Case Reports

Perioperative visual loss (POVL) is a well-documented yet uncommon complication of nonocular surgery. Patients undergoing cardiac and spinal surgery are at the greatest risk, though POVL may occur during other neurosurgical and vascular procedures as well. The most common causes of POVL are central retinal artery occlusion (CRAO) and ischemic optic neuropathy (ION),^1-3 though cases of orbital compartment syndrome (OCS) have also been reported.^4-7

We describe a case of POVL during a temporal meningioma excision using the pterional approach. Though the etiology is not fully understood, the patient’s clinical course was complicated by a third cranial nerve (CN III) palsy and CRAO, which, together with the patient’s presentation, were consistent with previously documented cases of OCS. The goals of this case report are to increase awareness of this surgical outcome, identify practices that may have contributed to its development, and delineate methods to minimize its occurrence.

Informed consent regarding this research was obtained from the patient and an institutional Health Insurance Portability and Accountability Act authorization form was completed. This manuscript adheres to the applicable Enhancing the Quality and Transparency of Health Research guideline.⁸

Case Presentation

A 47-year-old woman underwent a left temporal craniotomy for resection of a sphenoid wing meningioma discovered during a workup for persistent headaches. She had no medical history of diabetes, hypertension, coronary artery disease, or ophthalmic disease. Two months before her scheduled surgery, the patient reported bilateral blurry vision and underwent ophthalmologic evaluation. Her intraocular pressure (IOP) was normal, and she had no pupillary or retinal disease. She showed evidence of decreased vision in her left eye, suggesting a possible mass effect from her meningioma. Subsequent imaging of the optic nerve and retina had unremarkable physiology (Figure 1). Preoperative magnetic resonance imaging (MRI) demonstrated a stable enhancing mass involving the left great sphenoid wing and left cavernous sinus(Figure 2). There was a superior mass effect on the left middle cerebral artery, but all vessels were patent without evidence of thrombosis.

The patient underwent general anesthesia with invasive hemodynamic monitoring used throughout the procedure. She was induced with fentanyl, propofol, and rocuronium; anesthesia was maintained with isoflurane and a remifentanil infusion. Hypotension was treated with phenylephrine and intravenous fluids. Intraoperative neuromonitoring with electroencephalogram (EEG) and somatosensory evoked potentials was performed. During the surgery, the patient was positioned supine in a Mayfield 3-point head fixation system. All pressure points were padded appropriately and continually checked. A standard left pterional craniotomy was performed, and the scalp was reflected anteriorly and secured using fish hooks with rubber bands. The operation did not violate the cavernous sinus or orbital compartment. There was no evidence of active bleeding upon inspection nor with the Valsalva maneuver. No changes were noted in EEG or somatosensory evoked potentials; blood pressure remained within 20 mm Hg of the patient’s baseline. She was extubated at the end of the 10-hour case and was hemodynamically stable upon transport to the surgical intensive care unit. Postoperative imaging confirmed the successful removal of the left sphenoid wing meningioma.

The patient’s postoperative examination demonstrated a 5 mm dilated, nonresponsive left pupil, though the patient did not report visual loss at that time. Defects were noted in the inferior oblique, superior, inferior, and medial rectus muscles, consistent with CN III palsy. The surgery included manipulation of CN III, which made this a possible outcome, but an alternate causative pathology like OCS was not immediately suspected. Postoperative computed tomography (CT) showed an expected pneumocephalus and left scalp swelling without evidence of mass effect or midline shift.

 

On the morning of postoperative Day 1, the patient reported vision loss in her left eye, while her clinical examination revealed erythema and conjunctival chemosis with left eyelid swelling. The ophthalmologic evaluation was notable for a continued leftCN III palsy with intact lateral rectus and superior oblique function, a nonreactive and dilated left eye with 3+ afferent pupillary defect by reverse (light perception), pallor throughout, a flat cherry red macula with blurred disc margins, left upper eyelid edema, and 18 mm Hg intraocular pressure bilaterally (reference range, 8 to 21 mm Hg). Fundoscopic examination showed a clear vitreous without plaques or occlusions, no perivascular sheathing, and no retinal hemorrhages. CT angiography revealed small outpouchings at the superolateral aspect of the left and right cavernous carotid, consistent with atherosclerotic calcifications. An echocardiogram revealed a Valsalva-dependent patent foramen ovale, but a venous Doppler ultrasound yielded negative results.

Repeat MRI showed denervation of the left medial rectus and minimal left-sided proptosis. A 3-month ophthalmologic follow-up revealed a persistent CN III palsy, including an afferent pupillary defect, absence of light perception in her left eye, and continued ophthalmoplegia. Repeat examination showed a left-sided 4+ afferent pupillary defect unreactive to light, 4+ pallor surrounding the optic nerve, macular atrophy, sclerotic vessels, and 17 mm Hg intraocular pressure bilaterally. The eye had diffuse atrophy of the inner retina and significant patchy atrophy of the outer retinal components without neovascularization of the iris. Postoperative retinal imaging can be seen in Figure 3. Her vision loss persisted at this encounter and has continued through subsequent follow-up examinations.

Discussion

Perioperative visual loss is a rare surgical complication, with an estimated incidence of once in every 60,000 to 125,000 cases.⁹ The mechanism of injury is variable and dependent upon the type of surgical intervention, with cardiac and spine surgeries carrying the greatest risk.^10,11 The injury often results in either CRAO or ION, which may result in visual loss.^1-3 POVL can also occur in the aftermath of rapid changes in intracranial pressure during decompressive craniotomies, though the pathophysiology in such cases is not well understood.⁵

Among the myriad ways in which POVL can occur, neurosurgical cases carry the unique risk of direct cranial nerve injury. Such an insult can lead to vision loss via optic nerve damage or ophthalmoplegia if damage occurs to CN III, IV, or VI. This can occur during manipulation or resection, especially if the surgical approach involves the orbital cavity or the cavernous sinus. Though neither space was entered in this patient, direct injury cannot be ruled out as the etiology for either her vision loss or persistent ophthalmoplegia. An alternate causative scenario for both symptoms involve an impaired blood supply, with the vision loss potentially occurring secondary to CRAO and the ophthalmoplegia to an alternate cause of decreased blood flow. It is unclear which of these 2 conditions occurred first or if they occurred due to the same insult, but OCS could lead to both. Though it is a less common etiology for POVL, this patient’s presentation was similar to those in previously reported cases, and OCS was identified as the likely diagnosis.

OCS is precipitated by an elevated orbital pressure, which leads to ischemia of the retina and damage to orbital contents. Though associated with retrobulbar hemorrhage and orbital trauma, another proposed mechanism for OCS is extrinsic orbital compression, resulting in increased IOP and subsequent CRAO.¹⁰ A cherry red spot is visible on fundoscopy, as only the macula with its thin retinal layer will permit the choroidal vessels to be visualized. In a separate process, the relative increase in orbital pressure may lead to impaired perfusion or damage of CN III. However, a causative relationship between the 2 may be difficult to establish. Such an injury to the oculomotor nerve is demonstrated by impaired function of the inferior oblique, superior rectus, inferior rectus, and medial rectus muscles, which may persist even after the compressive symptoms of OCS have resolved.¹² Other reported symptoms of OCS include erythema, ophthalmoplegia, conjunctival chemosis, ptosis, corneal abrasion, and eyelid edema.^12-15

Alternate Diagnoses

OCS is a diagnosis of exclusion, and several alternate mechanisms were considered before identifying it as the likely etiology. The patient’s preoperative imaging demonstrated a stable enhancing mass involving the left great sphenoid wing and left cavernous sinus, with displacement of the left middle cerebral artery, left cavernous internal carotid artery, and left optic canal. Dissection and removal of this tumor could have compromised the arterial or venous blood supply to the orbit, thus causing ischemia to the retina and other ocular structures. CN III was manipulated during surgery, and it may have been inadvertently damaged during exposure or resection of the tumor.

 

The patient’s Valsalva-dependent patent foramen ovale put her at risk of a paroxysmal embolus as an alternate explanation, particularly as a Valsalva maneuver was utilized to confirm hemostasis. The patient did not, however, demonstrate any evidence of venous thromboembolism (VTE) on ultrasound, nor did she have the common risk factors of hypertension, diabetes, or smoking history that would increase VTE risk.¹⁶ Her cancer diagnosis and surgical status may have put her at risk of VTE, but she did not have any clinical or laboratory values suggestive of hypercoagulability. Had an embolism occurred, it may have compromised the orbital blood supply and led to the CRAO. A similar scenario may have occurred from an atherosclerotic plaque in either of her carotid arteries, as she did have evidence of atherosclerosis on postoperative CT angiography. However, atherosclerosis as a risk factor for POVL appears to be related more to its impact upon impaired blood supply rather than as an embolic source. The patient did not have any significant intraoperative hypotensive episodes, making ION in the setting of atherosclerosis and hypotension a less likely etiology.¹⁷

This patient differed from other reported OCS cases. She was never placed in a prone or jackknife position, nor was she agitated or straining for a sustained period. These factors, along with the fact that the orbital compartment was not entered, decreased the likelihood of intraorbital hemorrhage and other intrinsic causes of elevated IOP.¹² Additionally, the presentation of our patient’s vision loss was delayed compared with other cases, despite clinicians observing a dilated left pupil and CN III palsy on examination immediately after surgery.¹⁴ It is significant to note that OCS may not demonstrate a significant increase in IOP once the source of compression is removed, which may explain the absence of proptosis on her postoperative examination.

