Introduction

Charcot-Bouchard aneurysms are minute aneurysms (microaneurysms) in the brain that occur in small penetrating blood vessels with a diameter that is less than 300 micrometers. The most common vessels involved are the lenticulostriate branches (LSA) of the middle cerebral artery (MCA). LSAs originate from the MCA just before its bifurcation, and they can vary between 2 to 12 in number (average 8.1). Most branches arise medially (99.2%), close to the internal carotid artery. They supply the basal ganglia, and more specifically the putamen and caudate, followed by the thalamus, pons, and the cerebellum.[1] 

Charcot-Bouchard aneurysms are named after the French physicians Jean-Martin Charcot and his student Charles Joseph Bouchard. In the 19th century, Bouchard discovered these aneurysms during his research under Charcot. Cole and Yates strengthened Charcot and Bouchard's work by demonstrating that aneurysms truly exist using microangiographic techniques in the 1960s. However, it has been a topic of lively debated if it is, in fact, the rupture of these aneurysms that are responsible for the intracerebral bleeds.[2]

Individuals with chronic systemic hypertension are at high risk of developing atrophy of the outer muscular layer. With the loss of integrity of the vessel wall, microaneurysms develop in LSA, which are at high risk of rupture. Bleeding of aneurysms into the deep structures of the brain parenchyma is also referred to as intraparenchymal hemorrhage or, more broadly, as intracerebral hemorrhage. Clinically the deficits that present can point towards the location of the bleed. The first line diagnostic modality for these patients is a non-contrast computed tomography (CT) of the head to visualize the bleed. Depending on the severity and location of the hemorrhage the treatment options vary from observation to neurosurgical intervention.[3][4]

Etiology

Chronic systemic hypertension is the most critical risk factor for developing Charcot Bouchard aneurysms that subsequently rupture and cause hemorrhage. The risk factors broadly classify as follows:

Modifiable Factors 

• Hypertension
• High-fat diet
• High waist to hip ratio
• Smoking
• Excessive alcohol consumption
• Low low-density lipoprotein and triglyceride levels 
• Illicit drug use such as cocaine, heroin

Non-Modifiable Factors

• Old age
• Male sex
• Race and ethnicity such as Asians and African Americans who are at higher risk 

Systemic diseases such as chronic kidney disease, cerebral amyloid angiopathy, vascular malformations, and coagulopathies either hereditary, acquired, or due to drugs such as warfarin and antiplatelet medications also increase the risk of development of microaneurysms and intracerebral hemorrhages.[5][6][3]

Epidemiology

Intracerebral hemorrhage contributes to 10 to 20% of all strokes worldwide and about 8 to 15% of all strokes in the United States. The lifetime risk of stroke in individuals 25 years and older in 2016 was estimated to be 24.7% among men and 25.1% in women. The overall risk is thus, an estimated 24.9% compared to 22.8% in 1990. The highest risk is in East Asia and Europe and the lowest risk in countries with a low sociodemographic index such as Sub-saharan Africa. Similarly, the incidence and mortality of stroke are highest in Asia, especially China, and East European countries. Although the rates are declining, the absolute number of incidence cases in 2016 has doubled since 1990, with the majority of individuals being under the age of 70. The estimated case fatality of intracerebral at one month is 40% and at one year is 54%. Long term functional independence occurs in only 13 to 49% of the patients.[7][3]

Pathophysiology

LCAs branch-off at right angles from the MCA, rendering the blood flow through the LCA disturbed and non-laminar. The friction between the blood flow and lateral walls of the blood vessels gives rise to a sheer force. Furthermore, the changes in blood pressure, velocity, and diameter that occurs at the branching of arterioles to capillaries increase the sheer force in LCAs. Over time the increase in blood pressure and wall stress upregulates atherogenic factors and smooth muscle cell proliferation, causing abnormality in the cell junctions and formation of microaneurysms. Rupture of the microaneurysms leads to bleeding and hematoma formation in the deep structures of the brain - commonly in the basal ganglia. 

