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InternalMed_Harrison. able to its peripheral territory (Figs. 446-8 and 446-9). In addition to supplying the ipsilateral brain, the internal carotid poSterior cerebrAl Artery In 75% of cases, both PCAs arise from the artery perfuses the optic nerve and retina via the ophthalmic artery. bifurcation of the basilar artery; in 20%, one has its origin from the In ~25% of symptomatic internal carotid disease, recurrent transient ipsilateral internal carotid artery via the posterior communicating monocular blindness (amaurosis fugax) warns of the lesion. Patients artery; in 5%, both originate from the respective ipsilateral internal typically describe a horizontal shade that sweeps down or up across the carotid arteries (Figs. 446-8 and 446-9). The precommunal, or P1, segfield of vision. They may also complain that their vision was blurred ment of the true posterior cerebral artery is atretic in such cases. Ant. cerebral a. Post. communicating a. Visual Parietooccipital a. Internal carotid a.


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InternalMed_Harrison. Ant. cerebral a. Post. communicating a. Visual Parietooccipital a. Internal carotid a. Post. cerebral a. Ant. choroidal a. Medial posterior choroidal a. Mesencephalic paramedian As. Ant. temporal a. Splenial a. Hippocampal a. Calcarine a. Post. temporal a. Post. thalamic a. Lateral posterior choroidal a. FIGURE 446-9 Inferior aspect of the brain with the branches and distribution of the posterior cerebral artery and the principal anatomic structures shown. Signs and symptoms: Structures involved


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InternalMed_Harrison. Peripheral territory (see also Fig. 446-12). Homonymous hemianopia (often upper quadrantic): Calcarine cortex or optic radiation nearby. Bilateral homonymous hemianopia, cortical blindness, awareness or denial of blindness; tactile naming, achromatopia (color blindness), failure to see to-and-fro movements, inability to perceive objects not centrally located, apraxia of ocular movements, inability to count or enumerate objects, tendency to run into things that the patient sees and tries to avoid: Bilateral occipital lobe with possibly the parietal lobe involved. Verbal dyslexia without agraphia, color anomia: Dominant calcarine lesion and posterior part of corpus callosum. Memory defect: Hippocampal lesion bilaterally or on the dominant side only. Topographic disorientation and prosopagnosia: Usually with lesions of nondominant, calcarine, and lingual gyrus. Simultanagnosia, hemivisual neglect: Dominant visual cortex, contralateral hemisphere. Unformed visual hallucinations,


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InternalMed_Harrison. Usually with lesions of nondominant, calcarine, and lingual gyrus. Simultanagnosia, hemivisual neglect: Dominant visual cortex, contralateral hemisphere. Unformed visual hallucinations, peduncular hallucinosis, metamorphopsia, teleopsia, illusory visual spread, palinopsia, distortion of outlines, central photophobia: Calcarine cortex. Complex hallucinations: Usually nondominant hemisphere.


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InternalMed_Harrison. Central territory. Thalamic syndrome: sensory loss (all modalities), spontaneous pain and dysesthesias, choreoathetosis, intention tremor, spasms of hand, mild hemiparesis: Posteroventral nucleus of thalamus; involvement of the adjacent subthalamus body or its afferent tracts. Thalamoperforate syndrome: crossed cerebellar ataxia with ipsilateral third nerve palsy (Claude’s syndrome): Dentatothalamic tract and issuing third nerve. Weber’s syndrome: third nerve palsy and contralateral hemiplegia: Third nerve and cerebral peduncle. Contralateral hemiplegia: Cerebral peduncle. Paralysis or paresis of vertical eye movement, skew deviation, sluggish pupillary responses to light, slight miosis and ptosis (retraction nystagmus and “tucking” of the eyelids may be associated): Supranuclear fibers to third nerve, interstitial nucleus of Cajal, nucleus of Darkschewitsch, and posterior commissure. Contralateral rhythmic, ataxic action tremor; rhythmic postural or “holding” tremor (rubral tremor):


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InternalMed_Harrison. third nerve, interstitial nucleus of Cajal, nucleus of Darkschewitsch, and posterior commissure. Contralateral rhythmic, ataxic action tremor; rhythmic postural or “holding” tremor (rubral tremor): Dentatothalamic tract.


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InternalMed_Harrison. PCA syndromes usually result from atheroma formation or emboli that lodge at the top of the basilar artery; posterior circulation disease may also be caused by dissection of either vertebral artery or fibromuscular dysplasia. Two clinical syndromes are commonly observed with occlusion of 2575 the PCA: (1) P1 syndrome: midbrain, subthalamic, and thalamic signs, which are due to disease of the proximal P1 segment of the PCA or its penetrating branches (thalamogeniculate, Percheron, and posterior choroidal arteries); and (2) P2 syndrome: cortical temporal and occipital lobe signs, due to occlusion of the P2 segment distal to the junction of the PCA with the posterior communicating artery.


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InternalMed_Harrison. p1 SynDromeS Infarction usually occurs in the ipsilateral subthalamus and medial thalamus and in the ipsilateral cerebral peduncle and mid- brain (Figs. 446-9 and 446-14). A third nerve palsy with contralateral ataxia (Claude’s syndrome) or with contralateral hemiplegia (Weber’s syndrome) may result. The ataxia indicates involvement of the red nucleus or dentatorubrothalamic tract; the hemiplegia is localized to the cerebral peduncle (Fig. 446-14). If the subthalamic nucleus is involved, contralateral hemiballismus may occur. Occlusion of the artery of Percheron produces paresis of upward gaze and drowsiness and often abulia. Extensive infarction in the midbrain and sub-thalamus occurring with bilateral proximal PCA occlusion presents as coma, unreactive pupils, bilateral pyramidal signs, and decerebrate rigidity.


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InternalMed_Harrison. Occlusion of the penetrating branches of thalamic and thalamogeniculate arteries produces less extensive thalamic and thalamocapsular lacunar syndromes. The thalamic Déjérine-Roussy syndrome consists of contralateral hemisensory loss followed later by an agonizing, searing or burning pain in the affected areas. It is persistent and responds poorly to analgesics. Anticonvulsants (carbamazepine or gabapentin) or tricyclic antidepressants may be beneficial.


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InternalMed_Harrison. p2 SynDromeS (Figs. 446-8 and 446-9) Occlusion of the distal PCA causes infarction of the medial temporal and occipital lobes. Contralateral homonymous hemianopia with macula sparing is the usual manifestation. Occasionally, only the upper quadrant of visual field is involved. If the visual association areas are spared and only the calcarine cortex is involved, the patient may be aware of visual defects. Medial temporal lobe and hippocampal involvement may cause an acute disturbance in memory, particularly if it occurs in the dominant hemisphere. The defect usually clears because memory has bilateral representation. If the dominant hemisphere is affected and the infarct extends to involve the splenium of the corpus callosum, the patient may demonstrate alexia without agraphia. Visual agnosia for faces, objects, mathematical symbols, and colors and anomia with paraphasic errors (amnestic aphasia) may also occur, even without callosal involvement. Occlusion of the posterior cerebral


InternalMed_Harrison

InternalMed_Harrison. for faces, objects, mathematical symbols, and colors and anomia with paraphasic errors (amnestic aphasia) may also occur, even without callosal involvement. Occlusion of the posterior cerebral artery can produce peduncular hallucinosis (visual hallucinations of brightly colored scenes and objects).


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InternalMed_Harrison. Bilateral infarction in the distal PCAs produces cortical blindness (blindness with preserved pupillary light reaction). The patient is often unaware of the blindness or may even deny it (Anton’s syndrome). Tiny islands of vision may persist, and the patient may report that vision fluctuates as images are captured in the preserved portions. Rarely, only peripheral vision is lost and central vision is spared, resulting in “gun-barrel” vision. Bilateral visual association area lesions may result in Balint’s syndrome, a disorder of the orderly visual scanning of the environment (Chap. 36), usually resulting from infarctions secondary to low flow in the “watershed” between the distal PCA and MCA territories, as occurs after cardiac arrest. Patients may experience persistence of a visual image for several minutes despite gazing at another scene (palinopsia) or an inability to synthesize the whole of an image (asimultanagnosia). Embolic occlusion of the top of the basilar artery can produce


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InternalMed_Harrison. for several minutes despite gazing at another scene (palinopsia) or an inability to synthesize the whole of an image (asimultanagnosia). Embolic occlusion of the top of the basilar artery can produce any or all of the central or peripheral territory symptoms. The hallmark is the sudden onset of bilateral signs, including ptosis, pupillary asymmetry or lack of reaction to light, and somnolence.


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InternalMed_Harrison. VertebrAl AnD poSterior inferior cerebellAr ArterieS The vertebral artery, which arises from the innominate artery on the right and the subclavian artery on the left, consists of four segments. The first (V1) extends from its origin to its entrance into the sixth or fifth transverse vertebral foramen. The second segment (V2) traverses the vertebral Descending nucleus and tract 5th n. nucleus 12th n. Medullary syndrome: 12th n. 10th n. FIGURE 446-10 Axial section at the level of the medulla, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Note that in Figs. 446-10 through 446-14, all drawings are oriented with the dorsal surface at the bottom, matching the orientation of the brainstem that is commonly seen in all modern neuroimaging studies. Approximate regions involved in medial and lateral medullary stroke syndromes are shown. Signs and symptoms: Structures involved 1.


