Clinical Vignette

A 72-year-old woman with history of hypertension noticed tingling in the right arm. Within 30 minutes, her right leg buckled and she fell. Her husband helped her up and she was able to walk without support. She rested, but within an hour, she developed speech difficulties and more definite right-sided weakness.

She was brought to the emergency department (ED) and was noted to have mild right arm weakness and some word-finding difficulties. Her blood pressure was 140/80 mm Hg. She got up to go to the bathroom, walked approximately 10 ft, and collapsed on the floor. She was then globally aphasic, with left gaze deviation (i.e., paralysis of gaze to the right) and right hemiplegia. Within 10 minutes, she became gradually unresponsive.

She was intubated for airway protection and taken for brain CT scanning, which demonstrated a large left putaminal hemorrhage. Soon thereafter, she had bilaterally dilated fixed pupils. The vestibular-ocular reflexes were lost. Within another 10 minutes, she was determined brain dead.

The preceding vignette demonstrates the classic presentation of a primary intracerebral hemorrhage (ICH with a rapidly evolving focal neurologic deficit). Its progressively increasing size led to increased intracranial pressure with coma from downward herniation of the uncus onto the brainstem and ultimately irreversible neurologic damage. The only means to prevent ICH is appropriate therapy of its major risk factor, hypertension.

There are two forms of intrinsic cerebral hemorrhage, primary ICH, which has a predilection to affect the striatum, thalamus, midbrain, pons, and cerebellum, and subarachnoid hemorrhage (Chapter 57). ICH comprises approximately 10% of all strokes in the Caucasian population and up to 20% in the Asian population. Over the past several years, improved treatment of hypertension has decreased the number of patients experiencing ICH.

Hypertension is a major risk factor for intracerebral hemorrhages in patients between the ages of 40 and 70. A small proportion of intracerebral hemorrhages in patients older than age 60 years is not directly related to hypertension and is primarily caused by amyloid angiopathy. Furthermore, the increased use of oral anticoagulant therapy in the elderly population has led to higher rates of warfarin-associated ICH. Warfarin anticoagulation increases the risk of intracerebral hemorrhage fivefold, and some studies have estimated that 18% of intracerebral hemorrhages admitted to the hospital are related to its use. Of interest is that most bleeds in patients on warfarin occur when the INR is within the recommended therapeutic limits. Secondary, less common causes of intracerebral hemorrhages include primary and metastatic tumors of the brain and in younger individuals cerebral hemorrhage associated with underlying arterial venous malformation or cavernous angioma.

Pathophysiology of Hypertensisve Primary Ich

Intracranial hemorrhage is a rapidly evolving process that may progress over hours or days. The pressure effects of the initial hemorrhage lead to mechanical disruption and tearing of surrounding vessels with subsequent gradual expansion of the hematoma out from the original center. Rebleeding is the most feared early complication of ICH and occurs in approximately 40% of patients. Rebleeding usually occurs within the first 24 hours but, on occasion, has been reported up to a week later. The underlying pathological mechanism of primary hypertensive ICH is attributable to either the formation of miliary microaneurysms or primary arteriolar degeneration (lipohyalinosis and weakening of the blood vessel intima and media wall layers) (Fig. 58-1). The presence of miliary aneurysms is directly related to hypertension but is not necessarily the initial site of bleeding, and cases of hypertensive ICH outside the areas of microaneurysms have been noted. This suggests that degeneration of the arteriolar smooth muscle wall is likely an important factor in the evolution of ICH. Hypertensive intracerebral hemorrhages have a predilection to occur in the basal ganglia and the thalamus. The arterioles in these structures are likely more vulnerable to degenerative changes brought on by diffuse, large pressure pulses over time.

Figure 58-1 Hypertensive Intracerebral Hemorrhage: Pathogenesis.

Although hypertension is considered an important risk factor for ICH, studies are inconsistent in estimating the exact risk of ICH in hypertensive patients. It has been noted in some studies that up to 90% of patients with ICH have evidence of hypertension at the time of presentation. Other important risk factors include smoking, alcohol consumption, black race, and low total serum cholesterol levels. The latter is likely to be an anomaly of population studies. Patients with ICH and concomitantly low serum cholesterol levels tend to be older than age 80 years and, on average, have higher diastolic pressures. The effect of lower cholesterol levels, particularly LDL, on increasing the incidence of ICH is likely small and the mechanism remains unclear; whether it is causative or an epiphenomenon of another process warrants further investigation.

