Hydrocephalus

Hydrocephalus can be defined broadly as a disturbance of formation, flow, or absorption of cerebrospinal fluid (CSF) that leads to an increase in volume occupied by this fluid in the central nervous system (CNS). This condition also could be termed a hydrodynamic disorder of CSF. Acute hydrocephalus occurs over days, subacute over weeks, and chronic over months or years. Conditions such as cerebral atrophy and focal destructive lesions also lead to an abnormal increase of CSF in CNS. In these situations, loss of cerebral tissue leaves a vacant space that is filled passively with CSF. Such conditions are not the result of a hydrodynamic disorder and therefore are not classified as hydrocephalus. An older misnomer used to describe these conditions was hydrocephalus ex vacuo.

Normal pressure hydrocephalus (NPH) describes a condition that rarely occurs in patients younger than 60 years. Enlarged ventricles and normal CSF pressure at lumbar puncture (LP) in the absence of papilledema led to the term NPH. However, intermittent intracranial hypertension has been noted during monitoring of patients in whom NPH is suspected, usually at night. The classic Hakim triad of symptoms includes gait apraxia, incontinence, and dementia. Headache is not a typical symptom in NPH.

Benign external hydrocephalus is a self-limiting absorption deficiency of infancy and early childhood with raised intracranial pressure (ICP) and enlarged subarachnoid spaces. The ventricles usually are not enlarged significantly, and resolution within 1 year is the rule.

Communicating hydrocephalus occurs when full communication exists between the ventricles and subarachnoid space. It is caused by overproduction of CSF (rarely), defective absorption of CSF (most often), or venous drainage insufficiency (occasionally).

Noncommunicating hydrocephalus occurs when CSF flow is obstructed within the ventricular system or in its outlets to the arachnoid space, resulting in ventricular/subarachnoid space noncommunication.

Obstructive hydrocephalus results from obstruction of the flow of CSF (intraventricular or extraventricular). Most hydrocephalus is obstructive, and the term is used to contrast the hydrocephalus caused by overproduction of CSF.

Arrested hydrocephalus is defined as stabilization of known ventricular enlargement, probably secondary to compensatory mechanisms. These patients may decompensate, especially following minor head injuries.

Pathophysiology
Normal CSF production is 0.20-0.35 mL/min; a majority is produced by the choroid plexus, which is located within the ventricular system, mainly the lateral and fourth ventricles. The capacity of the lateral and third ventricles in a healthy person is 20 mL. Total volume of CSF in an adult is 120 mL.

Normal route of CSF from production to clearance is the following: From the choroid plexus, the CSF flows to the lateral ventricle, then to the interventricular foramen of Monro, the third ventricle, the cerebral aqueduct of Sylvius, the fourth ventricle, the 2 lateral foramina of Luschka and 1 medial foramen of Magendie, the subarachnoid space, the arachnoid granulations, the dural sinus, and finally into the venous drainage.

ICP rises if production of CSF exceeds absorption. This occurs if CSF is overproduced, resistance to CSF flow is increased, or venous sinus pressure is increased. CSF production falls as ICP rises. Compensation may occur through transventricular absorption of CSF and also by absorption along nerve root sleeves. Temporal and frontal horns dilate first, often asymmetrically. This may result in elevation of the corpus callosum, stretching or perforation of the septum pellucidum, thinning of the cerebral mantle, or enlargement of the third ventricle downward into the pituitary fossa (which may cause pituitary dysfunction).

The mechanism of NPH has not been elucidated completely. Current theories include increased resistance to flow of CSF within the ventricular system or subarachnoid villi; intermittently elevated CSF pressure, usually at night; and ventricular enlargement caused by an initial rise in CSF pressure; the enlargement is maintained despite normal pressure because of the Laplace law. Although pressure is normal, the enlarged ventricular area reflects increased force on the ventricular wall.

Frequency
United States
Incidence of congenital hydrocephalus is 3 per 1,000 live births, while the incidence of acquired hydrocephalus is not known exactly.

International
Incidence of acquired hydrocephalus is unknown. About 100,000 shunts are implanted each year in the developed countries, but little information is available for other countries.

Mortality/Morbidity
In untreated hydrocephalus, death may occur by tonsillar herniation secondary to raised ICP with compression of the brain stem and subsequent respiratory arrest.

Shunt dependence occurs in 75% of all cases of treated hydrocephalus and in 50% of children with communicating hydrocephalus.
Patients are hospitalized for scheduled shunt revisions or for treatment of shunt complications or shunt failure.
Poor development of cognitive function in infants and children, or loss of cognitive function in adults, can complicate untreated hydrocephalus. It may persist after treatment.
Visual loss can complicate untreated hydrocephalus and may persist after treatment.

Sex
Generally, incidence is equal in males and females. The exception is Bickers-Adams syndrome, an X-linked hydrocephalus transmitted by females and manifested in males. NPH has a slight male preponderance.

Age
Incidence of human hydrocephalus presents a bimodal age curve. One peak occurs in infancy and is related to the various forms of congenital malformations. Another peak occurs in adulthood, mostly resulting from NPH. Adult hydrocephalus represents approximately 40% of total cases of hydrocephalus.

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Headache, Migraine

Background
Migraine headaches are recurrent headaches that may be unilateral or bilateral. Migraine headaches may occur with or without a prodrome. The aura of a migraine may consist of neurologic symptoms, such as dizziness, tinnitus, scotomas, photophobia, or visual scintillations (eg, bright zigzag lines). The International Headache Society (IHS) redefined and classified headaches to formulate the current categorization, which has been maintained in the second edition. The headache previously described as classic migraine is now known as migraine with aura, and that described as common migraine is now termed migraine without aura. Migraines without aura are the most common, accounting for more than 80% of all migraines.
In April 2000, the US Headache Consortium, a multispecialty group that includes the American College of Emergency Physicians, released evidence-based guidelines for the diagnosis, treatment, and prevention of migraine headaches. Guidelines are also available from the American Academy of Neurology, the National Headache Foundation, and the Canadian Association of Emergency Physicians.

Pathophysiology
The pathophysiology of migraine headaches is not clearly understood. Growing evidence supports the role of neurogenic peptides, such as serotonin and dopamine, in the brain. These vasoactive neuropeptides stimulate an inflammatory cascade with the release of endothelial cells, mast cells, and platelets. This inflammation causes vasodilation and a perivascular reaction. The serotonin receptor (5-HT) is believed to be the most important receptor in the headache pathway.
Some of the symptoms associated with migraine headaches, such as nausea (80%), vomiting (50%), yawning, irritability, hypotension, and hyperactivity, can be associated with dopamine receptor activation. Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists such as apomorphine, bromocriptine, and pergolide. Dopamine antagonists, such as metoclopramide (Reglan), haloperidol (Haldol), and prochlorperazine (Compazine), have been shown clinically to treat migraine headaches effectively.

Frequency
United States
An estimated 10-20% of the US population suffers from migraine headaches. Frequency of headaches varies greatly by individual. An estimated 6% of men and 15-17% of women in the United States have migraine. Migraine is the second most common type of headache syndrome in the United States. Tension headaches are the most common.
Sex
Migraines most commonly are found in women, with a 3:1 female-to-male ratio. In childhood, however, migraines are more common in boys than in girls.
Age
The first attack often is in childhood, and incidence increases in adolescence. More than 80% of patients who develop migraines will have a first attack by age 30. Migraines continue through the patient's 30s and 40s. They may begin or occur at any age but are rare after age 50. With increased age, attacks usually decrease in severity and frequency. Age older than 55 years is a strong predictor for intracranial pathology.

History
Moderately severe to severe headache with or without a prodrome
Aura (20%) - A variety of preceding events that begins and ends days to hours prior to the headache itself. Visual aura symptoms are most common. Nonspecific prodrome may precede migraine without an aura.
Scotoma (blind spots)
Fortification (zig-zag patterns)
Scintilla (flashing lights)
Unilateral paresthesia/weakness
Hallucinations
Hemianopsia
Headache
Unilateral, also known as hemicrania (30-40% are bilateral)
Throbbing or pulsatile (More than 50% of people who suffer from migraines report nonthrobbing pain at some time during the attack.)
Lasts 4-72 hours
Systemic manifestations
Nausea (80-90%)
Vomiting (40-60%)
Photophobia (80%)
Phonophobia (75-80%)
Lightheadedness (70%)
The patient might prefer to be in a quiet and darkened room.
History factors suggesting a more serious underlying cause of headache
The first or worst headache of the patient's life, especially if the headache onset was rapid
A change in frequency, severity, or clinical features of the attack from what usually is experienced
New progressive headache that persists for days
Precipitation of headache with Valsalva maneuvers (ie, coughing, sneezing, bearing down)

Physical
Usually, patients have no specific physical findings other than the physical manifestations of the associated systemic symptoms listed above (photophobia, phonophobia); abnormality on physical examination may suggest another cause of headache.
The physician must perform a thorough screening neurologic examination.
Physical examination findings suggesting a more serious cause of headache include the following:
Systemic symptoms (eg, myalgia, fever, malaise, weight loss, scalp tenderness, jaw claudication)
Focal neurologic abnormalities or confusion, seizures, or any impairment of level of consciousness
Focal neurologic findings that occur with the headache and persist temporarily after the pain resolves suggest a migraine variant. In hemiplegic migraine, the patient may have unilateral paralysis or weakness. Aphasia, syncope, and balance problems may be seen in basilar migraines. In ophthalmoplegic migraine, the patient may present with a third nerve palsy, with ocular muscle paralysis, including or sparing the pupillary response, as well as ptosis. Ophthalmic migraines cause a visual disturbance (usually lateral field deficit). This diagnosis is more common in children, with the abnormal motor findings lasting hours to days after the headache.