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InternalMed_Harrison. Signs and symptoms: Structures involved 1. Medial medullary syndrome (occlusion of vertebral artery or of branch of vertebral or lower basilar artery) On side of lesion Paralysis with atrophy of one-half half the tongue: Ipsilateral twelfth nerve On side opposite lesion Paralysis of arm and leg, sparing face; impaired tactile and proprioceptive sense over one-half the body: Contralateral pyramidal tract and medial lemniscus 2. Lateral medullary syndrome (occlusion of any of five vessels may be responsible—vertebral, posterior inferior cerebellar, superior, middle, or inferior lateral medullary arteries) On side of lesion


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InternalMed_Harrison. Lateral medullary syndrome (occlusion of any of five vessels may be responsible—vertebral, posterior inferior cerebellar, superior, middle, or inferior lateral medullary arteries) On side of lesion Pain, numbness, impaired sensation over one-half the face: Descending tract and nucleus fifth nerve Ataxia of limbs, falling to side of lesion: Uncertain—restiform body, cerebellar hemisphere, cerebellar fibers, spinocerebellar tract (?) Nystagmus, diplopia, oscillopsia, vertigo, nausea, vomiting: Vestibular nucleus Horner’s syndrome (miosis, ptosis, decreased sweating): Descending sympathetic tract Dysphagia, hoarseness, paralysis of palate, paralysis of vocal cord, diminished gag reflex: Issuing fibers ninth and tenth nerves Loss of taste: Nucleus and tractus solitarius Numbness of ipsilateral arm, trunk, or leg: Cuneate and gracile nuclei Weakness of lower face: Genuflected upper motor neuron fibers to ipsilateral facial nucleus


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InternalMed_Harrison. On side opposite lesion Impaired pain and thermal sense over half the body, sometimes face: Spinothalamic tract 3. Total unilateral medullary syndrome (occlusion of vertebral artery): Combination of medial and lateral syndromes 4. Lateral pontomedullary syndrome (occlusion of vertebral artery): Combination of lateral medullary and lateral inferior pontine syndrome 5. Basilar artery syndrome (the syndrome of the lone vertebral artery is equivalent): A combination of the various brainstem syndromes plus those arising in the posterior cerebral artery distribution. Bilateral long tract signs (sensory and motor; cerebellar and peripheral cranial nerve abnormalities): Bilateral long tract; cerebellar and peripheral cranial nerves


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InternalMed_Harrison. Paralysis or weakness of all extremities, plus all bulbar musculature: Corticobulbar and corticospinal tracts bilaterally foramina from C6 to C2. The third (V3) passes through the transverse foramen and circles around the arch of the atlas to pierce the dura at the foramen magnum. The fourth (V4) segment courses upward to join the other vertebral artery to form the basilar artery; only the fourth segment gives rise to branches that supply the brainstem and cerebellum. The posterior inferior cerebellar artery (PICA) in its proximal segment supplies the lateral medulla and, in its distal branches, the inferior surface of the cerebellum.


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InternalMed_Harrison. Atherothrombotic lesions have a predilection for V1 and V4 segments of the vertebral artery. The first segment may become diseased at the origin of the vessel and may produce posterior circulation emboli; collateral flow from the contralateral vertebral artery or the ascending cervical, thyrocervical, or occipital arteries is usually sufficient to prevent low-flow TIAs or stroke. When one vertebral artery is atretic and an atherothrombotic lesion threatens the origin of the other, the collateral circulation, which may also include retrograde flow down the basilar artery, is often insufficient (Figs. 446-4 and 446-9). In this setting, low-flow TIAs may occur, consisting of syncope, vertigo, and alternating hemiplegia; this state also sets the stage for thrombosis. Disease of the distal fourth segment of the vertebral artery can promote thrombus formation manifest as embolism or with propagation as basilar artery thrombosis. Stenosis proximal to the origin of the PICA can threaten the


InternalMed_Harrison

InternalMed_Harrison. segment of the vertebral artery can promote thrombus formation manifest as embolism or with propagation as basilar artery thrombosis. Stenosis proximal to the origin of the PICA can threaten the lateral medulla and posterior inferior surface of the cerebellum.


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InternalMed_Harrison. If the subclavian artery is occluded proximal to the origin of the vertebral artery, there is a reversal in the direction of blood flow in the ipsilateral vertebral artery. Exercise of the ipsilateral arm may increase demand on vertebral flow, producing posterior circulation TIAs, or “subclavian steal.” 7th n. 6th n. peduncle 6th n. nucleus complex 7th n. nucleus cochlear Descending tract and nucleus of 5th n. 8th n. Inferior pontine syndrome: FIGURE 446-11 Axial section at the level of the inferior pons, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral inferior pontine stroke syndromes are shown. Signs and symptoms: Structures involved 1. Medial inferior pontine syndrome (occlusion of paramedian branch of basilar artery)


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InternalMed_Harrison. Signs and symptoms: Structures involved 1. Medial inferior pontine syndrome (occlusion of paramedian branch of basilar artery) On side of lesion Paralysis of conjugate gaze to side of lesion (preservation of convergence): Center for conjugate lateral gaze Nystagmus: Vestibular nucleus Ataxia of limbs and gait: Likely middle cerebellar peduncle Diplopia on lateral gaze: Abducens nerve On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract in lower pons Impaired tactile and proprioceptive sense over one-half of the body: Medial lemniscus 2. Lateral inferior pontine syndrome (occlusion of anterior inferior cerebellar artery)


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InternalMed_Harrison. On side of lesion Horizontal and vertical nystagmus, vertigo, nausea, vomiting, oscillopsia: Vestibular nerve or nucleus Facial paralysis: Seventh nerve Paralysis of conjugate gaze to side of lesion: Center for conjugate lateral gaze Deafness, tinnitus: Auditory nerve or cochlear nucleus Ataxia: Middle cerebellar peduncle and cerebellar hemisphere Impaired sensation over face: Descending tract and nucleus fifth nerve On side opposite lesion Impaired pain and thermal sense over one-half the body (may include face): Spinothalamic tract Although atheromatous disease rarely narrows the second and third segments of the vertebral artery, this region is subject to dissection, fibromuscular dysplasia, and, rarely, encroachment by osteophytic spurs within the vertebral foramina.


InternalMed_Harrison

InternalMed_Harrison. Embolic occlusion or thrombosis of a V4 segment causes ischemia of the lateral medulla. The constellation of vertigo, numbness of the ipsilateral face and contralateral limbs, diplopia, hoarseness, dysarthria, dysphagia, and ipsilateral Horner’s syndrome is called the lateral medullary (or Wallenberg’s) syndrome (Fig. 446-10). Most cases result from ipsilateral vertebral artery occlusion; in the remainder, PICA occlusion is responsible. Occlusion of the medullary penetrating branches of the vertebral artery or PICA results in partial syndromes. Hemiparesis is not a feature of vertebral artery occlusion; however, quadriparesis may result from occlusion of the anterior spinal artery. Rarely, a medial medullary syndrome occurs with infarction of the pyramid and contralateral hemiparesis of the arm and leg, sparing the face. If the medial lemniscus and emerging hypoglossal nerve fibers are involved, contralateral loss of joint position sense and ipsilateral tongue weakness occur.


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InternalMed_Harrison. Cerebellar infarction with edema can lead to sudden respiratory arrest due to raised ICP in the posterior fossa. Drowsiness, Babinski signs, dysarthria, and bifacial weakness may be absent, or present only briefly, before respiratory arrest ensues. Gait unsteadiness, headache, dizziness, nausea, and vomiting may be the only early symptoms and signs and should arouse suspicion of this impending complication, which may require neurosurgical decompression, often with an excellent outcome. Separating these symptoms from those of viral labyrinthitis can be a challenge, but headache, neck stiffness, and unilateral dysmetria favor stroke. bASilAr Artery Branches of the basilar artery supply the base of the pons and superior cerebellum and fall into three groups: (1) paramedian, 7–10 in number, which supply a wedge of pons on either side of the midline; (2) short circumferential, 5–7 in number, that supply 5th n. Lateral Superior cerebellar peduncle Midpontine syndrome:


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InternalMed_Harrison. Superior cerebellar peduncle Midpontine syndrome: Medial longitudinal fasciculus 5th n. sensory nucleus 5th n. motor nucleus Spinothalamic Medial lemniscus FIGURE 446-12 Axial section at the level of the midpons, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral midpontine stroke syndromes are shown. Signs and symptoms: Structures involved 1. Medial midpontine syndrome (paramedian branch of midbasilar artery) On side of lesion Ataxia of limbs and gait (more prominent in bilateral involvement): Pontine nuclei On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract Variable impaired touch and proprioception when lesion extends posteriorly: Medial lemniscus 2.


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InternalMed_Harrison. On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract Variable impaired touch and proprioception when lesion extends posteriorly: Medial lemniscus 2. On side of lesion Ataxia of limbs: Middle cerebellar peduncle Paralysis of muscles of mastication: Motor fibers or nucleus of fifth nerve Impaired sensation over side of face: Sensory fibers or nucleus of fifth nerve On side opposite lesion Impaired pain and thermal sense on limbs and trunk: Spinothalamic tract the lateral two-thirds of the pons and middle and superior cerebellar peduncles; and (3) bilateral long circumferential (superior cerebellar and anterior inferior cerebellar arteries), which course around the pons to supply the cerebellar hemispheres.


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InternalMed_Harrison. Atheromatous lesions can occur anywhere along the basilar trunk but are most frequent in the proximal basilar and distal vertebral segments. Typically, lesions occlude either the proximal basilar and one or both vertebral arteries. The clinical picture varies depending on the availability of retrograde collateral flow from the posterior communicating arteries. Rarely, dissection of a vertebral artery may involve the basilar artery and, depending on the location of true and false lumen, may produce multiple penetrating artery strokes. Although atherothrombosis occasionally occludes the distal portion of the basilar artery, emboli from the heart or proximal vertebral or basilar segments are more commonly responsible for “top of the basilar” syndromes.


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InternalMed_Harrison. Because the brainstem contains many structures in close apposition, a diversity of clinical syndromes may emerge with ischemia, reflecting involvement of the corticospinal and corticobulbar tracts, ascending sensory tracts, and cranial nerve nuclei (Figs. 446-11, 446-12, 446-13, and 446-14).


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InternalMed_Harrison. The symptoms of transient ischemia or infarction in the territory of the basilar artery often do not indicate whether the basilar artery itself or one of its branches is diseased, yet this distinction has important implications for therapy. The picture of complete basilar occlusion, however, is easy to recognize as a constellation of bilateral long tract signs (sensory and motor) with signs of cranial nerve and cerebellar dysfunction. A “locked-in” state of preserved consciousness with quadriplegia and cranial nerve signs suggests complete pontine and lower midbrain infarction. The therapeutic goal is to identify impending basilar occlusion before devastating infarction occurs. A series of TIAs and a slowly progressive, fluctuating stroke are extremely significant, because they often herald an atherothrombotic occlusion of the distal vertebral or proximal basilar artery.


