Secondary Headaches in Children and Adolescents

Secondary Headaches in Children and Adolescents Nicholas S. Abend, MD,* Donald Younkin, MD,* and Donald W. Lewis, MD† A majority of the children presented for evaluation of headache complaints, will have one of the primary headache disorder such as tension-type or migraine. During the course of the evaluation, consideration must be given to the diverse collection of other medical and systemic disorders which may also cause headache in children and adolescents. The purpose of this article is to review the spectrum of secondary headaches. In majority of the instances, a thorough medical and headache history coupled with physical and neurologic examination will uncover clues to the presence of these other disorders. This will also guide clinical decision making regarding the need for further diagnostic testing, including neuroimaging, electrophysiological testing, or specific laboratory testing. Semin Pediatr Neurol 17:123-133 © 2010 Elsevier Inc. All rights reserved.

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he International Headache Society classifies headaches into the 3 broad categories, including primary headaches (eg, tension type and migraines), cranial neuralgias (eg, trigeminal neuralgias), and secondary headaches (eg, neoplasms and idiopathic intracranial hypertension [IIH]).1 The focus of this article will be secondary headaches in children and adolescents; other sections of this monograph will cover primary headaches. We review the diverse collection of medical and systemic causes of headache in children according to the International Classification of Headache Disorders (ICHD-II). In the majority of instances, a thorough medical and headache history coupled with a physical and neurologic examination will guide clinical decision making as to the need for ancillary diagnostic testing, including neuroimaging, electrophysiological testing, or specific laboratory testing.

Headache Attributed to Head and/or Neck Trauma Any headache emerging within close proximity to head or neck trauma requires careful consideration for intracranial processes, such as subarachnoid hemorrhage, subdural hematoma or epidural hematoma, and vigilant evaluation for craniocervical injury. If suspected, an emergent noncontrast computed tomography (CT) scan of the head and cervical From the *Division of Neurology, the Children’s Hospital of Philadelphia University, Philadelphia, PA. †Department of Pediatrics, Children’s Hospital of The King’s Daughters, Eastern Virginia Medical School, Norfolk, VA. Address reprint requests to Donald W. Lewis, MD, Children’s Hospital of The King’s Daughters, Division of Pediatric Neurology, 850 Southampton Avenue, Norfolk, VA 23510. E-mail: [email protected]

1071-9091/10/$-see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2010.04.001

spine x-rays is (are) warranted. If focal neurologic symptoms or signs are present, then evaluation for vascular injury (ie, carotid dissection) may be indicated and detection may require specific magnetic resonance imaging (MRI) sequences (magnetic resonance angiography or T1 fat-saturated images or the neck). Posttraumatic headache is defined as a headache that begins within 2 weeks of closed head injury. Posttraumatic headache is furthermore divided into acute posttraumatic headache if the symptoms have been present ⬍3 months and chronic if symptoms present ⬎3 months. The precipitating head injury is considered “mild” if the loss of consciousness is ⬍30 minutes and “moderate or severe” if loss of consciousness is ⬎30 minute, the Glasgow Coma Scale is ⬍13, and/or the accompanying amnesia last ⬎48 hours. Chronic posttraumatic headache can be associated with dysequilibrium, irritability, depression, sleep disorder, and poor concentration. The prognosis for posttraumatic headaches in children and adolescents is good with most patients recovering within 3 to 6 months. A trauma-triggered migraine can be initiated by mild head injury, and the key features are aura (eg, visual, cognitive, motor or sensory), with a duration of 1 to 72 hours, frontal or unilateral location, moderate to severe pain, aggravation by routine activities, nausea and/or vomiting, and photophobia and phonophobia. A particular subset of posttraumatic migraine is termed “confusional” or “footballer’s migraine” wherein mild head injury triggers an acute confusional state, often with agitation, accompanied by a headache with migraine features. A recent prospective study of 117 children (81 males, 36 females; range, 3-15 years [mean age, 8.5 years]) admitted with a closed head injury (minor 79%, major 21%) found 123

124 that 8 (7%) children (5 males, 3 females; mean age, 10.5 years) reported chronic posttraumatic headaches. Five (4%) children had episodic tension-type headache, and 3 (2.5%) had migraine with or without aura. Headache resolved over 3 to 27 months in all patients.2

Headache Attributed to Vascular Disorders Hypertension It is unclear whether hypertension (HTN) alone causes headache in children. Furthermore, children with HTN often have coexisting renal or endocrine disease (ie, chronic renal failure and pheochromocytoma). Pheochromocytoma most commonly presents with sudden-onset headache that is often severe, frontal or occipital, and lasts less than 15 minutes to 1 hour in most patients. Other common adrenergic symptoms are tachycardia, diaphoresis, tremor, and anxiety. HTN has also been reported in association with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which can present with headaches. HTN is more frequent in adults with chronic migraine than episodic migraine headache, but no such correlation has been identified in children. HTN has also been reported to cause headache in posterior reversible encephalopathy syndrome (PRES). PRES denotes a hypertensive encephalopathy manifest as imaging changes that are most prominent in the posterior white matter but that may extend to other areas and also include gray matter. The pathogenesis of PRES is thought to be related to vascular injury caused by a toxin or HTN resulting in altered cerebral autoregulation and the development of vasogenic edema. The most frequent clinical manifestations in children are seizures, visual disturbances, headache, or altered mental status, and most children manifest several of these signs. Treatment is aimed at correcting the underlying condition or stopping the offending medication (ie, cytotoxic or immunosuppressive medications) and reducing blood pressure, often using short-acting intravenous antihypertensive agents. It is important to consider that headaches may be part of the prodrome of hypertensive encephalopathy.3

Patent Foramen Ovale Although there are no data on patent foramen ovale (PFO) and migraines in children, studies in adults have suggested an association between PFO and migraines with aura. As summarized recently, PFO is found in about 50% of adults with migraines with aura and in 20% of the general population. Furthermore, PFO is thought to contribute to cryptogenic strokes by allowing small thrombi to pass to the brain without being filtered by the pulmonary circulation. The incidence of migraine is about 50% in adults with cryptogenic stroke versus 12% of the general population.4 Small studies have shown that PFO closure because of cryptogenic stroke improves migraines in some patients, but at present there are insufficient data to determine whether children with mi-

N.S. Abend, D. Younkin, and D.W. Lewis graines with aura should be evaluated for PFO and whether PFO closure would have any impact on migraine.

