Head MRI was normal and ESR was 38 mm/h. The patient had been taking topiramate 100 mg/day for 2 years and indomethacin 75 mg for 5 months with no significant improvement in symptoms. There was a previous history of asthma and hypertension, and the neurological physical examination was normal. After adjusting the dose of indomethacin to 75mg tid the symptoms completely resolved. What is the etiology of headache in these patients? What is the clinical presentation and treatment? What are the similar primary or secondary migraine-like disorders?
Primary headache
1. Continuous migrainous cranial pain (HC).
Both of these patients were misdiagnosed because their symptoms were very similar to migraine, also presenting with new-onset daily persistent headache. 11% of patients with HC may present with unilateral symptoms. 25% of patients may not present with intracranial autonomic-related symptoms, as in the case 1 patient. Both patients were treated with indomethacin but at inadequate doses. A study showed that approximately 52% of HC patients were misdiagnosed with migraine, and 40% of these patients met the criteria for migraine diagnosis during the exacerbation phase. The time from consultation to correct diagnosis was 5 years, and the number of misdiagnosed physicians was 4.6. Patients may also experience unnecessary tooth extractions and paranasal sinus surgery.
HC is a relatively uncommon headache disorder with a prevalence of about 1%, more common in women, and a peak age of onset around 30 years. The pain is usually unilateral, with occasional flank switching, and bilateral pain is rare. 69% of the pain is pulsatile and can be triggered by a variety of factors. It is accompanied by photophobia, phonophobia, nausea and vomiting, and visual aura is rare. Intracranial autonomic symptoms, such as tearing, are present in 75% of patients; nasal mucosal congestion is more common than in migraine patients (56%). Many patients have a previous history of migraine. When pain symptoms are daily or persistent and pain-free for no more than 1 day and for a total duration of >1 year, it can be referred to as chronic HC. a case series reported the incidence of chronic HC to be about 82%.
Indomethacin therapeutic remission is defined as complete symptom relief using indomethacin trials when given at therapeutic doses of 50-300 mg daily, usually at doses <150 mg/day. Very few cases have been reported requiring 300 mg/day for remission. For most patients, the indomethacin trial was conducted by gradually increasing the dose until pain relief as follows: 25mg tid for 3 days; 50mg tid for 3 days; 75mg tid for 3 days; and 100mg tid for 3 days.
Because of the risk of adverse reactions, indomethacin should be treated at the lowest dose that provides symptomatic relief. Because of its damaging effect on the gastric mucosa, it is often given with proton pump inhibitors.
Treatment with other drugs is extremely ineffective in patients who are treated with indomethacin but cannot tolerate it. Studies have shown short-term efficacy rates of 35% and 33% for occipital major nerve block and intravenous dihydroergotamine, respectively, and prophylactic efficacy rates of approximately 41% for topiramate. Other studies have reported potentially effective medications including melatonin, ibuprofen, celecoxib, botulinum toxin, valproic acid, gabapentin, pregabalin, intravenous methylprednisolone, and occipital nerve stimulation.
2. Cluster headache.
Cluster headache can also have migraine manifestations. Although the ICHD-3 diagnostic criteria indicate an attack duration of 15-180 minutes, some studies have reported that the attack may last longer than 4 hours. A report of 155 patients showed that different proportions of patients had migraine-like attacks with features including nausea, vomiting, photophobia, and visual aura. Unlike migraine, 83% of patients exhibited fidgeting during cluster headache attacks.
3. Cluster migraine.
Some patients have both migraine and cluster headache features, but none of them meet the ICHD-3 diagnostic criteria; the term “cluster migraine” is used to define it.
4. New onset daily persistent headache (NDPH).
NDPH is defined as a daily attack from the onset of pain and persistent without relief for 24 hours, with symptoms lasting for more than 3 months. NDPH is associated with many migraine-like symptoms and 20% of patients have a previous history of migraine. Treatment medications and response are similar to those for chronic migraine.
Secondary headache
5. Cerebrovascular disease.
(1) Arteriovenous malformation (AVM).
Postmortem studies show a prevalence of approximately 0.5%. 48% of patients may present with an uncharacteristic headache. patients with AVM may present with migraine-like pain with or without visual symptoms, especially in patients with occipital lobe lesions. Although 95% of AVM patients present with ipsilateral symptoms, a minority of migraine patients may also present with similar symptoms. Since headaches due to AVM are usually atypical migraines, they rarely meet the ICHD-3 migraine diagnostic criteria. 95% of them present as non-pulsatile pain.
(2) Vascular malformations.
Brainstem vascular malformations may be associated with migraine-like attacks, including: brainstem cavernous angioma hemorrhage resulting in contralateral headache; brainbridge cavernous angioma hemorrhage resulting in ipsilateral headache and aura; residual hemorrhage from pontine capillary dilatation resulting in bilateral headache and aura; and brainstem and upper pontine AVM/cavernous angiomalacia hemorrhage resulting in contralateral headache and aura.
