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InternalMed_Harrison. 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 aNot 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.


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InternalMed_Harrison. enhance gastric absorption. In addition, dopamine receptor antago-the treatment of severe migraine is the administration over 2 min of a nists decrease nausea/vomiting and restore normal gastric motility. mixture of 5 mg of prochlorperazine and 0.5 mg of dihydroergotamine. Parenteral Dopamine receptor antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) by injection can also provide sig-OTHER MEDICATIONS FOR ACUTE MIGRAINE nificant acute relief of migraine; they can be used in combination with Oral The combination of acetaminophen, dichloralphenazone, and parenteral 5-HT receptor agonists. A common IV protocol used for isometheptene, one to two capsules, has been classified by the FDA Almotriptan 12.5 mg PO Zolmitriptan 2.5 mg PO Naratriptan 2.5 mg PO Frovatriptan 2.5 mg PO usually with caffeine) Naratriptan 2.5 mg PO Almotriptan 12.5 mg PO Tolerating acute treatments poorly Naratriptan 2.5 mg Almotriptan 12.5 mg


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InternalMed_Harrison. Naratriptan 2.5 mg PO Frovatriptan 2.5 mg PO usually with caffeine) Naratriptan 2.5 mg PO Almotriptan 12.5 mg PO Tolerating acute treatments poorly Naratriptan 2.5 mg Almotriptan 12.5 mg Dihydroergotamine 1 mg IM Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs. 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 to other agents. Nasal A nasal preparation of butorphanol is available for the treatment of acute pain. As with all opioids, the use of nasal butorphanol has little role in migraine treatment.


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InternalMed_Harrison. Parenteral Opioids are modestly effective in the acute treatment of migraine. For example, IV meperidine (50–100 mg) is given frequently in the emergency room. This regimen “works” in the sense that the pain of migraine is eliminated. However, this regimen is 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 to other therapies.


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InternalMed_Harrison. Acute attack medications, particularly opioid or barbiturate-containing compound analgesics, have a propensity to aggravate headache frequency and induce a state of refractory daily or near-daily headache called medication-overuse headache. This condition is likely not a separate headache entity but a reaction of the migraine patient 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. 21).


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InternalMed_Harrison. 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 the subset of 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.


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InternalMed_Harrison. Drugs that have the capacity to stabilize migraine are listed in Table 447-6. Drugs must be taken daily, and there is usually a lag of between 2 to 12 weeks before an effect is seen. The drugs that have been approved by the FDA for the prophylactic treatment of migraine include propranolol, timolol, sodium valproate, topiramate, and methysergide (not available). In addition, a number of other drugs appear to display prophylactic efficacy. This group includes amitriptyline, nortriptyline, flunarizine, phenelzine, gabapentin, 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. Phenelzine and methysergide are usually reserved for recalcitrant cases because of their serious potential side effects. Phenelzine is a monoamine oxidase inhibitor (MAOI); therefore, tyramine-containing foods, decongestants, and meperidine are contraindicated. Methysergide may


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InternalMed_Harrison. of their serious potential side effects. Phenelzine is a monoamine oxidase inhibitor (MAOI); therefore, tyramine-containing foods, decongestants, and meperidine are contraindicated. Methysergide may cause retroperitoneal or cardiac valvular fibrosis when it is used for >6 months, and thus monitoring is required for patients using this drug; the risk of fibrosis is about 1:1500 and is likely to reverse after the drug is stopped.


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InternalMed_Harrison. The probability of success with any one of the antimigraine drugs is 50–75%. Many patients are managed adequately with low-dose amitriptyline, propranolol, candesartan, topiramate, or valproate. If these agents fail or lead to unacceptable side effects, second-line agents such as methysergide or phenelzine can be used. Once effective stabilization is achieved, the drug is continued for ~6 months and then slowly tapered 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.


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InternalMed_Harrison. TENSION-TYPE HEADACHE Clinical Features The term tension-type headache (TTH) is commonly used to describe a chronic head-pain syndrome characterized by bilateral tight, band-like 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 reuptake inhibitors: fluoxetine aCommonly 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. bNot available in the United States. cNot currently available worldwide.


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InternalMed_Harrison. 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, dichotomizing 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).


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 447-6); 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, INCLUDING CLUSTER HEADACHE


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InternalMed_Harrison. TRIGEMINAL AUTONOMIC CEPHALALGIAS, INCLUDING CLUSTER HEADACHE The trigeminal autonomic cephalalgias (TACs) describe a grouping of primary headaches including cluster headache, paroxysmal hemicrania, 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 447-1). TACs are characterized by relatively short-lasting attacks of head pain associated with cranial autonomic symptoms, such as lacrimation, conjunctival injection, or nasal congestion (Table 447-7). 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.


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InternalMed_Harrison. TACs must be differentiated from short-lasting headaches that do not have prominent cranial autonomic syndromes, notably trigeminal neuralgia, 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 undergo pituitary imaging and pituitary function tests because there is an excess of TAC presentations in patients with pituitary tumor–related headache.


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InternalMed_Harrison. Cluster Headache Cluster headache is a relatively rare form of primary headache with a population frequency of approximately 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 aIf conjunctival injection and tearing are not present, consider SUNA. bNausea, photophobia, or phonophobia; photophobia and phonophobia are typically unilateral on the side of the pain. cIndicates 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.


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InternalMed_Harrison. relatively short-duration unilateral pain for 8 to 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 less than 1 month of sustained remission without treatment. Patients are generally perfectly well between episodes. Onset 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.


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InternalMed_Harrison. Cluster headache is associated with ipsilateral symptoms of cranial parasympathetic autonomic activation: conjunctival injection or lacrimation, 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 in the posterior hypothalamic region (Fig. 447-3).


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InternalMed_Harrison. 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. Cluster headache attacks peak rapidly, and thus a treatment with quick 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. Oral sumatriptan is not effective for prevention or for acute treatment of cluster headache.


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InternalMed_Harrison. The choice of a preventive treatment in cluster headache depends in part on the length of the bout. Patients with long bouts or those 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 or methysergide (not available in the United States) 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. Lithium (400–800 mg/d) appears to be particularly useful for the chronic form of the disorder.


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InternalMed_Harrison. Many experts favor verapamil as the first-line preventive treatment for patients with chronic cluster headache or 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 and leg swelling can be problematic. Of paramount concern, however, is the cardiovascular safety of verapamil, particularly Prednisone 1 mg/kg up to Verapamil 160–960 mg/d 60 mg qd, tapering over 21 days Gabapentinb 1200–3600 mg/d Melatoninb 9–12 mg/d aNot available worldwide. bUnproven but of potential benefit.


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InternalMed_Harrison. Prednisone 1 mg/kg up to Verapamil 160–960 mg/d 60 mg qd, tapering over 21 days Gabapentinb 1200–3600 mg/d Melatoninb 9–12 mg/d aNot available worldwide. bUnproven but of potential benefit. 2596 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.


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InternalMed_Harrison. When medical therapies fail in chronic cluster headache, neurostimulation strategies can be used. Deep-brain stimulation of the region of the posterior hypothalamic gray matter has proven successful in a substantial proportion of patients, although its risk-benefit ratio makes it inappropriate with so many other options now available. Favorable results have also been reported with the less-invasive approach of occipital nerve stimulation, with sphenopalatine ganglion stimulation and with a noninvasive vagal nerve stimulator.


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InternalMed_Harrison. 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 more than five a 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-tofemale ratio in PH is close to 1:1.


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InternalMed_Harrison. 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. Piroxicam has been used, although it is not as effective as indomethacin. Verapamil, an effective treatment for cluster headache, does not appear to be useful for PH. In occasional patients, PH can coexist with trigeminal neuralgia (PH-tic syndrome); similar to cluster-tic syndrome, each component may require separate treatment.