Vascular Dissection Neck pain and headaches are frequent symptoms in children with cervicocephalic vascular dissection, occurring in 68% with carotid artery dissection (47% as initial manifestation) and 69% with vertebral artery dissection (33% as initial manifestation) and may precede ischemic symptoms by hours or days (mean 4 days for carotid dissection and 14 hours for vertebral dissection).5 The headache is often constant, nonthrobbing, and unilateral (ipsilateral to the dissection), but throbbing, thunderclap, and gradually worsening headaches have been reported. Headaches generally last several days but may persist for months to years. Risk factors for arterial dissection include genetic disorders resulting in abnormal vessel walls (eg, Ehlers-Danlos syndrome, fibromuscular dysplasia, alpha-1-antitrypsin deficiency, Marfan syndrome, and homocystinemia), infection, coughing or vomiting, intraoral trauma, chiropractic manipulation, sports injury, and trivial neck turns or injury. A recent review of a pediatric stroke registry showed that head or neck trauma was present in 50%, and 38% had warning symptoms including headaches (44%), altered consciousness (25%), seizures (12.5%), and focal deficits (87.5%).6 Arterial dissection with focal neurologic symptoms must be differentiated from complicated migraines. Diagnosis is generally made by MRI/magnetic resonance angiography and may require specific neck sequences (T1 fat-saturated images). Treatment may involve emergent anticoagulation with heparin followed by several months of oral anticoagulation.

Headaches Attributed to Nonvascular Intracranial Disorders Idiopathic Intracranial Hypertension (Pseudo-tumor Cerebri) This subject is covered by Gladstein and Pakalnis elsewhere.

Intracranial Hypotension Low-pressure headaches may occur after lumbar puncture (LP) or other processes that cause a tear in the dura, including penetrating trauma or surgery. The cardinal clinical feature is orthostatic headache; the appearance of a severe pounding, nauseating headache upon standing or sitting; and a resolution of symptoms when the patient lies down. Specific diagnostic criteria are available (Table 1). Although most post spinal tap headaches resolve spontaneously, the persistence of disabling symptoms may necessitate consideration of a “blood patch” or other technique to repair the source of the CSF leak.

Mass Lesions (Neoplasm and Abscess) and Hydrocephalus Mass lesions, such as a brain tumor or an abscess, may produce increased intracranial pressure (ICP) and headaches not only by virtue mechanical pressure or traction on pain sen-

Secondary headaches Table 1 Diagnostic Criteria for Intracranial Hypotension7 A. Diffuse and/or dull headache that worsens within 15 minutes after sitting or standing, fulfilling criterion D and with 1 of the following: 1. Neck stiffness 2. Tinnitus 3. Hypacusia 4. Photophobia 5. Nausea B. At least 1 of the following: 1. Evidence of low CSF pressure on MRI (eg, pachymeningeal enhancement) 2. Evidence of CSF leakage on conventional myelography, CT myelography, or cisternography 5. CSF opening pressure 60 mm H2O in sitting position C. No history of dural puncture or other cause of CSF fistula D. Headache resolves within 72 hours after epidural blood patching

sitive structures but also by blockage of CSF pathways, venous outflow, or production of cerebral edema. Vasogenic edema around a tumor or an abscess is produced by leakage of plasma proteins and fluid through a damaged blood-brain barrier at the level of the endothelial cell. Caution must be exercised before an LP is performed in a patient with a suspected neoplasm or an abscess because the risks of transtentorial herniation are high because of the extensive unilateral white-matter edema. If these are suspected, imaging is often warranted before the LP is performed. Although there is no “characteristic” headache pattern of a brain tumor headache, the pattern is generally chronic and progressive, worsening over weeks or months (generally ⬍8 weeks), variably accompanied by nocturnal or morning nausea and vomiting, diplopia, ataxia, declining school performance, personality changes, and possibly seizures. Special consideration of a brain tumor must be given in children with neurofibromatosis and tuberous sclerosis. Brain abscesses usually present as mass lesions, producing focal neurologic signs and increased ICP. Symptoms of infection, including fever, malaise, anorexia, and stiff neck, may be subtle or absent. Brain edema around an abscess is usually severe and extends into the surrounding white matter. The diagnosis of a brain abscess is suspected in children with chronic cardiac or pulmonary disease that may embolize infected material to their brains. Hydrocephalus, with or with obstruction, usually produces a slowly evolving headache syndrome with increased ICP over weeks or months. The enlarging ventricles and interstitial edema in the periventricular white matter exert pressure. The edema is created by transudation of CSF through the ependymal barrier. As described earlier, the headache may initially be primarily nocturnal or noted in the early morning. In children with a ventriculoperitoneal shunt and headache, shunt malfunction must be considered because this may lead to rapid elevation in ICP, leading to herniation, and may require urgent surgical intervention. Neurosurgical

125 consultation, head CT and shunt imaging, and measurement of shunt pressure may be indicated.

Seizures Seizure-related headaches are covered by Kossoff and Andermann elsewhere.

Chiari Malformation Chiari malformations (type I) are among the most common incidental findings when performing neuroimaging in children with headache and are the source of a great deal of controversy. Tonsillar ectopia of 5 mm or less is not considered pathologic. Symptoms associated with Chiari I include occipital headache, neck pain or stiffness, arm weakness, and gait abnormalities. The headache may be aggravated by neck flexion or extension or Valsalva maneuver. Basal skull abnormalities or scoliosis may be identified. In a retrospective MRI analysis of 49 children with Chiari I malformation, 57% of children were asymptomatic. Headache and neck pain were the most frequent complaints. Syringomyelia was detected in 14% of patients and skull-base abnormalities in 50%. The magnitude of tonsillar ectopia (5-23 mm) correlated with severity score (P ⫽ .04) but not with other clinical measures. Children with greater amounts of tonsillar ectopia on MRI are more likely to be symptomatic.8 Vigilance must be exercised before embarking on surgical decompression. MRI with CSF flow studies may help to determine if suboccipital decompression is necessary.

