3362 PART 13 Neurologic Disorders

TABLE 430-4 Treatment of Acute Migraine

DRUG TRADE NAME DOSAGE

Simple Analgesics

Acetaminophen, aspirin, caffeine Excedrin Migraine Two tablets or caplets q6h (max 8 per day)

NSAIDs

Naproxen Aleve, Anaprox, generic 220–550 mg po bid

Ibuprofen Advil, Motrin, Nuprin, generic 400 mg po q3–4h

Tolfenamic acid Clotam Rapid 200 mg po; may repeat ×1 after 1–2 h

Diclofenac K Cambia 50 mg po with water

5-HT1B/1D Receptor Agonists—Triptans

Oral

Ergotamine 1 mg, caffeine 100 mg Cafergot One or two tablets at onset, then one tablet q½h (max 6 per day, 10 per week)

Naratriptan Amerge 2.5-mg tablet at onset

Rizatriptan Maxalt 5–10-mg tablet at onset

Maxalt-MLT

Sumatriptan Imitrex 50–100-mg tablet at onset

Frovatriptan Frova 2.5-mg tablet at onset

Almotriptan Axert 12.5-mg tablet at onset

Eletriptan Relpax 40 or 80 mg at onset

Zolmitriptan Zomig 2.5-mg tablet at onset

Zomig Rapimelt

Nasal

Dihydroergotamine Migranal Nasal Spray

Trudhesa Nasal Spray

Prior to nasal spray, the pump must be primed 4 times; 1 spray (0.5 mg) is

administered, followed in 15 min by a second spray

One spray into each nostril

Sumatriptan Imitrex Nasal Spray 5–20 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg spray

Zolmitriptan Zomig 5 mg intranasal spray as one spray

Parenteral

Dihydroergotamine DHE-45 1 mg IV, IM, or SC at onset and q1h (max 3 mg/d, 6 mg per week)

Sumatriptan Imitrex Injection

Alsuma

Sumavel DosePro

6 mg SC at onset (may repeat once after 1 h for max of 2 doses in 24 h)

CGRP Receptor Antagonists—Gepants

Oral

Rimegepant

Ubrogepant

Nurtec

Ubrelvy

75 mg ODT po

50 or 100 mg po; a second dose may be taken 2 hours after the first, if needed.

5-HT1F Receptor Agonist—Ditans

Oral

Lasmiditan Reyvow 50, 100, or 200 mg po

Dopamine Receptor Antagonists

Oral

Metoclopramide Reglan,a

 generica 5–10 mg/d

Prochlorperazine Compazine,a

 generica 1–25 mg/d

Parenteral

Chlorpromazine Generica 0.1 mg/kg IV at 2 mg/min; max 35 mg/d

Metoclopramide Reglan,a

 generic 10 mg IV

Prochlorperazine Compazine,a

 generica 10 mg IV

Other

Oral

Acetaminophen, 325 mg, plus dichloralphenazone,

100 mg, plus isometheptene, 65 mg

Midrin, generic Two capsules at onset followed by 1 capsule q1h (max 5 capsules)

Parenteral

Opioids

Other

Neuromodulation

Single-pulse transcranial magnetic stimulation (sTMS)

Noninvasive vagus nerve stimulation (nVNS)

Remote electrical neuromodulation

Transcutaneous supraorbital nerve stimulation

Generica

sTMSmini

gammaCore

Nerivio

Cefaly

Multiple preparations and dosages; see Table 13-1

Two pulses at onset followed by two further pulses

Two doses each of 120 s

30- to 45-min stimulation to the upper arm

60-min stimulation

a

Not all drugs are specifically indicated by the FDA for migraine. Local regulations and guidelines should be consulted.

Note: Antiemetics (e.g., domperidone 10 mg or ondansetron 4 or 8 mg) or prokinetics (e.g., metoclopramide 10 mg) are sometimes useful adjuncts.

Abbreviations: 5-HT, 5-hydroxytryptamine; NSAIDs, nonsteroidal anti-inflammatory drugs; ODT, orally disintegrating tablets.

3363 Migraine and Other Primary Headache Disorders CHAPTER 430

TABLE 430-5 Clinical Stratification of Acute Specific Migraine

Treatments

CLINICAL SITUATION TREATMENT OPTIONS

Failed NSAIDs/analgesics First tier

Sumatriptan 50 mg or 100 mg PO

Almotriptan 12.5 mg PO

Rizatriptan 10 mg PO

Eletriptan 40 mg PO

Zolmitriptan 2.5 mg PO

Rimegepant 75 mg

Ubrogepant 50 or 100 mg

Lasmiditan 50, 100, or 200 mg

Slower effect/better tolerability

Naratriptan 2.5 mg PO

Frovatriptan 2.5 mg PO

Infrequent headache

Ergotamine/caffeine 1–2/100 mg PO

Dihydroergotamine nasal spray 2 mg

Early nausea or difficulties

taking tablets

Zolmitriptan 5 mg nasal spray

Sumatriptan 20 mg nasal spray

Rizatriptan 10 mg MLT wafer

Headache recurrence Ergotamine 2 mg (most effective PR/usually with

caffeine)

Naratriptan 2.5 mg PO

Almotriptan 12.5 mg PO

Eletriptan 40 mg

Rimegepant 75 mg

Ubrogepant 50 or 100 mg

Tolerating acute treatments

poorly

Naratriptan 2.5 mg

Almotriptan 12.5 mg

Rimegepant 75 mg

Ubrogepant 50, 100 mg

Single-pulse transcranial magnetic stimulation

Noninvasive vagus nerve stimulation

Early vomiting Zolmitriptan 5 mg nasal spray

Sumatriptan 25 mg PR

Sumatriptan 6 mg SC

Menses-related headache Prevention

Ergotamine po at night

Estrogen patches

Rimegepant 75 mg po taken during the menses

Treatment

Triptans

Dihydroergotamine nasal spray

Very rapidly developing

symptoms

Zolmitriptan 5 mg nasal spray

Sumatriptan 6 mg SC

Dihydroergotamine 1 mg IM

Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.

be comparable to a single dose of oral sumatriptan. Important side

effects of NSAIDs include dyspepsia and gastrointestinal irritation.

5-HT1B/1D RECEPTOR AGONISTS—TRIPTANS

Oral Stimulation of 5-HT1B/1D receptors can stop an acute migraine

attack. Ergotamine and dihydroergotamine are nonselective receptor agonists, whereas the triptans are selective 5-HT1B/1D receptor

agonists. A variety of triptans—sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan—are

available for the treatment of migraine.

Each drug in the triptan class has similar pharmacologic properties, varying slightly in terms of clinical efficacy. Rizatriptan and

eletriptan are, on a population basis, the most efficacious of the

triptans. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, with an advantage of having multiple

formulations, whereas almotriptan has a similar rate of efficacy to

sumatriptan and is better tolerated, and frovatriptan and naratriptan are somewhat slower in onset and are also well tolerated.

Clinical efficacy appears to be related more to the t

max (time to peak

plasma level) than to the potency, half-life, or bioavailability. This

observation is consistent with a large body of data indicating that

faster-acting analgesics are more effective than slower-acting ones.

Unfortunately, monotherapy with a selective oral 5-HT1B/1D

receptor agonist does not result in rapid, consistent, and complete

relief of migraine in all patients. Triptans are generally not effective

in migraine with aura unless given after the aura is completed

and the headache initiated. Side effects are common, although

often mild and transient. Moreover, 5-HT1B/1D receptor agonists are

contraindicated in individuals with a history, symptoms, or signs

of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. Recurrence of headache, within the usual time course of

an attack, is another important limitation of triptan use and occurs

at least occasionally in most patients. Evidence from randomized

controlled trials shows that coadministration of a longer-acting

NSAID, naproxen 500 mg, with sumatriptan will augment the initial effect of sumatriptan and, importantly, reduce rates of headache

recurrence.

