Stroke & Vascular Disorders
Cerebellar infarction and cerebellar hemorrhage
Aug. 16, 2022
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The thalamus is a heterogeneous assembly of well-organized nuclei, most of which have extensive reciprocal connections with the cerebral cortex. Hence, the thalamus plays a critical role in sensory, motor, arousal, cognitive, and behavioral functions. The midbrain, which is the smallest and most rostral portion of the brainstem, gives rise mainly to the third and fourth cranial nerves and contains centers and pathways that mediate vertical gaze. The blood supply to both structures is elaborate. Thalamic infarcts are infrequent, and midbrain infarcts are even more so; however, both are associated with a large spectrum of clinical manifestations, which vary according to the vascular territory involved. In this article, the authors present in depth the clinical correlates of midbrain and thalamic ischemic lesions, while also summarizing the advances in treatment and prevention of ischemic lesions involving the different vascular territories of the thalamus and the midbrain.
The thalamus and midbrain infarcts account for 10% and 1% of all cerebral infarcts, respectively.
Decreased level of consciousness, vertical gaze paresis, and contralateral hypoesthesia are the main clinical manifestations of paramedian thalamic infarcts.
Posterolateral infarction syndrome is characterized by contralateral pure sensory deficit, sensory motor stroke, or sensory motor deficit with abnormal involuntary movements.
Oculomotor and supranuclear (conjugate or disconjugate) vertical gaze palsies are the most localizing manifestations of midbrain infarction.
Small vessel disease is the prime etiology in thalamic infarcts.
The etiology of midbrain infarcts remains undetermined in up to 50% of cases.
Thalamic syndrome due to vascular lesions involving the ventrolateral nucleus of the thalamus was first delineated early in the nineteenth century by Jules Déjerine and colleagues (26). The main clinical findings were considered to be hemihypesthesia, nonsensory components (mild hemiparesis and hemiataxia), followed by choreoathetosis and delayed onset of pain in the same affected limbs (26).
Approximately 25 years later, Charles Foix described the anatomy of the arterial supply of the thalamus and was the first to associate thalamic infarction to occlusive disease of the posterior cerebral artery (30). During the second half of the twentieth century, more important details of the vascular anatomy of the thalamus were provided mainly by Percheron (76).
Clinical manifestations of thalamic infarctions. Clinical findings of posterior cerebral artery territory infarctions depend heavily on the portion of the posterior cerebral artery occluded and the location and extent of infarction. The most common occlusion is in the ambient segment affecting one or more hemispheral branches. Posterior cerebral artery territory infarcts can be divided into four groups with unique characteristic findings: (1) occlusion of the precommunal P1 segment causing midbrain, thalamic, and hemispheric infarction; (2) occlusion of the posterior cerebral artery in the proximal ambient segment prior to branching in the thalamogeniculate pedicle causing lateral thalamic and hemispheral symptoms; (3) occlusion of a single posterior cerebral artery branch, primarily the calcarine artery; and (4) large hemisphere infarction of the posterior cerebral artery territory (16).
Thalamic infarcts are characterized by prototypical clinical findings such that the combination of clinical findings and topographical localization of the lesion in the thalamus allows one to infer the identity of the occluded vessels and the pathogenesis of the infarction. Several general features facilitate the understanding of the clinical manifestations of thalamic infarctions. Focal deficits are present at onset in almost all patients with thalamic infarction. Because of the compactness of the various thalamic nuclei, several of the nuclei may be simultaneously affected even by small infarctions. Most thalamic lesions involve neighboring areas in addition to the thalamus. Thus, paramedian thalamic vascular lesions tend to affect the midbrain as well, resulting in a decreased level of consciousness. Underlying motor and sensory findings may be masked in the acute period. Involvement of the internal capsule with laterally located thalamic lesions may affect the clinical picture of pure thalamic infarction. Lesions extending into the subjacent subthalamic nucleus of Luys may lead to contralateral hemiballismus.
In general, except for sensory deficits, unilateral thalamic lesions result in transient deficits. The clinical expression may also depend on the age of the lesion. As the effects of an acute lesion recede, neglect may disappear, and inability to walk may yield to mild ataxia. Conversely, other findings such as tremor or pain may develop only weeks after injury.
Depending on localization, infarctions of the thalamic nuclei may produce disturbance in consciousness, mood, affect, memory, sensation, motor function, ocular motility, and language (14). Thalamic syndromes are classified according to the 4 major vascular regions: (1) posterolateral, (2) anterior, (3) paramedian, and (4) dorsal. A specific set of blood vessels supply these subregions.
A summary of the major clinical findings of thalamic infarctions in these 4 subregions follows.
Posterolateral thalamic infarctions. Infarctions in this location result from occlusion of the thalamogeniculate branches of the posterior cerebral artery (07). Three common clinical syndromes may occur: (1) pure sensory stroke, (2) sensory motor stroke, and (3) a more extensive lateral infarction originally described by Déjerine and Roussy in 1906 as "thalamic syndrome" (26).
The first variant, pure sensory stroke, is characterized by onset of contralateral hemibody paresthesias with a subsequent development of hemibody sensory deficit. Sensory loss typically occurs maximally in the distal limbs and may spare the face because the ventral posterior median nucleus may be supplied by paramedian arteries or due to bilateral thalamic representation of the face (14). A restricted sensory syndrome (cheiro-oral with or without crural component), or sensory loss involving only the face, the upper limb, or the lower limb may occasionally occur (74; 04). More rarely, a contralateral hypoesthesia restricted to the distribution of the mental nerve (numb chin syndrome) may be observed in posterolateral thalamic infarcts (82).
Somatotopical organization of the ventro-postero-medial thalamic nuclei explains the preferential involvement of the tongue, face, and fingers (88). All sensory modalities may be affected; however, pinprick, temperature, touch, and vibration sensory modalities are more often compromised (13). A late painful syndrome may develop in the affected areas. The pain is referred to as thalamic pain and is the most discussed aspect of the thalamic syndrome of Déjerine and Roussy (26; 14). This excruciating pain may occur at onset of injury or in a delayed fashion when sensation begins to improve. Cutaneous stimuli elicit paroxysms of pain that often persist after the stimuli are removed. Because the pain occurs in areas where sensation is diminished, it is described as anesthesia dolorosa.
The second variant of posterolateral thalamic infarction is sensory motor stroke. It includes, in addition to sensory deficits, motor disturbances characterized by the presence of a transient or permanent hemiparesis (07). This is thought to be a function of a more lateral extension of the infarction into the posterior limb of the internal capsule adjacent to the ventral lateral nucleus.
The final variant of the posterolateral infarction syndrome consists of the classic thalamic syndrome of Déjerine and Roussy, in which a contralateral sensory motor deficit is associated with choreiform or choreoathetoid movements as a result of interruption of the extrapyramidal and cerebellar tracts synapsing in the lateral thalamus (07). Patients may have mimetic facial paresis (14). Patients may also show signs of contralateral hemiataxia, which usually occurs in association with sensory disturbance (hemiataxia-hypesthesia) or ataxic hemiparesis, or both; isolated contralateral hemiataxia without motor and sensory deficits, though rare, may also occur (37). As a result of damage to the dentato-rubro-thalamic projections to the ventral lateral nucleus, other cerebellar signs may also be present. Weeks after the injury tremor at a rate of about 3 to 5 Hz may appear (14). This occurs primarily in the distal musculature and increases during performance of any movement. Following an acute lesion, despite normal strength of the limbs, patients may be unable to stand or sit (62). This is known as thalamic astasia.
