Hypertension

High blood pressure has consistently been reported as a major risk factor for ICH.^27–31 A meta-analysis and review by Areisen and colleagues estimated a crude odds ratio (OR) of 3.68 for hypertension and ICH in comparison to normotensive individuals.²⁴

Sturgeon and associates studied risk factors for ICH in a pooled cohort of the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular Health Study (CHS).²¹ The ARIC cohort was recruited from 1987 to 1989 and included 15,792 men and women aged 45 to 64 years at baseline from four U.S. communities. The CHS cohort was recruited from 1989 to 1993 and included 5888 men and women 65 years or older at baseline from a sampling of four U.S. communities. Follow-up was in excess of 263,489 person-years. In this prospective study assessing baseline risk factors and subsequent occurrence of ICH, age, African American ethnicity (versus whites), and hypertension were positively associated with the development of ICH. Participants with systolic blood pressure of 160 mm Hg or greater or diastolic blood pressure of 110 mm Hg or greater had 5.55 (95% confidence interval [CI], 3.07 to 10.0) times the rate of ICH as nonhypertensive individuals.

Spontaneous ICH occurs predominantly in deep locations in the brain. The most common location is the putamen, followed by the subcortical white matter, cerebellum, and thalamus. In 100 unselected patients, Kase and associates found putaminal hemorrhage in 34, lobar hemorrhage in 24, thalamic hemorrhage in 20, cerebellar hemorrhage in 7, and pontine hemorrhage in 6.³²

Hemorrhages in the caudate nucleus, putamen, thalamus, brainstem, and cerebellum occur in the distribution of small perforating arteries with a diameter of 50 to 200 µm. These deep penetrating arteries are small nonbranching end arteries that arise directly from much larger arteries (e.g., middle cerebral artery, anterior choroidal artery, anterior cerebral artery, posterior cerebral artery, posterior communicating artery, cerebellar arteries, basilar artery). Their small size and proximal position predispose them to the development of microatheroma and lipohyalinosis. Electron microscopic studies suggest that most bleeding occurs at or near the bifurcation of affected arteries, where prominent degeneration of the media and smooth muscles can be seen.³³

The concept of ICH arising from rupture of miliary microaneurysms was first proposed by Charcot and Bouchard in 1868.³⁴ Studies by Russell³⁵ and by Cole and Yates³⁶ confirmed the occurrence of microaneurysms in an anatomic distribution closely correlated to that of hypertensive hemorrhages and further defined the epidemiology of microaneurysms. Russell identified a strong association between miliary aneurysms 300 to 900 µm in diameter and hypertension. A few aneurysms were observed in his control group of normotensive individuals (diastolic blood pressure <110 mm Hg), but 84% of this group were 60 years or older. Cole and Yates observed that microaneurysms 50 to 2500 µm in diameter were uncommon in those younger than 50 years, even in hypertensive subjects. Therefore, both hypertension and age appear to be major factors in the formation of microaneurysms.

Fisher has further defined the pathologic process affecting small cerebral arteries in hypertension and coined the term lipohyalinosis to specify a destructive vascular process previously referred to by a variety of names, including “fibrinoid necrosis,” “angionecrosis,” and “hyaline arterionecrosis.”^37–39 In Fisher’s view, raised arterial pressure alters the walls of small cerebral arterioles 80 to 300 µm in diameter and leads to focal subintimal fibrinoid deposition associated with the presence of fat-filled macrophages. As the process advances, the integrity of the elastica and media is lost, and the artery dilates locally to form a microaneurysm 500 to 1500 µm in diameter. Extravasation of red blood cells takes place through the damaged walls, and hemosiderin-filled macrophages are seen through and beyond the adventitia. Fisher found lipohyalinosis to be, by virtue of occlusion of the vascular lumen, the cause of many lacunar infarcts. He could not confirm that microaneurysms were the source of massive ICH.

Cerebral Amyloid Angiopathy

β-Amyloid protein is a peptide consisting of 39 to 43 amino acids. It is formed after cleavage of the amyloid precursor protein, a transmembranous protein of unknown function, by β- and γ-secretases.

