Intracerebral Hemorrhage

Etiology

Non-traumatic Intracerebral hemorrhage can be divided into primary and secondary, where primary bleeds account for 85% of all ICH and are related to chronic hypertension or amyloid angiopathy.[2] Secondary hemorrhage is considered to be related but not limited to bleeding diathesis (iatrogenic, congenital, acquired), vascular malformations, neoplasms, hemorrhagic conversion of an ischaemic stroke, and drug abuse.

Primary or spontaneous ICH accounts for over 85% of hemorrhagic strokes.[3] A primary ICH diagnosis is often one of exclusion where no other pathological or structural cause is found and is supported by a history of chronic hypertension, increased age, and location of the clot. In patients with chronic arterial hypertension, it is thought that lipohyalinosis and degenerative changes of penetrating arterioles result in Charcot-Bouchard aneurysms in the small arterial vessels supplying deep cerebral structures.[1] Over 60% of primary bleeds are related to hypertension, and these hematomas are most commonly seen in the posterior fossa, pons, basal ganglia, and thalamus.[1] Lobar hemorrhages in older patients are often the distinguishing feature of amyloid angiopathy. This is a degenerative disease, thought to be related to alleles of the apolipoprotein E gene, allowing for increased amyloid deposition within vessel walls.[4]

In contrast, when an ICH is due to an underlying structural pathology, such as vascular anomalies or malignant tissue, they are categorized as secondary ICH. Vascular lesions include arteriovenous malformations, cavernous angiomas, cerebral aneurysms, and aorto-venous fistulae, and these are often the cause of ICH in the young, otherwise healthy, population. Cerebral hematomas may also be secondary to a primary or metastatic lesion or even the hemorrhagic conversion of a recent ischaemic infarct[4]. Further, congenial and acquired bleeding diathesis is a common factor in ICH’s, becoming more common due to the large population of adults on an anticoagulant (i.e., warfarin) and antiplatelet (aspirin) therapy.[3]

Studies have elicited certain tendencies in the population that suffer ICHs, thereby hypothesizing both modifiable and non-modifiable risk factors. The latter include non-white ethnicity, older age, familial apolipoprotein syndromes, and being male.[5] The radiological finding of cerebral amyloid angiopathy also increases the risk of both lobar and recurrent ICH. Uncontrolled or untreated hypertension is a modifiable risk factor that increases the risk of ICH by two in the aging population. Other adjustable risk factors include abuse of drugs such and alcohol, nicotine, and cocaine.[3]

Epidemiology

The incidence of stroke, both ischemic and hemorrhagic, in 2010 was approximately 33 million worldwide, with hemorrhagic strokes accounting for nearly a third of cases and over half of all the deaths.[4] Though the worldwide incidence sits at nearly 20 cases per 100,000 people every year, the occurrence of ICH in low/middle-income regions is double compared to the rates in more economically developed countries.[5] Fortunately, however, the mortality from such strokes has decreased worldwide.[4] The increased risk in lower-economically developed countries is potentially related to the lack of education regarding primary prevention and inadequate access to medical care.[5]

Stroke, both ischaemic and hemorrhagic, ranks fourth in the list of the leading cause of death in the United States, with just under 20% of cerebrovascular incidents in the United States are ICHs.[6]

ICH is diagnosed more frequently in the elderly (> 55 years of age) and the male population, and a predilection is seen in the African and Asian populations.[7][5] Within the Japanese population, the incidence increases to 55 cases of ICH per 100,000 people, and studies postulate that this is accounted for by the increased prevalence of alcohol use and hypertension.[8]

Pathophysiology

Hemorrhages within cerebral parenchyma are often categorized into primary injury, i.e., the immediate tissue injury from the hematoma and secondary injury - the subsequent pathological change that results from the hemorrhage. Although ICH is commonly considered a single event disease, it is more recently being considered as a dynamic condition with multiple phases, these being:

