-type headache implies that pain is a product of nervous tension, but there is
no clear evidence for tension as an etiology.
Treatment
• For occasional mild tension-type headache, treatment with aspirin, acetaminophen, or NSAIDs
may be sufficient.

• The combination of acetaminophen with isometheptene and dichloralphenazone may be useful

for moderately severe headaches.

• The most effective prophylactic drug is possibly amitriptyline in usual dose of 50–150 mg/day
and better tolerated if given as a single bedtime dose.

• Other tricyclic antidepressants, gabapentin, mirtazapine, sodium valproate, or topiramate may

be used as prophylactics if amitriptyline is not tolerated or contraindicated.

• Techniques to promote relaxation of the scalp and neck muscles (e.g., biofeedback, neck
massage) can help in the short term.
 Migraine
Definition and Classification
• The term migraine derives from the ancient Greek word hemikranios, which means “half head,”
underscoring the unilateral distribution of head pain that is present in about 60%–75% of people
with migraine.

• Migraine is a recurring syndrome of headache associated with other symptoms of neurologic

dysfunction in varying admixtures.

• Although not all people with migraine experience all potential phases of a migraine attack, the
migraine attack can consist of up to four phases: the premonitory phase, aura, headache phase,
and postdrome.

• In addition to head pain, the “headache phase” consists of a combination of photophobia,

phonophobia, osmophobia, cutaneous allodynia, nausea, and vomiting.
Epidemiology
• The World Health Organization has declared migraine to be among the most disabling medical
conditions experienced worldwide.

• The lifetime prevalence of migraine is about 33% in women and 13% in men.

• Migraine afflicts prepubescent boys and girls with a similar frequency.

• At puberty, the incidence of migraine increases sharply in both boys and girls, but preferentially
so in girls.

• Peak migraine prevalence for both sexes occurs in the fourth decade of life.

• Migraine tends to manifest with fluctuating frequencies of attacks throughout one’s life, with a
typical trend towards milder and less frequent migraines late in life.
• There is a genetic predisposition for developing migraine.

• Compared to the general population, first-degree relatives of people who have migraine without
aura are about twice as likely to develop migraine without aura, while first-degree relatives of
people who have migraine with aura are about four times more likely to have migraine with
aura.

Migraine attack frequency

• The majority of people with migraine have attacks 1–4 times per month.

• These migraineurs are considered to have “episodic migraine,” meaning they have headaches on
fewer than 15 days per month.

• But 2% of the general population has “chronic migraine,” meaning that they have headaches on
at least 15 days per month, including at least 8 days per month on which they have symptoms of
full-blown migraine attacks.
Triggers of the migraine attack

• Migraineurs are particularly sensitive to environmental and sensory stimuli.

• Migraine-prone patients do not habituate easily to sensory stimuli.

• This sensitivity is amplified in females during the menstrual cycle.

• Headache can be initiated or amplified by various triggers, including glare, bright lights, sounds,
or other types of afferent stimulation; hunger; let-down from stress; physical exertion; stormy
weather or barometric pressure changes; hormonal fluctuations during menses; lack of or excess
sleep; and alcohol or other chemical stimulation, such as with nitrates.
Pathogenesis
• The sensory sensitivity of migraine is probably due to dysfunction of monoaminergic sensory
control systems located in the brainstem and hypothalamus.

• Activation of cells in the trigeminal nucleus results in the release of vasoactive neuropeptides,
particularly calcitonin gene–related peptide (CGRP), at vascular terminals of the trigeminal
nerve and within the trigeminal nucleus.

• Centrally, the second-order trigeminal neurons cross the midline and project to ventrobasal and
posterior nuclei of the thalamus for further processing.

• There are projections to the periaqueductal gray and hypothalamus, from which reciprocal
descending systems have established antinociceptive effects.

• Other brainstem regions likely to be involved in descending modulation of trigeminal pain

include the nucleus locus coeruleus in the pons and the rostroventromedial medulla.
• The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important
receptor in the headache pathway.