Ergotamine preparations offer a nonselective means of stimulating 5-HT1

 receptors. A nonnauseating dose of ergotamine should

be sought because a dose that provokes nausea is too high and may

intensify head pain. Oral (excluding sublingual) formulations of

ergotamine also contain 100 mg caffeine (theoretically to enhance

ergotamine absorption and possibly to add additional analgesic

activity). The average oral ergotamine dose for a migraine attack

is 2 mg. Because the clinical studies demonstrating the efficacy of

ergotamine in migraine predated the clinical trial methodologies

used with the triptans, it is difficult to assess the comparative

efficacy of ergotamine versus the triptans. In general, with use of

ergotamine there appears to be a much higher incidence of nausea

than with triptans but less headache recurrence.

Nasal Nasal formulations of dihydroergotamine, zolmitriptan, or

sumatriptan can be useful in patients requiring a nonoral route of

administration. The nasal sprays result in substantial blood levels

within 30–60 min. Although in theory nasal sprays might provide

faster and more effective relief of a migraine attack than oral formulations, their reported efficacy is only ~50–60%. Studies with a

new inhalational formulation of dihydroergotamine indicate that

its absorption problems can be overcome to produce rapid onset of

action with good tolerability.

Parenteral Administration of drugs by injection, such as dihydroergotamine and sumatriptan, is approved by the FDA for the rapid

relief of a migraine attack. Peak plasma levels of dihydroergotamine

are achieved 3 min after IV dosing, 30 min after intramuscular (IM)

dosing, and 45 min after subcutaneous (SC) dosing. If an attack has

not already peaked, SC or IM administration of 1 mg of dihydroergotamine is adequate for about 80–90% of patients. Sumatriptan,

4–6 mg SC, is effective in ~50–80% of patients and can now be

administered by a needle-free device.

CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR

ANTAGONISTS—GEPANTS

Oral gepants are small-molecule CGRP receptor antagonists that

are effective in the acute treatment of migraine. Two are currently

approved by the FDA: rimegepant and ubrogepant. Both were more

likely to render patients pain-free at 2 hours and most bothersome

symptom–free when compared with placebo in large phase 3 clinical trials. The most bothersome symptom is derived by asking

3364 PART 13 Neurologic Disorders

patients to identify which symptom—of nausea, photophobia and

phonophobia—was most bothersome during the treated attack;

success required that this symptom was eliminated at 2 hours. Gepants are extremely well tolerated with only a few percent of patients

reporting troublesome side effects, such as mild nausea.

5-HT1F RECEPTOR AGONISTS—DITANS

Lasmiditan, a highly selective, orally available, 5-HT1F receptor

agonist, has been approved by the FDA for the acute treatment

of migraine based on large phase 3 studies where it was superior

to placebo. Ditans have no vascular effects because the 5-HT1F

receptor is located in the central and peripheral nervous system but

not vasculature; the class thus unequivocally fills a gap in therapy

for patients with cardiovascular and cerebrovascular disease. The

major side effect is dizziness, occurring in about 15% of patients

in clinical trials, and somnolence in 6%. Patients are advised not to

drive for 8 hours after treatment.

DOPAMINE RECEPTOR ANTAGONISTS

Oral Oral dopamine receptor antagonists can be considered as

adjunctive therapy in migraine. Drug absorption is impaired during migraine because of reduced gastrointestinal motility. Delayed

absorption occurs even in the absence of nausea and is related to

the severity of the attack and not its duration. Therefore, when

oral NSAIDs and/or triptan agents fail, the addition of a dopamine

receptor antagonist, such as metoclopramide 10 mg or domperidone

10 mg (not available in the United States), should be considered to

enhance gastric absorption. In addition, dopamine receptor antagonists decrease nausea/vomiting and restore normal gastric motility.

Parenteral Dopamine receptor antagonists (e.g., chlorpromazine,

prochlorperazine, metoclopramide) by injection can also provide

significant acute relief of migraine; they can be used in combination

with parenteral 5-HT1B/1D receptor agonists. A common IV protocol

used for the treatment of severe migraine is the administration

over 2 min of a mixture of 5 mg of prochlorperazine and 0.5 mg of

dihydroergotamine.

OTHER OPTIONS FOR ACUTE MIGRAINE

Oral The combination of acetaminophen, dichloralphenazone,

and isometheptene, one to two capsules, has been classified by the

FDA as “possibly” effective in the treatment of migraine. Because

the clinical studies demonstrating the efficacy of this combination

analgesic in migraine predated the clinical trial methodologies used

with the triptans, it is difficult to compare the efficacy of this sympathomimetic compound with other agents.

Parenteral Opioids are modestly effective in the acute treatment

of migraine. For example, IV meperidine (50–100 mg) is given frequently in the emergency department (ED). This regimen “works”

in the sense that the pain of migraine is eliminated. Importantly,

it is clear from a recent randomized controlled trial that prochlorperazine is superior to hydromorphone in the ED setting. However,

opioids are clearly suboptimal for patients with recurrent headache.

Opioids do not treat the underlying headache mechanism; rather,

they act to alter the pain sensation, and there is evidence their use

may decrease the likelihood of a response to triptans in the future.

Moreover, in patients taking oral opioids, such as oxycodone or

hydrocodone, habituation or addiction can greatly confuse the

treatment of migraine. Opioid craving and/or withdrawal can

aggravate and accentuate migraine. Therefore, it is recommended

that opioid use in migraine be limited to patients with severe, but

infrequent, headaches that are unresponsive to other pharmacologic approaches or who have contraindications to other therapies.

Neuromodulation Single-pulse transcranial magnetic stimulation

(sTMS) is FDA approved for the acute treatment of migraine. Two

pulses can be applied at the onset of an attack, and this can be

repeated. The use of sTMS is safe where there is no cranial metal

implant, and offers an option to patients seeking nonpharmaceutical approaches to treatment. Similarly, a noninvasive vagus nerve

stimulator (nVNS) is FDA approved for the treatment of migraine

attacks in adults. One to two 120-s doses may be applied for attack

treatment. Remote electrical neuromodulation using a smartphone

app that stimulates the upper arm for 30–45 min is also effective for

treatment of acute migraine, as is transcutaneous supraorbital nerve

stimulation for 60 min; both are FDA approved.

MEDICATION-OVERUSE HEADACHE

Acute attack medications, particularly opioid or barbituratecontaining compound analgesics, have a propensity to aggravate

headache frequency and induce a state of refractory daily or neardaily headache called medication-overuse headache. This condition

is likely not a separate headache entity but a reaction of the patient’s

underlying migraine biology to a particular medicine. Migraine

patients who have two or more headache days a week should be

cautioned about frequent analgesic use (see “Chronic Daily

Headache” in Chap. 16).

PREVENTIVE TREATMENTS FOR MIGRAINE

Patients with an increasing frequency of migraine attacks or with

attacks that are either unresponsive or poorly responsive to abortive

treatments are good candidates for preventive agents. In general, a

preventive medication should be considered in patients with four

or more attacks a month. Significant side effects are associated with

the use of many of these agents; furthermore, determination of dose

can be difficult because the recommended doses have been derived

for conditions other than migraine. The mechanism of action of

these drugs is unclear; it seems likely that the brain sensitivity that

underlies migraine is modified. Patients are usually started on a low

dose of a chosen treatment; the dose is then gradually increased, up

to a reasonable maximum, to achieve clinical benefit.

