Cluster headache (CH) attacks are short-lasting (15–180 min), severe, unilateral, orbital, supra- orbital and/or temporal pain accompanied by at least one autonomic finding (ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, eyelid edema) and/or a sense of restlessness.5 Migraine subjects may also have unilateral headache. Although migraine subjects describe autonomic symptoms, they are less frequent, usually bilateral, and milder, generally patients report only one symptom.6

There are many similarities and differences between migraine and cluster type headache.7 The pain of CH is usually nocturnal, characterized by a circadian and circa-annual pattern. The CH attacks last shorter and tend to cluster. On the other hand, migraine attacks occur most frequently during the day and a seasonal rhythm has not been established. Also, patients who have more than two headache attacks a day are less likely to have migraine.6 Unlike migraine, there is a desire to wander instead of sitting still. However, about 24% of CH patients may have at least one migraineous feature.8 The term “cluster migraine” is used to describe patients with cluster headache and migraine overlap.9 CH may respond to many medications used in migraine preventive treatment, such as topiramate, verapamil, valproate, steroids, galcanezumab and peripheral nerve blocks.7,10,11 CH attacks also respond well to acute treatment with triptans (especially subcutaneous sumatriptan) and ergotamine. Compared to migraine, CH attacks responds well to high flow 100% oxygen mask and transnasal sphenopalatine block by 10% lidocaine.7 However, simple analgesics and non-steroidal anti-inflammatory drugs used in migraine attacks do not relieve pain in CH attacks.6 CH has striking circadian and circannual periodicity.12 This rhythmicity and accompanying altered hypothalamic hormonal secretion pattern emphasize the role of the hypothalamus in CH pathophysiology.13 Hypothalamic involvement usually occurs during the premonitory phase of the migraine attack, the patient experiences mood changes, food craving or loss of appetite, neck discomfort, and gastrointestinal disturbances.14 Both cluster and migraine demonstrate post-ganglionic parasympathetic outflow from the SPG, cluster to target organs.15

CH patients have premonitory and prodromal symptoms.10,11 The preictal and postictal symptoms were concentration difficulties, restlessness, and mood disturbances, and occurred 20 min before headache in approximately half of the attacks.15 Postictal concentration difficulties, decreased mood, and fatigue lasted for an hour on average in about a third of the patients.15

TTH is typically bilateral, pressing or tightening in quality, and of mild to moderate intensity, lasting 30 min to days. Routine physical activity does not aggravate pain, and usually TTH is not associated with nausea, although photophobia or phonophobia may be present, but not both.5 Headache begins at some point during the day and persists in the reminder of the day, with headache aggravation, usually by the afternoon or end of the day.16 Peripheral mechanisms may play a role in episodic TTH, whereas central pain mechanisms dominate in chronic TTH.

Increased peri-cranial tenderness is usually reported in TTH patients associated with stress. Neck pain may be present in about two-thirds of those with migraine, and stress is frequently reported as a migraine trigger, so these clinical symptoms do not help with differentiation.17 The main distinctive feature of migraine is aggravation of pain by common daily life physical activities, not generally present in TTH. However, precipitating and aggravating factors in TTH may also overlap with migraine. On the other hand, some chronic migraine patients may have comorbid medication overuse headache and the baseline ongoing headache characteristics may complicate the differential diagnóstico of chronic migraine from TTH.16

New Daily Persistent Headache (NDPH) is the abrupt onset of a continuous and unremitting headache on a remembered day. It is characterized by an acute and daily onset of headache that lasts for more than 3 months, never remitting. NDPH may have migraine and/or TTH features. It may be misdiagnosed as chronic migraine (CM).5 However, patients generally recall accurately the acute onset of continuous headache; if not, a clinician must consider other diagnoses. There may be a preexisting history of migraine in 20% of NDPH patients. In one study with NDPH patients, throbbing pain, photophobia, phonophobia, and increase in the severity of pain by physical activity were reported in about half of the patients. Even visual aura has rarely been reported with NDPH, which has migraineous features and which may sometimes, but rarely, respond to acute and preventive treatments for CM.5,18,19 Recently, NDPH has been reported following recovery from COVID 19 infection, which is characterized by holocranial, pressure-like pain starting within 2 weeks after recovery of respiratory symptoms.20

The pain is often felt unilaterally in the frontal, temporal, occipital, vertex or retro-orbital locations, and sometimes in more than one area. It may be accompanied by nausea or vomiting, may worsen with standing, kneeling, and coughing, and not relieved by sleep. Fever is reported in half of the patients, while nasal congestion or nasal obstruction is present in approximately 40% of patients. Compressing the frontal or maxillary sinus may evoke the pain.21,22