The characteristic feature of cerebral amyloid angiopathy (CAA) is the deposition of β-amyloid protein in the media and adventitia of small cortical and leptomeningeal arteries.⁴⁰ The incidence of CAA rises steeply after the age of 70 and reportedly ranges from 23% to 48% in the 8th decade, from 37% to 46% in the 9th decade, and from 57% to 58% in the 10th decade.⁴⁰ The most significant feature of CAA is the presence of multiple hemorrhages in unusual locations in the absence of hypertension.⁴¹ Vice versa, hypertension is present in only a minority of patients. Hematomas are mostly subcortical or lobar and are more frequently found in the occipital and parietal lobes. A distinct feature, in sharp contrast to nonamyloid ICH, is the multiplicity of hemorrhages over time and location. As for amyloid angiopathy in other locations in the body, the involved vessels exhibit Congo red birefringence in polarized light.⁴¹ Features of vessels with CAA include a severe degree of amyloid deposition and coexistent fibrinoid necrosis.⁴² Apolipoprotein E ε3/4 and ε4/4 seem to be associated with more severe forms of CAA, and severe degrees of CAA were associated with ICH. The annual risk for recurrent hemorrhage was found to be 10.5%.¹⁶

Anticoagulant Therapy

The incidence of ICH in patients taking warfarin after myocardial infarction is 1% per year.⁴³ Sixty-one percent of ICHs occur in the first 6 months of anticoagulation therapy.⁴⁴ Long-term anticoagulation therapy increases the risk for ICH 8- to 11-fold.⁴⁵

The mortality rate of spontaneous ICH is as high as 67% in patients receiving oral anticoagulant therapy (OAT).^45–47 The incidence of OAT-related ICH (OAT-ICH) is expected to increase in the coming years as a result of an anticipated rise in the incidence of atrial fibrillation attributable to an aging population.

A number of factors contribute to the increased risk for ICH in this group of patients, including advanced age, previous cerebrovascular disease, hypertension, and concomitant use of aspirin.^32,43 In the Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis (WASID) trial,⁴⁷ which compared the effectiveness of aspirin (1300 mg/day) and warfarin (target international normalized ratio, 2.0 to 3.0) in preventing strokes in patients with transient ischemic attack or stroke caused by angiographically verified 50% to 99% stenosis of a major intracranial artery, major hemorrhage occurred in 3.2% of the aspirin group and 8.3% of the warfarin group. The study was terminated early because of a statistically significant higher rate of bleeding in the warfarin group and no statistically significant benefit in the primary end point of the study. In a review of eight placebo-controlled clinical trials for the prevention of stroke, Mayo and colleagues found that the risk for hemorrhagic stroke was 0.7% in 2981 patients treated with aspirin versus 0.37% in 2187 patients receiving placebo.⁴⁸

ICH during treatment with heparin is rare and occurs mostly in patients being treated for acute embolic cerebral infarction and uncontrolled hypertension. In most patients, the activated partial thromboplastin time is excessively prolonged.^49,50

The efficacy of fibrinolytic agents in the treatment of myocardial infarction is well known. ICH has been reported in 0.4% to 1.3% of patients with acute myocardial infarction treated with the single-chain tissue plasminogen activator (t-PA) alteplase.⁵¹ Thrombolysis in acute ischemic stroke increases the risk for severe, life-threatening hemorrhagic complications by up to 10-fold in comparison to controls. Intravenous t-PA was used in two studies, the European Cooperative Acute Stroke Study (ECASS)⁵² and the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study,⁵³ with a therapeutic window of 6 and 3 hours, respectively. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group observed 2 patients (0.6%) with symptomatic and 1 patient (0.3%) with fatal hemorrhage in the placebo group (n = 312) and 20 patients (6.4%) with symptomatic and 9 patients (2.9%) with fatal hemorrhage in the recombinant tissue plasminogen activator (rt-PA) group (n = 312).⁵³ In both ECASS 1 and 2, rt-PA increased the risk for parenchymal hematoma (OR, 3.0 and 4.2).^52,54 However, the functional outcome at 3 months was better in the t-PA–treated group. Experimental focal cerebral ischemia causes a significant loss of the basal lamina components of cerebral microvessels.⁵⁵ The mechanisms for this microvascular damage may include degradation of plasmin-generated laminin, activation of matrix metalloproteinases, transmigration of leukocytes through the vessel wall, and other processes. This loss in vessel wall integrity is associated with the development of petechial hemorrhage. Revascularization, coupled with hypertension, may lead to life-threatening hemorrhagic complications.