Moreover, isolated abnormal involuntary movements comprising chorea, dystonia, tremor (including Holmes tremor), myoclonus (usually involving the hand and possibly the shoulder, though rarely), or complex patterns encompassing several components of all the foregoing may become apparent from the onset of infarct or, more often, after a variable latency period (43; 101; 61). All these involuntary movements occur more often in patients with marked sensory loss and ataxia. A sensory form of the alien hand syndrome may occur, although rarely, when the inferolateral vascular territory of the thalamus is involved (59).
Neuropsychological disturbances during the acute phase have been thought to be minor and transient or even absent. However, executive dysfunction, mainly in verbal and figural fluency, was observed in patients who underwent standard neuropsychological evaluation between three and six months after a lateral thalamic infarct (03). Mild transcortical motor aphasia, learning abilities and long-term memory were also affected, although to a lesser extent (03; 18).
Anterior thalamic infarction. These infarcts result from occlusion of the polar artery and account for 10% to 14% of all thalamic infarctions (13; 49; 42). The main clinical presentation consists of neuropsychological disturbances (11; 07; 88; 42; 71). Patients may be abulic and apathetic, as is seen with frontal lobe lesions. This may be due to dysfunction of the thalamo-frontal connections that help modulate complex human behavior (14). Palipsychism and perseverative thought behavior and speech output are notable features (17). Anomia and word-finding difficulty, probably due to a disconnection between anterior thalamic nuclei and the temporal lobe, has been found in six patients with left-sided subacute thalamic polar infarcts (71). In exceptional cases, pseudo-coprolalia a sudden alteration of emotional effect manifesting as excessive and uncontrollable coarse language with anomia, but no associated compulsions can be the sole manifestation of a left-side infarct involving the ventral oral and lateropolar nuclei and, to a lesser extent, the mammillothalamic tract (23). Anterograde memory deficits consist of verbal recall impairment with dominant side infarctions and visuospatial memory deficits with nondominant infarctions (36; 71). Inattention is seen primarily in patients with right-sided lesions. Moderate transcortical motor aphasia was found in 12 patients with anterior thalamic infarction, regardless of side of infarct, being mild in right-sided infarcts (36). In patients with bilateral polar artery territory infarctions, abulia and amnestic disturbances are severe and do not usually improve with time (07). Many deficits may be mediated by injury to the medial thalamic group. Deficits are primarily in storage of new information. Minor sensory and motor deficits on the contralateral side may also be noted. A postural tremor of the upper extremity, associated with a mild finger dystonia without sensory or motor deficits, has been reported. Both a disruption of the anterior thalamic-frontal loop, which participates in planned motor activity, and an alteration of the interneuronal GABAergic inhibitory pathways have been the mechanisms hypothesized (24).
Uncommonly, isolated ipsilateral ptosis without neurobehavioral disturbances has been found to be the major clinical sign of polar infarct. In such a case, ischemia may extend to adjacent hypothalamus, disrupting the sympathoexcitatory tract running from the posterior hypothalamus to the pretectal area and the ciliospinal center of Budge (05). An extremely rare variant of infarcts in this arterial territory is the occurrence of ipsilateral Horner syndrome associated with mild contralateral upper limb ataxia, the latter finding due to extension of the infarct to the anterior part of the internal capsules posterior limb (34). A tuberothalamic infarct and a paramedian midbrain infarct may occur simultaneously in rare cases. In the reported case, the main clinical manifestations were ipsilateral ptosis and contralateral ataxic hemiparesis. CT angiography disclosed stenosis of the proximal posterior cerebral artery along with absence of the posterior communicating artery, suggesting that both arterial territories had a similar blood supply arising from the posterior cerebral artery (56).
Paramedian thalamic infarctions. These result from occlusion of the paramedian or thalamic/subthalamic arteries. Unilateral or bilateral paramedian thalamic infarcts accounted for 1.4% of all ischemic strokes (33). The paramedian thalamic arterial syndrome is characterized by a classic triad of acute onset of decreased level of consciousness, neuropsychological disturbances, and vertical gaze abnormalities (13). Patients are lethargic and difficult to arouse acutely and subsequently may become hypersomnolent. Presentation with coma is not uncommon, whereas transient and recurrent episodes of paroxysmal unresponsiveness may also occur at onset, although more rarely (09). Involvement of the intralaminar nuclei and the rostral midbrain ascending reticular activating system accounts for the decreased level of consciousness. Generally, the alteration of consciousness is transient but can be prolonged if the infarct is bilateral or the lesion extends into the midbrain tegmentum, which would be accompanied by a third cranial nerve palsy (13; 33). Akinetic mutism may follow bilateral paramedian lesions.
Vertical gaze dysfunction is characterized by abnormalities of upgaze or combined upgaze and downgaze palsy. Other ocular findings include abnormal pupils (small reactive pupils and anisocoria with a smaller ipsilateral pupil), ptosis, and restriction of ocular adduction (07). Blepharospasm and bilateral internuclear ophthalmoplegia with ptosis and pseudo-sixth nerve palsies may occur (07; 14). Skew deviation is common. Pure downgaze palsy is seen with bilateral paramedian infarctions. Horizontal gaze dysfunction is less common. Dysconjugate abnormalities such as thalamic esotropia may be seen (14; 104). With improving level of consciousness, neuropsychological abnormalities become manifest; thus, confusion, severe apathy and loss of psychic self-activation may prevail, especially in bilateral infarct cases.
Other cognitive disorders include confabulation, either isolated or combined amnestic syndrome, and severe personality modifications, such as disinhibition, compulsive utilization behavior, cyclical psychosis, and mania (17). Thalamic neglect may be seen with nondominant lesions. Pure apraxic agraphia may also occur, although rarely, with smalls infarctions involving the dorsomedial nucleus (73).
Abnormal movements such as asterixis, tremor, or dystonia may occur in the contralateral limb in a delayed fashion (07). Diurnal severe bruxism has been associated with a paramedian thalamic infarct (92). More rarely, a single paramedian infarct may produce a transient bilateral hypogeusia when the gustatory pathways ascend from the solitary nucleus en route to the parietal operculum, traversing the ventral posterior medial nucleus (67).
Dorsal thalamic infarctions. These infarctions result from occlusion of the posterior choroidal arteries (91; 07). Pure dorsal thalamic infarctions are less frequent than the other vascular syndromes described (91; 70). A characteristic clinical finding is the presence of visual field deficits due to lateral geniculate body involvement. The visual deficits can be quadrantanopsic, incongruous wedge-shaped homonymous hemianopia, or more typically, a true wedge-shaped sectoranopia (16; 70; 97). Involvement of the pulvinar, posterolateral, and anterior thalamic nuclei may produce abnormalities in smooth pursuit, mild hemisensory and motor deficits, dystonia, delayed unilateral akathisia, transcortical aphasia, amnesia, abulia, and visual hallucinations. Pure dorsal thalamic infarctions are less frequent than the other vascular syndromes described (70).
Bilateral thalamic infarctions. Bilateral simultaneous ischemic lesions in the thalamus are uncommon (31). When they occur, involvement of the bilateral paramedian artery territory is the most common pattern found, followed by symmetric thalamogeniculate infarcts or combined ischemia in the paramedian and thalamogeniculate artery territories (48). Infrequently, an anatomic variant of the paramedian arteries occurs in which the precommunicating segment of the posterior cerebral artery gives off a single dominant thalamoperforating artery the artery of Percheron and supplies both medial thalamic nuclei with variable contribution to the rostral midbrain. In this case, four stroke patterns may occur. The most common is bilateral paramedian thalamic with midbrain infarct; the second, bilateral paramedian thalamic without midbrain infarct; the third, bilateral paramedian and polar thalamic infarct along with rostral midbrain involvement; and the least observed is bilateral paramedian and polar (anterior) thalamic infarct sparing the midbrain (51).
