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Intraoperative Fat Embolism During Core Decompression and Bone Grafting for Osteonecrosis of the Hip: Report of 3 Cases and Literature Review
Delayed Presentation of a Cervical Spine Fracture Dislocation With Posterior Ligamentous Disruption in a Gymnast
PSA flare after initiation of abiraterone acetate
Prostate cancer is the second-most common cause of male cancer-related death among US men. The American Cancer Society estimates that in 2014 there will be about 233,000 new cases of prostate cancer and about 29,500 deaths due to prostate cancer.1 Sixty percent of cases are diagnosed in men aged 65 years or older. Localized prostate cancers are managed with active surveillance or external beam radiation therapy or radical prostatectomy after risk stratification. Advanced prostate cancers are managed with hormonal therapy for castrate sensitive prostate cancer and with novel androgen blocking therapies, chemotherapy, or radio-immunotherapy for castrate resistant prostate cancers. Prostate-specific antigen (PSA) flare is characterized by a rise in the PSA level, followed by a decline to below baseline values after starting therapies such as androgen deprivation therapy, systemic chemotherapy, or local therapies such as brachytherapy or cryotherapy.
Click on the PDF icon at the top of this introduction to read the full article.
Prostate cancer is the second-most common cause of male cancer-related death among US men. The American Cancer Society estimates that in 2014 there will be about 233,000 new cases of prostate cancer and about 29,500 deaths due to prostate cancer.1 Sixty percent of cases are diagnosed in men aged 65 years or older. Localized prostate cancers are managed with active surveillance or external beam radiation therapy or radical prostatectomy after risk stratification. Advanced prostate cancers are managed with hormonal therapy for castrate sensitive prostate cancer and with novel androgen blocking therapies, chemotherapy, or radio-immunotherapy for castrate resistant prostate cancers. Prostate-specific antigen (PSA) flare is characterized by a rise in the PSA level, followed by a decline to below baseline values after starting therapies such as androgen deprivation therapy, systemic chemotherapy, or local therapies such as brachytherapy or cryotherapy.
Click on the PDF icon at the top of this introduction to read the full article.
Prostate cancer is the second-most common cause of male cancer-related death among US men. The American Cancer Society estimates that in 2014 there will be about 233,000 new cases of prostate cancer and about 29,500 deaths due to prostate cancer.1 Sixty percent of cases are diagnosed in men aged 65 years or older. Localized prostate cancers are managed with active surveillance or external beam radiation therapy or radical prostatectomy after risk stratification. Advanced prostate cancers are managed with hormonal therapy for castrate sensitive prostate cancer and with novel androgen blocking therapies, chemotherapy, or radio-immunotherapy for castrate resistant prostate cancers. Prostate-specific antigen (PSA) flare is characterized by a rise in the PSA level, followed by a decline to below baseline values after starting therapies such as androgen deprivation therapy, systemic chemotherapy, or local therapies such as brachytherapy or cryotherapy.
Click on the PDF icon at the top of this introduction to read the full article.
Gemicitabine-induced radiation recall phenomenon in 2 distinctive sites on the same patient
Radiation recall phenomenon is an acute inflammatory reaction that develops in previously irradiated areas after administration of inciting agents systemically. The most common agents are anticancer drugs.1 Gemcitabine, a fluorine-substituted deoxycytidine analog, is widely used as a chemotherapy medication. Its antitumor effect results from the blockade of DNA synthesis and DNA repair. It has been used in advanced pancreatic, non–small-cell lung, bladder, and ovarian cancers; soft-tissue sarcoma; and non-Hodgkin lymphoma.2 It has occasionally been reported to cause radiation recall phenomenon.3 The time between radiation and recall may range from weeks to almost a year.
Click on the PDF icon at the top of this introduction to read the full article.
Radiation recall phenomenon is an acute inflammatory reaction that develops in previously irradiated areas after administration of inciting agents systemically. The most common agents are anticancer drugs.1 Gemcitabine, a fluorine-substituted deoxycytidine analog, is widely used as a chemotherapy medication. Its antitumor effect results from the blockade of DNA synthesis and DNA repair. It has been used in advanced pancreatic, non–small-cell lung, bladder, and ovarian cancers; soft-tissue sarcoma; and non-Hodgkin lymphoma.2 It has occasionally been reported to cause radiation recall phenomenon.3 The time between radiation and recall may range from weeks to almost a year.
Click on the PDF icon at the top of this introduction to read the full article.
Radiation recall phenomenon is an acute inflammatory reaction that develops in previously irradiated areas after administration of inciting agents systemically. The most common agents are anticancer drugs.1 Gemcitabine, a fluorine-substituted deoxycytidine analog, is widely used as a chemotherapy medication. Its antitumor effect results from the blockade of DNA synthesis and DNA repair. It has been used in advanced pancreatic, non–small-cell lung, bladder, and ovarian cancers; soft-tissue sarcoma; and non-Hodgkin lymphoma.2 It has occasionally been reported to cause radiation recall phenomenon.3 The time between radiation and recall may range from weeks to almost a year.
Click on the PDF icon at the top of this introduction to read the full article.
Pain, Anxiety, and Dementia: A Catastrophic Outcome
Advanced psychiatric illness and dementia create a wide range of barriers to health care. These patients are unable to provide reliable details with respect to their illness or even discuss basic features of their medical history, forcing providers to rely on contributions from caregiver reports and medical records. Confounding the limits on medical information, physical examinations are often abbreviated or completely refused because of the patient’s distrust, discomfort, or delusion. Over time, the involvement of consulting services may amplify the impact of these barriers as the need for diagnostic and therapeutic interventions emerge. Meanwhile, this delay in definitive management opens a window of risk for deterioration, in which patients cannot be relied on to report important clinical changes.