Treatments that have the capacity to stabilize migraine are listed

in Table 430-6. Most treatments must be taken daily, and there is

usually a lag of 2–12 weeks before an effect is seen. The drugs that

have been approved by the FDA for the preventive treatment of

migraine include propranolol, timolol, rimegepant, sodium valproate, topiramate, eptinezumab, erenumab, fremanezumab, and

galcanezumab. In addition, a number of other drugs appear to

display preventive efficacy. This group includes amitriptyline, candesartan, nortriptyline, flunarizine, phenelzine, and cyproheptadine.

Placebo-controlled trials of onabotulinum toxin type A in episodic

migraine were negative, whereas, overall, placebo-controlled trials in

chronic migraine were positive. The FDA has approved sTMS for the

preventive treatment of migraine. It offers a well-tolerated, effective

option for patients. Phenelzine is a monoamine oxidase inhibitor

(MAOI); therefore, tyramine-containing foods, decongestants, and

meperidine are contraindicated, and it is reserved for only very

recalcitrant cases. Methysergide is now of historical interest only

because it is no longer manufactured. Melatonin has been reported

to be useful, with controlled trial evidence, but is not approved in

the United States. Monoclonal antibodies to the CGRP receptor

(erenumab) or to the peptide (eptinezumab, fremanezumab, and galcanezumab) have all proven effective and well tolerated in migraine

and are now available as novel, migraine-specific preventative agents.

The probability of success with any one of the antimigraine drugs

is ~50%. Many patients are managed adequately with well-tolerated

doses of candesartan, propranolol, amitriptyline, topiramate, or

valproate. If these agents fail or produce unacceptable side effects,

neuromodulation approaches, such as sTMS, or related agents from

the above classes, can be used (Table 430-6). Once effective stabilization is achieved, the drug is continued for ~6 months and then

slowly tapered, assuming the patient agrees, to assess the continued

need. Many patients are able to discontinue medication and experience fewer and milder attacks for long periods, suggesting that

these drugs may alter the natural history of migraine. The advent of

CGRP monoclonal antibodies and CGRP receptor antagonists has

significantly changed the landscape of preventive treatment; with

the combination of efficacy that is often within the first month and

excellent tolerability, expectations of outcomes are changing.

3365 Migraine and Other Primary Headache Disorders CHAPTER 430

TABLE 430-6 Preventive Treatments in Migrainea

DRUG DOSE SELECTED SIDE EFFECTS

Beta blocker

Propranolol 40–120 mg bid Reduced energy

Metoprolol 25–100 mg bid Tiredness

Postural symptoms

Contraindicated in asthma

Antidepressants

Amitriptyline 10–75 mg at night Drowsiness

Dosulepin 25–75 mg at night

Nortriptyline 25–75 mg at night Note: Some patients may only

need a total dose of 10 mg,

although generally 1–1.5 mg/kg

body weight is required.

Venlafaxine 75–150 mg/d

Anticonvulsants

Topiramate 25–200 mg/d Paresthesias

Cognitive symptoms

Weight loss

Glaucoma

Caution with nephrolithiasis

Valproate 400–600 mg bid Drowsiness

Weight gain

Tremor

Hair loss

Fetal abnormalities

Hematologic or liver

abnormalities

Serotonergic drugs

Pizotifenb

0.5–2 mg qd Weight gain

CGRP antagonists

Eptinezumab

Erenumab

Fremanezumab

Galcanezumab

100 or 300 mg IV every

12 weeks

70 or 140 mg SC monthly

225 mg monthly or

675 mg q3 months, SC

240 mg loading then

120 mg monthly, SC

Nasopharyngitis

Nasopharyngitis, constipation

Injection site reactions

Nasopharyngitis

Rimegepant 75 mg every other day Nausea abdominal pain/

dyspepsia

Other classes

Flunarizineb 5–15 mg qd Drowsiness

Weight gain

Depression

Parkinsonism

Candesartan 4–24 mg daily Dizziness

Memantine 5–20 mg daily Dizziness, tiredness

Melatonin 3–12 mg nightly Drowsiness

Neuromodulation

 Single-pulse

transcranial

magnetic

stimulation (sTMS)

4–24 pulses per day Lightheadedness

Tingling

Tinnitus

Chronic migraine

 Onabotulinum toxin

type A

155 U Loss of brow furrow

No convincing evidence from controlled trials

Verapamil

Controlled trials demonstrate no effect

Nimodipine

Clonidine

 Selective serotonin

reuptake inhibitors:

fluoxetine

a

Commonly used preventives are listed with typical doses and common side effects.

Not all listed medicines are approved by the U.S. Food and Drug Administration;

local regulations and guidelines should be consulted.

b

Not available in the United States.

■ TENSION-TYPE HEADACHE

Clinical Features The term tension-type headache is commonly

used to describe a chronic head-pain syndrome characterized by

bilateral tight, bandlike discomfort. The pain typically builds slowly,

fluctuates in severity, and may persist more or less continuously

for many days. The headache may be episodic or chronic (present

>15 days per month).

A useful clinical approach is to diagnose TTH in patients whose

headaches are completely without accompanying features such as

nausea, vomiting, photophobia, phonophobia, osmophobia, throbbing,

and aggravation with movement. Such an approach neatly separates

migraine, which has one or more of these features and is the main

differential diagnosis, from TTH. The International Headache Society’s

main definition of TTH allows an admixture of nausea, photophobia,

or phonophobia in various combinations, although the appendix definition does not; this illustrates the difficulty in distinguishing these two

clinical entities. In clinical practice, using the appendix definition to

dichotomize patients on the basis of the presence of associated features

(migraine) and the absence of associated features (TTH) is highly recommended. Indeed, patients whose headaches fit the TTH phenotype

and who have migraine at other times, along with a family history

of migraine, migrainous illnesses of childhood, or typical migraine

triggers to their migraine attacks, may be biologically different from

those who have TTH headache with none of the features. TTH may be

infrequent (episodic) or occur on 15 days or more a month (chronic).

Pathophysiology The pathophysiology of TTH is incompletely

understood. It seems likely that TTH is due to a primary disorder of

central nervous system pain modulation alone, unlike migraine, which

involves a more generalized disturbance of sensory modulation. Data

suggest a genetic contribution to TTH, but this may not be a valid

finding: given the current diagnostic criteria, the studies undoubtedly

included many migraine patients. The name tension-type headache

implies that pain is a product of nervous tension, but there is no clear

evidence for tension as an etiology. Muscle contraction has been considered to be a feature that distinguishes TTH from migraine, but there

appear to be no differences in contraction between the two headache

types.

TREATMENT

Tension-Type Headache

The pain of TTH can generally be managed with simple analgesics

such as acetaminophen, aspirin, or NSAIDs. Behavioral approaches

including relaxation can also be effective. Clinical studies have demonstrated that triptans in pure TTH are not helpful, although triptans are

effective in TTH when the patient also has migraine. For chronic

TTH, amitriptyline is the only proven treatment (Table 430-6); other

tricyclics, selective serotonin reuptake inhibitors, and the benzodiazepines have not been shown to be effective. There is no evidence for

the efficacy of acupuncture. Placebo-controlled trials of onabotulinum

toxin type A in chronic TTH were negative.

■ TRIGEMINAL AUTONOMIC CEPHALALGIAS

(TACs), INCLUDING CLUSTER HEADACHE

The TACs describe a grouping of primary headaches including cluster headache, paroxysmal hemicrania (PH), SUNCT (short-lasting

unilateral neuralgiform headache attacks with conjunctival injection

and tearing)/SUNA (short-lasting unilateral neuralgiform headache

attacks with cranial autonomic symptoms), and hemicrania continua

(Table 430-1). TACs are characterized by relatively short-lasting attacks

of head pain associated with lateralized cranial autonomic symptoms,

such as lacrimation, conjunctival injection, aural fullness, or nasal congestion (Table 430-7). Pain is usually severe and may occur more than

once a day. Because of the associated nasal congestion or rhinorrhea,

patients are often misdiagnosed with “sinus headache” and treated with

decongestants, which are ineffective.