Headache Attributed to a Substance or Its Withdrawal Many substances can cause headache. We list the most common and interesting substances that we see in our practice (Table 2).

Alcohol Although not frequently considered, adolescents are using alcohol at younger ages, and headache may occur during both the ingestion and hangover period. Potential mechanisms include vasodilation and altered serotonin metabolism. Alcohol may also precipitate migraine and cluster headaches. A recent survey study in children showed headache was more common in those using alcohol.9

Carbon Monoxide Carbon monoxide (CO) is a colorless, odorless, nonirritating gas. CO poisoning may occur when defective or improperly maintained gas heating and cooking appliances are used, especially in poorly ventilated areas because of fire and smoke exposure or because of purposeful exposure from car exhaust. Rare cases have been reported in people riding in the back of pickup trucks, riding in or swimming near boats, near ice-rink resurfacing machines, or near camping stoves. CO is also produced after exposure to methylene chloride, which is found in aerosol propellants and paint removers and is converted to CO by liver metabolism.

N.S. Abend, D. Younkin, and D.W. Lewis

126 Table 2 Medications Associated With Headaches Condition

Medication Considerations

Arrhythmia Asthma Cancer Cardiac failure Constipation Coronary artery disease Hepatic disease

TCAs may prolong QT internal or be proarrhythmic. Beta-blockers may worsen reactive airway disease. Medications affecting CYP enzymes may cause toxicity or reduce chemotherapeutic efficacy. Calcium channel blockers may have negative ionotropic effect. TCAs and anticholinergics and verapamil may worsen. Ergots and triptans may cause vasoconstriction. Acetaminophen and chlorpromazine and ASA and phenytoin and valproic acid and carbamazepine and topiramate are associated with hetapotoxicity. Medications metabolized by P450 may have increased levels due to reduced metabolism. CYP-3A4 affecting medications may alter antiretroviral levels. Valproic acid and TCAs and cyprohepatidine may cause weight gain. Topiramate may cause weight loss. NSAIDs may worsen renal function. Meperidine may produce toxic metabolites, SSRIs may worsen hyponatremia. Ergots and triptans may cause vasoconstriction. ASA and NSAIDs may affect coagulation. CYP-3A4 affecting medications may alter immunosuppressant levels.

HIV Obesity/eating disorders Renal disease SIADH Stroke/TIA Thrombotic disorders Transplantation

TCA, tricyclic antidepressants; ASA, aspirin.

CO binds to hemoglobin with a much higher affinity than oxygen and produces a leftward shirt in the oxygen hemoglobin dissociation curve, thereby decreasing oxygen delivery and producing tissue hypoxia. Although this mechanism likely plays some role CO likely also produces direct toxicity at the cellular level.10 CO may bind to heme-containing proteins other than hemoglobin, such as cytochromes and guanylyl cyclase. By binding to cytochromes involved in mitochondrial function, CO may directly alter oxidative metabolism and thus produce oxygen-free radicals. Thus, cellular metabolism may be altered even after normalization of CO hemoglobin levels. By binding to guanylyl cyclase, CO may cause vasodilation resulting in neurologic dysfunction. CO poisoning commonly presents with acute global pounding headache and confusion. Detecting CO related headache early may present the development of more severe and irreversible injury, including cerebral and myocardial infarction, coma, and death. Headache has been shown to resolve more slowly than the other early symptoms, and, thus, in a mild exposure, headache may be the only symptom at the time of presentation. Mild symptoms include headache, nausea, emesis, dizziness, and blurred vision. Moderate symptoms include confusion, syncope, chest pain, dyspnea, weakness, tachycardia, tachypnea, and rhabdomyolysis. Severe symptoms include palpitations, dysrhythmias, hypotension, myocardial ischemia, cardiac and respiratory arrest, pulmonary edema, seizures, and coma. Diagnosis may be made by blood carboxy-hemoglobin level. Normal levels are 1% to 3% although smokers may have levels of 10%. Low levels (⬍20%) may present with nausea and headache while high levels (⬎70%) have a more severe presentation and are often fatal. Middle levels are less well correlated with symptoms with wide overlaps between blood levels and symptoms. CO levels decline with time and

oxygen exposure, so remotely measured blood levels may not be reflective of the true exposure. Furthermore, as described earlier, not all manifestations are a result of CO-hemoglobin binding. MRI may show characteristic bilateral globus pallidus lesions. Screening for cardiac arrhythmias, rhabdomyolysis and acute renal failure, and noncardiogenic pulmonary edema may be warranted. Polycythemia and cardiomegally may occur with chronic exposure because of chronic hypoxia. If CO poisoning is suspected, then all gas appliances at home must be checked. Diagnosis may also be suspected if coinhabitants have similar symptoms. Treatment is with high-flow oxygen to improve dissociation of CO from hemoglobin. There remains controversy regarding whether the oxygen should be administered under increased pressure referred to as hyperbaric oxygen therapy (HBOT). HBOT has been shown to improve dissociation of CO from hemoglobin and other heme-containing proteins in animals, and several human studies have shown a benefit to HBOT. HBOT is often considered for patients with neurologic findings, such as altered mental status, coma, or seizures but not just headaches. HBOT is sometimes used if symptoms persist despite normobaric oxygen administration. After the initial diagnosis, close follow-up is warranted because there may be recovery from acute poisoning followed by delayed behavioral and neurologic effects after days to months. Manifestations include memory loss, confusion, ataxia, seizures, urinary and fecal incontinence, emotional lability, disorientation, hallucinations, Parkinsonism, mutism, cortical blindness, psychosis, and gait and other motor disturbances Delayed effects occur in about 3% of patients and are more likely in older patients and those with more severe initial presentation (especially with coma). Issues related to pathogenesis, presentation, and treatment have been recently reviewed.11

Secondary headaches

Lead The main sources of lead exposure are paints, water, food, dust, soil, kitchen utensils, and leaded gasoline. Deficits in hearing and intellectual function may be seen with lead levels as low as 10 to 20 ␮g/dL. Within the nervous system, low levels of exposure (⬍5 ␮g/dL) may cause headache, poor attention, decreased play activity, school problems, and lower intelligence quotient. At higher levels (⬎100 ␮g/dL), lead encephalopathy may occur, presenting with emesis, impaired consciousness, coma, seizures, and papilledema. In young children with headaches and possible lead exposure, checking a lead level may not only lead to treatment that improves headache but also reduces the likelihood of other lead-related deficits.