The diagnosis of OCS was primarily implicated by the positioning of the myocutaneous flap during the pterional approach to craniotomy. It was retracted anteriorly and superiorly, ultimately resting over her left orbit for most of the 10-hour surgery. Kim and colleagues found that myocutaneous flaps may increase IOP as much as 17.5 mm Hg if improperly positioned, providing an unrecognized source of compression and increasing the risk of damage to orbital contents. According to their review, elevated IOP > 40 mm Hg, particularly over several hours, can compromise blood flow to the optic nerve and increase the risk for POVL.¹⁸ The flap was secured using fish hooks and rubber bands. However, it is suspected that the orbital rim did not fully support its pressure, thereby resting to some degree directly on the globe for an extended period and compromising the orbital blood supply. There are no current methods for measuring intraoperative IOP, though surrogate markers are under investigation and may yield clinical utility.¹⁸ The myocutaneous flap was created and positioned by the surgeons, but it may be that increased vigilance and communication from the anesthesia and nursing teams could have prevented it from remaining in an improper position.

Conclusions

Despite having few reported cases, OCS must be considered in neurosurgical patients with ophthalmoplegia and CRAO on postoperative examinations. Myocutaneous flaps that are retracted across the orbit can lead to significant elevations in IOP, leading to vision loss, which likely occurred with the patient in this case. Though protecting neurovascular structures is within the purview of the surgeon, all members of the intraoperative team should assist with ensuring proper flap positioning. These measures can help ensure adequate blood flow to the ophthalmic artery, decrease the likelihood of elevated IOP due to extrinsic compression, and help prevent the development of POVL and OCS in these patients.

Perioperative visual loss (POVL) is a well-documented yet uncommon complication of nonocular surgery. Patients undergoing cardiac and spinal surgery are at the greatest risk, though POVL may occur during other neurosurgical and vascular procedures as well. The most common causes of POVL are central retinal artery occlusion (CRAO) and ischemic optic neuropathy (ION),^1-3 though cases of orbital compartment syndrome (OCS) have also been reported.^4-7

We describe a case of POVL during a temporal meningioma excision using the pterional approach. Though the etiology is not fully understood, the patient’s clinical course was complicated by a third cranial nerve (CN III) palsy and CRAO, which, together with the patient’s presentation, were consistent with previously documented cases of OCS. The goals of this case report are to increase awareness of this surgical outcome, identify practices that may have contributed to its development, and delineate methods to minimize its occurrence.

Informed consent regarding this research was obtained from the patient and an institutional Health Insurance Portability and Accountability Act authorization form was completed. This manuscript adheres to the applicable Enhancing the Quality and Transparency of Health Research guideline.⁸

Case Presentation

A 47-year-old woman underwent a left temporal craniotomy for resection of a sphenoid wing meningioma discovered during a workup for persistent headaches. She had no medical history of diabetes, hypertension, coronary artery disease, or ophthalmic disease. Two months before her scheduled surgery, the patient reported bilateral blurry vision and underwent ophthalmologic evaluation. Her intraocular pressure (IOP) was normal, and she had no pupillary or retinal disease. She showed evidence of decreased vision in her left eye, suggesting a possible mass effect from her meningioma. Subsequent imaging of the optic nerve and retina had unremarkable physiology (Figure 1). Preoperative magnetic resonance imaging (MRI) demonstrated a stable enhancing mass involving the left great sphenoid wing and left cavernous sinus(Figure 2). There was a superior mass effect on the left middle cerebral artery, but all vessels were patent without evidence of thrombosis.

The patient underwent general anesthesia with invasive hemodynamic monitoring used throughout the procedure. She was induced with fentanyl, propofol, and rocuronium; anesthesia was maintained with isoflurane and a remifentanil infusion. Hypotension was treated with phenylephrine and intravenous fluids. Intraoperative neuromonitoring with electroencephalogram (EEG) and somatosensory evoked potentials was performed. During the surgery, the patient was positioned supine in a Mayfield 3-point head fixation system. All pressure points were padded appropriately and continually checked. A standard left pterional craniotomy was performed, and the scalp was reflected anteriorly and secured using fish hooks with rubber bands. The operation did not violate the cavernous sinus or orbital compartment. There was no evidence of active bleeding upon inspection nor with the Valsalva maneuver. No changes were noted in EEG or somatosensory evoked potentials; blood pressure remained within 20 mm Hg of the patient’s baseline. She was extubated at the end of the 10-hour case and was hemodynamically stable upon transport to the surgical intensive care unit. Postoperative imaging confirmed the successful removal of the left sphenoid wing meningioma.

The patient’s postoperative examination demonstrated a 5 mm dilated, nonresponsive left pupil, though the patient did not report visual loss at that time. Defects were noted in the inferior oblique, superior, inferior, and medial rectus muscles, consistent with CN III palsy. The surgery included manipulation of CN III, which made this a possible outcome, but an alternate causative pathology like OCS was not immediately suspected. Postoperative computed tomography (CT) showed an expected pneumocephalus and left scalp swelling without evidence of mass effect or midline shift.

 

On the morning of postoperative Day 1, the patient reported vision loss in her left eye, while her clinical examination revealed erythema and conjunctival chemosis with left eyelid swelling. The ophthalmologic evaluation was notable for a continued leftCN III palsy with intact lateral rectus and superior oblique function, a nonreactive and dilated left eye with 3+ afferent pupillary defect by reverse (light perception), pallor throughout, a flat cherry red macula with blurred disc margins, left upper eyelid edema, and 18 mm Hg intraocular pressure bilaterally (reference range, 8 to 21 mm Hg). Fundoscopic examination showed a clear vitreous without plaques or occlusions, no perivascular sheathing, and no retinal hemorrhages. CT angiography revealed small outpouchings at the superolateral aspect of the left and right cavernous carotid, consistent with atherosclerotic calcifications. An echocardiogram revealed a Valsalva-dependent patent foramen ovale, but a venous Doppler ultrasound yielded negative results.

Repeat MRI showed denervation of the left medial rectus and minimal left-sided proptosis. A 3-month ophthalmologic follow-up revealed a persistent CN III palsy, including an afferent pupillary defect, absence of light perception in her left eye, and continued ophthalmoplegia. Repeat examination showed a left-sided 4+ afferent pupillary defect unreactive to light, 4+ pallor surrounding the optic nerve, macular atrophy, sclerotic vessels, and 17 mm Hg intraocular pressure bilaterally. The eye had diffuse atrophy of the inner retina and significant patchy atrophy of the outer retinal components without neovascularization of the iris. Postoperative retinal imaging can be seen in Figure 3. Her vision loss persisted at this encounter and has continued through subsequent follow-up examinations.

Discussion

Perioperative visual loss is a rare surgical complication, with an estimated incidence of once in every 60,000 to 125,000 cases.⁹ The mechanism of injury is variable and dependent upon the type of surgical intervention, with cardiac and spine surgeries carrying the greatest risk.^10,11 The injury often results in either CRAO or ION, which may result in visual loss.^1-3 POVL can also occur in the aftermath of rapid changes in intracranial pressure during decompressive craniotomies, though the pathophysiology in such cases is not well understood.⁵

Among the myriad ways in which POVL can occur, neurosurgical cases carry the unique risk of direct cranial nerve injury. Such an insult can lead to vision loss via optic nerve damage or ophthalmoplegia if damage occurs to CN III, IV, or VI. This can occur during manipulation or resection, especially if the surgical approach involves the orbital cavity or the cavernous sinus. Though neither space was entered in this patient, direct injury cannot be ruled out as the etiology for either her vision loss or persistent ophthalmoplegia. An alternate causative scenario for both symptoms involve an impaired blood supply, with the vision loss potentially occurring secondary to CRAO and the ophthalmoplegia to an alternate cause of decreased blood flow. It is unclear which of these 2 conditions occurred first or if they occurred due to the same insult, but OCS could lead to both. Though it is a less common etiology for POVL, this patient’s presentation was similar to those in previously reported cases, and OCS was identified as the likely diagnosis.

OCS is precipitated by an elevated orbital pressure, which leads to ischemia of the retina and damage to orbital contents. Though associated with retrobulbar hemorrhage and orbital trauma, another proposed mechanism for OCS is extrinsic orbital compression, resulting in increased IOP and subsequent CRAO.¹⁰ A cherry red spot is visible on fundoscopy, as only the macula with its thin retinal layer will permit the choroidal vessels to be visualized. In a separate process, the relative increase in orbital pressure may lead to impaired perfusion or damage of CN III. However, a causative relationship between the 2 may be difficult to establish. Such an injury to the oculomotor nerve is demonstrated by impaired function of the inferior oblique, superior rectus, inferior rectus, and medial rectus muscles, which may persist even after the compressive symptoms of OCS have resolved.¹² Other reported symptoms of OCS include erythema, ophthalmoplegia, conjunctival chemosis, ptosis, corneal abrasion, and eyelid edema.^12-15

Alternate Diagnoses

OCS is a diagnosis of exclusion, and several alternate mechanisms were considered before identifying it as the likely etiology. The patient’s preoperative imaging demonstrated a stable enhancing mass involving the left great sphenoid wing and left cavernous sinus, with displacement of the left middle cerebral artery, left cavernous internal carotid artery, and left optic canal. Dissection and removal of this tumor could have compromised the arterial or venous blood supply to the orbit, thus causing ischemia to the retina and other ocular structures. CN III was manipulated during surgery, and it may have been inadvertently damaged during exposure or resection of the tumor.

