3354 PART 13 Neurologic Disorders

Aneurysm size and site are important in predicting risk of rupture.

Those >7 mm in diameter and those at the top of the basilar artery

and at the origin of the posterior communicating artery are at greater

risk of rupture.

Clinical Manifestations Most unruptured intracranial aneurysms are completely asymptomatic. Symptoms are usually due to

rupture and resultant SAH, although some unruptured aneurysms

present with mass effect on cranial nerves or brain parenchyma. At

the moment of aneurysmal rupture with major SAH, the intracranial pressure (ICP) suddenly rises. This may account for the sudden

transient loss of consciousness that occurs in nearly half of patients.

Sudden loss of consciousness may be preceded by a brief moment of

excruciating headache, but most patients first complain of headache

upon regaining consciousness. In 10% of cases, aneurysmal bleeding is

severe enough to cause loss of consciousness for several days. In ~45%

of cases, severe headache associated with exertion is the presenting

complaint. The patient often calls the headache “the worst headache of

my life”; however, the most important characteristic is sudden onset.

Occasionally, these ruptures may present as headache of only moderate

intensity or as a change in the patient’s usual headache pattern. The

headache is usually generalized, often with neck stiffness, and vomiting

is common.

Although sudden headache in the absence of focal neurologic symptoms is the hallmark of aneurysmal rupture, focal neurologic deficits

may occur. Anterior communicating artery or MCA bifurcation aneurysms may rupture into the adjacent brain or subdural space and form

a hematoma large enough to produce mass effect. The deficits that

result can include hemiparesis, aphasia, and mental slowness (abulia).

Occasionally, prodromal symptoms suggest the location of a progressively enlarging unruptured aneurysm. A third cranial nerve palsy,

particularly when associated with pupillary dilation, loss of ipsilateral

(but retained contralateral) light reflex, and focal pain above or behind

the eye, may occur with an expanding aneurysm at the junction of

the posterior communicating artery and the internal carotid artery. A

sixth nerve palsy may indicate an aneurysm in the cavernous sinus, and

visual field defects can occur with an expanding supraclinoid carotid or

anterior cerebral artery (ACA) aneurysm. Occipital and posterior cervical pain may signal a posterior inferior cerebellar artery or anterior

inferior cerebellar artery aneurysm (Chap. 426). Pain in or behind the

eye and in the low temple can occur with an expanding MCA aneurysm. Thunderclap headache is a variant of migraine that simulates an

SAH. Before concluding that a patient with sudden, severe headache

has thunderclap migraine, a definitive workup for aneurysm or other

intracranial pathology is required.

Aneurysms can undergo small ruptures and leaks of blood into

the subarachnoid space, so-called sentinel bleeds. Sudden unexplained

headache at any location should raise suspicion of SAH and be investigated because a major hemorrhage may be imminent.

The initial clinical manifestations of SAH can be graded using the

Hunt-Hess or World Federation of Neurosurgical Societies classification schemes (Table 429-1). For ruptured aneurysms, prognosis for

good outcomes falls as the grade increases. For example, it is unusual

for a Hunt-Hess grade 1 patient to die if the aneurysm is treated, but

the mortality rate for grade 4 and 5 patients may be as high as 60%.

Delayed Neurologic Deficits There are four major causes of

delayed neurologic deficits: rerupture, hydrocephalus, delayed cerebral

ischemia (DCI), and hyponatremia.

1. Rerupture. The incidence of rerupture of an untreated aneurysm in

the first month following SAH is ~30%, with the peak in the first

7 days. Rerupture is associated with a 50% mortality rate and poor

outcome. Early treatment eliminates this risk.

2. Hydrocephalus. Acute hydrocephalus can cause stupor and coma

and can be mitigated by placement of an external ventricular drain.

More often, subacute hydrocephalus may develop over a few days

or weeks and causes progressive drowsiness or slowed mentation

with incontinence. Hydrocephalus is differentiated from cerebral

TABLE 429-1 Grading Scales for Subarachnoid Hemorrhage

GRADE HUNT-HESS SCALE

WORLD FEDERATION OF

NEUROSURGICAL SOCIETIES

(WFNS) SCALE

1 Mild headache, normal mental

status, no cranial nerve or motor

findings

GCSa

 score 15, no motor

deficits

2 Severe headache, normal mental

status, may have cranial nerve

deficit

GCS score 13–14, no motor

deficits

3 Somnolent, confused, may have

cranial nerve or mild motor deficit

GCS score 13–14, with motor

deficits

4 Stupor, moderate to severe motor

deficit, may have intermittent

reflex posturing

GCS score 7–12, with or

without motor deficits

5 Coma, reflex posturing or flaccid GCS score 3–6, with or

without motor deficits

a

Glasgow Coma Scale; see Table 443-1.

vasospasm with a CT scan, CT angiogram, transcranial Doppler

(TCD) ultrasound, or conventional x-ray angiography. Hydrocephalus may clear spontaneously or require temporary ventricular

drainage. Chronic hydrocephalus may develop weeks to months

after SAH and manifest as gait difficulty, incontinence, or impaired

mentation. Subtle signs may be a lack of initiative in conversation or

a failure to recover independence.