Solvents Organic solvents may be abused (glue sniffing) and can cause symptoms similar to an alcohol hangover with headache, malaise, and emesis. Diagnostic clues may be lesions around the nose or mouth and unusual odors.

Caffeine Excessive caffeine intake in the forms of coffee, tea, or soda is common in children, and headaches are associated with both excessive consumption and withdrawal of caffeine. Caffeine is a known risk factor for headache in children. Studies have shown that many children with chronic daily headaches and high caffeine containing soda consumption experienced resolution of headache when soda was gradually withdrawn. A study of 26 children between the ages of 9 to 11 years showed that children with high caffeine intake had headaches after a brief period of abstinence, which was rapidly reversed by caffeine administration.12 Some over-the-counter analgesics contain caffeine as a component and must be avoided when withdrawing caffeine. Amitriptyline may reduce headaches during the withdrawal period.

Iron Iron deficiency is known to have multiple neurologic manifestations, including pseudo-tumor cerebri, which can be reversed with iron administration. Iron deficiency has also been associated with burning mouth syndrome. Other common manifestations of iron deficiency include developmental delay, stroke, breath-holding episodes, and cranial nerve palsies.13 One case study reported the association of iron overload (hereditary hemochromatosis) with headaches that improved as iron stores were reduced.14

Headache Attributed to Infection Viral Uri Headaches are frequently a component of viral upper-respiratory tract infections. About 40% of children presenting to the emergency department with headache have viral infections.15 The headaches are nonspecific and associated with malaise and fever. If there is any possibility of meningitis or

127 encephalitis, CSF must be analyzed. Headaches secondary to viral infection are treated with antipyretics and nonsteroidal anti-inflammatory medications.

Rhinosinusitis The maxillary and ethmoid sinuses are present from birth and are the most commonly involved sinuses in children. The frontal sinus develops at about 6 years of age and the sphenoid sinus develops during puberty. Mucus within the sinuses traps debris, which is then transported out of the sinuses to the nasal passages by beating cilia. When mucociliary flow is obstructed by mass lesions, congenital anomalies, or mucus because of a virus infection or allergies, bacteria can multiply behind the obstruction resulting in bacterial sinusitis. The American Academy of Otolaryngology–Head and Neck Surgery classification system proposes that the diagnosis of rhinosinusitis (RS) is made by 2 major criteria (purulent nasal discharge, nasal congestion, facial pain/pressure, and fever) or 1 major criteria and 2 minor criteria (cough, headache, halitosis, and earache).16 According to IHS criteria, to qualify as headaches associated with RS, there must be a frontal headache accompanied by pain in the face, ears, or teeth; evidence of acute or acute on chronic RS (by CT, MRI, nasal endoscopy, or clinical criteria); simultaneous onset of headache/facial pain and RS; and resolution within 7 days of successful treatment of RS. Thus, headache and facial pain alone is not sufficient to diagnose RS. The IHS criteria also state that chronic sinusitis is “not validated as a cause of headache or facial pain unless relapsing into an acute stage.” Sinus disease on neuroimaging and headache alone are not sufficient for diagnosis because a large number of patients with no clinical evidence of RS have radiologic changes consistent with RS. Diagnostic rhinoscopy commonly shows mucosal thickening in the general population but may also show purulent material consistent with acute RS. Pain originating in different sinuses is thought traditionally to localize to different regions although some studies have suggested the lack of such a correspondence. Maxillary sinus pain localizes to the cheek and upper teeth; ethmoid sinus pain localizes between the eyes or within the globe; frontal sinus pain localizes to the forehead and may radiate to the vertex or behind the eyes; and sphenoid sinus pain is more diffuse and localizes to the retro-orbital, vertex, temples, occiput, or neck. Because the sphenoid sinus is very near the middle cranial fossa, pituitary gland, and cavernous sinuses, it requires prompt aggressive management to prevent intracranial complications. Bacterial sinusitis can result in intracranial complications, including meningitis, abscess, osteomyelitis, or venous thrombosis. As reviewed recently, there is great overlap between migraine and sinus-related headache, and many patients diagnosed with RS really have migraines.17 RS pain is often dull and pressure-like, is often bilateral (although it can be unilateral if an anatomical anomaly results in unilateral obstruction), is worse in the morning (because of the development of sinus congestion when supine overnight), lasts for days at a

N.S. Abend, D. Younkin, and D.W. Lewis

128 time, and is not associated with migrainous features (photophobia, phonophobia, nausea, emesis, or visual changes).18 Several studies have shown that most adults diagnosed with sinus headaches in fact have migraine. In 1 study of 100 adults who self-diagnosed sinus-related headache, only 3% actually had sinus-related headache, whereas 86% had migraine or migrainous headache. Of patients diagnosed with migraine, 75% reported cranial autonomic symptoms, such as nasal congestion, eyelid edema, and rhinorrhea that resulted in the initial misdiagnosis of sinus-related headache. Similar studies have not been reported in children. The treatment of nonpurulent sinusitis generally involves a 1-month trial of a nasal steroid and/or a systemic decongestant. The treatment of bacterial sinusitis involves broad-spectrum antibiotics (intravenously if sphenoid sinus is involved), decongestants, possibly steroids to reduce ostial swelling, and sometimes surgical drainage. In treatment failure or recurrent infection, sinus sampling for culture and endoscopic investigation of potential obstructions are indicated.