(3) Carotid artery entrapment (CAD).
8% of patients with spontaneous CAD may present with only headache or neck pain, similar to migraine-like attacks, without aura; 20% of patients may present with thunderclap-like pain attacks; 60%-95% of patients with internal carotid artery entrapment (ICAD) may present with headache 4 days before the onset of neurological signs and symptoms; 91% of patients with ICAD have ipsilateral headache, mainly in the frontotemporal region, jaw, and ear In 91% of ICAD patients, the headache is ipsilateral, usually stabbing rather than pulsating, and may be accompanied by nausea and vomiting; in 25% of patients, Horner’s syndrome is present, as well as ptosis and miosis.
In 70% of patients with vertebral artery dissection (VAD), headache and neck pain are present 14.5 hours before the onset of neurological signs and symptoms. However, it is rarely accompanied by migraine-like features such as nausea, vomiting, photophobia and phonophobia.
(4) Cerebral venous thrombosis.
Headache is the most common manifestation of cerebral venous thrombosis (CVT) (80-90% of patients) and can be the only symptom or the first symptom. A case series study that included 123 patients with CVT showed that patients presented with a variety of migraine-like features, including pulsating, severe pain, mostly unilateral, with photophobia, vomiting, and in a very small number of patients, visual aura. If the patient has recent persistent headache or thunderclap headache, and the pain worsens during exertion, sleep, or Valsalva movements, CVT should be suspected.
(5) Reversible cerebral artery constriction syndrome (RCVS).
RCVS occurs in about 60% of patients after postpartum or exposure to vasoconstrictive drugs. 94% of patients have severe bilateral, throbbing, thunderclap headaches with nausea, vomiting, and photophobia for an average of 1 week, either spontaneously or triggered by other actions. One of the features of RCVS is transient vasoconstriction, which may resolve within 1-3 months.
(6) Temporal arteritis (TA).
The possibility of TA needs to be considered in patients older than 50 years with new onset headache. The incidence is approximately 29.6/100,000/year in people over 70 years of age. 72% of patients have headache as the most common symptom and 33% have headache as the first symptom. The pain is pulsating or stabbing in nature, acute or subacute in onset, may be persistent or intermittent, varies in intensity, and may be located anywhere on the head.
(7) Subarachnoid hemorrhage (SAH).
About 1/3 of patients with SAH present with headache only, usually unilateral, and can be located anywhere on the head, starting mildly and gradually increasing in severity. SAH can also be a trigger for migraine with aura. SAH can also be a trigger for migraine with aura and can be relieved by treatment with triton.
(8) Autosomal dominant disease with subcortical infarction and leukoencephalopathy (CADASIL).
CADASIL is caused by a mutation in the NOTCH3 gene on chromosome 19. Migraine attacks may occur in approximately 30% of patients, usually with the first symptom being migraine with aura. Of these patients with migraine with aura, 56% are accompanied by some other less common symptoms, such as simple aura or prolonged aura.
6. Vascular.
(1) Hypertension.
When systolic blood pressure is acutely elevated to ≥180 mmHg or diastolic blood pressure ≥120 mmHg, bilateral throbbing headache usually occurs. Pain may also resolve when blood pressure returns to normal. Mild or moderate chronic hypertension does not cause headache.
(2) Cardiogenic headache or anginal headache.
Patients with myocardial ischemia may experience pain unilaterally or bilaterally in any part of the head during exercise, which may be relieved at rest. Patients with unstable angina may also have headache at rest. 27% of patients with angina may present with cardiogenic headache only; 30% of patients have photophobia and vocal aversion, nausea and other symptoms.
7. Tumor.
Studies have reported that patients with third ventricular colloid cysts, craniopharyngiomas, brain metastases, brainstem gliomas, and pituitary tumors may present with migraine or migraine-like attacks, with or without aura. Ruptured pituitary tumors with hemorrhage may produce acute migraine-like headache attacks; pituitary infarction may present with severe headache, photophobia, and increased cerebrospinal fluid cell count, with initial symptoms similar to aseptic meningitis or meningoencephalitis; up to 15% of primary or metastatic brain tumors may present with migraine-like pain, with normal neurological physical examination and no seizures.
8. Stroke-like migraine attacks after radiotherapy (SMART) syndrome.
A study that included more than 40 patients showed that patients with intracranial tumors can develop migraine-like headache attacks after radiotherapy with other neurological symptoms, including dysarthria, visual impairment, confusion, hemianesthesia, and seizures. MRI showed unilateral cortical gyrus thickening in the area of prior radiotherapy, which can resolve within 14-35 days, and symptoms can last 11-84 days. The mechanism of its occurrence is not clear.
9. Infections.
(1) Acute or chronic ipsilateral pterygoid sinusitis.