Bilateral paramedian thalamic infarcts are characterized by prominent and long-lasting memory dysfunction, deficit in executive functions, and mood changes (40). Gaze disorder and decreased level of consciousness may be the first noticeable clinical findings and may lead, mainly in the latter case, to an erroneous diagnosis of conversion disorder when a brain MRI is not performed during the evaluation in the emergency department (57; 31). Acute hypersomnia may be a main, though uncommon, clinical finding in bilateral thalamic infarcts (86). There have been reports of pure downgaze palsy and selective bilateral abduction deficit during horizontal gaze, the latter with bilateral intact pupillary light reaction and absent pupillary constriction on attempted convergence (104). Disorders of sexual behavior (masturbation stereotypes) occur rarely and usually become apparent when coma and oculomotor nerve palsy resolve (65). Although a rare occurrence, acute pseudobulbar palsy combined with upward gaze palsy may be the predominant clinical finding in cases of bilateral paramedian infarcts (53). Damage to anteroventral or ventrolateral nuclei by bilateral ischemic lesions has been suggested to explain pseudobulbar palsy. Anteroventral nuclei have connections with the medial and the caudal orbitofrontal cortex, and ventrolateral nuclei send projections to Brodmann areas 4 and 6. Fibers from the medial part of the ventrolateral nuclei in particular reach areas mediating facial movement (53).
When simultaneous infarcts are found in more than one vascular thalamic territory other than both paramedian territories, there is no specific clinical picture. Confusion occurs, as well as sensory and language deficits and neuro-ophthalmological disturbances in different patterns. When infarct involves both paramedian thalami and the polar region, the most important clinical manifestation is severe memory impairment. Specific visual-field defects (such as a bow-tie pattern) and sudden, painless, complete bilateral amaurosis have been reported in the rare cases of isolated bilateral infarcts of the posterior choroidal arteries with involvement of the lateral geniculate bodies (06; 63). Moreover, the clinical picture in one third of patients with bilateral thalamic infarcts may resemble multiple superficial cerebral infarcts either in the anterior or posterior circulation (48).
Infarcts outside classical thalamic territories. One fourth to one third of infarcts restricted to the thalamus are located outside classical thalamic territories. Anteromedian, posterolateral, and central infarcts have been described. The most frequent topographic pattern was the anteromedian, whereas central infarct was the least often observed. Cognitive impairment (amnesia, aphasia, loss of self-activation), vertical gaze paresis, and mild decrease of consciousness constituted the most frequent clinical findings of the anteromedian variant, which involves the anterior and paramedian territories (18). Hemihypesthetic ataxic hemiparesis associated with aphasia and executive dysfunction in dominant side lesions was the main finding in posterolateral infarcts, which involve the inferolateral and posterior territories. Contralateral hypesthesia, ataxia, and vertical gaze paresis were common clinical features of central thalamic infarcts (18). One fourth of multiple acute thalamic infarcts in a series of 21 patients were located outside the classical thalamic territories. Both thalami were involved in 14 cases, which included nine patients with combined classical and variant territories, which was the most common pattern, followed by unilateral multiple variant infarcts and then bilateral multiple variant infarcts, as the least common pattern. Cardioembolism was the leading suspected cause in all three of the above-mentioned patterns. Contralateral sensory deficit and decreased level of consciousness were particularly noteworthy, in addition to vertical eye paresis, hemiataxia, immediate and short-term memory deficits, and loss of self-activation or abulia in patients with combined classical and variant territory infarcts, whereas motor weakness was slight and transient when present (47). The outstanding clinical manifestations in patients with unilateral thalamic infarcts (anteromedian, central, and posterolateral territories) were short-lived consciousness disturbances, long-term memory deficits, and executive dysfunction; additionally, vertical gaze paresis and contralateral paresis may be found as clinical manifestations. These may be accompanied by nonfluent aphasia in the case of a dominant-side lesion. Finally, the main clinical findings in patients with bilateral multiple variant infarcts were alterations of consciousness, sensory-motor deficits, and particularly severe and long-lasting cognitive dysfunction, which manifested as memory deficit, executive dysfunction, and aphasia (47).
Clinical manifestations of midbrain infarctions. Signs and symptoms of midbrain infarction depend on the size and location of the lesion and the presence or absence of thalamic or occipital lobe involvement. The most localizing manifestations of a midbrain infarction are oculomotor and supranuclear vertical gaze palsies (39; 38; 72). These can occur in isolation or in association with other clinical findings (52; 64).
Isolated third cranial nerve palsy can be due to nuclear or fascicular lesions. Infarction of the third cranial nerve nucleus can be distinguished from fascicular involvement because nuclear lesions cause paresis of the contralateral superior rectus and bilateral ptosis (39; 14). In a short series of isolated unilateral oculomotor paresis due to midbrain stroke, five patients had a paramedian infarct exclusively involving the oculomotor fascicles; a partial involvement of the third nerve occurred, which was characterized by paresis of the levator palpebrae superioris, superior rectus, inferior oblique, and medial rectus muscles; whereas sparing of pupillary sphincter and inferior rectus muscles was noted in all patients with this fascicular disturbance (01). Isolated medial rectus palsy with impaired convergence ipsilateral to lesion and no pupil involvement may be a rare outstanding clinical finding in cases of a minute paramedian midbrain infarct (29). Midbrain infarcts affecting the intra-mesencephalic (intra-axial) segment of the third oculomotor nerve are usually associated with additional, mainly contralateral, long tract signs described as the classical crossed brainstem syndromes and their variants. Thus, Weber syndrome is due to infarction in the distribution of the penetrating branches of the posterior cerebral artery affecting the cerebral peduncle, especially medially with damage to the fascicle of the third cranial nerve and the pyramidal fibers. The resultant clinical findings are contralateral hemiplegia of the face, arm, and leg due to corticospinal and corticobulbar tract involvement and ipsilateral oculomotor paresis, including a dilated pupil (38; 46). A slight variation of this syndrome is the midbrain syndrome of Foville in which the supranuclear fibers for horizontal gaze are interrupted in the middle cerebral peduncle, causing a conjugate palsy to the opposite side (14).
Benedikt syndrome is caused by a lesion affecting the mesencephalic tegmentum in its ventral portion, with involvement of the red nucleus, brachium conjunctivum, and fascicle of the third cranial nerve (38; 46). This syndrome is due to infarction in the distribution of the penetrating branches of the posterior cerebral artery to the midbrain. The clinical manifestations are ipsilateral oculomotor paresis, usually with pupillary dilation and contralateral involuntary movements, including intention tremor, hemiathetosis, or hemichorea. An isolated unilateral ptosis and mydriasis (without extraocular muscular paresis) associated with a transient contralateral hand postural tremor has been reported as a partial form of Benedikt syndrome (20).
Claude syndrome is caused by lesions that are more dorsally placed in the midbrain tegmentum than those with Benedikt syndrome (38). There is an ipsilateral oculomotor paresis and contralateral cerebellar signs due to injury to the dorsal red nucleus. Involuntary movements are absent (10). Ipsilateral ataxia may also occur in this so-called reverse Claude syndrome, in which case the dentatorubrothalamic tract is involved at the rostral end before its decussation, which has been demonstrated on tractography of the midbrain (100; 94). In rare instances, Claude syndrome may be present with third-nerve palsy with pupil sparing or without ptosis (95; 08).
Nothnagel syndrome is characterized by an ipsilateral oculomotor palsy with contralateral cerebellar ataxia. Infarction in the distribution of the penetrating branches of the posterior cerebral artery to the midbrain is the cause of this syndrome.