Headache is the predominant symptom accompanied by fever, neck stiffness, and neurological features (altered mental status, focal neurological deficits, or seizures). Headache is due to the irritation/activation of the meningeal nociceptors and thus may resemble migraine. Bilateral throbbing headache and accompanied by nausea, vomiting, and photophobia. Headache is temporary with the resolution of infection. However, meningitis may persist for months, leading to chronic headache, and may rarely persist for more than three months.5,9 Unlike bacterial meningitis, fever and neck stiffness may not appear in viral meningitis. Fever is also not expected in recurrent benign aseptic meningitis (Mollaret's meningitis), which is frequently associated with herpes virus.18,23

Patients who suffer from HaNDL, may present with bilateral or hemicranial, throbbing, migrainous headache of moderate to severe intensity. Duration is between 1 h–1 week, (mean of 19 h). It may be accompanied by nausea, vomiting, photophobia, phonophobia, and neurological deficits including hemi-paresthesias, hemiparesis, and/or dysphasia. The transient attacks last 5 min–1 week and can repeat several times a week. However, visual symptoms similar to migraine aura are relatively rare.5 Elevated lumbar puncture opening pressure, high protein content (up to 250 mg/dl), and lymphocytic pleocytosis in the cell count of CSF confirms the diagnóstico. All patients recover completely within 1 day–3 months.18,24

The prevalence of headache in patients with intracranial tumors ranges from 32% to 71%. In patients with primary CNS tumors or metastasis, migraine-like headache may be present in 15%.5,25,26 In a population-based study, compared to unaffected controls, patients with brain tumors had 2.5- fold increased risk of having prior migraine.27 Worsening of migraine may be considered as a red flag. Migraine-like headaches are reported in patients with craniopharyngioma, colloid cysts, pituitary tumors, brainstem glioma, and cerebral metastases.28–32 Headaches may occur due to infiltration of bones or meninges, increased intracranial pressure or venous congestion/thrombosis. Regular medical follow-up after migraine diagnóstico can aid in early recognition of key symptoms of brain tumors. Clinicians should be careful about the key symptoms of CNS tumor which are unexpected in migraineurs such as numbness, seizures, sensory changes, nausea or vomiting.27 The prevalence of headache reported in pituitary adenomas (PAs) ranges from 33% to 72%.33,34 Multiple pathophysiological mechanisms have been proposed, the mechanical effect of tumor growth and the neuroendocrine effects of the functional pituitary tumors. Mechanical and structural factors are cavernous sinus invasion and infiltration of nociceptive structures.35 Increase in intrasellar pressure could be another mechanism leading to PA-related headaches. PAs are also associated with the development of secondary short lasting unilateral neuralgiform headaches with conjunctival injection and tearing (SUNCT).35

Brain abscess can mimic migraine status. The headache is typically moderate to severe and may be exacerbated by Valsalva maneuver. Headache was reported to be present in 70%, fever in 50%, and focal neurological deficits in 50% of the patients with brain abscess, 20% patient report all 3 symptoms. Half of the patients reported nausea or vomiting.36,37 Seizures and cerebral venous thrombophlebitis may be present in these patients.36

Patients with IIH may present with chronic or subacute daily headache. Headache is described predominantly early in the morning or awakening, frontal and bilateral localization, accompanied by vomiting without nausea, visual changes, cranial nerve palsies (especially sixth cranial nerve palsy), and pulsating tinnitus.9 Neuroimaging findings such as an empty sella, distention of the peri-optic subarachnoid space, flattening of the posterior sclera, and protrusion of the optic nerve (papilledema), support the diagnóstico of IIH, but the key finding is elevated CSF pressure (>250 mm H20) on lumbar puncture. Although headache attributed to IIH can mimic CM and CTTH, these disorders commonly coexist with IIH.38