The pathophysiology of ICH in patients maintained on a regimen of anticoagulation therapy is not well known, but various factors have been hypothesized. Hart and colleagues theorized that the use of OAT merely unmasks intracerebral bleeding that would otherwise remain asymptomatic, especially in patients with underlying hypertension or cerebrovascular disease.⁵⁶ This hypothesis is supported by the fact that gradient echo MRI indicates that microbleeding can be found even in neurologically normal individuals and is strongly associated with increased age and hypertension.⁵⁷ The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) and the European Atrial Fibrillation Trial (EAFT) indicated that patients with primary underlying cerebrovascular disease had a remarkably higher risk for OAT-ICH.^58–60 Furthermore, the presence of white matter lesions, so-called leukoaraiosis, is an independent predictor of spontaneous ICH.⁶¹ Therefore, the underlying mechanism of spontaneous ICH and OAT-ICH may be the same, with OAT acting as an exacerbating factor. This may also explain why the distribution of locations in the brain where OAT-ICH occurs is no different from that seen in patients with spontaneous ICH.^46,47,62

OAT may also cause ICH directly. This is supported by the observation that higher intensities of anticoagulation clearly increase the risk for OAT-ICH.^{46,47,63–65} Oral anticoagulants interfere with the synthesis of vitamin K–dependent clotting factors, thereby resulting in low levels of factors VII, IX, and X and prothrombin. It is possible that adequate levels and functional forms of these clotting factors are essential to counteract the stress placed on blood vessels as part of normal daily activities and to prevent bleeding.^66,67

The dynamics of hematoma expansion in OAT-ICH remain to be firmly elucidated. Because of persistent coagulopathy, hematoma expansion in OAT-ICH may be more common and occur over a longer time frame than seen with spontaneous ICH. In a retrospective study of 47 patients with OAT-ICH, hematoma expansion was found in 28% of those evaluated within 24 hours of onset.⁶⁸ In another study, hematoma expansion up to the seventh day was found in 16% (9/57) of patients who were not receiving OAT versus 54% (7/13) of those who were.⁶⁹

Although the evolution of hematomas in patients managed with anticoagulation therapy is protracted, their hematomas are about twice the size of those in patients not receiving anticoagulation therapy, and their mortality rate increases to 60% to 65%.⁴³

Drug Abuse, Alcohol, and Smoking

Secondary Deterioration

A third to a fourth of the patients who are initially alert deteriorate in their level of consciousness within the first 24 hours.^93,94 Rather than the initial clinical signs, the most accurate predictor is large hematoma volume and ventricular extension.⁹⁴ Consequently, these patients need to be very closely monitored during the first 24 hours, especially if they are still awake and alert despite large hematoma volume. Expansion of the hematoma is the most common cause of neurological deterioration and death^93,94 within the first 3 hours after the ictus. Progression of the mass effect secondary to edema can essentially occur within two distinct time intervals: early within the first 2 days and late within the second and third weeks.⁹⁵

Baseline laboratory studies should essentially detect coagulopathies so that they can be treated accordingly. Therefore, these studies include a complete blood count, prothrombin time, partial thromboplastin time, and liver and renal function tests, as well as serum glucose, electrocardiography, and chest radiography.

The initial radiologic work-up consists of a plain CT scan of the brain. It is fast and easy to interpret. The location and size of the hematoma and the presence or absence of a mass effect, perilesional edema, and ventricular extension can be depicted (i.e., all the imaging criteria that are important in the acute phase to decide on a management plan). Contrast enhancement can offer the possibility of diagnosing associated abnormalities such as AVMs, aneurysms, and tumors, but this depends on the size of the masking blood clot. Blood on a CT scan is usually seen as hyperdense signal within 4 hours. Severely hemodiluted or anemic patients with hematocrits below 30, however, can show isodense to hypodense lesions. In patients with acute bleeding caused by ICH, MRI would not provide more useful information and is in fact frequently a source of confusion because of the variable interpretation of a blood clot producing signal inhomogeneities. After about 7 to 10 days, the high attenuation values of the hematoma start decreasing peripherally. Depending on its size, the entire hematoma may become isodense in 2 to 3 weeks and resolve completely to an area of decreased density within 2 months. Occasionally, a resolving hematoma may give the appearance of ring enhancement because of either increased vascularity at the periphery or disruption of the blood-brain barrier.

MRI, although superior in resolution and anatomic and functional detail, as already alluded to, is rarely instrumental in the acute evaluation of patients with ICH. The presence of blood and its confusing signal characteristics can mask an underlying structural lesion. MRI, however, often reveals associated lesions that may not be detected with CT. Thus, MRI in the acute setting should be reserved for highly atypical cases in which the clinical findings or the CT studies are unusual.