Lyme Disease Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne (deer tick) infection in the United States, especially in the Northeast and North Central states in the summer months, and frequently affects children. A large study in children showed that headaches are one of the most common manifestations of Lyme disease, occurring in 70% with early disseminated disease, 42% with early localized disease (single erythema migrans lesion), and 31% with late presenting disease. However, headache was never an isolated presenting symptom and always occurred in the context of multiple other systemic symptoms. There was often no known tick bite. Treatment with antibiotics generally led to symptom resolution in 1 week.19 A recent study compared children with lyme and aspectic meningitis and found that those with lyme had headache duration longer than 3 days (59% vs 25%) in addition to more frequent cranial neuritis and elevated CSF monocytes (⬎86%).20 Lyme disease can cause elevated ICP and can present with papilledema, chronic headache, nausea, emesis, and photophobia in the absence of usual systemic and neurologic manifestations of lyme. These children may develop permanent vision loss and can be treated effectively with antibiotics and acetazolamide,21 thus necessitating a high degree of suspicion for this potentially dangerous but reversible condition.

Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Headaches may occur as part of the initial human immunodeficiency virus (HIV) infection.22 Headaches as a component of acute HIV infection are frequently associated with other viral symptoms, including fever, fatigue, myalgias, arthralgias, night sweats, weight loss, rash, pharyngitis, lymphadenopathy, oral or genital ulcers, emesis, and diarrhea. The headache can last from days to a month and is frequently associated with photophobia. Laboratory findings at seroconversion include leukopenia, thrombocytopenia, and ele-

vated transaminases. HIV may also cause acute or chronic aseptic meningitis with high CSF lymphocytes and protein; meningitis can occur at the initial seroconversion or later. Headaches in patients with HIV can also be secondary to intracranial infections, usually caused by toxoplasmosis, Cryptococcus, tuberculosis (TB), cytomegalovirus (CMV), or lymphoma.

Headache Attributed to Homoeostasis or Other Medical Disorders Hypoxia Hypoxia has many causes, including pulmonary disease, cardiac disease, anemia, high altitude, or obstructive airway conditions. Low oxygen (PO2 below 70 mm Hg) may cause headaches by inducing cerebral vasodilatation with resulting increased cerebral blood flow and increased ICP. The headaches are often bifrontal and throbbing and may be worsened by exertion, straining, or laying down. Acute mountain sickness (AMS) may result in headaches in children and is often associated with anorexia, emesis, fatigue, insomnia, shortness of breath, and dizziness. Above 2,835 m, AMS occurred in 28% of children.23 AMS may be treated with acetazolamide or dexamethasone or by descending to a lower altitude.

Hypercapnia Plasma CO2 levels above 50 mm Hg may induce headaches that are global and throbbing. Treatment consists of correcting the underlying metabolic or respiratory abnormality.

Hypoglycemia Hypoglycemia may result in a nonspecific headache in patients without primary headache disorders and may also trigger migraine headaches.

Fasting and Dieting Fasting is common in children either because they are dieting or have irregular schedules. The ICHD-II diagnostic criteria for headaches attributed to fasting are listed in (Table 3).

Table 3 Diagnostic criteria for fasting headache A. Headache with at least one of the following characteristics and fulfilling criteria C and D: 1. Frontal location 2. Diffuse pain 3. Non-pulsating quality 4. Mild or moderate intensity B. The patient has fasted for >16 hours C. Headache develops during fasting D. Headache resolves within 72 hours after resumption of food intake Comment: Headache with fasting is significantly more common in individuals with a prior history of headache. In those individuals with a prior history of migraine, the headache may resemble Migraine without aura.

Secondary headaches Fasting is associated with a nonpulsatile frontal headache in about 40% of adults. Those with a history of recurrent headache are more likely to develop fasting-related headache. Headaches appeared within 1 hour of fasting in some patients but generally took about 12 hours to develop. The fastingrelated headaches are not caused by hypoglycemia.24 Children must be asked about diet and meal schedules as part of a headache evaluation because fasting may cause headaches or trigger headaches in those with primary headache disorders.

Chronic Renal Failure and Dialysis Most patients with chronic renal failure complain of headaches, usually migraines, and less frequently of tension-type headaches or headaches secondary to HTN. Headaches usually improve with dialysis. However, dialysis can cause de novo secondary headache and/or trigger migraine. Headaches occur in most adults receiving dialysis but in only 14% of children. Dialysis disequilibrium syndrome occurs during or immediately after dialysis. Mild cases have headache, nausea, and muscle cramps but can progress to obtundation, seizures, and coma.25 The pathogenesis remains unclear, but cerebral edema probably results from a dialysis-induced osmotic gradient between blood and brain or from the accumulation of urea or other idiogenic osmoles in the brain.

Mitochondrial Disorders Causing Headache Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder characterized by ragged red fibers evident on muscle biopsy; normal early development; short stature; seizures; and hemiparesis, hemianopia, or cortical blindness. Diagnosis requires stroke-like episodes (typically before age 40), encephalopathy with seizures and/or dementia, mitochondrial myopathy (evidenced by lactic acidosis and/or ragged red fibers on muscle biopsy) and 2 features, including normal early psychomotor development, recurrent headache, and/or recurrent vomiting. As genetic testing becomes more common, the phenotype of MELAS is expected to expand. The initial presentations are seizures in 28%, recurrent headache in 28%, gastrointestinal symptoms (emesis or anorexia) in 25%, limb weakness in 18%, short stature in 18%, and stroke in 17%. Onset age is ⬍2 years in 8%, 2 to 5 years in 20%, 6 to 10 years in 31%, 11 to 20 years in 17%, 21 to 40 years in 23%, and older than age 40 in only 1%.26 Headaches occur as part of the syndrome in nearly all patients. Neuronal hyperexcitability may contribute to the stroke-like episodes by increasing energy demand causing cortical necrosis if severe or migraine-like symptoms if more mild. The triptan medications are reported to improve headache, possibly working by vasoconstriction that inhibits the release of neuropeptides or inhibiting pain signal transmission. Mitochondrial dysfunction may alter capillary permeability resulting in plasma extravasation that activates trigem-

