As most children who present to a physician with headache have primary headache disorders (ie, disorders with no underlying identifiable organic brain disease) such as migraine and tension-type headache, life-threatening headaches may go unnoticed by a busy clinician. In this article, we outline some causes of headache that require rapid recognition, as failure to identify them in an expeditious manner may have devastating consequences for the child and carry a heavy medico-legal burden for the pediatrician.
The first half of this review focuses on headaches that present in a sudden manner, and the second half examines headaches that are of a subacute nature and caused by raised intracranial pressure. Some overlap in the characteristics of headache may occur. Table 1 provides an overview of symptoms, signs, and appropriate imaging modalities that can lead to a definitive diagnosis.
The term “thunderclap headache” (TCH) is applied to a severe, unanticipated headache that quickly (usually within a minute) reaches a crescendo. Adults often describe it as “the worst headache of my life.” TCH was initially used in reference to the pain of an unruptured cerebral aneurysm or the pain associated with subarachnoid hemorrhage. Nonetheless, several disease states have been recognized as presenting with TCH.1 These include (1) leaking intracranial aneurysm “sentinel headache”; (2) pituitary apoplexy; (3) arterial dissection; (4) reversible cerebral vasoconstriction syndrome; (5) posterior reversible encephalopathy; (6) venous sinus thrombosis; (7) hypertensive crisis; and (8) spontaneous intracranial hypotension
Causes of TCH that are commonly encountered in the pediatric age group are addressed in the following text.
Cervical Artery Dissection
Dissection is caused by extravasation of blood into the wall of the artery, leading to occlusion of the vessel distal to the site of pathology, which is a common cause of stroke in children.2–4 Dissection of the carotid or vertebral arteries classically presents with pain at the site of pathology (ie, the affected side of the neck), but may also cause referred pain to the region of the ipsilateral orbit, jaw, and ear. It is estimated that up to 25% of children with dissection present with an explosive headache that is of a thunderclap nature.5 The child may complain of painful pulsatile tinnitus, loss of vision in the affected eye, focal limb weakness on the side opposite to the dissection, tongue weakness, and altered taste. On physical examination, Horner's syndrome (ptosis, miosis, and lack of sweating on the affected side) and a bruit over the dissected vessel are classic signs that can guide the physician to a prompt diagnosis.
Although in most instances an event such as a fall, roller-coaster ride, or unusual stretching of the neck may precede the dissection, several examples of spontaneous dissection or dissection following a bout of coughing or sneezing have been noted.6,7 Interestingly, young adults with migraine are more prone to developing dissection.8
Children with suspected dissection should be referred immediately to the emergency department of a hospital with resources to perform appropriate imaging studies. Diagnosis is established by magnetic resonance angiography (MRA) of the neck that shows tapering of the vessel at the site of the dissection (ie, “string sign” or “flame sign” (Figure 1). Magnetic resonance imaging (MRI) may also reveal stroke in the region of the vascular territory. Patients with confirmed dissection should be admitted for inpatient evaluation, neurological consultation, and, in some cases, neurosurgical consultation. Antiplatelet or anticoagulant therapy is commonly employed in cases of dissection to prevent further occlusion of the affected vessel.
Magnetic resonance angiogram of the brain demonstrating dissection leading to “flame sign” of the carotid vessel and lack of blood flow distally.
Venous Sinus Thrombosis
Headache is the most common presentation of venous sinus thrombosis and occurs in more than 75% of cases.8Although in most instances the pain tends to be insidious and occurs over days to weeks, in about 10% of children the pain is of explosive onset.9 The pain worsens with recumbency and with coughing or sneezing. In addition, there are usually symptoms and signs of raised intracranial pressure, such as vomiting, diplopia, and papilledema. Seizures and stroke-like symptoms occur in up to 50% of children.10 The manifestations of venous thrombosis can be highly varied and mimic that of a brain tumor, stroke, or infection. Children have a particular predilection to venous thrombosis, especially when dehydrated or in the setting of cancer, sepsis, meningitis, hypercoagulable states, and estrogen therapy.11
Over-reliance on computed tomography scans of the brain may miss the diagnosis; therefore, imaging of the veins using magnetic resonance venography (MRV) is preferred. Treatment includes a multidisciplinary approach with involvement of a hematologist, neurologist, and inpatient admission for anticoagulant therapy.