3. Delayed cerebral ischemia. Vasospasm is the narrowing of the arteries

at the base of the brain following SAH. This may cause symptomatic

ischemia and infarction in ~30% of patients and is the major cause

of delayed morbidity and death. Signs of DCI appear 4–14 days

after the hemorrhage, most often at 7 days. The severity and distribution of vasospasm determine whether infarction will occur.

a. Vasospasm is believed to result from direct effects of clotted

blood and its breakdown products on the arteries within the

subarachnoid space. In general, the more blood that surrounds

the arteries, the greater is the chance of symptomatic vasospasm.

Spasm of major arteries produces symptoms referable to the

appropriate vascular territory (Chap. 426). All of these focal

symptoms may present abruptly, fluctuate, or develop over a

few days. In most cases, focal spasm is preceded by a decline in

mental status.

b. Vasospasm of the large arteries can be detected reliably with

conventional x-ray angiography, but this procedure is invasive

and carries the risk of stroke and other complications. TCD

ultrasound is based on the principle that the velocity of blood

flow within an artery will rise as the lumen diameter is narrowed.

By directing the probe along the MCA and proximal ACA,

carotid terminus, and vertebral and basilar arteries on a daily or

every-other-day basis, vasospasm can be reliably detected and

treatments initiated to prevent cerebral ischemia (see below). CT

angiography is another method that can detect vasospasm. The

addition of CT perfusion imaging may help identify reversible

ischemic deficits.

c. Severe cerebral edema in patients with infarction from vasospasm

may increase the ICP enough to reduce cerebral perfusion pressure.

Treatment may include cerebrospinal fluid (CSF) drainage, mannitol

or hypertonic saline, and, for intractable cases, hemicraniectomy;

moderate hypothermia may have a role as well.

4. Hyponatremia. Hyponatremia may be profound and can develop

quickly in the first 2 weeks following SAH. There is both natriuresis and volume depletion with SAH, so that patients become both

hyponatremic and hypovolemic. Both atrial natriuretic peptide and

brain natriuretic peptide have a role in producing this “cerebral

salt-wasting syndrome.” Typically, it clears over the course of 1–2 weeks

and, in the setting of SAH, should not be treated with free-water

restriction as this may increase the risk of stroke (see below).

3355 Subarachnoid Hemorrhage CHAPTER 429

Laboratory Evaluation and Imaging (Fig. 429-1) The hallmark of aneurysmal rupture is blood in the CSF. More than 95% of

cases have enough blood to be visualized on a high-quality noncontrast

CT scan obtained within 72 h. If the scan fails to establish the diagnosis of SAH and no mass lesion or obstructive hydrocephalus is found,

a lumbar puncture should be performed to establish the presence of

subarachnoid blood. Lysis of the red blood cells and subsequent conversion of hemoglobin to bilirubin stains the spinal fluid yellow within

6–12 h. This xanthochromic spinal fluid peaks in intensity at 48 h and

lasts for 1–4 weeks, depending on the amount of subarachnoid blood.

The extent and location of subarachnoid blood on a noncontrast

CT scan help locate the underlying aneurysm, identify the cause of any

neurologic deficit, and predict the occurrence of vasospasm. A high

incidence of symptomatic vasospasm in the MCA and ACA has been

found when early CT scans show subarachnoid clots >5 × 3 mm in the

basal cisterns or layers of blood >1 mm thick in the cerebral fissures.

CT scans less reliably predict vasospasm in the vertebral, basilar, or

posterior cerebral arteries.

Lumbar puncture prior to an imaging procedure is indicated only

if a CT scan is not available at the time of the suspected SAH. Once

the diagnosis of hemorrhage from a ruptured saccular aneurysm is

suspected, four-vessel conventional x-ray angiography (both carotids

and both vertebrals) is generally performed to localize and define the

anatomic details of the aneurysm and to determine if other unruptured

aneurysms exist (Fig. 429-1C). At some centers, the ruptured aneurysm

can be treated using endovascular techniques at the time of the initial

angiogram as a way to expedite treatment and minimize the number

of invasive procedures. CT angiography is an alternative method for

locating the aneurysm and may be sufficient to plan definitive therapy.

Close monitoring (daily or twice daily) of electrolytes is important

because hyponatremia can occur precipitously during the first 2 weeks

following SAH (see above).

The electrocardiogram (ECG) frequently shows ST-segment and

T-wave changes similar to those associated with cardiac ischemia.