This case report describes a patient with significant cognitive dysfunction who developed a rare and devastating complication of a hematologic disorder. As the case illustrates, transferring a patient from the psychiatric ward to Internal Medicine (IM) can create unique diagnostic and management challenges.
CASE REPORT
A 64-year-old man developed hematochezia after having been hospitalized in a locked psychiatric ward for the preceding 6 months following a suicide attempt. The episode of hematochezia occurred while on anticoagulation treatment with warfarin for chronic lower extremity deep venous thrombosis (DVT), which prompted the IM consultation. The patient’s past medical history was notable for dementia, hypothyroidism, Crohn disease, and primary sclerosing cholangitis.
The IM Consult Service recommended holding anticoagulation therapy and reversing the coagulopathy with vitamin K. The patient’s stool returned hemoccult and toxin positive for Clostridium difficile (C difficile). The hematochezia was attributed to the infection with C difficile in the setting of anticoagulation. Oral metronidazole was started. Hemoglobin remained stable without further episodes of bleeding. Seven days after the episode of hematochezia, the patient experienced worsening generalized pain and new skin findings. He was transferred to the general medical ward for further management.
The patient’s medical records revealed early cognitive decline with recommendations for supervised residential care as early as age 59 years. An extensive neurocognitive assessment indicated a diagnosis of semantic dementia. He also had a history of recurrent DVT with anticoagulation therapy for > 10 years with no prior workup for a hypercoagulable state. A recent baseline mental status report described a childlike demeanor, profound global speech deficits with marked difficulty understanding even basic medical concepts (eg, the need for a peripheral intravenous catheter), and generalized anxiety disorder complicated by hyperesthesia. The patient frequently refused physical examinations and blood draws as a result. He devoted himself to simple puzzles of kittens and puppies.
Vital signs were normal as were the head and neck, pulmonary, cardiac, and abdominal examinations. The patient’s neurocognitive examination was remarkable for his dependence on instrumental activities of daily living, global aphasia, impaired short- and long-term recall, and poor judgment. He scored 21 out of 30 on a recent mini-mental state examination: failure to achieve 3-word recall; disorientation to month, season, hospital, and county; and an inability to write a sentence or identify a pen. Otherwise, he had fluent speech, facial symmetry, intact strength and sensation throughout, and normal reflexes.
A skin examination revealed diffuse tender subcutaneous lesions. The largest lesion was about 5 cm, located in the left anterolateral thigh. Smaller lesions of about 1 cm were noted in the abdominal wall, right thigh, and bilateral upper extremities. An exquisitely tender, well-demarcated 20-cm elliptical lesion with central necrosis and an erythematous border developed in the left axilla the following day (Figure 1A). Pain limited adduction of the left arm.
The initial laboratory evaluation demonstrated a stable hemoglobin level of 11.1 g/dL, a platelet count of 128 k/mL, and no leukocytosis. Electrolytes and renal indexes were normal. D-dimer and fibrin split products were > 10,000 ng/mL and 20 mg/mL, respectively. Fibrinogen level was 351 mg/dL. The prothrombin time and international normalized ratio were 15.1 seconds and 1.4, respectively. The activated partial thromboplastin time (aPTT) was measured at 40 seconds. High sensitivity C-reactive protein was 4.59. Recent head imaging included a brain magnetic resonance imaging (MRI) notable for enlarged sulci and ventricles with temporal predominance. Positron emission tomography (PET) brain imaging was significant for diffuse hypometabolism in bilateral parietal and temporal lobes with preservation of sensorimotor and occipital cortexes. There was no clear radiographic evidence of cerebral embolic phenomenon or focal cerebrovascular events.
Enoxaparin treatment was initiated for a suspected hypercoagulable state. Ceftriaxone was administered for a urinary tract infection (UTI). Despite premedication, the bedside biopsy of his necrotic skin lesion was aborted due to severe anxiety and generalized somatic pain. A surgical excisional biopsy was thus obtained under general anesthesia. Enoxaparin was held the night before and the morning of surgery. There were no immediate complications related to the biopsy, and malignancy was not seen on intraoperative frozen sections.
Generalized somatic pain persisted the morning after the surgical biopsy, but the patient remained clinically unchanged. An hour later, he was found unresponsive with no pulse. Despite extensive resuscitative efforts, the patient died.
Postmortem
There was a high index of suspicion for a hemostatic perturbation given the skin findings and recent manipulation of anticoagulation with a prior thrombotic event. The axillary lesion closely resembled warfarin-related skin necrosis. Management included enoxaparin with supportive care, pending definitive pathologic findings.
Postmortem examination confirmed diffuse multiorgan involvement similar to the process seen in the thigh biopsy. Ischemic injury secondary to small vessel microthrombi were evident in the skin, subcutaneous fat, large bowel, urinary bladder, and associated pericystic fat (Figure 1B). Interpretation of the surgical thigh biopsy became available after the patient died. It demonstrated infarcted fat with fat necrosis and hemorrhage (Figure 2).
The results of the laboratory investigations for thrombophilia also came back after the patient died. A potent lupus anticoagulant (LA) was demonstrated. It manifested primarily in the intrinsic pathway as a strongly positive LA-sensitive-aPTT (delta time = 20.5 seconds) assay with a weakly positive dilute Russell’s viper venom time assay. The antigenic specificity of the LA antibodies was not uncovered, as the plasma levels of both IgM and IgG anticardiolipin and anti-Β2-glycoprotein-I antibodies were within the reference range. Factor (F) II and FV genotyping revealed wild-type FV, and the prothrombin gene G20210A was without mutation.
Assays for plasma levels of protein S and antithrombin activity were also normal, which excluded deficiencies in these proteins. The assay for protein C activity was slightly decreased. This may have exacerbated the hemostatic imbalance caused by the LA, as the FVII level had normalized. However, the etiology of the protein C deficiency is not clear. Considerations include (1) a warfarin disequilibrium state due to the discontinuation of oral anticoagulation and institution of vitamin K therapy; (2) an epiphenomenon resulting from active thromboses; or (3) a possible hereditary protein C deficiency.