Reversible Cerebral Vasoconstriction Syndrome
Reversible cerebral vasoconstriction syndrome (RCVS) is a condition in which there is transient dysregulation of cerebral vascular tone leading to areas of constriction and microdilatation. RCVS may be a primary entity, or as being increasingly recognized, it may be secondary to a variety of factors. Illicit drugs such as cocaine, sympathomimetics such as pseudoephedrine (a frequent component of over-the-counter cough and cold preparations), selective serotonin reuptake inhibitors, diet pills, oral contraceptives, and binge drinking can be predisposing substances, as can the postpartum state.12 The classic clinical manifestation is an abrupt onset of recurrent headaches that are brief yet extremely painful, occurring for a couple of weeks prior to presentation, sometimes associated with hypertension.13 Often, the headache is accompanied by an altered level of consciousness and/or focal neurological symptoms such as seizures, motor weakness, loss of vision, or aphasia. RCVS can sometimes overlap with another clinic-radiological syndrome referred to as posterior reversible encephalopathy syndrome (PRES), which usually occurs in children with uncontrolled hypertension.
In addition to classic features of “strings and beads” on angiography or MRA, imaging may also reveal stroke or cerebral edema (Figure 2).
Magnetic resonance angiogram of a child with reversible cerebral vasoconstriction syndrome showing beaded appearance of the posterior cerebral arteries.
RCVS should be recognized as a medical emergency that requires immediate admission to an intensive care unit and withdrawal of trigger factors. Initiation of calcium channel blockers or magnesium has been shown to be effective in many instances. Over 90% of patients do well, with complete reversal of neurological manifestations when managed appropriately;14 however some children may develop stroke or hemorrhage and suffer long-term consequences.
A diagnosis of primary TCH can only be made after other etiologies have been excluded by appropriate investigations, including MRI, MRA, and MRV. Normal cerebrospinal fluid (CSF) levels must also be established before one can label a headache as primary TCH. Primary TCH can occur after cough, sexual activity, or physical exertion, but the same meticulous evaluation as discussed earlier must be completed before one can diagnose a pediatric patient with these entities.
Increased Intracranial Pressure
Idiopathic Intracranial Hypertension
Idiopathic intracranial hypertension (IIH), otherwise referred to as pseudutumor cerebri, is a condition characterized by elevated intracranial pressure without ventriculomegaly or evidence of a mass lesion on imaging. Fortunately, the term “benign” intracranial hypertension has been abandoned as it is now recognized that IIH may cause serious consequences in the form of irreversible vision loss. In postpubertal children, obese girls tend to be disproportionally affected, whereas in young children there is equal predisposition in both boys and girls.15,16 Although the term “idiopathic” is used (because in most instances there is no clear-cut predisposing factor), secondary causes such as use of minocycline, vitamin A, and oral retinoids should be actively sought.
Classic symptoms include daily headache that is of a constant, nonpulsatile nature and aggravated by coughing or straining, pulsatile tinnitus (ie, “whooshing” sound in the ear), diplopia due to sixth cranial nerve palsy, and a unique phenomenon referred to as transient visual obscurations. The latter occurs in more than 75% of patients, is characterized by loss of vision for less than 60 seconds at a time, and may affect one or both eyes.17 The most characteristic feature on physical examination is the presence of papilledema, which need not be bilateral.
Evaluation includes urgent brain imaging with MRI and MRV and referral to a neurologist and, in many instances, an ophthalmologist for dilated fundus examination. The absence of space-occupying lesions or enlarged ventricles favors the diagnosis of IIH, although an astute radiologist may identify certain positive features on imaging (eg, flattening of the globe, which is indicative of papilledema or transverse sinus stenosis) that alert the clinician to the correct diagnosis (Figure 3). Confirmation of the diagnosis requires measurement of opening pressure during a lumbar puncture. Values of greater than 28 cm of water, measured in the recumbent position, are considered abnormal in children in the appropriate clinical context.18
Magnetic resonance venogram of the brain in a child with idiopathic intracranial hypertension demonstrating stenosis of the right transverse sinus.