Causes
Exact etiology is unknown.
Family history of migraine headaches (70-80%)
Medications (ie, birth control pills, vasodilators)
Fatigue or emotional stress
Specific foods or alcohol
Exertion

DIFFERENTIALS
Other Problems to be Considered
Brain tumor (increased intracranial pressure) Opiate dependance/opiate withdrawal headache Pseudotumor cerebri Vascular pathology (eg, aneurysm)
WORKUP

Lab Studies
Laboratory and radiographic evaluation excludes other potential diagnoses in the differential.

Imaging Studies
CT scan of the head is indicated to rule out intracranial mass or hemorrhage in selected or atypical cases. A negative CT scan may miss some small subarachnoid hemorrhages, tumors, and strokes, particularly those in the posterior fossa. A CT scan without intravenous contrast also may miss some aneurysms. MRI and magnetic resonance angiography are more sensitive. Neuroimaging is rarely productive in patients who have a normal neurologic examination. Neuroimaging is not warranted in patients with a diagnosis of migraine who present with a typical event. They are useful if neurologic examination findings are abnormal, the migraine occurs for the first time after age 40 years, the frequency or intensity is increasing, and the accompanying symptoms of the attack change.

Procedures
Lumbar puncture (LP): In selected patients with appropriately concerning histories, an LP should be performed to rule out infection or small subarachnoid hemorrhage not visible on CT scan of the head.

TREATMENT
Prehospital Care
Patients should be transported in a way that minimizes visual and auditory stimulation. Most patients should not receive opiate analgesics until a thorough neurologic examination can be completed by the responsible physician.
Emergency Department Care
While the emergency physician must be able to identify patients with serious headache etiology, note that more than 90% of patients in the ED have migraine, tension, or mixed-type benign headache. Therefore, providing symptomatic relief should be a priority.
Migraine-specific medications and analgesia are the keys of ED care.
Rest in a darkened, quiet room is helpful.
Some patients find cool compresses to painful areas helpful.

Consultations
Neurologic consultation may be required in complex cases, though referral to a primary care provider often is sufficient.