A prolonged QRS complex, increased QT interval, and prominent

“peaked” or deeply inverted symmetric T waves are usually secondary

to the intracranial hemorrhage. There is evidence that structural myocardial lesions produced by circulating catecholamines and excessive

discharge of sympathetic neurons may occur after SAH, causing these

ECG changes and a reversible cardiomyopathy sufficient to cause

shock or congestive heart failure. Echocardiography reveals a pattern

of regional wall motion abnormalities that follow the distribution

of sympathetic nerves rather than the major coronary arteries, with

relative sparing of the ventricular wall apex. The sympathetic nerves

themselves appear to be injured by direct toxicity from the excessive catecholamine release. An asymptomatic troponin elevation is

common. Serious ventricular dysrhythmias occurring in-hospital are

unusual.

TREATMENT

Subarachnoid Hemorrhage

Early aneurysm repair prevents rerupture and allows the safe

application of techniques to improve blood flow (e.g., induced

hypertension) should vasospasm and DCI develop. At many centers, definitive repair is carried out within 24 h of the bleed in

all patients who are stable enough to tolerate the procedure. An

aneurysm can be “clipped” by a neurosurgeon or “coiled” by an

endovascular surgeon. Surgical repair involves placing a metal clip

across the aneurysm neck, thereby immediately eliminating the

risk of rebleeding. This approach requires craniotomy and brain

retraction, which is associated with neurologic morbidity. Endovascular techniques involve placing platinum coils, or other embolic

material, within the aneurysm via a catheter that is passed from the

femoral artery. The aneurysm is packed tightly to enhance thrombosis and over time is walled off from the circulation (Fig. 429-1D).

There have been two prospective randomized trials of surgery versus endovascular treatment for ruptured aneurysms: the first was

the International Subarachnoid Aneurysm Trial (ISAT), which was

terminated early when 24% of patients treated with endovascular

therapy were dead or dependent at 1 year compared to 31% treated

with surgery, a significant 23% relative reduction. After 5 years, risk

of death was lower in the coiling group, although the proportion

of survivors who were independent was the same in both groups.

Risk of rebleeding was low but more common in the coiling group.

These results favoring coiling at 1 year were confirmed in a second

trial, although the differences in functional outcome were no longer

significant at 3 years. Because some aneurysms have a morphology

that is not amenable to endovascular treatment, surgery remains

an important treatment option. Newer endovascular techniques

using balloon-assisted coiling or placement of flow-diverting stents

are increasing the types of aneurysms amenable to endovascular

intervention. Centers that combine both endovascular and neurosurgical expertise likely offer the best outcomes for patients, and

there are reliable data showing that specialized aneurysm treatment

centers can improve mortality rates.

The medical management of SAH focuses on protecting the airway, managing blood pressure before and after aneurysm treatment,

preventing rebleeding prior to treatment, managing vasospasm

and DCI, treating hydrocephalus, treating hyponatremia, limiting

secondary brain insults, and preventing pulmonary embolus (PE).

Intracranial hypertension following aneurysmal rupture occurs

secondary to subarachnoid blood, parenchymal hematoma, acute

hydrocephalus, or loss of vascular autoregulation. Patients who are

stuporous should undergo emergent ventriculostomy to measure

ICP and to treat high ICP in order to prevent cerebral ischemia.

A B

C D

FIGURE 429-1 Subarachnoid hemorrhage. A. Computed tomography (CT)

angiography revealing an aneurysm of the left superior cerebellar artery. B. Noncontrast

CT scan at the level of the third ventricle revealing subarachnoid blood (bright)

in the left sylvian fissure and within the left lateral ventricle. C. Conventional

anteroposterior x-ray angiogram of the right vertebral and basilar artery showing

the large aneurysm. D. Conventional angiogram following coil embolization of

the aneurysm, whereby the aneurysm body is filled with platinum coils delivered

through a microcatheter navigated from the femoral artery into the aneurysm neck.

3356 PART 13 Neurologic Disorders

A B

FIGURE 429-2 Vasospasm of the right middle cerebral artery. A. Catheter

angiography demonstrates significant narrowing of the right middle cerebral

artery (MCA). B. Because of symptomatic delayed cerebral ischemia, soft-balloon

angioplasty was used to dilate the proximal portion of the main MCA stem.

Medical therapies designed to combat raised ICP (e.g., osmotic

therapy and sedation) can also be used as needed. High ICP refractory to treatment is a poor prognostic sign.

Prior to definitive treatment of the ruptured aneurysm, care is

required to maintain adequate cerebral perfusion pressure while

avoiding excessive elevation of arterial pressure. If the patient is

alert, it is reasonable to lower the systolic blood pressure to below

160 mmHg using nicardipine, labetalol, or esmolol. If the patient

has a depressed level of consciousness, ICP should be measured

and the cerebral perfusion pressure targeted to 60–70 mmHg. If

headache or neck pain is severe, mild sedation and analgesia are

prescribed. Extreme sedation is avoided if possible because it can

obscure the ability to clinically detect changes in neurologic status.

Adequate hydration is necessary to avoid a decrease in blood volume predisposing to brain ischemia.