The definitive diagnosis of the catastrophic antiphospholipid antibody (APA) syndrome relies on multiorgan failure in < 1 week, histopathologic evidence of small vessel thrombosis, and a positive LA.1 The study patient fulfilled these criteria (Table).
DISCUSSION
Catastrophic progression of APA syndrome is an infrequent and devastating complication of this autoimmune disorder with a mortality rate of nearly 50%.1 Antiphospholipid antibody syndrome typically presents with thromboses of the larger vessels, and it more commonly affects the venous system. In contrast, diffuse small vessel thromboses underlie the pathogenesis of catastrophic APA syndrome (CAPS).2 This catastrophic progression occurs in < 1 out of 100 patients with the APA syndrome, more frequently in women (69%), and over an age range of 7 decades (mean 38 years).2 A case series analysis identified older age (aged > 36 years), history of systemic lupus erythematous, and broader organ involvement as prognostic indicators of a poor outcome. Better outcomes are associated with thrombocytopenia and anticoagulation treatment. However, gender did not influence mortality.3
Prevention is key to APA management, given the lack of efficacious treatment.2 Preventive measures are focused on avoiding triggers and aggressively treating those triggers that may arise. Possible triggers in this case included cessation of anticoagulation due to hematochezia and in anticipation of surgery, infection (C difficile colitis, suspected necrotic skin wound super infection, and a UTI), and biopsy-related trauma.
Initial clinical stability in this patient with abrupt decompensation along with pending laboratory and pathology results limited the opportunity for more aggressive therapeutic intervention for CAPS. Moreover, the relative sparing of the cardiopulmonary and renal systems contrasted with the more classical systemic involvement usually seen in CAPS. Second-line therapies for CAPS include plasma exchange and high-dose steroids.2 Third-line therapeutics include immunosuppressive agents, such as cyclophosphamide.2
The rapid decompensation, described on postoperative day 1, after a low-risk surgical biopsy highlights the importance of perioperative care in patients with this autoimmune condition. Following a review of surgical cases, Erkan and colleagues concluded that standard antithrombotic regimens for general and orthopedic surgery are likely to undertreat patients with APA syndrome.4 They recommend the following guidelines in place of standard antithrombotic management: preoperative platelet count > 100 k/µL, higher threshold before proceeding with surgery/interventional procedures, limiting intravascular manipulations, and minimizing periods without anticoagulation therapy.4
A case report of a 31-year-old female undergoing mitral valve replacement complicated postoperatively by CAPS-associated biventricular failure, despite preoperative transition of warfarin to unfractionated heparin, illustrates this significant perioperative risk.5 Evidence-based guidelines recommend holding enoxaparin 24 hours before surgery and 24 hours after invasive procedures in patients requiring bridging anticoagulation therapy.6
Treatment of the patient in this case was complicated by his cognitive impairment. Dementia is a less common but well-documented consequence of APA syndrome. A case review of 28 patients with the APA syndrome and dementia suggests an early onset of cognitive decline with a mean age of 49 years. There may be no clear preceding history of stroke in > 50% of patients.7 Interestingly, dementia followed initial manifestations of disease by an average of 3.5 years, even in some patients receiving anticoagulation therapy.7
A nuclear medicine study of 22 patients with APA syndrome and mild neuropsychiatric symptoms demonstrated a 73% incidence of cerebral hypoperfusion (55% diffuse and 18% local) based on PET imaging despite unremarkable MRI findings.8 Extended periods of hypoperfusion secondary to arterial thromboses in the temporal and parietal lobes may have been the primary etiology for dementia in this case. As such, the coexistence of neurologic abnormalities and a hypercoagulability state warrants a thorough diagnostic workup for similar disorders, despite the higher prevalence of dementia in advanced age.
Unfortunately, this patient’s cognitive disorder prevented a timely and less invasive bedside biopsy and required a surgical biopsy for which anticoagulation therapy was interrupted. A less invasive biopsy and timelier laboratory findings may have avoided triggers, including trauma from the surgical biopsy and interruptions in anticoagulation therapy, which may have contributed to the onset of CAPS.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. Asherson RA, Cervera R, Piette J, et al. Catastrophic antiphospholipid syndrome: Clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore). 2001;80(6):355-377.
2. Cervera R, Asherson RA. Multiorgan failure due to rapid occlusive vascular disease in antiphospholipid syndrome: The ‘catastrophic’ antiphospholipid syndrome. APLAR J Rheumatol. 2004;7(3):254-262.
3. Bayraktar UD, Erkan D, Bucciarelli S, Epinosa G, Asherson R; Catastrophic Antiphospholipid Syndrome Project Group. The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus. J Rheumatol. 2007;34(2):346-352.
4. Erkan D, Leibowitz E, Berman J, Lockshin MD. Perioperative medical management of antiphospholipid syndrome: Hospital for special surgery experience, review of literature, and recommendations. J Rheumatol. 2002;29(4):843-849.
5. Dornan RIP. Acute postoperative biventricular failure associated with antiphospholipid antibody syndrome. Br J Anaesth. 2004;92(5):748-754.
6. Douketis JD, Berger PD, Dunn AS, et al; American College of Chest Physicians. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(suppl 6):S299-S339.
7. Gómez-Puerta JA, Cervera R, Calvo LM, et al. Dementia associated with the antiphospolipid syndrome: Clinical and radiological characteristics of 30 patients. Rheumatology (Oxford). 2005;44(1):95-99.
8. Kao C-H, Lan J-L, Hsieh J-F, Ho Y-J, ChangLai S-P, Lee J-K, et al. Evaluation of regional cerebral blood flow with 99mTc-HMPAO in primary antiphospholipid antibody syndrome. J Nucl Med. 1999;40:1446-1450.