Treatment of IIH in the acute phase consists of acetazolamide, a carbonic anhydrase inhibitor that reduces CSF production. Common side effects of acetazolamide include paresthesia and altered taste. Other medications that have been utilized in IIH are topiramate and furosemide. If the child presents with acute loss of vision (not transient obscurations), immediate referral to a neurosurgeon is critical. Surgical options to reduce CSF pressure may be undertaken to restore vision. The choice of procedure may vary depending on the expertise of the surgeon. Lumbo-peritoneal shunts are avoided in many institutions due to potential risks of infection and need for revisions in the future, although evidence-based guidelines regarding which intervention is most beneficial are lacking. In the long term, weight loss should be encouraged. Repeated lumbar puncture or draining of large volumes of CSF is not usually beneficial.
Neoplasms of the Central Nervous System
Brain tumors are the second most prevalent cancer in childhood. The incidence is 5 to 6.22 per 100,000 in children age 0 to 14 years. Most children younger than age 14 years with brain tumors have low grade gliomas.19 Nearly one-half of all brain tumors of childhood arise below the tentorium (ie, close to the cerebellum and brain stem) and therefore present with relatively easily recognizable signs and symptoms20 (Figure 4).
Magnetic resonance image of the brain. Axial images with contrast, showing subependymal giant cell astrocytoma in a child with tuberous sclerosis impinging on the foramen of Munro.
Headache tends to be the first presenting symptom of intracranial tumors, and when accompanied by certain red flags, appropriate imaging is mandatory. The cardinal associated symptoms include a headache that awakens a child at night from sleep, early morning headaches, posterior/occipital location of pain, projectile emesis, new onset of lethargy or somnolence, and diplopia. Photophobia and phonophobia, as seen with migraines, are unusual with space-occupying brain lesions. Nausea is often seen in children who have tumors that either directly or indirectly (through edema) impinge on the floor of the fourth ventricle where the nausea center, or area postrema, is located. Focal deficits such as cranial nerve involvement, especially restriction of upward gaze, hemiparesis, or ataxia, are signs suggestive of intracranial pathology. An abducens nerve palsy with failure of abduction of the eye is an important physical finding that raises suspicion for increased intracranial pressure. Papilledema is noted in only 41% of children with hydrocephalus; therefore, overreliance on this physical finding should be avoided.21
Importantly, response to treatment with nonsteroidal anti-inflammatory drugs does not exclude a secondary cause for headaches. About 44% of patients with secondary headache report significant reduction of symptoms from nonsteroidal anti-inflammatory drugs and antiemetics.22
In addition to a detailed and directed history and a bedside neurological evaluation, a thorough general physical examination can lead an astute physician to look for certain brain tumors. For instance, hypomelanotic macules, facial angiofibroma, ungual fibromas, or shagreen patches are findings that suggest tuberous sclerosis complex (TSC). These patients may develop a subependymal giant cell astrocytoma (SEGA). SEGA is observed in 5% to 15% of patients with TSC, and can produce clinical symptoms secondary to obstructive hydrocephalus, which include headache, emesis, and cranial neuropathies23 (Figure 5).
Magnetic resonance image of brain in a sagittal view demonstrating astrocytoma posterior to the cerebellum.
A computed tomography scan is indicated in situations in which the child has altered mental status, focal prolonged seizures, and if there are contraindications to MRI. The radiation exposure to the patient, however, limits its use. MRI of the brain, with and without contrast, is the gold standard to evaluate and diagnose a brain tumor. However, there is some evidence that repeated exposure to gadolinium in pediatric patients leads to deposition of contrast in the brain parenchyma.24 The possible long-term neurotoxic effects of contrast deposition have not yet been clearly elucidated.25
Treatment of tumors is based on histology. Most require neurosurgical intervention. Low-grade tumors may only require curative resection whereas atypical or high-grade tumors such as medulloblastomas, require resection, chemotherapy, and/or radiation therapy. Secondary headaches are often difficult to treat in the setting of a brain tumor. Decreasing the edema with steroids can be a helpful preliminary measure.
Infectious etiologies of the central nervous system should be considered when evaluating a patient with acute onset headache in the setting of systemic illness, fever, and/or altered mental status.