Clinical Presentation

Intraparenchymal hemorrhages vary in presentation depending on the site of the bleeding (Fig. 58-2). In approximately 60% of patients, neurologic symptoms develop gradually or stepwise over a period of hours. To some extent, the location and size of the hematoma predict clinical outcome.

Figure 58-2 Intracerebral Hemorrhage: Clinical Manifestations Related to Site.

Headache occurs at presentation in approximately 40% of patients with ICH. Less commonly, headache develops within a few days after the ictus. Intracerebral hemorrhages presenting with headache are often located at the brain surface or within the cerebellum. Depression in the level of consciousness and vomiting occur in 50% of patients, particularly those with large cerebellar bleeds. Seizures occur at onset in up to 10% and are seen most commonly with lobar bleeds in the anterior circulation. There are rare incidences of patients with deep hemorrhages having seizures. The subsequent risk for seizures in ICH patients is up to 29% for those with lobar hemorrhages but only 4% for those with deep hemorrhages. Other symptoms seen in association with ICH include low-grade fever without obvious infection, cardiac arrhythmias, and dysautonomia, especially with pontine bleeds. A description of some of the most common symptoms at different sites of ICH follows.

Secondary Intracerebral Hemorrhage

ICH not directly caused by hypertension is encountered with vascular malformations, hemorrhagic transformation of ischemic stroke, anticoagulants, as well as fibrinolytic agents or irreversible antiplatelet therapy (Box 58-1). Primary amyloid angiopathy is often the underlying cause of nonhypertensive lobar hemorrhage. Less common causes include primary and metastatic malignancies, sinus thrombosis with venous infarctions and bleeds, acquired or inherited coagulopathies, induced or autoimmune vasculitides and systemic granulomatous disorders, central infectious processes, and trauma (Box 58-2).

In most cases of ICH, especially when hypertension is absent, follow-up imaging studies are essential to investigate the possibilities of underlying predisposing pathology. Contrast-enhanced brain MRI scanning performed about 3 months later, after extravasated blood has been allowed to reabsorb, may uncover an underlying lesion initially obscured by the acute hematoma.

Occult vascular malformations were possibly the most underdiagnosed causes of lobar hemorrhages prior to CT and MRI scanning and were frequently missed by early angiography due to the presence of clot and mass effect on the brain. They were diagnosed only during surgical or pathologic specimen inspection after hematoma removal. The most common occult vascular lesions include small AVMs and cavernous angiomas (Fig. 58-3A–D).

Figure 58-3 Common Causes of Intracerebral Hemorrhage.

Hemorrhagic brain infarct (HBI), in contrast to primary intracranial hemorrhage, is a secondary phenomenon that occurs as a result of ischemic damage to both the brain parenchyma and the vessel wall distal to the site of occlusion. The vascular wall endothelium and the blood–brain barrier are subsequently damaged and leak with reperfusion as they no longer tolerate normal arterial pressure. Petechial bleeding and, at times, gross hemorrhage through the damaged vessel into the infracted area may be seen (Fig. 58-3E&F). It is estimated that petechial bleeding develops in more than 50% of patients with embolic infarcts. Although it is often implied that cardioembolic strokes are more likely to be associated with development of HBI, some investigators suggest that any large infarct, regardless of mechanism, is predisposed to such bleeding. The use of IV heparin or heparinoid for secondary stroke prevention also promotes the development of HBI. However, the presence of petechial hemorrhage without frank hematoma formation does not seem to worsen neurologic outcome.

Along with typical subarachnoid hemorrhage, aneurysmal rupture can, at times, cause intraparenchymal hematoma with focal neurologic signs (Fig. 58-4A&B). The location of the blood often hints to the site of the aneurysm. Lateral temporal lobe hematomas suggest MCA aneurysmal rupture while medially located bleeds are associated with carotid artery aneurysms. Frontal hematomas indicate anterior communicating artery aneurysm. Posterior communicating artery aneurysms cause thalamic hemorrhages, often with intraventricular extension.

Figure 58-4 Uncommon Causes of Intracerebral Hemorrhage.