3366 PART 13 Neurologic Disorders

TACs must be differentiated from short-lasting headaches that do

not have prominent cranial autonomic syndromes, notably trigeminal

neuralgia (TN), primary stabbing headache, and hypnic headache. The

cycling pattern and length, frequency, and timing of attacks are useful

in classifying patients. Patients with TACs should be considered, if clinically indicated, to undergo pituitary imaging and pituitary function

tests because there is an excess of TAC presentations in patients with

pituitary tumor–related headache, particularly prolactin and growth

hormone secreting tumors.

Cluster Headache Cluster headache is a relatively rare form of

primary headache, although nonetheless a common condition, with

a population frequency of ~0.1%. The pain is deep, usually retroorbital, often excruciating in intensity, nonfluctuating, and explosive in

quality. A core feature of cluster headache is periodicity. At least one

of the daily attacks of pain recurs at about the same hour each day for

the duration of a cluster bout. The typical cluster headache patient has

daily bouts of one to two attacks of relatively short-duration unilateral

pain for 8–10 weeks a year; this is usually followed by a pain-free interval that averages a little less than 1 year. Cluster headache is characterized as chronic when there is <3 months of sustained remission without

treatment. Patients are generally perfectly well between episodes. Onset

of attacks is nocturnal in about 50% of patients, and men are affected

three times more often than women. Patients with cluster headache

tend to move about during attacks, pacing, rocking, or rubbing their

head for relief; some may even become aggressive during attacks. This

is in sharp contrast to patients with migraine, who prefer to remain

motionless during attacks.

Cluster headache is associated with ipsilateral symptoms of cranial

parasympathetic autonomic activation: conjunctival injection or lacrimation, aural fullness, rhinorrhea or nasal congestion, or cranial sympathetic dysfunction such as ptosis. The sympathetic deficit is peripheral

and likely to be due to parasympathetic activation with injury to ascending sympathetic fibers surrounding a dilated carotid artery as it passes

into the cranial cavity. When present, photophobia and phonophobia are

far more likely to be unilateral and on the same side of the pain, rather

than bilateral, as is seen in migraine. This phenomenon of unilateral

photophobia/phonophobia is characteristic of TACs. Cluster headache is

likely to be a disorder involving central pacemaker neurons and neurons

in the posterior hypothalamic region (Fig. 430-3).

TREATMENT

Cluster Headache

The most satisfactory treatment is the administration of drugs to prevent cluster attacks until the bout is over. However, treatment of acute

attacks is required for all cluster headache patients at some time.

ACUTE ATTACK TREATMENT

Cluster headache attacks peak rapidly, and thus a treatment with

rapid onset is required. Many patients with acute cluster headache

respond very well to oxygen inhalation. This should be given as

100% oxygen at 10–12 L/min for 15–20 min. It appears that high

flow and high oxygen content are important. Sumatriptan 6 mg SC

is rapid in onset and will usually shorten an attack to 10–15 min;

there is no evidence of tachyphylaxis. Sumatriptan (20 mg) and

zolmitriptan (5 mg) nasal sprays are both effective in acute cluster

headache, offering a useful option for patients who may not wish

to self-inject daily. Noninvasive vagus nerve stimulation (nVNS)

is FDA approved for the acute treatment of attacks in episodic

cluster headache using three 2-min stimulation cycles applied consecutively at the onset of headache on the side of pain; this may be

repeated after 9 min. Oral sumatriptan is not effective for prevention or for acute treatment of cluster headache.

PREVENTIVE TREATMENTS (TABLE 430-8)

The choice of a preventive treatment in cluster headache depends

in part on the length of the bout. Patients with long bouts or those

TABLE 430-7 Clinical Features of the Trigeminal Autonomic Cephalalgias

CLUSTER HEADACHE PAROXYSMAL HEMICRANIA SUNCT/SUNA

Gender M > F F = M F ~ M

Pain

Type Stabbing, boring Throbbing, boring, stabbing Burning, stabbing, sharp

Severity Excruciating Excruciating Severe to excruciating

Site Orbit, temple Orbit, temple Periorbital

Attack frequency 1/alternate day–8/d 1–20/d (>5/d for more than half the time) 3–200/d

Duration of attack 15–180 min 2–30 min 5–240 s

Autonomic features Yes Yes Yes (prominent conjunctival injection

and lacrimation)a

Migrainous featuresb Yes Yes Yes

Alcohol trigger Yes No No

Cutaneous triggers No No Yes

Indomethacin effect — Yesc —

Abortive treatment Sumatriptan injection or nasal spray

Zolmitriptan nasal spray

No effective treatment Lidocaine (IV)

Oxygen

nVNSc

Preventive treatment Verapamil

Galcanezumab

Indomethacind Lamotrigine

Topiramate

Melatonin

Topiramate

Lithium Gabapentin

a

If conjunctival injection and tearing are not present, consider SUNA. b

Nausea, photophobia, or phonophobia; photophobia and phonophobia are typically unilateral on the

side of the pain. c

Noninvasive vagus nerve stimulation is FDA approved in episodic cluster headache d

Indicates complete response to indomethacin.

Abbreviations: SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic features; SUNCT, short-lasting unilateral neuralgiform headache

attacks with conjunctival injection and tearing.

3367 Migraine and Other Primary Headache Disorders CHAPTER 430

with chronic cluster headache require medicines that are safe when

taken for long periods. For patients with relatively short bouts,

limited courses of oral glucocorticoids can be very useful. A 10-day

course of prednisone, beginning at 60 mg daily for 7 days and

followed by a rapid taper, may interrupt the pain bout for many

patients. Greater occipital nerve injection with lidocaine and corticosteroids has been shown to be effective in randomized controlled

trials, with a benefit that lasts up to 6–8 weeks. The CGRP monoclonal antibody galcanezumab has been approved by the FDA for

treatment of episodic cluster headache; it reduces attack frequency,

is well tolerated, and is often an effective option.

Most experts favor verapamil as the first-line preventive treatment for patients with chronic cluster headache or with prolonged

bouts. While verapamil compares favorably with lithium in practice,

some patients require verapamil doses far in excess of those administered for cardiac disorders. The initial dose range is 40–80 mg

twice daily; effective doses may be as high as 960 mg/d. Side effects

such as constipation, leg swelling, or gingival hyperplasia can be problematic. Of paramount concern, however, is the cardiovascular safety

of verapamil, particularly at high doses. Verapamil can cause heart

block by slowing conduction in the atrioventricular node, a condition

that can be monitored by following the PR interval on a standard

electrocardiogram (ECG). Approximately 20% of patients treated with

verapamil develop ECG abnormalities, which can be observed with

doses as low as 240 mg/d; these abnormalities can worsen over time

in patients on stable doses. A baseline ECG is recommended for all

patients. The ECG is repeated 10 days after a dose change in patients

whose dose is being increased above 240 mg daily. Dose increases are

usually made in 80-mg increments. For patients on long-term verapamil, ECG monitoring every 6 months is advised.

NEUROMODULATION THERAPY

When medical therapies fail in chronic cluster headache, neuromodulation strategies can be used. Sphenopalatine ganglion (SPG)

stimulation with an implanted battery-free stimulator has been

shown in randomized controlled trials to be effective in aborting

attacks and reducing their frequency over time. nVNS compares

favorably with standard-of-care in open-label experience. Similarly,

occipital nerve stimulation has been used open label and appears to

be beneficial. Deep-brain stimulation of the region of the posterior

hypothalamic gray matter is successful in about 50% of patients

treated, although its risk-versus-benefit ratio makes it inappropriate

before all other less invasive options have been explored.