Seizures are uncommon at the onset of aneurysmal rupture. The

quivering, jerking, and extensor posturing that often accompany

loss of consciousness with SAH are probably related to the sharp

rise in ICP rather than seizures. However, anticonvulsants are

sometimes given as prophylactic therapy because a seizure could

theoretically promote rebleeding.

Glucocorticoids may help reduce the head and neck ache caused

by the irritative effect of the subarachnoid blood. There is no good

evidence that they reduce cerebral edema, are neuroprotective,

or reduce vascular injury, and their routine use therefore is not

recommended.

Antifibrinolytic agents are not routinely prescribed but may be

considered in patients in whom aneurysm treatment cannot proceed immediately. They are associated with a reduced incidence of

aneurysmal rerupture but may also increase the risk of DCI and

deep-vein thrombosis (DVT). Several recent studies suggest that

a shorter duration of use (until the aneurysm is secured or for the

first 3 days) may decrease rerupture and be safer than found in

earlier studies of longer duration treatment.

DCI remains the leading cause of morbidity and mortality

following aneurysmal SAH. Treatment with the calcium channel

antagonist nimodipine (60 mg PO every 4 h) improves outcome,

perhaps by preventing ischemic injury rather than reducing the

risk of vasospasm. Nimodipine can cause significant hypotension

in some patients, which may worsen cerebral ischemia in patients

with vasospasm. Symptomatic cerebral vasospasm can also be

treated by increasing the cerebral perfusion pressure by raising

mean arterial pressure through plasma volume expansion and the

judicious use of IV vasopressor agents, usually phenylephrine or

norepinephrine. Raised perfusion pressure has been associated with

clinical improvement in many patients, but high arterial pressure

may promote rebleeding in unprotected aneurysms. Treatment with

induced hypertension and intravenous fluids generally requires

monitoring of arterial and central venous pressures; it is best to

infuse pressors through a central venous line as well. Euvolemia

should be targeted as significant hypervolemia may lead to cardiopulmonary complications. Hypovolemia should be strictly avoided.

If DCI due to vasospasm persists despite optimal medical

therapy, intraarterial vasodilators and percutaneous transluminal

angioplasty are considered (Fig. 429-2). Vasodilatation by direct

angioplasty appears to be permanent, allowing hypertensive therapy

to be tapered sooner. The pharmacologic vasodilators (verapamil

and nicardipine) do not last more than about 24 h, and therefore,

multiple treatments may be required until the subarachnoid blood

is reabsorbed. Although intraarterial papaverine is an effective

vasodilator, there is evidence that papaverine may be neurotoxic, so

its use should generally be avoided.

DCI may occur in the absence of significant large-vessel vasospasm. Potential mechanisms include microthrombosis, activation

of the inflammatory cascade, microvascular dysregulation and

constriction, and cortical spreading depolarization. Targeted treatments for these mechanisms are under investigation.

Acute hydrocephalus can cause stupor or coma. It may clear

spontaneously or require temporary ventricular drainage. When

chronic hydrocephalus develops, ventricular shunting is the treatment of choice.

Free-water restriction is contraindicated in patients with SAH at

risk for DCI because hypovolemia and hypotension may occur and

precipitate cerebral ischemia. Many patients continue to experience

a decline in serum sodium despite receiving parenteral fluids containing normal saline. Frequently, supplemental oral salt coupled

with normal saline will mitigate hyponatremia, but often patients

also require intravenous hypertonic saline. Care must be taken

not to correct serum sodium too quickly in patients with marked

hyponatremia of several days’ duration, as the osmotic demyelination syndrome (Chap. 307) may occur.

All patients should have pneumatic compression stockings

applied to prevent PE. Unfractionated heparin administered subcutaneously for DVT prophylaxis can be initiated within 1–2 days following endovascular treatment or craniotomy with surgical clipping

and is a useful adjunct to pneumatic compression stockings. Treatment of PE depends on whether the aneurysm has been treated and

whether or not the patient has had a craniotomy. Systemic anticoagulation with heparin is contraindicated in patients with ruptured

and untreated aneurysms. It is a relative contraindication following

craniotomy for several days, and it may delay thrombosis of a coiled

aneurysm. If DVT or PE occurs within the first days following

craniotomy, use of an inferior vena cava filter may be considered

to prevent additional PEs, whereas systemic anticoagulation with

heparin is preferred following successful endovascular treatment.

■ FURTHER READING

Diringer MN et al: Critical care management of patients following

aneurysmal subarachnoid hemorrhage: Recommendations from the

Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care 15:211, 2011.

Molyneux AJ et al: The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up

of the UK cohort of the International Subarachnoid Aneurysm Trial

(ISAT). Lancet 385:691, 2015.

Tawk RG et al: Diagnosis and treatment of unruptured intracranial

aneurysms and aneurysmal subarachnoid hemorrhage. Mayo Clin

Proc 96:1970, 2021.