MEDICATION
The goals of pharmacotherapy are to prevent attacks or alter the migraine attack once it is underway. Specifically, this is done by reducing the severity and the duration of the attack. Preventive therapy encompasses these same objectives and decreases the frequency of attacks, improves responsiveness to treatment, and improves function while decreasing disability.
An estimated half of migraine patients stop seeking care for their headaches, partly because they are dissatisfied with therapy.
Drug Category: Analgesics
Initial therapy for patients with infrequent migraines can be simple analgesics.
Drug Name
Acetaminophen and codeine (Tylenol #3)
Description
Drug combination indicated for treatment of mild to moderately severe headache.Note: Some patients may respond to maximal acetaminophen alone, without codeine.
Adult Dose
30-60 mg/dose based on codeine content PO q4-6h or 1-2 tab q4h; not to exceed 12 tab/d (4 g acetaminophen/d)
Pediatric Dose
0.5-1 mg/kg/dose based on codeine content PO q4-6h; 10-15 mg/kg/dose based on acetaminophen content; not to exceed 2.6 g/d of acetaminophen
Contraindications
Documented hypersensitivity
Interactions
CNS depressants or tricyclic antidepressants increase toxicity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients dependent on opiates because this substitution may result in acute opiate-withdrawal symptoms; caution in severe renal or hepatic dysfunction
Drug Name
Acetaminophen (Tylenol, Aspirin Free Anacin, Panadol)
Description
DOC for treatment of pain in patients with documented hypersensitivity to aspirin or NSAIDs, in those with upper GI disease, or in those taking oral anticoagulants.
Adult Dose
325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric Dose
<12>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h
Contraindications
Documented hypersensitivity; G-6-PD deficiency
Interactions
Rifampin can reduce analgesic effects; barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Hepatotoxicity possible in chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate serious illness; acetaminophen contained in many OTC products, and combined use with these products may result in cumulative acetaminophen doses exceeding recommended maximum dose
Drug Name
Aspirin (Anacin, Ascriptin, Bayer Aspirin)
Description
May alleviate migraine attacks by inhibiting prostaglandin synthesis. Mild migraines usually respond well to this medication.
Adult Dose
325-650 mg PO q4-6h prn; not to exceed 4 g/d
Pediatric Dose
10-15 mg/kg/dose PO q4-6h; not to exceed 60-80 mg/kg/d
Contraindications
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthmaBecause of association with Reye syndrome, do not use in children (<16>2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, in those with history of blood coagulation defects, or in those taking anticoagulants
Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)
These agents may alleviate migraine pain by inhibiting prostaglandin synthesis, reducing serotonin release, and blocking platelet aggregation. Although the effects of NSAIDs in the treatment of migraine pain tend to be patient specific, ibuprofen usually is the DOC for the initial therapy. Other options include naproxen, ketoprofen, and ketorolac.
Drug Name
Naproxen (Anaprox, Naprelan, Naprosyn)
Description
Used for relief of mild to moderately severe headaches. Inhibits inflammatory reactions and pain by decreasing activity of enzyme cyclooxygenase, thus inhibiting prostaglandin synthesis.
Adult Dose
500 mg PO followed by 250 mg q6-8h; not to exceed 1.25 g/d
Pediatric Dose
<2>2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d
Contraindications
Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
Interactions
Aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effects of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT in patients taking anticoagulants (monitor PT closely and instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase phenytoin levels
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug
Drug Name
Ketoprofen (Oruvail, Orudis, Actron)
Description
Used for relief of mild to moderately severe headaches and inflammation.Administer small dosages initially to patients with small body size, elderly patients, and patients with renal or liver disease.Doses >75 mg does not increase therapeutic effects. Administer high doses with caution, and closely observe the patient for response.
Adult Dose
25-50 mg PO q6-8h prn; not to exceed 300 mg/d
Pediatric Dose
<3>12 years: Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
Aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effects of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT in patients taking anticoagulants (monitor PT closely and instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase phenytoin levels
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy
Drug Name
Ketorolac (Toradol)
Description
Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors.PO form available, but no advantage vs other less expensive PO NSAIDs.
Adult Dose
30 mg IV single dose (most common route used in ED)>65 years, renal impairment, or body weight <50>2 years: 0.25-1 mg/kg PO/IV/IM/PR q4-6h prn
Contraindications
Documented hypersensitivity; children younger than 2 y (incidences of death due to respiratory depression)
Interactions
May have additive effects with other CNS depressants or anticonvulsants; with epinephrine may cause hypotension
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in cardiovascular disease, impaired liver function, seizures, sleep apnea, and asthma
Drug Name
Metoclopramide (Reglan)
Description
Indicated for migraine-associated nausea. Works by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS. Can be used as an alternative to prochlorperazine. Studies have shown that prochlorperazine is better.
Adult Dose
5-10 mg PO or 5-20 mg IV/IM tid
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction or perforation; history of seizure disorders
Interactions
Anticholinergic agents may antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in history of mental illness and Parkinson disease
Drug Name
Droperidol (Inapsine)
Description
Neuroleptic agent that may reduce emesis by blocking dopamine stimulation of chemoreceptor trigger zone.
Adult Dose
2.5-10 mg IV/IM q3-4h prn (2.5 mg for headache)
Pediatric Dose
<2>12 years: Administer as in adults
Contraindications
Documented hypersensitivity; prolonged QT interval
Interactions
May increase toxicity of CNS depressants
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypovolemic patients may experience hypotension; droperidol may decrease pulmonary arterial pressure; tardive dyskinesia in patients receiving droperidol is 40%; elderly persons may experience high rate of extrapyramidal reactions; life-threatening arrhythmias may occur in patients receiving this medication (for droperidol, the black box warning: potentially fatal QT prolongation; many institutions recommend an ECG or rhythm strip to look for QT prolongation before administering)
Drug Category: Ergot alkaloids and derivatives
These are direct vasoconstrictors of smooth muscle in cranial blood vessels. Their activity depends on the CNS vascular tone at the time of administration.
Drug Name
Ergotamine tartrate (Cafergot, Cafatine, Cafetrate)
Description
Has alpha-adrenergic antagonist and serotonin antagonist effects. Causes constriction of peripheral and cranial blood vessels.
Adult Dose
2 tab PO at onset of attack, 1 tab q30min prn; not to exceed 6 tab per attack or 10 tab/wk1 tab SL at first sign of attack and 1 tab q30min; not to exceed 3 tab/d or 5 tab/wk1 supp PR at first sign of attack with second dose after 1 h prn; not to exceed 2 supp/attack or 5 supp/wk
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; hepatic or renal disease; peptic ulcer disease; sepsis; peripheral vascular disease
Interactions
Increases effects of heparin; increases toxicity of nitroglycerin, propranolol, erythromycin, and clarithromycin
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Avoid using prolonged regimens because of danger of causing gangrene or dependency
Drug Name
Dihydroergotamine (D.H.E. 45, Migranal Nasal Spray)
Description
More effective when given early in migraine attack. Has alpha-adrenergic antagonist and serotonin antagonist effects.
Adult Dose
1 mg IM at first sign of headache, repeat q1h; not to exceed 3 mg total dose2 mg IV maximum dose for faster effects; most commonly given at 0.5-1 mg IV with antiemetic; not to exceed 6 mg/wkIntranasal: 1 spray into each nostril and repeat prn within 15 min; not to exceed 6 sprays/d or 8 sprays/wk
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; sumatriptan or zolmitriptan within last 24 h; MAOIs in last 2 wk
Interactions
Increases effects of heparin; increases toxicity of nitroglycerin, propranolol, erythromycin, and clarithromycin
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in angina, hypertension, impaired renal or hepatic function, or peripheral vascular disease
Drug Category: 5- HT1 Serotonin receptor agonist
The stimulation of 5-HT1 receptors produce a direct vasoconstrictive effect.
Drug Name
Sumatriptan (Imitrex)
Description
Selective agonist for serotonin 5-HT1 receptors in cranial arteries. Suppresses inflammation associated with migraine headaches.
Adult Dose
25 mg PO; if satisfactory response not observed in 2 h, additional dose of up to 100 mg may be administered; additional doses at intervals of 2 h prn; not to exceed 300 mg/d6 mg SC; if satisfactory response not observed in 1 h, an additional 6 mg SC may be administered; not to exceed 2 injections/dIntranasal: Single dose of 5, 10, or 20 mg may be administered in 1 nostril; give 10-mg dose by administering single 5-mg dose in each nostril; if satisfactory response not observed in 2 h, additional dose may be administered; not to exceed 40 mg/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension; coadministration or within 2 wk of MAOIs
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin) may increase plasma concentration and subsequent toxicity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Flushing and chest pain are common;hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, and bloody diarrhea may occur rarelyPatients with known or suspected coronary artery disease may have increased risk of myocardial ischemia, infarction, or other cardiac or cerebrovascular events (5-HT1 agonists may cause coronary vasospasm)
Drug Name
Zolmitriptan (Zomig, Zomig-ZMT)
Description
Selective agonist for serotonin 5-HT1 receptors in cranial arteries. Suppresses inflammation associated with migraine headaches.
Adult Dose
2.5 mg or 5 mg PO; repeat dose after 2 h prn; not to exceed 10 mg/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension; another serotonin agonist or ergotamine within last 24 h; MAOI within last 2 wk
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin) may increase plasma concentration and subsequent toxicity
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Flushing and chest pain are common; hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occurDecrease dose of almotriptan and do not exceed 12.5 mg/d in renal or hepatic impairment
Drug Name
Frovatriptan (Frova)
Description
Used to treat acute migraine. Selective 5-HT1B/1D receptor agonist with long half-life of 24 h and low headache recurrence rate within 24-hour period of taking the drug. Results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways. Has unique characteristics and benefits in the acute treatment of migraine.
Adult Dose
2.5 mg PO once at onset of migraine attack
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; hemiplegic or basilar migraine; ischemic heart disease; uncontrolled hypertension
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occur
Drug Name
Eletriptan (Relpax)
Description
Selective serotonin agonist. Specifically acts at 5-hydroxytryptamine 1B/1D/1F (5-HT1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings to relieve pain associated with acute migraine.
Adult Dose
20-40 mg/dose PO at onset of migraine; if initial dose ineffective, may repeat dose once after 2 h; not to exceed 80 mg/d
Pediatric Dose
<18>65 y; administration within 72 h of potent CYP450 3A4 inhibitors
Interactions
Potent CYP450 3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) may increase toxicity; concurrent administration with ergot-containing drugs may increase vasospastic reactions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients with known or suspected coronary artery disease may have increased risk of myocardial ischemia, infarction, or other cardiac or cerebrovascular events (5-HT1 agonists may cause coronary vasospasm)
Drug Name
Almotriptan (Axert)
Description
Used to treat acute migraine. Selective 5-HT1B/1D receptor agonist. Results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways.
Adult Dose
6.25-12.5 mg PO at onset of migraine; may repeat once, not to exceed 25 mg/d
Pediatric Dose
<18>18 years: Administer as in adults
Contraindications
Documented hypersensitivity; hemiplegic or basilar migraine; ischemic heart disease; uncontrolled hypertension
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination; CYP450-3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin) may increase plasma concentration and subsequent toxicity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Decrease dose and do not exceed 12.5 mg/d in renal or hepatic impairment
Drug Name
Rizatriptan (Maxalt, Maxalt-MLT)
Description
Selective agonist for serotonin 5-HT1 receptors in cranial arteries and suppresses the inflammation associated with migraine headaches.
Adult Dose
5-10 mg PO q2h prn for headache; not to exceed 30 mg/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity
Interactions
Toxicity increases when administered concomitantly with ergot-containing drugs, selective serotonin reuptake inhibitors, and MAOIs
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occur when administering this medication
Drug Category: Combination antimigraine drugs
These agents are useful in aborting migraine attacks.
Drug Name
Isometheptene dichloralphenazone acetaminophen (Midrin)
Description
Has sympathomimetic properties. Dilates cranial and cerebral arterioles, causing reduction in stimuli that lead to vascular headaches.
Adult Dose
2 cap PO at once followed by 1 cap q1h until satisfactory response obtained; not to exceed 5 cap/12 h
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; glaucoma; hypertension; organic heart disease; severe renal disease; hepatic disease; MAOI within last 2 wk
Interactions
Concurrent MAOIs may result in severe headache, hypertension, and hyperpyrexia, which, in turn, may result in hypertensive crisis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in hypertension, peripheral vascular disease, and recent cardiovascular injuries
Drug Category: Barbiturates
These agents are used in combination with aspirin and acetaminophen for pain relief and to induce sleep. Caffeine is also used to increase GI absorption. However, butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms.
Drug Name
Acetaminophen/butalbital/caffeine (Fioricet)
Description
Drug combination used to relieve tension headaches. Barbiturate component has generalized depressant effect on CNS.
Adult Dose
1-2 tab or cap PO q4h; not to exceed 6 tab or cap/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity
Interactions
Effects decreased by phenothiazines, quinidine, tricyclic antidepressants, theophylline, haloperidol, chloramphenicol, ethosuximide, corticosteroids, warfarin, doxycycline, and beta-blockers; effects increased by CNS depressants, methylphenidate, valproic acid, propoxyphene, and benzodiazepines
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Risk of rebound headache and overuse; caution in patients with history of substance abuse
Drug Name
Aspirin/butalbital/caffeine (Fiorinal)
Description
Drug combination used to relieve tension headaches. Barbiturate component has generalized depressant effect on CNS.
Adult Dose
1-2 tab or cap PO q4h; not to exceed 6 tab or cap/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; children or adolescents experiencing flulike symptoms or chickenpox
Interactions
Effects decreased by phenothiazines, quinidine, tricyclic antidepressants, theophylline, haloperidol, chloramphenicol, ethosuximide, corticosteroids, warfarin, doxycycline, and beta-blockers; effects increased by CNS depressants, methylphenidate, valproic acid, propoxyphene, and benzodiazepines
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Risk of rebound headache and overuse; caution in patients with history of substance abuse

FOLLOW-UP
Further Outpatient Care
Avoid precipitants of attacks, if possible.
Follow-up with primary care physician and neurologist after first or subsequent attacks.

In/Out Patient Meds
Multitude of drugs used for migraine prophylaxis
Beta-blockers: Atenolol, propranolol, timolol
Antidepressants: Amitriptyline (Elavil), nortriptyline (Pamelor)
Ergot derivatives: Methysergide (Sansert)
Antihistamines: Cyproheptadine (Periactin)
Anticonvulsants: Valproic acid (Depakene, Depakote)
Abortive therapies
Alpha2-adrenergic receptor agonists (Clonidine)
Calcium channel blockers: Nimodipine, nifedipine, verapamil
NSAIDs

Patient Education
For excellent patient education resources, see eMedicine's Headache Center. Also, visit eMedicine's patient education articles Causes and Treatments of Migraine and Related Headaches, Migraine Headache, Alternative and Complementary Approaches to Migraine and Cluster Headaches, Migraine Headache FAQs, and Understanding Migraine and Cluster Headache Medications.
For more information, see Medscape's Headache Resource Center.

MISCELLANEOUS
Medical/Legal Pitfalls
Must rule out other potentially life-threatening forms of headache (eg, subarachnoid hemorrhage, meningitis).