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InternalMed_Harrison. 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, magnetic resonance imaging (MRI) is indicated to exclude a pituitary lesion.


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InternalMed_Harrison. SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) 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 (short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms) can be made.


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InternalMed_Harrison. 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. The diagnosis of SUNCT/SUNA is often confused with trigeminal neuralgia (TN) particularly in first-division TN (Chap. 455). Minimal or no cranial autonomic symptoms and a clear refractory period to triggering indicate a diagnosis of TN.


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InternalMed_Harrison. 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. 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. 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.


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InternalMed_Harrison. Surgical approaches such as microvascular decompression or destructive trigeminal procedures are seldom useful and often produce long-term complications. Greater occipital nerve injection has produced limited benefit in some patients. Occipital nerve stimulation is probably helpful in a subgroup of these patients. Complete control with deep-brain stimulation of the posterior hypothalamic region was reported in a single patient. For intractable cases, short-term prevention with IV lidocaine can be effective, as can occipital nerve stimulation.


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InternalMed_Harrison. 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 11 to 58 years; women are affected twice as often as men. The cause is unknown.


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InternalMed_Harrison. 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. Occipital nerve stimulation probably has a role in patients with hemicrania continua who are unable to tolerate indomethacin.


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InternalMed_Harrison. OTHER PRIMARY HEADACHES Primary Cough Headache Primary cough headache is a generalized headache that begins suddenly, lasts for 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.


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InternalMed_Harrison. 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 exertional 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, which can last from 5 min to 24 h, is bilateral and 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 exertional headache can be prevented by avoiding excessive exertion, particularly in hot weather or at high altitude.


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InternalMed_Harrison. The mechanism of primary exertional 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 exertion can result in headache in a number of serious underlying conditions, these must be considered in patients with exertional headache. Pain from angina may be referred to the head, probably by central connections of vagal afferents, and may present as exertional headache (cardiac cephalgia). The link to exercise is the main clinical clue that headache is of cardiac origin. Pheochromocytoma may occasionally cause exertional headache. Intracranial lesions and stenosis of the carotid arteries are other possible etiologies.


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InternalMed_Harrison. Exercise regimens should begin modestly and progress gradually to higher levels of intensity. Indomethacin at daily doses from 25 to 150 mg is generally effective in benign exertional headache. Indomethacin (50 mg), ergotamine (1 mg orally), dihydroergotamine (2 mg by nasal spray), and methysergide (1–2 mg orally given 30–45 min before exercise) are useful prophylactic measures.


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InternalMed_Harrison. 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 that resembles the headache of low CSF pressure. The last arises from vigorous sexual activity and is a form of low CSF pressure headache (Chap. 21). 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 develop 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. About half of patients with sex headache have a history of exertional 2597 headaches, but there is no excess of cough headache. Migraine is probably more common in patients with 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 to 200 mg/d. An alternative is the calcium channel–blocking agent diltiazem, 60 mg tid. Ergotamine (1 mg) or indomethacin (25–50 mg) taken 30–45 min prior to sexual activity can also be helpful.


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InternalMed_Harrison. 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 computed tomography (CT) scans and CSF findings were negative, ~15% had recurrent episodes of thunderclap headache, and nearly half subsequently developed migraine or TTH.


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InternalMed_Harrison. The first presentation of any sudden-onset severe headache should be diligently investigated with neuroimaging (CT or, when possible, MRI with MR angiography) and CSF examination. Formal cerebral angiography should be reserved for those cases in which no primary diagnosis is forthcoming and for clinical situations that are particularly suggestive of intracranial aneurysm. Reversible segmental cerebral vasoconstriction may be seen in primary thunderclap headache without an intracranial aneurysm. 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 by definition, the vasoconstriction of primary thunderclap headache resolves spontaneously.


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InternalMed_Harrison. Cold-Stimulus Headache This refers to head pain triggered by application or ingestion/inhalation of something cold. It is bought 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 or minutes and occurring as a alzheimer’s Disease and other Dementias William W. Seeley, Bruce L. Miller ALZHEIMER’S DISEASE Approximately 10% of all persons over the age of 70 years have sig-448 2598 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). 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.


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InternalMed_Harrison. 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; tricyclics, such as amitriptyline, or anticonvulsants, such as topiramate or valproate, are most often tried.


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InternalMed_Harrison. Hypnic Headache This headache syndrome typically begins a few hours after sleep onset. The headaches last from 15 to 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 bilateral in most, 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.


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InternalMed_Harrison. Patients with hypnic headache generally respond to a bedtime dose of lithium carbonate (200–600 mg). For those intolerant of lithium, verapamil (160 mg) or methysergide (1–4 mg at bedtime) may be alternative strategies. 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, can be effective.


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InternalMed_Harrison. New Daily Persistent Headache Primary new daily persistent headache (NDPH) occurs in both males and females. It can be of the migrainous type, with features of migraine, or it can be featureless, appearing as new-onset TTH. Migrainous features are common 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. At 24 months, ~86% of patients are headache-free. 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


InternalMed_Harrison

InternalMed_Harrison. 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. 21).


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InternalMed_Harrison. nificant memory loss, and in more than half, the cause is Alzheimer’s disease (AD). 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 young as the third decade, 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 that evolves over years. In typical amnestic AD, brain imaging reveals atrophy that begins in the medial temporal lobes before spreading to lateral and medial parietal and temporal lobes and lateral frontal cortex. Microscopically, there are neuritic plaques containing amyloid beta (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and Aβ accumulation of in blood vessel walls in cortex and leptomeninges (see “Pathology,” below). The identification of causative mutations


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InternalMed_Harrison. (NFTs) composed of hyperphosphorylated tau filaments, and Aβ accumulation of in blood vessel walls in cortex and leptomeninges (see “Pathology,” below). The identification of causative mutations and susceptibility genes for AD has provided a foundation for rapid progress in understanding the biological basis of the disorder. The major genetic risk for AD is apolipoprotein ε4 (Apo ε4). Carrying one Ε4 allele increases the risk for AD by 2to 3-fold, whereas two alleles increase the risk 16-fold.


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InternalMed_Harrison. The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and progressing to language and visuospatial deficits. Yet, approximately 20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In other patients, upstream visual processing dysfunction (referred to as posterior cortical atrophy syndrome) or a progressive “logopenic” aphasia 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 akineticrigid-dystonic (“corticobasal”) syndrome or a dysexecutive “frontal variant” of AD.


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InternalMed_Harrison. In the early stages of typical amnestic AD, the memory loss may go unrecognized or be ascribed to benign forgetfulness of aging. Once the memory loss becomes noticeable to the patient and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term mild cognitive impairment (MCI) is applied. This construct provides useful prognostic information, because approximately 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, “prodromal AD” refers to a person with biomarker evidence of AD (amyloid imaging positive with positron emission tomography or low cerebrospinal Aβ42 and mildly elevated tau) in the absence of symptoms. These refinements have been developed in


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InternalMed_Harrison. evidence of AD (amyloid imaging positive with positron emission tomography or low cerebrospinal Aβ42 and mildly elevated tau) in the absence of symptoms. These refinements have been developed in anticipation of early-stage treatment and prevention trials that have already begun in humans. New evidence suggests that partial and sometimes generalized seizures herald AD and can occur even prior to dementia onset.


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InternalMed_Harrison. 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. 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.


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InternalMed_Harrison. 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, and patients have trouble performing learned sequential motor tasks. 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.