3357 Migraine and Other Primary Headache Disorders CHAPTER 430

The general approach to headache as a cardinal symptom is covered elsewhere (Chap. 16); here, disorders in which headache and

associated features occur in the absence of any exogenous cause are

discussed. The most common are migraine, tension-type headache

(TTH), and the trigeminal autonomic cephalalgias (TACs), notably

cluster headache; the complete list is summarized in Table 430-1.

■ MIGRAINE

Migraine, the second most common cause of headache, and the most

common headache-related, and indeed neurologic, cause of disability

in the world, afflicts ~15% of women and 6% of men over a 1-year

period. It is usually an episodic headache associated with certain features such as sensitivity to light, sound, or movement; nausea and vomiting often accompany the headache. A useful description of migraine

is a recurring syndrome of headache associated with other symptoms

of neurologic dysfunction in varying admixtures (Table 430-2).

A migraine attack has three phases: premonitory (prodrome), headache phase, and postdrome; each has distinct and sometimes disabling

symptoms, which may overlap. About 20–25% of migraine patients

have a fourth, aura, phase. Migraine can often be recognized by its

activators, referred to as triggers.

Migraineurs are particularly sensitive to environmental and sensory

stimuli; migraine-prone patients do not habituate easily to sensory

stimuli. This sensitivity is amplified in women during the menstrual

cycle. Headache can be initiated or amplified by various triggers,

including glare, bright lights, sounds, or other types of afferent stimulation; hunger; let-down from stress; physical exertion; stormy weather

or barometric pressure changes; hormonal fluctuations during menses;

lack of or excess sleep; and alcohol or other chemical stimulation,

such as with nitrates. Knowledge of a patient’s susceptibility to specific

triggers can be useful in management strategies involving lifestyle

adjustments, although it is becoming recognized that some apparent

triggers may in fact be part of the initial phase of the attack; i.e., the

premonitory phase or prodrome.

Pathogenesis The sensory sensitivity that is characteristic of

migraine is probably due to dysfunction of monoaminergic sensory

control systems located in the brainstem and hypothalamus (Fig. 430-1).

Activation of cells in the trigeminal nucleus results in the release of

vasoactive neuropeptides, particularly calcitonin gene–related peptide

(CGRP), at vascular terminals of the trigeminal nerve and within the

trigeminal nucleus. CGRP receptor antagonists, gepants, have now

been shown to be effective in the acute and preventive treatment of

migraine, and four monoclonal antibodies to CGRP, or its receptor,

have been shown to be effective in migraine prevention. Centrally,

the second-order trigeminal neurons cross the midline and project to

ventrobasal and posterior nuclei of the thalamus for further processing.

Additionally, there are projections to the periaqueductal gray and hypothalamus, from which reciprocal descending systems have established

antinociceptive effects. Other brainstem regions likely to be involved

in descending modulation of trigeminal pain include the nucleus locus

coeruleus in the pons and the rostroventromedial medulla.

Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin)

in migraine. In the late 1950s, methysergide was found to antagonize

certain peripheral actions of 5-HT and was introduced, based on its

anti-inflammation properties, as a migraine preventive. The triptans

were designed to stimulate selectively subpopulations of 5-HT receptors; at least 14 different 5-HT receptors exist in humans. The triptans

are potent agonists of 5-HT1B and 5-HT1D receptors, and some are

430 Migraine and Other

Primary Headache

Disorders

Peter J. Goadsby

active at the 5-HT1F receptor; the latter’s exclusive agonists are called

ditans. Triptans arrest nerve signaling in the nociceptive pathways

of the trigeminovascular system, at least in the trigeminal nucleus

caudalis and trigeminal sensory thalamus, in addition to promoting

cranial vasoconstriction, whereas ditans, now shown conclusively to be

effective in acute migraine, act only at neural and not vascular targets.

A range of other neural targets are currently under investigation for the

acute and preventive management of migraine.

Data also support a role for dopamine in the pathophysiology of

migraine. Most migraine symptoms can be induced by dopaminergic

stimulation. Moreover, there is dopamine receptor hypersensitivity in

migraineurs, as demonstrated by the induction of yawning, nausea,

vomiting, hypotension, and other symptoms of a migraine attack by

dopaminergic agonists at doses that do not affect nonmigraineurs.

Dopamine receptor antagonists are effective therapeutic agents in

migraine, especially when given parenterally or concurrently with

other antimigraine agents. Moreover, hypothalamic activation, anterior

to that seen in cluster headache, has now been shown in the premonitory (prodromal) phase of migraine using functional imaging, and this

may hold a key to understanding some part of the role of dopamine in

the disorder.

Migraine genes identified by studying families with familial hemiplegic migraine (FHM) reveal involvement of ion channels, suggesting

that alterations in membrane excitability can predispose to migraine.

Mutations involving the Cav

2.1 (P/Q)–type voltage-gated calcium

channel CACNA1A gene are now known to cause FHM 1; this mutation is responsible for about 50% of FHM cases. Mutations in the

Na+-K+ATPase ATP1A2 gene, designated FHM 2, are responsible for

about 20% of FHMs. Mutations in the neuronal voltage-gated sodium

channel SCN1A cause FHM 3. Functional neuroimaging has suggested

that brainstem regions in migraine (Fig. 430-2) and the posterior hypothalamic gray matter region close to the human circadian pacemaker

cells of the suprachiasmatic nucleus in cluster headache (Fig. 430-3) are

good candidates for specific involvement in these primary headaches.