• Immunohistochemical studies have detected 5-hydroxytryptamine–1D (5-HT1D) receptors in

trigeminal sensory neurons, including peripheral projections to the dura and within the
trigeminal nucleus caudalis (TNC) and solitary tract.

• 5-HT1B receptors are present on smooth muscle cells in meningeal vessels.

• However, both can be found in both tissues to some extent and even in coronary vessels.
• Some authors have proposed a dopaminergic basis for migraine.

• In 1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is present in patients

with migraine.

• Some of the symptoms associated with migraine headaches, such as nausea, vomiting, yawning,
irritability, hypotension, and hyperactivity, can be attributed to relative dopaminergic
stimulation.

• Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists (eg,
apomorphine).

• Dopamine antagonists (eg, prochlorperazine) completely relieve almost 75% of acute migraine
attacks.
• Migraine genes identified by studying families with familial hemiplegic migraine (FHM) reveal
involvement of ion channels, suggesting that alterations in membrane excitability can
predispose to migraine.

• Mutations involving the Cav2.1 (P/Q)–type voltage-gated calcium channel CACNA1A gene are
now known to cause FHM 1 and this mutation is responsible for about 50% of FHM cases.

• Mutations in the Na+-K+ ATPase ATP1A2 gene, designated FHM 2, are responsible for about
20% of FHMs.

• Mutations in the neuronal voltage-gated sodium channel SCN1A cause FHM 3.

• Functional neuroimaging has suggested that brainstem regions in migraine and the posterior
hypothalamic gray matter region close to the human circadian pacemaker cells of the
suprachiasmatic nucleus in cluster headache are good candidates for specific involvement in
these primary headaches.
Clinical features
History
• Migraine attacks commonly occur when the migraineur is awake.

• The typical migraine headache is throbbing or pulsatile.

• The headache is initially unilateral and localized in the frontotemporal and ocular area, but pain
can be felt anywhere around the head or neck.

• The pain typically builds up over a period of 1–2 hours, progressing posteriorly and becoming
diffuse and headache typically lasts from 4–72 hours.

• Among females, more than two thirds of patients report attacks lasting longer than 24 hours.
Other symptoms
• Nausea and vomiting usually occur later in the attack in about 80% and 50% of patients,
respectively, along with anorexia and food intolerance.

• Photophobia and/or phonophobia also commonly are associated with the headache.

• Lightheadedness is frequent.

• Other neurologic symptoms that may be observed include the following:

Hemiparesis (this symptom defines hemiplegic migraine)

Aphasia

Confusion

Paresthesias or numbness
Prodrome
• About 60% of people who experience migraines report premonitory symptoms that
occur hours to days before headache onset and include the following:
Heightened sensitivity to light, sound, and odors

Lethargy or uncontrollable yawning

Food cravings

Mental and mood changes (eg, depression, anger, euphoria)

Excessive thirst and polyuria

Fluid retention

Anorexia

Constipation or diarrhea
Aura
• The migraine aura is a complex of neurologic symptoms that may precede or accompany the
headache phase or may occur in isolation and usually develops over 5–20 minutes and lasts less
than 60 minutes.
• The aura can be visual, sensory, or motor or any combination of these.
• Visual symptoms─ Auras most commonly consist of visual symptoms, which may be negative
or positive and include:
Homonymous hemianopic or quadrantic field defects

Central scotomas

Tunnel vision

Altitudinal visual defects

Complete blindness
Migraine headache.
Frank visual field loss
can also occur
associated with
migraine. This
example shows loss of
the entire right visual
field as described by a
person who
experiences migraines.
Migraine headache. Example of a central scotoma
as described by a person who experiences
migraines. Note the visual loss in the center of
vision.
Migraine headache.
Example of a central
scotoma as described
by a person who
experiences migraine
headaches. Again note
the visual loss in the
center of vision.
• The most common positive visual phenomenon is the scintillating scotoma.