Advanced psychiatric illness and dementia create a wide range of barriers to health care. These patients are unable to provide reliable details with respect to their illness or even discuss basic features of their medical history, forcing providers to rely on contributions from caregiver reports and medical records. Confounding the limits on medical information, physical examinations are often abbreviated or completely refused because of the patient’s distrust, discomfort, or delusion. Over time, the involvement of consulting services may amplify the impact of these barriers as the need for diagnostic and therapeutic interventions emerge. Meanwhile, this delay in definitive management opens a window of risk for deterioration, in which patients cannot be relied on to report important clinical changes.
This case report describes a patient with significant cognitive dysfunction who developed a rare and devastating complication of a hematologic disorder. As the case illustrates, transferring a patient from the psychiatric ward to Internal Medicine (IM) can create unique diagnostic and management challenges.
CASE REPORT
A 64-year-old man developed hematochezia after having been hospitalized in a locked psychiatric ward for the preceding 6 months following a suicide attempt. The episode of hematochezia occurred while on anticoagulation treatment with warfarin for chronic lower extremity deep venous thrombosis (DVT), which prompted the IM consultation. The patient’s past medical history was notable for dementia, hypothyroidism, Crohn disease, and primary sclerosing cholangitis.
The IM Consult Service recommended holding anticoagulation therapy and reversing the coagulopathy with vitamin K. The patient’s stool returned hemoccult and toxin positive for Clostridium difficile (C difficile). The hematochezia was attributed to the infection with C difficile in the setting of anticoagulation. Oral metronidazole was started. Hemoglobin remained stable without further episodes of bleeding. Seven days after the episode of hematochezia, the patient experienced worsening generalized pain and new skin findings. He was transferred to the general medical ward for further management.
The patient’s medical records revealed early cognitive decline with recommendations for supervised residential care as early as age 59 years. An extensive neurocognitive assessment indicated a diagnosis of semantic dementia. He also had a history of recurrent DVT with anticoagulation therapy for > 10 years with no prior workup for a hypercoagulable state. A recent baseline mental status report described a childlike demeanor, profound global speech deficits with marked difficulty understanding even basic medical concepts (eg, the need for a peripheral intravenous catheter), and generalized anxiety disorder complicated by hyperesthesia. The patient frequently refused physical examinations and blood draws as a result. He devoted himself to simple puzzles of kittens and puppies.
Vital signs were normal as were the head and neck, pulmonary, cardiac, and abdominal examinations. The patient’s neurocognitive examination was remarkable for his dependence on instrumental activities of daily living, global aphasia, impaired short- and long-term recall, and poor judgment. He scored 21 out of 30 on a recent mini-mental state examination: failure to achieve 3-word recall; disorientation to month, season, hospital, and county; and an inability to write a sentence or identify a pen. Otherwise, he had fluent speech, facial symmetry, intact strength and sensation throughout, and normal reflexes.
A skin examination revealed diffuse tender subcutaneous lesions. The largest lesion was about 5 cm, located in the left anterolateral thigh. Smaller lesions of about 1 cm were noted in the abdominal wall, right thigh, and bilateral upper extremities. An exquisitely tender, well-demarcated 20-cm elliptical lesion with central necrosis and an erythematous border developed in the left axilla the following day (Figure 1A). Pain limited adduction of the left arm.
The initial laboratory evaluation demonstrated a stable hemoglobin level of 11.1 g/dL, a platelet count of 128 k/mL, and no leukocytosis. Electrolytes and renal indexes were normal. D-dimer and fibrin split products were > 10,000 ng/mL and 20 mg/mL, respectively. Fibrinogen level was 351 mg/dL. The prothrombin time and international normalized ratio were 15.1 seconds and 1.4, respectively. The activated partial thromboplastin time (aPTT) was measured at 40 seconds. High sensitivity C-reactive protein was 4.59. Recent head imaging included a brain magnetic resonance imaging (MRI) notable for enlarged sulci and ventricles with temporal predominance. Positron emission tomography (PET) brain imaging was significant for diffuse hypometabolism in bilateral parietal and temporal lobes with preservation of sensorimotor and occipital cortexes. There was no clear radiographic evidence of cerebral embolic phenomenon or focal cerebrovascular events.
Enoxaparin treatment was initiated for a suspected hypercoagulable state. Ceftriaxone was administered for a urinary tract infection (UTI). Despite premedication, the bedside biopsy of his necrotic skin lesion was aborted due to severe anxiety and generalized somatic pain. A surgical excisional biopsy was thus obtained under general anesthesia. Enoxaparin was held the night before and the morning of surgery. There were no immediate complications related to the biopsy, and malignancy was not seen on intraoperative frozen sections.
Generalized somatic pain persisted the morning after the surgical biopsy, but the patient remained clinically unchanged. An hour later, he was found unresponsive with no pulse. Despite extensive resuscitative efforts, the patient died.
Postmortem
There was a high index of suspicion for a hemostatic perturbation given the skin findings and recent manipulation of anticoagulation with a prior thrombotic event. The axillary lesion closely resembled warfarin-related skin necrosis. Management included enoxaparin with supportive care, pending definitive pathologic findings.
Postmortem examination confirmed diffuse multiorgan involvement similar to the process seen in the thigh biopsy. Ischemic injury secondary to small vessel microthrombi were evident in the skin, subcutaneous fat, large bowel, urinary bladder, and associated pericystic fat (Figure 1B). Interpretation of the surgical thigh biopsy became available after the patient died. It demonstrated infarcted fat with fat necrosis and hemorrhage (Figure 2).