Diagnosis and Clinical Features Classic diagnostic criteria for

migraine headache are listed in Table 430-3 and should be considered

together with the extended features in Table 430-2. A high index of

suspicion is required to diagnose migraine: the migraine aura, consisting of visual disturbances with flashing lights or zigzag lines moving

across the visual field or of other neurologic symptoms, is reported in

only 20–25% of patients. It should be distinguished from the pan-field

television static-like disturbance now recognized as the visual snow

syndrome. The first phase of a migraine attack for most patients is the

premonitory (prodromal) phase consisting of some or all of the following: yawning, tiredness, cognitive dysfunction, mood change, neck discomfort, polyuria, and food cravings; this can last from a few hours to

days. Typically, the headache phase follows with its associated features,

such as nausea, photophobia, and phonophobia as well as allodynia.

When questioned, these typical migraine symptoms also emerge in the

premonitory phase, and typical premonitory symptoms also continue

into the headache phase. As the headache lessens, many patients enter

a postdrome, most commonly feeling tired/weary, having problems

concentrating, and experiencing mild neck discomfort that can last for

hours and sometimes up to a day. A headache diary can often be helpful

in making the diagnosis; this is also helpful in assessing disability and

the frequency of acute attacks. Patients with episodes of migraine on

8 or more days per month and with at least 15 total days of headache

per month are considered to have chronic migraine (see “Chronic

Daily Headache” in Chap. 16). Migraine must be differentiated from

TTH (discussed below), which is reported to be the most common primary headache syndrome. Migraine has several forms that have been

defined (Table 430-1): migraine with and without aura and chronic

migraine are the most important. Migraine at its most basic level is

headache with associated features, and TTH is headache that is featureless. Most patients with disabling headache probably have migraine.

Patients with acephalgic migraine (typical aura without headache,

1.2.1.2 in Table 430-1) experience recurrent neurologic symptoms,

often with nausea or vomiting, but with little or no headache. Vertigo

3358 PART 13 Neurologic Disorders

TABLE 430-1 Primary Headache Disorders, Modified from International Classification of Headache Disorders-III-Beta (Headache Classification

Committee of the International Headache Society, 2018)

1. Migraine 1.1 Migraine without aura

1.2 Migraine with aura

1.2.1 Migraine with typical aura

1.2.1.1 Typical aura with headache

1.2.1.2 Typical aura without headache

1.2.2 Migraine with brainstem aura

1.2.3 Hemiplegic migraine

1.2.3.1 Familial hemiplegic migraine (FHM)

1.2.3.1.1 Familial hemiplegic migraine type 1

1.2.3.1.2 Familial hemiplegic migraine type 2

1.2.3.1.3 Familial hemiplegic migraine type 3

1.2.3.1.4 Familial hemiplegic migraine, other loci

1.2.3.2 Sporadic hemiplegic migraine

1.2.4 Retinal migraine

1.3 Chronic migraine

1.4 Complications of migraine

1.4.1 Status migrainosus

1.4.2 Persistent aura without infarction

1.4.3 Migrainous infarction

1.4.4 Migraine aura-triggered seizure

1.5 Probable migraine

1.5.1 Probable migraine without aura

1.5.2 Probable migraine with aura

1.6 Episodic syndromes that may be associated with migraine

1.6.1 Recurrent gastrointestinal disturbance

1.6.1.1 Cyclical vomiting syndrome

1.6.1.2 Abdominal migraine

1.6.2 Benign paroxysmal vertigo

1.6.3 Benign paroxysmal torticollis

2. Tension-type headache 2.1 Infrequent episodic tension-type headache

2.2 Frequent episodic tension-type headache

2.3 Chronic tension-type headache

2.4 Probable tension-type headache

3. Trigeminal autonomic cephalalgias 3.1 Cluster headache

3.1.1 Episodic cluster headache

3.1.2 Chronic cluster headache

3.2 Paroxysmal hemicrania

3.2.1 Episodic paroxysmal hemicrania

3.2.2 Chronic paroxysmal hemicrania

3.3 Short-lasting unilateral neuralgiform headache attacks

3.3.1 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)

3.3.1.1 Episodic SUNCT

3.3.1.2 Chronic SUNCT

3.3.2 Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA)