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InternalMed_Harrison. In the late stages, some persons remain ambulatory, wandering aimlessly. Loss of judgment and reasoning is inevitable. Delusions are common, usually simple, with common themes of theft, infidelity, or misidentification. Approximately 10% of AD patients develop Capgras’ syndrome, believing that a caregiver has been replaced by an impostor. In contrast to dementia with Lewy bodies (DLB), where Capgras’ syndrome is an early feature, in AD this syndrome emerges late. 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. 449) but rarely have a high-amplitude, low-frequency tremor at rest. There is a strong overlap between Parkinson’s disease (PD) and AD, and some AD patients develop


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InternalMed_Harrison. often look parkinsonian (Chap. 449) but rarely have a high-amplitude, low-frequency tremor at rest. There is a strong overlap between Parkinson’s disease (PD) and AD, and some AD patients develop more classical PD features.


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InternalMed_Harrison. In the end stages, AD patients become rigid, mute, incontinent, and bedridden, and help is needed 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 AD is 8–10 years, but the course ranges from 1 to 25 years. For unknown reasons, some patients with AD show a steady decline in function while others have prolonged plateaus without major deterioration.


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InternalMed_Harrison. Early in the disease course, other etiologies of dementia should be excluded (see Tables 35-1, 35-3, and 35-4). Neuroimaging studies (computed tomography [CT] and magnetic resonance imaging [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 Chap. 35, Fig. 35-1). 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) or Creutzfeldt-Jacob disease (CJD), which feature distinctive imaging patterns. Functional imaging studies, such as positron emission tomography (PET), reveal hypometabolism in the posterior temporal-parietal cortex in AD


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InternalMed_Harrison. (CJD), which feature distinctive imaging patterns. Functional imaging studies, such as positron emission tomography (PET), reveal hypometabolism in the posterior temporal-parietal cortex in AD (see Fig. 35-1). PET can also be used to detect the presence of fibrillar amyloid in the brain (see Fig. 35-4), and amyloid PET positivity is becoming required for entry into treatment trials for AD. Barriers to interpretation continue, however, to limit the use of amyloid PET in routine clinical evaluation. Although amyloid binding with PET is typical for AD, many asymptomatic healthy older individuals show amyloid uptake, and the likelihood that these individuals will convert to clinical AD is still under study. Similarly, dementia due to a non-AD disorder can be the underlying etiology in a patient who is amyloid positive on imaging. Electroencephalogram (EEG) is normal or shows nonspecific slowing; prolonged EEG can be used to seek out intermittent non-convulsive seizures. Routine spinal


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InternalMed_Harrison. who is amyloid positive on imaging. Electroencephalogram (EEG) is normal or shows nonspecific slowing; prolonged EEG can be used to seek out intermittent non-convulsive seizures. Routine spinal fluid examination is also normal. Cerebrospinal fluid (CSF) Aβ42 level is reduced, whereas the tau protein is elevated, but the test characteristics of these assays still make interpretation challenging in individual patients. Slowly progressive decline in memory and orientation, normal results on laboratory tests, and an MRI 2599 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 about 90% of the time, with misdiagnosed cases usually representing one of the other dementing disorders described later in this chapter, a mixture of AD with vascular pathology, or DLB.


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InternalMed_Harrison. 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. 449). 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 Lewy body disease 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 (Chap. 456). Early onset of a focal seizure suggests a metastatic or primary brain neoplasm (Chap. 118). Previous or ongoing depression raises suspicion for depression-related


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InternalMed_Harrison. vitamin B12 deficiency (Chap. 456). Early onset of a focal seizure suggests a metastatic or primary brain neoplasm (Chap. 118). Previous or ongoing depression raises suspicion for depression-related cognitive impairment, although AD can feature a depressive 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. 453e). Prominent behavioral changes with intact navigation and focal anterior-predominant 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 (see below), HD (see below), prion disease (Chap. 453e), or rare hereditary ataxias (Chap. 450).


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InternalMed_Harrison. The most important risk factors for AD are old age and a positive family history. The prevalence of AD increases with each decade of adult life, reaching 20–40% of the population over the age of 85. A positive family history of dementia suggests a genetic contribution to AD, although autosomal dominant inheritance occurs in only 2% of patients. Female sex is a risk factor independent of the greater longevity of women, and women who carry an Apo ε4 allele are more susceptible than are male ε4 carriers. A history of head trauma with concussion increases the risk for AD. AD is more common in groups with low educational attainment, but education influences test-taking ability, and it is clear that AD can affect persons of all intellectual levels. One study found that the capacity to express complex written language in early adulthood correlated with a decreased risk for AD. Numerous environmental factors, including aluminum, mercury, and viruses, have been proposed as causes of AD, but


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InternalMed_Harrison. complex written language in early adulthood correlated with a decreased risk for AD. Numerous environmental factors, including aluminum, mercury, and viruses, have been proposed as causes of AD, but rigorous studies have failed to demonstrate to a significant role for any of these exposures. Similarly, several studies suggest that the use of nonsteroidal anti-inflammatory agents is associated with a decreased risk of AD, but this risk has not been confirmed in large prospective studies. Vascular disease, and stroke in particular, seems to lower the threshold for the clinical expression of AD. Also, in many patients with AD, amyloid angiopathy can lead to microhemorrhages, large lobar hemorrhages, ischemic infarctions most often in the subcortical white matter, or in rare cases an inflammatory leukoencephalopathy. Diabetes increases the risk of AD threefold. Elevated homocysteine and cholesterol levels; hypertension; diminished serum levels of folic acid; low dietary intake of fruits,


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InternalMed_Harrison. leukoencephalopathy. Diabetes increases the risk of AD threefold. Elevated homocysteine and cholesterol levels; hypertension; diminished serum levels of folic acid; low dietary intake of fruits, vegetables, and red wine; and low levels of exercise are all being explored as potential risk factors for AD.


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InternalMed_Harrison. At autopsy, the earliest and most severe degeneration is usually found in the medial temporal lobe (entorhinal/perirhinal cortex and hippocampus), lateral temporal cortex, and nucleus basalis of Meynert. The characteristic microscopic findings are neuritic plaques and NFTs (Fig. 448-1). These lesions may accumulate in small numbers during FIGURE 448-1 Neuropathology of Alzheimer’s disease. A. Early neurofibrillary degeneration, consisting of neurofibrillary tangles and neuropil threads, preferentially affects the medial temporal lobes, especially the stellate pyramidal neurons that compose the layer 2 islands of entorhinal cortex, as shown. B. Higher magnification view reveals the fibrillary nature of tangles (arrows) and the complex structure of neuritic plaques (arrowheads), whose major component is Aβ (inset shows immunohistochemistry for Aβ). Scale bars are 500 μM in A, 50 μM in B, and 20 μM in B inset.


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InternalMed_Harrison. normal brain aging but dominate the picture in AD. Increasing evidence suggests that soluble amyloid species called oligomers may cause cellular dysfunction and represent the early toxic molecule in AD. Eventually, further amyloid polymerization and fibril formation lead to neuritic plaques, which contain a central core of amyloid, proteoglycans, Apo ε4, α-antichymotrypsin, and other proteins. Aβ is a protein of 39–42 amino acids that is derived proteolytically from a larger transmembrane protein, amyloid precursor protein (APP), when APP is cleaved by β and γ secretases (Fig. 448-2). The normal Step 1: Cleavage by either ˜ or ˛ secretase Step 2: Cleavage by ˝ secretase


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InternalMed_Harrison. Step 1: Cleavage by either ˜ or ˛ secretase Step 2: Cleavage by ˝ secretase FIGURE 448-2 Amyloid precursor protein (APP) is catabolized by α, β, and γ secretases. A key initial step is the digestion by either β secretase (BASE) or α secretase (ADAM10 or ADAM17 [TACE]), producing smaller nontoxic products. Cleavage of the β secretase product by γ secretase (Step 2) results in either the toxic Aβ42 or the nontoxic Aβ40 peptide; cleavage of the α secretase product by γ secretase produces the nontoxic P3 peptide. Excess production of Aβ42 is a key initiator of cellular damage in Alzheimer’s disease (AD). Therapeutics for AD have focused on attempts to reduce accumulation of Aβ42 by antagonizing β or γ secretases, promoting α secretase, or clearing Aβ42 that has already formed by use of specific antibodies.