It usually leads to pain in a single part of the frontal, temporal, occipital, cephalic, and retro-orbital regions, or these parts simultaneously, often with nausea and vomiting; it is aggravated by movements such as standing, walking, bending, and coughing, with no relief during sleep. More than 50% of patients have fever and 40% of patients have purulent nasal discharge or nasal congestion.
(2) Viral meningitis.
May present with severe bilateral throbbing headache with nausea, vomiting, and photophobia; may not be associated with fever or neck stiffness.
(3) Transient headache, neurological deficit with cerebrospinal fluid lymphocytosis syndrome (H(#ad#)L).
Caused by viral infection resulting in activation of the immune system. The headache is usually throbbing, moderate to severe, bilateral or lateral, and may be accompanied by nausea, vomiting, and photophobia, lasting from 1 hour to 1 week, with a mean duration of 19 hours. 80% of patients have neurologic symptoms confined to one side. 6% of patients have symptoms in the basilar artery distribution, which may last from 5 minutes to 1 week; they may also recur multiple times over days or weeks. The most common focal neurological symptoms are sensory symptoms, speech disturbances, and hemiparesis. 60-70% of patients have elevated lumbar puncture pressure. Cerebrospinal fluid examination shows increased lymphocyte counts and elevated protein levels in up to 96% of patients. All patients recover completely within 1-84 days. Patients with suspected H(#ad#)L syndrome may present with confusion and agitation, both of which are not typical of their presentation, in which case the possibility of other diseases, such as anti-NMDA receptor encephalitis, should be suspected.
(4) Brain abscess.
A meta-analysis that included 9484 patients with brain abscesses showed that 69% of patients could present with headache, 53% with fever, and 48% with focal neurological deficits; the mean duration of symptoms was 8.3 days, and 47% had nausea and vomiting. The headache was moderate to severe and could be aggravated by exertion or Valsalva maneuvers.
10. High or low cerebrospinal fluid pressure disorders.
(1) Pseudotumor cerebri syndrome.
A prospective study showed that 73% of patients can present with daily headache, and 70% of patients present with focal unilateral headache (located in the frontotemporo-occipital lobe or retro-orbital), which can also progress to whole head pain. It varies in severity and is more difficult to differentiate from migraine or tension headache.
A study showed that 41% of patients with idiopathic intracranial hypertension had a previous history of migraine and 17% had a history of migraine with aura. Daily chronic headache due to idiopathic intracranial hypertension without optic papilledema is difficult to distinguish from chronic migraine.
(2) Hydrocephalus.
Obstructive hydrocephalus may lead to migraine-like visual aura attacks, and idiopathic aqueductal stenosis may lead to paroxysmal severe headaches as well as transient visual blindness. Recurrent migraine-like headache attacks are also seen in the lacunar ventricular syndrome.
(3) Spontaneous intracranial low pressure.
It can lead to migraine-like headache symptoms with nausea, vomiting, and sensitivity to sound and light. Although postural headache is the predominant symptom, it may also progress to non-postural daily chronic headache. The pain can be dull, throbbing or pressure pain, varying in severity, usually not always unilateral, and can be located in the frontal lobe, orbitofrontal region, occipital lobe or the whole head.
11. Epilepsy.
Migraine-like headache attacks can occur before, during, and after seizures; 5%-15% of patients with epilepsy will have a pre-seizure headache, 3%-5% of patients may have a seizure headache, and 10%C50% of patients may have a post-seizure headache. Headache during seizures is a rare disorder, with migraine-like or tension headache-like seizures being the only manifestation of this type of epilepsy. Studies have shown that focal epilepsy of occipital lobe origin, nonconvulsive epileptic continuity, and generalized idiopathic epilepsy may present with headache during seizures.
Epilepsy of occipital origin may present similarly to migraine with aura, with visual hallucinations, illusions, and hypermetropia. However, epileptiform visual hallucinations usually occur within seconds and last for several minutes, usually with colored and circular patterns. In contrast, migraine-like visual aura usually occurs within minutes, lasts 5-60 minutes, and is usually non-colored and linear in pattern. For cases that are difficult to identify clinically, an electroencephalogram during the attack can make the distinction.
12. Glaucoma.
In rare cases, subacute, closed-angle glaucoma symptoms can resemble migraine without aura and may recur over several years.
13. Alice in Wonderland syndrome (AIWS).
AIWS is a rare migraine attack with aura in which patients experience distortions and illusions of body perception, including a sense of magnification, reduction and distortion of the entire body and parts of the limbs that the patient knows are not real. The disease is more common in childhood. The etiology may be migraine-like ischemia in the posterior parietal lobe of the nondominant hemisphere. In a review that included 81 patients, 11% were due to migraine and 48% were due to EBV infection. Studies have shown that topiramate treatment may be effective.