3.3.2.1 Episodic SUNA

3.3.2.2 Chronic SUNA

3.4 Hemicrania continua

3.5 Probable trigeminal autonomic cephalalgia

4. Other primary headache disorders 4.1 Primary cough headache

4.2 Primary exercise headache

4.3 Primary headache associated with sexual activity

4.4 Primary thunderclap headache

4.5 Cold-stimulus headache

4.5.1 Headache attributed to external application of a cold stimulus

4.5.2 Headache attributed to ingestion or inhalation of a cold stimulus

4.6 External-pressure headache

4.6.1 External-compression headache

4.6.2 External-traction headache

4.7 Primary stabbing headache

4.8 Nummular headache

4.9 Hypnic headache

4.10 New daily persistent headache (NDPH)

3359 Migraine and Other Primary Headache Disorders CHAPTER 430

Dura

Cortex

Dorsal raphe

nucleus

Locus

coeruleus

Superior

salivatory nucleus

Magnus raphe

nucleus

Thalamus

Hypothalamus

Cortex

Dorsal raphe

nucleus

Locus

coeruleus

Superior

salivatory nucleus

Magnus raphe

nucleus

Sphenopalatine

ganglion

Trigeminal

ganglion

TCC

Thalamus

Hypothalamus

Quintothalamic

tract

FIGURE 430-1 Brainstem pathways that modulate sensory input. The key pathway for pain in migraine is the trigeminovascular input from the meningeal vessels, which

passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex (TCC). These neurons in turn project in the quintothalamic

tract and, after decussating in the brainstem, synapse on neurons in the thalamus. Important modulation of the trigeminovascular nociceptive input comes from the dorsal

raphe nucleus, locus coeruleus, and nucleus raphe magnus.

TABLE 430-2 Migraine Symptoms by Attack Phase

Premonitory (prodromal)

- Neck discomfort

- Higher center

• Cognitive impairment (brain “fog”)

• Mood change

• Fatigue

- Homeostatic

• Yawning/sleepiness

• Polyuria/polydipsia

• Food cravings

Aura

- Neurologic disturbance, such as scintillating scotoma

Headache Phase

- Pain

- Nausea/vomiting

- Sensory sensitivity

• Photophobia

• Phonophobia

• Osmophobia

• Allodynia

• Vertigo

Postdrome

- Tiredness

- Weariness

- Concentration impairment

Source: Adapted from PJ Goadsby et al: Pathophysiology of migraine: A disorder of

sensory processing. Physiol Rev 97:553, 2017.

can be prominent; it has been estimated that one-third of patients

referred for vertigo or dizziness have a primary diagnosis of migraine.

Migraine aura can have prominent brainstem symptoms, and the terms

basilar artery and basilar-type migraine have now been replaced by

migraine with brainstem aura (Table 430-1).

TREATMENT

Migraine Headache

Once a diagnosis of migraine has been established, it is important to

assess the extent of a patient’s disease and disability. The Migraine

Disability Assessment Score (MIDAS) is a well-validated, easy-touse tool (Fig. 430-4).

Patient education is an important aspect of migraine management. Information for patients is available at websites such as the

American Migraine Foundation (www.americanmigrainefoundation.

org) and the Migraine Trust (www.migrainetrust.org). It is helpful

for patients to understand that migraine is an inherited tendency to

headache; that migraine can be modified and controlled by lifestyle

adjustments and medications, but it cannot be eradicated; and that,

except on some occasions in women on oral estrogens or contraceptives, migraine is not associated with serious or life-threatening

illnesses.

NONPHARMACOLOGIC MANAGEMENT

Migraine can often be managed to some degree by a variety of

nonpharmacologic approaches. When patients can identify reliable triggers, their avoidance can be useful. A regulated lifestyle

is helpful, including a healthy diet, regular exercise, regular sleep

patterns, avoidance of excess caffeine and alcohol, and avoidance

3360 PART 13 Neurologic Disorders

A B

C D

FIGURE 430-2 Positron emission tomography (PET) activation in migraine. Hypothalamic, dorsal midbrain, and dorsolateral pontine activation are seen in triggered attacks

in the premonitory phase before pain, whereas in migraine attacks, dorsolateral pontine activation persists, as it does in chronic migraine (not shown). The dorsolateral

pontine area, which includes the noradrenergic locus coeruleus, is fundamental to the expression of migraine. Moreover, lateralization of changes in this region of the

brainstem correlates with lateralization of the head pain in hemicranial migraine; the scans shown in panels C and D are of patients with acute migraine headache on the right

and left side, respectively. (Panel A from FH Maniyar et al: Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 137:232, 2014; panel B

reproduced with permission from SK Afridi et al: A positron emission tomographic study in spontaneous migraine. Arch Neurol 62:1270, 2005.; Panels C and D from SK Afridi

et al: A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128:932, 2005.)

A B

FIGURE 430-3 A. Posterior hypothalamic gray matter region activation demonstrated by positron emission tomography in a patient with acute cluster headache. B. Highresolution T1-weighted magnetic resonance image obtained using voxel-based morphometry demonstrates increased gray matter activity, lateralized to the side of pain in

a patient with cluster headache. (Panel A from A May et al: Hypothalamic activation in cluster headache attacks. Lancet 352:275, 1998. Panel B from A May et al: Correlation

between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 5:836, 1999.)