Supranuclear conjugate gaze palsies can arise as a result of (1) occlusion of the paramedian mesencephalic arteries producing small paramedian upper midbrain infarctions; (2) occlusion of the superior cerebellar artery producing infarction in the posterior commissure or periaqueductal gray region; and (3) occlusion of the thalamic or mesencephalic artery, which may give rise to upper paramedian midbrain and thalamic infarction (38). Upgaze palsy may result from unilateral or bilateral infarction of the posterior commissure, periaqueductal gray, and nucleus of rostral interstitial medial longitudinal fasciculus (39; 38). Downgaze palsies arise due to bilateral infarctions of more caudally placed upper midbrain infarctions. Dysconjugate vertical gaze palsies, monocular elevation palsy, and vertical one-and-a-half syndrome occur as a result of ipsilateral or contralateral/unilateral infarction of the upper paramedian midbrain. Parinaud syndrome, also called dorsal rostral midbrain or Sylvian aqueduct syndrome, can result from infarctions in the midbrain territory of the posterior cerebral artery penetrating branches. This syndrome is characterized by supranuclear paralysis of vertical gaze, defective convergence, convergence retraction nystagmus, pupillary light near disassociation, lid retraction (Collier sign), and skew deviation (38). Monocular ophthalmoplegia and partial supranuclear vertical gaze palsy may be produced by unilateral paramedian rostral midbrain infarction. It has been suggested that, in such cases, combined incomplete oculomotor and pseudo-abducens palsies may explain these unusual findings (93).
It is exceedingly uncommon, though possible, for an infarct located at the thalamomesencephalic junction to involve the anatomical structures of supranuclear control of vertical gaze (nucleus of posterior commissure and interstitial nucleus of Cajal), the third nerve fascicle, the superior cerebellar peduncle, and the red nucleus. In such a case, a combination of plus-minus lid syndrome (ipsilateral ptosis and contralateral eyelid retraction), vertical one-and-a-half syndrome, and Claude syndrome may occur (80). Another unusual eye movement disorder, characterized by a vertical one-and-a-half syndrome (a combination of supranuclear conjugate upgaze palsy and fascicular third nerve palsy) and contralesional pseudo-abducens palsy, has been reported (28). This neuro-ophthalmological profile results from two simultaneous infarcts, the first at the level of the thalamomesencephalic junction and the second at the base of the upper midbrain. Moreover, another unusual neuro-ophthalmological pattern may result from unilateral minute infarcts involving the paramedian region of the thalamus and the midbrain. In this setting, acute esotropia and convergence-retraction nystagmus may result from a lesion of the supranuclear fibers having an inhibitory effect on the convergence neurons or producing damage to the divergence neurons; contralateral vertical gaze paresis and partial palpebral ptosis may be produced by concomitant damage to the rostral interstitial medial longitudinal fasciculus, the interstitial nucleus of Cajal, and the nucleus of the posterior commissure (58). Crossed vertical gaze palsy, an uncommon neuro-ophthalmologic finding, may be due to unilateral infarction involving the mesodiencephalic junction (75). In this peculiar pattern of vertical gaze palsy, a monocular elevation paresis and a concomitant depression gaze paresis or slowed downward saccades may be found in the fellow eye. A combined upward and downward gaze palsy may also be observed in both eyes, with more marked depression paresis in the ipsilesional eye and more elevation deficit in the contralesional eye. It has been hypothesized that ischemia may involve crossed and uncrossed fibers from the rostral interstitial nucleus of the medial longitudinal fasciculus directed to oculomotor nuclei mediating vertical gaze in both directions.
Unilateral or bilateral paramedian caudal midbrain infarction are less frequent than infarction in the upper paramedian area (72). Eye-movement abnormalities and bilateral cerebellar dysfunction (dysarthric speech, truncal, and limb ataxia), often more marked on one side, are the main clinical findings due to lesion in the decussation of the superior cerebellar peduncle and its dentatorubrothalamic pathway (66; 106). Although infrequent, there may be a slow frequency rest tremor in both upper extremities with intention and postural components in the first hours after stroke onset and a palatal tremor or palatal myoclonus appearing months after caudal midbrain infarct (66). Superior oblique palsy in the eye contralateral to the side of the lesion may be found, although rarely, due to damage of the trochlear nucleus or the adjacent trochlear nerve fascicle before it decussates, as an isolated sign of restricted midbrain infarct (54; 83; 22). Another uncommon clinical finding, which occurs when infarcts involve the caudal paramedian midbrain, is multifocal dystonic movement in the tongue, hands, and feet, along with upper and lower limb ataxia, dysarthria, and gait disturbance secondary to a lesion of the cerebellar motor loop (25) and acute contralateral hemiparkinsonism due to a lacunar infarct restricted to the substantia nigra (84).
In 2 series of patients (40 in one, 21 in the other) with pure midbrain infarcts, distribution of infarcts as revealed by MRI findings showed that the paramedian (anteromedial) territory was most frequently involved (44; 72). The main clinical findings in midbrain infarcts involving the paramedian territory may be oculomotor abnormalities ‒ third nerve palsy, internuclear ophthalmoplegia, and pseudo sixth nerve palsy ‒ and ataxia (44; 64). Divergence paralysis, an uncommon supranuclear disorder characterized by uncrossed horizontal diplopia at far distances with little or minimal deviation at near distances, has been reported in a patient with acute ischemia involving the surrounding area of periaqueductal gray matter, and consequently, the mesencephalic reticular formation (96). When ischemia affects the paramedian territory, hypesthesia restricted to perioral or perioral-hand areas may be found, though less often than oculomotor abnormalities. In this case, the ischemia involves the inner part of the medial lemniscus (44). Very rarely, an axial contralesional lateropulsion may be the single manifestation of a paramedian upper midbrain infarct, which may affect the ascending graviceptive pathway, located in the vicinity of the red nucleus (68; 64). Moreover, ipsilateral hemiageusia combined with vertical gaze palsy and truncal ataxia has been reported in a young adult with a unilateral rostral paramedian midbrain infarct. In this unusual case, the minute ischemia affected the ascending gustatory pathway that runs through the central tegmental area, sparing the medial lemniscus (55). The main clinical manifestations of unilateral midbrain infarcts may be bilateral ageusia and tongue anesthesia in some very uncommon cases. In such cases, ischemia may involve the gustatory pathway decussating in the midbrain and projecting to the ventroposteromedial and dorsomedial thalamic nuclei (87).
Anterolateral infarcts were characterized by ataxic hemiparesis or, less commonly, by hypesthetic ataxic hemiparesis (44; 72). Pure sensory deficits, caused by involvement of the laterally located lemniscal sensory fibers, occurred in 2 patients with ischemic lesions restricted to the lateral midbrain (44).
Though uncommonly, midbrain infarcts may have other clinical manifestations besides the above-mentioned neuro-ophthalmological and sensory findings. Acute episodic, recurrent, short-lasting (one to three hours), unilateral throbbing headache with nausea and photophobia was reported in an older woman without a history of previous headaches who showed a small infarct involving the periaqueductal gray matter on MRI performed five days after headache onset (103). Acute tetraplegia and altered level of consciousness were the main clinical findings in a retrospective study of 14 Chinese patients (eight men, six women) with bilateral cerebral peduncular infarction confirmed by brain MRI (21). These infarcts are rare and accounted for 0.26% of all ischemic strokes in this study. The mean age of the 14 patients was 72 years, and the mean NIHSS score was 19. Bilateral peduncular ischemia often occurred with multiple infarcts in the posterior circulation territories; simultaneous pontine involvement, usually bilateral, was observed in 88% (12 patients), and cerebellar infarcts were found in 43% of the patients. Large artery disease, the most common etiology, was identified in 79% (11 patients) and was associated with severe stenosis or occlusion either in the vertebral or basilar arteries and a lack of collateral patency of the posterior communicating artery on angiographic studies. A high signal on the bilateral cerebral peduncle simulating Mickey Mouse ears --a sign considered indicative of an infarction in this location--was observed in several patients on diffusion-weighted MRI. Prognosis was dismal: 9 patients (64%) died, 4 patients had moderate to severe disability, and only 1 patient had a favorable outcome (21).