REFERENCES
Bussone G, Grazzi L, D'Amico D, et al. Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potassium, in comparison to oral sumatriptan and placebo. The Diclofenac- K/Sumatriptan Migraine Study Group. Cephalalgia. May 1999;19(4):232-40. [Medline].
Cady R. Migraine. In: Five Minute Clinical Consult. 1997:676-77.
Caesar R. Acute headache management: the challenge of deciphering etiologies to guide assessment and treatment. Emerg Med Rep. 1995;16(13):117-28.
Capobianco DJ, Cheshire WP, Campbell JK. An overview of the diagnosis and pharmacologic treatment of migraine. Mayo Clin Proc. Nov 1996;71(11):1055-66. [Medline].
Diener HC, Kaube H, Limmroth V. A practical guide to the management and prevention of migraine. Drugs. Nov 1998;56(5):811-24. [Medline].
Ducharme J. Canadian Association of Emergency Physicians Guidelines for the acute management of migraine headache. J Emerg Med. Jan-Feb 1999;17(1):137-44. [Medline].
Evans RW. Diagnostic testing for the evaluation of headaches. Neurol Clin. Feb 1996;14(1):1-26. [Medline].
Members of the task force; Evers S, Afra J, Frese A, Goadsby PJ, Linde M. EFNS guideline on the drug treatment of migraine - report of an EFNS task force. Eur J Neurol. Jun 2006;13(6):560-72. [Medline].
Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl 1:9-160. [Medline].
Henry GL. Headache. In: Emergency Medicine Concepts and Clinical Practice. 3rd ed. 1992:1751-66.
Hoffman GL. Headache and facial pain. In: Emergency Medicine. 4th ed. 1996:chap192/1008-14.
Lance JW. Current concepts of migraine pathogenesis. Neurology. Jun 1993;43(6 Suppl 3):S11-5. [Medline].
Matchar DB, Young WB, Rosenberg JA, et al. Evidence-based guidelines for migraine headache in the primary care setting: Pharmacological management of acute attacks. American Academy of Neurology. Available at http://www.aan.com/. Accessed October 31, 2007.
Ramirez-Lassepas M, Espinosa CE, Cicero JJ, et al. Predictors of intracranial pathologic findings in patients who seek emergency care because of headache. Arch Neurol. Dec 1997;54(12):1506-9. [Medline].
Saper JR. Diagnosis and symptomatic treatment of migraine. Headache. 1997;37 Suppl 1:S1-14. [Medline].
Sheftell FD, Tepper SJ. New paradigms in the recognition and acute treatment of migraine. Headache. Jan 2002;42(1):58-69. [Medline].
Silberstein SD. Evaluation and emergency treatment of headache. Headache. Sep 1992;32(8):396-407. [Medline].
Solomon GD, Cady RK, Klapper JA, Ryan RE Jr. Standards of care for treating headache in primary care practice. National Headache Foundation. Cleve Clin J Med. Jul-Aug 1997;64(7):373-83. [Medline].
Stewart WF, Lipton RB, Celentano DD, et al. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA. Jan 1 1992;267(1):64-9. [Medline].
Stewart WF, Shechter A, Rasmussen BK. Migraine prevalence. A review of population-based studies. Neurology. Jun 1994;44(6 Suppl 4):S17-23. [Medline].
Tfelt-Hansen P. Efficacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat. Cephalalgia. Oct 1998;18(8):532-8. [Medline].
Thomas SH, Stone CK. Emergency department treatment of migraine, tension, and mixed-type headache. J Emerg Med. Sep-Oct 1994;12(5):657-64. [Medline].
Thomas SH, Stone CK, Ray VG, et al. Intravenous versus rectal prochlorperazine in the treatment of benign vascular or tension headache: a randomized, prospective, double-blind trial. Ann Emerg Med. Nov 1994;24(5):923-7. [Medline].
Headache, Migraine excerpt
Article Last Updated: Jan 3, 2008