The results of the laboratory investigations for thrombophilia also came back after the patient died. A potent lupus anticoagulant (LA) was demonstrated. It manifested primarily in the intrinsic pathway as a strongly positive LA-sensitive-aPTT (delta time = 20.5 seconds) assay with a weakly positive dilute Russell’s viper venom time assay. The antigenic specificity of the LA antibodies was not uncovered, as the plasma levels of both IgM and IgG anticardiolipin and anti-Β2-glycoprotein-I antibodies were within the reference range. Factor (F) II and FV genotyping revealed wild-type FV, and the prothrombin gene G20210A was without mutation.
Assays for plasma levels of protein S and antithrombin activity were also normal, which excluded deficiencies in these proteins. The assay for protein C activity was slightly decreased. This may have exacerbated the hemostatic imbalance caused by the LA, as the FVII level had normalized. However, the etiology of the protein C deficiency is not clear. Considerations include (1) a warfarin disequilibrium state due to the discontinuation of oral anticoagulation and institution of vitamin K therapy; (2) an epiphenomenon resulting from active thromboses; or (3) a possible hereditary protein C deficiency.
The definitive diagnosis of the catastrophic antiphospholipid antibody (APA) syndrome relies on multiorgan failure in < 1 week, histopathologic evidence of small vessel thrombosis, and a positive LA.1 The study patient fulfilled these criteria (Table).
DISCUSSION
Catastrophic progression of APA syndrome is an infrequent and devastating complication of this autoimmune disorder with a mortality rate of nearly 50%.1 Antiphospholipid antibody syndrome typically presents with thromboses of the larger vessels, and it more commonly affects the venous system. In contrast, diffuse small vessel thromboses underlie the pathogenesis of catastrophic APA syndrome (CAPS).2 This catastrophic progression occurs in < 1 out of 100 patients with the APA syndrome, more frequently in women (69%), and over an age range of 7 decades (mean 38 years).2 A case series analysis identified older age (aged > 36 years), history of systemic lupus erythematous, and broader organ involvement as prognostic indicators of a poor outcome. Better outcomes are associated with thrombocytopenia and anticoagulation treatment. However, gender did not influence mortality.3
Prevention is key to APA management, given the lack of efficacious treatment.2 Preventive measures are focused on avoiding triggers and aggressively treating those triggers that may arise. Possible triggers in this case included cessation of anticoagulation due to hematochezia and in anticipation of surgery, infection (C difficile colitis, suspected necrotic skin wound super infection, and a UTI), and biopsy-related trauma.
Initial clinical stability in this patient with abrupt decompensation along with pending laboratory and pathology results limited the opportunity for more aggressive therapeutic intervention for CAPS. Moreover, the relative sparing of the cardiopulmonary and renal systems contrasted with the more classical systemic involvement usually seen in CAPS. Second-line therapies for CAPS include plasma exchange and high-dose steroids.2 Third-line therapeutics include immunosuppressive agents, such as cyclophosphamide.2
The rapid decompensation, described on postoperative day 1, after a low-risk surgical biopsy highlights the importance of perioperative care in patients with this autoimmune condition. Following a review of surgical cases, Erkan and colleagues concluded that standard antithrombotic regimens for general and orthopedic surgery are likely to undertreat patients with APA syndrome.4 They recommend the following guidelines in place of standard antithrombotic management: preoperative platelet count > 100 k/µL, higher threshold before proceeding with surgery/interventional procedures, limiting intravascular manipulations, and minimizing periods without anticoagulation therapy.4
A case report of a 31-year-old female undergoing mitral valve replacement complicated postoperatively by CAPS-associated biventricular failure, despite preoperative transition of warfarin to unfractionated heparin, illustrates this significant perioperative risk.5 Evidence-based guidelines recommend holding enoxaparin 24 hours before surgery and 24 hours after invasive procedures in patients requiring bridging anticoagulation therapy.6
Treatment of the patient in this case was complicated by his cognitive impairment. Dementia is a less common but well-documented consequence of APA syndrome. A case review of 28 patients with the APA syndrome and dementia suggests an early onset of cognitive decline with a mean age of 49 years. There may be no clear preceding history of stroke in > 50% of patients.7 Interestingly, dementia followed initial manifestations of disease by an average of 3.5 years, even in some patients receiving anticoagulation therapy.7
A nuclear medicine study of 22 patients with APA syndrome and mild neuropsychiatric symptoms demonstrated a 73% incidence of cerebral hypoperfusion (55% diffuse and 18% local) based on PET imaging despite unremarkable MRI findings.8 Extended periods of hypoperfusion secondary to arterial thromboses in the temporal and parietal lobes may have been the primary etiology for dementia in this case. As such, the coexistence of neurologic abnormalities and a hypercoagulability state warrants a thorough diagnostic workup for similar disorders, despite the higher prevalence of dementia in advanced age.
Unfortunately, this patient’s cognitive disorder prevented a timely and less invasive bedside biopsy and required a surgical biopsy for which anticoagulation therapy was interrupted. A less invasive biopsy and timelier laboratory findings may have avoided triggers, including trauma from the surgical biopsy and interruptions in anticoagulation therapy, which may have contributed to the onset of CAPS.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Advanced psychiatric illness and dementia create a wide range of barriers to health care. These patients are unable to provide reliable details with respect to their illness or even discuss basic features of their medical history, forcing providers to rely on contributions from caregiver reports and medical records. Confounding the limits on medical information, physical examinations are often abbreviated or completely refused because of the patient’s distrust, discomfort, or delusion. Over time, the involvement of consulting services may amplify the impact of these barriers as the need for diagnostic and therapeutic interventions emerge. Meanwhile, this delay in definitive management opens a window of risk for deterioration, in which patients cannot be relied on to report important clinical changes.
This case report describes a patient with significant cognitive dysfunction who developed a rare and devastating complication of a hematologic disorder. As the case illustrates, transferring a patient from the psychiatric ward to Internal Medicine (IM) can create unique diagnostic and management challenges.