Migraine headache.
Example of a visual
migraine aura as
described by a person
who experiences
migraines. This patient
reported that these visual
auras preceded her
headache by 20-30
minutes.
Migraine headache.
Example of visual
changes during
migraine. Multiple
spotty scotomata are
described by a person
who experiences
migraines.
Sensory symptoms

• Paresthesias, occurring in 40% of cases, constitute the next most common aura.
• They are often cheiro-oral, with numbness starting in the hand, migrating to the arm, and then
jumping to involve the face, lips, and tongue.
• The rate of spread of sensory aura is helpful in distinguishing it from transient ischemic attack
(TIA) or a sensory seizure.

Motor symptoms

• Motor symptoms may occur in 18% of patients and usually are associated with sensory
symptoms.
• Motor symptoms often are described as a sense of heaviness of the limbs before a headache but
without any true weakness.
• Speech and language disturbances have been reported in 17–20% of patients.
Postdromal symptoms
• Postdromal symptoms may persist for 24 hours after the headache and can include the
following:

Tired, “washed out,” or irritable feeling

Unusually refreshed or euphoric feeling

Muscle weakness or myalgias

Anorexia or food cravings

Diagnosis
Migraine with aura─ Diagnostic criteria
Episodic disabling headache of more
than 6 months duration with normal
neurological examination is migraine
until proven otherwise.
Treatment
Approach Considerations
• Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy.

• Patients with frequent attacks usually require both.

• Measures directed toward reducing migraine triggers are also generally advisable.

• The Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-to-use tool.

Nonpharmacologic management
• Avoidance of identified triggers.

• A regulated lifestyle is helpful, including a healthy diet, regular exercise, regular sleep patterns,
avoidance of excess caffeine and alcohol, and avoidance of acute changes in stress levels, being
particularly wary of the let-down effect.

• Biofeedback, cognitive-behavioral therapy, and relaxation therapy are frequently effective

against migraine headaches and may be used adjunctively with pharmacologic treatments.

• Occipital nerve stimulators may be helpful in patients whose headaches are refractory to other
forms of treatment.

• In December 2013, the FDA approved the Cerena Transcranial Magnetic Stimulator (Cerena
TMS), the first device to relieve pain caused by migraine headache with aura for use in patients
aged 18 years and older.
• In January 2018, the FDA approved a vagus nerve stimulator (vNS) for the treatment of
migraine pain in adults.

• Another noninvasive neuromodulation device for the relief of acute migraine pain was approved
by the FDA in May 2019.

• The device is worn on the upper arm and uses smartphone-controlled electronic pulses to relieve
migraine through conditioned pain modulation.
Acute attack therapies for migraine
• The combination of acetaminophen (paracetamol), aspirin, and caffeine has been approved for
use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate
migraine.

• The combination of aspirin and metoclopramide has been shown to be comparable to a single
dose of oral sumatriptan.

• Important side effects of NSAIDs include dyspepsia and gastrointestinal irritation.

• Side effects are common, although often mild and transient. Moreover, 5-HT1B/1D receptor
agonists are contraindicated in individuals with a history of cardiovascular and cerebrovascular
disease.

• With use of ergotamine there appears to be a much higher incidence of nausea than with triptans
but less headache recurrence.
Preventive treatments for migraine
• The following may be considered indications for prophylactic migraine therapy:
Frequency of migraine attacks is greater than 2 per month

Duration of individual attacks is longer than 24 hours

The headaches cause major disruptions in the patient’s lifestyle, with significant disability
that lasts 3 or more days

Abortive therapy fails or is overused

Symptomatic medications are contraindicated or ineffective

Use of abortive medications more than twice a week

Migraine variants such as hemiplegic migraine or rare headache attacks producing profound
disruption or risk of permanent neurologic injury
Drugs for prophylaxis of migraine
• Neurological Society of India recommendations:
• 1st line drugs- Propranolol, TCA’s, Topiramate
• 2nd line drugs- Telmisartan, Venlafaxine, Valproate
• 3rd line drugs- Pizotifen, Flunarizine, Clonidine
Calcitonin gene-related peptide inhibitors
• Inhibiting the calcitonin gene-related peptide (CGRP) pathway is a new method to prevent
migraines.