Bacterial and viral meningitis can present as severe holocephalic headache with associated photophobia and neck stiffness. In addition, physical examination findings such as tachycardia and hypotension, a generalized rash, and irritation when neck is flexed or legs are raised (ie, Brudzinski and Kernig signs, respectively) may encourage the clinician to pursue testing for meningitis. Encephalitis refers to inflammation of the brain parenchyma and presents with symptoms suggestive of meningitis, including holocephalic headache, but with additional abnormalities in brain function such as altered mental status (drowsiness, irritability), motor or sensory deficits, altered behavior and personality, and seizures. Encephalitis can be caused by viral, bacterial, and autoimmune conditions.
Autoimmune encephalitis is a newly described entity with a progressive clinical course. The hallmark features include headache in association with a constellation of psychiatric and behavioral symptoms such as hallucinations and psychosis, seizures, memory dysfunction with short-term memory loss, speech disorders, and decrease in level of consciousness.26 A conversion disorder is often suspected in such children; therefore, knowledge of this entity is crucial to clinicians.
Brain abscess, although rare, should be considered in the differential diagnosis of a child with localized headache, focal neurological signs, and a recent history of an infection in the central nervous system or other organ systems such as the heart or blood. Clinical situations associated with intracranial abscess include otitis media, mastoiditis, infective endocarditis, and patients who are immune compromised. The edema surrounding an abscess may lead to a headache that is very difficult to treat. Children with a brain abscess also present with symptoms and signs of raised intracranial pressure such as vomiting, papilledema, and abducens palsy, as noted earlier in this article.
MRI findings may aid in the differential diagnosis of an infectious etiology for headache. Herpes encephalitis, for instance, has a propensity to involve the temporal lobes and the frontal lobes.27 MRI of a brain abscess reveals a “ring enhancing” lesion (Figure 6), whereas in autoimmune encephalitis imaging abnormalities may not be present in more than 50% of children.26
Magnetic resonance axial images of the brain in a child with brain abscess and marked surrounding edema (arrow).
Treatment is based on etiology. When an infection of the central nervous system is suspected, the child should be admitted for immediate initiation of antibiotics or antiviral therapy (acyclovir for herpes simplex encephalitis), supportive treatment such as pain management, neurological evaluation, and close supervision. Imaging, spinal fluid analysis, and other laboratory investigations should not take precedence over initiation of treatment and stabilization of airway and circulation.
Structural causes other than a tumor can lead to persistent headaches that are often refractory to medical treatment. Chiari I malformation is one such example. Chiari malformation refers to the downward displacement of the cerebellar tonsils (the inferior-most portion of the cerebellum) into the foramen of magnum24 (Figure 7). The prevalence of Chiari I malformation is estimated to be 0.6% to 0.9% in the general population and about 1% in children.28 Chiari malformation is most often found incidentally when imaging is performed for headache, but it rarely causes symptoms unless the displacement of the tonsil is more than 5 mm in relation to the foramen magnum. Certain systemic diseases such as Ehlers-Danlos syndrome may predispose a child to Chiari lesions.29
Chiari I malformation with herniation of the tonsils of the cerebellum (upper arrow) and associated syrinx in the spinal cord (lower arrow). Magnetic resonance image of the brain and spine sagittal view T2-weighted images.
Pain is present in 60% to 70% of affected children.30 These headaches have a characteristic feature of worsening upon neck extension or with Valsalva maneuvers such as coughing or sneezing. They may also be associated with scoliosis. Young children may show signs of failure to thrive and/or brainstem dysfunction such as respiratory irregularities, dysphagia, cough, and tongue atrophy, in addition to headache. Cerebellar signs such as truncal and limb ataxia may also be seen. Children older than age 3 years often present with neck pain, occipital headache, vertigo, sensory changes such as numbness or pins and needles sensation in their arms and legs, ataxia, syncope, sleep apnea, and drop attack.31
When Chiari malformation is suspected in a child, an MRI of the brain with and without contrast should be performed. Contrast material will help rule out a parenchymal mass that can also cause similar symptoms. If Chiari I malformation is found, the complete spine should be imaged with an MRI with and without contrast to identify a syrinx (a fluid-filled cavity that forms within the spinal cord). A Chiari malformation that is symptomatic requires neurosurgical referral and intervention. Symptoms can recur and patients may need a second decompression. In a series of 256 children with Chiari I malformation, 22% had symptom recurrence and 7% of patients required repeat decompression.32 The patients that benefit the most from a surgical procedure are those who are carefully chosen based on herniation size, anatomy, and clinical symptoms.