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InternalMed_Harrison. TIAs in the proximal basilar distribution may produce vertigo (often described by patients as “swimming,” “swaying,” “moving,” “unsteadiness,” or “light-headedness”). Other symptoms that warn of basilar thrombosis include diplopia, dysarthria, facial or circumoral numbness, and hemisensory symptoms. In general, symptoms of basilar branch TIAs affect one side of the brainstem, whereas symptoms of basilar artery TIAs usually affect both sides, although a “herald” hemiparesis has been emphasized as an initial symptom of basilar occlusion. Most often, TIAs, whether due to impending occlusion of the basilar artery or a basilar branch, are short lived (5–30 min) and repetitive, occurring several times a day. The pattern suggests intermittent reduction of flow. Many neurologists treat with heparin to prevent clot propagation. Atherothrombotic occlusion of the basilar artery with infarction usually causes bilateral brainstem signs. A gaze paresis or internuclear Superior pontine syndrome:


InternalMed_Harrison

InternalMed_Harrison. Atherothrombotic occlusion of the basilar artery with infarction usually causes bilateral brainstem signs. A gaze paresis or internuclear Superior pontine syndrome: FIGURE 446-13 Axial section at the level of the superior pons, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral superior pontine stroke syndromes are shown. Signs and symptoms: Structures involved 1. Medial superior pontine syndrome (paramedian branches of upper basilar artery) On side of lesion Cerebellar ataxia (probably): Superior and/or middle cerebellar peduncle Internuclear ophthalmoplegia: Medial longitudinal fasciculus Myoclonic syndrome, palate, pharynx, vocal cords, respiratory apparatus, face, oculomotor apparatus, etc.: Localization uncertain—central tegmental bundle, dentate projection, inferior olivary nucleus


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InternalMed_Harrison. On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract Rarely touch, vibration, and position are affected: Medial lemniscus 2. Lateral superior pontine syndrome (syndrome of superior cerebellar artery) On side of lesion Ataxia of limbs and gait, falling to side of lesion: Middle and superior cerebellar peduncles, superior surface of cerebellum, dentate nucleus Dizziness, nausea, vomiting; horizontal nystagmus: Vestibular nucleus Paresis of conjugate gaze (ipsilateral): Pontine contralateral gaze Skew deviation: Uncertain Miosis, ptosis, decreased sweating over face (Horner’s syndrome): Descending sympathetic fibers Tremor: Localization unclear—Dentate nucleus, superior cerebellar peduncle


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InternalMed_Harrison. On side opposite lesion Impaired pain and thermal sense on face, limbs, and trunk: Spinothalamic tract Impaired touch, vibration, and position sense, more in leg than arm (there is a tendency to incongruity of pain and touch deficits): Medial lemniscus (lateral portion) ophthalmoplegia associated with ipsilateral hemiparesis may be the only manifestation of bilateral brainstem ischemia. More often, unequivocal signs of bilateral pontine disease are present. Complete basilar thrombosis carries a high mortality. Occlusion of a branch of the basilar artery usually causes unilateral symptoms and signs involving motor, sensory, and cranial nerves. As long as symptoms remain unilateral, concern over pending basilar occlusion should be reduced.


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InternalMed_Harrison. Occlusion of the superior cerebellar artery results in severe ipsilateral cerebellar ataxia, nausea and vomiting, dysarthria, and contra-lateral loss of pain and temperature sensation over the extremities, body, and face (spinoand trigeminothalamic tract). Partial deafness, ataxic tremor of the ipsilateral upper extremity, Horner’s syndrome, and palatal myoclonus may occur rarely. Partial syndromes occur frequently (Fig. 446-13). With large strokes, swelling and mass effects may compress the midbrain or produce hydrocephalus; these symptoms may evolve rapidly. Neurosurgical intervention may be lifesaving in such cases.


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InternalMed_Harrison. Occlusion of the anterior inferior cerebellar artery produces variable degrees of infarction because the size of this artery and the territory it supplies vary inversely with those of the PICA. The principal symptoms include: (1) ipsilateral deafness, facial weakness, vertigo, nausea and vomiting, nystagmus, tinnitus, cerebellar ataxia, Horner’s syndrome, and paresis of conjugate lateral gaze; and (2) contralateral loss of pain and temperature sensation. An occlusion close to the origin of the artery may cause corticospinal tract signs (Fig. 446-11). Occlusion of one of the short circumferential branches of the basilar artery affects the lateral two-thirds of the pons and middle or superior cerebellar peduncle, whereas occlusion of one of the paramedian branches affects a wedge-shaped area on either side of the medial pons (Figs. 446-11 through 446-13). See also Chap. 440e. 2580 3rd n. Midbrain syndrome:


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InternalMed_Harrison. See also Chap. 440e. 2580 3rd n. Midbrain syndrome: FIGURE 446-14 Axial section at the level of the midbrain, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral midbrain stroke syndromes are shown. Signs and symptoms: Structures involved 1. Medial midbrain syndrome (paramedian branches of upper basilar and proximal posterior cerebral arteries) On side of lesion Eye “down and out” secondary to unopposed action of fourth and sixth cranial nerves, with dilated and unresponsive pupil: Third nerve fibers On side opposite lesion Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract descending in crus cerebri 2. Lateral midbrain syndrome (syndrome of small penetrating arteries arising from posterior cerebral artery)


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InternalMed_Harrison. On side of lesion Eye “down and out” secondary to unopposed action of fourth and sixth cranial nerves, with dilated and unresponsive pupil: Third nerve fibers and/or third nerve nucleus On side opposite lesion Hemiataxia, hyperkinesias, tremor: Red nucleus, dentatorubrothalamic pathway CT Scans CT radiographic images identify or exclude hemorrhage as the cause of stroke, and they identify extraparenchymal hemorrhages, neoplasms, abscesses, and other conditions masquerading as stroke. Brain CT scans obtained in the first several hours after an infarction generally show no abnormality, and the infarct may not be seen reliably for 24–48 h. CT may fail to show small ischemic strokes in the posterior fossa because of bone artifact; small infarcts on the cortical surface may also be missed.


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InternalMed_Harrison. Contrast-enhanced CT scans add specificity by showing contrast enhancement of subacute infarcts and allow visualization of venous structures. Coupled with multidetector scanners, CT angiography (CTA) can be performed with administration of IV iodinated contrast allowing visualization of the cervical and intracranial arteries, intracranial veins, aortic arch, and even the coronary arteries in one imaging session. Carotid disease and intracranial vascular occlusions are readily identified with this method (Fig. 446-3). After an IV bolus of contrast, deficits in brain perfusion produced by vascular occlusion can also be demonstrated (Fig. 446-15) and used to predict the region of infarcted brain and the brain at risk of further infarction (i.e., the ischemic penumbra, see “Pathophysiology of Ischemic Stroke” above). CT imaging is also sensitive for detecting SAH (although by itself does not rule it out), and CTA can readily identify intracranial aneurysms (Chap. 330). Because of its


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InternalMed_Harrison. of Ischemic Stroke” above). CT imaging is also sensitive for detecting SAH (although by itself does not rule it out), and CTA can readily identify intracranial aneurysms (Chap. 330). Because of its speed and wide availability, noncontrast head CT is the imaging modality of choice in patients with acute stroke (Fig. 446-1), and CTA and CT perfusion imaging may also be useful and convenient adjuncts.


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InternalMed_Harrison. MRI reliably documents the extent and location of infarction in all areas of the brain, including the posterior fossa and cortical surface.


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InternalMed_Harrison. It also identifies intracranial hemorrhage and other abnormalities and, using special sequences, can be as sensitive as CT for detecting acute intracerebral hemorrhage. MRI scanners with magnets of higher field strength produce more reliable and precise images. Diffusion-weighted imaging is more sensitive for early brain infarction than standard MR sequences or CT (Fig. 446-16), as is fluid-attenuated inversion recovery (FLAIR) imaging (Chap. 440e). Using IV administration of gadolinium contrast, MR perfusion studies can be performed. Brain regions showing poor perfusion but no abnormality on diffusion provide, compared to CT, an equivalent measure of the ischemic penumbra. MR angiography is highly sensitive for steno-sis of extracranial internal carotid arteries and of large intracranial vessels. With higher degrees of stenosis, MR angiography tends to overestimate the degree of stenosis when compared to conventional x-ray angiography. MRI with fat saturation is an imaging sequence


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InternalMed_Harrison. vessels. With higher degrees of stenosis, MR angiography tends to overestimate the degree of stenosis when compared to conventional x-ray angiography. MRI with fat saturation is an imaging sequence used to visualize extra or intracranial arterial dissection. This sensitive technique images clotted blood within the dissected vessel wall. Iron-sensitive imaging (ISI) is helpful to detect cerebral microbleeds that may be present in cerebral amyloid angiopathy and other hemorrhagic disorders.


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InternalMed_Harrison. MRI is more expensive and time consuming than CT and less readily available. Claustrophobia and the logistics of imaging acutely critically ill patients also limit its application. Most acute stroke protocols use CT because of these limitations. However, MRI is useful outside the acute period by more clearly defining the extent of tissue injury and discriminating new from old regions of brain infarction. MRI may have particular utility in patients with TIA, because it is also more likely to identify new infarction, which is a strong predictor of subsequent stroke.


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InternalMed_Harrison. FIGURE 446-15 Acute left middle cerebral artery (MCA) stroke with right hemiplegia but preserved language. A. Computed tomography (CT) perfusion mean-transit time map showing delayed perfusion of the left MCA distribution (blue). B. Predicted region of infarct (red) and penumbra (green) based on CT perfusion data. C. Conventional angiogram showing occlusion of the left internal carotid–MCA bifurcation (left panel), and revascularization of the vessels following successful thrombectomy 8 h after stroke symptom onset (right panel). D. The clot removed with a thrombectomy device (L5, Concentric Medical, Inc.). E. CT scan of the brain 2 days later; note infarction in the region predicted in B but preservation of the penumbral region by successful revascularization.


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InternalMed_Harrison. Cerebral Angiography Conventional x-ray cerebral angiography is the gold standard for identifying and quantifying atherosclerotic stenoses of the cerebral arteries and for identifying and characterizing other pathologies, including aneurysms, vasospasm, intraluminal thrombi, fibromuscular dysplasia, arteriovenous fistulae, vasculitis, and collateral channels of blood flow. Conventional angiography carries risks of arterial damage, groin hemorrhage, embolic stroke, and renal failure from contrast nephropathy, so it should be reserved for situations where less invasive means are inadequate. As reviewed earlier in this chapter, endovascular stroke therapy has not been proven effective in three randomized trials, and this remains an area of ongoing investigation.