Putaminal Hemorrhage

Putaminal hemorrhage is the most common form of ICH and can be manifested in different ways, depending on the size and extent of the hematoma. Initially, there is an acute onset of headaches. However, these headaches are different from the thunderclap type noted in patients with SAH. They are soon followed by a gradual progression of focal neurological signs and, depending on the overall size, by a worsening level of consciousness. A marked deficit from the beginning is unusual. Common neurological findings are hemiparesis, hemisensory syndrome, homonymous hemianopia, horizontal gaze palsy, and either aphasia (dominant hemisphere) or hemineglect (nondominant hemisphere).^37,96 The pronounced neurological deficits associated with coma suggest large hematomas and carry a poor prognosis. Intraventricular extension of the hemorrhage is a sign of extensive parenchymal dissection or destruction and a bad prognosticator (Fig. 358-1).^97,98 In contrast, patients who are alert and have only limited motor deficits, normal extraocular movements, full visual fields, and a hematoma that does not extend laterally or upward out of the putaminal region fare better. This has been ascribed to reversible compression of capsular fibers as opposed to destruction.⁹⁷

FIGURE 358-1 Extension of a primarily putaminal hemorrhage into the rest of the basal ganglia, internal capsule, thalamus, and ventricle was evident at autopsy.

Thalamic Hemorrhage

Thalamic hemorrhages account for 10% to 15% of all ICHs (Fig. 358-2).^37,99 The bleeding originates from thalamic perforators of the posterior cerebral arteries and may extend laterally into the internal capsule, medially into the ventricles, superiorly into the corona radiata, and inferiorly into subthalamus and midbrain.¹⁰⁰

FIGURE 358-2 This medium-sized hypertensive thalamic hemorrhage, which spared the capsular fibers laterally, is well confined.

The signs and symptoms depend on the size and pattern of extension of the hematoma. In contrast to putaminal hemorrhages, thalamic bleeding will instantly result in gross neurological deficits with sensorimotor loss, a higher likelihood of vomiting, variable presence of headaches, and occasionally coma.^6,99,101 The ocular findings in patients with thalamic lesions are pathognomonic: upward gaze palsy, convergence gaze, miotic unreactive pupils because of compression of the midbrain tectum, and less commonly, retraction nystagmus on upward gaze and skew deviation (vertical misalignment of the eyes because of abnormal prenuclear vestibular input to the ocular motor nuclei).^6,37,99,101

Different characteristics of the so-called thalamic syndrome had already been described at the beginning of the 19th century by Dejerine and Roussy,¹⁰² followed by Lhermitte in 1925¹⁰³ and Baudouin and associates in 1930.¹⁰⁴ Fisher in 1959 emphasized language disorders and disturbances in ocular motility.¹⁰⁵

Kumral and colleagues presented an excellent study from 1995 based on 100 patients and provided a very detailed correlation of different symptoms (sensorimotor, oculomotor, and neurobehavioral) to four defined topographic types of thalamic hemorrhage¹⁰⁶:

Lobar Hemorrhage

Lobar cerebral hemorrhages constitute a separate group of supratentorial hemorrhages with heterogeneous etiology and include AVMs, trauma, anticoagulation therapy, and in the elderly, amyloidosis of the cerebral vessels.

Lobar hemorrhages usually occur in the subcortical white matter and have a predilection for the parietal, temporal, and occipital lobes.^107,108 In Ropper and Davis’ series of 26 patients with lobar hemorrhages, 11 (42%) were within the occipital lobe, 7 (27%) were in the temporal lobe, 4 (15%) were in the frontal lobe (Fig. 358-3), and 3 (12%) were in the parietal lobe.¹⁰⁸ The frequent occurrence of lobar hemorrhages in the parieto-occipital lobes has been attributed to the higher concentration of intracerebral microaneurysms reported in anatomic studies.¹⁰⁹

FIGURE 358-3 An extensive medial frontal intracerebral hematoma secondary to amyloid angiopathy caused this patient’s death.

Hypertension as a cause of lobar hemorrhage is unusual.^107,108,110 Only 31% of the patients reported by Ropper and Davis had chronic hypertension.¹⁰⁸ Kase and associates reported elevated blood pressure in only 50% of their patients on admission.¹⁰⁷ In a series reported by Broderick and colleagues, hypertension contributed almost equally to lobar and deep hemispheric, cerebellar, and pontine hemorrhages.¹⁹ Other causes of lobar hemorrhages are AVMs, tumors, anticoagulation therapy, blood dyscrasias, and CAA.^41,111,112 In a significant number of cases, no definite cause can be found.¹⁰⁷ CAA is probably the most common cause in nonhypertensive patients 70 years and older.