• CGRP is a potent vasodilator and is a key neuropeptide that is central to migraine

pathophysiology.

• CGRP concentrations decrease following administration of triptans when treating a migraine

attack.

• Three monoclonal antibodies that bind to the CGRP receptor were approved in the United States
in 2018 (ie, erenumab, fremanezumab, galcanezumab).

• The first IV CGRP monoclonal antibody, eptinezumab, was approved for migraine prophylaxis
in 2020.
Status migrainosus is described as
a debilitating migraine attack
lasting for more than 72 hours
(IHS, 2018).
Trigeminal autonomic cephalalgias
• TACs are characterized by relatively short-lasting attacks of head pain associated with cranial
autonomic symptoms, such as lacrimation, conjunctival injection, aural fullness, or nasal
congestion.

• Pain is usually severe and may occur more than once a day.

• Because of the associated nasal congestion or rhinorrhea, patients are often misdiagnosed with
“sinus headache” and treated with decongestants, which are ineffective.
Cluster headache
• The pain is deep, usually retroorbital, often excruciating in intensity, nonfluctuating, and
explosive in quality.

• Young males (M:F=3:1)

• Episodic.

• At least one of the daily attacks of pain recurs at about the same hour each day for the duration
of a cluster bout.

• Stabbing, boring pain.

• Cluster headache is characterized as chronic when there is <3 months of sustained remission
without treatment.
• Lasts for 15 mins-3 hrs.

• Symptoms for 8-10 weeks followed by remission for 3-4 months only to recur.

• 1-8 attacks per day.

• Pain occurs mostly at night.

• Alcohol is a trigger.

• Some migrainous features may be present.

• Cluster headache is likely to be a disorder involving central pacemaker neurons and neurons in
the posterior hypothalamic region.
• At least one of the following autonomic symptoms should be present:
Conjunctival congestion

Lacrimation

Nasal congestion

Rhinorrhoea

Flushing

Sweating

Miosis

Ptosis
Treatment
Acute attack treatment
• Oxygen inhalation given as 100% oxygen at 10–12 L/min for 15–20 min.

• Sumatriptan 6 mg SC is rapid in onset and will usually shorten an attack to 10–15 min.

• Sumatriptan (20 mg) and zolmitriptan (5 mg) nasal sprays are both effective in acute cluster
headache.

• Noninvasive vagus nerve stimulation (nVNS) is FDA approved for the acute treatment of
attacks in episodic cluster headache using three 2-min stimulation cycles applied consecutively
at the onset of headache on the side of pain; this may be repeated after nine minutes.
Non-rebreather oxygen mask with reservoir for
the acute treatment of cluster headache.
Neuromodulation therapy

• Sphenopalatine ganglion (SPG) stimulation with an implanted battery-free stimulator has been
shown in randomized controlled trials to be effective in aborting attacks and reducing their
frequency over time.

• nVNS compares favorably to standard-of-care in open label experience.

• Similarly, occipital nerve stimulation has been used open label and appears to be beneficial.

• Deep-brain stimulation of the region of the posterior hypothalamic gray matter is successful in
about 50% of patients treated.
Thunderclap headache
• A “thunderclap headache” is a severe headache that reaches maximal intensity in less than 1
minute (IHS, 2018).
• It is the rapidity with which the headache reaches maximum intensity that differentiates a
thunderclap headache from other severe headache types.
• Causes:
Subarachnoid hemorrhage,
Spontaneous spine CSF leak,
RCVS,
Cervical artery dissection,
Cerebral venous sinus thrombosis,
Pheochromocytoma,
Hypertensive crisis
SECONDARY HEADACHE DISORDERS
• Associated with increased intracranial pressure.
• Causes:

CNS infections

Vascular causes

Benign intracranial hypertension

Brain tumours (SOL), tuberculoma, neurocysticercosis

Haemorrhage
Features of dangerous headache
Cerebral venous thrombosis
• Also known as Idiopathic intracranial hypertension or pseudotumour cerebri.
Aetiology
• Sinusitis
• Trauma and surgery
• Hypercoagulable states
• Intracranial hypotension
• Lumbar puncture
• Medications: Oral contraceptives - Including the third-generation formulations, Corticosteroids,
Epsilon-aminocaproic acid, Thalidomide, Tamoxifen, Erythropoietin, Phytoestrogens, L-
asparaginase, Heparin.
Presentation
• Headache, maybe thunderclap in nature.

• Patients with lateral sinus thrombosis may present with a pseudotumor cerebri–like syndrome.

• Nausea and vomiting

• In some cases, seizures, which can be recurrent, occur.

• Focal neurologic deficit may develop

• Cranial nerve syndromes are seen with venous sinus thrombosis such as Vestibular
neuronopathy, Pulsatile tinnitus, Unilateral deafness, Double vision, Facial weakness,
Obscuration of vision.
Investigations & management
CT scan brain:
Cord sign- hyperdensity along lines of transverse sinus
Dense triangle sign-delta sign
Empty delta sign in CECT.
MR Venography
Investigation of choice
Empty delta sign
• Specific therapy for CVT involves anticoagulation or thrombolytic therapy.
Benign intracranial hypertension
• Disorder of unknown etiology that predominantly affects obese women of childbearing age.
• The primary problem is chronically elevated intracranial pressure (ICP), and the most important
neurologic manifestation is papilloedema, which may lead to secondary progressive optic
atrophy, visual loss, and possible blindness.
Drugs associated with IIH
• Cimetidine, corticosteroids, danazol, isotretinoin, levothyroxine, lithium, minocycline, nalidixic
acid, nitrofurantoin, tamoxifen, tetracycline, and trimethoprim-sulfamethoxazole.

• All- trans-retinoic acid (ATRA) used in the treatment of promyelocytic leukemia, cyclosporine,
levonorgestrel implant, pancreatin.

• Recombinant human growth hormone/natural growth hormone (somatotropin).

• Vitamin A in infants.
Presentation
• Headaches (typically nonspecific and varying in type, location, and frequency)

• Visual loss (typically visual field but rarely visual acuity loss)

• Transient visual obscurations (typically lasting seconds at a time)

• Diplopia (typically horizontal due to nonlocalizing sixth nerve palsy but rarely vertical)

• Pulsatile tinnitus

• Radicular pain (typically in the arms, uncommon symptom)

• Nonspecific symptoms such as nausea and vomiting may also be present.

Investigations
• Complete blood count

• Electrolytes, bicarbonate

• Full procoagulant profile (typically obtained only in patients with a previous history of
thrombosis or magnetic resonance imaging [MRI] or MR venographic evidence of a dural
venous sinus)

• Neuroimaging studies (preferably cranial MRI with magnetic resonance venography [MRV]
with and without gadolinium) are essential to rule out the possibility of an intracranial lesion
prior to performing a lumbar puncture.

• Lumbar puncture
Management
• Diet and weight loss (Most important).

• Acetazolamide ( 1-4 g per day) or topiramate.

• Acetazolamide plus furosemide combination more effective than acetazolamide alone.

• Repeated lumbar puncture (20-30 mL) gives symptomatic relief.

• Surgery: Optic Nerve Sheath Fenestration (ONSF) or shunting (VP or LP shunts).

• In acute setting:
Elevate head end
Mannitol (15-30 mins for action)
Sedation
Hyperventilation (pCO2 <25-35 mm Hg)
Pressor therapy to maintain cerebral perfusion pressure >60 mm Hg
 REFERENCES

• Harrison’s Principles of Internal Medicine, 20/e.

• Bradley and Daroff's Neurology in Clinical Practice, 8th Edition.
• Adams and Victor's Principles of Neurology, 11e
• The International Classification of Headache Disorders, 3rd edition
• [Link]