Daily headache is not required for the diagnóstico of IIH.5 Almost 41% of IIH patients are reported to have migraine, while 17% reported migraine with aura.38 Patients with IIH tend to be overweight or obese.9 Diagnosis of IIH without papilledema (IIHWOP) requires a constellation of unequivocal MRI findings and/or cranial nerve palsies.39 Unexpected comorbidity reports of IIH, IIHWOP, and CM noted that these syndromes can be linked with each other.40 One potential mechanism connecting the three headaches is temporary venous insufficiency due to increased cerebral perfusion, initially described with migraine attacks.41 Another mechanism is the trigeminovascular firing from dural sinus veins and bridge veins that lead sensitization in central pain pathways.42 In both IIH and IIHWOP, patients may have dural sinus stenosis. Congestion of the dural sinuses may lead to CGRP - dependent trigeminovascular nociceptive firing, which could result in sensitization of central pain pathways and progression of migraine to its chronic form.43 There is peptidergic trigeminovascular innervation of the dural sinuses. This feature may lead to function as an intracranial venous pressure sensor, leading to central pain pathway sensitization.42 Plateau waves consist of a sudden rapid elevation of intracranial pressure (ICP) to 50–100 mmHg for 5 to 20 min. Changes in ICP are thought to produce corresponding changes that include visual obscuration. In this period, patients may experience transient scotomas which last only a few minutes.44

New headache or significant worsening of prexisting headache (implies a two-fold or greater increase in frequency and/or severity), accompanid by papiledema may be due to increased intracranial pressure.5 In hydrocephalus, migraine-like recurrent headache has been reported, such as in slit ventricle syndrome.18,45 Obstructive hydrocephalus may lead to visual auras as seen in migraine. Idiopathic stenosis of aqueduct may cause episodic severe headaches characterized by temporary scotomas.46

Low CSF pressure; either spontaneous or secondary CSF leakage, causes orthostatic headache. Classically, there is a strong relation between headache severity and upright position. Headache significantly worsens soon after sitting upright or standing and/or improves

after lying horizontally.5 The headache may be throbbing, dull, or pressure-like. The location is usually bilateral, frontal, occipital, fronto-occipital or generalized. Low CSF pressure may lead to a migraine-like headaches with accompanying symptoms such as nausea, vomiting, and sensitivity to light or noise.18,47 Other symptoms are neck pain, changes in hearing/tinnitus, diplopia, and facial paresthesia.48 Brain imaging demonstrates brain sagging or pachymeningeal enhancement, or spine imaging (spine MRI,or MRI, CT or digital subtraction myelography) disclose extradural CSF.5

Headache is the most common symptom in any acute or chronic phase after traumatic brain injury (TBI). Headaches usually resolve within 6 months. Minority of patients continue to experience headaches, often attributed to PTH. PTH may resemble migraine, tension, or cluster headache.49

Due to TBI, microglia are activated. The secretion of CGRP and NO may lead to trigeminovascular system activation and may trigger migraine-like headaches.50 TBI may induce glutamate release from astrocytes and microglia. Excessive glutamate release may lead to neuronal excitotoxicity, which may trigger CSD and generate central sensitization.51 CSD has been described in other pathological conditions besides migraine and TBI, such as stroke, epilepsy, and intracranial hemorrhage.52 Structural brain damage has been described even in minor TBI, and any injury at any stage of pain pathways, including spinothalamic or thalamocortical pathways, may be a source of central pain.53

SAH causes severe “thunderclap” headache.54 Headache is mostly (55%) reported in occipital location in the SAH group. Headache is described as “stabbing” (35%), meningismus in 80%.54 Headache may be the only symptom in one third of the SAH patients. Headaches are generally bilateral, and 19% of patients noted gradual increase in severity, as opposed to the thunderclap onset. SAH is usually associated with nausea and vomiting, but 36% of patients do not even have a stiff neck.55 Twenty five percent of SAH patients may be misdiagnosed as migraine due lack of proper neuroimaging or not performing a lumbar puncture when necessary.5 SAH may also trigger migraine aura and be relieved transiently by triptans.55 SAH can mimic so-called “crash migraine” or “migraine with a severe sudden onset”, and the “worst migraine ever”.18,56 On the other hand, similar thunderclap headache may be seen in up to 20% of patients with an unruptured cerebral aneurysm. This may result from acute aneurysm expansion in the absence of subarachnoid blood and indicate a higher risk of near future aneurysm rupture.57,58

Headache is reported in about half of the AVM patients.59 Patients report headache localized always in the same side, ipsilateral to the AVM. Twenty percent of parenchymal AVMs are located in the occipital lobe, and migraine-like headaches may be present, regardless of whether they are accompanied by visual symptoms.60 The aura should be differentiated from focal seizure or blood stealing phenomena.18 Frequency of migraine-like headaches, vomiting, and atypical auras is 10%, shorter headache attacks in 20%, seizures in 25%, and unusual signs in 65%.61 Non-pulsatile headache was reported in 95% of patients with AVM, while only 4.7% of them had the trio of nausea, vomiting, and phonophobia. Duration of headache episodes was less than 3 h, with a frequency of 1–2 per month.62