Top of the basilar syndrome is due to infarction of the midbrain, thalamus, and parts of the temporal and occipital lobes. A multitude of signs may be present including (1) neurobehavioral abnormalities such as somnolence, peduncular hallucinosis, memory disturbances, agitated delirium, constructional apraxia, visual agnosia, and alexia without agraphia; (2) ocular findings including unilateral or bilateral paralysis of upward or downward gaze, pseudo-abducens palsy, convergence retraction nystagmus, abnormalities of abduction, Collier sign, skew deviation, and oscillatory eye movements; (3) other visual defects including unilateral or bilateral homonymous hemianopia, color agnosia, cortical blindness, Balint syndrome, and Anton syndrome; (4) pupillary abnormalities including either small and reactive pupils or large or mid-position and fixed pupils, corectopia, and occasionally oval pupils; and (5) motor and sensory deficits (15). A variant of top-of-the-basilar syndrome, characterized by bilateral internuclear ophthalmoplegia, ataxia, rubral tremor, hypersomnolence, and inversion of the sleep-wake cycle, has been reported, though rarely (90).
Prognosis and complications related to thalamic and midbrain infarctions are based on extent and mechanism of infarction. Steinke and colleagues found no acute deaths as a result of infarction of the thalamus (91). Bogousslavsky and colleagues recorded only one sudden death due to pulmonary embolism among a series of 40 patients with thalamic infarctions (13). Such favorable outcome may not be seen with patients who have a large embolus lodged at the basilar artery apex. Propagation of clot proximally along the entire basilar artery trunk may also occur over the course of days to weeks following an acute event. Likewise, embolus from an incompletely thrombosed site can precipitously and abruptly change the neurologic course. Furthermore, a completely thrombosed vessel can be a source of further emboli. Brain herniation is less likely with unilateral posterior cerebral artery occlusion than with cerebellar or middle cerebral artery territory infarctions. In general, the neurologic status improves over time. With lacunar thalamic and midbrain infarctions, improvement within a matter of days to weeks is the rule (44; 35). However, severe deficits especially cognitive deficits, may show little or no recovery, particularly when produced by bilateral thalamic infarcts due to interruption of thalamo-fronto-limbic loop. Dementia may develop as a result of strategic infarcts or bilateral thalamic ischemia (48). Hemiparesis may improve over time and may give way to chorea or tremor and ataxia.
Case 1. An 81-year-old man in good health suddenly experienced paresthesias in the left leg, and immediately afterward in the left arm and on the left side of his face. Approximately five minutes later, he also noted a weakness in the left leg and left arm. He could not walk without assistance. He had had arterial hypertension during the previous 10 years and had taken enalapril on an irregular basis. He had had a history of weekly alcohol consumption but had stopped 10 years before. His blood pressure was 170/95, and his pulse was 80. His heartbeat at a normal rhythm. He experienced a loss of light touch, pinprick, temperature, graphesthesia, positional, and vibrational modalities on the left hemibody. He also had a flaccid hemiparesis involving both the left arm and leg. A brain CT scan performed in the emergency room was normal. The brain MRI showed a right thalamic infarct in the territory of the thalamogeniculate arteries. A transthoracic echocardiography disclosed a left ventricular hypertrophy. This patient was treated with aspirin in daily doses of 100 mg and 10 mg of enalapril per day. On leaving the hospital, he required assistance to walk.
Case 2. A 54-year-old right-handed woman with no previous history of vascular risk factors suddenly developed horizontal diplopia when working at home, with right upper arm incoordination and gait instability presenting several minutes later. Five days after stroke onset, the patient was admitted at our institution with a 180/100 mmHg blood pressure reading, regular heart rate, and an unrevealing cardiac auscultation. Neurologic examination disclosed a left, complete oculomotor palsy, with the left pupil 1 mm larger than the right and without reaction to light and severe right-limb and gait ataxia.
Speech was normal and there were no motor or sensory deficits. Blood analyses showed only a dyslipidemia; the electrocardiogram was normal, and a transthoracic echocardiogram showed a left ventricular hypertrophy. The CT scan was normal, and cranial MRI showed an acute left ventromedial midbrain infarct. Digital subtraction angiography showed no abnormality. Antiplatelet therapy was started with clopidogrel (75 mg/day), atorvastatin (80 mg/day), and angiotensin-converting enzyme inhibitor (20 mg/day of enalapril).
Intrinsic small artery disease is the prime cause of infarcts involving either one thalamus or both. Embolic occlusion from the heart as well as from vertebrobasilar occlusive disease may be associated, in each case, with 10% to 20% of thalamic infarcts (13; 48; 89). Moderate to severe atherosclerotic stenosis of the posterior cerebral artery was found to be associated with around one fifth of isolated posterolateral infarcts. In this case, infarcts were associated with ataxic hypesthetic hemiparesis rather than pure sensory stroke. A larger initial lesion volume and higher NIHSS scores at discharge were observed compared with patients with posterolateral infarcts due to small vessel disease (50). The main etiology in adults between the ages of 18 and 45 is cardioembolism due to patent foramen ovale (77). Arteritis, lupus anticoagulant, migraine, meningovascular syphilis, and Marfan syndrome are uncommon causes of thalamic infarcts. According to a retrospective cohort study from a coronavirus disease (COVID-19) dataset, acute ischemic stroke may occur in about 1.3% of patients with COVID-19 (79). Thalamic infarcts have been reported in SARS-CoV-2infected patients with and without cardiovascular risk factors (85; 105). Finally, despite extensive workup, 15% to 30% of patients had no known etiology for their ischemic stroke (13; 77; 89).
In a cohort of 48 patients with bilateral thalamic infarcts, the most common vascular pathologies on MRA (mainly at 1.5 Tesla) and CTA were top of basilar artery occlusion, basilar artery occlusion, and stenosis and occlusion of posterior cerebral artery (31). Configuration of the posterior part of the circle of Willis was assessed in 45 patients after arterial recanalization was established on follow-up neuroimaging. In approximately 40% of patients, the precommunicating segment of posterior cerebral artery was found to be either hypoplastic (1 mm mean diameter, 1.8 mm mean normal diameter) or altogether absent.
Large artery disease, small artery disease, and cardiac embolism show an equal distribution in the etiology of infarcts restricted to the midbrain. The etiology of approximately one fifth of all pure midbrain infarcts remains unknown (10; 44), though in a cohort of 21 patients, etiology could not be determined in nearly half the patients (72). In a cohort of 40 patients with isolated midbrain ischemic stroke, small vessel disease was the leading etiology in patients with deep infarcts of the anteromedial territory, whereas large vessel disease was the predominant etiology in large lesions of the anteromedial territory and of the anterolateral group (44). Small vessel disease and branch atheromatous disease were the leading etiologies in paramedian infarcts (72). The latter cause was associated with anterolateral lesions, although MR angiography was performed in only two of six patients. In the last few months, small vessel disease was found to be the leading etiology in almost all cases in a small cohort of 9 patients with isolated midbrain infarcts. The only exception was a patient with a high source of cardioembolism. As with other larger cohorts, the anteromedial territory was found to be the most frequently involved. Interestingly, seven patients in this small cohort had anomalies in the vertebrobasilar circulation, which were identified either by cerebral CTA or MRA (four vertebral and three basilar hypoplasia), a situation that has rarely been reported. These anomalies in the vertebrobasilar system may be associated with hypoperfusion or microembolism to penetrant perforators mainly supplying the anteromedial midbrain (35).