The clinical manifestations of lobar ICH depend on the location and size of the hematoma.¹⁰⁸ When compared with other forms of ICH, the frequency of associated hypertension and coma on admission is lower. The low incidence of coma is probably related to the peripheral location of the hematoma.¹⁰⁸ Most patients complain of headache and vomiting. Seizures are also frequent.^22,107,113 Hemiparesis is seldom pronounced.

The prognosis of patients with lobar ICH is relatively better than that of patients with other forms of ICH. Mortality rates range from 11% to 29%.^107,108,114 Functional outcome in survivors also tends to be better.¹¹⁴ In their series of 22 patients, Kase and coauthors reported good outcomes in those with hematoma volumes of less than 20 cm³.¹⁰⁷ Seventy percent survived after the surgical removal of hematomas that were 20 to 60 cm³. No patient with a hematoma volume greater than 60 cm³ survived.

Caudate Hemorrhage

Caudate hematomas represent approximately 5% to 7% of cases of ICH.⁹⁸ The most common cause of caudate hemorrhage has been arterial hypertension.^98,115–119

The head of the caudate nucleus receives its blood supply from Heubner’s artery and the anterior lenticulostriate and lateral lenticulostriate arteries, which also supply the anterior internal capsule and putamen.¹¹⁹ A rupture in these arteries causes parenchymal hemorrhage.

Patients have an abrupt headache and vomiting, followed by a decreased level of consciousness. They are usually disoriented, with evidence of neck stiffness.⁹⁸ Occasional patients suffer seizures and exhibit horizontal gaze paresis. On CT, ventricular extension of the hematoma into the frontal horn with secondary hydrocephalus is common. Occasionally, the hemorrhage extends into the anterior portion of the thalamus. Such patients have transient, but significant short-term memory deficits.⁹⁷ In Stein and colleagues’ series of 8 patients, most recovered fully with no significant neurological deficits.⁹⁸ Weisberg also reported a small series of caudate hemorrhages, but the outcome in this series was poor, and stupor and a massive amount of intraventricular hemorrhage were associated with poor outcome.¹¹⁵ Liliang and coworkers looked at clinical data from 36 consecutive patients with hypertensive caudate hemorrhage.¹²⁰ In this relatively large study, multivariate analysis and stepwise logistic regression revealed that hydrocephalus was the only independent prognostic factor for a poor outcome (P < .001).

Cerebellar Hemorrhage

The frequency of cerebellar hemorrhage ranges from 5% to 10%.^{37,49,121,122} One of the major differences from supratentorial hemorrhages is the entirely different prognosis once coma has occurred. If the diagnosis is made early and surgical intervention is prompt, coma is reversible after a cerebellar hemorrhage.^{109,123–126} A very recent study by Smajlović and colleagues on the 30-day prognosis and risk factors in 352 patients treated for ICH confirmed once again that when compared with all other ICHs, cerebellar hematomas had the best outcome after the first month; brainstem and multilobar ICHs had the worst.⁸⁷ The dentate nuclei are the most common substrate. The hematoma extends into the hemispheric white matter and often into the fourth ventricle, where it causes either brainstem compression or direct invasion (Fig. 358-4). Rarely, cerebellar hemorrhage involves only the vermis. Hypertension and anticoagulation are the two most important causative factors for cerebellar hemorrhage.^123,127

FIGURE 358-4 This extensive hypertensive cerebellar hemisphere hematoma started in the deep nuclei and extended. Brainstem compression, hydrocephalus, and death ensued.

Patients usually have headache and an inability to walk or stand. Vomiting is common and may or may not be associated with headache.^123,127 Other symptoms include dizziness, neck stiffness, dysarthria, tinnitus, and singultus. Loss of consciousness at the onset is rare. On admission to the hospital, about a third of patients are obtunded.¹²³ The early physical signs are appendicular or truncal ataxia, dysarthria, ipsilateral horizontal gaze palsy, peripheral facial palsy, nystagmus, and sixth nerve palsy. At least two of the three characteristic clinical signs—appendicular ataxia, ipsilateral gaze palsy, and peripheral facial palsy—were present in 73% of the patients reported by Ott and coworkers.¹²³ In two patients with cerebellar hematomas and a peripheral facial nerve palsy on the hematoma side, Messert observed spontaneous unilateral eye closure on the contralateral side. In an effort to compensate for gaze dissociations and extraocular motor palsies, the eye on the noninvolved side of the face was closed. In other words, the open eye is on the hematoma side.¹²⁸