Headache is often the only symptom at onset of cerebral venous thrombosis (CVT).63 In more than 90% of cases, focal neurologic symptoms and / or signs of raised intracranial pressure signs may be present.5 Headache features that raise suspicion for CVT even in patients without papilledema or focal neurologic findings are recent onset of persistent headache, thunderclap headache, and worsened headache with straining, lying down, or Valsalva maneuvers.64 Patients may rarely experience migraine-like visual phenomena.65 In a case series of patients with CVT, 14% reported headache as the only symptom and migrainous features such as throbbing pain in 76%, severe intensity in 76%, unilateral headache in 76% and nausea, vomiting, and/or phono/photophobia in 59%.66

RCVS is characterized by severe thunderclap headache.9 It may be indistinguishable from migraine. Severe, bilateral, throbbing thunderclap headaches accompanied by nausea, vomiting, and photophobia are the most common presenting features of cases.18 About two thirds of cases have an underlying cause such as pregnancy, hypertension, or vasoactive substances or drugs.9

It may occur spontaneously or triggered by cough, exertion, or Valsalva is experienced over about a week. Visual blurring, scotomas, and transient blindness are also common in RCVS.18 Vasospasm may also occur during migraine and lead to infarction, and it is impossible to distinguish from RCVS.67 When stroke or vasospasm are present in multiple arterial territories, the etiology is most likely RCVS or vasospasm due to subarachnoid hemorrhage (SAH).67

SMART syndrome describes stroke-like migraine attacks that occur after radiation therapy for intracranial neoplasms. There are cases in the literature reporting migraine-like headaches accompanied by neurological deficits, such as visual loss, confusion, hemiparesis, hemisensory changes, and dysphasia. Seizures are also more frequent in SMART syndrome. The duration of neurological findings in this syndrome may vary from less than 2 h to as long as 3 months.18

Headache or neck pain is the only symptom in 8% of spontaneous carotid artery dissection (CAD) patients68 and thunderclap headache at onset in 20% of patients.69 CAD can mimic migraine with or without aura, and it may also mimic migraine status.68 The rapid onset of dull pain may sometimes help to differentiate from migraine, but the presence of accompanying visual aura may resemble migraine. The ipsilateral neck pain to a headache or Horner syndrome is alarming, as the headache may precede ischemic manifestations.9 In cases with internal carotid artery dissection (ICAD), headache is usually the first presentation of disease, even 4 days before other neurological features and is more often aching type. In these cases, headache is the clinician's most important clue for diagnóstico, as some patients may present with a stroke several days after dissection. However, patients should be questioned about history of chiropractic maneuvers or mild cervical trauma and newly onset pulsatile tinnitus. The headache is often ipsilateral, and it can be felt in the frontal or temporal zones, extend to ipsilateral ear, chin or orbit. Horner syndrome is reported ¼ of patients. ICAD may have migraineous features such as nausea and vomiting, and aura.18,69 Headaches occur in 70% of vertebral artery dissection (VAD) cases, on average 14.5 h before other neurological features. Usually severe ipsilateral occipito-nuchal throbbing pain or pressure headache is reported. Headache is rarely associated with migraine features such as nausea, vomiting, photophobia, phonophobia, or visual aura.70 VAD is also associated with neck and arm pain, which may mimic the abrupt onset of pain in Parsonage-Turner Syndrome.71

During therapeutic embolization, segmental vascular stimulation may cause headache. It is sudden and reaches a maximum intensity at the beginning of the procedure. The headache is focal, unilateral, ipsilateral to the occluded artery, non-pulsatile, and short duration. Some patients may report delayed (24–72 h after procedure) or longer headache.72

CADASIL is characterized by middle- age onset cerebrovascular disease, and often progresses to dementia due to mutations in the NOTCH3 gene on chromosome 19. Approximately 30% of patients describe typical migraine as the initial symptom, and 80–90% of those may have migraine with aura.18,73

MELAS is a mitochondrial disorder, migraine-like attacks, encephalopathy, lactic acidosis and stroke-like episodes. The high frequency of migraine-like attacks as a part of MELAS has led to the hypothesis that mitochondrial mutations may play a role in migraine with aura.5

Temporal arteritis is usually associated with new onset headaches in patients over 50 years of age.74 Headache may be throbbing or aching, with an acute or subacute onset, and can be persistent or intermittent.75 Factors such as scalp tenderness, jaw claudication, weight loss, fatigue, and myalgia, elevated ESR, and CRP levels are important clues for the diagnóstico.9 Sudden visual loss (unilateral or bilateral) accompanied with proximal polymyalgia symptoms reinforces the suspicion of TA.76 A monocular scintillating scotoma, usually similar to the migraine aura, has rarely been reported.18

