Grand Rounds: Man, 82, With New-Onset Headaches

An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.

The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.

The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.

His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.

The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.

On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.

The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.

CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.

Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.

Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.

Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.

Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.^1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.^3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.⁶ Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.⁴

Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.^7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al⁸ found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.

In addition, excessive anticoagulation has been associated with increased morbidity and mortality.^5,9,10 Pieracci et al⁹ found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.

Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.

Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.¹¹ For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.

Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.¹¹ Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.

Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.^11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.

Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.¹³

Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.¹³ The mortality rate for SDH is 31% to 36%.^14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.¹⁶ Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.^16,17

Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.^4,12,18,19

The risk factors for CSDH are listed in Table 1.^4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.^4,14

Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.^14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.

Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.^9,22-24 The choice of agents depends on the timing of intervention.

Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.²⁵

Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al²⁶ found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.

In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.^23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.²⁷

Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al¹⁴ found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.

Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.^20,28 Merlicco et al²⁹ found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.

Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.

Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.

Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.

Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.    

An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.

The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.

The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.

His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.

The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.

On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.

The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.

CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.

Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.

Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.

Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.

Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.^1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.^3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.⁶ Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.⁴

Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.^7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al⁸ found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.

In addition, excessive anticoagulation has been associated with increased morbidity and mortality.^5,9,10 Pieracci et al⁹ found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.

Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.

Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.¹¹ For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.

Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.¹¹ Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.

Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.^11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.

Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.¹³

Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.¹³ The mortality rate for SDH is 31% to 36%.^14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.¹⁶ Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.^16,17

Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.^4,12,18,19

The risk factors for CSDH are listed in Table 1.^4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.^4,14

Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.^14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.

Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.^9,22-24 The choice of agents depends on the timing of intervention.

Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.²⁵

Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al²⁶ found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.

In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.^23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.²⁷

Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al¹⁴ found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.

Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.^20,28 Merlicco et al²⁹ found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.

Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.

Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.

Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.

Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.    

An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.

The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.

The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.

His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.

The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.

On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.

The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.

CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.

Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.

Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.

Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.

Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.^1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.^3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.⁶ Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.⁴

Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.^7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al⁸ found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.

In addition, excessive anticoagulation has been associated with increased morbidity and mortality.^5,9,10 Pieracci et al⁹ found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.

Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.

Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.¹¹ For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.

Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.¹¹ Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.

Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.^11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.

Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.¹³

Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.¹³ The mortality rate for SDH is 31% to 36%.^14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.¹⁶ Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.^16,17

Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.^4,12,18,19

The risk factors for CSDH are listed in Table 1.^4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.^4,14

Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.^14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.

Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.^9,22-24 The choice of agents depends on the timing of intervention.

Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.²⁵

Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al²⁶ found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.

In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.^23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.²⁷

Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al¹⁴ found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.

Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.^20,28 Merlicco et al²⁹ found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.

Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.

Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.

Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.

Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.