129 inal fibers resulting in headache and vasogenic edema resulting in the typical imaging findings. Diagnostic genetic testing is available. Making this diagnosis is important because associated features are common and require evaluation. A study of 110 patients with MELAS investigated associated clinical features.27 Short stature occurs in 87% so height and weight must be tracked. Hearing deficits occur in 75%, necessitating audiologic evaluation. Hearing improvement has been reported with cochlear implantation. Ophthalmologic problems occur frequently and require ophthalmologic examination (hemianopsia [79%], pigmentary retinopathy [16%], and progressive external ophthalmoplegia [13%]). Learning disabilities occur in 60% so cognitive and learning testing should be completed. Hemiparesis occurs in 83% and may require physical therapy. Cardiac problems (congestive heart failure [18%], Wolff-Parkinson-White [14%], and conductive heart blocks [6%]) are common and require cardiac evaluation. Diabetes may occur in 5%, requiring screening with fasting serum glucose and a glucose tolerance test. Furthermore, coenzyme Q10 administration may be of benefit in some patients. CADASIL CADASIL is a mitochondrial disorder that usually affects young adults but can be seen in children. It should be considered in patients with subcortical infarcts; migraines (especially with aura); multifocal T2/FLAIR hyperintensities in the deep white matter; and an autosomal dominant family history of migraine, early stroke, and/or dementia. The clinical spectrum varies. Migraines occur in more than a third of patients and are the only manifestation in some. A recent case report described a 14-year-old girl with a 3-year history of episodic headaches, 3 episodes of right hemiparesis, persistent HTN, negative family history, normal MRI, and a Notch3 mutation. This raises the possibility of screening for CADASIL in children with headaches and hemiplegia episodes (suggestive of complicated migraine) even when MRI is normal and family history is negative.28

Thyroid and Parathyroid Dysfunction A study in adults with newly diagnosed hypothyroidism showed headaches in 30%, which were often bilateral, nonpulsating, continuous, and mild intensity. Headaches resolved in about half of the patients within 2 weeks of initiating thyroid-replacement medications and resolved in all within 1 year.29 Hashimoto thyroiditis commonly presents with headaches. A recent review of reported pediatric cases found that headache never occurred in isolation. The median age was 14 years, and only 2 patients under 10 years old have been reported. The most common presentations included seizures, psychiatric disturbances, and recurrent hemiparesis. The neurologic symptoms are related to autoimmune encephalitis and can be diagnosed by elevated antibodies titers to the thyroid microsomal antigen or thyroid peroxidase. The diagnosis is not related to the thyroid status, and the level of antibodies does not correlate with disease severity. Early di-

130 agnosis is important because if treated early with immune suppression the condition is fully reversible. Hyperparathyroidism is known to cause severe headaches, and a headache is the presenting symptom in 35% of children. Other common presenting symptoms include fatigue and lethargy, nephrolithiasis, nausea, abdominal pain, vomiting, and polydipsia. Parathyroidectomy is the treatment of choice in most children. In children, the average time between the onset of symptoms and diagnosis is 2 years, but early diagnosis may reduce the incidence of end organ damage, which occurred in 44% and included nephrocalcinosis, nephrolithiasis, and bone involvement.30

Sleep Disorders Headaches and sleep disorders are related. Obstructive sleep apnea may cause morning or nocturnal headaches. Polysomnography is recommended for patients with poorly defined nocturnal or awakening headaches. Identifying and treating obstructive sleep apnea can lead to improvement in chronic headaches. Children with headaches have a high occurrence of cosleeping with parents and a higher frequency of disturbances in sleep quality, night-time awakenings, and daytime sleepiness. Children with migraines have frequent parasomnias and sleep breathing disorders. Children who received instruction in improving sleep hygiene had significantly reduced frequency and duration of migraine headaches.31 A recent survey study of 64 children with headaches compared with controls showed a higher prevalence of excessive daytime sleepiness, narcolepsy, and insomnia but not sleep apnea or parasomnias.32 Serotonin abnormalities have been linked to migraines, headaches, and rapid eye movement sleep disorders and may explain the link between headaches and sleep disorders.

N.S. Abend, D. Younkin, and D.W. Lewis of many strokes is delayed because children are assumed to be having a typical pain crisis. Therefore, a detailed neurologic examination is required for all children with SCD presenting with acute or worsened headache. Prompt treatment and stroke management, including transfusion, are critical. SCD is a risk factor for moyamoya disease. A recent study of children with moyamoya showed that 44 of 204 had headaches before bypass surgery. After bypass, 24 of those 44 still had headaches, as did 10 of 160 who did not have preoperative headache. The authors suggested that because headaches continued after reperfusion, headaches could not be only caused by cerebral ischemia but must also relate to the recruitment and redistribution of blood flow.34 A headache has been reported as the presenting symptom of moyamoya in children with SCD, showing the need for careful evaluation of any child with SCD and headaches. Anemia Headaches may occur after acute blood loss or in chronic anemia, possibly because of vasodilation. Headaches related to sickle cell anemia were discussed previously. IIH has been reported in children with anemia because of SCD, aplastic anemia, and iron-deficiency anemia.

Obesity is covered elsewhere by Pakalnis and Gladstein.

Systemic Lupus Erythematosus Neuropsychiatric manifestations are common in children with systemic lupus erythematosus (SLE) and include headaches, psychiatric disorders, seizures, behavioral abnormalities, and stroke. The neuropsychiatric manifestations may be the initial presentation of sole. Although 32% of SLE patients have migraines and 24% have tension-type headaches, a recent meta-analysis concluded that there was no evidence of a particular “lupus headache,” and no specific association could be found between SLE severity and headaches.35 Children with SLE and headaches require careful evaluation because they are at high risk for intracranial secondary causes of headaches, including infection, hypertensive encephalopathy, venous thrombosis, and cerebritis.