 

The patient’s Valsalva-dependent patent foramen ovale put her at risk of a paroxysmal embolus as an alternate explanation, particularly as a Valsalva maneuver was utilized to confirm hemostasis. The patient did not, however, demonstrate any evidence of venous thromboembolism (VTE) on ultrasound, nor did she have the common risk factors of hypertension, diabetes, or smoking history that would increase VTE risk.¹⁶ Her cancer diagnosis and surgical status may have put her at risk of VTE, but she did not have any clinical or laboratory values suggestive of hypercoagulability. Had an embolism occurred, it may have compromised the orbital blood supply and led to the CRAO. A similar scenario may have occurred from an atherosclerotic plaque in either of her carotid arteries, as she did have evidence of atherosclerosis on postoperative CT angiography. However, atherosclerosis as a risk factor for POVL appears to be related more to its impact upon impaired blood supply rather than as an embolic source. The patient did not have any significant intraoperative hypotensive episodes, making ION in the setting of atherosclerosis and hypotension a less likely etiology.¹⁷

This patient differed from other reported OCS cases. She was never placed in a prone or jackknife position, nor was she agitated or straining for a sustained period. These factors, along with the fact that the orbital compartment was not entered, decreased the likelihood of intraorbital hemorrhage and other intrinsic causes of elevated IOP.¹² Additionally, the presentation of our patient’s vision loss was delayed compared with other cases, despite clinicians observing a dilated left pupil and CN III palsy on examination immediately after surgery.¹⁴ It is significant to note that OCS may not demonstrate a significant increase in IOP once the source of compression is removed, which may explain the absence of proptosis on her postoperative examination.

The diagnosis of OCS was primarily implicated by the positioning of the myocutaneous flap during the pterional approach to craniotomy. It was retracted anteriorly and superiorly, ultimately resting over her left orbit for most of the 10-hour surgery. Kim and colleagues found that myocutaneous flaps may increase IOP as much as 17.5 mm Hg if improperly positioned, providing an unrecognized source of compression and increasing the risk of damage to orbital contents. According to their review, elevated IOP > 40 mm Hg, particularly over several hours, can compromise blood flow to the optic nerve and increase the risk for POVL.¹⁸ The flap was secured using fish hooks and rubber bands. However, it is suspected that the orbital rim did not fully support its pressure, thereby resting to some degree directly on the globe for an extended period and compromising the orbital blood supply. There are no current methods for measuring intraoperative IOP, though surrogate markers are under investigation and may yield clinical utility.¹⁸ The myocutaneous flap was created and positioned by the surgeons, but it may be that increased vigilance and communication from the anesthesia and nursing teams could have prevented it from remaining in an improper position.

Conclusions

Despite having few reported cases, OCS must be considered in neurosurgical patients with ophthalmoplegia and CRAO on postoperative examinations. Myocutaneous flaps that are retracted across the orbit can lead to significant elevations in IOP, leading to vision loss, which likely occurred with the patient in this case. Though protecting neurovascular structures is within the purview of the surgeon, all members of the intraoperative team should assist with ensuring proper flap positioning. These measures can help ensure adequate blood flow to the ophthalmic artery, decrease the likelihood of elevated IOP due to extrinsic compression, and help prevent the development of POVL and OCS in these patients.

Perioperative visual loss (POVL) is a well-documented yet uncommon complication of nonocular surgery. Patients undergoing cardiac and spinal surgery are at the greatest risk, though POVL may occur during other neurosurgical and vascular procedures as well. The most common causes of POVL are central retinal artery occlusion (CRAO) and ischemic optic neuropathy (ION),^1-3 though cases of orbital compartment syndrome (OCS) have also been reported.^4-7

We describe a case of POVL during a temporal meningioma excision using the pterional approach. Though the etiology is not fully understood, the patient’s clinical course was complicated by a third cranial nerve (CN III) palsy and CRAO, which, together with the patient’s presentation, were consistent with previously documented cases of OCS. The goals of this case report are to increase awareness of this surgical outcome, identify practices that may have contributed to its development, and delineate methods to minimize its occurrence.

Informed consent regarding this research was obtained from the patient and an institutional Health Insurance Portability and Accountability Act authorization form was completed. This manuscript adheres to the applicable Enhancing the Quality and Transparency of Health Research guideline.⁸

Case Presentation

A 47-year-old woman underwent a left temporal craniotomy for resection of a sphenoid wing meningioma discovered during a workup for persistent headaches. She had no medical history of diabetes, hypertension, coronary artery disease, or ophthalmic disease. Two months before her scheduled surgery, the patient reported bilateral blurry vision and underwent ophthalmologic evaluation. Her intraocular pressure (IOP) was normal, and she had no pupillary or retinal disease. She showed evidence of decreased vision in her left eye, suggesting a possible mass effect from her meningioma. Subsequent imaging of the optic nerve and retina had unremarkable physiology (Figure 1). Preoperative magnetic resonance imaging (MRI) demonstrated a stable enhancing mass involving the left great sphenoid wing and left cavernous sinus(Figure 2). There was a superior mass effect on the left middle cerebral artery, but all vessels were patent without evidence of thrombosis.

The patient underwent general anesthesia with invasive hemodynamic monitoring used throughout the procedure. She was induced with fentanyl, propofol, and rocuronium; anesthesia was maintained with isoflurane and a remifentanil infusion. Hypotension was treated with phenylephrine and intravenous fluids. Intraoperative neuromonitoring with electroencephalogram (EEG) and somatosensory evoked potentials was performed. During the surgery, the patient was positioned supine in a Mayfield 3-point head fixation system. All pressure points were padded appropriately and continually checked. A standard left pterional craniotomy was performed, and the scalp was reflected anteriorly and secured using fish hooks with rubber bands. The operation did not violate the cavernous sinus or orbital compartment. There was no evidence of active bleeding upon inspection nor with the Valsalva maneuver. No changes were noted in EEG or somatosensory evoked potentials; blood pressure remained within 20 mm Hg of the patient’s baseline. She was extubated at the end of the 10-hour case and was hemodynamically stable upon transport to the surgical intensive care unit. Postoperative imaging confirmed the successful removal of the left sphenoid wing meningioma.

The patient’s postoperative examination demonstrated a 5 mm dilated, nonresponsive left pupil, though the patient did not report visual loss at that time. Defects were noted in the inferior oblique, superior, inferior, and medial rectus muscles, consistent with CN III palsy. The surgery included manipulation of CN III, which made this a possible outcome, but an alternate causative pathology like OCS was not immediately suspected. Postoperative computed tomography (CT) showed an expected pneumocephalus and left scalp swelling without evidence of mass effect or midline shift.

 

On the morning of postoperative Day 1, the patient reported vision loss in her left eye, while her clinical examination revealed erythema and conjunctival chemosis with left eyelid swelling. The ophthalmologic evaluation was notable for a continued leftCN III palsy with intact lateral rectus and superior oblique function, a nonreactive and dilated left eye with 3+ afferent pupillary defect by reverse (light perception), pallor throughout, a flat cherry red macula with blurred disc margins, left upper eyelid edema, and 18 mm Hg intraocular pressure bilaterally (reference range, 8 to 21 mm Hg). Fundoscopic examination showed a clear vitreous without plaques or occlusions, no perivascular sheathing, and no retinal hemorrhages. CT angiography revealed small outpouchings at the superolateral aspect of the left and right cavernous carotid, consistent with atherosclerotic calcifications. An echocardiogram revealed a Valsalva-dependent patent foramen ovale, but a venous Doppler ultrasound yielded negative results.

Repeat MRI showed denervation of the left medial rectus and minimal left-sided proptosis. A 3-month ophthalmologic follow-up revealed a persistent CN III palsy, including an afferent pupillary defect, absence of light perception in her left eye, and continued ophthalmoplegia. Repeat examination showed a left-sided 4+ afferent pupillary defect unreactive to light, 4+ pallor surrounding the optic nerve, macular atrophy, sclerotic vessels, and 17 mm Hg intraocular pressure bilaterally. The eye had diffuse atrophy of the inner retina and significant patchy atrophy of the outer retinal components without neovascularization of the iris. Postoperative retinal imaging can be seen in Figure 3. Her vision loss persisted at this encounter and has continued through subsequent follow-up examinations.

Discussion

Perioperative visual loss is a rare surgical complication, with an estimated incidence of once in every 60,000 to 125,000 cases.⁹ The mechanism of injury is variable and dependent upon the type of surgical intervention, with cardiac and spine surgeries carrying the greatest risk.^10,11 The injury often results in either CRAO or ION, which may result in visual loss.^1-3 POVL can also occur in the aftermath of rapid changes in intracranial pressure during decompressive craniotomies, though the pathophysiology in such cases is not well understood.⁵

Among the myriad ways in which POVL can occur, neurosurgical cases carry the unique risk of direct cranial nerve injury. Such an insult can lead to vision loss via optic nerve damage or ophthalmoplegia if damage occurs to CN III, IV, or VI. This can occur during manipulation or resection, especially if the surgical approach involves the orbital cavity or the cavernous sinus. Though neither space was entered in this patient, direct injury cannot be ruled out as the etiology for either her vision loss or persistent ophthalmoplegia. An alternate causative scenario for both symptoms involve an impaired blood supply, with the vision loss potentially occurring secondary to CRAO and the ophthalmoplegia to an alternate cause of decreased blood flow. It is unclear which of these 2 conditions occurred first or if they occurred due to the same insult, but OCS could lead to both. Though it is a less common etiology for POVL, this patient’s presentation was similar to those in previously reported cases, and OCS was identified as the likely diagnosis.