Usually, midbrain infarcts are associated with pontine infarcts. In situ thrombosis and embolus arising from the intracranial vertebral arteries or the basilar artery are the main etiologies (60). Embolism from a cardiac source and artery-to-artery embolism are the potential causes in instances of midbrain infarcts associated with infarcts involving the thalamus, superior cerebellum, or temporal/occipital lobes.
Midbrain infarcts are not commonly associated with infarcts involving the proximal posterior circulation (medulla or postero-inferior cerebellum). In situ thrombosis or artery-to-artery embolism are the main etiologies (60).
Functional anatomy of the thalamus. The thalamus is the largest part of the diencephalon, which also is made up of the epithalamus (pineal and habenular complex), subthalamic nucleus, and hypothalamus. The paired thalamic nuclei are oval structures on either side of the third ventricle. The thalamus serves to relay both sensory and motor information to the primary sensory and motor areas of the cerebral cortex. Distinct sensory nuclei receive input about different sensory modalities including somatic sensation (pain, temperature, light-touch, proprioception, and vibration), audition, and vision. Likewise, specific nuclei convey information from the cerebellum and the basal ganglia to the primary motor cortex. In addition, the thalamus is involved in autonomic reaction and maintenance of consciousness. Although almost all thalamic nuclei project to and receive input from the cerebral cortex, specific thalamic nuclei receive input primarily from certain structures and have efferents to specific structures. The regional classification of thalamic nuclei into anterior, posterior, medial, and lateral groups by the Y-shaped internal medullary lamina and its nuclei is important clinically and pathophysiologically. The thalamic nuclei can also be subclassified into 2 functional groups: (1) relay nuclei, and (2) diffuse projection nuclei. Diffuse projection nuclei have more widespread interactions and influence activity of cells not only in the cerebral cortex but also in the thalamus. They serve to dictate the level of arousal of the brain. Relay nuclei process single sensory modality or an input from a distinct part of the motor system.
The division of the thalamus into these four major anatomic subregions allows one to better understand the clinical manifestations of thalamic infarctions. Regions composed of the midline, intralaminar, and reticular nuclei mediate general cortical alertness and are nonspecific thalamic relay nuclei. Bilateral lesions to these structures cause impairment of alertness. The medial (dorsomedial) and anterior thalamic group regulate emotion and autonomic activity as a result of their connections with the hypothalamus, limbic lobe (cingulate gyrus, medial temporal region, and amygdala), and frontal lobe. Unilateral lesions of these structures may cause recent memory disturbance. The lateral nuclei are divided into two tiers, ventral and dorsal. The ventral anterior and ventral lateral nuclei are important for motor function. The integration of the information from the cerebellum, basal ganglia, and mechanical receptors contributes to the coordination of finer, distal motor movements with proximal axial movements that support them. The ventral posterior nuclear group integrates taste and somatosensory information to the primary somatosensory cortex. Information from the receptors in the head reaches the ventral posterior median nuclei through the trigeminal thalamic pathway. Ventral posterior lateral nuclei process somatosensory information from the spinal thalamic tract and the medial lemniscus (88). The medial geniculate and lateral geniculate bodies are included with the nuclear group of the ventral tier. The medial geniculate body mediates information about hearing and the lateral geniculate body about vision. Finally, the thalamic nuclei of the dorsal tier are the lateral dorsal, lateral posterior, and pulvinar. These nuclei, particularly the pulvinar, modulate cortical attention necessary for language-related tasks in the dominant hemisphere and visuospatial tasks in the nondominant hemisphere (88).
Functional anatomy of the mesencephalon. The midbrain, or mesencephalon, has its rostral boundary in a plain across the superior colliculus and the mamillary bodies, and its caudal boundary is a plain just caudal to the inferior colliculus. Cross-sectionally, the midbrain is divided into the dorsal tectum (colliculi), the tegmentum, and the cerebral peduncles. The tegmentum of the midbrain contains the following important functional structures: (1) the oculomotor nucleus and its fascicles and, caudal to the oculomotor nuclear group, the trochlear nucleus and its fascicle; (2) the medial lemniscus and the lateral spinothalamic tract; (3) the reticular formation (descending sympathetic tract and medial tegmental tract); (4) the medial longitudinal fasciculus; and (5) the dentatorubrothalamic tract (brachium conjunctivum).
From a functional anatomic viewpoint, the midbrain can be divided into the upper midbrain at the level of the posterior commissure, the middle midbrain at the level of the superior colliculus, and the lower midbrain at the level just below the inferior colliculus. The upper midbrain contains the structures that mediate supranuclear conjugate vertical gaze, the rostral interstitial medial longitudinal fasciculus in the mesencephalic reticular formation, the posterior commissure, and the third and fourth cranial nerve nuclei (39; 38). Cells that mediate downward gaze are distinct from those that mediate upward gaze but are interspersed within the rostral interstitial medial longitudinal fasciculus. The efferent projections for upgaze from the rostral interstitial medial longitudinal fasciculus nucleus cross the posterior commissure before synapsing with the third and fourth cranial nerve nuclei. Efferents mediating downgaze exit medially and caudally and do not travel in the posterior commissure (39).
The third cranial nerve nucleus, a V-shaped cell mass on either side of the midline below the central gray of the periaqueductal region, has a unique somatotopic organization. Both levator palpebrae muscles are innervated by the caudate nucleus in the midline caudal third of the oculomotor nuclear complex. Furthermore, each superior rectus muscle is innervated by a contralateral subnucleus.
Vascular supply to the thalamus and midbrain. The thalamus receives most of its blood supply from perforating vessels that arise from the basilar artery at or near its bifurcation, the posterior communicating artery, and the posterior cerebral artery. The posterior cerebral artery is a major blood supply to the midbrain, thalamus, occipital lobes, inferior and medial aspects of the temporal lobes, and portion of the inferior parietal lobes (16). The posterior cerebral artery originates from the bifurcation of the basilar artery in 90% of patients. However, 10% of individuals have a fetal pattern of origin of the posterior cerebral artery from the internal carotid artery. The posterior cerebral artery courses laterally around the midbrain above the third cranial nerve.
The superior cerebellar artery courses laterally below the third cranial nerve and runs below the tentorium, whereas the posterior cerebral artery courses between the uncus and the cerebral peduncles. The posterior cerebral artery divides into its cortical branches as it reaches the dorsal surface of the midbrain. During its course, the posterior cerebral artery traverses the interpeduncular, ambient, and quadrigeminal cisterns. The portion of the posterior cerebral artery from the bifurcation of the basilar artery to the ostia of the posterior communicating artery is referred to as the P1 segment, mesencephalic artery, precommunal portion, or basilar communicating artery (30; 07).
From the superior and posterior aspect of the P1 segment, directly adjacent to the basilar artery bifurcation, arise perforating arteries. These perforating arteries supply the interpeduncular fossa, mamillary bodies, cerebral peduncle, and posterior mesencephalic region. These branches are referred to as the paramedian thalamic artery, thalamic-subthalamic artery, posterior internal optic, deep interpeduncular profundi, or posterior thalamoperforators (07). They specifically provide the vascular supply of the posteromedial thalamus including the nucleus of the rostral interstitial medial longitudinal fasciculus, the posterior-inferior portion of the dorsal medial nucleus of the thalamus, the intralaminar nuclei, and sometimes the mamillothalamic tract. In about one third of subjects, these arteries arise from one side or a common pedicle. Thus, one posterior cerebral artery supplies both medial thalamic territories, and occlusion of one paramedian thalamic artery produces bilateral butterfly-shaped lesions.