Hematologic Disorders

Gastrointestinal Causes

Sickle Cell Disease Sickle cell disease (SCD) is associated with a high incidence of primary and secondary headaches. A survey study of 50 children with SCD showed that 76% had a headache within a 3-month period, and 31% had headaches occurring more than once per week.33 Headaches lasted a mean of 5 hours. Based on ICHD-2 criteria, 44% had migraine headaches and 50% had tension-type headaches. The overall prevalence of migraine was 33% among 9- to 14-year olds and 47% among 15- to 17-year olds, which is somewhat higher than the migraine prevalence reported by population studies. Migraine headaches were associated with more functional disability in terms of depression and missed school than tension-type headaches. Those children with and without headaches were not different in the types and frequencies of SCD complications, such as stroke, severe anemia, or acute chest syndrome. Children with SCD are also at risk for stroke, which may present with headaches in addition to focal signs. Diagnosis

Abdominal pain is common in children and may be associated with chronic tension-type headaches.36 Both conditions are associated with a high incidence of depression and anxiety. Organic causes of abdominal pain are more likely when there is weight loss, gastrointestinal bleeding, persistent fever, chronic severe diarrhea, and significant vomiting. More general symptoms, such as headache, nausea, anorexia, and joint pain, do not discriminate between organic and functional disease. Organic gastrointestinal diseases may predispose to organic causes of headache, such as inflammatory bowel disease and cerebral venous thrombosis. Irritable bowel syndrome is also associated with nonspecific headaches. Constipation is 1 cause of episodic headaches but will often be denied by children and adolescents. Detecting the condition is important because treating with laxatives can improve the headache. Celiac disease is a multisystem autoimmune disorder that generally presents without neurologic symptoms but can be associated with chronic headaches. In

Obesity

Secondary headaches rare cases, a chronic headache is the only manifestation of celiac disease and resolves completely after initiating a gluten-free diet. Conversely, treating celiac disease with a gluten-free diet may result in headaches.

Headache or Facial Pain Attributed to a Disorder of the Cranium, Neck, Eyes, Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial or Cranial Structures Disorders of the Eye The typical symptoms of asthenopia (eyestrain and weakness of sight) include mild, dull, aching, soreness of the eyes that improves when the eyes are closed, is not present on awakening, and worsens with prolonged visual tasks. The pain is muscular and is caused by constant effort to maintain visual acuity. Asthenopia can occur in nearsightedness, farsightedness, or astigmatism. Children very rarely present with headaches caused by eyestrain. However, children with headaches should be screened for visual problems with ophthalmologic referral if needed because these problems are easily corrected with refractive lenses. Headaches may also result from disorders of motility. Symptoms are similar to those of refractive error. Children with headaches should be evaluated for eye movement abnormalities because some of the conditions responsible require specific treatment (inflammatory, infectious, neoplastic lesions, or myasthenia gravis). Disorders of motility may occur with elevated ICP, so neuroimaging to evaluate for structural lesions and LP to evaluate opening pressure may be indicated. Glaucoma is much less frequent in children than adults but must be considered when a child presents with eye or periorbital pain because rapid treatment is required to prevent vision loss. Typical features include pain in or behind the eye, conjunctival injection, blurred vision or colored halos, and visual disturbance. As intraocular pressure rises, the pupil may become middilated and fixed to light (because of sphincter muscle ischemia). Permanent vision loss may occur because of corneal edema and anterior ischemic optic neuropathy. Emergent ophthalmologic evaluation is required if glaucoma is suspected. Some medications used to treat headaches such as topiramate may cause angle closure glaucoma, and pressure measurements may be required if orbital symptoms and signs develop in a child being treated with topiramate. Optic neuritis may result in periocular pain on eye movement and must be identified because specific evaluation is required and steroid administration improves the time to vision return. Ocular inflammatory disorders can also present with periorbital pain. Corneal irritation may cause sharp, severe, stabbing pain, whereas intraorbital inflammation may cause boring constant pain. The differential diagnosis is diverse, including infections (bacterial, herpes simplex virus [HSV], TB, and CMV),

131 autoimmune conditions (rheumatoid arthritis and HLA-B27 associated), or neoplastic conditions (leukemia and lymphoma). Diagnosis is made by slit-lamp examination. Ketatoconjunctivitis sicca (dry eyes) results from tear film dysfunction and presents with diffuse eye pain; a feeling of grit within the eye; an increase in blink rate; and sometimes eye pain that is brief, jabbing, and severe. Diagnosis is by slitlamp examination or the Schirmers (strip wetting) test, and treatment is with tear substitutes. In the recurrent erosion syndrome, there is dysfunctional corneal adherence to the basement membrane, and patients awaken with intense eye pain, lacrimation, and blurred vision. Slit-lamp examination is diagnostic, and treatment is with lubricants. These corneal disorders must be differentiated from primary headache syndromes that also present with eye pain and tearing, such as cluster headache, primary stabbing headache, or short-lasting unilateral neuralgiform headache attacks with conjunctival irritation and tearing syndrome. IIH (discussed earlier) may present with transient visual obscurations that are often associated with visual field deficits, bifrontal headache, pulsatile tinnitus, and cranial palsy (most commonly CN VI). Identifying papilledema or visual field defects in a child with headaches must lead to the consideration of IIH in addition to other causes of intracranial HTN.

Disorders of the Mouth and Teeth Temporomandibular Joint Temporomandibular joint (TMJ) dysfunction in children is often associated with bruxism and other abnormal jaw behaviors. The pain may be constant or throbbing and is often triggered by jaw movement or pressure on the masticatory muscles. Examination may show a click on jaw movement, tenderness on the masticatory muscles or TMJ, or reduced jaw opening. A 20-year longitudinal study of 100 children with TMJ dysfunction showed that although progression to severe pain and dysfunction was rare, the continuation of mild frequent symptoms was common.37 Thus, when TMJ dysfunction is suspected, the child should be evaluated by a dentist or oral-maxillary surgeon. Treatment may include dental occlusive splints, anti-inflammatory or muscle relaxant medications, psychological counseling, and very rarely surgery. Many children with TMJ dysfunction have comorbid psychiatric conditions including depression, conversion and adjustment disorders, overanxious behavior, and anorexia nervosa and may need psychiatric evaluation. Other Dental Disease Generally, pain from dental or oral disease is localized to the mouth. However, they may present as facial pain or headache, especially in younger children who have difficulty localizing pain accurately. The examination of children with headaches should include a detailed examination of the teeth and gums and dental referral if needed. A dental abscess may present as poorly localized pain in young children. Pain arising from the salivary gland is generally well localized and precipitated by eating. Fever may be present, and the salivary glands are tender to palpation. Burning sensations of the oral

132 mucosa may be idiopathic (burning mouth syndrome) but are also associated with systemic diseases such as Sjogren syndrome, iron-deficiency anemia, mercury hypersensitivity (from fillings), and psychiatric conditions. In burning mouth syndrome, patients generally present with additional symptoms including gustatory changes, xerostomia, back and joint muscle pain, headache, and dizziness. Underlying dental etiologies include TMJ, masticatory, and tongue muscle dysfunction and lesions in the oral mucosa.