OCS is precipitated by an elevated orbital pressure, which leads to ischemia of the retina and damage to orbital contents. Though associated with retrobulbar hemorrhage and orbital trauma, another proposed mechanism for OCS is extrinsic orbital compression, resulting in increased IOP and subsequent CRAO.¹⁰ A cherry red spot is visible on fundoscopy, as only the macula with its thin retinal layer will permit the choroidal vessels to be visualized. In a separate process, the relative increase in orbital pressure may lead to impaired perfusion or damage of CN III. However, a causative relationship between the 2 may be difficult to establish. Such an injury to the oculomotor nerve is demonstrated by impaired function of the inferior oblique, superior rectus, inferior rectus, and medial rectus muscles, which may persist even after the compressive symptoms of OCS have resolved.¹² Other reported symptoms of OCS include erythema, ophthalmoplegia, conjunctival chemosis, ptosis, corneal abrasion, and eyelid edema.^12-15

Alternate Diagnoses

OCS is a diagnosis of exclusion, and several alternate mechanisms were considered before identifying it as the likely etiology. The patient’s preoperative imaging demonstrated a stable enhancing mass involving the left great sphenoid wing and left cavernous sinus, with displacement of the left middle cerebral artery, left cavernous internal carotid artery, and left optic canal. Dissection and removal of this tumor could have compromised the arterial or venous blood supply to the orbit, thus causing ischemia to the retina and other ocular structures. CN III was manipulated during surgery, and it may have been inadvertently damaged during exposure or resection of the tumor.

 

The patient’s Valsalva-dependent patent foramen ovale put her at risk of a paroxysmal embolus as an alternate explanation, particularly as a Valsalva maneuver was utilized to confirm hemostasis. The patient did not, however, demonstrate any evidence of venous thromboembolism (VTE) on ultrasound, nor did she have the common risk factors of hypertension, diabetes, or smoking history that would increase VTE risk.¹⁶ Her cancer diagnosis and surgical status may have put her at risk of VTE, but she did not have any clinical or laboratory values suggestive of hypercoagulability. Had an embolism occurred, it may have compromised the orbital blood supply and led to the CRAO. A similar scenario may have occurred from an atherosclerotic plaque in either of her carotid arteries, as she did have evidence of atherosclerosis on postoperative CT angiography. However, atherosclerosis as a risk factor for POVL appears to be related more to its impact upon impaired blood supply rather than as an embolic source. The patient did not have any significant intraoperative hypotensive episodes, making ION in the setting of atherosclerosis and hypotension a less likely etiology.¹⁷

This patient differed from other reported OCS cases. She was never placed in a prone or jackknife position, nor was she agitated or straining for a sustained period. These factors, along with the fact that the orbital compartment was not entered, decreased the likelihood of intraorbital hemorrhage and other intrinsic causes of elevated IOP.¹² Additionally, the presentation of our patient’s vision loss was delayed compared with other cases, despite clinicians observing a dilated left pupil and CN III palsy on examination immediately after surgery.¹⁴ It is significant to note that OCS may not demonstrate a significant increase in IOP once the source of compression is removed, which may explain the absence of proptosis on her postoperative examination.

The diagnosis of OCS was primarily implicated by the positioning of the myocutaneous flap during the pterional approach to craniotomy. It was retracted anteriorly and superiorly, ultimately resting over her left orbit for most of the 10-hour surgery. Kim and colleagues found that myocutaneous flaps may increase IOP as much as 17.5 mm Hg if improperly positioned, providing an unrecognized source of compression and increasing the risk of damage to orbital contents. According to their review, elevated IOP > 40 mm Hg, particularly over several hours, can compromise blood flow to the optic nerve and increase the risk for POVL.¹⁸ The flap was secured using fish hooks and rubber bands. However, it is suspected that the orbital rim did not fully support its pressure, thereby resting to some degree directly on the globe for an extended period and compromising the orbital blood supply. There are no current methods for measuring intraoperative IOP, though surrogate markers are under investigation and may yield clinical utility.¹⁸ The myocutaneous flap was created and positioned by the surgeons, but it may be that increased vigilance and communication from the anesthesia and nursing teams could have prevented it from remaining in an improper position.

Conclusions

Despite having few reported cases, OCS must be considered in neurosurgical patients with ophthalmoplegia and CRAO on postoperative examinations. Myocutaneous flaps that are retracted across the orbit can lead to significant elevations in IOP, leading to vision loss, which likely occurred with the patient in this case. Though protecting neurovascular structures is within the purview of the surgeon, all members of the intraoperative team should assist with ensuring proper flap positioning. These measures can help ensure adequate blood flow to the ophthalmic artery, decrease the likelihood of elevated IOP due to extrinsic compression, and help prevent the development of POVL and OCS in these patients.

The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.^1,2

The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.² Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.³ Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.²

Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.⁴ However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.⁴ Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.^5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.^5,6

When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.^7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.^10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.

 

Case 1

A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.

Case 2

A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.

Case 3

A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.

Case 4

A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.

Case 5

A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).

 

Discussion

Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.² Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.¹² The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.¹³ Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.¹³ Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.¹²

New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.² The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.² In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.

This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI, BHAGs are rare in these locations.^1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.

Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.^7-10

Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.⁷ In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.¹⁴

The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.

 

CONCLUSIONS

Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.

There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.¹⁵ However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.⁸ BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.

 

The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.^1,2

The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.² Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.³ Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.²

Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.⁴ However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.⁴ Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.^5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.^5,6

When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.^7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.^10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.

 

Case 1

A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.

Case 2

A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.

Case 3

A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.

Case 4

A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.

Case 5

A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).

 

Discussion

Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.² Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.¹² The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.¹³ Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.¹³ Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.¹²

New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.² The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.² In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.

This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI, BHAGs are rare in these locations.^1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.

Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.^7-10

Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.⁷ In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.¹⁴

The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.

 

CONCLUSIONS

Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.

There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.¹⁵ However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.⁸ BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.

 

The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.^1,2

The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.² Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.³ Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.²

Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.⁴ However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.⁴ Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.^5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.^5,6

When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.^7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.^10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.

 

Case 1

A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.

Case 2

A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.

Case 3

A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.

Case 4

A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.

Case 5

A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).

 

Discussion

Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.² Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.¹² The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.¹³ Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.¹³ Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.¹²

New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.² The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.² In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.

This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI, BHAGs are rare in these locations.^1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.

Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.^7-10

Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.⁷ In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.¹⁴

The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.

 

CONCLUSIONS

Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.

There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.¹⁵ However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.⁸ BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.

 

Allergic rhinoconjunctivitis causes onerous symptoms of sneezing, rhinorrhea, postnasal drip, nasal congestion, and itchy, watery eyes. It is a common condition that affects 10% to 25% of the US population and up to 23% of military members with increased symptoms during deployments.^1-3 Allergen immunotherapy (AIT), commonly known as allergy shots, is an effective treatment for allergic rhinoconjunctivitis, especially for patients whose symptoms are not controlled by allergy medications.⁴ Many military personnel who would like to receive AIT cannot continue with their immunotherapy because of frequent moves, deployments, and temporary duty assignments. This case report highlights the difficulty of managing AIT in the Military Health System.

Case Presentation

A 34-year-old active-duty US Air Force male surgeon with a medical history of allergic rhinoconjunctivitis was referred to the allergy clinic for evaluation and consideration of AIT. His symptoms included rhinorrhea, sneezing, nasal congestion, and itchy, watery eyes. The symptoms had been present for several years, occurring predominantly in the spring and fall, but also perennially when exposed to animals such as cats, dogs, and horses. The patient was raised on a ranch where he was exposed to these animals.

The patient had prior skin testing at the University of Nebraska Medical Center (UNMC) for aeroallergens and was positive for trees, grasses, weeds, molds, dust mites, cats, dogs, and horses. He received AIT at UNMC with great success for18 months. Regrettably, the patient discontinued AIT following a military move to Keesler Air Force Base in Mississippi. The patient’s examination was notable for injected conjunctiva, nasal mucosa edema, and a cobblestone throat. His symptoms were not alleviated with oral cetirizine and nasal fluticasone.

His skin testing was positive for trees, weeds, mold, cats, dogs, dust mites, and horsehair (Table). The risks and benefits of AIT were discussed with the patient, who elected to proceed with restarting AIT and received counseling on aeroallergen avoidance. The patient was unable to continue AIT at Keesler Medical Center because of a military deployment.

 

Discussion

There are several barriers to receiving AIT for active-duty patients with allergies. Due to previous skin test extracts, our patient had become desensitized to them. Though he had received aeroallergen immunotherapy with success for 18 months, the patients had to restart the build up phase of AIT due to a military-related move.

For patients to benefit from AIT, they must build up and maintain their immunotherapy injections for at least 3 to 5 years.⁴ The build-up period of immunotherapy lasts about 3 to 4 months. Patients typically receive weekly injections until they reach a maintenance immunotherapy dose of 0.5 mL of a 1:1 concentration ratio.⁴

Frequent deployments or temporary duty assignments are other barriers to AIT for active-duty patients. AIT is not usually given on deployments or temporary duty assignments unless the patient is located near a major military medical center. The US Air Force and Army operate allergy extender clinics at smaller bases and overseas locations to facilitate the maintenance of immunotherapy for military patients. Primary care physicians act as allergy extenders. These smaller allergy clinics are supervised by regional allergists at major military medical centers via telehealth and electronic/telephonic communication. These allergy clinics are not more widely available because there are not enough allergists and allergy medical technicians.

Allergen immunotherapy is not standardized, meaning civilian allergists use different aeroallergen immunotherapy formulations. While AIT is standardized in the US military through the Extract Laboratory Management System (ELMS), many active-duty patients are evaluated by civilian allergists in the TRICARE system who do not use ELMS, and when they move, AIT is not maintained.