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InternalMed_Harrison. function of the Aβ peptides remains uncertain. APP has neurotrophic and neuroprotective properties. The plaque core is surrounded by a halo, which contains dystrophic, tau-immunoreactive neurites and activated microglia. The accumulation of Aβ in cerebral arterioles is termed amyloid angiopathy. NFTs are composed of silver-staining neuronal cytoplasmic fibrils composed of abnormally phosphorylated tau protein; they appear as paired helical filaments by electron microscopy. Tau binds to and stabilizes microtubules, supporting axonal transport of organelles, glycoproteins, neurotransmitters, and other important cargoes throughout the neuron. Once hyperphosphorylated, tau can no longer bind properly to microtubules and redistributes from the axon to throughout the neuronal cytoplasm and distal dendrites, compromising function. Finally, patients with AD often show comorbid DLB or vascular pathology. In animal models of AD, diminishing neuronal tau ameliorates the cognitive deficits and


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InternalMed_Harrison. dendrites, compromising function. Finally, patients with AD often show comorbid DLB or vascular pathology. In animal models of AD, diminishing neuronal tau ameliorates the cognitive deficits and seizures, even though Aβ42 continues to accumulate, raising hope for tau-lowering therapies in humans. Biochemically, AD is associated with a decrease in the cortical levels of several proteins and neurotransmitters, especially acetylcholine, its synthetic enzyme choline acetyltransferase, and nicotinic cholinergic receptors. Reduction of acetylcholine reflects degeneration of cholinergic neurons in the nucleus basalis of Meynert that project throughout the cortex. There is also noradrenergic and serotonergic depletion due to degeneration of brainstem nuclei such as the locus coeruleus and dorsal raphe, where tau-immunoreactive neuronal cytoplasmic inclusions can be identified even in individuals lacking entorhinal cortex NFTs.


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InternalMed_Harrison. Several genes play an important role in the pathogenesis of AD. One is the APP gene on chromosome 21. Adults with trisomy 21 (Down’s syndrome) consistently develop the typical neuropathologic hallmarks of AD if they survive beyond age 40 years, and many develop a progressive dementia superimposed on their baseline mental retardation. The extra dose of the APP gene on chromosome 21 is the initiating cause of AD in adult Down’s syndrome and results in excess cerebral amyloid production. Supporting this hypothesis, some families with early age-of-onset familial AD (FAD) have point mutations in APP. Although very rare, these families were the first examples of single-gene autosomal dominant transmission of AD.


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InternalMed_Harrison. Investigation of large families with multigenerational FAD led to the discovery of two additional AD-causing genes, the presenilins. Presenilin-1 (PS-1) is on chromosome 14 and encodes a protein called S182. Mutations in this gene cause an early-age-of-onset AD, with onset before the age of 60 and often before age 50, transmitted in an autosomal dominant, highly penetrant fashion. More than 100 different mutations have been found in the PS-1 gene in families from a wide range of ethnic backgrounds. Presenilin-2 (PS-2) is on chromosome 1 and encodes a protein called STM2. A mutation in the PS-2 gene was first found in a group of American families with Volga German ethnic background. Mutations in PS-1 are much more common than those in PS-2. The presenilins are highly homologous and encode similar proteins that at first appeared to have seven transmembrane domains (hence the designation STM), but subsequent studies have suggested eight such domains, with a ninth submembrane region. Both


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InternalMed_Harrison. proteins that at first appeared to have seven transmembrane domains (hence the designation STM), but subsequent studies have suggested eight such domains, with a ninth submembrane region. Both S182 and STM2 are cytoplasmic neuronal proteins that are widely expressed throughout the nervous system. They are homologous to a cell-trafficking protein, sel 12, found in the nematode Caenorhabditis elegans. Patients with mutations in the presenilin genes have elevated plasma levels of Aβ42, and PS-1 mutations produce increased Aβ42 in the media in cell culture. There is evidence that PS-1 is involved in the cleavage of APP at the γ secretase site and mutations in either gene (PS-1 or APP) may disturb γ secretase cleavage. Mutations in PS-1 are the most common cause of early-age-of-onset FAD, representing perhaps 40–70% of all cases. Mutations in PS-1 tend to produce AD with an earlier age of onset (mean onset 45 years) and a shorter, more rapidly progressive course (mean duration 6–7 years)


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InternalMed_Harrison. perhaps 40–70% of all cases. Mutations in PS-1 tend to produce AD with an earlier age of onset (mean onset 45 years) and a shorter, more rapidly progressive course (mean duration 6–7 years) than the disease caused by mutations in PS-2 (mean onset 53 years; duration 11 years). Although some carriers of PS-2 mutations have had onset of dementia after the age of 70, mutations in the presenilins rarely lead to late-ageof-onset AD. Clinical genetic testing for these uncommon mutations is available but likely to be revealing only in early-age-of-onset FAD and should be performed in association with formal genetic counseling.


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InternalMed_Harrison. The Apo ε gene on chromosome 19 is involved in the pathogenesis of AD. The protein, apolipoprotein E, participates in cholesterol transport (Chap. 421), and the gene has three alleles: ε2, ε3, and ε4. The Apo ε4 allele confers increased risk of AD in the general population, including sporadic and late-age-of-onset familial forms. Approximately 24–30% of the nondemented white population has at least one ε4 allele (12–15% allele frequency), and about 2% are ε4/ε4 homozygotes. Among patients with AD, 40–65% have at least one ε4 allele, a highly significant elevation compared with controls. Conversely, many AD patients have no ε4 allele, and ε4 carriers may never develop AD. Therefore, ε4 is neither necessary nor sufficient to cause AD. Nevertheless, the Apo ε4 allele represents the most important genetic risk factor for sporadic AD and acts as a dose-dependent disease modifier, with the earliest age of onset associated with the ε4 homozygosity. Precise mechanisms through which Apo ε4


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InternalMed_Harrison. genetic risk factor for sporadic AD and acts as a dose-dependent disease modifier, with the earliest age of onset associated with the ε4 homozygosity. Precise mechanisms through which Apo ε4 confers AD risk or hastens onset remain unclear, but ε4 leads to less efficient amyloid clearance and to the production of toxic fragments from cleavage of the molecule. Apo ε can be identified in neuritic plaques and may also be involved in neurofibrillary tangle formation, because it binds to tau protein. Apo ε4 decreases neurite outgrowth in dorsal root ganglion neuronal cultures, perhaps indicating a deleterious role in the brain’s response to injury. Some evidence suggests that the ε2 allele may reduce AD risk. Use of Apo ε testing in AD diagnosis remains controversial. It is not indicated as a predictive test in normal persons because its precise predictive value is unclear, and many individuals with the ε4 allele never develop dementia. Many cognitively normal ε4 heterozygotes and


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InternalMed_Harrison. as a predictive test in normal persons because its precise predictive value is unclear, and many individuals with the ε4 allele never develop dementia. Many cognitively normal ε4 heterozygotes and homozygotes show decreased cerebral cortical metabolic function with PET, suggesting presymptomatic abnormalities due to AD or an inherited vulnerability of the AD-targeted network. In demented persons who meet clinical criteria for AD, finding an ε4 allele increases the reliability of diagnosis; however, the absence of an ε4 allele cannot be considered evidence against AD. Furthermore, all patients with dementia, including those with an ε4 allele, require a search for reversible causes of their cognitive impairment. Nevertheless, Apo ε4 remains the single most important biologic marker associated with 2601 AD risk, and studies of ε4’s functional role and diagnostic utility are progressing rapidly. The ε4 allele is not associated with risk for FTD, DLB, or CJD, although some evidence