■ PAROXYSMAL HEMICRANIA

Paroxysmal hemicrania (PH) is characterized by frequent unilateral,

severe, short-lasting episodes of headache. Like cluster headache, the

pain tends to be retroorbital but may be experienced all over the head

and is associated with autonomic phenomena such as lacrimation and

nasal congestion. Patients with remissions are said to have episodic

PH, whereas those with the nonremitting form are said to have chronic

PH. The essential features of PH are: unilateral very severe pain;

short-lasting attacks (2–45 min); very frequent attacks (usually >5 a

TABLE 430-8 Preventive Management of Cluster Headache

SHORT-TERM PREVENTION LONG-TERM PREVENTION

EPISODIC CLUSTER HEADACHE

EPISODIC CLUSTER HEADACHE AND

PROLONGED CHRONIC CLUSTER

HEADACHE

Prednisone 1 mg/kg up to 60 mg qd,

tapering over 21 days

Verapamil 160–960 mg/d

Galcanezumab 300 mg SC

Greater occipital nerve injection

Verapamil 160–960 mg/d

nVNSb

 6–24 stimulations/d

Melatonina

 9–12 mg/d

Topiramatea

 100–400 mg/d

Lithium 400–800 mg/d

Gabapentina

 1200–3600 mg/d

a

Unproven but of potential benefit. b

Noninvasive vagus nerve stimulation.

day); marked autonomic features ipsilateral to the pain; rapid course

(<72 h); and excellent response to indomethacin. In contrast to cluster

headache, which predominantly affects males, the male-to-female ratio

in PH is close to 1:1.

Indomethacin (25–75 mg tid), which can completely suppress

attacks of PH, is the treatment of choice. Although therapy may be

complicated by indomethacin-induced gastrointestinal side effects,

currently there are no consistently effective alternatives. Topiramate

is helpful in some cases. Verapamil, an effective treatment for cluster

headache, does not appear to be useful for PH. nVNS can be very effective in these patients. In occasional patients, PH can coexist with TN

(PH-tic syndrome); similar to cluster-tic syndrome, each component

may require separate treatment.

Secondary PH has been reported with lesions in the region of the

sella turcica, including arteriovenous malformation, cavernous sinus

meningioma, pituitary pathology, and epidermoid tumors. Secondary

PH is more likely if the patient requires high doses (>200 mg/d) of

indomethacin. In patients with apparent bilateral PH, raised cerebrospinal fluid (CSF) pressure should be suspected. It is important to

note that indomethacin reduces CSF pressure. When a diagnosis of PH

is considered, MRI is indicated to exclude a pituitary lesion.

■ SUNCT/SUNA

SUNCT is a rare primary headache syndrome characterized by severe,

unilateral orbital or temporal pain that is stabbing or throbbing in

quality. Diagnosis requires at least 20 attacks, lasting for 5–240 s;

ipsilateral conjunctival injection and lacrimation should be present. In

some patients, conjunctival injection or lacrimation is missing, and the

diagnosis of SUNA can be made.

DIAGNOSIS The pain of SUNCT/SUNA is unilateral and may be

located anywhere in the head. Three basic patterns can be seen: single

stabs, which are usually short-lived; groups of stabs; or a longer attack

comprising many stabs between which the pain does not completely

resolve, thus giving a “saw-tooth” phenomenon with attacks lasting

many minutes. Each pattern may be seen in the context of an underlying continuous head pain. Characteristics that lead to a suspected

diagnosis of SUNCT are the cutaneous (or other) triggers of attacks, a

lack of refractory period to triggering between attacks, and the lack of a

response to indomethacin. Apart from trigeminal sensory disturbance,

the neurologic examination is normal in primary SUNCT/SUNA.

The diagnosis of SUNCT/SUNA is often confused with TN particularly in first-division TN (Chap. 441). Minimal or no cranial autonomic symptoms and a clear refractory period to triggering indicate a

diagnosis of TN.

SECONDARY (SYMPTOMATIC) SUNCT SUNCT can be

seen with posterior fossa or pituitary lesions. All patients with SUNCT/

SUNA should be evaluated with pituitary function tests and a brain

MRI with pituitary views.

TREATMENT

SUNCT/SUNA

ABORTIVE THERAPY

Therapy of acute attacks is not a useful concept in SUNCT/SUNA

because the attacks are of such short duration. However, IV lidocaine, which arrests the symptoms, can be used in hospitalized

patients.

PREVENTIVE THERAPY

Long-term prevention to minimize disability and hospitalization is

the goal of treatment. The most effective treatment for prevention

is lamotrigine, 200–400 mg/d. Topiramate and gabapentin may also

be effective. Carbamazepine, 400–500 mg/d, has been reported by

patients to offer modest benefit.

Surgical approaches such as microvascular decompression or

destructive trigeminal procedures are seldom useful and often produce long-term complications. Greater occipital nerve injection has

3368 PART 13 Neurologic Disorders

produced limited benefit in some patients. Occipital nerve stimulation is probably helpful in a subgroup of these patients. For intractable cases, short-term prevention with IV lidocaine can be effective.

■ HEMICRANIA CONTINUA

The essential features of hemicrania continua are moderate and continuous unilateral pain associated with fluctuations of severe pain;

complete resolution of pain with indomethacin; and exacerbations

that may be associated with autonomic features, including conjunctival

injection, lacrimation, and photophobia on the affected side. The age

of onset ranges from 10 to 70 years; women are affected twice as often

as men. The cause is unknown.

TREATMENT

Hemicrania Continua

Treatment consists of indomethacin; other NSAIDs appear to be

of little or no benefit. The IM injection of 100 mg of indomethacin

has been proposed as a diagnostic tool, and administration with a

placebo injection in a blinded fashion can be very useful diagnostically. Alternatively, a trial of oral indomethacin, starting with 25 mg

tid, then 50 mg tid, and then 75 mg tid, can be given. Up to 2 weeks

at the maximal dose may be necessary to assess whether a dose has

a useful effect. Topiramate can be helpful in some patients. nVNS

can be very useful in these patients. Occipital nerve stimulation

probably has a role in patients with hemicrania continua who are

unable to tolerate indomethacin.

■ OTHER PRIMARY HEADACHE DISORDERS

Primary Cough Headache Primary cough headache is a generalized headache that begins suddenly, lasts for seconds or several

minutes, sometimes up to a few hours, and is precipitated by coughing;

it is preventable by avoiding coughing or other precipitating events,

which can include sneezing, straining, laughing, or stooping. In all

patients with this syndrome, serious etiologies must be excluded before

a diagnosis of “benign” primary cough headache can be established. A

Chiari malformation or any lesion causing obstruction of CSF pathways or displacing cerebral structures can be the cause of the head pain.

Other conditions that can present with cough or exertional headache

as the initial symptom include cerebral aneurysm, carotid stenosis, and

vertebrobasilar disease. Benign cough headache can resemble benign

exertional headache (below), but patients with the former condition

are typically older.

TREATMENT

Primary Cough Headache

Indomethacin 25–50 mg two to three times daily is the treatment

of choice. Some patients with cough headache obtain complete

cessation of their attacks with lumbar puncture; this is a simple

option when compared to prolonged use of indomethacin, and it

is effective in about one-third of patients. The mechanism of this

response is unclear.