The thalamogeniculate branches arise predominantly from the P2 segment of the posterior cerebral artery to the lateral geniculate body in the ambient cistern (16). These branches supply the posterolateral aspects of the thalamus including the ventral posterior lateral, the ventral posterior median, the lateral central medial nuclei, the rostral pulvinar, and the geniculate bodies. In addition, long and short circumflex arteries arise from the distal P1 or proximal P2 segment around the midbrain parallel to the superior cerebellar artery. The long circumflex vessels extend to the colliculi and supply the quadrigeminal plate, cerebral peduncles, geniculate bodies, and tegmentum. The short circumflex vessels pass around to reach the geniculate body and supply primarily the cerebral peduncle. From the posterior and lateral aspect of the upper 5 mm of the basilar artery and prior to its bifurcation, arise paramedian mesencephalic perforators that enter the midbrain and pons near the midline.
The medial and lateral posterior choroidal artery originates from the distal P1 and P2 segments after the thalamogeniculate arteries. They supply the posterior, superior, and anterior thalamus, choroid plexus, hippocampus, and decussations of the fornices (07).
The anteromedial and anterolateral regions of the thalamus including the reticular nucleus, mamillothalamic tract, and part of the ventral lateral nucleus are supplied by the perforators from the posterior choroidal artery. On average, about two to 10 perforators arise from the superior and lateral aspect of the posterior communicating artery in its anterior half. These branches have been referred to as the polar artery, tuberothalamic, anterior internal optic, anterior thalamoperforators, or premammillary pedicles (76; 07). About 30% of the hemispheres may lack this artery, and its territories are supplied by the paramedian thalamic perforators (07). Shortly after the posterior cerebral artery departs from the ambient cistern, it branches into its cortical branches: anterior temporal, posterior temporal, posterior pericallosal, parieto-occipital, and calcarine artery, consecutively (16).
Thalamic infarcts account for 3.7% to 10% of all ischemic strokes (42; 33) and 20% of cerebral infarcts involving the posterior circulation (102). In a cohort of 168 patients with acute thalamic infarcts, 40% were restricted exclusively to the thalamus and predominantly involved the territory supplied by the thalamogeniculate artery (89). The remaining patients in this cohort had other territorial infarcts as well, either in the neighborhood of the thalamus or extended infarcts in the posterior circulation. Thalamic infarcts without involvement of midbrain or other territories in the posterior circulation accounted for 3% of 8400 first-ever strokes (47).
Midbrain infarcts account for only 0.6% to 2% of all ischemic strokes (10; 60; 46; 44; 35). When midbrain infarcts occur, it is often with associated lesions involving neighboring structures, whereas isolated midbrain involvement has been found in 0.7% to 8% of posterior circulation infarcts (10; 60; 46).
In general, prevention of thalamic and midbrain infarctions should include control of risk factors associated with the development of cervical and intracranial atherosclerosis, lipohyalinosis of the small penetrating arteries, and embolus from the heart. Approximately 70% of patients with thalamic infarcts had arterial hypertension (91; 49); frequency was slightly lower in patients with midbrain infarcts (10; 60; 46). Available evidence from randomized controlled trials on the effects of antihypertensive drug treatment shows a reduction on the order of 30% in first-ever and recurrent stroke rates (81). An absolute target blood pressure level should be individualized, but benefit has been associated with an average reduction of approximately 10/5 mmHg. In adult hypertensive patients with or without previous antihypertensive therapy, treatment should be initiated or restarted at a level higher than 140/90 mmHg several days after stroke onset. The recommended target level of systolic and diastolic blood pressure seems to be lower than 130/80 mmHg (45). The pharmacological treatment of arterial hypertension should go hand in hand with reduced sodium intake; weight loss; regular physical aerobic activity; limited alcohol consumption; and a healthy, balanced diet rich in fruits, vegetables, and low-fat dairy products (45). Selection of a specific antihypertensive agent and target should be individualized, taking into consideration pharmacological properties, mechanism of action, and the particular characteristics of the patient (45). Diabetes mellitus was a prevalent risk factor among patients suffering thalamic and midbrain infarctions (91; 10; 46). According to the current stroke prevention guidelines from the American Heart Association, glycated hemoglobin (HbA1c) less than 7% may be a reasonable goal for long-term macrovascular risk reduction in adult diabetics (45).
Hypercholesterolemia has been found in about 10% of patients with thalamic and midbrain infarctions (10; 48; 46). Lipid-lowering therapies may be useful in primary and secondary prevention of ischemic stroke. The latest American Heart Association guidance for recurrent stroke prevention recommends different lipid-lowering therapies in accordance with the patients atherosclerotic cardiovascular risk (45). An 80 mg daily dose of atorvastatin is recommended for patients with a previous ischemic stroke who have no major cardiac sources of embolism, no known coronary artery disease, and low-density lipoprotein cholesterol of 100 mg/dl or more. In patients with clinical atherosclerotic disease and either a previous transient ischemic attack or ischemic stroke, lipid-lowering therapy should include a statin, and ezetimibe may be added, if needed. The target for low-density lipoprotein cholesterol is less than 70 mg/dl.
In an exploratory analysis of statin therapy in patients with a history of prior ischemic stroke, a target control of 4 cardiovascular risk factors (LDL cholesterol less than 70 mg/dL, HDL cholesterol greater than 50 mg/dL, triglycerides less than 150 mg/dL, and blood pressure of less than 120/80 mmHg) resulted in a progressively smaller risk of stroke in proportion to the number of risk factors optimally controlled. Thus, 65% lower risk for recurrent stroke was observed when all four risk factors were controlled as opposed to none (02).
According to the latest American Heart Association guidelines, secondary stroke prevention for patients with an index noncardioembolic ischemic stroke or transient ischemic attack includes either aspirin 50 to 325 mg daily, clopidogrel 75 mg daily, or aspirin 25 mg along with extended-release dipyridamole 200 mg twice daily (45).
Nonvalvular atrial fibrillation increases the risk of cerebral infarct 5-fold over patients in sinus rhythm and is the leading source of embolism in patients with ischemic stroke of cardiac origin. The frequency of permanent nonvalvular atrial fibrillation ranged from 10% to 20% in patients with ischemia involving the thalamus and the midbrain (10; 48; 46).
Currently, anticoagulation remains the optimal treatment choice for secondary stroke prevention in patients with atrial fibrillation, regardless of its pattern (45). The updated American Heart Association guidelines for secondary stroke prevention recommend anticoagulation with new oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) over vitamin K antagonists for patients with atrial fibrillation and either ischemic stroke or transient ischemic attack who do not have moderate to severe mitral stenosis or a mechanical heart valve. Anticoagulation with a vitamin K antagonist with an INR target of 3.0 is indicated in patients with mechanical heart valves and either atrial fibrillation or sinus rhythm.
The major differential diagnosis of thalamic and midbrain infarctions is limited to thalamic or midbrain hemorrhages. Studies have shown that it is extremely difficult to distinguish, by the initial neurologic presentation, thalamic hemorrhages from thalamic infarctions (91). Because of treatment implications, hemorrhages must immediately be distinguished from infarction with an early, unenhanced CT scan. Other vascular lesions such as basilar-tip or P1 segment aneurysms and arteriovenous malformations may mimic midbrain and thalamic infarctions. In the young patient, migraine is an important cause of posterior cerebral artery territory ischemia. Furthermore, unilateral and bilateral posterior cerebral artery territory infarctions can result as a consequence of a mass lesion in and around the thalamus and midbrain. Acute metabolic conditions may mimic posterior cerebral artery distribution strokes. Brainstem cavernous malformation with repeated microhemorrhages may mimic lacunar strokes in the rostral brainstem and thalamus. Demyelinating processes may also mimic strokes in this region. The combination of contralateral hemiparesis, mild hemianopia, hemispatial neglect, and sensory loss or sensory inattention may present a picture similar to a middle cerebral territory infarction (19). Brainstem findings such as ophthalmic signs and subtle posterior hemispheric cortical signs related to inferior parietal lobe or temporal lobe problems may allow distinction between posterior cerebral artery territory and middle cerebral artery territory infarction.