1. The initial extravasation of blood into the parenchyma
2. Subsequent bleeding around the clot causing expansion
3. Swelling or edema around the hematoma[3] 

An acute ICH causes a sudden increase in mass within the parenchyma of the brain, which causes compression and disruption of the surrounding neuronal tissue, leading to a potential compromise of the nearby cell signaling pathways and causing a focal neurological deficit[4]. Blood dissipates within white-matter, leaving small focuses of intact neural tissue amongst the hematoma and around it, which is, in theory, salvageable.[5]

When the hematoma is within the brainstem, the initial manifestation can be a decreased level of consciousness, along with cardiorespiratory distress or even arrest. One important factor in predicting patients' prognosis and functional outcome is the expansion of the initial hematoma, which is defined on repeat CT scanning as a volume increase of 33 to 50%.[9] Clot expansion of this volume is seen in just under 40% of patients and is related to increased morbidity and poorer outcomes.[4]

Over 70% of ICHs have been noted to expand in the first 24hours from the onset due to continued or repeat bleeding. Studies by Brott et al. revealed that 26% of patients with ICH had hematoma expansion within 1 hour of the first CT scan.[10] Though the mechanism of hematoma growth is not fully understood, it is hypothesized that there is upregulation of the inflammatory cascade, which causes an imbalance in hemostatic mechanisms and increased expression of matrix metalloproteinase.[9] Both untreated hypertension and bleeding diathesis increase the incidence of hematoma growth.[5] It is proposed that there is a disintegration of the blood-brain-barrier, and the mass effect of the clot causes a sudden rise in intracranial pressure (ICP), leading to distortion of the local tissue architecture, which can disrupt venous outflow, thereby causing vascular engorgement. The local mass effect on the tissues may result in stretching and microscopic rupture of the surrounding vasculature (venules and arterioles), allowing for small focuses of bleeding around the borders of the ICH.[9] The increased ICP results in tissue movement or mass effect, which may lead to herniation syndromes and also causes lower cerebral perfusion pressures (CPP), causing secondary brain injury.[4]

Following the vascular bleeding phenomenon, other pathological events occur, which results in secondary brain injury. As a consequence of acute bleeding, the brain parenchyma recruits inflammatory cytokines and thrombin, which causes edema or tissue swelling around the acute hemorrhage.[4] The perihematomal edema is a complication within the hyperacute phase of an ICH and reaches its’ peak at approximately 72 hours post-ictus.[7] The potential mechanism of early edema around the clot is considered to be a vasogenic reaction to pro-osmotic substances such as electrolytes and protein, which are released from the acute hematoma. This is followed by activation of the coagulation cascade and increased thrombin expression, which may propagate swelling. After the first week, any further edema is related to the cytotoxic effects of hemoglobin breakdown and the formation of reactive oxygen species[9]. The cause of cerebral ischemia following a hypertensive bleed was considered secondary to the compression of cerebral tissue by adjacent hematoma and oedematous tissue under raised pressure. However, studies have now found necrotic tissue in the region around the ICH, thus suggesting apoptosis caused by the expression of nuclear factor-kB within neural-cell nucleoli.[5]

History and Physical

As with all acute presentations, a concise but thorough history is crucial to forming a diagnosis. Relevant details in the history of ICH include the chronicity of symptoms and the time of ictus. Most commonly, vascular events are sudden and may be precipitated by high energy activities such as exercise or heavy lifting or using drugs like cocaine and alcohol. A significant smoking history has implications in vascular disease such as hypertension and vasculitis, which both are risk factors for ICH.

The most common feature of ICH is a sudden onset focal neurological deficit, which is determined by the location of the hemorrhage and subsequent edema. This is often associated with a decrease in the patients’ conscious level, measured using the Glasgow coma scale (GCS). Other common symptoms and signs include headache, nausea/vomiting, seizures (both convulsive and non-convulsive), and a raised diastolic blood pressure (>110 mmHg).[2] Extension of the clot into the ventricles can cause obstructive hydrocephalus, which manifests itself with signs and symptoms of raised intracranial pressure, including postural headaches (worse on lying flat), papilledema, nausea, vomiting, diplopia, confusion, and a reduced conscious level.