InternalMed_Harrison

InternalMed_Harrison. with 2601 AD risk, and studies of ε4’s functional role and diagnostic utility are progressing rapidly. The ε4 allele is not associated with risk for FTD, DLB, or CJD, although some evidence suggests that ε4 may exacerbate the phenotype of non-AD degenerative disorders, head trauma, and other brain injuries. Additional genes are also likely to be involved in AD, especially as minor risk alleles for sporadic forms of the disease. Genome-wide association studies have implicated the clusterin (CLU), phosphatidylinositol-binding clathrin assembly protein (PICALM), and complement component (3b/4b) receptor 1 (CR1) genes. CLU may play a role in synapse turnover, PICALM participates in clathrinmediated endocytosis, and CR1 may be involved in amyloid clearance through the complement pathway. TREM2 is a gene involved with inflammation that increases the likelihood of dementia. Homozygous mutation carriers develop a frontal dementia with bone cysts (Nasu-Hakola disease), whereas heterozygotes


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InternalMed_Harrison. is a gene involved with inflammation that increases the likelihood of dementia. Homozygous mutation carriers develop a frontal dementia with bone cysts (Nasu-Hakola disease), whereas heterozygotes are predisposed to the development of AD.


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InternalMed_Harrison. The management of AD is challenging and gratifying despite the absence of a cure or a robust pharmacologic treatment. The primary focus is on long-term amelioration of associated behavioral and neurologic problems, as well as providing caregiver support.


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InternalMed_Harrison. Building rapport with the patient, family members, and other caregivers is essential to successful management. In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful. Family members should emphasize activities that are pleasant while curtailing those that increase stress on the patient. Kitchens, bathrooms, stairways, and bedrooms need to be made safe, and eventually patients will need to stop driving. Loss of independence and change of environment may worsen confusion, agitation, and anger. Communication and repeated calm reassurance are necessary. Caregiver “burnout” is common, often resulting in nursing home placement of the patient or new health problems for the caregiver. Respite breaks for the caregiver help to maintain a successful long-term therapeutic milieu. Use of adult day care centers can be helpful. Local and national support groups, such as the Alzheimer’s Association and the Family Caregiver Alliance, are valuable resources.


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InternalMed_Harrison. therapeutic milieu. Use of adult day care centers can be helpful. Local and national support groups, such as the Alzheimer’s Association and the Family Caregiver Alliance, are valuable resources. Internet access to these resources has become available to clinicians and families in recent years.


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InternalMed_Harrison. Donepezil (target dose, 10 mg daily), rivastigmine (target dose, 6 mg twice daily or 9.5-mg patch daily), galantamine (target dose 24 mg daily, extended-release), and memantine (target dose, 10 mg twice daily) are approved by the Food and Drug Administration (FDA) for the treatment of AD. Due to hepatotoxicity, tacrine is no longer used. Dose escalations for each of these medications must be carried out over 4–6 weeks to minimize side effects. The pharmacologic action of donepezil, rivastigmine, and galantamine is inhibition of the cholinesterases, primarily acetylcholinesterase, with a resulting increase in cerebral acetylcholine levels. Memantine appears to act by blocking overexcited N-methyl-D-aspartate (NMDA) glutamate receptors. Double-blind, placebo-controlled, crossover studies with cholinesterase inhibitors and memantine in moderate to severe AD have shown them to be associated with improved caregiver ratings of patients’ functioning and with an apparent decreased rate of


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InternalMed_Harrison. with cholinesterase inhibitors and memantine in moderate to severe AD have shown them to be associated with improved caregiver ratings of patients’ functioning and with an apparent decreased rate of decline in cognitive test scores over periods of up to 3 years. The average patient on an anticholinesterase inhibitor maintains his or her mini-mental state examination (MMSE) score for close to a year, whereas a placebo-treated patient declines 2–3 points over the same time period. Memantine, used in conjunction with cholinesterase inhibitors or by itself, slows cognitive deterioration and decreases caregiver burden for patients with moderate to severe AD but is not approved for mild AD. Each of these compounds has only modest efficacy for AD. Cholinesterase inhibitors are relatively easy to administer, and their major side effects are gastrointestinal symptoms (nausea, diarrhea, cramps), altered sleep with unpleasant or vivid dreams, bradycardia (usually benign), and muscle cramps.


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InternalMed_Harrison. 2602 In a prospective observational study, the use of estrogen replacement therapy appeared to protect—by about 50%—against development of AD in women. This study seemed to confirm the results of two earlier case-controlled studies. Sadly, a prospective placebo-controlled study of a combined estrogen-progesterone therapy for asymptomatic postmenopausal women increased, rather than decreased, the prevalence of dementia. This study markedly dampened enthusiasm for hormonal treatments to prevent dementia. Additionally, no benefit has been found in the treatment of AD with estrogen alone. A controlled trial of an extract of Ginkgo biloba found modest improvement in cognitive function in subjects with AD and vascular dementia. Unfortunately, a comprehensive 6-year multicenter prevention study using ginkgo found no slowing of progression to dementia in the treated group. Vaccination against Aβ42 has proved highly efficacious in mouse models of AD, helping clear brain amyloid and preventing


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InternalMed_Harrison. using ginkgo found no slowing of progression to dementia in the treated group. Vaccination against Aβ42 has proved highly efficacious in mouse models of AD, helping clear brain amyloid and preventing further amyloid accumulation. In human trials, this approach led to life-threatening complications, including meningoencephalitis, in a minority of patients. Another experimental approach to AD treatment has been the use of β and γ secretase inhibitors that diminish the production of Aβ42, but the first two placebo-controlled trials of γ secretase inhibitors, tarenflurbil and semagacestat, were negative, and semagacestat may have accelerated cognitive decline compared to placebo. Passive immunization with monoclonal antibodies against Aβ42 has been tried in mild to moderate AD. These studies were negative, leading some to suggest that the patients treated were too advanced to respond to amyloid-lowering therapies. Therefore, new trials have started in asymptomatic individuals with mild


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InternalMed_Harrison. were negative, leading some to suggest that the patients treated were too advanced to respond to amyloid-lowering therapies. Therefore, new trials have started in asymptomatic individuals with mild AD, in asymptomatic autosomal dominant forms of AD, and in cognitively normal elderly who are amyloid positive with PET. Medications that modify tau phosphorylation and aggregation, including tau antibodies, are beginning to be studied as possible treatments for both AD and non-AD tau-related disorders including FTD and progressive supranuclear palsy. Several retrospective studies suggest that nonsteroidal anti-inflammatory agents and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) may have a protective effect on dementia if used prior to the onset of disease but do not influence clinically symptomatic AD. Finally, there is now a strong interest in the relationship between diabetes and AD, and insulin-regulating studies are being conducted. Mild to moderate


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InternalMed_Harrison. do not influence clinically symptomatic AD. Finally, there is now a strong interest in the relationship between diabetes and AD, and insulin-regulating studies are being conducted. Mild to moderate depression is common in the early stages of AD and may respond to antidepressants or cholinesterase inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are commonly used due to their low anticholinergic side effects (for example, escitalopram, target dose 5–10 mg daily). Seizures can be treated with levetiracetam unless the patient had a different regimen that was effective prior to the onset of AD. Agitation, insomnia, hallucinations, and belligerence are especially troublesome characteristics of some AD patients, and these behaviors can lead to nursing home placement. The newer generation of atypical antipsychotics, such as risperidone, quetiapine, and olanzapine, are being used in low doses to treat these neuropsychiatric symptoms. The few controlled studies comparing drugs


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InternalMed_Harrison. of atypical antipsychotics, such as risperidone, quetiapine, and olanzapine, are being used in low doses to treat these neuropsychiatric symptoms. The few controlled studies comparing drugs against behavioral intervention in the treatment of agitation suggest mild efficacy with significant side effects related to sleep, gait, and cardiovascular complications, including an increased risk of death. All antipsychotics carry a black box FDA warning and should be used with caution in the demented elderly; however, careful, daily, nonpharmacologic behavior management is often not available, rendering medications necessary for some patients. Finally, medications with strong anticholinergic effects should be vigilantly avoided, including prescription and over-the-counter sleep aids (e.g., diphenhydramine) or incontinence therapies (e.g., oxybutynin).