Migraine Variants

Migraine is a paroxysmal headache disorder affecting more than 13% of the general population in the United States. Migraine is a syndrome and not a disease; it is characterized by paroxysmal headache associated with others signs and symptoms. About 80% of migraineurs have migraine without aura, while migraine with typical aura accounts for 15-20% of cases. Isolated migraine aura without headache (acephalic migraine) may be encountered in 5% of patients.
Migraine variant (MV) or migraine equivalent is the term applied to migraine, which exhibits itself in a form other than head pain. MV is characterized by paroxysmal episodes of prolonged visual auras; atypical sensory, motor, or visual aura; confusion; dysarthria; focal neurologic deficits; or gastrointestinal manifestations or other constitutional symptoms with or without a headache.
The diagnosis of MV is determined by history of paroxysmal signs and symptoms with or without cephalgia, a prior history of migraine with aura, in the absence of other medical disorders that may contribute to the symptoms. Many of these patients usually have a family history of migraine.
MVs are less recognized and poorly understood. They are less common than typical migraine without and with aura, and they usually affect children and young adults.
MVs should be differentiated from trigeminal cephalic neuralgias and other primary headaches such as stabbing and thunderclap headaches, cough headaches, or hypnic headaches. MVs should also be differentiated from exertional headaches, a group of headache syndromes associated with physical activity such as running, coughing, sneezing, or sexual intercourse.
Many MVs have been defined by the International Classification of Headache Disorders (ICHD-II) 2004 classification. These include hemiplegic migraines, basilar migraine, childhood periodic syndromes, retinal migraine, complicated migraines, and ophthalmoplegic migraine. Vertiginous migraine, acute confusional migraine of childhood, and nocturnal migraine, although well recognized entities, remain unclassified by the IHCD-II.
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Pathophysiology
Although activation and sensitization of the trigeminovascular in migraine is believed to generate and maintain migraine pain, cortical spreading depression (CSD) is recognized as the phenomenon underlying migraine aura. CSD is believed to begin in the occipital region and to gradually spread rostrally. This phenomenon is accompanied by a transient oligemia, followed by hyperemia in other parts of the cortex. Various molecular and cellular mechanisms may lead to the increased susceptibility of CSD in migraineurs, which could potentially play an important role in the pathophysiology of MVs. Researchers have suggested that a vasogenic leakage from leptomeningeal vessels, with activation of the trigeminovascular system, probably contribute to the prolonged aura in patients with hemiplegic migraine.
Migraine with prolonged aura
The typical duration of a migraine aura, predominantly visual, is up to 30 minutes. In rare cases, the aura could be prolonged, lasting up to 60 minutes, raising concerns of possible stroke.
Migraine aura without headache or acephalic migraine
Around 3-5% of migraineurs experience an aura without headache. This presentation is more common in older patients who have had a history of migraine with aura during early age. Symptoms may include scintillating scotomata, formed stereotyped visual hallucinations in a single visual field or bilaterally, micropsia, and tunnel vision. Other auras include paroxysmal vertigo, hemisensory dysesthesias, and rarely auditory hallucinations. Acephalic migraine should be differentiated from transient ischemic attack, occipital lobe seizures, or temporal lobe seizures.
Hemiplegic migraine
Hemiplegic migraine is a very rare but well described form of MV. It was initially described in 1910 as a type of migraine consisting of recurrent headaches associated with temporary unilateral hemiparesis or hemiplegia, at times accompanied by ipsilateral numbness or tingling, with or without a speech disturbance. The focal neurologic deficit may precede or accompany the headache, which is usually less dramatic than motor deficit. Other migraine symptoms may variably be present. Patients may also experience disturbance of consciousness, and rarely coma. The neurologic deficit is transient and usually clears in minutes to hours, or resolves with the beginning of the headache phase.
Two forms of hemiplegic migraine are known: familial and sporadic. Both familial hemiplegic migraine (FHM) and sporadic hemiplegic migraine (SHM) are phenotypically similar subtypes of migraine with aura, differentiated only by the unilateral motor symptoms.
Familial hemiplegic migraine
FHM is an autosomal dominant disorder. FHM is a channelopathy; most of the affected families bear mutations in the CACNA1A gene (a defect linked to abnormal voltage-dependent P/Q-type calcium channel alpha-1A) on 19p13. Mutations in ATP1A2 (R548H) on 1q23 (Mendelian Inheritance in Man #182340) and other genes have been identified.
Alternating hemiplegic migraine (primarily in childhood)
Alternating hemiplegia of childhood (AHC) is a chronic progressive disorder, associated with high prevalence of neurologic deficit. It is distinguished from familial hemiplegic migraine by its infantile onset and by its characteristic associated symptoms. The onset of the disorder is before age 18 months. It is characterized by vomiting, headache, alternating hemiplegia, loss of consciousness, paroxysmal ocular palsies, choreoathetosis, autonomic dysfunction, and mental retardation. Single-photon emission computed tomography (SPECT) studies have shown progressive decrease of cerebral perfusion in cases of alternating hemiplegic migraine.
Sporadic hemiplegic migraine
SHM is defined as migraine attacks associated with motor weakness in the absence of family history of similar attacks. Cases of SHM have also been linked to the CACNA1A gene.
Diagnosis of FHM is usually confirmed with repeated stereotyped reversible episodes, particularly in the presence of positive family history of similar attacks. The absence of first- and or second-degree relatives with similar disorder raises suspicion of SHM. Differential diagnosis includes focal seizures with postictal paralysis, mitochondrial cytopathies, intracranial hemorrhage, mass, infection, or cerebral infarction.
Basilar-type migraine
Basilar migraine (BM), also known as Bickerstaff syndrome, consists of headache accompanied by dizziness, ataxia, tinnitus, decreased hearing, nausea and vomiting, dysarthria, diplopia, loss of balance, bilateral paresthesias or paresis, altered consciousness, syncope, and sometimes loss of consciousness. BM is observed most frequently in adolescent girls and young women. Localized vertebrobasilar vasoconstriction leading to transient posterior circulation ischemia may contribute to the symptomatology of the disorder. A novel mutation in the ATP1A2 gene, similar to FHM, has been reported in members of one family with BM. Differential diagnosis includes various causes of syncopal, inner ear disease, intoxication, and posterior fossa pathologies.
Childhood periodic syndromes that are commonly precursors of migraine
Childhood periodic syndromes are characterized by multiple cyclic attacks of pain or vomiting with our without migraine headaches. They are common in children and adolescents.
Cyclic vomiting syndrome
Cyclic vomiting of childhood is characterized by recurrent attacks of violent or prolonged vomiting without headache, which may last for hours. Attacks may be precipitated by infection, menstruation, or physical or emotional stress. During the attacks, patients characteristically show other symptoms of migraine such as nausea, lethargy, yawning, and drowsiness. Cyclic vomiting is thought to result from abnormal activity in the area postrema. Additionally, gastroparesis, which occurs during migraine, has been implicated as an etiologic factor for cyclic vomiting and abdominal migraine.
Abdominal migraine
Abdominal migraine most typically occurs in children, although it has been reported in adults. Patients usually complain of paroxysmal midabdominal pain lasting form 1-72 hours, associated with nausea and vomiting, flushing, or pallor. Like cyclic vomiting, attacks may be associated with other migraine prodromes such as fatigue and drowsiness. Aura and headaches are frequently absent or minimal. Patients may develop migraine late in their life, and family history of migraine is common. Gastroenterologic evaluation and workup is unremarkable.
Benign paroxysmal vertigo of childhood
Benign paroxysmal vertigo of childhood (BPVC) is another MV characterized by brief episodes of vertigo and disequilibrium lasting for hours, without headache, aura, hearing loss, or tinnitus. It affects children aged 1-4 years. Children usually complain of a spinning sensation during the attack. Typical migraine is common later in life, and a family history of migraine is helpful in confirming the diagnosis.
Retinal migraine
Retinal migraine (ophthalmic, ocular) is not an uncommon cause of transient monocular blindness in young adults. It is manifested by recurrent attacks of unilateral visual disturbance or blindness lasting from minutes to 1 hour, associated with minimal or no headache. This phenomenon is frightening to patients, who usually seek medical help to exclude amaurosis fugax due to ischemia of the retinal arteries. Patients describe a gradual visual disturbance in a mosaic pattern of scotomata that gradually enlarge, producing total unilateral visual loss. Postural changes, exercise, and oral contraceptive agents may precipitate attacks. The condition is thought to result from transient vasospasm of the choroidal or retinal arteries. A personal or family history of migraine confirms the diagnosis. The condition needs to be differentiated from ocular or vascular causes of transient monocular blindness, mainly carotid artery disease.
Complicated migraine
Complications of migraine include chronic migraine, status migrainosus, persistent aura without infarction, migrainous infarction, and migraine-triggered seizure. Complicated migraines are rare, accounting for less than 1% of total patients with migraine. Chronic migraine and status migrainosus are not considered MVs and therefore are not included in this article.
Persistent aura
A typical migraine aura usually lasts 20-60 minutes. When the aura of migraine is prolonged, lasting for hours or days, complicated migraine including ischemic strokes need to be excluded. Prolonged aura lasting beyond 60 minutes, in the absent of radiographic evidence of cerebral infarction, is referred to as migraine with persistent aura.
Migraine infarctions
The relationship between migraine, mostly migraine with aura, and ischemic stroke has been well recognized. Migraine, generally a benign condition, has been recognized as an independent risk factor for ischemic stroke. Additionally, migraine, predominantly migraine with aura, is associated with the presence of silent infarctions or white matter changes on brain MRI. When a cerebral infarction occurs during a typical migraine aura attack, the term migrainous infarction is used. The mechanism of migrainous infarction is complex. Whether the relationship between migraine and stroke is the consequence of other underlying etiologies or the presence of similar ischemic risk factors, or whether migraine is associated with conditions that could potentially cause stroke, is yet to be determined.
Migraine-triggered seizures (migralepsy)
Migraine and epilepsy are highly comorbid conditions probably sharing the same pathophysiology, but the nature of their association is unclear. Migralepsy is the term used when a seizure occurs during or within 1 hour of a typical migraine aura attack. Reversible brain MRI abnormalities have been reported in a patient with migraine-triggered seizure, possibly due to supratentorial focal cerebral edema. Electroencephalogram (EEG) findings are usually normal interictal, although various abnormalities, mainly diffuse slowing, have been reported in migraineurs.
Ophthalmoplegic migraine
This is a very rare condition in children, characterized by a migrainelike attack, followed within days by periorbital pain and diplopia secondary to cranial neuropathies. The oculomotor nerve is most commonly involved, with pupillary abnormality and ptosis, followed by the abducens, and rarely the trochlear nerve. The attack usually lasts from days to months and resolves spontaneously. A number of adult cases have been reported. Although previously considered an MV, the condition has been classified as neuralgia by the IHCD-II. The condition is thought to be due to recurrent demyelinating cranial neuropathies. Differential diagnosis includes conditions involving the parasellar, orbital, and posterior fossa leading to headache and ophthalmoplegia.
Acute confusional migraine (primarily in childhood)
Acute confusional migraine is a rare MV, almost exclusively seen in young children, manifested by episodes of confusion, disorientation, and vomiting, with or without headaches. The attacks are usually relieved by sleep. The condition should be differentiated from seizures, and various causes of confusion, including toxic, metabolic, mitochondrial, or infectious encephalopathies.
Vertiginous migraine
Growing evidence suggests that recurrent episodes of vertigo are related to migraine. Vertigo, a common complaint among migraineurs, has been reported in one third of cases. Recurrent episodes of vertigo lasting between 5 minutes and 1 hour, with or without nausea, vomiting, photophobia, or headache, in the setting of a previous personal history or a positive family history of migraine supports the diagnosis of vestibular or vertiginous migraine. The pathophysiology of migraine-related vertigo is not fully understood. Differential diagnosis includes vertebrobasilar insufficiency and paroxysmal vestibular syndromes.
Nocturnal migraine
Although not a true MV, nocturnal migraine is unique because of its occurrence during the middle of the night or early morning hours. Its nocturnal occurrence is thought to be related to circadian activation of certain neurotransmitters during sleep, which are known to trigger a migraine attack.
Frequency
United States
Migraine affects nearly 13% of the adult US population, with a postpubertal female-to-male ratio of 4:1. The frequency of the less common MVs varies with type and age. The prevalence of hemiplegic migraine is 0.03%; both familial and sporadic forms are equally frequent. The prevalence of the distinct alternating hemiplegic migraine of infancy is unknown. Similarly, the frequency of ophthalmoplegic, retinal, and confusional migraine is unknown.
Sex
Sex prevalence may be observed in some types of MVs. Basilar migraine and migraine aura without headaches are more common in women than in men. Similarly, hemiplegic migraine is more common in women, with a sex ratio (male-to-female) of 1:3.
Basilar migraine in adults is more common in women than in men.
Benign coital headache has a male-to-female ratio of 4:1.

Age
Specific MVs are observed at a higher incidence in different age groups. Ophthalmoplegic migraine, childhood periodic vomiting, and abdominal migraine are almost exclusively of childhood onset, affecting children younger than 10 years. In contrary, basilar and retinal migraines are more frequent in adolescents and young adults, while migraine aura without headache is mainly encountered in adults with long-standing history of migraine aura in early life. Hemiplegic migraine in its familial and sporadic forms has been reported in all age groups, while alternating hemiplegia of childhood is exclusive to children younger than 18 months.