Initial evaluation of the patient should include checking for airway patency and appropriate ventilation. Circulation must be assessed next, and one must secure wide bore venous access and aim for systolic blood pressure targets between 120 to 140 mmHg to maintain cerebral perfusion. A very low consciousness level (GCS<8) must be treated as an emergency, and obtaining a secure airway in a patient with a low conscious level is a priority. The patient must then have a complete peripheral inspection and examination- this includes checking the patients' pupils as dilation and inactivity of the pupils is a sign of cerebral herniation and must be treated immediately.

Once medically stable, it is pertinent to confirm a clear history of anticoagulant/ antiplatelet therapy or coagulation disorders and check the patients' clotting function and other routine blood tests. Any coagulation abnormalities should be discussed with hematologists and corrected appropriately.

Evaluation

A non-contrast CT head remains the gold-standard imaging modality in the initial diagnosis of ICH, as it is easily accessible and fast.[2] A CT head can differentiate between the various intracranial pathology, including subarachnoid hemorrhage, ischemic stroke, and ICH. It can also reveal the extent of the hemorrhage with regards to size, surrounding edema, mass effect, intraventricular clot extension, and raised intracranial pressure. MRI, particularly T2* weighted and gradient-echo sequences, is also a good imaging modality for ICH identification and can also help reveal old clots, but has the downfall of taking more time and being less readily available.[11]

Acute ICH is noted on CT of the head as an area of hyperdensity within the parenchyma, with surrounding hypodensity, which would indicate perivascular edema. Approximate volumes of the clot can be calculated by multiplying the maximum depth, height, and length of the clot in centimeters and dividing this by two.[7]

As clot expansion and rebleeding is a major immediate risk in ICH affecting up to 38% of patients with ICH[11], CT head with contrast and CT Angiography (CTA) of the intracranial vessels may be used to help identify vascular pathology that may be the cause for the ICH. The diagnosis of a vascular abnormality can also be useful prior to clot evacuation in the emergent setting, as often surgeons prefer to deal with vascular malformations in a more elective/planned setting. On a contrast CT scan, a hyperdense signal within the hematoma may indicate active bleeding and is colloquially known as the ‘spot sign.’ More numerous areas of contrast enhancement may indicate increased areas of active bleeding and, therefore, a higher risk of clot enlargement.[11] 

Vascular lesions causing the ICH is most often suspected in young patients with risk factors, but radiological hints include the presence of SAH, calcification within the hematoma (hyperdense on CT), hematoma shape, and its location to major territorial vessels.[11] Aside from CT angiography, vascular abnormalities such as arteriovenous malformations and cavernomas can also be detected on MR angiography and MR venography.[11] An interventional intracranial catheter angiogram is usually performed to confirm the diagnosis of a vascular malformation as this is a dynamic study that gives more information regarding the active filling/emptying phases of the veins and arteries.

Treatment / Management

In the prehospital setting, the mainstay of treatment involves airway, breathing, and circulatory support, aiming to get the patient to the closest emergency department (with capabilities of managing stroke). A detailed history from any witnesses or family/carers at the site of the incident is always useful as it may provide pertinent information regarding trauma, medical, and drug history.[11]

Aggressive early medical management once in an acute hospital setting has been shown to have a direct impact on morbidity and mortality following an ICH. The immediate aim following diagnosis is to minimize the risk of rebleeding and hematoma expansion within the first 24 to 72 hours.[2] Initially, any and all coagulation abnormalities need to be corrected- this includes treatment of known factor deficiencies and reversal of any anticoagulation agents the patient is known to be on, with the help of the hematologists. In patients known to be taking vitamin K antagonists, guidelines for the management of spontaneous ICH recommends correction (aiming INR < 1.4) using fresh frozen plasma (FFP), vitamin K, prothrombin complex concentrates as well as newly developed recombinant activated factor VIIa.[11] Studies are still ongoing regarding the definitive indication for platelet transfusion in those affected by antiplatelet medication. However, analysis of a smaller case series revealed a smaller final ICH size in those who underwent a platelet transfusion within 12 hours of ictus.[11](B3)