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InternalMed_Harrison. Ultrasound Techniques Stenosis at the origin of the internal carotid artery can be identified and quantified reliably by ultrasonography that combines a B-mode ultrasound image with a Doppler ultrasound assessment of flow velocity (“duplex” ultrasound). Transcranial Doppler (TCD) assessment of MCA, ACA, and PCA flow and of vertebrobasilar flow is also useful. This latter technique can detect stenotic lesions in the large intracranial arteries because such lesions increase systolic flow velocity. TCD can assist thrombolysis and improve large artery recanalization following rtPA administration; the potential clinical benefit of this treatment is the subject of ongoing study. TCD can also detect microemboli from otherwise asymptomatic carotid plaques. In many cases, MR angiography combined with carotid and transcranial ultrasound studies eliminates the need for conventional x-ray angiography in evaluating vascular stenosis. Alternatively, CT angiography of the entire head and neck can be


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InternalMed_Harrison. carotid and transcranial ultrasound studies eliminates the need for conventional x-ray angiography in evaluating vascular stenosis. Alternatively, CT angiography of the entire head and neck can be performed during the initial imaging of acute stroke. Because this images the entire arterial system relevant to stroke, with the exception of the heart, much of the clinician’s stroke workup can be completed with this single imaging study.


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InternalMed_Harrison. Perfusion Techniques Both xenon techniques (principally xenon-CT) and positron emission tomography (PET) can quantify cerebral blood flow. These tools are generally used for research (Chap. 440e) but can be useful for determining the significance of arterial stenosis and planning for revascularization surgery. Single-photon emission computed tomography (SPECT) and MR perfusion techniques report relative cerebral blood flow. As noted above, CT imaging is used as the initial imaging modality for acute stroke, and some centers combine both CT angiography and CT perfusion imaging together with the noncontrast CT scan. CT perfusion imaging increases the sensitivity for detecting ischemia and can measure the ischemic penumbra (Fig. 446-15). Alternatively, MR perfusion can be combined with MR diffusion imaging to identify the ischemic penumbra as the mismatch between these two imaging sequences (Fig. 446-16).


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InternalMed_Harrison. Hemorrhages are classified by their location and the underlying vascular pathology. Bleeding into subdural and epidural spaces is


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InternalMed_Harrison. FIGURE 446-16 Magnetic resonance imaging (MRI) of acute stroke. A. MRI diffusion-weighted image (DWI) of an 82-year-old woman 2.5 h after onset of right-sided weakness and aphasia reveals restricted diffusion within the left basal ganglia and internal capsule (colored regions). B. Perfusion defect within the left hemisphere (colored signal) imaged after administration of an IV bolus of gadolinium contrast. The discrepancy between the region of poor perfusion shown in B and the diffusion deficit shown in A is called diffusion-perfusion mismatch and provides an estimate of the ischemic penumbra. Without specific therapy, the region of infarction will expand into much or all of the perfusion deficit. C. Cerebral angiogram of the left internal carotid artery in this patient before (left) and after (right) successful endovascular embolectomy. The occlusion is within the carotid terminus. D. Fluid-attenuated inversion recovery image obtained 3 days later showing a region of infarction


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InternalMed_Harrison. and after (right) successful endovascular embolectomy. The occlusion is within the carotid terminus. D. Fluid-attenuated inversion recovery image obtained 3 days later showing a region of infarction (coded as white) that corresponds to the initial DWI image in A, but not the entire area at risk shown in B, suggesting that successful embolectomy saved a large region of brain tissue from infarction. (Courtesy of Gregory Albers, MD, Stanford University; with permission.) principally produced by trauma. SAH results from trauma or the rupture of an intracranial aneurysm or arteriovenous malformation (AVM) (Chap. 330). Intracerebral and intraventricular hemorrhage will be considered here.


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InternalMed_Harrison. Intracranial hemorrhage is often discovered on noncontrast CT imaging of the brain during the acute evaluation of stroke. Because CT is more widely available and may be logistically easier, CT imaging is the preferred method for acute stroke evaluation (Fig. 446-1). The location of the hemorrhage narrows the differential diagnosis to a few entities. Table 446-6 lists the causes and anatomic spaces involved in hemorrhages.


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InternalMed_Harrison. Close attention should be paid to airway management because a reduction in the level of consciousness is common and often progressive. The initial blood pressure should be maintained until the results of the CT scan are reviewed and demonstrate an intracerebral hemorrhage (ICH). In theory, a higher blood pressure should promote hematoma expansion, but it remains unclear if lowering of blood pressure reduces hematoma growth. Recent clinical trials have shown that systolic blood pressure (SBP) can be safely lowered acutely and rapidly to <140 mmHg in patients with spontaneous ICH whose initial SBP was 150–220 mmHg.


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InternalMed_Harrison. The INTERACT2 trial is the only large phase 3 clinical trial to address the effect of acute blood pressure lowering on ICH functional outcome. INTERACT2 randomized patients with spontaneous ICH within 6 h of onset and a baseline SBP of 150–220 mmHg to two different SBP targets (<140 mmHg and <180 mmHg). In those with the target SBP <140 mmHg, 52% had an outcome of death or major disability at 90 days compared with 55.6% of those with a target SBP <180 mmHg (p = .06). There was a significant shift to improved outcomes in the lower blood pressure arm, whereas both groups had a similar mortality. This study shows that it is not harmful, and may be modestly beneficial, to lower blood pressure in acute ICH. Thus, it is reasonable to target an SBP <140 mmHg initially in this group of patients. In patients who have higher SBP on presentation or who are deeply comatose with possible elevated ICP, it is unclear whether the INTERACT2 results apply. In patients who have ICP monitors in place,


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InternalMed_Harrison. In patients who have higher SBP on presentation or who are deeply comatose with possible elevated ICP, it is unclear whether the INTERACT2 results apply. In patients who have ICP monitors in place, current recommendations are to maintain the cerebral perfusion pressure (mean arterial pressure [MAP] minus ICP) above 60 mmHg. Blood pressure should be lowered with nonvasodilating IV drugs such as nicardipine, labetalol, or esmolol. Patients with cerebellar hemorrhages or with depressed mental status and radiographic evidence of hydrocephalus should undergo urgent neurosurgical evaluation; these patients require close monitoring because they can deteriorate rapidly. Based on the clinical examination and CT findings, further imaging studies may be necessary, including MRI or conventional x-ray angiography. Stuporous or comatose patients with clinical and imaging signs of herniation are generally treated presumptively for elevated ICP, with tracheal intubation, administration of osmotic


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InternalMed_Harrison. angiography. Stuporous or comatose patients with clinical and imaging signs of herniation are generally treated presumptively for elevated ICP, with tracheal intubation, administration of osmotic diuretics such as mannitol or hypertonic saline, and elevation of the head of the bed while surgical consultation is obtained (Chap. 330). Reversal of coagulopathy and consideration of surgical evacuation of the hematoma (detailed below) are two other principal aspects of initial emergency management.


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InternalMed_Harrison. ICH accounts for ~10% of all strokes, and about 35–45% of patients die within the first month. Incidence rates are particularly high in Asians and blacks. Hypertension, coagulopathy, sympathomimetic drugs (cocaine, methamphetamine), and cerebral amyloid angiopathy cause the majority of these hemorrhages. Advanced age and heavy alcohol consumption increase the risk, and cocaine and methamphetamine use is one of the most important causes in the young.


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InternalMed_Harrison. Hypertensive Intracerebral Hemorrhage • pAthophySiology Hypertensive ICH usually results from spontaneous rupture of a small penetrating artery deep in the brain. The most common sites are the basal ganglia (especially the putamen), thalamus, cerebellum, and pons. The small arteries in these areas seem most prone to hypertension-induced vascular injury. When hemorrhages occur in other brain areas or in nonhypertensive patients, greater consideration should be given to other causes such as hemorrhagic disorders, neoplasms, vascular malformations, and cerebral amyloid angiopathy. The hemorrhage may be small, or a large clot may form and compress adjacent tissue, causing herniation and death. Blood may also dissect into the ventricular space, which substantially increases morbidity and may cause hydrocephalus.


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InternalMed_Harrison. Most hypertensive ICHs initially develop over 30–90 min, whereas those associated with anticoagulant therapy may evolve for as long as 24–48 h. However, it is now recognized that about a third of patients even with no coagulopathy may have significant hematoma expansion with the first day. Within 48 h, macrophages begin to phagocytize the hemorrhage at its outer surface. After 1–6 months, the hemorrhage is generally resolved to a slitlike orange cavity lined with glial scar and hemosiderin-laden macrophages. clinicAl mAnifeStAtionS ICH generally presents as the abrupt onset of a focal neurologic deficit. Seizures are uncommon. Although clinical symptoms may be maximal at onset, commonly the focal deficit worsens over 30–90 min and is associated with a diminishing level of consciousness and signs of increased ICP such as headache and vomiting.


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InternalMed_Harrison. The putamen is the most common site for hypertensive hemorrhage, and the adjacent internal capsule is usually damaged (Fig. 446-17). Contralateral hemiparesis is therefore the sentinel sign. When mild, the face sags on one side over 5–30 min, speech becomes slurred, the arm and leg gradually weaken, and the eyes deviate away from the side of the hemiparesis. The paralysis may worsen until the affected limbs become flaccid or extend rigidly. When hemorrhages are large, drowsiness gives way to stupor as signs of upper brainstem compression appear. Coma ensues, accompanied by deep, irregular, or intermittent respiration, a dilated and fixed ipsilateral pupil, and decerebrate rigidity. In milder cases, edema in adjacent brain tissue may cause progressive deterioration over 12–72 h.


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InternalMed_Harrison. Thalamic hemorrhages also produce a contralateral hemiplegia or hemiparesis from pressure on, or dissection into, the adjacent internal capsule. A prominent sensory deficit involving all modalities is usually present. Aphasia, often with preserved verbal repetition, may occur after hemorrhage into the dominant thalamus, and constructional apraxia or mutism occurs in some cases of nondominant hemorrhage. There may also be a homonymous visual field defect. Thalamic hemorrhages cause several typical ocular disturbances by virtue of extension FIGURE 446-17 Hypertensive hemorrhage. Transaxial noncontrast computed tomography scan through the region of the basal ganglia reveals a hematoma involving the left putamen in a patient with rapidly progressive onset of right hemiparesis. Occurs in 1–6% of ischemic strokes with predilection for large hemispheric infarctions Lung, choriocarcinoma, melanoma, renal cell carcinoma, thyroid, atrial myxoma Cocaine, amphetamine


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InternalMed_Harrison. Occurs in 1–6% of ischemic strokes with predilection for large hemispheric infarctions Lung, choriocarcinoma, melanoma, renal cell carcinoma, thyroid, atrial myxoma Cocaine, amphetamine Risk is ~2–3% per year for bleeding if previously unruptured Mycotic and nonmycotic forms of aneurysms Degenerative disease of intracranial vessels; associated with dementia, rare in patients <60 years Multiple cavernous angiomas linked to mutations in KRIT1, CCM2, and PDCD10 genes Rare cause of hemorrhage inferiorly into the upper midbrain. These include deviation of the eyes downward and inward so that they appear to be looking at the nose, unequal pupils with absence of light reaction, skew deviation with the eye opposite the hemorrhage displaced downward and medially, ipsilateral Horner’s syndrome, absence of convergence, paralysis of vertical gaze, and retraction nystagmus. Patients may later develop a chronic, contralateral pain syndrome (Déjérine-Roussy syndrome).