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InternalMed_Harrison. Dementia associated with cerebrovascular disease can be divided into two general categories: multi-infarct dementia and diffuse white matter disease (also called leukoaraiosis, subcortical arteriosclerotic leukoencephalopathy, or Binswanger’s disease). Cerebrovascular disease appears to be a more common cause of dementia in Asia than in Europe and North America, perhaps due to the increased prevalence of intra-cranial atherosclerosis. Individuals who have had strokes may develop chronic cognitive deficits, commonly called multi-infarct dementia. The strokes may be large or small (sometimes lacunar) and usually involve several different brain regions. The occurrence of dementia depends partly on the total volume of damaged cortex. Patients typically report previous discrete episodes of sudden neurologic deterioration. Many patients with multi-infarct dementia have a history of hypertension, diabetes, coronary artery disease, or other manifestations of widespread atherosclerosis.


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InternalMed_Harrison. of sudden neurologic deterioration. Many patients with multi-infarct dementia have a history of hypertension, diabetes, coronary artery disease, or other manifestations of widespread atherosclerosis. Physical examination may show focal neurologic deficits such as hemiparesis, a unilateral Babinski sign, a visual field defect, or pseudobulbar palsy. Recurrent strokes result in a stepwise disease progression. Neuroimaging reveals multiple areas of infarction. Thus, the history and neuroimaging findings differentiate this condition from AD; however, both AD and multiple infarctions are common and sometimes co-occur. With normal aging, there is also an accumulation of amyloid in cerebral blood vessels, leading to a condition called cerebral amyloid angiopathy (without dementia), which predisposes older persons to lobar hemorrhage and brain microhemorrhages. AD patients appear to be at increased risk for amyloid angiopathy, and this association may explain some of the observed links


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InternalMed_Harrison. older persons to lobar hemorrhage and brain microhemorrhages. AD patients appear to be at increased risk for amyloid angiopathy, and this association may explain some of the observed links between AD and stroke.


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InternalMed_Harrison. Some individuals with dementia are discovered on MRI to have bilateral T2 signal hyperintensities in the subcortical white matter, termed diffuse white matter disease, often occurring in association with lacunar infarctions (see Fig. 35-2). The dementia may be insidious in onset and progress slowly, features that distinguish it from multi-infarct dementia, but other patients show a stepwise deterioration more typical of multi-infarct dementia. Early symptoms include mild confusion, apathy, anxiety, psychosis, and memory, spatial, or executive deficits. Marked difficulties in judgment and orientation and dependence on others for daily activities develop later. Euphoria, elation, depression, or aggressive behaviors are common as the disease progresses. Pyramidal and cerebellar signs may be present, and a gait disorder is seen in at least half of these patients. With advanced disease, urinary incontinence and dysarthria with or without other pseudobulbar features (e.g., dysphagia,


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InternalMed_Harrison. be present, and a gait disorder is seen in at least half of these patients. With advanced disease, urinary incontinence and dysarthria with or without other pseudobulbar features (e.g., dysphagia, emotional lability) are frequent. Seizures and myoclonic jerks appear in a minority of patients. Often, this disorder results from chronic ischemia due to occlusive disease of small, penetrating cerebral arteries and arterioles (microangiopathy). Any disease-causing stenosis of small cerebral vessels may be the critical underlying factor, although hypertension is the major cause. The term Binswanger’s disease should be used with caution, because it does not clearly identify a single entity.


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InternalMed_Harrison. Other rare causes of white matter disease also present with dementia, such as adult metachromatic leukodystrophy (arylsulfatase A deficiency) and progressive multifocal leukoencephalopathy (Chap. 164). A dominantly inherited form of white matter disease is known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), discussed later in “Other Causes of Dementia.” Mitochondrial disorders can present with stroke-like episodes and can selectively injure basal ganglia or cortex. Many such patients show other findings suggestive of a neurologic or systemic disorder such as ophthalmoplegia, retinal degeneration, deafness, myopathy, neuropathy, or diabetes. Diagnosis is difficult, but serum or (especially) CSF levels of lactate and pyruvate may be abnormal, and biopsy of affected tissue, preferably muscle, may be diagnostic.


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InternalMed_Harrison. Treatment of vascular dementia must be focused on preventing new ischemic injury by stabilizing or removing the underlying causes, such as hypertension, diabetes, smoking, or lack of exercise. Recovery of lost cognitive function is not likely, although fluctuations with periods of improvement are common. Frontotemporal dementia (FTD) refers to a group of clinical syndromes united by underlying frontotemporal lobar degeneration (FTLD) pathology. FTD most often begins in the fifth to seventh decades and


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InternalMed_Harrison. FIGURE 448-3 Three major frontotemporal dementia (FTD) clinical syndromes. Coronal magnetic resonance imaging sections from representative patients with behavioral variant FTD (left), semantic dementia (center), and progressive nonfluent aphasia (right). Areas of early and severe atrophy in each syndrome are highlighted (white arrowheads). The behavioral variant features anterior cingulate and frontoinsular atrophy, spreading to orbital and dorsolateral prefrontal cortex. Semantic variant primary progressive aphasia (PPA) shows prominent temporopolar atrophy, more often on the left. Nonfluent/agrammatic variant PPA is associated with dominant frontal opercular and dorsal insula degeneration. is nearly as prevalent as AD in this age group. Early studies suggested that FTD may be more common in men than women, although more recent reports cast doubt on this finding. Although a family history of dementia is common, autosomal dominant inheritance is seen in only 10–20% of all FTD cases.


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InternalMed_Harrison. The clinical heterogeneity seen in familial and sporadic FTD is remarkable. Three core clinical syndromes have been described (Fig. 448-3). In the behavioral variant (bvFTD), the most common FTD syndrome, social and emotional systems dysfunction manifests as apathy, disinhibition, compulsivity, loss of empathy, and overeating, often but not always accompanied by deficits in executive control. Two forms of primary progressive aphasia (PPA), the semantic and nonfluent/agrammatic variants, are commonly due to FTLD and included under the FTD umbrella. In the semantic variant, patients slowly lose the ability to decode word, object, person-specific, and emotion meaning, whereas patients with the nonfluent/agrammatic variant develop profound inability to produce words, often with prominent motor speech impairment. Any of these three clinical syndromes, but most often bvFTD, may be accompanied by motor neuron disease (MND), in which case the term FTD-MND is applied. In addition, the


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InternalMed_Harrison. motor speech impairment. Any of these three clinical syndromes, but most often bvFTD, may be accompanied by motor neuron disease (MND), in which case the term FTD-MND is applied. In addition, the corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSP-S) can be considered part of the FTLD clinical spectrum. Furthermore, patients may evolve from any of the major syndromes described above to have prominent features of another syndrome.


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InternalMed_Harrison. Findings at the bedside are dictated by the anatomic localization of the disorder. Right hemisphere-predominant or symmetric anterior cingulate/medial prefrontal, orbital, and anterior insular degeneration predicts bvFTD. Patients with nonfluent/agrammatic PPA show left (dominant) frontal opercular and precentral gyrus degeneration, whereas left anterior temporal atrophy presents with semantic variant PPA. Visuoconstructive ability, arithmetic calculations, and navigation may remain normal late into any FTD syndrome. Many patients with nonfluent aphasia or bvFTD later develop PSP-S, as disease spreads into diencephalic and brainstem structures, or CBS-like features, as disease moves into dorsal and lateral perirolandic cortices.