Primary or metastatic brain tumors can lead to ICH (Box 58-3; Fig. 58-4C&D). A single small hemorrhage from a metastatic lesion, as can be seen with melanomas or hypernephromas, may be difficult to distinguish from primary ICH unless evidence of other lesions is identified. Other clues, such as an atypical cortical or subcortical location of the bleed, irregular margins, and unexpected contrast enhancement of the lesion must prompt further investigations to exclude systemic disorders. A detailed dermatologic examination may reveal irregularly pigmented lesions, suggesting melanoma, and ultrasound or body CT scan may uncover a renal tumor.

Amyloid Angiopathy

Amyloid angiopathy is an uncommon arteriolar and venular vasculopathy with hyaline eosinophilic depositions and subsequent weakness of the vessel wall and microaneurysm formation. It is the cause of ICH in 10% of patients age 60 years or older and 20% in patients older than age 70 years. The usual areas of ICH are lobar, both in the subcortical area and the cortex, routinely sparing the basal ganglia, the thalamus, and the brainstem. In the Dutch and Icelandic familial forms of amyloid angiopathy, the mean age for ICH occurrence is as young as 30 years of age. In contrast to the nonfamilial form, ICH in the familial forms of amyloid angiopathy may also affect the brainstem and the cerebellum along with the more typical cortical and subcortical loci.

MRI evidence of previous asymptomatic small hemorrhages is encountered in many patients (Fig. 58-5). However, cases of rapidly successive, small intracranial hemorrhages within a short time period with progressive disability and death have been described. The presence of subcortical white matter disease seen on CT or MRI scans may be a reflection of chronic ischemia from amyloid-laden arterioles. These changes may suggest a higher risk for future hemorrhages and therefore a more cautionary approach to anticoagulation or the potential use of thrombolytic agents is advised.

Figure 58-5 Amyloid Angiopathy.

Management and Prognosis

Many ICH patients initially presenting with a modest neurologic deficit may rapidly worsen during the first 24 hours. Serial CT scans demonstrate that ICH can recur or worsen even up to 7 days after the ictus. As in the first vignette of this chapter, recurrent or progressive ICH is often rapid and fatal, particularly if the hemorrhage extends to the ventricular system and produces acute hydrocephalus. Sudden volume increase, and mass effect from enlarging ICH compromises the surrounding microvasculature and leads to both mechanical and ischemic tissue damage to the surrounding brain structures. Tissue shifts compounded by evolving vasogenic cerebral edema over 24 hours may lead to transtentorial herniation. Excessive increases in blood pressure, concomitant infection, fever, hyperglycemia or hypoglycemia, and other medical conditions all worsen outcome. The initial management of ICH, after ensuring adequate ventilation and hemodynamic stability, involves correcting coagulopathies, treating hypertension, and addressing the possibility of increased intracranial pressure. In patients with intraventricular blood and early hydrocephalus, placement of a temporary external drain should be considered. Beyond these basics principles, the best treatment of ICH remains unclear and quite variable from center to center and in different countries. Although some advocate invasive techniques for hematoma evacuation, others rely mostly on medical treatment and supportive care.

At present, there are no strict recommendations for blood pressure control in the setting of primary hypertensive ICH. There is evidence to indicate that elevated BP greater than 210 mm Hg is associated with recurrent or expanding ICH but lower BP measurement may not be. Indeed, far too aggressive lowering of BP may lead to a potential drop in cerebral perfusion pressure (CPP), especially in the presence of elevated ICP, and cause secondary ischemia with worsening outcomes. The present guidelines set by the American Heart Association/American Stroke Association council suggest definite treatment of SBP above 210 mm Hg or of MAP of 150 mm Hg with a continuous infusion of a titratable IV medication such as nicardipine, a beta-blocker, or nitroprusside if needed. For measurements below this level but above 180 mm Hg systolic or MAP of 130 mm Hg and in the presence of suspected ICP, a decrease of BP to keep the CPP above 60 mm Hg is recommended. If ICP is not present, careful monitoring with an attempt to avoid hypertensive episodes is suggested. It is often useful to obtain patients’ prior BP measurements from outpatient records or from primary care providers if available. This may help guide blood pressure control by providing a sense of where each individual patient’s BP range of cerebral autoregulation was before the ICH.