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InternalMed_Harrison. In pontine hemorrhages, deep coma with quadriplegia often occurs over a few minutes. Typically, there is prominent decerebrate rigidity and “pinpoint” (1 mm) pupils that react to light. There is impairment of reflex horizontal eye movements evoked by head turning (doll’s-head or oculocephalic maneuver) or by irrigation of the ears with ice water (Chap. 328). Hyperpnea, severe hypertension, and hyperhidrosis are common. Most patients with deep coma from pontine hemorrhage ultimately die, but small hemorrhages are compatible with survival.


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InternalMed_Harrison. Cerebellar hemorrhages usually develop over several hours and are characterized by occipital headache, repeated vomiting, and ataxia of gait. In mild cases, there may be no other neurologic signs except for gait ataxia. Dizziness or vertigo may be prominent. There is often paresis of conjugate lateral gaze toward the side of the hemorrhage, forced deviation of the eyes to the opposite side, or an ipsilateral sixth nerve palsy. Less frequent ocular signs include blepharospasm, involuntary closure of one eye, ocular bobbing, and skew deviation. Dysarthria and dysphagia may occur. As the hours pass, the patient often becomes stuporous and then comatose from brainstem compression or obstructive hydrocephalus; immediate surgical evacuation before brainstem compression occurs may be lifesaving. Hydrocephalus from fourth ventricle compression can be relieved by external ventricular drainage, but definitive hematoma evacuation is recommended. If the deep cerebellar nuclei are spared, full


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InternalMed_Harrison. Hydrocephalus from fourth ventricle compression can be relieved by external ventricular drainage, but definitive hematoma evacuation is recommended. If the deep cerebellar nuclei are spared, full recovery is common.


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InternalMed_Harrison. Lobar Hemorrhage The major neurologic deficit with an occipital hemorrhage is hemianopia; with a left temporal hemorrhage, aphasia and delirium; with a parietal hemorrhage, hemisensory loss; and with frontal hemorrhage, arm weakness. Large hemorrhages may be associated with stupor or coma if they compress the thalamus or midbrain. Most patients with lobar hemorrhages have focal headaches, and more than one-half vomit or are drowsy. Stiff neck and seizures are uncommon. Other Causes of Intracerebral Hemorrhage Cerebral amyloid angiopathy is a disease of the elderly in which arteriolar degeneration occurs and amyloid is deposited in the walls of the cerebral arteries. Amyloid angiopathy causes both single and recurrent lobar hemorrhages and is probably the most common cause of lobar hemorrhage in the elderly.


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InternalMed_Harrison. 2584 It accounts for some intracranial hemorrhages associated with IV thrombolysis given for MI. This disorder can be suspected in patients who present with multiple hemorrhages (and infarcts) over several months or years or in patients with “microbleeds” seen on brain MRI sequences sensitive for hemosiderin (iron-sensitive imaging), but it is definitively diagnosed by pathologic demonstration of Congo red staining of amyloid in cerebral vessels. The ε2 and ε4 allelic variations of the apolipoprotein E gene are associated with increased risk of recurrent lobar hemorrhage and may therefore be markers of amyloid angiopathy. Currently, there is no specific therapy. OACs are typically avoided. Cocaine and methamphetamine are frequent causes of stroke in young (age <45 years) patients. ICH, ischemic stroke, and SAH are all associated with stimulant use. Angiographic findings vary from completely normal arteries to large-vessel occlusion or stenosis, vasospasm, or changes consistent with


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InternalMed_Harrison. ischemic stroke, and SAH are all associated with stimulant use. Angiographic findings vary from completely normal arteries to large-vessel occlusion or stenosis, vasospasm, or changes consistent with vasculopathy. The mechanism of sympathomimetic-related stroke is not known, but cocaine enhances sympathetic activity causing acute, sometimes severe, hypertension, and this may lead to hemorrhage. Slightly more than one-half of stimulant-related intracranial hemorrhages are intracerebral, and the rest are subarachnoid. In cases of SAH, a saccular aneurysm is usually identified. Presumably, acute hypertension causes aneurysmal rupture. Head injury often causes intracranial bleeding. The common sites are intraparenchymal (especially temporal and inferior frontal lobes) and into the subarachnoid, subdural, and epidural spaces. Trauma must be considered in any patient with an unexplained acute neurologic deficit (hemiparesis, stupor, or confusion), particularly if the deficit occurred in the


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InternalMed_Harrison. subdural, and epidural spaces. Trauma must be considered in any patient with an unexplained acute neurologic deficit (hemiparesis, stupor, or confusion), particularly if the deficit occurred in the context of a fall (Chap. 457e). Intracranial hemorrhages associated with anticoagulant therapy can occur at any location; they are often lobar or subdural. Anticoagulant-related ICHs may continue to evolve over 24–48 h, especially if coagulopathy is insufficiently reversed. Coagulopathy and thrombocytopenia should be reversed rapidly, as discussed below. ICH associated with hematologic disorders (leukemia, aplastic anemia, thrombocytopenic purpura) can occur at any site and may present as multiple ICHs. Skin and mucous membrane bleeding may be evident and offers a diagnostic clue. Hemorrhage into a brain tumor may be the first manifestation of neoplasm. Choriocarcinoma, malignant melanoma, renal cell carcinoma, and bronchogenic carcinoma are among the most common metastatic tumors


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InternalMed_Harrison. into a brain tumor may be the first manifestation of neoplasm. Choriocarcinoma, malignant melanoma, renal cell carcinoma, and bronchogenic carcinoma are among the most common metastatic tumors associated with ICH. Glioblastoma multiforme in adults and medulloblastoma in children may also have areas of ICH. Hypertensive encephalopathy is a complication of malignant hypertension. In this acute syndrome, severe hypertension is associated with headache, nausea, vomiting, convulsions, confusion, stupor, and coma. Focal or lateralizing neurologic signs, either transitory or permanent, may occur but are infrequent and therefore suggest some other vascular disease (hemorrhage, embolism, or atherosclerotic thrombosis). There are retinal hemorrhages, exudates, papilledema (hypertensive retinopathy), and evidence of renal and cardiac disease. In most cases, ICP and CSF protein levels are elevated. MRI brain imaging shows a pattern of typically posterior (occipital > frontal) brain edema that is


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InternalMed_Harrison. and evidence of renal and cardiac disease. In most cases, ICP and CSF protein levels are elevated. MRI brain imaging shows a pattern of typically posterior (occipital > frontal) brain edema that is reversible and termed reversible posterior leukoencephalopathy. The hypertension may be essential or due to chronic renal disease, acute glomerulonephritis, acute toxemia of pregnancy, pheochromocytoma, or other causes. Lowering the blood pressure reverses the process, but stroke can occur, especially if blood pressure is lowered too rapidly. Neuropathologic examination reveals multifocal to diffuse cerebral edema and hemorrhages of various sizes from petechial to massive. Microscopically, there are necrosis of arterioles, minute cerebral infarcts, and hemorrhages. The term hypertensive encephalopathy should be reserved for this syndrome and not for chronic recurrent headaches, dizziness, recurrent TIAs, or small strokes that often occur in association with high blood pressure. Primary


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InternalMed_Harrison. should be reserved for this syndrome and not for chronic recurrent headaches, dizziness, recurrent TIAs, or small strokes that often occur in association with high blood pressure. Primary intraventricular hemorrhage is rare and should prompt investigation for an underlying vascular anomaly. Sometimes bleeding begins within the periventricular substance of the brain and dissects into the ventricular system without leaving signs of intraparenchymal hemorrhage. Alternatively, bleeding can arise from periependymal veins. Vasculitis, usually polyarteritis nodosa or lupus erythematosus, can produce hemorrhage in any region of the central nervous system; most hemorrhages are associated with hypertension, but the arteritis itself may cause bleeding by disrupting the vessel wall. Nearly one-half of patients with primary intraventricular hemorrhage have identifiable bleeding sources seen using conventional angiography.


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InternalMed_Harrison. Sepsis can cause small petechial hemorrhages throughout the cerebral white matter. Moyamoya disease, mainly an occlusive arterial disease that causes ischemic symptoms, may on occasion produce ICH, particularly in the young. Hemorrhages into the spinal cord are usually the result of an AVM, cavernous malformation, or metastatic tumor. Epidural spinal hemorrhage produces a rapidly evolving syndrome of spinal cord or nerve root compression (Chap. 456). Spinal hemorrhages usually present with sudden back pain and some manifestation of myelopathy.


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InternalMed_Harrison. Laboratory and Imaging Evaluation Patients should have routine blood chemistries and hematologic studies. Specific attention to the platelet count and PT/PTT/INR is important to identify coagulopathy. CT imaging reliably detects acute focal hemorrhages in the supratentorial space. Rarely very small pontine or medullary hemorrhages may not be well delineated because of motion and bone-induced artifact that obscure structures in the posterior fossa. After the first 2 weeks, x-ray attenuation values of clotted blood diminish until they become isodense with surrounding brain. Mass effect and edema may remain. In some cases, a surrounding rim of contrast enhancement appears after 2–4 weeks and may persist for months. MRI, although more sensitive for delineating posterior fossa lesions, is generally not necessary for primary diagnosis in most instances. Images of flowing blood on MRI scan may identify AVMs as the cause of the hemorrhage. MRI, CT angiography (CTA), and conventional x-ray


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InternalMed_Harrison. not necessary for primary diagnosis in most instances. Images of flowing blood on MRI scan may identify AVMs as the cause of the hemorrhage. MRI, CT angiography (CTA), and conventional x-ray angiography are used when the cause of intracranial hemorrhage is uncertain, particularly if the patient is young or not hypertensive and the hematoma is not in one of the usual sites for hypertensive hemorrhage. CTA or postcontrast CT imaging may reveal one or more small areas of enhancement within a hematoma; this “spot sign” is thought to represent ongoing bleeding. The presence of a spot sign is associated with an increased risk of hematoma expansion, increased mortality, and lower likelihood of favorable functional outcome. Some centers routinely perform CT with CTA and postcontrast CT at the time of initial imaging to rapidly identify any macrovascular etiology of the hemorrhage and provide prognostic information at the same time. Because patients typically have focal neurologic signs and


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InternalMed_Harrison. of initial imaging to rapidly identify any macrovascular etiology of the hemorrhage and provide prognostic information at the same time. Because patients typically have focal neurologic signs and obtundation and often show signs of increased ICP, a lumbar puncture is generally unnecessary and should usually be avoided because it may induce cerebral herniation.