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InternalMed_Harrison. The most common autosomal dominantly inherited mutations causing FTD involve the C9ORF72 (chromosome 9), GRN (chromosome 17), and MAPT (chromosome 17) genes. Hexanucleotide (GGGGCC) expansions in the noncoding portion of C9ORF72 are the most recently identified and represent the most common genetic cause of familial or sporadic FTD (usually presenting as bvFTD with or without MND) and amyotrophic lateral sclerosis (ALS). The expansion is associated with reduced C9ORF72 mRNA expression, nuclear mRNA foci containing transcribed portions of the expansion and other mRNAs, neuronal cytoplasmic inclusions containing dipeptide repeat proteins translated from the repeat mRNA, and transactive response DNA-binding protein of 43 kDa (TDP-43) neuronal cytoplasmic and glial inclusions. The pathogenic significance of these various features is a topic of vigorous investigation. MAPT mutations lead to a change in the alternate splicing of tau or cause loss of function in the tau molecule, thereby


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InternalMed_Harrison. significance of these various features is a topic of vigorous investigation. MAPT mutations lead to a change in the alternate splicing of tau or cause loss of function in the tau molecule, thereby altering microtubule binding. With GRN, mutations in the coding sequence of the gene encoding progranulin protein result in mRNA degradation due to nonsense-mediated decay, providing a rare example of an autosomal dominant mutation that leads to haploinsufficiency and leads to a ~50% reduction in circulating progranulin protein levels. Intriguingly, a patient with GRN mutations on both chromosomes was recently reported to develop neuronal ceroid lipofuscinosis, focusing investigators on the lysosome as a site of molecular dysfunction in GRN-related FTD. Progranulin is a growth factor that binds to tumor necrosis factor (TNF) receptors and participates in tissue repair and tumor growth. How progranulin mutations lead to FTD remains unknown, but the most likely mechanisms include lysosomal


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InternalMed_Harrison. to tumor necrosis factor (TNF) receptors and participates in tissue repair and tumor growth. How progranulin mutations lead to FTD remains unknown, but the most likely mechanisms include lysosomal dysfunction and enhanced neuroinflammation. Both MAPT and GRN mutations are associated with parkinsonian features, whereas ALS is rare. Infrequently, mutations in the valosin-containing protein (VCP, chromosome 9) and charged multivesicular body protein 2b (CHMP2b, chromosome 3) genes also lead to autosomal dominant familial FTD. Mutations in the TARDBP (encoding TDP-43) and FUS (encoding fused in sarcoma [FUS]) genes (see below) cause familial ALS, sometimes in association with an FTD syndrome, although a few patients presenting with FTD alone have been reported.


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InternalMed_Harrison. The gross pathologic hallmark of FTLD is a focal atrophy of frontal, insular, and/or temporal cortex, which can be visualized with neuroimaging studies (Fig. 448-3) and is often profound at autopsy. Despite the appearance of advanced disease, however, imaging studies suggest that atrophy often begins focally in one hemisphere before spreading to anatomically interconnected regions, including basal ganglia. Loss of cortical serotonergic innervation is seen in many patients. In contrast to AD, the cholinergic system is relatively spared in FTD, which accounts for the poor efficacy of acetylcholinesterase inhibitors in this group.


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InternalMed_Harrison. Although early studies suggested that 15–30% of patients with FTD showed underlying AD at autopsy, progressive refinement in clinical diagnosis has improved pathologic prediction accuracy, and most patients diagnosed with FTD at a dementia clinic with expertise in FTD will show underlying FTLD pathology. Microscopic findings seen across all patients with FTLD include gliosis, microvacuolation, and neuronal loss, but the disease is subtyped according to the protein composition of neuronal and glial inclusions, which contain either tau or TDP-43 in ~90% of patients, with the remaining ~10% showing inclusions containing FUS (Fig. 448-4).


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InternalMed_Harrison. The toxicity and spreading capacity of tau aggregates underlies the pathogenesis of many familial cases and is emerging as a key factor in sporadic tauopathies, although loss of tau microtubule stabilizing function may also play a role. TDP-43 and FUS, in contrast, are RNA/ DNA binding proteins whose roles in neuronal function are still being actively investigated, but one key role may be the chaperoning of Pick’s 3R tau FTDP-17 MAPTOther: CTE, AGD, MST, GGT CBD 4R tau PSP 4R tau aFTLD-U BIBD NIFID/ NIBD FUS NOS FUSType U (C9ORF72)(TARDBP)Type D VCPType A (PGRN)(C9ORF72)Type B (C9ORF72)Type C Alzheimer’s disease bvFTD svPPA nfvPPA FTD-MND CBS PSPS FTLD-tau FTLD-TDP* FTLD-FUS FTLD-3 CHMP2BFrontotemporal lobar degeneration (FTLD)


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InternalMed_Harrison. FIGURE 448-4 Frontotemporal dementia syndromes are united by underlying frontotemporal lobar degeneration pathology, which can be divided according to the presence of tau, TPD-43, or FUS-containing inclusions in neurons and glia. Correlations between clinical syndromes and major molecular classes are shown with colored shading. Despite improvements in clinical syndromic diagnosis, a small percentage of patients with some frontotemporal dementia syndromes will show Alzheimer’s disease neuropathology at autopsy (gray shading). aFTLD-U, atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions; AGD, argyrophilic grain disease; BIBD, basophilic inclusion body disease; bvFTD, behavioral variant frontotemporal dementia; CBD, corticobasal degeneration; CBS, corticobasal syndrome; CTE, chronic traumatic encephalopathy; FTD-MND, frontotemporal dementia with motor neuron disease; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; FUS, fused in


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InternalMed_Harrison. syndrome; CTE, chronic traumatic encephalopathy; FTD-MND, frontotemporal dementia with motor neuron disease; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; FUS, fused in sarcoma; GGT, globular glial tauopathy; MST, multisystem tauopathy; nfvPPA, nonfluent/agrammatic variant primary progressive aphasia; NIBD, neurofilament inclusion body disease; NIFID, neuronal intermediate filament inclusion disease; PSP, progressive supranuclear palsy; PSPS, progressive supranuclear palsy syndrome; svPPA, semantic variant primary progressive aphasia; Type U, unclassifiable type.


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InternalMed_Harrison. mRNAs to the distal neuron for activity-dependent translation within dendritic spines. Because these proteins also form intracellular aggregates and produce similar anatomic progression, protein toxicity and spreading may also factor heavily in the pathogenesis of these FTLDTDP and FTLD-FUS. Increasingly, misfolded proteins in neurodegenerative disease are being recognized as having “prion-like” properties in that they can template the misfolding of their natively folded protein counterparts, a process that creates exponential amplification of protein misfolding within a cell and may promote transcellular and even transsynaptic protein propagation between cells. This hypothesis could provide a unifying explanation for the stereotypical patterns of disease spread observed in each syndrome (Chap. 444e).


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InternalMed_Harrison. Although the term Pick’s disease was once used to describe a progressive degenerative disorder characterized by selective involvement of the anterior frontal and temporal neocortex and pathologically by intraneuronal cytoplasmic inclusions (Pick bodies), it is now used only in reference to a specific FTLD-tau histopathologic entity. Classical Pick bodies are argyrophilic, staining positively with the Bielschowsky silver method (but not with the Gallyas method) and also with immunostaining for hyperphosphorylated tau. Recognition of the three FTLD major molecular classes has allowed delineation of distinct FTLD subtypes within each class. These subtypes, based on the morphology and distribution of the neuronal and glial inclusions (Fig. 448-5), account for the vast majority of patients, and some subtypes show strong clinical or genetic associations (Fig. 448-4). Despite this progress, available data do not allow reliable prediction of the underlying FTLD subtype, or even the major


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InternalMed_Harrison. and some subtypes show strong clinical or genetic associations (Fig. 448-4). Despite this progress, available data do not allow reliable prediction of the underlying FTLD subtype, or even the major molecular class, based on clinical features alone. Molecular PET imaging with ligands chosen to bind misfolded tau protein shows great promise and is already being applied to the study of patients with AD and FTD. Because FTLD-tau and FTLD-TDP account for 90% of FTLD patients, the ability to detect pathologic tau protein deposition in vivo will greatly improve prediction accuracy, especially when amyloid PET imaging is negative.