The acute evaluation of patients with thalamic or midbrain infarctions or suspected infarction begins with an unenhanced CT scan to rule out hemorrhage. It should be realized, however, that patients with paramedian thalamic infarctions may present in stupor and coma and, thus, require the proper workup to evaluate metabolic, toxic, or other etiologies of unresponsiveness. Because of its superior sensitivity, brain MRI--with diffusion-weighted sequences, in particular--is an extremely important study to localize ischemia on the thalamus (12; 102). In the case of midbrain infarcts, it is useful to keep in mind that 1.5 T brain MRI on day one may be unable to reveal changes in weighted images in patients with brainstem strokes, the so-called invisible brainstem infarcts. In fact, in a retrospective study of 221 stroke patients, 17% of brainstem infarcts (mainly in the dorsolateral medulla) were not visible on diffusion-weighted MRI sequences on day 1, but all were visible on subsequent MRI on the third or fourth day after stroke onset. The invisible lesions had a mean size of 2.7 mm2, were located in the dorsolateral medulla, and sensory disturbance was the main clinical manifestation (98).
Other routine studies are obtained on admission, including a 12-lead ECG and standard blood tests. The next set of tests is geared toward investigation of the heart or vascular system as a potential source of embolus.
Transthoracic echocardiography is obtained in those patients with clinical indications for heart disease and in all patients younger than 45 years of age with otherwise unexplained focal ischemia. We reserve transesophageal echocardiography for selected patients in whom a high clinical suspicion has not demonstrated a potential cardiac source or in whom technical problems prohibit good evaluation of the heart through a transthoracic procedure.
Digital subtraction cerebral angiography is used in selective cases in which a potential surgical or interventional treatment is being contemplated. CT angiography will also delineate other potential etiologies such as vertebral artery dissection as a cause for embolus. Extensive cardiac and arterial examination must be carried out in these patients using the same techniques as anterior territory infarctions in order to determine the mechanism of infarction. The role of extracranial artery disease may be underestimated in the subgroup of patients with posterior circulation strokes. Finally, hematologic disorders such as polycythemia, sickle cell anemia, thrombocytosis, and other prothrombotic states including the antiphospholipid antibody syndrome should be considered as potential causes of infarction in the young patients.
The rationale for management of the acute phase of vertebrobasilar infarcts includes measures to restore the circulation and arrest the pathological processes, physical therapy and rehabilitation to help cope with existing neurologic deficits, and measures to prevent recurrence and medical complications of stroke. First, measures toward securing a clear airway and establishing adequate breathing and circulation should be implemented. Impairment of cerebral autoregulation occurs during the acute phase of ischemic stroke, and overaggressive blood pressure reduction may decrease cerebral perfusion pressure. In the acute setting of cerebral infarct, treatment of arterial hypertension must be judicious in order to maintain adequate cerebral blood flow.
In highly selected patients with cerebral infarct, intravenous thrombolysis with recombinant tissue plasminogen activator has been found to be beneficial when administered within three hours after the onset of ischemia. In this time window, systemic thrombolysis has achieved a 33% reduction in disability at three months with a 6.4% rate of intracerebral hemorrhage (69). Although intravenous thrombolysis should be delivered as soon as possible in eligible patients, the time window has now been extended to up to 4.5 hours, based on benefits observed in two trials, the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry (SIST-ISTR) and the Third European Co-operative Acute Stroke Study (ECASS III) (27).
Local direct delivery of a thrombolytic agent has been thought to be the appropriate route in vertebrobasilar thrombosis, which is often associated with a high mortality rate in patients treated with standard therapy that includes systemic anticoagulation. Vessel recanalization occurred in two thirds of patients who had intra-arterial thrombolysis in the posterior circulation, whereas 6.5% and 12% of patients, respectively, experienced symptomatic hemorrhage and hemorrhagic transformation of the infarct (41).
The effectiveness of early anticoagulation with unfractionated heparin, low-molecular-weight heparin, or heparinoid in patients with infarcts in the vertebrobasilar circulation has not been established. Therefore, urgent anticoagulation in acute stroke is not currently recommended (78).
Neuroprotective pharmacological strategies directed toward limiting the neuronal injury resulting from ischemic brain cascade are still lacking. At present, there is no convincing clinical benefit of neuroprotective pharmacological therapy in the setting of acute ischemic stroke (78).
Moreover, fluid and electrolyte disturbances, hyperglycemia, fever, pneumonia, pulmonary embolism, deep vein thrombosis, decubitus ulcers, and urinary tract infection should be prevented through appropriate medical therapies.
Aspirin (160 to 300 mg initial dose) should be administered orally within 24 to 48 hours of stroke onset (78). Aspirin or other antiplatelet agents should be delayed for 24 hours in patients who have undergone thrombolysis. Intravenous antiplatelet agents, aspirin, or glycoprotein IIb/IIIa receptor blockers (abciximab, tirofiban, and eptifibatide) are not currently recommended in the acute phase of ischemic stroke (78).
Antiplatelet agents are the mainstay therapy in long-term secondary prevention in patients with noncardioembolic ischemic stroke. Currently, aspirin (50 to 325 mg/day), clopidogrel (75 mg/day), and extended-release dipyridamole (400 mg/day) plus aspirin (50 mg/day) are all acceptable options for secondary prevention. Choice of antiplatelet agent depends mainly on the risk factor profile, cost, tolerance, and comorbid illness.
Due to the high risk of stroke recurrence, long-term oral anticoagulation is indicated in patients with valvular and nonvalvular atrial fibrillation and prior stroke (target INR 2.5, range 2.0 to 3.0). As previously mentioned, the newer anticoagulants may be an option in patients with nonvalvular atrial fibrillation. Anticoagulation should preferably be initiated between 2 and 12 days of ischemic stroke, except in patients with larger infarcts or at high risk of bleeding, in which case a longer delay should be considered (45)
Thalamic pain syndrome is often resistant to medical treatment. Amitriptyline and lamotrigine are the only drugs that have proved to be effective in the treatment of central post-stroke pain in a placebo-controlled study (32). Minimally invasive treatment options may include transcranial stimulation, deep brain stimulation, and neuromodulation, which need to be properly evaluated in the setting of refractory central poststroke pain (99).
Heparin does not cross the placenta and is the anticoagulant of choice in treating patients with acute thromboembolic disorders during pregnancy. Warfarin and other coumarin agents cross the placenta and may be associated with teratogenic effects. The use of oral anticoagulants should always be avoided in the first trimester of pregnancy and in the last 3 weeks before term.
Patients in the acute or subacute phase of a stroke can have worsening deficit following a general anesthesia, particularly if care is not given to maintain adequate cerebral perfusion pressure and fluid status. Particular care should be taken to maintain systemic blood pressure, oxygenation, and intracranial blood flow during surgical procedures, especially in the elderly patient. Hypotensive agents, whether given therapeutically or for diagnostic procedures, should be administered with extreme caution. Oversedation in the elderly patient should be avoided. Severe anemia should be avoided. All of these factors exacerbate an acute ischemic infarction.
Steven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.See Profile
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