Following this sequence of events is the disruption of the surrounding parenchymal structure, mass effect on surrounding structures, disruption in neurotransmitter release, and membrane depolarisations. Through different mechanisms, several inflammatory pathways become activated. Some of these mechanisms include: 

• Release of inflammatory substances from the blood into the perihematomal region  
• Mechanical destruction of surrounding neural and glial tissue
• Breakdown of hemoglobin that causes neuronal insult
• Activation of the clotting cascade and increase in thrombin levels that further increases pro-inflammatory processes

Most of the hematoma enlargement occurs within the first 3 hours of onset, but it can continue to expand post 12 hours of onset. The perihematomal edema peaks at five days from onset. With increased intracranial pressure the cerebral perfusion decreases, and patients are at risk of global cerebral hypoxia.[8][4]

Histopathology

Like in any other blood vessel, the wall comprises of, from inside out, the tunica intima, media, and adventitia. The intima layer is sensitive to endothelial nitric oxide synthase, which produces potent vasodilation in response to acetylcholine, substance P, and bradykinin. The nerve fibers, the majority of which are sympathetic, are distributed in the tunica media and adventitia layers.[1] 

Chronic hypertension causes hypertrophy of the smooth muscle layer in response to the consistently higher pressures within the vessel lumen. Hypoxia to the outer smooth muscle layers leads to their degeneration and fibrinoid necrosis. Following this is sclerosis of the media layer and overtime of the entire vessel wall.

A similar sequence of events occurs in cerebral amyloid angiopathy, where there is a deposit of beta-amyloid in the vessel wall that leads to hypoxia and fibrinoid necrosis.

Finally, the collagen fiber network then gets replaced with hyalin. These hyalinized areas are points of low resistance and are thus susceptible to aneurysmal dilatation and rupture with sudden increases in blood pressure. The size of the hematoma correlates with the size of the ruptured aneurysm. The LCAs are especially vulnerable since the deep structures in the brain surrounding these arterioles and capillaries do not allow them to withstand high-pressure variations.[9]

History and Physical

History:

The history should begin with asking the patient about the time of symptom onset and progression of symptoms. Intracerebral hemorrhage could present during physical activity, emotional stress, or even at rest in individuals with risk factors. General symptoms that the patient (or accompanying bystanders) complain of at presentation include[10]

• Headache due to meningeal irritation
• Vomiting (usually projectile in nature) and nausea due to increased intracranial pressure and appears in 50% of patients 
• A decreased level of consciousness ranging from confusion to coma depending on the size of the hematoma, usually only very large bleeds cause coma due to a mass effect causing compression of the brain stem 
• Seizures within the first 24 hours that occur in about 10% of patients

Also, screening for risk factors such as systemic hypertension, as well as medications such as anticoagulant drugs, antiplatelet drugs, is crucial. Important comorbid states to look for in these patients include liver disease and malignancies as they are associated with coagulopathies. In patients with cerebral amyloid angiopathy, cognitive dysfunction might be additionally present.[4]

Physical:

Accurate measurement of vital signs, a baseline GCS score, and a complete physical exam with a structured neurological exam is required. With the worsening of cerebral edema and an increase in the size of the hematoma, neurological symptoms progress within minutes to hours. The specific neurological deficits seen reflect the location of hemorrhage, such as:

• Putamen involvement presents with hemiparesis with depression of consciousness.
• Thalamic hemorrhages produce hemianesthesia more prominently than hemiparesis, along with an upward gaze.
• Pontine hemorrhages present with pinpoint pupils, quadriparesis, dysconjugate ocular mobility disorder, and coma.
• Lobar hemorrhages present with hemiparesis, hemisensory deficits along with speech impairment.
• Cerebellar hemorrhages present with vertigo, ataxia, and paralysis of conjugate gaze on one side.

Evaluation

Laboratory evaluation:

• A complete blood count to check for infection and anemia. Coagulopathy (PT, INR, aPTT) and lipid profile are essential in all patients along with daily electrolytes, creatinine, and liver function tests. As patients may develop hyperglycemia as a complication of intracerebral hemorrhage, it is essential to establish the baseline blood glucose and HbA1c levels and monitor them closely. Blood culture and sensitivity are necessary for patients with suspected systematic infections
• Cardiac-specific troponins are associated with worse outcomes in these patients 
• A urine toxicology screen must be ordered as drugs such as cocaine are risk factors for intracerebral hemorrhage
• Lumbar puncture only to rule out infection in patients with clinical suspicion or in patients with subarachnoid hemorrhage to look for hemolysis where the diagnosis is unclear

Radiographic evaluation:

• Non-contrast CT head is the first line for diagnosing intracerebral hemorrhage. The findings on the non-contrast CT can be staged based on the timing from the onset of initial symptoms. In the hyperacute state, the hematoma shows as smooth and hyperdense. Over 48 hours, the hematoma begins to show some fluid collection alongside the hyperintensity. Blood-fluid volumes have high specificity for coagulopathies. Next, over 72 hours, a mass effect with midline shift and a hypodensity due to edema surrounding the hematoma becomes visible. Finally, 3 to 20 days later, the hypodense region shrinks and has uneven borders with a ring-like appearance. A repeat CT scan is required with signs of neurological deterioration to diagnose complications. The spot sign is visible in a contrast-enhanced CT in patients with hematoma expansion
• Magnetic Resonance Imaging (MRI) MRI of the brain with gradient-echo can be used to more accurately detect microhemorrhages that appear as hyperintense areas surround by hypointense boundaries. However, to distinguish an acute bleed from a chronic bleed, a non-contrast CT head is performed. 
• Cerebral angiography is useful to diagnose secondary causes of intracerebral hemorrhage, such as microaneurysms and arteriovenous malformations.[11]

Electroencephalography:

• Electroencephalography is indicated for patients with unexplained neurological deterioration or suspected seizures 

Electrocardiogram:

• To assess cardiac events and arrhythmias 

Differential Diagnosis

It is critical to differentiate intracerebral hemorrhage from lacunar hemorrhages. Intracerebral hemorrhages occur due to microaneurysm formation in the LCAs versus lacunar hemorrhages that occur secondary to ischemia and reperfusion injuries. Although they both have systemic hypertension as an important predisposing risk factor, patients with lacunar hemorrhage are more likely to have type 2 diabetes mellitus and a higher body mass index.[14]

Pertinent Studies and Ongoing Trials

The following are relevant studies for the management of intracerebral hemorrhage and its complications:

• The FAST trial was critical in establishing the efficacy of recombinant factor VIIa in controlling the expansion of the hematoma in intracerebral hemorrhage along with the associated survival and functional benefits.[15]
• However, the SPOTLIGHT and STOP-IT trials did not show radiographic or clinical improvement in patients with spot sign positive that represents hematoma expansion in patients with intracerebral hemorrhage treated at a median 3-hour from symptom onset.[16]
• The STITCH, I and STITCH II trial, evaluated the benefit of early surgical intervention versus medical management in patients with intracerebral hemorrhage. The study concluded that early surgical intervention has a clinically relevant survival advantage in patients with intracerebral hemorrhage with no ventricular hemorrhage, and it does not increase the rate of death or disability at six months in these patients.[17]
• The ATTACH II trial evaluated the efficacy of rapidly lowering the systolic blood pressure in patients with acute hypertensive intracerebral hemorrhage. The study found that intensive lowering of the systolic blood pressure to 110 to 139 mm Hg did not lower mortality compared to standard lowering of systolic blood pressure to 140 to 179 mm Hg.[18]
• The INTERACT II trial aimed to analyze if the rapid lowering of blood pressure would improve outcomes in patients with acute intracerebral hemorrhage. The target systolic blood pressure in the study arm with intensive lowering was below 140 mm Hg, and this compared to the standard reduction of systolic blood pressure to over 180 mm Hg. The trial concluded that intensive lowering blood pressure does not significantly reduce mortality or severe disability in patients with intracerebral hemorrhage.[19]

Prognosis

Determining prognosis in patients with intracerebral hemorrhage is critical. Underestimation of the prognosis would lead to unnecessary procedures and prolonged hospitalization, while overestimation would lead to a limitation of care. Three important independent prognostic indicators of early neurologic deterioration and mortality are hematoma expansion with perihematomal edema, intraventricular hemorrhage, and hyperglycemia.

Complications

Complications of intracerebral hemorrhage secondary to rupture of Charcot-Bouchard aneurysms are as follows,

• Hematoma expansion: 

Hematoma expansion, also referred to as rebleeds, is an independent predictor of early neurological deterioration and mortality. Maximal hematoma expansion occurs in the first 3 hours and can occur up 24 hours from symptom onset. The "spot sign" or contrast extravasation into the hematoma is seen on the CT angiogram and is an indication of the expansion of the hematoma. The spot sign has been described as a heterogeneous marker due to its different shapes and sizes, depending on the timing of imaging relative to the onset of symptoms. Management of hematoma expansion includes administering hemostatic therapy with recombinant factor VIIa, cautious lowering of blood pressure, and craniotomy with surgical evacuation.