Primary Exercise Headache Primary exercise headache has

features resembling both cough headache and migraine. It may be

precipitated by any form of exercise; it often has the pulsatile quality

of migraine. The pain lasts <48 h, is bilateral, and is often throbbing

at onset; migrainous features may develop in patients susceptible to

migraine. The duration tends to be shorter in adolescents than in older

adults. Primary exercise headache can be prevented by avoiding excessive exertion, particularly in hot weather or at high altitude.

The mechanism of primary exercise headache is unclear. Acute

venous distension likely explains one syndrome—the acute onset

of headache with straining and breath holding, as in weightlifter’s

headache. Because exercise can trigger headache in a number of serious

underlying conditions (Chap. 16), these must be considered in patients

with exercise headache. Pain from angina may be referred to the head,

probably by central connections of vagal afferents, and may present as

exercise headache (cardiac cephalgia). The link to exercise is the main

clinical clue that headache is of cardiac origin. Pheochromocytoma

may occasionally cause exercise headache. Intracranial lesions and

stenosis of the carotid arteries are other possible etiologies.

TREATMENT

Primary Exercise Headache

Exercise regimens should begin modestly and progress gradually

to higher levels of intensity. Indomethacin at daily doses from

25–150 mg is generally effective in benign exertional headache.

Indomethacin (50 mg), a gepant, ergotamine (1 mg orally), and dihydroergotamine (2 mg by nasal spray) are useful preventive measures.

Primary Headache Associated with Sexual Activity Three

types of sex headache are reported: a dull bilateral ache in the head and

neck that intensifies as sexual excitement increases; a sudden, severe,

explosive headache occurring at orgasm; and a postural headache

developing after coitus. The last arises from vigorous sexual activity

and is a form of low CSF pressure headache and thus not a primary

headache disorder (Chap. 16). Headaches developing at the time

of orgasm are not always benign; 5–12% of cases of subarachnoid

hemorrhage are precipitated by sexual intercourse. Sex headache is

reported by men more often than women and may occur at any time

during the years of sexual activity. It may appear on several occasions

in succession and then not trouble the patient again, even without an

obvious change in sexual activity. In patients who stop sexual activity

when headache is first noticed, the pain may subside within a period of

5 min to 2 h. In about half of patients, sex headache will subside within

6 months. Most patients with sex headache do not have exercise or

cough headache; this clinical paradox is generally a marker of primary

sex headache. Migraine is probably more common in patients with sex

headache.

TREATMENT

Primary Sex Headache

Benign sex headaches recur irregularly and infrequently. Management can often be limited to reassurance and advice about ceasing

sexual activity if a mild, warning headache develops. Propranolol

can be used to prevent headache that recurs regularly or frequently,

but the dosage required varies from 40–200 mg/d. An alternative is the calcium channel–blocking agent diltiazem, 60 mg tid.

Indomethacin (25–50 mg), frovatriptan (2.5 mg), or a gepant taken

30–45 min prior to sexual activity can also be helpful.

Primary Thunderclap Headache Sudden onset of severe headache may occur in the absence of any known provocation. The differential diagnosis includes the sentinel bleed of an intracranial aneurysm,

cervicocephalic arterial dissection, and cerebral venous thrombosis.

Headaches of explosive onset may also be caused by the ingestion of

sympathomimetic drugs or of tyramine-containing foods in a patient

who is taking MAOIs, or they may be a symptom of pheochromocytoma. Whether thunderclap headache can be the presentation of an

unruptured cerebral aneurysm is uncertain. When neuroimaging studies and lumbar puncture exclude subarachnoid hemorrhage, patients

with thunderclap headache usually do very well over the long term. In

one study of patients whose CT scans and CSF findings were negative,

~15% had recurrent episodes of thunderclap headache, and nearly half

subsequently developed migraine or TTH.

The first presentation of any sudden-onset severe headache should

be diligently investigated with neuroimaging (CT or, when possible,

3369 Migraine and Other Primary Headache Disorders CHAPTER 430

MRI with MR angiography) and CSF examination. Reversible segmental cerebral vasoconstriction may be seen in primary thunderclap headache without an intracranial aneurysm, and it is thought

that this may be an underdiagnosed condition. In the presence of

posterior leukoencephalopathy, the differential diagnosis includes

cerebral angiitis, drug toxicity (cyclosporine, intrathecal methotrexate/

cytarabine, pseudoephedrine, or cocaine), posttransfusion effects,

and postpartum angiopathy. Treatment with nimodipine may be helpful, although the vasoconstriction of primary thunderclap headache

resolves spontaneously.

Cold-Stimulus Headache This refers to head pain triggered by

application or ingestion/inhalation of something cold. It is brought on

quickly and typically resolves within 10–30 min of the stimulus being

removed. It is best recognized as “brain-freeze” headache or ice-cream

headache when due to ingestion. Although cold may be uncomfortable

at some level for many people, it is the reliable, severe, and somewhat

prolonged nature of these pains that set them apart. The transient

receptor potential cation subfamily M member 8 (TRPM8) channel, a

known cold-temperature sensor, may be a mediator of this syndrome.

Naproxen 500 mg taken 30 min prior to exposure can be helpful for

this problem.

External Pressure Headache External pressure from compression or traction on the head can produce a pain that may have some

generalized component, although the pain is largely focused around

the site of the pressure. It typically resolves within an hour of the stimulus being removed. Examples of stimuli include helmets, swimming

goggles, or very long ponytails. Treatment is to recognize the problem

and remove the stimulus.

Primary Stabbing Headache The essential features of primary

stabbing headache are stabbing pain confined to the head or, rarely,

the face, lasting from 1 to many seconds and occurring as a single stab

or a series of stabs; absence of associated cranial autonomic features;

absence of cutaneous triggering of attacks; and a pattern of recurrence

at irregular intervals (hours to days). When present in adolescents,

primary stabbing headache may be a presenting and very troublesome

problem for the patient. The pains have been variously described as

“ice-pick pains” or “jabs and jolts.” They are more common in patients

with other primary headaches, such as migraine, the TACs, and hemicrania continua. A key clinical feature is an irregular cadence compared

to the regular cadence of the throbbing or pounding that characterizes

migraine.

TREATMENT

Primary Stabbing Headache

The response of primary stabbing headache to indomethacin

(25–50 mg two to three times daily) is usually excellent. As a general

rule, the symptoms wax and wane, and after a period of control on

indomethacin, it is appropriate to withdraw treatment and observe

the outcome.

Nummular Headache Nummular headache is felt as a round or

elliptical discomfort that is fixed in place, ranges in size from 1–6 cm, and

may be continuous or intermittent. Uncommonly it may be multifocal.

It may be episodic but is more often continuous during exacerbations.

Accompanying the pain there may be a local sensory disturbance, such

as allodynia or hypesthesia. Local dermatologic or bony lesions need

to be excluded by examination and investigation. This condition can be

difficult to treat when present in isolation; tricyclics, such as amitriptyline, or anticonvulsants, such as topiramate or valproate, are most

often tried. This phenotype can be seen in combination with migraine

and the TACs, in which cases treatment of the associated condition is

often effective for the nummular headache as well.

Hypnic Headache This headache syndrome typically begins a

few hours after sleep onset. The headaches last from 15–30 min and

are typically moderately severe and generalized, although they may

be unilateral and can be throbbing. Patients may report falling back

to sleep only to be awakened by a further attack a few hours later; up

to three repetitions of this pattern occur through the night. Daytime

naps can also precipitate head pain. Most patients are female, and the

onset is usually after age 60 years. Headaches are typically bilateral but

may be unilateral. Photophobia, phonophobia, and nausea are usually

absent. The major secondary consideration in this headache type is

poorly controlled hypertension; 24-h blood pressure monitoring is

recommended to detect this treatable condition.