The clinical course of cerebellar hemorrhage is unpredictable. These patients, whether alert or lethargic on admission, can deteriorate quickly to coma and die with no warning.^123,129 Although the prognosis and final outcome are largely related to the patient’s initial preoperative condition, even comatose patients can make a good recovery.¹²⁹ Little and colleagues reported on two groups of patients with cerebellar hemorrhage.¹³⁰ The first group had an abrupt onset, progressive course, and low level of consciousness. CT in this group of patients, who required surgery, showed cerebellar hematomas 3 cm or greater in diameter, obstructive hydrocephalus, and extension of hemorrhage into the fourth ventricle.^131,132 The second group of patients was awake and stable and had hematomas smaller than 3 cm in diameter. They were treated medically, with good outcomes.¹³⁰

Brainstem Hemorrhage

The pons is the most common location for nonvascular causes of ICH in the brainstem. Spontaneous nontraumatic midbrain and medullary hematomas are comparably rare. The first to evaluate a large number of pontine hemorrhages was Attwater in 1911.¹³³ After performing autopsies on 77 subjects with pontine hemorrhages, Attwater was able to differentiate between primary and secondary brainstem hemorrhages. He attributed some pontine hemorrhages to elevated ICP. Several years later in a monograph, Duret also described this phenomenon, which now bears his name as an eponym.¹³⁴ Under the so-called Duret hemorrhage, we understand a characteristic slit-like bleeding in the upper brainstem (mesencephalon and pons).¹³⁵ It needs to be mentioned, however, that this does not automatically imply spontaneous ICH as a cause. As Parizel and colleagues pointed out, they also occur in victims of craniocerebral trauma.¹³⁵

The location of a pontine hematoma depends on the causative perforating artery, which can be the basilar paramedian perforators or the short or long circumferential branches. Thus, these hematomas can be divided into paramedian, basal pontine, and lateral tegmental hemorrhages.

In an autopsy review of 30 patients with pontine hemorrhages among 511 cases of ICH at Boston City Hospital, two thirds of the patients were comatose on initial evaluation and had massive hemorrhages that extended into the midbrain or fourth ventricle. Within 48 hours, 78% of the patients died. Fisher suggested that primary hemorrhage, by virtue of a pressure effect, causes the surrounding vessels to rupture and initiates a cascade of gradual enlargement of the hematoma.¹³⁶ The bleeding in hypertensive patients was attributed to leakage from tiny penetrating vessels damaged by lipohyalinosis and containing small microaneurysms.^49,109,136

Rupture of the paramedian perforating branches of the basilar artery is thought to be the cause of massive pontine hematomas (Fig. 358-5). The lesion usually begins in the midpons at the junction of the tegmentum and basis pontis and extends along the longitudinal axis of the brainstem into the midbrain, middle cerebellar peduncle, or the fourth ventricle.¹²¹

FIGURE 358-5 Large hypertensive pontine hematoma expanding and distorting the pons.

The clinical course of a hypertensive patient is typically one of rapid onset of coma. Awake patients may become symptomatic with headache, vomiting, and focal pontine signs such as facial or limb numbness, deafness, diplopia, quadriparesis, paraparesis, or hemiparesis. Occasionally, seizure (which can be a true convulsive episode), spasmodic decerebrate posturing, or violent shivering associated with autonomic dysfunction and rapidly developing hypothermia is reported. On examination, patients have an abnormal breathing pattern, apnea, cranial nerve and long-tract deficits, occasional decerebrate posturing, and multiple oculomotor findings.^121,137,138 Weakness of the pontine and bulbar musculature is invariably associated with large median pontine hemorrhages, but it is seldom appreciated because of the depressed level of consciousness.

Pinpoint (miotic) reactive pupils are a hallmark of pontine lesions. Among the possible various ophthalmic findings in patients with pontine hemorrhage are absent horizontal gaze movement when the paramedian pontine reticular formation is bilaterally damaged, one-and-a-half syndrome after a unilateral pontine tegmental or abducens nucleus lesion that results in a horizontal conjugate gaze palsy in one direction and internuclear ophthalmoplegia in the other,¹³⁹ and ocular bobbing. Fisher was the first to describe brisk, conjugate downward eye movements, followed by a slower “bobbing” back up to the primary position.¹⁴⁰

Massive pontine hemorrhages are always fatal, but death may not be instantaneous.¹³⁷ Some patients with medium-sized hematomas and most patients with small basal or lateral tegmental hematomas survive, but with various degrees of residual neurological deficits.