CLINICAL

History
A detailed headache history is necessary to establish the diagnosis of MVs. As many as 20% of patients with MV may experience prodromal symptoms without subsequent headaches. Such paroxysmal symptoms, with the recurrent attacks of transient neurologic symptoms, whether a headache is absent or present, with a positive family history of migraine, and with a normal neurologic examination interictally are confirmatory.
History of recurrent transient hemiplegia or hemiparesis that occurs during an attack of migraine headache suggests hemiplegic migraine. The hemiparesis may resolve prior to the headache or may persist for days to week.
Migraine aura without headaches is suspected in patients with history of recurrent attacks of unilateral transient monocular blindness in patients with otherwise absent risk factors for other causes of carotid disease and a personal or family history of migraine.
Patients with basilar migraine usually present with symptoms of vertebrobasilar insufficiency, which may precede a headache. The most common symptoms are dizziness and vertigo. Other symptoms, including visual disturbance (usually bilateral), dysarthria, acroparesthesias, tinnitus, confusion, or diplopia, may occur.
Ophthalmoplegic migraine present with diplopia and periorbital pain with or without headache. Other symptoms include alteration of consciousness, acute confusion, recurrent vomiting, or seizures.
Retinal migraine: A history of recurrent attacks of transient monocular visual disturbance or blindness with or without a headache, in the absence of other neurological symptoms is suggestive of retinal migraine.
Cyclic vomiting should be suspected in children presenting with recurrent attacks of vomiting without headache, especially when a family history of migraine is present.
A history of recurrent episodes of vertigo accompanied by other migrainous symptoms such as photophobia, headache, nausea, or vomiting is suggestive of vestibular migraine, predominantly in patients with a personal or family history of migraine.

Physical
The neurologic examination in between attack is nonfocal. Ictally, hemiparesis, ophthalmoplegia, or altered consciousness may be observed. Abnormalities of oculomotor nerve with pupillary involvement are seen in ophthalmoplegic migraine, followed by the abducens, and less commonly trochlear nerve palsy. Children with abdominal migraine or cyclic vomiting may show subtle clumsiness, attention deficit, or development delay. In migrainous infarction, some form of neurologic deficit with abnormal neuroimaging is present. Rarely, when patients with retinal migraine are evaluated and examined during an attack of visual loss, optic pallor or narrowing of the retinal vessels can be seen.

DIFFERENTIALS
Section 4 of 9
Other Problems to be Considered
Cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) Episodic ataxia Gastrointestinal motility disorders Miller-Fisher syndrome Volvulus
WORKUP

Imaging Studies
Patients with MV usually undergo unnecessary extensive and invasive diagnostic and laboratory evaluations before the diagnosis is made. A careful history of multiple attacks with complete recovery, with a symptom-free period in between attacks, and a family history of migraine or similar disorder is usually helpful in confirming the diagnosis.
Neuroimaging (CT, MRI) is indicated when the patient presents with a first attack of focal neurologic deficits or altered mental status, or when focal findings persist between attacks. Neuroimaging studies are frequently obtained to exclude other acute causes of the symptoms and to exclude migrainous infarction in patients with persistent aura.
Imaging with MRI of the brain and MRA of the circle of Willis is indicated in ophthalmoplegic migraine to exclude posterior fossa or orbital pathologies associated with ophthalmoplegia. Abnormal enhancement on MRI and enlargement of the cisternal portion of the oculomotor nerve, have been reported. Further assessment may include a CT angiogram or lumbar puncture.
The yield for diagnostic testing in basilar migraine is low. Transient abnormalities on CT scan and MRI have been reported during or immediately following attacks. SPECT studies suggest decreased regional cerebral blood flow in the posterior circulation in basilar migraine during attacks, but transcranial Doppler studies have not revealed changes in blood flow velocities.
Invasive testing in children with periodic syndromes with a strong family history of migraine is unnecessary. A high-resolution MRI and magnetic resonance angiography (MRA) are indicated in suspicious cases in the absence of supportive family history.
In retinal migraine, ruling out eye disease or vascular causes, especially when risk factors for arteriosclerosis exist, is important. Carotids Duplex sonography, transcranial Doppler study, MRA, or CT angiography examinations of the brain are helpful. Fluorescein or cerebral angiographies are rarely necessary. Hypercoagulability workup and sedimentation rate may be useful in excluding other coagulation disorders associated with retinal vasculopathy.

Other Tests
EEG is unnecessary in MVs, except in conditions where seizure disorders need to be excluded, such as migraine-triggered seizure, and in patients with recurrent episodes of confusion. EEG generally does not offer additional information in migraineurs. In general, nonspecific interictal EEG abnormalities, including epileptiform activity, are reported in higher frequencies in migraineurs during or immediately after an episode, with slowing in focal or generalized patterns, and occipital spike-wave complexes.
Continuous ambulatory or video EEG may be useful in patients with episodic confusion or recurrent focal neurologic deficits to exclude partial seizures or nonconvulsive status epilepticus.
Genetic testing is now available for familial hemiplegic migraine using polymerase chain reaction to detect point mutations in the CACNA1A and ATP1A2 genes using and DNA sequencing is now available. Genetic testing may also be performed for other conditions associated with migraine such as CADASIL, an autosomal dominant disorder in which patients may present with migraine, multiple subcortical strokes, and dementia in early adulthood.
In children with cyclic vomiting, a serum lactate level is helpful in excluding mitochondrial disorders. Other tests including, upper and lower gastrointestinal series and vagal autonomic function testing, are rarely indicated.
More recently, functional neuroimaging studies during and immediately after an attack of migraine have demonstrated abnormalities of perfusion and have helped in understanding the pathophysiology of auras. Similarly, SPECT might show hypoperfusion during the aura phase.

Medical Care
The first step in treatment is to establish the diagnosis. Once the syndromes are recognized, MVs respond to typical migraine preventive medications.
Treatment is divided into eliminating particular triggers, acute management of the specific attack, and long-term preventive approach. Patients should follow risk factor modifications including smoking cessation, and they should avoid the use of hormonal replacement therapy and birth control pills, all of which could potentially increase the risk of hypercoagulability migraineurs.
In hemiplegic migraine, acute treatment options include antiemetics, nonsteroidal anti-inflammatory drugs, and nonnarcotic pain relievers. Triptans and ergotamine preparations are contraindicated because of their potential vasoconstrictive effects. Prophylactic treatment is generally warranted because of the severity of the attacks. No data are available to support the use of any particular antimigraine agent. Beta-blockers, low-dose tricyclics, anticonvulsants, and calcium channel blockers can be administered. Acetazolamide has been frequently prescribed to patients with hemiplegic migraine, but its benefit in decreasing the frequency or severity of the attacks is questionable. No data support the use of antiplatelet therapy to decrease the risk of stroke.
In ophthalmoplegic migraine, prednisone has been used with mixed results. The data on the benefit of prophylactic therapy with beta-blockers, such as propranolol, are anecdotal.
In retinal migraine, vasoconstrictive agents such as triptans and ergots should be avoided. The use of prophylactic therapy is also anecdotal; when considered, calcium channel blockers are preferred.
In migraine-triggered seizures, antiepileptic agents are drugs of choice because of their dual benefit in migraine prevention and seizure control
In childhood periodic vomiting syndrome, early use of intravenous fluids containing adequate glucose (to prevent a catabolic state) and analgesics may abort the attack. Some patients respond to the triptans or ergotamine classes of medication. Antiemetic drugs are usually not effective, but ondansetron may be more efficacious given its central mechanism of action. Preventive medications such as cyproheptadine and tricyclic antidepressants are preferred in children.
Abdominal migraine symptoms are usually relieved with sleep. Antiemetics may help aborting an acute attack. For chronic prevention, low doses of tricyclic antidepressants and flunarizine, a calcium channel blocker, are effective. Other migraine prevention medications are occasionally of some benefit.
Triptans, ergots, and dihydroergotamine are contraindicated in patients with migrainous infarction. These patients may respond to nonsteroidal anti-inflammatory drugs (NSAIDs), antiemetics, and non-narcotic pain relievers. Prophylactic therapy is recommended, with tricyclics, beta-blockers, calcium channel blockers, or antiepileptic drugs. Long-term antiplatelet therapy is indicated in patients with migrainous infarction.
Patients with vertiginous migraine rarely respond to migraine prophylactic therapy. Anecdotal data are available on the benefit of verapamil, a calcium channel blocker, and amitriptyline, a tricyclic antidepressant, because of their anticholinergic properties, which may help control the vertigo.