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InternalMed_Harrison. Although about 40% of patients with a hypertensive ICH die, others have a good to complete recovery if they survive the initial hemorrhage. The ICH Score (Table 446-7) is a validated clinical grading scale that is useful for stratification of mortality risk and clinical outcome. Any identified coagulopathy should be corrected as soon as possible. For patients taking VKAs, rapid correction of coagulopathy can be achieved by infusing prothrombin complex concentrates (PCC), which can be administered quickly, with vitamin K administered concurrently. Fresh frozen plasma is an alternative but generally requires larger fluid volumes and longer time to achieve adequate reversal than PCC. There is no effective antidote to ICH associated with oral thrombin inhibitor dabigatran, although FEIBA (factor VIII inhibitor bypassing activity) and recombinant factor VIIa have been tried in individual cases. PCC may partially reverse the effects of oral factor Xa inhibitors and are reasonable to


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InternalMed_Harrison. (factor VIII inhibitor bypassing activity) and recombinant factor VIIa have been tried in individual cases. PCC may partially reverse the effects of oral factor Xa inhibitors and are reasonable to administer if available. When ICH is associated with thrombocytopenia (platelet count <50,000/μL), transfusion of fresh platelets is indicated. The role of platelet transfusions either empirically or based on urgent platelet inhibition assays remains unclear.


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InternalMed_Harrison. Total Score Sum of each category above Note: Although an ICH Score of 6 is possible with the scale, this is rarely observed and is considered highly likely to be fatal. Abbreviations: CI, confidence interval; ICH, intracerebral hemorrhage. Sources: JC Hemphill et al: Stroke 32:891, 2001; JC Hemphill et al: Neurology 73:1088, 2009. Hematomas may expand for several hours following the initial hemorrhage, even in patients without coagulopathy. However, the precise mechanism is unclear. A phase 3 trial of treatment with recombinant factor VIIa reduced hematoma expansion; however, clinical outcomes were not improved, so use of this drug cannot be advocated at present. The theoretical risk of acutely elevated blood pressure on hematoma expansion forms the basis of the consideration for recently completed and ongoing clinical trials of acute blood pressure lowering.


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InternalMed_Harrison. Evacuation of supratentorial hematomas does not appear to improve outcome for most patients. The International Surgical Trial in Intracerebral Haemorrhage (STICH) randomized patients with supratentorial ICH to either early surgical evacuation or initial medical management. No benefit was found in the early surgery arm, although analysis was complicated by the fact that 26% of patients in the initial medical management group ultimately had surgery for neurologic deterioration. The follow-up study STICH-II found that surgery within 24 h of lobar, supratentorial hemorrhage did not improve overall outcome, but might have a role in select severely affected patients. Therefore, existing data do not support routine surgical evacuation of supratentorial hemorrhages in stable patients. However, many centers still consider surgery for patients deemed salvageable and who are having progressive neurologic deterioration due to herniation. Surgical techniques continue to evolve, and minimally


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InternalMed_Harrison. many centers still consider surgery for patients deemed salvageable and who are having progressive neurologic deterioration due to herniation. Surgical techniques continue to evolve, and minimally invasive endoscopic hematoma evacuation is currently being investigated in clinical trials.


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InternalMed_Harrison. For cerebellar hemorrhages, a neurosurgeon should be consulted immediately to assist with the evaluation; most cerebellar hematomas >3 cm in diameter will require surgical evacuation. If the patient is alert without focal brainstem signs and if the hematoma is <1 cm in diameter, surgical removal is usually unnecessary. Patients with signs of impaired consciousness, progressive hydrocephalus, and precipitous respiratory failure. Hydrocephalus due to cerebellar hematoma should not be treated solely with ventricular drainage. Tissue surrounding hematomas is displaced and compressed but not necessarily infarcted. Hence, in survivors, major improvement commonly occurs as the hematoma is reabsorbed and the adjacent tissue regains its function. Careful management of the patient during the acute phase of the hemorrhage can lead to considerable recovery.


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InternalMed_Harrison. Surprisingly, ICP is often normal even with large ICHs. However, if the hematoma causes marked midline shift of structures with consequent obtundation, coma, or hydrocephalus, osmotic agents can be instituted in preparation for placement of a ventriculostomy or parenchymal ICP monitor (Chap. 330). Once ICP is recorded, CSF drainage (if available), osmotic therapy, and blood pressure management can be tailored to the individual patient to keep cerebral perfusion pressure (MAP minus ICP) above 60 mmHg. For example, if ICP is found to be high, CSF can be drained from the ventricular space and osmotic therapy continued; persistent or progressive elevation in ICP may prompt surgical evacuation of the clot. Alternately, if ICP is normal or only mildly elevated, interventions such as osmotic therapy may be tapered. Because hyperventilation may actually produce ischemia by cerebral vasoconstriction, induced hyperventilation should be limited to acute resuscitation of the patient with


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InternalMed_Harrison. therapy may be tapered. Because hyperventilation may actually produce ischemia by cerebral vasoconstriction, induced hyperventilation should be limited to acute resuscitation of the patient with presumptive high ICP and eliminated once other treatments (osmotic therapy or surgical treatments) have been instituted. Glucocorticoids are not helpful for the edema from intra-cerebral hematoma.


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InternalMed_Harrison. Hypertension is the leading cause of primary ICH. Prevention is aimed at reducing chronic hypertension, eliminating excessive alcohol use, and discontinuing use of illicit drugs such as cocaine and amphetamines. Patients with amyloid angiopathy should generally avoid OACs, but antiplatelet agents may be administered if there is an indication based on atherothrombotic vascular disease. Vascular anomalies can be divided into congenital vascular malformations and acquired vascular lesions. True arteriovenous malformations (AVMs), venous anomalies, and capillary telangiectasias are lesions that usually remain clinically silent through life. AVMs are probably congenital, but cases of acquired lesions have been reported.


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InternalMed_Harrison. True AVMs are congenital shunts between the arterial and venous systems that may present with headache, seizures, and intracranial hemorrhage. AVMs consist of a tangle of abnormal vessels across the cortical surface or deep within the brain substance. AVMs vary in size from a small blemish a few millimeters in diameter to a large mass of tortuous channels composing an arteriovenous shunt of sufficient magnitude to raise cardiac output and precipitate heart failure. Blood vessels forming the tangle interposed between arteries and veins are usually abnormally thin and histologically resemble both arteries and veins. AVMs occur in all parts of the cerebral hemispheres, brainstem, and spinal cord, but the largest ones are most frequently in the posterior half of the hemispheres, commonly forming a wedge-shaped lesion extending from the cortex to the ventricle.


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InternalMed_Harrison. Bleeding, headache, and seizures are most common between the ages of 10 and 30, occasionally as late as the fifties. AVMs are more frequent in men, and rare familial cases have been described. Familial AVM may be a part of the autosomal dominant syndrome of hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syndrome due to mutations in either endoglin or activin receptor-like kinase 1, both involved in transforming growth factor (TGF) signaling and angiogenesis.


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InternalMed_Harrison. 2586 Headache (without bleeding) may be hemicranial and throbbing, like migraine, or diffuse. Focal seizures, with or without generalization, occur in ~30% of cases. One-half of AVMs become evident as ICHs. In most, the hemorrhage is mainly intraparenchymal with extension into the subarachnoid space in some cases. Blood is usually not deposited in the basal cisterns, and symptomatic cerebral vasospasm is rare. The risk of AVM rupture is strongly influenced by a history of prior rupture. Although unruptured AVMs have a hemorrhage rate of ~2–4% per year, previously ruptured AVMs may have a rate as high as 17% a year, at least for the first year. Hemorrhages may be massive, leading to death, or may be as small as 1 cm in diameter, leading to minor focal symptoms or no deficit. The AVM may be large enough to steal blood away from adjacent normal brain tissue or to increase venous pressure significantly to produce venous ischemia locally and in remote areas of the brain. This is seen most


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InternalMed_Harrison. large enough to steal blood away from adjacent normal brain tissue or to increase venous pressure significantly to produce venous ischemia locally and in remote areas of the brain. This is seen most often with large AVMs in the territory of the MCA. Large AVMs of the anterior circulation may be associated with a systolic and diastolic bruit (sometimes self-audible) over the eye, forehead, or neck and a bounding carotid pulse. Headache at the onset of AVM rupture is generally not as explosive as with aneurysmal rupture. MRI is better than CT for diagnosis, although noncontrast CT scanning sometimes detects calcification of the AVM and contrast may demonstrate the abnormal blood vessels. Once identified, conventional x-ray angiography is the gold standard for evaluating the precise anatomy of the AVM. Surgical treatment of AVMs presenting with hemorrhage often done in conjunction with preoperative embolization to reduce operative bleeding is usually indicated for accessible lesions.


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InternalMed_Harrison. of the AVM. Surgical treatment of AVMs presenting with hemorrhage often done in conjunction with preoperative embolization to reduce operative bleeding is usually indicated for accessible lesions. Stereotaxic radiation, an alternative to surgery, can produce a slow sclerosis of the AVM over 2–3 years. Several angiographic features can be used to help predict future bleeding risk. Paradoxically, smaller lesions seem to have a higher hemorrhage rate. The presence of deep venous drainage, venous outflow stenosis, and intranidal aneurysms may increase rupture risk. Because of the relatively low annual rate of hemorrhage and the risk of complications due to surgical or endovascular treatment, the indication for surgery in asymptomatic AVMs is debated. The ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) trial randomized patients to medical management versus intervention (surgery, endovascular embolization, combination embolization and surgery, or gamma-knife). The


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InternalMed_Harrison. Brain Arteriovenous Malformations) trial randomized patients to medical management versus intervention (surgery, endovascular embolization, combination embolization and surgery, or gamma-knife). The trial was stopped prematurely for harm, with the medical arm achieving the combined endpoint of death or symptomatic stroke in 10.1% of patients compared to 30.7% in the intervention group at an average follow-up time of 33 months. This highly significant finding argues against routine intervention for patients presenting without hemorrhage, although debate ensues regarding the generalizability of these results. Venous anomalies are the result of development of anomalous cerebral, cerebellar, or brainstem venous drainage. These structures, unlike AVMs, are functional venous channels. They are of little clinical significance and should be ignored if found incidentally on brain imaging studies. Surgical resection of these anomalies may result in venous infarction and hemorrhage. Venous


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InternalMed_Harrison. are of little clinical significance and should be ignored if found incidentally on brain imaging studies. Surgical resection of these anomalies may result in venous infarction and hemorrhage. Venous anomalies may be associated with cavernous malformations (see below), which do carry some bleeding risk. Capillary telangiectasias are true capillary malformations that often form extensive vascular networks through an otherwise normal brain structure. The pons and deep cerebral white matter are typical locations, and these capillary malformations can be seen in patients with hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syndrome. If bleeding does occur, it rarely produces mass effect or significant symptoms. No treatment options exist.