Most ICH presentations include raised blood pressure for various physiological reasons, including pain, stress, a history of increased blood pressure, and raised ICP. The potential consequence of a persistently raised systolic blood pressure is hematoma expansion, and therefore initial medical management must include treatment of elevated blood pressure. However, blood pressure reduction should take into account the patients' regular blood pressure, as a hypertensive patient may not be able to maintain cerebral perfusion at a significantly lower SBP. American stroke guidelines recommend reducing blood pressure to an SBP <140 mmHg in those with SBP ranging between 150 to 220 mmHg. In the population of patients with ICH presenting with SBP > 220 mmHg, it remains pertinent to lower their blood pressure, but in a more controlled way using an infusion with continuous monitoring.[11]

Randomized trials initially proved strict blood glucose measurement to be beneficial to the prognosis of ICH; however, further studies have revealed increased mortality in those with cerebral hypoglycemia. Guidelines, therefore, suggest aiming for normoglycemia with strict avoidance of hypoglycemia.[11] Patients presenting to hospitals with seizures should be managed with antiseizure medication, such as phenytoin or levetiracetam. However, there is no evidence to suggest that prophylactic anti-seizure medication has a role in reducing the rate of ICH-related epilepsy.[11]

To prevent secondary brain injury, the aim is to keep CPP>70mmHg. Conservative measures to reduce ICP include keeping the patient's head up at 30 degrees, appropriate analgesia, laxatives to avoid straining, hyperventilation, and sedation. In patients who have CT scans that reveal significant mass effect with indications of imminent parafalcine or uncal herniation, osmotic diuretics such as mannitol or hypertonic saline may be rapidly administered, although the benefit from this is not proven.[7] In patients who require large amounts of sedation to manage seizures or raised ICP, an intracranial pressure monitor can be inserted to guide the patients’ status while they are not assessable clinically.

Urgent complications of ICH include intraventricular extension and hydrocephalus; the latter developed more quickly in posterior fossa hemorrhages due to the anatomical proximity of the fourth ventricle and, therefore, its ability to become obstructed. CSF diversion is the mainstay of treatment in these cases, and an external ventricular drain (EVD) can be inserted, most commonly into the right lateral ventricle. This allows for a reduction in ICP and herniation.[2](B3)

Studies have shown that in ICH within the posterior fossa, surgical evacuation of the clot improves outcomes in good surgical candidates if the clot is > 3 cm and is causing brainstem compression, decreased level of consciousness, and/or hydrocephalus.[12] Patients with a higher GCS and decreased volume of blood at the time of surgery are more likely to have a favorable prognosis following the surgical intervention.[7](B3)

The ‘Surgical intervention for supratentorial ICH’ or STITCH trial is the largest randomized trial looking into the surgical benefit. In this trial, over 1000 patients with clinical equipoise were randomized to having surgery within 72 hours or undergoing medical management. The trial concluded that there was no significant benefit from surgical intervention. However, the need for clinical equipoise meant that the patients randomized were already clinically worse off[2]. Further examination of the results revealed that a small group of patients with lobar hemorrhages <1cm from the cortical surface had more encouraging outcomes from surgery with a relative benefit of 29% compared to medical management, while those patients who presented with a CGS <8 had poorer results.[7][11] This led to another trial, STICH II, aiming to understand the potential outcomes of patients with lobar clots <1 cm from the cortical surface without IVH, with and without surgery. Patients either underwent medical management or medical management with early surgery (<12 hours from the time of randomization). The results of the trial revealed no statistical significance in the two arms, although early surgery benefited the clinically unwell patients more than those who would have likely done well even without surgery.[11] As a result of these two large trials, the role of surgical intervention in supratentorial ICH remains controversial. It is largely considered a life-saving intervention in those who are clinically declining.[6](B3)