Brain Edema after Intracerebral Hemorrhage

One of the major challenges after primary ICH is the development of perihematomal edema, which forms rapidly after the ICH¹⁴¹ and contributes to a documented increase in perihematomal volume by approximately 75%. The causes of this perihematomal area of edema and cell death are not known decisively. Experimental data indicate that the presence of whole blood, but not intact red blood cells, induces the formation of edema. As red blood cells lyse, however, edema is observed, and the volume of the edema correlates with the volume of the lysed red blood cells. Hemoglobin and its degradation products induce edema formation and accumulation of reactive glial cells at the site of delivery.¹⁴² There are three distinct phases of edema formation after ICH. In the first hours after ICH, retraction of the clot begins. Intact red blood cells within the hematoma area have not been found to contribute to edema formation. As the coagulation cascade becomes activated over the following 24 to 48 hours, however, thrombin becomes activated and promotes edema formation and further disruption of the integrity of the blood-brain barrier.¹⁴³ The third phase of edema formation starts when red blood cells in the hematoma begin to lyse and hemoglobin and its degradation products are deposited into the brain parenchyma, thus initiating a potent inflammatory reaction.¹⁴⁴

In an observational study, Wu and colleagues studied 17 patients with spontaneous ICH treated medically.¹⁴⁵ Hematoma size and absolute and relative brain edema volumes were measured. Hematoma enlargement occurred in 4 of the 17 ICH patients (24%) within the first 24 hours. Hematoma sizes were reduced significantly at day 10 (P < .05) because of clot lysis. However, both absolute and relative brain edema increased gradually with time (P < .01). These results suggest that delayed brain edema after ICH may result from hematoma lysis. The authors concluded that reducing early hematoma growth and limiting clot lysis–induced brain toxicity could be potential therapies for ICH.

Steroids

The use of steroids in patients with ICH is controversial. Batjer and associates used steroids (4 mg dexamethasone intravenously every 6 hours) in their protocol.¹⁴⁸ The rationale for using steroids for the treatment of ICH is that they might lessen the damaging effects of cerebral edema, increased ICP, a disrupted blood-brain barrier, and stress. The first randomized study included 40 patients with ICH but showed no statistical difference in outcome associated with the use of steroids.¹⁴⁹ This study, however, lacked case uniformity and appropriate, relevant stratification. Therefore, a well-designed, randomized, placebo-controlled study was performed in 1987.¹⁵⁰ In their paper, Poungvarin and coworkers studied 93 patients 40 to 80 years old in a double-blind randomized design. Patients with documented primary supratentorial ICHs were randomly assigned to either dexamethasone (10 mg intravenously and then 5 mg every 6 hours) or placebo. The death rate at the 21st day was identical in both groups (dexamethasone versus placebo, 21 of 46 versus 21 of 47; P = .93). In contrast, the rate of complications (mostly infections and complications of diabetes) was 11 times higher in the dexamethasone group (P < .001). This led to early termination of the study.

Blood Pressure Management

The single most important factor in determining rapid expansion of an ICH is blood pressure. In studies of patients with hypertensive ICH, persistently elevated blood pressure increased the risk for hematoma progression.^151–153 In a retrospective review of 320 patients with hypertensive ICH, 10 showed rapid expansion of the hematoma on serial CT.¹⁵³ The consecutive scans were obtained an average of 1.7 and 48.9 hours after hemorrhage. Of the 10 patients with radiographic evidence of expansion, all had persistent hypertension, and half deteriorated neurologically. The average blood pressure in this group on admission was 179/110 mm Hg, and the average blood pressure recorded before deterioration was 190/121 mm Hg. The first 24 hours seems to be particularly critical. In a more recent retrospective study of 76 consecutive patients with hypertensive ICH, Ohwaki and colleagues observed that maximum systolic blood pressure was significantly associated with hematoma enlargement (P = .0074).¹⁵⁴ A target systolic blood pressure of 160 mm Hg or greater was significantly associated with hematoma enlargement when compared with a pressure of 150 mm Hg or less (P = .025).