• Perihematomal edema:

Perihematomal edema develops secondary to vasogenic and cytotoxic effects due to the hematoma formation and exerts a mass effect on surrounding structures. It is maximal at two weeks from the onset of symptoms. The management goal is to minimize any increase in the intracranial pressure by elevating the head to 20 to 30 degrees, analgesics for pain, infection control, sedatives, osmotic diuretics such as mannitol, and hyperventilation. 

• Seizures:

Seizures can be either a presenting symptom or complication of intracerebral hemorrhage. Treatment includes antiepileptic drugs based on the patient's medication regimen and contraindications. 

• Intraventricular hemorrhage (IVH) with hydrocephalus:

IVH is also an independent predictor of early neurological deterioration and mortality due to IVH-induced inflammation and damage to periventricular structures, the brain stem, and leading to hydrocephalus with subsequent herniation. Relieving the IVH with external ventricular drainage is a life-saving procedure. For stable clots, intraventricular fibrinolytic (low-dose alteplase) can be administered. Lumbar drainage is less invasive, with a lower complication rate for communicating hydrocephalus. 

Other complications include:

• Venous thromboembolism presenting as deep vein thrombosis or pulmonary embolisms 
• Hyperglycemia due to stress
• Hyperpyrexia due to brain damage or infections
• Hypertension due to activation of the neuroendocrine systems[15][16][20]

Deterrence and Patient Education

It is critical to set age-appropriate blood pressure goals for patients and motivate them to be compliant with their medications. Counseling regarding modifiable risk factors such as smoking, excessive alcohol consumption, and high-fat diets must be pursued when appropriate. 

Since the initial symptoms of a stroke are non-specific, patients (and caregivers) might delay getting medical attention, which limits their treatment options. Ischemia greater than 4 to 6 hours can produce permanent damage to the neurovascular tissue, and yet a study found only half the patients present within the first 24 hours of the onset of stroke.[21] It is essential to educate them (and reiterate for patients with uncontrolled hypertension and multiple risk factors) on the presenting symptoms of headache with nausea and vomiting to encourage them to come to the hospital sooner.[22]

Enhancing Healthcare Team Outcomes

It is imperative to have a multi-specialty interprofessional team approach to care for patients with Charcot-Bouchard aneurysms and intracerebral hemorrhage.

Optimizing management for hypertension and other risk factors by the primary care team is the first step, along with adequate patient education about the signs and symptoms of a stroke to encourage early presentation to the emergency department. 

Next, a baseline severity score must be established in the emergency department for patients with spontaneous intracerebral hemorrhage followed by rapid neuroimaging with CT or MRI to distinguish an ischemic and hemorrhagic stroke. 

Initial management of patients with intracerebral hemorrhage must be in intensive care set up or stroke unit with neuroscience expertise amongst physicians and nursing staff. 

Management of hemostasis should be as follows:

• Factor deficiency or thrombocytopenic patients should receive factors and platelets respectively 
• Pneumatic compression for lower extremities to prevent deep vein thrombosis (DVT) from day 1 of hospitalization
• Patients on vitamin K antagonists should have them held and have the INR normalized with intravenous vitamin K and replacement of vitamin K dependent factors 

Patients presenting with systolic blood pressure between 150 to 200 mm Hg and without contraindications to acute lowering of blood pressure, should have systolic blood pressure lowered to 140 mm Hg. 

Monitoring of glucose to avoid hyper- or hypoglycemia, treatment of seizures, and assessment of dysphagia to prevent aspiration pneumonia should be performed in all patients.

All medications, including IV fluids, should have the pharmacist examine them in the context of the patient's entire medication record, ruling out interactions, verifying dosing and administration, and consulting with the team in the event there are any issues in the regimen. Nursing needs to be aware of proper administration and also the adverse events associated with the drugs given so that they can alert the clinicians of any concerns. These interprofessional interactions can help drive improved patient outcomes. [Level 5]

Lastly, patients requiring surgical interventions due to neurological deterioration should be referred to neurosurgery as early as possible to improve results. 

Patients with intracerebral hemorrhage must have not only access to interprofessional rehabilitation as an inpatient but also have continued rehabilitation services available in the community and at home to promote recovery.[12] [Level 1]