Some surgeons would consider a decompressive craniectomy (with or without evacuation of the clot) for selected patients who show little improvement with medical therapy to relieve the mass effect caused by a supratentorial, large ICH. The results of a systematic review of decompressive craniectomy in the setting of supratentorial ICH has shown improved survival rates, though morbidity remains high.[13]

More recently, ICH treatment using minimally invasive techniques is being developed and undertaken worldwide, providing the benefit of less parenchymal brain trauma and reduced surgical time. The current techniques involve stereotactic guidance and insertion of a catheter, which can deliver thrombolysis into the clot and also allow for aspiration if appropriate. The MISTIE trial (Minimally invasive surgery plus rtPA (recombinant tissue plasminogen activator) for intracerebral hemorrhage evacuation) has proposed that the use of rtPA into the clot provides improved hematoma clearance when compared to conservative management.[3] Further, the ‘Clot Lysis Evaluating Accelerated Resolution on Intra-Ventricular Hemorrhage’ (CLEAR-IVH) trial has also concluded that rtPA may provide improved clearance of blood load within the ventricles.[3]

Differential Diagnosis

Many pathologies can present themselves acutely with symptoms and signs similar to that of acute ICH. The common symptoms of headache and nausea along with clinical manifestations of decreased consciousness, confusion, seizures, and focal neurological deficit are often seen with other intracranial hemorrhages, such as a subarachnoid hemorrhage (SAH) and a subdural hemorrhage (both acute and chronic), neoplasms (primary and secondary), and infection.

The primary feature of a SAH is the pathognomonic sudden onset, severe headache ‘like being hit at the back of the head.’ Apart from this feature, which may not always be expressed so eloquently, patients may present much the same way as those with acute ICH. In a SAH, an unenhanced CT Head would reveal blood within the subarachnoid space and ventricular cisterns rather than within the parenchyma, as seen in an ICH. An acute subdural hematoma may have similar symptoms. However, the key differentiating factor is a history of recent trauma preceding the presentation. Chronic subdural hemorrhages are most commonly seen in the elderly, particularly those on blood-thinning medication, and history is often of recurrent falls followed by a longer duration of headaches and/or confusion and/or focal neurological deficit. Both acute and chronic subdural hematomas can be differentiated on a plain CT head as a crescentic extra-axial collection- hypodense if the blood is chronic and hyperdense in the acute setting.

Brain tumors frequently present insidiously. Due to their gradual growth, most patients can compensate until the intracranial pressure is high enough to produce symptoms of headache, nausea, vomiting, seizures, and decreased GCS. On closer examination of the history, there is often evidence of a subtle progressive history, and contrasted CT imaging is often required to make a diagnosis. Patients with neoplastic lesions may present with hemorrhages into a primary or secondary brain tumor in some situations. This can cause diagnostic uncertainty that often requires delayed imaging, in the form of MR, to make a more accurate diagnosis of underlying pathology.

Lastly, infectious collections such as subdural empyema and abscesses can present similarly to acute ICH; however, patients commonly have a history of recent infections in the nasofacial region (ear, sinuses) and/or systemic symptoms of pyrexia and/or rigors. Once again, contrast-enhanced CT and MRI can assist in differentiating the pathology.

Prognosis

Acute ICH can be a catastrophic event with the mortality largely predicted by the hematoma size, location, and the patients' GCS on admission.  At 30 days, the mortality rate can be as high as 50%, with most of these deaths occurring within 24 hours of the initial insult, with intraventricular blood and hydrocephalus often playing a large part in the patient's deterioration.[3][7] Patients presenting to the hospital with a GCS <9 and a clot size of 60 ml or more have a nearly 90% mortality rate. Posterior fossa and brainstem hemorrhages carry a poorer prognosis due to the propensity for the development of obstructive hydrocephalus and life-sustaining function, respectively. Less than 20% of patients that survive are seen to be autonomous at 6 months following the acute hemorrhage.[3] Further, factors such as the patients' age and comorbidities also affect outcomes following ICH.