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InternalMed_Harrison. The burden on caregivers of patients with FTD is extremely high, especially when the illness disrupts core emotional and personality functions of the loved one. Treatment is symptomatic, and there are currently no therapies known to slow progression or improve symptoms. Many of the behaviors that may accompany FTD, such as depression, hyperorality, compulsions, and irritability, can be ameliorated with antidepressants, especially SSRIs. The co-association with motor disorders such as parkinsonism necessitates the careful use of antipsychotics, which can exacerbate this problem.


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InternalMed_Harrison. Progressive supranuclear palsy syndrome (PSP-S; also known as Steele-Richardson-Olszewski syndrome) is a degenerative disorder that involves the brainstem, basal ganglia, limbic structures, and selected areas of cortex. Clinically, PSP-S begins with falls and executive or subtle personality changes (such as mental rigidity, impulsivity, or apathy). Shortly thereafter, a progressive oculomotor syndrome ensues that begins with square wave jerks, followed by slowed saccades (vertical worse than horizontal) before resulting in progressive supranuclear ophthalmoparesis. Dysarthria, dysphagia, and symmetric axial rigidity can be prominent features that emerge at any point in the illness. A stiff, unstable posture with hyperextension of the neck and a slow, jerky, toppling gait are characteristic. Frequent unexplained and sometimes spectacular falls are common secondary to a combination of axial rigidity, inability to look down, and poor judgment. Even once patients have severely limited


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InternalMed_Harrison. Frequent unexplained and sometimes spectacular falls are common secondary to a combination of axial rigidity, inability to look down, and poor judgment. Even once patients have severely limited voluntary eye movements, they retain oculocephalic reflexes (demonstrated using a vertical doll’s head maneuver); thus, the oculomotor disorder is supranuclear. The dementia overlaps with bvFTD, featuring apathy, frontal-executive dysfunction, poor judgment, slowed thought processes, impaired verbal fluency, and difficulty with sequential actions and with shifting from one task to another. These features are common at presentation and often precede the motor syndrome. Some patients with a pathologic diagnosis of PSP begin with a nonfluent aphasia or motor speech disorder and progress to classical PSP-S. Response to l-dopa is limited or absent; no other treatments exist. Death occurs within 5–10 years of onset. Like Pick’s disease, increasingly the term PSP is used to refer to a specific


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InternalMed_Harrison. PSP-S. Response to l-dopa is limited or absent; no other treatments exist. Death occurs within 5–10 years of onset. Like Pick’s disease, increasingly the term PSP is used to refer to a specific histopathologic entity within the FTLD-tau class. In PSP, accumulation of hyperphosphorylated 4-repeat tau is seen within neurons and glia. Neuronal inclusions often take the form of NFTs, which may


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InternalMed_Harrison. FIGURE 448-5 Neuropathology in frontotemporal lobar degeneration (FTLD). FTLD-tau (A–C) and FTLD-TDP (D–F) account for over 90% of patients with FTLD, and immunohistochemistry reveals characteristic lesions in each of the major histopathologic subtypes within each class: small compact or crescentic neuronal cytoplasmic inclusions and short, then neuropil threads in FTLD-TDP, type A; (E) diffuse/granular neuronal cytoplasmic inclusions (with a relative paucity of neuropil threads) in FTLD-TDP, type B; and (F) long, tortuous dystrophic neurites in FTLD-TDP, type C. TDP can be seen within the nucleus in neurons lacking inclusions but mislocalizes to the cytoplasm and forms inclusions in FTLD-TDP. Immunostains are 3-repeat tau (A), phospho-tau (B and C), and TDP-43 (D–F). Sections are counterstained with hematoxylin. Scale bar applies to all panels and represents 50 μm in A, B, C, and E and 100 μm in D and F.


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InternalMed_Harrison. be large, spherical (“globose”), and coarse in brainstem, cerebellar dentate, and diencephalic neurons. Tau deposition is most prominent in subcortical structures (including the subthalamic nucleus, globus pallidus, substantia nigra, locus coeruleus, periaqueductal gray, tectum, oculomotor nuclei, and dentate nucleus of cerebellum). Neocortical NFTs, like those in AD, often take on a more flame-shaped morphology, but on electron microscopy, PSP tangles can be shown to consist of straight tubules rather than the paired helical filaments found in AD. Furthermore, PSP is associated with prominent tau-positive glial pathologies, such as tufted astrocytes (Fig. 448-5), thorny astrocytes, and coiled oligodendroglial inclusions (“coiled bodies”). Most patients with PSP-S show PSP at autopsy, although small numbers will show another tauopathy (corticobasal degeneration [CBD] or Pick’s disease; Fig. 448-4).


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InternalMed_Harrison. In addition to its overlap with FTD and CBS (see below), PSP is often confused with idiopathic Parkinson’s disease (PD). Although elderly patients with PD may have restricted upgaze, they do not develop downgaze paresis or other abnormalities of voluntary eye movements typical of PSP. Dementia occurs in ~20% of patients with PD, often due to the emergence of a full-blown DLB-like syndrome. Furthermore, the behavioral syndromes seen with DLB differ from PSP (see below). Dementia in PD becomes more likely with increasing age, increasing severity of extrapyramidal signs, long disease duration, and the presence of depression. Patients with PD who develop dementia also show cortical atrophy on brain imaging. Neuropathologically, there may be AD-related changes in the cortex, LBD-related α-synuclein inclusions in both the limbic system and cortex, or no specific microscopic changes other than gliosis and neuronal loss. PD is discussed in detail in Chap. 449.


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InternalMed_Harrison. Corticobasal syndrome (CBS) is a slowly progressive dementia-movement disorder associated with severe atrophy in perirolandic cortex and basal ganglia (substantia nigra and striatopallidum). Patients typically present with asymmetric onset of rigidity, dystonia, myoclonus, and apraxia of one limb, at times associated with alien limb phenomena in which the limb exhibits unintended motor actions such as grasping, groping, drifting, or undoing. Eventually CBS becomes bilateral and leads to dysarthria, slow gait, action tremor, and typically a frontal-predominant dementia. Whereas CBS refers to the clinical syndrome, CBD refers to a specific histopathologic FTLD-tau entity (Fig. 448-4). Although CBS was once thought to be pathognomonic for CBD, increasingly it has been recognize that CBS can be due to CBD, PSP, FTLD-TDP, or even AD. In CBD, the microscopic features include ballooned, achromatic, tau-positive neurons; astrocytic plaques (Fig. 448-5); and other dystrophic glial tau


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InternalMed_Harrison. CBS can be due to CBD, PSP, FTLD-TDP, or even AD. In CBD, the microscopic features include ballooned, achromatic, tau-positive neurons; astrocytic plaques (Fig. 448-5); and other dystrophic glial tau pathomorphologies that overlap with those seen in PSP. Most specifically, CBD features a severe tauopathy burden in the subcortical white matter, consisting of threads and oligodendroglial coiled bodies. As shown in Fig. 448-4, patients with bvFTD, nonfluent/agrammatic PPA, and PSP-S may also show CBD at autopsy, emphasizing the importance of distinguishing clinical and pathologic constructs and terminology. Treatment of CBS remains symptomatic; no disease-modifying therapies are available.