TREATMENT

Hypnic Headache

Patients with hypnic headache generally respond to a bedtime dose

of lithium carbonate (200–600 mg). For those intolerant of lithium,

verapamil (160 mg) is an alternative strategy. One to two cups

of coffee, or caffeine 60 mg orally, at bedtime may be effective in

approximately one-third of patients. Case reports also suggest that

flunarizine, 5 mg nightly, or indomethacin, 25–75 mg nightly, can

be effective.

New Daily Persistent Headache Primary new daily persistent

headache (NDPH) occurs in both men and women. It can be of the

migrainous type, with features of migraine, or it can be featureless,

appearing as new-onset TTH. Those with migrainous features are the

most common form and include unilateral headache and throbbing

pain; each feature is present in about one-third of patients. Nausea,

photophobia, and/or phonophobia occur in about half of patients.

Some patients have a previous history of migraine; however, the proportion of NDPH sufferers with preexisting migraine is no greater than

the frequency of migraine in the general population. NDPH may be

more common in adolescents. Treatment of migrainous-type primary

NDPH consists of using the preventive therapies effective in migraine

(see above). Featureless NDPH is one of the primary headache forms

most refractory to treatment. Standard preventive therapies can be

offered but are often ineffective. The secondary NDPHs are discussed

elsewhere (Chap. 16).

Acknowledgment

The editors acknowledge the contributions of Neil H. Raskin to earlier

editions of this chapter.

■ FURTHER READING

Ashina M. Migraine. N Engl J Med 383:1866, 2020.

Goadsby PJ: Primary headache disorders—five new things. Neurology

Clinical Practice 9:233, 2019.

Goadsby PJ et al: A controlled trial of erenumab for episodic migraine.

N Engl J Med 377:2123, 2017.

Goadsby PJ et al: Pathophysiology of migraine: A disorder of sensory

processing. Physiol Rev 97:553, 2017.

Goadsby PJ et al: Trial of galcanezumab in prevention of episodic

cluster headache. N Engl J Med 381:132, 2019.

Hoffmann J, May A: Diagnosis, pathophysiology, and management of

cluster headache. Lancet Neurol 17:75, 2018.

Lipton RB et al: Migraine prevalence, disease burden, and the need for

preventive therapy. Neurology 68:343, 2007.

Schankin CJ et al: “Visual snow”—a disorder distinct from persistent

migraine aura. Brain 137:1419, 2014.

Silberstein SD et al: Fremanezumab for the preventive treatment of

chronic migraine. N Engl J Med 377:2113, 2017.

Tolner EA et al: From migraine genes to mechanisms. Pain 156 Suppl 1:

S64, 2015.

Wei DY, Goadsby PJ: Cluster headache pathogenesis—mechanisms

from current and emerging treatments. Nat Rev Neurol 17:308,

2021.

3370 PART 13 Neurologic Disorders

ALZHEIMER’S DISEASE

Approximately 50 million people across the world are living with

dementia. Alzheimer’s disease (AD) is the most common cause of

dementia, contributing to an estimated 60–70% of all cases. It is estimated that the median annual total cost of caring for a single patient

with advanced AD is >$50,000, while the emotional toll for family

members and caregivers is immeasurable. AD can manifest as early as

the third decade of life, but it is the most common cause of dementia

in the elderly. Patients most often present with an insidious loss of

episodic memory followed by a slowly progressive dementia. In typical amnestic AD, brain atrophy begins in the medial temporal lobes

before spreading to the inferior temporal, lateral, medial parietal, and

dorsolateral frontal cortices. Microscopically, there are widespread

neuritic plaques containing amyloid beta (Aβ), neurofibrillary tangles

(NFTs) composed of hyperphosphorylated tau filaments, and Aβ accumulation in blood vessel walls in cortex and leptomeninges (amyloid

angiopathy, see “Pathology,” below). The identification of causative

mutations and susceptibility genes for AD has provided a foundation

for progress in understanding the biologic basis of the disorder. The

major genetic risk factor for AD is the ε4 allele of the apolipoprotein E

(ApoE) gene. Carrying one ε4 allele increases the risk for AD by twoto threefold in women whereas carrying two alleles increases the risk

ten- to fifteenfold in both sexes. Rapid progress in the development of

imaging, cerebrospinal fluid (CSF), and plasma biomarkers of Aβ and

phosphorylated tau has enabled detection of AD pathologic hallmarks

in living people, opening the door to early detection and intervention

with biologically specific therapies.

■ CLINICAL MANIFESTATIONS

The cognitive changes of AD tend to follow a characteristic pattern,

beginning with memory impairment and progressing to deficits in

executive, language, and visuospatial functions. Yet ~20% of patients

with AD present with nonmemory complaints such as word-finding,

organizational, or navigational difficulty. In other patients, visual

processing dysfunction (referred to as posterior cortical atrophy

syndrome) or a progressive “logopenic” aphasia characterized by difficulties with naming and repetition are the primary manifestations

of AD for years before progressing to involve memory and other cognitive domains. Still, other patients may present with an asymmetric

akinetic-rigid-dystonic (“corticobasal”) syndrome or a dysexecutive/

behavioral, i.e., “frontal” variant of AD. Depression, social withdrawal,

and anxiety occur in early disease stages and may represent a prodrome

before cognitive symptoms are apparent.

In early stages of typical amnestic AD, the memory loss may go

unrecognized or be ascribed to benign forgetfulness of aging. The

term subjective cognitive decline refers to self-perceived worsening

in memory or other cognitive abilities that may not be noticeable

to others or apparent on formal neuropsychologic testing. Once the

memory loss becomes noticeable to the patient and family and friends

and is confirmed on standardized memory tests, the term mild cognitive impairment (MCI) is often used. This construct provides useful

prognostic information, because ~50% of patients with MCI (roughly

12% per year) will progress to AD over 4 years. Increasingly, the MCI

construct is being replaced by the notion of “early symptomatic AD” to

signify that AD is considered the underlying disease (based on clinical

or biomarker evidence) in a patient who remains functionally compensated. Even earlier in the course, “preclinical AD” refers to a person

with CSF or positron emission tomography (PET) biomarker evidence

of amyloid pathology (with or without tau pathology) in the absence

of symptoms. It is estimated that preclinical biomarker changes may

precede clinical symptoms by 20 years or more, creating a window of

431

opportunity for early-stage treatment and prevention trials. New evidence suggests that partial and sometimes generalized seizures herald

AD and can occur even prior to dementia onset, especially in younger

patients and patients with autosomal dominant AD-causing mutations.

Eventually, with AD, the cognitive problems begin to interfere with

daily activities, such as keeping track of finances, following instructions

on the job, driving, shopping, and housekeeping. Some patients are

unaware of these difficulties (anosognosia), but most remain acutely

attuned to their deficits in early disease stages. Changes in environment

(travel, relocation, hospitalization) tend to destabilize the patient. Over

time, patients become lost on walks or while driving. Social graces,

routine behavior, and superficial conversation may be surprisingly

intact, even into the later stages of the illness.

In the middle stages of AD, the patient is unable to work, is easily

lost and confused, and requires daily supervision. Language becomes

impaired—first naming, then comprehension, and finally fluency.

Word-finding difficulties and circumlocution can be evident in the

early stages, even when formal testing demonstrates intact naming and

fluency. Apraxia emerges, manifesting as trouble performing learned

sequential motor tasks such as using utensils or appliances. Visuospatial deficits begin to interfere with dressing, eating, or even walking,

and patients fail to solve simple puzzles or copy geometric figures.

Simple calculations and clock reading become difficult in parallel.