Although there are no definitive ways of predicting outcomes, early withdrawal of care can, in itself, lead to a self-fulfilling prophecy. Therefore full medical care and treatment should be offered to all patients with acute ICH who do not have an advance directive or known wishes for the first 24 to 48 hours post ictus.[6]

Complications

Approximately 30% to 50% of patients with ICH are seen to have an extension of the clot into the ventricles. It is thought to be particularly common in thalamic hemorrhages due to the anatomical relations to the third ventricle and the natural tendency for blood to move medially.[9] Patients with intraventricular hemorrhage (IVH) have been seen to have poorer functional outcomes, which may be caused by compression and injury to periventricular tissue, inflammatory mediator response to blood products within the ventricular system, as well as obstructive hydrocephalus and its complications.[14]

Obstructive hydrocephalus is a complication of IVH and can lead to potentially lethal complications of raised ICP. It is seen more frequently in patients with a larger blood volume within the ventricular channels[9]. Pacchioni granulations within the arachnoid villi may become partially blocked by intraventricular blood products, thereby resulting in communicating hydrocephalus, which once again can lead to significant morbidity.

Seizures commonly occur as part of the presenting symptoms of ICH, but in some cases may be a delayed complication (two hours post hemorrhage). Just under 70% of seizures are seen within 24 hours of the initial ictus, and the vast majority (90%) occur within 72 hours. Seizures that occur within two hours of the initial ICH (early seizures) are a result of changes in the architecture of neuronal tissues and biochemical dysfunction, whereas delayed seizures are more likely a result of gliosis and tissue scarring.[9] Non-convulsive seizures, detected on cEEG monitoring, are also seen in those with ICH with an incidence rate as high as 28% within 72 hours of presentation and are often considered when a patient has a sudden drop in GCS and imaging revealing clot in seizure-prone parts of the brain, i.e., temporal lobe, cortical surface. Delayed seizures are most commonly associated with increased mass effect and midline shift on imaging and, therefore, may be a clinical sign of hematoma expansion.[9] A study by Passero et al. described the risk of delayed recurrent seizures or epilepsy in those post-ICH to be in the range of 5 to 27%.[15]

Venous thromboembolism (VTE), in the form of deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication seen in most unwell patients admitted to the hospital but has a rate of about 3% to 7% in those with ICH.[9] Symptomatic DVTs are less common, though rates of asymptomatic DVTs are described as being up to 17%.[16] The high rate of VTE is likely related to the immobility of those with ICH, as many will suffer from hemiplegia/hemiparesis. Further catalyzing the development of VTE is the largely elderly population that develop ICH, the discontinuation of anticoagulant therapy, the diagnostic dilemma of starting prophylactic anticoagulation, as well as an increase in prothrombotic activity seen following acute hemorrhage.[9]

Approximately 60% of patients with ICH are seen to develop transient hyperglycemia in the acute setting, lasting up to 72 hours, as part of the body’s natural stress response. Studies show a positive correlation between blood glucose levels and the size of the hematoma, hematoma expansion, and surrounding edema, thus making raised blood glucose an independent predictor of worse functional outcomes.[9]

Within the acute phase following an ICH, over 70% of patients are found to be hypertensive (BP greater than or equal to 140/90 mmHg), despite having no such history before admission. The reasons for this phenomenon are unclear, but the hypothesized theory is that there may be upregulation of neuroendocrine pathways (sympathetic nervous system, renin-angiotensin axis) and increased cardiac output as part of the stress response to raised ICP.[9] Though raised blood pressure following ICH is associated with high rates of re-bleed and hematoma expansion and therefore poorer outcomes, the effect of blood pressure levels on mortality exhibits a U-distribution due to hypotension also acting as a factor for poor prognosis due to reduced cerebral perfusion and resultant cerebral ischemia.[9]