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InternalMed_Harrison. Cavernous angiomas are tufts of capillary sinusoids that form within the deep hemispheric white matter and brainstem with no normal intervening neural structures. The pathogenesis is unclear. Familial cavernous angiomas have been mapped to several different genes: KRIT1, CCM2, and PDCD10. Both KRIT1 and CCM2 have roles in blood vessel formation, whereas PDCD10 is an apoptotic gene. Cavernous angiomas are typically <1 cm in diameter and are often associated with a venous anomaly. Bleeding is usually of small volume, causing slight mass effect only. The bleeding risk for single cavernous malformations is 0.7–1.5% per year and may be higher for patients with prior clinical hemorrhage or multiple malformations. Seizures may occur if the malformation is located near the cerebral cortex. Surgical resection eliminates bleeding risk and may reduce seizure risk, but it is usually reserved for those malformations that form near the brain surface. Radiation treatment has not been shown to be of


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InternalMed_Harrison. resection eliminates bleeding risk and may reduce seizure risk, but it is usually reserved for those malformations that form near the brain surface. Radiation treatment has not been shown to be of benefit.


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InternalMed_Harrison. Dural arteriovenous fistulas are acquired connections usually from a dural artery to a dural sinus. Patients may complain of a pulse-synchronous cephalic bruit (“pulsatile tinnitus”) and headache. Depending on the magnitude of the shunt, venous pressures may rise high enough to cause cortical ischemia or venous hypertension and hemorrhage, particularly SAH. Surgical and endovascular techniques are usually curative. These fistulas may form because of trauma, but most are idiopathic. There is an association between fistulas and dural sinus thrombosis. Fistulas have been observed to appear months to years following venous sinus thrombosis, suggesting that angiogenesis factors elaborated from the thrombotic process may cause these anomalous connections to form. Alternatively, dural arteriovenous fistulas can produce venous sinus occlusion over time, perhaps from the high pressure and high flow through a venous structure. Peter J. Goadsby, Neil H. Raskin


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InternalMed_Harrison. Peter J. Goadsby, Neil H. Raskin The general principles around headache as a cardinal symptom are covered elsewhere (Chap. 21); here we discuss disorders in which headache and associated features occur in the absence of any exogenous cause. The most common are migraine, tension-type headache, and the trigeminal autonomic cephalalgias, notably cluster headache; the complete list is summarized in Table 447-1.


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InternalMed_Harrison. Migraine, the second most common cause of headache, and the most common headache-related, and indeed neurologic, cause of disability in the world, afflicts approximately 15% of women and 6% of men over a 1-year period. It is usually an episodic headache associated with certain features such as sensitivity to light, sound, or movement; nausea and vomiting often accompany the headache. A useful description of migraine is a recurring syndrome of headache associated with other symptoms of neurologic dysfunction in varying admixtures (Table 447-2). Migraine can often be recognized by its activators, referred to as triggers.


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InternalMed_Harrison. The brain of the migraineur is particularly sensitive to environmental and sensory stimuli; migraine-prone patients do not habituate easily to sensory stimuli. This sensitivity is amplified in females during the menstrual cycle. Headache can be initiated or amplified by various triggers, including glare, bright lights, sounds, or other afferent stimulation; hunger; let-down from stress; physical exertion; stormy weather or barometric pressure changes; hormonal fluctuations during menses; lack of or excess sleep; and alcohol or other chemical stimulation, such as with nitrates. Knowledge of a patient’s susceptibility to specific triggers can be useful in management strategies involving lifestyle adjustments. Pathogenesis The sensory sensitivity that is characteristic of migraine is probably due to dysfunction of monoaminergic sensory control systems located in the brainstem and hypothalamus (Fig. 447-1).


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InternalMed_Harrison. Activation of cells in the trigeminal nucleus results in the release of vasoactive neuropeptides, particularly calcitonin gene–related peptide primary heaDaChe DisorDers, moDifieD from iNterNatioNaL CLassifiCatioN of heaDaChe DisorDers-iii-Beta (heaDaChe CLassifiCatioN Committee of the iNterNatioNaL heaDaChe soCiety, 2013) 1. 2. 3. 4.


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InternalMed_Harrison. 1.1 Migraine without aura 1.2 Migraine with aura 1.2.1 Migraine with typical aura 1.2.1.1 Typical aura with headache 1.2.1.2 Typical aura without headache 1.2.2 Migraine with brainstem aura 1.2.3 Hemiplegic migraine 1.2.3.1 Familial hemiplegic migraine (FHM) 1.2.3.1.1 Familial hemiplegic migraine type 1 1.2.3.1.2 Familial hemiplegic migraine type 2 1.2.3.1.3 Familial hemiplegic migraine type 3 1.2.3.2 Sporadic hemiplegic migraine 1.2.4 Retinal migraine 1.3 Chronic migraine 1.4 Complications of migraine 1.4.1 Status migrainosus 1.4.2 Persistent aura without infarction 1.4.3 Migrainous infarction 1.4.4 Migraine aura-triggered seizure 1.5 Probable migraine 1.5.1 Probable migraine without aura 1.5.2 Probable migraine with aura 1.6 Episodic syndromes that may be associated with migraine 1.6.1 Recurrent gastrointestinal disturbance 1.6.1.1 Cyclical vomiting syndrome 1.6.1.2 Abdominal migraine 1.6.2 Benign paroxysmal vertigo 1.6.3 2.1 2.2 Frequent episodic tension-type headache 2.3 3.1 3.1.1


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InternalMed_Harrison. gastrointestinal disturbance 1.6.1.1 Cyclical vomiting syndrome 1.6.1.2 Abdominal migraine 1.6.2 Benign paroxysmal vertigo 1.6.3 2.1 2.2 Frequent episodic tension-type headache 2.3 3.1 3.1.1 Episodic cluster headache 3.1.2 Chronic cluster headache 3.2 Paroxysmal hemicrania 3.2.1 Episodic paroxysmal hemicrania 3.2.2 Chronic paroxysmal hemicrania 3.3 Short-lasting unilateral neuralgiform headache attacks 3.3.1 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) 3.3.2 Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) 3.4 4.1 4.2 Primary exercise headache 4.3 Primary headache associated with sexual activity 4.4 Primary thunderclap headache 4.5 Cold-stimulus headache 4.5.1 Headache attributed to external application of a cold stimulus 4.5.2 Headache attributed to ingestion or inhalation of a cold stimulus 4.6 External-pressure headache 4.6.1 External-compression headache 4.6.2 External-traction


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InternalMed_Harrison. application of a cold stimulus 4.5.2 Headache attributed to ingestion or inhalation of a cold stimulus 4.6 External-pressure headache 4.6.1 External-compression headache 4.6.2 External-traction headache 4.7 Primary stabbing headache 4.8 Nummular headache 4.9 Hypnic headache 4.10 New daily persistent headache (NDPH)


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InternalMed_Harrison. Symptom Patients Affected, % Source: From NH Raskin: Headache, 2nd ed. New York, Churchill Livingston, 1988; with permission. (CGRP), at vascular terminations of the trigeminal nerve and within the trigeminal nucleus. CGRP receptor antagonists, gepants, have now been shown to be effective in the acute treatment of migraine, and monoclonal antibodies to CGRP have been shown effective in two early phase clinical trials. Centrally, the second-order trigeminal neurons cross the midline and project to ventrobasal and posterior nuclei of the thalamus for further processing. Additionally, there are projections to the periaqueductal gray and hypothalamus, from which reciprocal descending systems have established antinociceptive effects. Other brainstem regions likely to be involved in descending modulation of trigeminal pain include the nucleus locus coeruleus in the pons and the rostroventromedial medulla.


InternalMed_Harrison

InternalMed_Harrison. Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraines. Approximately 60 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. The triptans were designed to stimulate selectively subpopulations of 5-HT receptors; at least 14 different 5-HT receptors exist in humans. The triptans are potent agonists of 5-HT1B and 5-HT1D receptors, and some are active at the 5-HT1F receptors; the latter’s exclusive agonists are called ditans. Triptans arrest nerve signaling in the nociceptive pathways of the trigeminovascular system, at least in the trigeminal nucleus caudalis and trigeminal sensory thalamus, in addition to cranial vasoconstriction, while ditans, now shown conclusively to be effective in acute migraine, act only at neural targets. An interesting range of neural targets is now being actively


InternalMed_Harrison

InternalMed_Harrison. addition to cranial vasoconstriction, while ditans, now shown conclusively to be effective in acute migraine, act only at neural targets. An interesting range of neural targets is now being actively pursed for the acute and preventive management of migraine.


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InternalMed_Harrison. Data also support a role for dopamine in the pathophysiology of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. Moreover, hypothalamic activation, anterior to that seen in cluster headache, has now been shown in the premonitory phase of migraine using functional imaging, and this may hold a key to understanding some part of the role of dopamine in the disorder.


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InternalMed_Harrison. Dura Dorsal raphe nucleusLocuscoeruleusSuperior salivatory nucleus Magnus raphenucleusThalamusHypothalamusDorsal raphe nucleus Locus coeruleus Superior salivatory nucleus Magnus raphe nucleus Sphenopalatine ganglion Trigeminal ganglion TCC Thalamus Hypothalamus QuintothalamictractQuintothalamic tract FIGURE 447-1 Brainstem pathways that modulate sensory input. The key pathway for pain in migraine is the trigeminovascular input from the meningeal vessels, which passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex (TCC). These neurons in turn project in the quintothalamic tract and, after decussating in the brainstem, synapse on neurons in the thalamus. Important modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus.