CASE REPORT
A 64-year-old man developed hematochezia after having been hospitalized in a locked psychiatric ward for the preceding 6 months following a suicide attempt. The episode of hematochezia occurred while on anticoagulation treatment with warfarin for chronic lower extremity deep venous thrombosis (DVT), which prompted the IM consultation. The patient’s past medical history was notable for dementia, hypothyroidism, Crohn disease, and primary sclerosing cholangitis.
The IM Consult Service recommended holding anticoagulation therapy and reversing the coagulopathy with vitamin K. The patient’s stool returned hemoccult and toxin positive for Clostridium difficile (C difficile). The hematochezia was attributed to the infection with C difficile in the setting of anticoagulation. Oral metronidazole was started. Hemoglobin remained stable without further episodes of bleeding. Seven days after the episode of hematochezia, the patient experienced worsening generalized pain and new skin findings. He was transferred to the general medical ward for further management.
The patient’s medical records revealed early cognitive decline with recommendations for supervised residential care as early as age 59 years. An extensive neurocognitive assessment indicated a diagnosis of semantic dementia. He also had a history of recurrent DVT with anticoagulation therapy for > 10 years with no prior workup for a hypercoagulable state. A recent baseline mental status report described a childlike demeanor, profound global speech deficits with marked difficulty understanding even basic medical concepts (eg, the need for a peripheral intravenous catheter), and generalized anxiety disorder complicated by hyperesthesia. The patient frequently refused physical examinations and blood draws as a result. He devoted himself to simple puzzles of kittens and puppies.
Vital signs were normal as were the head and neck, pulmonary, cardiac, and abdominal examinations. The patient’s neurocognitive examination was remarkable for his dependence on instrumental activities of daily living, global aphasia, impaired short- and long-term recall, and poor judgment. He scored 21 out of 30 on a recent mini-mental state examination: failure to achieve 3-word recall; disorientation to month, season, hospital, and county; and an inability to write a sentence or identify a pen. Otherwise, he had fluent speech, facial symmetry, intact strength and sensation throughout, and normal reflexes.
A skin examination revealed diffuse tender subcutaneous lesions. The largest lesion was about 5 cm, located in the left anterolateral thigh. Smaller lesions of about 1 cm were noted in the abdominal wall, right thigh, and bilateral upper extremities. An exquisitely tender, well-demarcated 20-cm elliptical lesion with central necrosis and an erythematous border developed in the left axilla the following day (Figure 1A). Pain limited adduction of the left arm.
The initial laboratory evaluation demonstrated a stable hemoglobin level of 11.1 g/dL, a platelet count of 128 k/mL, and no leukocytosis. Electrolytes and renal indexes were normal. D-dimer and fibrin split products were > 10,000 ng/mL and 20 mg/mL, respectively. Fibrinogen level was 351 mg/dL. The prothrombin time and international normalized ratio were 15.1 seconds and 1.4, respectively. The activated partial thromboplastin time (aPTT) was measured at 40 seconds. High sensitivity C-reactive protein was 4.59. Recent head imaging included a brain magnetic resonance imaging (MRI) notable for enlarged sulci and ventricles with temporal predominance. Positron emission tomography (PET) brain imaging was significant for diffuse hypometabolism in bilateral parietal and temporal lobes with preservation of sensorimotor and occipital cortexes. There was no clear radiographic evidence of cerebral embolic phenomenon or focal cerebrovascular events.
Enoxaparin treatment was initiated for a suspected hypercoagulable state. Ceftriaxone was administered for a urinary tract infection (UTI). Despite premedication, the bedside biopsy of his necrotic skin lesion was aborted due to severe anxiety and generalized somatic pain. A surgical excisional biopsy was thus obtained under general anesthesia. Enoxaparin was held the night before and the morning of surgery. There were no immediate complications related to the biopsy, and malignancy was not seen on intraoperative frozen sections.
Generalized somatic pain persisted the morning after the surgical biopsy, but the patient remained clinically unchanged. An hour later, he was found unresponsive with no pulse. Despite extensive resuscitative efforts, the patient died.
Postmortem
There was a high index of suspicion for a hemostatic perturbation given the skin findings and recent manipulation of anticoagulation with a prior thrombotic event. The axillary lesion closely resembled warfarin-related skin necrosis. Management included enoxaparin with supportive care, pending definitive pathologic findings.
Postmortem examination confirmed diffuse multiorgan involvement similar to the process seen in the thigh biopsy. Ischemic injury secondary to small vessel microthrombi were evident in the skin, subcutaneous fat, large bowel, urinary bladder, and associated pericystic fat (Figure 1B). Interpretation of the surgical thigh biopsy became available after the patient died. It demonstrated infarcted fat with fat necrosis and hemorrhage (Figure 2).
The results of the laboratory investigations for thrombophilia also came back after the patient died. A potent lupus anticoagulant (LA) was demonstrated. It manifested primarily in the intrinsic pathway as a strongly positive LA-sensitive-aPTT (delta time = 20.5 seconds) assay with a weakly positive dilute Russell’s viper venom time assay. The antigenic specificity of the LA antibodies was not uncovered, as the plasma levels of both IgM and IgG anticardiolipin and anti-Β2-glycoprotein-I antibodies were within the reference range. Factor (F) II and FV genotyping revealed wild-type FV, and the prothrombin gene G20210A was without mutation.
Assays for plasma levels of protein S and antithrombin activity were also normal, which excluded deficiencies in these proteins. The assay for protein C activity was slightly decreased. This may have exacerbated the hemostatic imbalance caused by the LA, as the FVII level had normalized. However, the etiology of the protein C deficiency is not clear. Considerations include (1) a warfarin disequilibrium state due to the discontinuation of oral anticoagulation and institution of vitamin K therapy; (2) an epiphenomenon resulting from active thromboses; or (3) a possible hereditary protein C deficiency.