Headache can occur immediately or after a delay following acute exposure to an NO donor. Glyceryl-trinitrate (GTN) induced frontotemporal and pulsating headache resolves spontaneously. Tolerance develops within a week, and headaches disappear in most patients. GTN induces immediate headache in most people, but it may cause delayed headache in people with migraine or other types of primary headaches.5

Headache occurring on 15 or more days/month in a patient with a pre-existing primary headache and developing as a consequence of regular overuse (>3 months) of acute or symptomatic headache medication. Medication overuse headache is due to an interaction between an overused therapeutic agent and a susceptible patient who has previously been diagnosed with migraine or tension-type headache. The majority of patients with MOH improve after discontinuation of the overused medication, as does their responsiveness to preventative treatment.5

Headache induced by alcohol is usually bilateral and pulsating in quality. Physical activity may aggravate the headache. The immediate headache develops within 3 h of alcohol ingestion and resolves within 72 h, a delayed alcohol headache may develop within 5–12 h after ingestion and resolve within 72 h.5 The possibility of the diagnóstico of cluster headache should be kept in mind as alcohol may trigger CH attacks.

Caffeine withdrawal headache develops within 24 h after regular caffeine consumption of more than 200 mg/day if consumed for at least two weeks. It recovers spontaneously within 7 days after cessation of caffeine consumption. Headache may also be relieved within 1 h after 100 mg caffeine intake.5 Headache is typically diffuse, severe, throbbing and is aggravated by exercise or Valsalva maneuver.77

Drug- induced migraine type headaches may be due to sex hormones, including intrauterin device with active hormone delivery and oral contraceptives particularly those with higher estrogen concentration, nitroglycerin, phosphodiesterase inhibitors, calcium-channel blockers, dipyridamole, cyclosporin, interferon-beta, ondansetron, tacrolimus, SSRIs (sertraline, fluoxetine), MAO inhibitors, L-dopa, proton pump inhibitors (omeprazole) and nasal decongestants, etc.78,79

Comorbidity of migraine with benign occipital epilepsy or benign rolandic epilepsy is reported.80 The ICHD-3 lists 3 epilepsy-migraine/headache disorders: hemicrania epileptica, post-ictal headache, and migralepsy.5,81 Although migraine-like headaches may occur before a seizure, there are also three types of headache associated with epilepsy, including preictal, ictal, and a postictal headache.82 Ictal epileptic headache is a rare disorder in which migraine or tension- like headache is the only manifestation of seizures. Occipital lobe epilepsies can be associated with migraine-like auras such as visual illusions or vision loss, and approximately half of those with occipital lobe seizures experience post-ictal headache.83 Unlike migraine aura, epileptic visual hallucinations occur within a few seconds, last a few minutes, and often involve colored and circular illusions.18

Acute closed-angle glaucoma is an emergency. Severe pain localized to one eye accompanied by tenderness, blurred vision or vision loss, red eye, or haloes around objects confirm the diagnóstico.9 Patients present with mydriasis during the pain attack. Rarely, subacute angle-closure glaucoma may mimic migraine with or without aura, which can recur over years.84

Hypertension is often associated with a bilateral and pulsating headache, and this pain is related to an acute increase in systolic blood pressure to ≥180 mmHg, diastolic to ≥120 mmHg. It is relieved after normalizing the blood pressure.18 In cases of new migraine-like headaches or worsening migraine, it is essential to check blood pressure.9

Patients with cardiac cephalalgia (CC) experience unilateral or bilateral migraine-like headache which is usually aggravated by exercise, during an episode of myocardial ischemia. Headache is relieved by nitroglycerine.5 Cardiac cephalalgia can be the only manifestation of angina in 27% of cases. Thirty % of cases may describe migraine-like features accompanying headache, such as photophobia, phonophobia, osmophobia, and nausea.85

Dialysis headache develops during a session of hemodialysis and resolves within 72 h. It associated with hypotension and dialysis disequilibrium syndrome. It can present initially with headache and then progresses to obtundation and finally to coma.5

Patients with sleep apnea may experience a morning headache. It is usually bilateral and of pressing quality, with a duration of less than 4 h. The apnea - hypopnea index should be more than 5, and the headache should demonstrate temporal relation with sleep apnea.5

AIWS is a rare migraine aura characterized by an altered body image, as enlarged, diminutive, or distorted. Migraine was reported in 11% of patients, and Epstein–Barr virus in 48% of patients.86