Because up to 25% of active-duty personnel suffer from allergic rhinoconjunctivitis and AIT is not administered in many deployed settings, this issue could affect mission readiness and capabilities.^3-6 These personnel may suffer from frequent and severe nasal and ocular allergy symptoms without being able to continue AIT. There is the potential for adverse effects on the military missions because of these impaired military personnel.^5,6

Potential steps to improve the availability of allergen immunotherapy in the deployed setting include training deployed physicians, medical technicians, and other health care practitioners in administering and treating AIT so deployed personnel can receive therapy. Additionally, AIT should be standardized and ordered via the ELMS. Civilian allergists should be highly encouraged to use ELMS. This would create standardization of AIT for all active-duty allergy patients. The allergy extender system could be expanded to all military treatment facilities to provide easy access to allergen immunotherapy. The US Navy has the fewest allergists and allergy extenders, and would need to expand its network of allergy extenders to provide AIT at its health care facilities.

Conclusions

We present an active-duty servicemember with allergic rhinoconjunctivitis to trees, grasses, weeds, cats, dogs, dust mites, mold, and horses who had intermittent therapy that was interrupted by deployments. Our case highlights the difficulty of managing AIT in the military health system due to frequent moves, deployments, and temporary duty assignments. We also suggest steps that could help expand AIT for military personnel, including those deployed internationally.

Allergic rhinoconjunctivitis causes onerous symptoms of sneezing, rhinorrhea, postnasal drip, nasal congestion, and itchy, watery eyes. It is a common condition that affects 10% to 25% of the US population and up to 23% of military members with increased symptoms during deployments.^1-3 Allergen immunotherapy (AIT), commonly known as allergy shots, is an effective treatment for allergic rhinoconjunctivitis, especially for patients whose symptoms are not controlled by allergy medications.⁴ Many military personnel who would like to receive AIT cannot continue with their immunotherapy because of frequent moves, deployments, and temporary duty assignments. This case report highlights the difficulty of managing AIT in the Military Health System.

Case Presentation

A 34-year-old active-duty US Air Force male surgeon with a medical history of allergic rhinoconjunctivitis was referred to the allergy clinic for evaluation and consideration of AIT. His symptoms included rhinorrhea, sneezing, nasal congestion, and itchy, watery eyes. The symptoms had been present for several years, occurring predominantly in the spring and fall, but also perennially when exposed to animals such as cats, dogs, and horses. The patient was raised on a ranch where he was exposed to these animals.

The patient had prior skin testing at the University of Nebraska Medical Center (UNMC) for aeroallergens and was positive for trees, grasses, weeds, molds, dust mites, cats, dogs, and horses. He received AIT at UNMC with great success for18 months. Regrettably, the patient discontinued AIT following a military move to Keesler Air Force Base in Mississippi. The patient’s examination was notable for injected conjunctiva, nasal mucosa edema, and a cobblestone throat. His symptoms were not alleviated with oral cetirizine and nasal fluticasone.

His skin testing was positive for trees, weeds, mold, cats, dogs, dust mites, and horsehair (Table). The risks and benefits of AIT were discussed with the patient, who elected to proceed with restarting AIT and received counseling on aeroallergen avoidance. The patient was unable to continue AIT at Keesler Medical Center because of a military deployment.

 

Discussion

There are several barriers to receiving AIT for active-duty patients with allergies. Due to previous skin test extracts, our patient had become desensitized to them. Though he had received aeroallergen immunotherapy with success for 18 months, the patients had to restart the build up phase of AIT due to a military-related move.

For patients to benefit from AIT, they must build up and maintain their immunotherapy injections for at least 3 to 5 years.⁴ The build-up period of immunotherapy lasts about 3 to 4 months. Patients typically receive weekly injections until they reach a maintenance immunotherapy dose of 0.5 mL of a 1:1 concentration ratio.⁴

Frequent deployments or temporary duty assignments are other barriers to AIT for active-duty patients. AIT is not usually given on deployments or temporary duty assignments unless the patient is located near a major military medical center. The US Air Force and Army operate allergy extender clinics at smaller bases and overseas locations to facilitate the maintenance of immunotherapy for military patients. Primary care physicians act as allergy extenders. These smaller allergy clinics are supervised by regional allergists at major military medical centers via telehealth and electronic/telephonic communication. These allergy clinics are not more widely available because there are not enough allergists and allergy medical technicians.

Allergen immunotherapy is not standardized, meaning civilian allergists use different aeroallergen immunotherapy formulations. While AIT is standardized in the US military through the Extract Laboratory Management System (ELMS), many active-duty patients are evaluated by civilian allergists in the TRICARE system who do not use ELMS, and when they move, AIT is not maintained.

Because up to 25% of active-duty personnel suffer from allergic rhinoconjunctivitis and AIT is not administered in many deployed settings, this issue could affect mission readiness and capabilities.^3-6 These personnel may suffer from frequent and severe nasal and ocular allergy symptoms without being able to continue AIT. There is the potential for adverse effects on the military missions because of these impaired military personnel.^5,6

Potential steps to improve the availability of allergen immunotherapy in the deployed setting include training deployed physicians, medical technicians, and other health care practitioners in administering and treating AIT so deployed personnel can receive therapy. Additionally, AIT should be standardized and ordered via the ELMS. Civilian allergists should be highly encouraged to use ELMS. This would create standardization of AIT for all active-duty allergy patients. The allergy extender system could be expanded to all military treatment facilities to provide easy access to allergen immunotherapy. The US Navy has the fewest allergists and allergy extenders, and would need to expand its network of allergy extenders to provide AIT at its health care facilities.

Conclusions

We present an active-duty servicemember with allergic rhinoconjunctivitis to trees, grasses, weeds, cats, dogs, dust mites, mold, and horses who had intermittent therapy that was interrupted by deployments. Our case highlights the difficulty of managing AIT in the military health system due to frequent moves, deployments, and temporary duty assignments. We also suggest steps that could help expand AIT for military personnel, including those deployed internationally.

Allergic rhinoconjunctivitis causes onerous symptoms of sneezing, rhinorrhea, postnasal drip, nasal congestion, and itchy, watery eyes. It is a common condition that affects 10% to 25% of the US population and up to 23% of military members with increased symptoms during deployments.^1-3 Allergen immunotherapy (AIT), commonly known as allergy shots, is an effective treatment for allergic rhinoconjunctivitis, especially for patients whose symptoms are not controlled by allergy medications.⁴ Many military personnel who would like to receive AIT cannot continue with their immunotherapy because of frequent moves, deployments, and temporary duty assignments. This case report highlights the difficulty of managing AIT in the Military Health System.

Case Presentation

A 34-year-old active-duty US Air Force male surgeon with a medical history of allergic rhinoconjunctivitis was referred to the allergy clinic for evaluation and consideration of AIT. His symptoms included rhinorrhea, sneezing, nasal congestion, and itchy, watery eyes. The symptoms had been present for several years, occurring predominantly in the spring and fall, but also perennially when exposed to animals such as cats, dogs, and horses. The patient was raised on a ranch where he was exposed to these animals.

The patient had prior skin testing at the University of Nebraska Medical Center (UNMC) for aeroallergens and was positive for trees, grasses, weeds, molds, dust mites, cats, dogs, and horses. He received AIT at UNMC with great success for18 months. Regrettably, the patient discontinued AIT following a military move to Keesler Air Force Base in Mississippi. The patient’s examination was notable for injected conjunctiva, nasal mucosa edema, and a cobblestone throat. His symptoms were not alleviated with oral cetirizine and nasal fluticasone.

His skin testing was positive for trees, weeds, mold, cats, dogs, dust mites, and horsehair (Table). The risks and benefits of AIT were discussed with the patient, who elected to proceed with restarting AIT and received counseling on aeroallergen avoidance. The patient was unable to continue AIT at Keesler Medical Center because of a military deployment.

 

Discussion

There are several barriers to receiving AIT for active-duty patients with allergies. Due to previous skin test extracts, our patient had become desensitized to them. Though he had received aeroallergen immunotherapy with success for 18 months, the patients had to restart the build up phase of AIT due to a military-related move.

For patients to benefit from AIT, they must build up and maintain their immunotherapy injections for at least 3 to 5 years.⁴ The build-up period of immunotherapy lasts about 3 to 4 months. Patients typically receive weekly injections until they reach a maintenance immunotherapy dose of 0.5 mL of a 1:1 concentration ratio.⁴

Frequent deployments or temporary duty assignments are other barriers to AIT for active-duty patients. AIT is not usually given on deployments or temporary duty assignments unless the patient is located near a major military medical center. The US Air Force and Army operate allergy extender clinics at smaller bases and overseas locations to facilitate the maintenance of immunotherapy for military patients. Primary care physicians act as allergy extenders. These smaller allergy clinics are supervised by regional allergists at major military medical centers via telehealth and electronic/telephonic communication. These allergy clinics are not more widely available because there are not enough allergists and allergy medical technicians.

Allergen immunotherapy is not standardized, meaning civilian allergists use different aeroallergen immunotherapy formulations. While AIT is standardized in the US military through the Extract Laboratory Management System (ELMS), many active-duty patients are evaluated by civilian allergists in the TRICARE system who do not use ELMS, and when they move, AIT is not maintained.

Because up to 25% of active-duty personnel suffer from allergic rhinoconjunctivitis and AIT is not administered in many deployed settings, this issue could affect mission readiness and capabilities.^3-6 These personnel may suffer from frequent and severe nasal and ocular allergy symptoms without being able to continue AIT. There is the potential for adverse effects on the military missions because of these impaired military personnel.^5,6

Potential steps to improve the availability of allergen immunotherapy in the deployed setting include training deployed physicians, medical technicians, and other health care practitioners in administering and treating AIT so deployed personnel can receive therapy. Additionally, AIT should be standardized and ordered via the ELMS. Civilian allergists should be highly encouraged to use ELMS. This would create standardization of AIT for all active-duty allergy patients. The allergy extender system could be expanded to all military treatment facilities to provide easy access to allergen immunotherapy. The US Navy has the fewest allergists and allergy extenders, and would need to expand its network of allergy extenders to provide AIT at its health care facilities.