Consultations
Consultation with a neuro-ophthalmologist is warranted in patients who present with persistent visual aura, retinal migraine, or recurrent ophthalmoplegia. Children with cyclic vomiting syndrome rarely require an evaluation by a gastroenterologist to exclude other gastrointestinal disorders. An evaluation by an audiologist may be necessary to exclude other vestibulopathies in patients with vertiginous migraine.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Carbonic anhydrase inhibitors (diuretic)
Carbonic anhydrase (CA) is an enzyme found in many tissues. It catalyzes a reversible reaction whereby carbon dioxide becomes hydrated and carbonic acid dehydrated. These changes may result in a decrease in cerebrospinal fluid by the choroid plexus.
Drug Name
Acetazolamide (Diamox)
Description
For familial hemiplegic migraine. This recommended medication not typically used in migraine, but in hemiplegic MV. Available in 125 mg and 250 mg tab.
Adult Dose
8-30 mg/kg IV/IM divided qid; optimal adult dose 250-1000 mg/dose
Pediatric Dose
5-25 mg/kg IV/IM divided qid
Contraindications
Documented hypersensitivity; hepatic disease; severe renal disease; adrenocortical insufficiency; severe pulmonary obstruction; coadministration with aspirin
Interactions
Can decrease therapeutic levels of lithium and alter excretion of drugs (eg, amphetamines, quinidine, phenobarbital, salicylates) by alkalinizing urine
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients with impaired hepatic function may go into coma; may cause substantial increase in blood glucose in some diabetic patients
Drug Category: Antiemetics
These agents typically are used in migraine and MVs, especially when nausea and vomiting are prominent.
Drug Name
Ondansetron (Zofran)
Description
Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally.
Adult Dose
8 mg PO bid
Pediatric Dose
4-12 years: 4 mg PO tid>12 years: Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
Although potential for cytochrome P-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance, dosage adjustment not usually required
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
To be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting
Drug Name
Promethazine (Phenergan)
Description
Used to control symptoms of nausea and vomiting.
Adult Dose
12.5-25 mg PO/IV/IM/PR q6h
Pediatric Dose
<2>2 years: 12.5-25 mg PO/PR q6h prn
Contraindications
Documented hypersensitivity; asthma; children younger than 2 y (incidences of death due to respiratory depression)
Interactions
May have additive effects when used concurrently with other CNS depressants or anticonvulsants; coadministration with epinephrine may cause hypotension
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in cardiovascular disease, impaired liver function, seizures, sleep apnea, asthma, bone marrow depression, compromised respiratory function, stenosing peptic ulcer, seizure disorders, pediatric patients > 2 y
Drug Category: Calcium channel blockers
These agents inhibit calcium ions from entering slow channels, select voltage-sensitive areas, or vascular smooth muscle.
Drug Name
Verapamil (Calan, Calan SR, Covera-HS, Verelan)
Description
Relaxes smooth muscles and increases oxygen delivery during vasospasms. Used for migraine prophylaxis.
Adult Dose
80 mg PO 3-4 times/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; severe CHF; sick sinus syndrome or second- or third-degree AV block; hypotension (<90>40 kg: 10 mg PO qd
Contraindications
Documented hypersensitivity; depression; extrapyramidal symptoms
Interactions
Avoid with beta-blockers
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause drowsiness
Drug Category: Antihistamines
These agents prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.
Drug Name
Cyproheptadine (Periactin)
Description
Occasionally useful for migraine prophylaxis. An antihistamine that has been used for migraine prevention in children more than in adults. Usually well tolerated. Mechanism of action not clarified and hypotheses include antihistaminic and anti-5-HT 2 effects.
Adult Dose
4 mg PO bid/tid; not to exceed 20 mg/d
Pediatric Dose
<2>14 years: Administer as in adults
Contraindications
Documented hypersensitivity; narrow-angle glaucoma; stenosing peptic ulcer; symptomatic prostatic hypertrophy; bladder neck obstruction; pyloroduodenal obstruction; lower respiratory tract symptoms
Interactions
Potentiates effects of CNS depressants; MAOIs may prolong and intensify anticholinergic and sedative effects of antihistamines
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in patients with a predisposition to urinary retention, history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension; may thicken bronchial secretions caused by anticholinergic properties and may inhibit expectoration and sinus drainage
Drug Category: Tricyclic antidepressants
These agents are used for migraine prophylaxis that is effective independent of antidepressant effect. Mechanism of action is unknown. These agents inhibit activity of such diverse agents as histamine, 5-HT, and acetylcholine.
Drug Name
Amitriptyline (Elavil)
Description
Tricyclic antidepressant used traditionally for migraine prophylaxis. Antimigraine effect is independent from antidepressant effects. Mechanism of action is not clear, but possibly is due to enhanced central serotoninergic and noradrenergic. Cannot be formally recommended for individuals <12>12 years: 10-25 mg PO; titrate up slowly
Contraindications
Documented hypersensitivity; use of MAOIs within 14 d of initiating therapy; history of seizures, cardiac arrhythmias, glaucoma, or urinary retention
Interactions
Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase amitriptyline levels; amitriptyline inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; avoid using in elderly persons
Drug Category: Anticonvulsants
Anticonvulsants, particularly those that interact with the GABAergic system, seem to have a positive effect in reducing migraine attacks. Valproate and gabapentin are most commonly used in this manner.
Drug Name
Topiramate (Topamax)
Description
Indicated for migraine headache prophylaxis. Precise mechanism unknown, but the following properties may contribute to its efficacy: (1) electrophysiological and biochemical evidence showing blockage of voltage-dependent sodium channels, (2) augments the activity of the neurotransmitter GABA at some GABA-A receptor subtypes, (3) antagonizes AMPA/kainate subtype of the glutamate receptor, and (4) inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
Adult Dose
100 mg/d PO divided bid
Pediatric Dose
<2>2 years: 50 mg/d PO divided bid
Contraindications
Documented hypersensitivity
Interactions
Phenytoin, carbamazepine, and valproic acid can significantly decrease topiramate levels; reduces digoxin and norethindrone levels, when administered concomitantly; concomitant use with carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; extreme caution when administering concurrently with CNS depressants since may have an additive effect in CNS depression as well as other cognitive or neuropsychiatric adverse events
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Risk of developing a kidney stone formation is increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; patients taking topiramate should seek immediate medical attention if they experience blurred vision or periorbital pain; continued usage after symptoms develop can lead to glaucoma; primary treatment is discontinuation of topiramate; if left untreated, serious sequelae, including permanent vision loss, may occurOligohidrosis and hyperthermia have been reported predominantly in children during vigorous exercise or exposure to warm environmental temperatures (ensure proper hydration prior and during activity and warm temperatures); may cause hyperchloremic, nonanion gap metabolic acidosis or acute or chronic metabolic acidosis resulting in hyperventilation and nonspecific symptoms, such as fatigue and anorexia, or more severe adverse effects including cardiac arrhythmias or stupor; chronic, untreated metabolic acidosis may increase nephrolithiasis or nephrocalcinosis risk, osteomalacia (ie, rickets in pediatric patients), or osteoporosis with an increased risk for bone fractures; chronic metabolic acidosis in pediatric patients may also reduce growth rates; measure baseline and periodic serum bicarbonate
Drug Name
Valproic acid (Depakote, Depakene)
Description
Delayed-release or extended-release dosage forms are used for prophylaxis of migraine headaches. Although mechanism of action is not established, activity may be related to increased brain levels of GABA, or enhanced GABA action.
Adult Dose
Delayed-release: 250 mg PO bid initially; may titrate upward, not to exceed 1000 mg/d divided bidExtended-release: 500 mg PO qd initially; may increase dose, not to exceed 1000 mg/d
Pediatric Dose
<10>10 years: 250 mg PO bid; 1000 mg/d maximum
Contraindications
Documented hypersensitivity; hepatic disease/dysfunction; hyperammonemic encephalopathy and urea cycle disorders
Interactions
Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce valproate levels; in pediatric patients, protein binding and metabolism of valproate decrease when taken concomitantly with salicylates; coadministration with carbamazepine may result in variable changes of carbamazepine concentrations with possible loss of seizure control; valproate may increase diazepam and ethosuximide toxicity (monitor closely); valproate may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; valproate may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; at periodic intervals and prior to surgery, determine platelet counts and bleeding time before initiating therapy; reduce dose or discontinue therapy if hemorrhage, bruising, or a hemostasis/coagulation disorder occur; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

In/Out Patient Meds
Acetazolamide
Ondansetron

Patient Education
Benign coital headache: If coital headaches have been a problem for a significant period of time, the patient or couple may need psychological counseling.

TREATING PATIENTS WITH COMPLICATED ADHD

INTRODUCTION
According to parental surveys, nearly 8% of children in the United States have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) at some point during their childhood. Slightly over half of these children have taken medications for the condition, with boys outnumbering girls at a ratio of more than 2:1. Approximately one third of children with ADHD outgrow the disorder; an estimated 4.4% of adults have ADHD. Significant morbidity and mortality is associated with ADHD in children with the condition, which leads to an increased likelihood of failure in school and an increased chance of use or abuse of illicit substances. The symptoms of ADHD are also associated with numerous other undesirable social and injury-related statistics, such as an increased number of speeding tickets, more vehicular crashes, more license suspensions, and fewer friends.

Countless theories abound regarding the pathogenesis of ADHD, ranging from an association with the genetics of dopamine-mediated neural pathways to the supposition of a cause and effect relationship with extensive television viewing. Family, twin, and adoption data support the theory that ADHD is heritable, with more than twenty different genes having been studied to date. Current pharmacologic treatment strategies, however, base their therapeutic principles on empirical studies of the cerebral spinal fluid (CSF) in affected individuals. Such studies have demonstrated depletions of dopamine and norepinephrine in the nucleus accumbens and locus coeruleus, respectively. Mild cases of ADHD may respond to environmental restructuring and behavioral therapy. Very young children are often treated with these nonpharmacologic therapies before the demands of school become more strenuous.