The definitive diagnosis of the catastrophic antiphospholipid antibody (APA) syndrome relies on multiorgan failure in < 1 week, histopathologic evidence of small vessel thrombosis, and a positive LA.1 The study patient fulfilled these criteria (Table).
DISCUSSION
Catastrophic progression of APA syndrome is an infrequent and devastating complication of this autoimmune disorder with a mortality rate of nearly 50%.1 Antiphospholipid antibody syndrome typically presents with thromboses of the larger vessels, and it more commonly affects the venous system. In contrast, diffuse small vessel thromboses underlie the pathogenesis of catastrophic APA syndrome (CAPS).2 This catastrophic progression occurs in < 1 out of 100 patients with the APA syndrome, more frequently in women (69%), and over an age range of 7 decades (mean 38 years).2 A case series analysis identified older age (aged > 36 years), history of systemic lupus erythematous, and broader organ involvement as prognostic indicators of a poor outcome. Better outcomes are associated with thrombocytopenia and anticoagulation treatment. However, gender did not influence mortality.3
Prevention is key to APA management, given the lack of efficacious treatment.2 Preventive measures are focused on avoiding triggers and aggressively treating those triggers that may arise. Possible triggers in this case included cessation of anticoagulation due to hematochezia and in anticipation of surgery, infection (C difficile colitis, suspected necrotic skin wound super infection, and a UTI), and biopsy-related trauma.
Initial clinical stability in this patient with abrupt decompensation along with pending laboratory and pathology results limited the opportunity for more aggressive therapeutic intervention for CAPS. Moreover, the relative sparing of the cardiopulmonary and renal systems contrasted with the more classical systemic involvement usually seen in CAPS. Second-line therapies for CAPS include plasma exchange and high-dose steroids.2 Third-line therapeutics include immunosuppressive agents, such as cyclophosphamide.2
The rapid decompensation, described on postoperative day 1, after a low-risk surgical biopsy highlights the importance of perioperative care in patients with this autoimmune condition. Following a review of surgical cases, Erkan and colleagues concluded that standard antithrombotic regimens for general and orthopedic surgery are likely to undertreat patients with APA syndrome.4 They recommend the following guidelines in place of standard antithrombotic management: preoperative platelet count > 100 k/µL, higher threshold before proceeding with surgery/interventional procedures, limiting intravascular manipulations, and minimizing periods without anticoagulation therapy.4
A case report of a 31-year-old female undergoing mitral valve replacement complicated postoperatively by CAPS-associated biventricular failure, despite preoperative transition of warfarin to unfractionated heparin, illustrates this significant perioperative risk.5 Evidence-based guidelines recommend holding enoxaparin 24 hours before surgery and 24 hours after invasive procedures in patients requiring bridging anticoagulation therapy.6
Treatment of the patient in this case was complicated by his cognitive impairment. Dementia is a less common but well-documented consequence of APA syndrome. A case review of 28 patients with the APA syndrome and dementia suggests an early onset of cognitive decline with a mean age of 49 years. There may be no clear preceding history of stroke in > 50% of patients.7 Interestingly, dementia followed initial manifestations of disease by an average of 3.5 years, even in some patients receiving anticoagulation therapy.7
A nuclear medicine study of 22 patients with APA syndrome and mild neuropsychiatric symptoms demonstrated a 73% incidence of cerebral hypoperfusion (55% diffuse and 18% local) based on PET imaging despite unremarkable MRI findings.8 Extended periods of hypoperfusion secondary to arterial thromboses in the temporal and parietal lobes may have been the primary etiology for dementia in this case. As such, the coexistence of neurologic abnormalities and a hypercoagulability state warrants a thorough diagnostic workup for similar disorders, despite the higher prevalence of dementia in advanced age.
Unfortunately, this patient’s cognitive disorder prevented a timely and less invasive bedside biopsy and required a surgical biopsy for which anticoagulation therapy was interrupted. A less invasive biopsy and timelier laboratory findings may have avoided triggers, including trauma from the surgical biopsy and interruptions in anticoagulation therapy, which may have contributed to the onset of CAPS.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. Asherson RA, Cervera R, Piette J, et al. Catastrophic antiphospholipid syndrome: Clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore). 2001;80(6):355-377.
2. Cervera R, Asherson RA. Multiorgan failure due to rapid occlusive vascular disease in antiphospholipid syndrome: The ‘catastrophic’ antiphospholipid syndrome. APLAR J Rheumatol. 2004;7(3):254-262.
3. Bayraktar UD, Erkan D, Bucciarelli S, Epinosa G, Asherson R; Catastrophic Antiphospholipid Syndrome Project Group. The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus. J Rheumatol. 2007;34(2):346-352.
4. Erkan D, Leibowitz E, Berman J, Lockshin MD. Perioperative medical management of antiphospholipid syndrome: Hospital for special surgery experience, review of literature, and recommendations. J Rheumatol. 2002;29(4):843-849.
5. Dornan RIP. Acute postoperative biventricular failure associated with antiphospholipid antibody syndrome. Br J Anaesth. 2004;92(5):748-754.
6. Douketis JD, Berger PD, Dunn AS, et al; American College of Chest Physicians. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(suppl 6):S299-S339.
7. Gómez-Puerta JA, Cervera R, Calvo LM, et al. Dementia associated with the antiphospolipid syndrome: Clinical and radiological characteristics of 30 patients. Rheumatology (Oxford). 2005;44(1):95-99.
8. Kao C-H, Lan J-L, Hsieh J-F, Ho Y-J, ChangLai S-P, Lee J-K, et al. Evaluation of regional cerebral blood flow with 99mTc-HMPAO in primary antiphospholipid antibody syndrome. J Nucl Med. 1999;40:1446-1450.
1. Asherson RA, Cervera R, Piette J, et al. Catastrophic antiphospholipid syndrome: Clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore). 2001;80(6):355-377.