3361 Migraine and Other Primary Headache Disorders CHAPTER 430

of acute changes in stress levels, being particularly wary of the letdown effect.

The measures that benefit a given individual should be used

routinely because they provide a simple, cost-effective approach to

migraine management. Patients with migraine do not encounter

more stress than headache-free individuals; overresponsiveness

to changes in stress appears to be the issue. Because the stresses

of everyday living cannot be eliminated, lessening one’s response

to stress by various techniques is helpful for many patients. These

may include yoga, transcendental meditation, hypnosis, and conditioning techniques such as biofeedback. For most patients seen

in clinical practice, this approach is, at best, an adjunct to pharmacotherapy. Nonpharmacologic measures are unlikely to prevent all

migraine attacks, and pharmacologic approaches are often needed.

ACUTE ATTACK THERAPIES FOR MIGRAINE

The mainstay of pharmacologic therapy is the judicious use of

one or more of the many medicines that are effective in migraine

(Table 430-4). The selection of the optimal regimen for a given

TABLE 430-3 Simplified Diagnostic Criteria for Migraine

REPEATED ATTACKS OF HEADACHE LASTING 4–72 H IN PATIENTS WITH A

NORMAL PHYSICAL EXAMINATION, NO OTHER REASONABLE CAUSE FOR THE

HEADACHE, AND:

AT LEAST 2 OF THE FOLLOWING

FEATURES:

PLUS AT LEAST 1 OF THE FOLLOWING

FEATURES:

Unilateral pain Nausea/vomiting

Throbbing pain Photophobia and phonophobia

Aggravation by movement

Moderate or severe intensity

Source: Adapted from the International Headache Society Classification (Headache

Classification Committee of the International Headache Society, Cephalalgia 38:1,

2018).

On how many days in the last 3 months did you miss work or school because

of your headaches?

How many days in the last 3 months was your productivity at work or school

reduced by half or more because of your headaches (do not include days

you counted in question 1 where you missed work or school)?

On how many days in the last 3 months did you not do household work

because of your headaches?

How many days in the last 3 months was your productivity in household work

reduced by half or more because of your headaches (do not include days

you counted in question 3 where you did not do household work)?

On how many days in the last 3 months did you miss family, social, or leisure

activities because of your headaches?

On how many days in the last 3 months did you have a headache? (If a

headache lasted more than one day, count each day.)

On a scale of 0–10, on average how painful were these headaches? (Where

0 = no pain at all, and 10 = pain as bad as it can be.)

*Migraine Disability Assessment Score

(Questions 1−5 are used to calculate the MIDAS score.)

Grade I—Minimal or Infrequent Disability: 0–5

Grade II—Mild or Infrequent Disability: 6–10

Grade III—Moderate Disability: 11–20

Grade IV—Severe Disability: > 20

© Innovative Medical Research 1997

1.

2.

3.

4.

5.

A.

B.

days

days

days

days

days

days

...............................................................................................

............................

................................................................................

.....................

.................................................................

.........................................

..........................................

INSTRUCTIONS: Please answer the following questions about ALL headaches you have had

over the last 3 months. Write zero if you did not do the activity in the last 3 months.

*MIDAS Questionnaire

FIGURE 430-4 The Migraine Disability Assessment Score (MIDAS) Questionnaire.

patient depends on a number of factors, the most important of

which is the severity of the attack. Mild migraine attacks can usually be managed by oral agents; the average efficacy rate is 50–70%.

Severe migraine attacks may require parenteral therapy. Most drugs

effective in the treatment of migraine are members of one of

five major pharmacologic classes: nonsteroidal anti-inflammatory

drugs; 5-HT1B/1D receptor agonists—triptans; CGRP receptor antagonists—gepants; 5-HT1F receptor agonists—ditans; and dopamine

receptor antagonists.

In general, an adequate dose of whichever agent is chosen should

be used as soon as possible after the onset of an attack. If additional

medication is required within 60 min because symptoms return or

have not abated, the initial dose should be increased for subsequent

attacks or a different class of drug tried as first-line treatment.

Repeat dosing of the same medicine at 2 hours while safe, has been

established to be ineffective for triptans. An exception to this rule

may be gepants, for which there are data to show that retreatment

with the same dose is helpful. Migraine therapy must be individualized; a standard approach for all patients is not possible. A

therapeutic regimen may need to be constantly refined until one is

identified that provides the patient with rapid, complete, and consistent relief with minimal side effects (Table 430-5).

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Both the severity and duration of a migraine attack can be reduced significantly

by NSAIDs (Table 430-4). Indeed, many undiagnosed migraineurs

self-treat with nonprescription NSAIDs. A general consensus is that

NSAIDs are most effective when taken early in the migraine attack.

However, the effectiveness of these agents in migraine is usually

less than optimal in moderate or severe migraine attacks. The

combination of acetaminophen (paracetamol), aspirin, and caffeine

has been approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate migraine. The

combination of aspirin and metoclopramide has been shown to