Surgical Trial in Intracerebral Hemorrhage (STICH, 2005) was a multicenter international prospective randomized trial to compare early surgery with initial conservative treatment for patients with spontaneous supratentorial intracerebral hemorrhage. In this study, no overall benefit from early surgery when compared to conservative treatment could be demonstrated. Surgery demonstrated slightly better outcome (26.1% vs. 23.8%), but survival rates appeared to be similar in surgically and medically treated patients. Subgroup analysis suggested that large hemorrhages, older age, and blood in the ventricles predicted poor outcome. Also the subgroup with superficial bleeds and no intraventricular hemorrhage tended to fare better with surgery than with medical treatment alone (49% vs. 37%). The outcome from surgery likely depends on several factors, including the fact that deep-seated basal ganglia or thalamic hemorrhages are difficult to evacuate without disrupting surrounding normal structures and exacerbating brain damage, especially with open craniotomy. A trial to evaluate the role of early surgery in superficial supratentorial lobar hematomas without intraventricular hemorrhage is ongoing. However, when a nondominant hemispheric or cerebellar ICH threatens impending herniation and before the patient’s level of consciousness significantly deteriorates, emergent surgery may be lifesaving and may provide a reasonably good recovery, especially in younger patients.

Patients who have small hematomas (smaller than 30 cm³) seem to do generally well without surgical evacuation. However, larger hematomas (larger than 60 cm³) do poorly, even when evacuated surgically. Hematomas between 30 and 40 cm³ may do best after surgical evacuation. There is no evidence that minimally invasive surgery (microsurgery or endoscopy) hold any advantage over open craniotomy, and the advantage of these technique is yet to be determined. A few neurosurgical studies have investigated the benefits of evacuating deep hematomas using a continuous infusion of thrombolytic agents and suction method. Thrombolytic agents such as tissue plasminogen activator have been infused into the hematoma. Although they produce more rapid hematoma resolution, the long-term clinical outcome seems unchanged. Generally, the therapeutic approach must be individualized.

Rebleeding and hematoma expansion is a common cause of acute deterioration and holds up to a 70% risk of death or unfavorable outcome. Prevention of hemorrhage progression, therefore, has become a central theme in the acute treatment of primary ICH. To that end, pro-coagulants, such as activated Factor VII, have been tested in patients with intracerebral hemorrhage (Factor Seven for Acute Hemorrhagic Stroke [FAST]). Activated Factor VII initiates the clotting cascade by binding to the surface of platelets and generating aX, which, in turn, induces surface thrombin formation. This reaction is specific to the site of bleeding as Factor VII works in the presence of tissue factor released at the site of injured tissue. A safety study in 2005 demonstrated that patients treated within 3 hours of presentation with activated Factor VII had the hematoma increase only by 11–16% compared to a 29% increase in the placebo group. Mortality in this Phase II trial decreased from 29 to 18%. Clotting events such as myocardial infarctions, deep venous thrombosis, pulmonary emboli, and ischemic strokes increased from 2% to 7%. A Phase III trial demonstrated that Factor VIIa did indeed decrease ICH volume, but failed to show a clinical effect with mortality and severe disability rates found comparable in the treatment groups and the placebo group. It was postulated that age might have played a role in diluting out the result and that relatively healthy individuals below the age of 70 years may be the ideal patients to respond to such treatments. At this time, however, no pharmacological treatment is available to limit the expansion of the spontaneous intracerebral hemorrhage in the absence of a coagulopathy.

Expansion of the hematoma or rebleeding in patients taking warfarin is another difficult management issue. Obviously, reversing the effects of warfarin is the first step in trying to limit bleeding. The administration of vitamin K and fresh-frozen plasma is often given acutely, but the benefits are not realized for another 24 hours. Some have advocated the use of prothrombin complex concentrate a (conglomerate of high levels of vitamin K–dependent factors) or activated Factor VII to help reverse the effects of warfarin. However, as mentioned previously, there is a significantly increased risk of thromboembolic events, and there are no studies at this time to help guide such treatment.

Summary

The overall mortality of patients with ICH is approximately 50% with lobar and basal ganglionic bleeds and up to 75% when involving the brainstem. Of those who survive, only half will achieve independent living. Initial presentation is predictive of outcome. Individuals who present with coma and signs of herniation have poor prognoses. Rapid increase in intracranial pressure with concurrent brainstem Duret hemorrhages leads to irreversible reticular activating system damage and coma. Patients in whom intraventricular blood leads to hydrocephalus do not fare well either, with 90% suffering poor outcomes or death.

The size of the initial hematoma, as defined by CT, is also predictive. There is a mortality rate of approximately 50–75% in patients with more than 40 mL of blood on CT at presentation. If the patient survives the bleed, the ultimate neurologic recovery depends on the hemorrhage location and residual deficits.