Conclusions

We present an active-duty servicemember with allergic rhinoconjunctivitis to trees, grasses, weeds, cats, dogs, dust mites, mold, and horses who had intermittent therapy that was interrupted by deployments. Our case highlights the difficulty of managing AIT in the military health system due to frequent moves, deployments, and temporary duty assignments. We also suggest steps that could help expand AIT for military personnel, including those deployed internationally.

Rosai Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis first described in 1965 by Destombes and again in 1969 by Rosai and Dorfman to depict patients who presented with massive cervical lymphadenopathy.¹ The classification for histiocytosis was revised in 2016 based on new insights into the pathologic, genetic, and molecular features of RDD.^2,3 Now, RDD is listed under the R group, which includes familial, sporadic, classical (nodal), extranodal RDD, and other noncutaneous, non-Langerhans cell histiocytosis.³ Cutaneous RDD is classified under the C group and typically presents as painless papules, plaques, or nodules without significant lymphadenopathy, or systemic symptoms usually seen in the presentation of RDD.⁴

The etiology of RDD is poorly understood, although an underlying infectious or genetic component is suspected.⁵ Several pathogens—including human herpesvirus 6, parvovirus B19, Epstein-Barr virus, cytomegalovirus, Brucella, and Klebsiella—have all been investigated. A link to kinase mutations has been described in nodal and extranodal RDD; however, the molecular profile of cutaneous RDD remains unknown.² Histologic findings for RDD typically include cells that are S100 positive, CD68 positive, and CD163 positive, and CD1a and langerin (CD207) negative, thus excluding Langerhans cell histiocytosis.² The hallmark finding of RDD is emperipolesis, which results from “histiocyte-mediated phagocytosis of intact lymphocytes and other immune cells.”⁶ Immunoglobulin G (Ig) G4-positive plasma cells are also common, but the significance of this finding is controversial. We present a case of a patient with recurrent RDD within a right medial thigh lipoma and include a literature review to explore the significance of histologic findings and various treatment options in the setting of emerging treatment and diagnostic criteria.

Case Presentation

A 56-year-old African American male was evaluated in the rheumatology clinic at the Central Texas Veterans Affairs Medical Center in Temple, Texas, in 2022 for a cutaneous mass of his right medial thigh. The patient previously reported the onset of a right medial thigh mass in 2005 after he had been deployed in Iraq for about 1 year. A biopsy of the mass from 2005 showed infiltration of plasma cells, lymphocytes, and histiocytes and occasional neutrophils with noted reactivity of S100 protein and CD163, but not CD1a. The patient’s original biopsy report from March 2005 was obtained secondhand from an addendum to a Dermatology Consult note. Surgical excision of the mass was not performed until 2012 and systemic therapy was not initiated.

In 2021, the mass recurred and gradually increased in size, prompting a second surgical removal. Pathology results from the 2021 mass showed a lipoma with areas of fibrosis with a mixed inflammatory cell infiltrate, including abundant lymphocytes, plasma cells, occasional hemosiderin-laden histiocytes, and clusters of enlarged histiocytes with foamy to pale eosinophilic, finely granular cytoplasm, and large, round, vesicular nuclei with prominent nucleoli. Emperipolesis was also present (Figure 1).

Special immunohistochemical staining showed most of the lymphocytes were CD20 positive B-cells with a minority of CD3 positive T-cells. Histiocytes were CD163 positive and CD68 positive with patchy reactivity for S100 protein. The plasma cells were CD138 positive. There were > 125 IgG4-positive plasma cells present in a single high-powered field and the overall IgG4:IgG plasma cell ratio was > 40%. Pertinent imaging included a whole-body positron emission tomography/computed tomography (PET/CT) hypermetabolic activity scan of a small right femoral lymph node (9 mm) and nearby medial right femoral lymph node (13 mm) (Figure 2A). A well-defined mass in the medial aspect of the right thigh (2.5 cm x 3.2 cm x 3.9 cm) and a cutaneous/subcutaneous lesion of the anterior medial aspect of the proximal right thigh superior to the mass (2.9 cm) were also evident on imaging (Figure 2B). Each area of hypermetabolic activity had decreased in size and activity when compared to a previous PET/CT obtained 1 month earlier. There was no evidence of skeletal malignancy. A physical examination did not reveal any other soft tissue masses, palpable lymphadenopathy, or areas of skin involvement. Given the patient’s reassuring imaging findings and a lack of any new physical examination findings, no systemic therapy was initiated, and following shared decision making, the patient agreed to a period of watchful waiting. 

 

 

Discussion

RDD is rare with a prevalence of 1:200,000. It has been reported that multisystem involvement occurs in 19% of cases and the prognosis of RDD correlates with the number of extranodal systems involved in the disease process.⁷ Although sporadic RDD is usually self-limited with favorable outcomes, it is estimated that 10% of patients may die of RDD due to direct complications, infections, and amyloidosis.^2,7 RDD commonly affects young male children and young adults with a mean age of 20 years and has a higher incidence among African American children.^2,7,8 Although patients with RDD present bilateral, painless cervical lymphadenopathy in 90% of cases, about 43% of patients with RDD and associated adenopathy present with ≥ 1 site of extranodal involvement, and only 23% of patients with RDD present with isolated extranodal sites without adenopathy.⁹ As was the case with our patient, the most common extranodal sites are found in the skin and soft tissue (16%).^6,9 However, histopathologic diagnosis of RDD in a lipoma is exceedingly rare. We found only 1 other case report of a patient with a history of multiple lipomas who developed a new solitary nodule that was excised and demonstrated RDD upon immunohistochemical staining.⁴ There has been no documented association between multiple lipomas and RDD.⁴

Histologically, RDD is often characterized by emperipolesis (the presence of an intact cell within the cytoplasm of anther cell) and a mixed cell infiltrate that includes S100 positive histiocytes, mononuclear cells, plasma cells, and lymphocytes.¹⁰ Despite these shared histologic features among the various phenotypes of RDD, other type-specific characteristics may also be present. When compared to nodal RDD, extranodal disease tends to demonstrate a lack of nodal architecture, more fibrosis and collagen deposition, fewer RDD cells, a lower degree of emperipolesis, and alternating pale (histiocyte rich) and dark (lymphocyte rich) regions with notable polygonal histiocytes arranged in a storiform pattern.^5,10

Our patient’s histology showed an overall IgG4:IgG plasma cell ratio > 40%. RDD frequently presents with IgG4-positive plasma cells, which has confounded the diagnosis of IgG4-related diseases and hyper-IgG4 disease.¹¹ Given this association, the Histiocyte Society revised classification recommends that all cases of RDD be evaluated for IgG4-positive cell infiltration.^2,3 Further discussion on this matter was recently provided after an expert panel published a consensus statement in 2015 detailing the evaluation of IgG4. The panel advocates for stricter terminology and criteria on this issue, advises that isolated IgG4-positive plasma cells are nonspecific, and states that the diagnosis of IgG4 disease should be based on careful judgment and correlation with the clinical scenario and supportive findings.¹² Therefore, while IgG4 positivity continues to be misleading in RDD cases, further evaluation for IgG4 disease is recommended. 

Sporadic RDD is usually self-limited with a reported remission rate of up to 50%, according to a case series of 80 patients with RDD.¹³ This leads to the recommendation of a period of watchful monitoring in patients with limited disease.¹³ In patients with unifocal extranodal disease, surgical excision has shown positive remission results; however, local recurrence of soft tissue lesions can occur at a rate of 21.4% to 51%.¹⁴ Although initiation of systemic therapy should be considered in patients with recurrent disease, there is currently no standardized regimen or medication of choice for treatment. Treatment with steroids, including prednisone 40 to 70 mg daily or dexamethasone 8 to 20 mg daily, have been shown to be effective in reducing the nodal size and symptoms, especially in cases of nonresectable multifocal extranodal disease of the central nervous system, bone, and orbital.^7,15,16 However, cases of orbital, tracheal, renal, or soft tissue RDD have reported failure in treatment with steroids.^17,18

According to the consensus recommendations for the treatment of RDD released in 2018, treatment with chemotherapy has shown mixed results. Anthracycline and alkylating agents have shown minimal efficacy, but combination regimens with vinca alkaloids, methotrexate, and 6-mercaptopurine have helped patients experience remission.^19,20 Due to the rarity of RDD and lack of clinical trials, the exact efficacy of these treatment regimens remains unknown and is largely limited to case reports described within the medical literature. Treatment with nucleoside analogs, such as cladribine 2.1 to 5 mg/m² or clofarabine 25 mg/m² per day for 5 days every 28 days for 6 months, have shown promising results and helped achieve complete remission in patients with refractory or recurrent RDD.^7,21-23 Immunomodulator therapies including TNF-α inhibitor, such as thalidomide and lenalidomide, have also shown to be effective, particularly in patients with refractory disease.^24,25 Low-dose thalidomide (100 mg daily) was effective for cases of refractory cutaneous RDD, though no standard dosing regimen exists. Lenalidomide has shown to be effective in patients with multiple refractory nodal or bone RDD, but is associated with more complications given that it is more myelosuppressive than thalidomide.⁷ Radiotherapy has also been initiated in patients with refractory soft tissue disease or persistent symptoms after resection and in patients who are not candidates for surgery or systemic therapy, though no standard doses of radiotherapy have been established.^7,26,27

Conclusions

RDD is a rare histiocytic disorder that presents in a wide range of age groups, different locations in the body, and with variable disease behavior. Multidisciplinary management of the disease and research for mutations and microenvironment of RDD is needed to better understand its clinicopathological nature and improve targeted novel therapies.