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InternalMed_Harrison. Migraine genes identified by studying families with familial hemiplegic migraine (FHM) reveal involvement of ion channels, suggesting that alterations in membrane excitability can predispose to migraine. Mutations involving the Cav2.1 (P/Q)–type voltage-gated calcium channel CACNA1A gene are now known to cause FHM 1; this mutation is responsible for about 50% of FHMs. Mutations in the Na+-K+ATPase ATP1A2 gene, designated FHM 2, are responsible for about 20% of FHMs. Mutations in the neuronal voltage-gated sodium channel SCN1A cause FHM 3. Functional neuroimaging has suggested that brainstem regions in migraine (Fig. 447-2) and the posterior hypothalamic gray matter region close to the human circadian pacemaker cells of the suprachiasmatic nucleus in cluster headache (Fig. 447-3) are good candidates for specific involvement in primary headache.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis and Clinical Features Diagnostic criteria for migraine headache are listed in Table 447-3. A high index of suspicion is required to diagnose migraine: the migraine aura, consisting of visual disturbances with flashing lights or zigzag lines moving across the visual field or of other neurologic symptoms, is reported in only 20–25% of patients. 2589


InternalMed_Harrison

InternalMed_Harrison. A headache diary can often be helpful in making the diagnosis; this is also helpful in assessing disability and the frequency of treatment for acute attacks. Patients with episodes of migraine that occur daily or near-daily are considered to have chronic migraine (see “Chronic Daily Headache” in Chap. 21). Migraine must be differentiated from tension-type headache (discussed below), the most common primary headache syndrome seen in the population. Migraine has several forms that have been defined (Table 447-1): migraine with and without aura and chronic migraine, the latter occurring 15 days or more a month, as the most important. Migraine at its most basic level is headache with associated features, and tension-type headache is headache that is featureless. Most patients with disabling headache probably have migraine.


InternalMed_Harrison

InternalMed_Harrison. Patients with acephalgic migraine (typical aura without headache, 1.2.1.2 in Table 447-1) experience recurrent neurologic symptoms, often with nausea or vomiting, but with little or no headache. Vertigo can be prominent; it has been estimated that one-third of patients referred for vertigo or dizziness have a primary diagnosis of migraine. Migraine aura can have prominent brainstem symptoms, and the terms basilar artery and basilar-type migraine have now been replaced by migraine with brainstem aura (Table 447-1).


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InternalMed_Harrison. FIGURE 447-2 Positron emission tomography (PET) activation in migraine. Hypothalamic, dorsal midbrain, and dorsolateral pontine activation is seen in triggered attacks in the premonitory phase before pain, whereas in migraine attacks, dorsolateral pontine activation persists, as it does in chronic migraine (not shown). The dorsolateral pontine area, which includes the noradrenergic locus coeruleus, is fundamental to the expression of migraine. Moreover, lateralization of changes in this region of the brainstem correlates with lateralization of the head pain in hemicranial migraine; the scans shown in panels C and D are of patients with acute migraine headache on the right and left side, respectively. (Panel A from FH Maniyar et al: Brain 137:232, 2014; panel B from SK Afridi et al: Arch Neurol 2005;62:1270; Panels C and D from SK Afridi et al: Brain 128:932, 2005.)


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InternalMed_Harrison. (Panel A from FH Maniyar et al: Brain 137:232, 2014; panel B from SK Afridi et al: Arch Neurol 2005;62:1270; Panels C and D from SK Afridi et al: Brain 128:932, 2005.) FIGURE 447-3 A. Posterior hypothalamic gray matter activation by positron emission tomography in a patient with acute cluster headache. (From A May et al: Lancet 352:275, 1998.) B. High-resolution T1-weighted magnetic resonance image obtained using voxel-based morphometry demonstrates increased gray matter activity, lateralized to the side of pain in a patient with cluster headache. (From A May et al: Nat Med 5:836, 1999.) Once a diagnosis of migraine has been established, it is important to assess the extent of a patient’s disease and disability. The Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-to-use tool (Fig. 447-4).


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InternalMed_Harrison. Patient education is an important aspect of migraine management. Information for patients is available at sites such as www.achenet.org, the website of the American Council for Headache Education (ACHE). It is helpful for patients to understand that migraine is an inherited tendency to headache; that migraine can be modified and controlled by lifestyle adjustments and medications, but it cannot be eradicated; and that, except in some occasions in women on oral estrogens or contraceptives, migraine is not associated with serious or life-threatening illnesses. Migraine can often be managed to some degree by a variety of nonpharmacologic approaches. Most patients benefit by the identification and avoidance of specific headache triggers. A regulated lifestyle is helpful, including a healthy diet, regular exercise, regular sleep patterns, avoidance of excess caffeine and alcohol, and avoidance of acute changes in stress levels, being particularly wary of the let-down effect.


InternalMed_Harrison

InternalMed_Harrison. The measures that benefit a given individual should be used routinely because they provide a simple, cost-effective approach to migraine management. Patients with migraine do not encounter more stress than headache-free individuals; over-responsiveness to changes in stress appears to be the issue. Because the stresses of everyday living cannot be eliminated, lessening one’s response to stress by various techniques is helpful for many patients. These may Repeated attacks of headache lasting 4–72 h in patients with a normal physical examination, no other reasonable cause for the headache, and: At Least 2 of the Plus at Least 1 of the Following Features: Following Features: Source: Adapted from the International Headache Society Classification (Headache Classification Committee of the International Headache Society, 2013).


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InternalMed_Harrison. Source: Adapted from the International Headache Society Classification (Headache Classification Committee of the International Headache Society, 2013). include yoga, transcendental meditation, hypnosis, and conditioning techniques such as biofeedback. For most patients, this approach is, at best, an adjunct to pharmacotherapy. Nonpharmacologic measures are unlikely to prevent all migraine attacks. If these measures fail to prevent an attack, pharmacologic approaches are then needed to abort an attack.


InternalMed_Harrison

InternalMed_Harrison. The mainstay of pharmacologic therapy is the judicious use of one or more of the many medicines that are effective in migraine (Table 447-4). The selection of the optimal regimen for a given patient depends on a number of factors, the most important of which is the severity of the attack. Mild migraine attacks can usually be managed by oral agents; the average efficacy rate is 50–70%. Severe migraine attacks may require parenteral therapy. Most drugs effective in the treatment of migraine are members of one of three major pharmacologic classes: nonsteroidal anti-inflammatory drugs, 5-HT receptor agonists, and dopamine receptor antagonists.


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InternalMed_Harrison. In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks or a different class of drug tried as first-line treatment. Migraine therapy must be individualized; a standard approach for all patients is not possible. A therapeutic regimen may need to be constantly refined until one is identified that provides the patient with rapid, complete, and consistent relief with minimal side effects (Table 447-5).


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InternalMed_Harrison. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Both the severity and duration of a migraine attack can be reduced significantly by NSAIDs (Table 447-4). Indeed, many undiagnosed migraineurs self-treat with nonprescription NSAIDs. A general consensus is that NSAIDs are most effective when taken early in the migraine attack. However, the effectiveness of these agents in migraine is usually less than optimal in moderate or severe migraine attacks. The combination of acetaminophen, aspirin, and caffeine has been approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate migraine. The combination of aspirin and metoclopramide has been shown to be comparable to a single dose of oral sumatriptan. Important side effects of NSAIDs include dyspepsia and gastrointestinal irritation. Oral Stimulation of 5-HT receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective receptor


InternalMed_Harrison

InternalMed_Harrison. Oral Stimulation of 5-HT receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective receptor INSTRUCTIONS: Please answer the following questions about ALL headaches you have had FIGURE 447-4 The Migraine Disability Assessment Score (MIDAS) Questionnaire. agonists, whereas the triptans are selective 5-HT receptor ago nists. A variety of triptans, 5-HT receptor agonists—sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan—are now available for the treatment of migraine.


InternalMed_Harrison

InternalMed_Harrison. Each drug in the triptan class has similar pharmacologic properties but varies slightly in terms of clinical efficacy. Rizatriptan and eletriptan are the most efficacious of the triptans currently available in the United States. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, with an advantage of having multiple formulations, whereas almotriptan has a similar rate of efficacy to sumatriptan and is better tolerated, and frovatriptan and naratriptan are somewhat slower in onset and are better tolerated. Clinical efficacy appears to be related more to the t max (time to peak plasma level) than to the potency, half-life, or bioavailability. This observation is consistent with a large body of data indicating that faster-acting analgesics are more effective than slower-acting agents.


InternalMed_Harrison

InternalMed_Harrison. Unfortunately, monotherapy with a selective oral 5-HT recep tor agonist does not result in rapid, consistent, and complete relief of migraine in all patients. Triptans are generally not effective in migraine with aura unless given after the aura is completed and the headache initiated. Side effects are common, although often mild and transient. Moreover, 5-HT receptor agonists are contraindi cated in individuals with a history of cardiovascular and cerebrovascular disease. Recurrence of headache, within usual time course of an attack, is another important limitation of triptan use and occurs at least occasionally in most patients. Evidence from randomized controlled trials show that coadministration of a longer-acting NSAID, naproxen 500 mg, with sumatriptan will augment the initial effect of sumatriptan and, importantly, reduce rates of headache recurrence.


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InternalMed_Harrison. Ergotamine preparations offer a nonselective means of stimulating 5-HT1 receptors. A nonnauseating dose of ergotamine should be sought because a dose that provokes nausea is too high and may intensify head pain. Except for a sublingual formulation of ergotamine, oral formulations of ergotamine also contain 100 mg caffeine (theoretically to enhance ergotamine absorption and possibly to add additional analgesic activity). The average oral ergotamine dose for a migraine attack is 2 mg. Because the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of ergotamine versus the triptans. In general, ergotamine appears to have a much higher incidence of nausea than triptans but less headache recurrence.


InternalMed_Harrison

InternalMed_Harrison. Nasal Nasal formulations of dihydroergotamine (Migranal), zolmitriptan (Zomig nasal), or sumatriptan can be useful in patients requiring a nonoral route of administration. The nasal sprays result in substantial blood levels within 30–60 min. Although in theory nasal sprays might provide faster and more effective relief of a migraine attack than oral formulations, their reported efficacy is only approximately 50–60%. Studies with a new inhalational formulation of dihydroergotamine indicate that its absorption problems can be overcome to produce rapid onset of action with good tolerability.


InternalMed_Harrison

InternalMed_Harrison. Parenteral Administration of drugs by injection, such as dihydroergotamine and sumatriptan, is approved by the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min after IV dosing, 30 min after IM dosing, and 45 min after SC dosing. If an attack has not already peaked, SC or IM administration of 1 mg of dihydroergotamine suffices for about 80–90% of patients. Sumatriptan, 4–6 mg SC, is effective in ~50–80% of patients, and can now be administered by a needle-free device.