In the late stages, some persons remain ambulatory, wandering

aimlessly. Loss of judgment and reasoning is inevitable. Delusions are

prevalent and usually simple, with common themes of theft, infidelity,

or misidentification. Disinhibition and uncharacteristic belligerence

may occur and alternate with passivity and withdrawal. Sleep-wake

patterns are disrupted, and nighttime wandering becomes disturbing to

the household. Some patients develop a shuffling gait with generalized

muscle rigidity associated with slowness and awkwardness of movement. Patients often look parkinsonian (Chap. 435) but rarely have a

high-amplitude, low-frequency tremor at rest. There is a strong overlap

between dementia with Lewy bodies (DLB) (Chap. 434) and AD, and

some AD patients develop more classical parkinsonian features.

In the end stages, patients with AD become rigid, mute, incontinent,

and bedridden, and need help with eating, dressing, and toileting.

Hyperactive tendon reflexes and myoclonic jerks (sudden brief contractions of various muscles or the whole body) may occur spontaneously or in response to physical or auditory stimulation. Often death

results from malnutrition, secondary infections, pulmonary emboli,

heart disease, or, most commonly, aspiration. The typical duration of

symptomatic AD is 8–10 years, but the course ranges from 1–25 years.

For unknown reasons, some patients with AD show a steady decline

in function while others have prolonged plateaus without major

deterioration.

■ DIAGNOSIS

A detailed discussion of the diagnosis of dementia is presented in

Chap. 29. Early in the disease course, other etiologies of dementia

should be excluded (see Tables 29-1, 29-3, and 29-4). Neuroimaging

studies (CT and MRI) do not show a single specific pattern with AD

and may be normal early in the disease. As AD progresses, more distributed but usually posterior-predominant cortical atrophy becomes

apparent, along with atrophy of the medial temporal memory structures (see Fig. 29-1). The main purpose of imaging is to exclude other

disorders, such as primary and secondary neoplasms, vascular dementia, diffuse white matter disease, and normal-pressure hydrocephalus

(NPH). Imaging also helps to distinguish AD from other degenerative

disorders, such as frontotemporal dementia (FTD) (Chap. 432) or the

prion disorder Creutzfeldt-Jakob disease (CJD) (Chap. 438), which

feature imaging patterns that are different from AD. Functional imaging studies, such as fluorodeoxyglucose (FDG) PET, reveal hypometabolism in the posterior temporal-parietal cortex in AD (see Fig. 29-1).

Amyloid PET imaging (e.g., with radiotracers [11C]PIB, [18F]florbetapir, [18F]florbetaben, or [18F]flutemetamol) confirms the presence of

neuritic and diffuse Aβ plaques throughout the neocortex (Fig. 431-1).

Although amyloid PET binding is detected in AD, approximately 25%

of cognitively unimpaired older individuals also have positive scans,

Alzheimer’s Disease

Gil D. Rabinovici, William W. Seeley,

Bruce L. Miller

3371Alzheimer’s Disease CHAPTER 431

thought to represent preclinical disease and an increase in the risk of

converting to clinical AD. Similarly, dementia due to a non-AD disorder can be the underlying etiology in a patient who tests positively on

amyloid PET. Amyloid PET ligands also bind to vascular Aβ deposits

in cerebral amyloid angiopathy (Chap. 428). Therefore, clinical use of

amyloid PET should be restricted to specific scenarios in which knowledge of amyloid status is expected to impact diagnosis and change

management. For example, a negative amyloid PET scan in a patient

with dementia makes an AD diagnosis unlikely.

Tau PET radiotracers (e.g., [18F]flortuacipir, [18F]MK-6240) bind to

the paired helical filaments that form NFTs and are primarily available

in the research setting. The pattern of binding is largely consistent with

Braak neuropathologic staging of NFTs, with early retention in medial

temporal regions, followed by spread into temporoparietal and cingulate cortices, dorsolateral prefrontal regions, and, ultimately, primary

sensory and motor areas.

Routine spinal fluid examination is generally normal, but CSF

reductions in Aβ42 levels and the Aβ42/Aβ40 ratio correlate with amyloid deposition, increases in phosphorylated tau (at residue 181 or

217) correlate with tangle inclusions, and increases in total tau levels

represent a nonspecific finding seen in AD but also in other causes of

neurodegeneration. Plasma measurements of Aβ and phosphorylated

tau with ultra-sensitive immunoassays or mass spectrometry show

great promise and are likely to increase access and affordability of AD

molecular biomarkers.

Electroencephalogram (EEG) is normal or shows nonspecific slowing; prolonged EEG can be used to seek out intermittent nonconvulsive

seizures.

Slowly progressive decline in memory and orientation, normal results

on laboratory tests, and an MRI or CT scan showing only distributed or

posteriorly predominant cortical and hippocampal atrophy are highly

suggestive of AD. A clinical diagnosis of AD reached after careful evaluation is confirmed at autopsy 70–90% of the time, with misdiagnosed

cases usually resulting from pathologic limbic-predominant agerelated TDP-43 encephalopathy (LATE) neuropathologic changes

with or without hippocampal sclerosis, primary age-related tauopathy, DLB, vascular pathology, or frontotemporal lobar degeneration

(FTD).

Simple clinical clues are useful in the differential diagnosis. Early

prominent gait disturbance with only mild memory loss suggests vascular dementia or, rarely, NPH (see below). Resting tremor with stooped

posture, bradykinesia, and masked facies suggest PD (Chap. 435)

or DLB (Chap. 434). When dementia occurs after a well-established

diagnosis of PD, PD dementia (PDD) is usually the correct diagnosis,

but many patients with this diagnosis will show a mixture of AD and

DLB at autopsy. The early appearance of parkinsonian features in

association with fluctuating alertness, visual hallucinations, or delusional misidentification suggests DLB. Chronic alcoholism should

prompt the search for vitamin deficiency. Loss of joint position and

vibration sensibility accompanied by Babinski signs suggests vitamin

B12 deficiency, especially in a patient with a history of autoimmune

disease, small bowel resection or irradiation, or veganism (Chap. 99).

Early onset of a focal seizure suggests a metastatic or primary brain

neoplasm (Chap. 90). Previous or ongoing depression raises suspicion

for depression-related cognitive impairment, although significant cognitive changes with depression are uncommon and AD and DLB can

feature a depressive or anxious prodrome. A history of treatment for

insomnia, anxiety, psychiatric disturbance, or epilepsy suggests chronic

drug intoxication. Rapid progression over a few weeks or months

associated with rigidity and myoclonus suggests CJD (Chap. 438). Prominent behavioral changes with intact navigation and focal anteriorpredominant atrophy on brain imaging are typical of FTD. A positive

family history of dementia suggests either one of the familial forms of

AD or one of the other genetic disorders associated with dementia,

such as FTD (Chap. 432), Huntington’s disease (HD) (Chap. 436),

prion disease (Chap. 438), or rare hereditary ataxias (Chap. 439).

FIGURE 431-1 Molecular imaging of Alzheimer’s disease pathophysiology in an 81-year-old with mild Alzheimer’s disease. A. Aβ positron emission tomography (PET)

with [11C]PIB reveals extensive radiotracer retention in neocortex, consistent with the known distribution of amyloid plaques. B. Tau PET with [18F]FTP shows asymmetric

uptake predominantly in left temporal cortex, consistent with intermediate-stage NFTs. Tracer uptake in midbrain and basal ganglia represents “off-target” (non-tau related)

tracer retention. C. FDG-PET reveals reduced tracer uptake in left greater than right temporal and parietal cortex, indicative of decreased synaptic activity. The pattern of

hypometabolism corresponds more closely to the pattern of tau than amyloid deposition. A–C. Axial brain slices are shown in neurologic orientation. L, left; R, right; SUVR,

standardized uptake value ratio, a quantitative measure of PET radiotracer retention.