The degree to which blood pressure should be controlled is controversial. Patients with a history of chronic hypertension have impaired autoregulation, and overzealous lowering of blood pressure can lower cerebral perfusion pressure and produce secondary ischemic damage, especially in those with a decreased level of consciousness, who may have elevated ICP. Some authors recommend lowering systolic blood pressure to less than 160 mm Hg¹⁵⁵; others recommend lowering it to normotensive levels but not below.¹⁵⁶ In a prospective, randomized trial of putaminal ICH in which craniotomy was compared with medical therapy, patients were initially treated with sodium nitroprusside (Nipride) to decrease systolic blood pressure by 25% during the first 24 hours. During the next 48 to 72 hours, blood pressure decreased to normotensive levels.¹⁴⁸ In this study, the mean admission systolic blood pressure was 234 mm Hg. Despite the tight control of blood pressure, the 6-month mortality rate was 77%. Because this study did not report the cause of death or the time of deterioration, it is difficult to determine whether the degree of blood pressure control was adequate.

In theory, there might be at least two conflicting trends in the immediate hours after ICH, namely, the development of perilesional microcirculatory insufficiency with a propensity to render the brain ischemic and, on the other hand, a propensity to rehemorrhage. The former would necessitate increased perfusion and the latter strict blood pressure control. Qureshi and colleagues looked at the rate of 24-hour blood pressure decline and mortality after spontaneous ICH.¹⁵⁷ One hundred five patients with ICH were included in this retrospective study. Logistic regression analysis showed that the rate of decline in blood pressure in the first 24 hours was an independent predictor of mortality but did not affect the functional outcome of survivors. More recently, The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) trial set out to answer the question about the optimal blood pressure range in the first 24 hours after ICH. This trial is a multicenter open-labeled pilot trial to determine the tolerability and safety of three escalating goals of antihypertensive therapy (110 to 140 mm Hg, 140 to 170 mm Hg, 170 to 210 mm Hg) for acute hypertension in 60 subjects with supratentorial ICH. The initial results of this trial were presented at the 2008 International Stroke Conference¹⁵⁸: “Aggressive systolic blood pressure reduction to 110-140 mmHg in the first 24 hours using intravenous nicardipine was well tolerated with a low risk of hematoma expansion, neurological deterioration and in-hospital mortality. The results favor pharmacological reduction of systolic blood pressure in patients with acute ICH.”

Experimental rat studies suggest that although transient alterations in blood flow occur within minutes of hemorrhage, the severe alterations in perihematomal microcirculation that cause ischemia are not maximal until 4 hours thereafter.^159,160 In addition, the formation of edema is not maximal until after 6 to 8 hours.¹⁶¹ However, the period associated with the maximal risk for progression of hemorrhage in the presence of persistent hypertension is 3 to 6 hours.^{23,153,162,163} Therefore, an argument can be made to reduce blood pressure dramatically during the first 4 hours after hemorrhage to decrease the risk for rehemorrhage and then to raise blood pressure slowly to perfuse ischemic areas.

The discussion whether an ischemic penumbra in ICH exists is ongoing. At present, a majority of researchers seem to favor that there is no ischemic penumbra, but rather a perilesional area with depressed metabolism (metabolic penumbra?) that can be detected with positron emission tomography,¹⁶⁴ an area of reduced metabolic demand as detected by diffusion- and perfusion-weighted MRI,¹⁶⁵ or only a perilesional area with no significant changes at all. This was suggested after sampling in eight dogs and serially measuring regional cerebral blood flow (CBF) with radiolabeled microspheres, cerebral oxygen extraction, the cerebral metabolic rate of oxygen consumption, glucose utilization, and lactate production.¹⁶⁶

The last entry to date demonstrated vasogenic edema and only a mild perfusion deficit above the threshold for ischemia in an MRI rat ICH model, thus making a perihematomal penumbra unlikely.¹⁶⁷ A prospective clinical study with perfusion-weighted MRI performed during the treatment of 18 ICH patients, however, confirmed the presence of a hypoperfused area around the ICH that disappeared completely after 1 week.¹⁶⁸ Similar results were obtained from a single-photon emission CT study that compared early uptake within hours of hemorrhage and 6 to 9 months postictally.¹⁶⁹ An interesting microdialysis study in 2006 revealed that the immediate zone around an evacuated ICH exhibits a similar biochemical pattern as the penumbra zone surrounding focal traumatic brain contusions.¹⁷⁰

Intracranial Pressure Management