Acknowledgments

The authors thank Veterans Affairs Central Texas Health Care Section Chief of Rheumatology, Swastika Jha, MD, for her guidance in this case and Bo Wang, MD, for his preparation of the pathological specimens. 

Rosai Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis first described in 1965 by Destombes and again in 1969 by Rosai and Dorfman to depict patients who presented with massive cervical lymphadenopathy.¹ The classification for histiocytosis was revised in 2016 based on new insights into the pathologic, genetic, and molecular features of RDD.^2,3 Now, RDD is listed under the R group, which includes familial, sporadic, classical (nodal), extranodal RDD, and other noncutaneous, non-Langerhans cell histiocytosis.³ Cutaneous RDD is classified under the C group and typically presents as painless papules, plaques, or nodules without significant lymphadenopathy, or systemic symptoms usually seen in the presentation of RDD.⁴

The etiology of RDD is poorly understood, although an underlying infectious or genetic component is suspected.⁵ Several pathogens—including human herpesvirus 6, parvovirus B19, Epstein-Barr virus, cytomegalovirus, Brucella, and Klebsiella—have all been investigated. A link to kinase mutations has been described in nodal and extranodal RDD; however, the molecular profile of cutaneous RDD remains unknown.² Histologic findings for RDD typically include cells that are S100 positive, CD68 positive, and CD163 positive, and CD1a and langerin (CD207) negative, thus excluding Langerhans cell histiocytosis.² The hallmark finding of RDD is emperipolesis, which results from “histiocyte-mediated phagocytosis of intact lymphocytes and other immune cells.”⁶ Immunoglobulin G (Ig) G4-positive plasma cells are also common, but the significance of this finding is controversial. We present a case of a patient with recurrent RDD within a right medial thigh lipoma and include a literature review to explore the significance of histologic findings and various treatment options in the setting of emerging treatment and diagnostic criteria.

Case Presentation

A 56-year-old African American male was evaluated in the rheumatology clinic at the Central Texas Veterans Affairs Medical Center in Temple, Texas, in 2022 for a cutaneous mass of his right medial thigh. The patient previously reported the onset of a right medial thigh mass in 2005 after he had been deployed in Iraq for about 1 year. A biopsy of the mass from 2005 showed infiltration of plasma cells, lymphocytes, and histiocytes and occasional neutrophils with noted reactivity of S100 protein and CD163, but not CD1a. The patient’s original biopsy report from March 2005 was obtained secondhand from an addendum to a Dermatology Consult note. Surgical excision of the mass was not performed until 2012 and systemic therapy was not initiated.

In 2021, the mass recurred and gradually increased in size, prompting a second surgical removal. Pathology results from the 2021 mass showed a lipoma with areas of fibrosis with a mixed inflammatory cell infiltrate, including abundant lymphocytes, plasma cells, occasional hemosiderin-laden histiocytes, and clusters of enlarged histiocytes with foamy to pale eosinophilic, finely granular cytoplasm, and large, round, vesicular nuclei with prominent nucleoli. Emperipolesis was also present (Figure 1).

Special immunohistochemical staining showed most of the lymphocytes were CD20 positive B-cells with a minority of CD3 positive T-cells. Histiocytes were CD163 positive and CD68 positive with patchy reactivity for S100 protein. The plasma cells were CD138 positive. There were > 125 IgG4-positive plasma cells present in a single high-powered field and the overall IgG4:IgG plasma cell ratio was > 40%. Pertinent imaging included a whole-body positron emission tomography/computed tomography (PET/CT) hypermetabolic activity scan of a small right femoral lymph node (9 mm) and nearby medial right femoral lymph node (13 mm) (Figure 2A). A well-defined mass in the medial aspect of the right thigh (2.5 cm x 3.2 cm x 3.9 cm) and a cutaneous/subcutaneous lesion of the anterior medial aspect of the proximal right thigh superior to the mass (2.9 cm) were also evident on imaging (Figure 2B). Each area of hypermetabolic activity had decreased in size and activity when compared to a previous PET/CT obtained 1 month earlier. There was no evidence of skeletal malignancy. A physical examination did not reveal any other soft tissue masses, palpable lymphadenopathy, or areas of skin involvement. Given the patient’s reassuring imaging findings and a lack of any new physical examination findings, no systemic therapy was initiated, and following shared decision making, the patient agreed to a period of watchful waiting. 

 

 

Discussion

RDD is rare with a prevalence of 1:200,000. It has been reported that multisystem involvement occurs in 19% of cases and the prognosis of RDD correlates with the number of extranodal systems involved in the disease process.⁷ Although sporadic RDD is usually self-limited with favorable outcomes, it is estimated that 10% of patients may die of RDD due to direct complications, infections, and amyloidosis.^2,7 RDD commonly affects young male children and young adults with a mean age of 20 years and has a higher incidence among African American children.^2,7,8 Although patients with RDD present bilateral, painless cervical lymphadenopathy in 90% of cases, about 43% of patients with RDD and associated adenopathy present with ≥ 1 site of extranodal involvement, and only 23% of patients with RDD present with isolated extranodal sites without adenopathy.⁹ As was the case with our patient, the most common extranodal sites are found in the skin and soft tissue (16%).^6,9 However, histopathologic diagnosis of RDD in a lipoma is exceedingly rare. We found only 1 other case report of a patient with a history of multiple lipomas who developed a new solitary nodule that was excised and demonstrated RDD upon immunohistochemical staining.⁴ There has been no documented association between multiple lipomas and RDD.⁴

Histologically, RDD is often characterized by emperipolesis (the presence of an intact cell within the cytoplasm of anther cell) and a mixed cell infiltrate that includes S100 positive histiocytes, mononuclear cells, plasma cells, and lymphocytes.¹⁰ Despite these shared histologic features among the various phenotypes of RDD, other type-specific characteristics may also be present. When compared to nodal RDD, extranodal disease tends to demonstrate a lack of nodal architecture, more fibrosis and collagen deposition, fewer RDD cells, a lower degree of emperipolesis, and alternating pale (histiocyte rich) and dark (lymphocyte rich) regions with notable polygonal histiocytes arranged in a storiform pattern.^5,10

Our patient’s histology showed an overall IgG4:IgG plasma cell ratio > 40%. RDD frequently presents with IgG4-positive plasma cells, which has confounded the diagnosis of IgG4-related diseases and hyper-IgG4 disease.¹¹ Given this association, the Histiocyte Society revised classification recommends that all cases of RDD be evaluated for IgG4-positive cell infiltration.^2,3 Further discussion on this matter was recently provided after an expert panel published a consensus statement in 2015 detailing the evaluation of IgG4. The panel advocates for stricter terminology and criteria on this issue, advises that isolated IgG4-positive plasma cells are nonspecific, and states that the diagnosis of IgG4 disease should be based on careful judgment and correlation with the clinical scenario and supportive findings.¹² Therefore, while IgG4 positivity continues to be misleading in RDD cases, further evaluation for IgG4 disease is recommended. 

Sporadic RDD is usually self-limited with a reported remission rate of up to 50%, according to a case series of 80 patients with RDD.¹³ This leads to the recommendation of a period of watchful monitoring in patients with limited disease.¹³ In patients with unifocal extranodal disease, surgical excision has shown positive remission results; however, local recurrence of soft tissue lesions can occur at a rate of 21.4% to 51%.¹⁴ Although initiation of systemic therapy should be considered in patients with recurrent disease, there is currently no standardized regimen or medication of choice for treatment. Treatment with steroids, including prednisone 40 to 70 mg daily or dexamethasone 8 to 20 mg daily, have been shown to be effective in reducing the nodal size and symptoms, especially in cases of nonresectable multifocal extranodal disease of the central nervous system, bone, and orbital.^7,15,16 However, cases of orbital, tracheal, renal, or soft tissue RDD have reported failure in treatment with steroids.^17,18

According to the consensus recommendations for the treatment of RDD released in 2018, treatment with chemotherapy has shown mixed results. Anthracycline and alkylating agents have shown minimal efficacy, but combination regimens with vinca alkaloids, methotrexate, and 6-mercaptopurine have helped patients experience remission.^19,20 Due to the rarity of RDD and lack of clinical trials, the exact efficacy of these treatment regimens remains unknown and is largely limited to case reports described within the medical literature. Treatment with nucleoside analogs, such as cladribine 2.1 to 5 mg/m² or clofarabine 25 mg/m² per day for 5 days every 28 days for 6 months, have shown promising results and helped achieve complete remission in patients with refractory or recurrent RDD.^7,21-23 Immunomodulator therapies including TNF-α inhibitor, such as thalidomide and lenalidomide, have also shown to be effective, particularly in patients with refractory disease.^24,25 Low-dose thalidomide (100 mg daily) was effective for cases of refractory cutaneous RDD, though no standard dosing regimen exists. Lenalidomide has shown to be effective in patients with multiple refractory nodal or bone RDD, but is associated with more complications given that it is more myelosuppressive than thalidomide.⁷ Radiotherapy has also been initiated in patients with refractory soft tissue disease or persistent symptoms after resection and in patients who are not candidates for surgery or systemic therapy, though no standard doses of radiotherapy have been established.^7,26,27

Conclusions

RDD is a rare histiocytic disorder that presents in a wide range of age groups, different locations in the body, and with variable disease behavior. Multidisciplinary management of the disease and research for mutations and microenvironment of RDD is needed to better understand its clinicopathological nature and improve targeted novel therapies.