Headache Attributed to Psychiatric Disorder Psychiatric Comorbidity Many children with headaches have comorbid psychiatric diagnoses, and this may contribute to disability. Up to 80% of children with headaches have comorbid psychiatric disorders, most commonly anxiety or depression, and comorbid depression is associated with increased disability. Conversely, children with psychiatric disorders have a higher incidence of primary headache disorders. Multiple studies using a variety of psychological assessment instruments have shown that children with migraines and tension-type headaches have higher levels of depression and anxiety than controls. Patients with comorbidity are less likely to become headache free. Elevated levels of anxiety and psychosocial symptoms are associated with increased headache severity, and elevated levels of depression are associated with higher rates of school absenteeism.

Psychosocial Factors Related to Headaches Children with recurrent pain have wide-ranging variation in functional ability, and potential influences on the effect of chronic pain include family characteristics, parental responses, perceived competence, and child coping skills as well as frank psychiatric/psychological comorbid conditions. Strategies to improve the outcomes for children with chronic pain syndromes include behavioral management techniques (eg, guided imagery, hypnosis, cognitive control, biofeedback) which can minimize parental reaction to their child’s pain and improve the child’s coping skills. Insistence upon the child participating in normal activities, including school regular school attendance, is imperative.38 Headache in Children With Coexisting Medical Disease Coexisting medical disorders may cause headaches or may be entirely unrelated but affect headache treatment. Certain headache medications are contraindicated in the presence of specific medical diseases (eg, beta-blockers with asthma and valproic acid with liver disease). Furthermore, some medical diseases involving the liver or kidney may alter the metabolism and excretion of medications. HTN impacts medication choice in treating headaches. Triptans and dihydroergotamine are contraindicated in the presence of HTN. Nifedipine may cause headaches. Many antihypertensives (ie, beta-blockers and calcium channel

N.S. Abend, D. Younkin, and D.W. Lewis blockers) are known to have efficacy in migraine prophylaxis and could be used to treat both disorders.39 Coronary artery disease is rare in children but can occur in the contexts of congenital heart disease or Kawasaki disease. The triptans and ergotamine medications act by producing vasoconstriction and are contraindicated in patients with coronary artery disease. Medications that produce arrhythmias must be avoided in patients with preexisting arrhythmias (ie, tricyclic antidepressants and ventricular tachycardia). Asthma may be worsened by the administration of beta-blockers. Chronic respiratory failure may be worsened by benzodiazepines that can decrease respiratory drive. Renal failure decreases glomerular filtration, necessitating lower doses of certain medications. Triptans are excreted renally and must be avoided or used in low doses. Metabolites from meperidine may accumulate in renal disease. NSAIDs may worsen chronic renal failure. Liver disease may be a contraindication to medications, such as acetaminophen, chlorpromazine, acetylsalicylic acid, phenytoin, valproic acid, carbamazepine, and topiramate, which are associated with hepatotoxicity.40 Furthermore, hepatic disease affecting P450 enzymes alters the metabolism of P450 metabolized headache medications, necessitating avoidance or lower doses of these medications. Thus, triptans and dihydroergotamine are contraindicated in patients with liver disease. Medications that produce weight gain must be avoided in obese patients, or weight must be carefully monitored. These include tricyclic antidepressants, cyproheptadine, selective serotonin reuptake inhibitors, and valproic acid. Topiramate produces weight loss and could be a good medication in these patients. Conversely, topiramate and other medications that decrease the appetite should be avoided in patients with eating disorders. In HIV patients with headache, CNS infection and tumor must be considered carefully.41 When considering the treatment of headaches in HIV patients, drug interactions must be considered. The protease inhibitor medications inhibit CYP-3A4 liver enzymes, which metabolize ergot and triptan medications and ergotism has been reported with coadministration.42 Topiramate induces CYP-3A4 and may decrease protease inhibitor levels, whereas valproic acid and antidepressants, including fluoxatine and fluvoxamine, inhibit CYP-3A4 and may raise levels.43,44 Zidovudine levels may be decreased by the coadministration of acetaminophen, indomethacin, and valproic acid. Furthermore, valproic acid may lead to increased HIV replication.45 Immune-suppressing drugs, such as cyclosporine, sirolimus, and tacrolimus, are metabolized by CYP-3A4 enzymes, and the levels must be monitored carefully if they are coadministered with headache medications that induce (carbamezepine, topiramate, and phenytoin) or inhibit (fluoxetine, fluvoxamine, verapamil, and valproic acid) this enzyme.46 Many chemotherapeutic agents are substrates within the liver cytochrome P450 system. Headache medications that induce this system could lower the serum concentrations of these chemotherapeutic agents, which would lower their effectiveness. Headache medications that inhibit this system

Secondary headaches might raise the serum levels and increase toxicity. Renal excretion may also be affected. For example, NSAIDs reduce renal excretion of methotrexate and may result in toxicity.

Conclusions The overwhelmingly vast majority of children and adolescents who present to us for care have primary headaches. We have presented a long and exhaustive list of causes of secondary headaches. Many of the causes are easily diagnosed by the history, and some are more difficult. We hope you use this article as a reference when a perplexing youngster presents with symptoms not typical for primary headaches.

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