Stimulants are the first line of treatment and are considered the most effective therapy.1 Stimulant drugs currently in use (eg, methylphenidate [MPH], amphetamine [AMP]) act within the dopaminergic system. The results of the Multimodal Treatment Study of ADHD have suggested a linear relationship between stimulant dose and clinical response, though each patient has his or her own dose-response curve. Additionally, longer-acting formulations of stimulants are now available, such as dextromethylphenidate. These newer, longer-acting stimulants are associated with less diversion for abuse, greater persistence, and reduced stimulant switching.2 Atomoxetine, a norepinephrine reuptake inhibitor, has proven effectiveness and has replaced pemoline for treatment of refractory symptoms. Bupropion or a tricyclic antidepressant can also be added to further treat refractory symptoms in ADHD.3

While evidence that polypharmacy generally offers an advantage over stimulants alone is not available, patients with comorbidities may be helped by the addition of other classes of medication.


ADHD COMPLICATED BY PSYCHIATRIC COMORBIDITIES
ADHD is commonly complicated by several different psychiatric conditions. The discussion to follow reviews 3 psychiatric comorbidities that are common in patients with ADHD and the evidence-based treatments for these conditions when they appear concomitantly with ADHD.


ADHD and aggression
ADHD may be accompanied by aggressive behavior that ranges from stealing or fighting to severe aggressive outbursts. In these cases, ADHD can commonly be associated with anxiety, depression, or both. Aggression is of obvious concern to caregivers and anyone else exposed to the behavior. Aggressive behaviors should be quantified using one of many available rating scales that include instruments for both caregivers and clinicians. Specific different diagnoses may accompany the aggression, such as oppositional defiant disorder or intermittent explosive disorder. Irrespective of the exact categorization of the behavior and diagnosis, the aggressive behavior can be targeted and reduced.

Treatment begins with standard ADHD treatments. Pharmacologically, this means starting with MPH or AMP. After initiation of standard therapy, the aggression should be reassessed. If treatment elicits improvement of the ADHD symptoms but the aggression is unsatisfactorily improved, a behavioral intervention should be carried out next. This intervention should target the aggressive behavior and contributing factors, such as family or social contacts.

If attenuation of the aggression is unsuccessful after the initiation of standard pharmacologic therapy for ADHD and behavioral interventions, or if the aggression is considered a danger to the patient or others, an atypical antipsychotic should be added to the initial stimulant. Of the atypical antipsychotics, risperidone has been studied most often in randomized controlled trials, but any atypical antipsychotic may be tried. The patient and his or her family should be counseled on the risks associated with atypical antipsychotic treatment, such as extrapyramidal symptoms and gastrointestinal adverse effects.4 If the aggression still does not abate with the addition of atypical antipsychotics, a trial of divalproex sodium or lithium is recommended. Some evidence also suggests efficacy of clonidine in treatment of comorbid aggression with ADHD.5

ADHD and anxiety
Comorbidity rates for ADHD and anxiety are estimated at 20-45%. Levy postulates that comorbidity of ADHD and anxiety is related to a deficit in the synaptic gating mechanism between the prefrontal cortex, hippocampus, and amygdala.6 At the level of the nucleus accumbens, this synapse is impaired by decreased prefrontal cortex inhibition, which allows anxiety-related processes greater impact as a result of greater influence by the amygdala. This damaged “gating of anxiety” at the accumbens allows increased amygdala-based fear or anxiety to manifest in some children with ADHD.6

Atomoxetine was initially developed for depression but was observed to be effective in treating ADHD and, as some literature suggests, in treating anxiety. Its adverse effect profile is very similar to that of the stimulants, with the notable exceptions that atomoxetine does not worsen anxiety or reduce growth rates. It is recommended as an alternative initial therapy to address ADHD, especially when associated with anxiety. This recommendation complements previously recommended treatments, specifically therapy that starts with stimulants and adds selective serotonin reuptake inhibitors (SSRIs) for refractory anxiety.

In effect, the treatment of coexisting ADHD and anxiety has 3 optional initial treatment strategies: atomoxetine, stimulants such as MPH or AMP, and nonpharmacologic alternatives. If atomoxetine is used as a first trial with subsequent failure to improve symptoms, stimulants should be tried next. On the other hand, if stimulants are the first class of medications initiated, and the symptoms of ADHD improve but the symptoms of anxiety worsen or do not improve for the patient, an SSRI should be added. If neither ADHD nor anxiety responds to stimulants, atomoxetine should be tried.7 Indeed, these coexisting but separate disorders are just that and must often be treated separately.

ADHD and depression
In treating the patient with both ADHD and major depressive disorder (MDD), whichever disorder is the most severe and impairing should be treated first. Treatment of one of these coexisting disorders often results in improvement in or abatement of symptoms of the other.

The Children’s Medication Algorithm Project consensus conference held in June of 2007 updated recommendations for approaching the patient with coexisting MDD and ADHD. The conference reinforced the notion that the disorder with the most severe symptoms should be treated first. If monotherapy improves symptoms in one category but not the other, the next step in each separate algorithm should be followed.8 For example, if the treatment of MDD results in improvement of depression but not of the symptoms of ADHD, stimulant therapy may be added to antidepressant therapy. If, on the other hand, ADHD treatment is initiated first with stimulants or atomoxetine, and depression does not improve, cognitive behavioral therapy, SSRIs, or both may be added to stimulant treatment.9

The 2 conditions are assessed separately between regimen changes, and treatment is augmented or altered, as needed. For depression, this may mean starting with monotherapy with an SSRI, cognitive behavioral therapy (CBT), or both, followed by a change in SSRI monotherapy, if needed. If only a partial response is elicited, this treatment can be augmented with lithium, bupropion, or mirtazapine. An alternative to augmenting the SSRI is to discontinue the SSRI and instead treat with monotherapy of a drug from a different class (eg, venlafaxine, bupropion, mirtazapine, duloxetine). Evidence-based psychotherapy can be used at any time during treatment; CBT and interpersonal therapy have also demonstrated efficacy in clinical trials.

ADHD and other comorbidities
Several other comorbidities can occur with ADHD. Among these are learning disorders, substance abuse, Tourette syndrome or other tic disorders, sleep and arousal problems, and bipolar disorder.

ADHD and learning disorders
Children with ADHD repeat grades more often, have lower grades, are more often placed in special classes, and need more tutoring than children without ADHD. Conservative estimates of the prevalence of learning disorders among children with ADHD are about 20-25%.10 One randomized placebo-controlled trial suggested that children with learning disabilities tended to respond more poorly to treatment with MPH than did children without learning disabilities (55% vs 75 %). This was mainly because children with mathematics disabilities were particularly unresponsive.11

ADHD and substance abuse
Retrospective and prospective data demonstrate that children with ADHD are at increased risk for substance abuse. Current data suggest that these children become involved with cigarettes, alcohol, and then drugs. In addition, persons with ADHD, regardless of comorbidity, tend to remain addicted longer than peers without ADHD. However, research shows that children who are treated with stimulants for ADHD have lower rates of substance use disorders than those who are untreated.

ADHD and tourette syndrome or other tic disorders
Children with tic disorders frequently have comorbid ADHD. MPH or AMP is an appropriate first-line agent, as most patients do not experience increased tics with these medications. If tics worsen, whichever stimulant was not used initially should be tried sequentially. The addition of an alpha agonist is the next line of treatment. If response is insufficient, an atypical antipsychotic should be tried in its place. Finally, haloperidol or pimozide is added to the stimulant of choice.12

ADHD and sleep or arousal problems
Parental-report studies demonstrate sleep problems in children with ADHD, though numerous objective studies have not indicated consistent concomitant differences in sleep architecture. Many sleep disturbances, such as restless sleep, night awakening, and difficulty with sleep latency, can be attributed to either medication effects or common psychiatric comorbidities. Many other sleep disorders, such as sleep-disordered breathing, restless legs syndrome, periodic limb movement disorder, delayed sleep phase syndrome, and narcolepsy, may also present concomitantly with the symptoms of ADHD. Evidence has linked the same neurotransmitters that regulate sleep and attention or arousal with ADHD; abnormalities in noradrenergic and dopaminergic systems may be found in both ADHD and sleep disorders.13

ADHD and bipolar disorder
Since many features of ADHD and bipolar disorder overlap (eg, distractibility, inattention, impulsivity, hyperactivity), the rate of comorbidity of these two conditions may be overestimated. The misdiagnosis of bipolar disorder as ADHD can lead to inappropriate treatment resulting in mania or rapid cycling.14 In one study, however, in pediatric patients with both established ADHD and bipolar disorder, after the patients’ manic symptoms were controlled with valproic acid, a randomized placebo-controlled trial of AMP was undertaken. The trial demonstrated the combination of these two medications as both safe and effective treatment. Valproic acid alone did not effectively treat the symptoms of ADHD in these patients with concurrent bipolar disorder.15

CONCLUSION
ADHD is a common disorder in childhood, with a significant percentage of patients continuing to experience the symptoms of their ADHD into adulthood. The symptoms of ADHD often coexist with other psychiatric disorders, such as aggression, depression, and anxiety. Evidence-based treatments for these comorbidities are available, including both pharmacologic and nonpharmacologic therapy. In most cases, and especially when the patient has comorbid depression, treatment of the most debilitating condition should begin first. Symptoms should be reassessed at periodic intervals and after each regimen change.