Acknowledgments

The authors thank Veterans Affairs Central Texas Health Care Section Chief of Rheumatology, Swastika Jha, MD, for her guidance in this case and Bo Wang, MD, for his preparation of the pathological specimens. 

Rosai Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis first described in 1965 by Destombes and again in 1969 by Rosai and Dorfman to depict patients who presented with massive cervical lymphadenopathy.¹ The classification for histiocytosis was revised in 2016 based on new insights into the pathologic, genetic, and molecular features of RDD.^2,3 Now, RDD is listed under the R group, which includes familial, sporadic, classical (nodal), extranodal RDD, and other noncutaneous, non-Langerhans cell histiocytosis.³ Cutaneous RDD is classified under the C group and typically presents as painless papules, plaques, or nodules without significant lymphadenopathy, or systemic symptoms usually seen in the presentation of RDD.⁴

The etiology of RDD is poorly understood, although an underlying infectious or genetic component is suspected.⁵ Several pathogens—including human herpesvirus 6, parvovirus B19, Epstein-Barr virus, cytomegalovirus, Brucella, and Klebsiella—have all been investigated. A link to kinase mutations has been described in nodal and extranodal RDD; however, the molecular profile of cutaneous RDD remains unknown.² Histologic findings for RDD typically include cells that are S100 positive, CD68 positive, and CD163 positive, and CD1a and langerin (CD207) negative, thus excluding Langerhans cell histiocytosis.² The hallmark finding of RDD is emperipolesis, which results from “histiocyte-mediated phagocytosis of intact lymphocytes and other immune cells.”⁶ Immunoglobulin G (Ig) G4-positive plasma cells are also common, but the significance of this finding is controversial. We present a case of a patient with recurrent RDD within a right medial thigh lipoma and include a literature review to explore the significance of histologic findings and various treatment options in the setting of emerging treatment and diagnostic criteria.

Case Presentation

A 56-year-old African American male was evaluated in the rheumatology clinic at the Central Texas Veterans Affairs Medical Center in Temple, Texas, in 2022 for a cutaneous mass of his right medial thigh. The patient previously reported the onset of a right medial thigh mass in 2005 after he had been deployed in Iraq for about 1 year. A biopsy of the mass from 2005 showed infiltration of plasma cells, lymphocytes, and histiocytes and occasional neutrophils with noted reactivity of S100 protein and CD163, but not CD1a. The patient’s original biopsy report from March 2005 was obtained secondhand from an addendum to a Dermatology Consult note. Surgical excision of the mass was not performed until 2012 and systemic therapy was not initiated.

In 2021, the mass recurred and gradually increased in size, prompting a second surgical removal. Pathology results from the 2021 mass showed a lipoma with areas of fibrosis with a mixed inflammatory cell infiltrate, including abundant lymphocytes, plasma cells, occasional hemosiderin-laden histiocytes, and clusters of enlarged histiocytes with foamy to pale eosinophilic, finely granular cytoplasm, and large, round, vesicular nuclei with prominent nucleoli. Emperipolesis was also present (Figure 1).

Special immunohistochemical staining showed most of the lymphocytes were CD20 positive B-cells with a minority of CD3 positive T-cells. Histiocytes were CD163 positive and CD68 positive with patchy reactivity for S100 protein. The plasma cells were CD138 positive. There were > 125 IgG4-positive plasma cells present in a single high-powered field and the overall IgG4:IgG plasma cell ratio was > 40%. Pertinent imaging included a whole-body positron emission tomography/computed tomography (PET/CT) hypermetabolic activity scan of a small right femoral lymph node (9 mm) and nearby medial right femoral lymph node (13 mm) (Figure 2A). A well-defined mass in the medial aspect of the right thigh (2.5 cm x 3.2 cm x 3.9 cm) and a cutaneous/subcutaneous lesion of the anterior medial aspect of the proximal right thigh superior to the mass (2.9 cm) were also evident on imaging (Figure 2B). Each area of hypermetabolic activity had decreased in size and activity when compared to a previous PET/CT obtained 1 month earlier. There was no evidence of skeletal malignancy. A physical examination did not reveal any other soft tissue masses, palpable lymphadenopathy, or areas of skin involvement. Given the patient’s reassuring imaging findings and a lack of any new physical examination findings, no systemic therapy was initiated, and following shared decision making, the patient agreed to a period of watchful waiting. 

 

 

Discussion

RDD is rare with a prevalence of 1:200,000. It has been reported that multisystem involvement occurs in 19% of cases and the prognosis of RDD correlates with the number of extranodal systems involved in the disease process.⁷ Although sporadic RDD is usually self-limited with favorable outcomes, it is estimated that 10% of patients may die of RDD due to direct complications, infections, and amyloidosis.^2,7 RDD commonly affects young male children and young adults with a mean age of 20 years and has a higher incidence among African American children.^2,7,8 Although patients with RDD present bilateral, painless cervical lymphadenopathy in 90% of cases, about 43% of patients with RDD and associated adenopathy present with ≥ 1 site of extranodal involvement, and only 23% of patients with RDD present with isolated extranodal sites without adenopathy.⁹ As was the case with our patient, the most common extranodal sites are found in the skin and soft tissue (16%).^6,9 However, histopathologic diagnosis of RDD in a lipoma is exceedingly rare. We found only 1 other case report of a patient with a history of multiple lipomas who developed a new solitary nodule that was excised and demonstrated RDD upon immunohistochemical staining.⁴ There has been no documented association between multiple lipomas and RDD.⁴

Histologically, RDD is often characterized by emperipolesis (the presence of an intact cell within the cytoplasm of anther cell) and a mixed cell infiltrate that includes S100 positive histiocytes, mononuclear cells, plasma cells, and lymphocytes.¹⁰ Despite these shared histologic features among the various phenotypes of RDD, other type-specific characteristics may also be present. When compared to nodal RDD, extranodal disease tends to demonstrate a lack of nodal architecture, more fibrosis and collagen deposition, fewer RDD cells, a lower degree of emperipolesis, and alternating pale (histiocyte rich) and dark (lymphocyte rich) regions with notable polygonal histiocytes arranged in a storiform pattern.^5,10

Our patient’s histology showed an overall IgG4:IgG plasma cell ratio > 40%. RDD frequently presents with IgG4-positive plasma cells, which has confounded the diagnosis of IgG4-related diseases and hyper-IgG4 disease.¹¹ Given this association, the Histiocyte Society revised classification recommends that all cases of RDD be evaluated for IgG4-positive cell infiltration.^2,3 Further discussion on this matter was recently provided after an expert panel published a consensus statement in 2015 detailing the evaluation of IgG4. The panel advocates for stricter terminology and criteria on this issue, advises that isolated IgG4-positive plasma cells are nonspecific, and states that the diagnosis of IgG4 disease should be based on careful judgment and correlation with the clinical scenario and supportive findings.¹² Therefore, while IgG4 positivity continues to be misleading in RDD cases, further evaluation for IgG4 disease is recommended. 

Sporadic RDD is usually self-limited with a reported remission rate of up to 50%, according to a case series of 80 patients with RDD.¹³ This leads to the recommendation of a period of watchful monitoring in patients with limited disease.¹³ In patients with unifocal extranodal disease, surgical excision has shown positive remission results; however, local recurrence of soft tissue lesions can occur at a rate of 21.4% to 51%.¹⁴ Although initiation of systemic therapy should be considered in patients with recurrent disease, there is currently no standardized regimen or medication of choice for treatment. Treatment with steroids, including prednisone 40 to 70 mg daily or dexamethasone 8 to 20 mg daily, have been shown to be effective in reducing the nodal size and symptoms, especially in cases of nonresectable multifocal extranodal disease of the central nervous system, bone, and orbital.^7,15,16 However, cases of orbital, tracheal, renal, or soft tissue RDD have reported failure in treatment with steroids.^17,18

According to the consensus recommendations for the treatment of RDD released in 2018, treatment with chemotherapy has shown mixed results. Anthracycline and alkylating agents have shown minimal efficacy, but combination regimens with vinca alkaloids, methotrexate, and 6-mercaptopurine have helped patients experience remission.^19,20 Due to the rarity of RDD and lack of clinical trials, the exact efficacy of these treatment regimens remains unknown and is largely limited to case reports described within the medical literature. Treatment with nucleoside analogs, such as cladribine 2.1 to 5 mg/m² or clofarabine 25 mg/m² per day for 5 days every 28 days for 6 months, have shown promising results and helped achieve complete remission in patients with refractory or recurrent RDD.^7,21-23 Immunomodulator therapies including TNF-α inhibitor, such as thalidomide and lenalidomide, have also shown to be effective, particularly in patients with refractory disease.^24,25 Low-dose thalidomide (100 mg daily) was effective for cases of refractory cutaneous RDD, though no standard dosing regimen exists. Lenalidomide has shown to be effective in patients with multiple refractory nodal or bone RDD, but is associated with more complications given that it is more myelosuppressive than thalidomide.⁷ Radiotherapy has also been initiated in patients with refractory soft tissue disease or persistent symptoms after resection and in patients who are not candidates for surgery or systemic therapy, though no standard doses of radiotherapy have been established.^7,26,27

Conclusions

RDD is a rare histiocytic disorder that presents in a wide range of age groups, different locations in the body, and with variable disease behavior. Multidisciplinary management of the disease and research for mutations and microenvironment of RDD is needed to better understand its clinicopathological nature and improve targeted novel therapies.

Acknowledgments

The authors thank Veterans Affairs Central Texas Health Care Section Chief of Rheumatology, Swastika Jha, MD, for her guidance in this case and Bo Wang, MD, for his preparation of the pathological specimens. 

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

 

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

 

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

 

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.