2. Cervera R, Asherson RA. Multiorgan failure due to rapid occlusive vascular disease in antiphospholipid syndrome: The ‘catastrophic’ antiphospholipid syndrome. APLAR J Rheumatol. 2004;7(3):254-262.
3. Bayraktar UD, Erkan D, Bucciarelli S, Epinosa G, Asherson R; Catastrophic Antiphospholipid Syndrome Project Group. The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus. J Rheumatol. 2007;34(2):346-352.
4. Erkan D, Leibowitz E, Berman J, Lockshin MD. Perioperative medical management of antiphospholipid syndrome: Hospital for special surgery experience, review of literature, and recommendations. J Rheumatol. 2002;29(4):843-849.
5. Dornan RIP. Acute postoperative biventricular failure associated with antiphospholipid antibody syndrome. Br J Anaesth. 2004;92(5):748-754.
6. Douketis JD, Berger PD, Dunn AS, et al; American College of Chest Physicians. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(suppl 6):S299-S339.
7. Gómez-Puerta JA, Cervera R, Calvo LM, et al. Dementia associated with the antiphospolipid syndrome: Clinical and radiological characteristics of 30 patients. Rheumatology (Oxford). 2005;44(1):95-99.
8. Kao C-H, Lan J-L, Hsieh J-F, Ho Y-J, ChangLai S-P, Lee J-K, et al. Evaluation of regional cerebral blood flow with 99mTc-HMPAO in primary antiphospholipid antibody syndrome. J Nucl Med. 1999;40:1446-1450.
Rare Case of Dual Lesion: Nonossifying Fibroma and Osteochondroma
Necrotizing Fasciitis of Lower Extremity Caused by Haemophilus influenzae in a Healthy Adult With a Closed Lisfranc Injury
Vomiting, abdominal pain, compulsive bathing—Dx?
THE CASE
A 33-year-old multiparous pregnant woman at 7 weeks gestation came to our clinic after 3 days of vomiting. She had been vomiting up to 7 times a day and had right lower quadrant pain radiating into her flank. She described the pain as continuous, severe, and “crampy” in nature. The patient also complained of a loss of appetite, nonbloody diarrhea, fever, chills, night sweats, and urinary urgency. She’d tried acetaminophen without relief and repeatedly took hot showers—for up to 6 hours each day—which she said temporarily improved her symptoms.
At presentation, the patient’s vital signs were normal, with no orthostatic changes in blood pressure or heart rate. A physical and pelvic examination revealed tenderness in her right lower quadrant and flank and a mildly tender uterus. Chlamydia culture was positive. Pelvic ultrasound showed a normal intrauterine pregnancy, a surgically absent right ovary and tube, and a normal left ovary and tube. Her appendix was not visualized. Laboratory results, including a basic metabolic panel, complete blood count, liver function tests, amylase test, lipase test, and urinalysis were normal.
On admission, the patient received intravenous (IV) fluids, oral ondansetron 4 mg every 6 hours and IV hydromorphone 2 mg every 3 to 6 hours. Because her symptoms did not respond to initial therapy, we administered IV metoclopramide 10 mg every 6 to 8 hours and promethazine 12.5 mg rectally 3 times daily. After a discussion of the risks associated with benzodiazepine use during pregnancy, the patient agreed to treatment with IV lorazepam 2 mg. She was also informed of the risks of radiation during pregnancy,1 and opted to undergo an abdominal computed tomography (CT) scan and ultrasound. No abnormalities were found.
The patient said that in prior pregnancies, she had experienced nausea and vomiting during the first trimester, but that her current symptoms were much worse. She also said she’d been smoking cannabis twice a day for a year.
THE DIAGNOSIS
Based on our patient’s symptoms, her history of daily cannabis use, and the lack of improvement from antiemetics and analgesics, we concluded that she was suffering from cannabinoid hyperemesis. By Day 3, her symptoms improved and she could tolerate oral fluids. We advised her to stop using cannabis and discharged her.
One week later, the patient reported that she had not smoked cannabis since she’d been admitted to the hospital and that her symptoms, including her compulsive bathing, continued to improve. The patient subsequently delivered a healthy newborn at term.
DISCUSSION
A drug sometimes used to relieve nausea may make it much worse
First described in 2004, cannabinoid hyperemesis is a triad of vomiting, abdominal pain, and compulsive bathing in patients with chronic cannabis use.2 Other symptoms include subjective fevers, chills, and diaphoresis. Symptoms of cannabinoid hyperemesis may persist for weeks and spontaneously remit for weeks to months. The syndrome can lead to serious complications, including volume depletion, weight loss of 5 to 10 kg per episode, burns caused by frequent hot showers, and esophageal rupture.2-4 The frequent hot baths or showers associated with cannabinoid hyperemesis are potentially harmful to the fetus—hyperthermia during early gestation can cause fetal mental deficiency, seizures, and neural tube defects.5-8
The association between cannabinoid hyperemesis and pregnancy is unknown. However, because 11% of pregnant women use cannabis,9 many women may be at risk for the condition. Pregnant women may use cannabis recreationally or to combat morning sickness. The high rate of cannabis use in this population may be due in part to a lack of perceived risk to the fetus, although prenatal cannabis exposure is associated with reduced fetal growth.10
Active component of cannabis may trigger vomiting, pain
While chronic cannabis use causes cannabinoid hyperemesis, the pathogenesis and pathophysiology of the disease remain unknown. Delta-9-tetrahydrocannabinol (THC), the active ingredient in cannabis, appears to be to blame.11-15
THC is lipophilic and accumulates in the body with chronic cannabis use. At higher accumulated levels, THC binds to cannabinoid receptors in the intestinal nerve plexus, causing lower esophageal sphincter relaxation and gastrointestinal motility inhibition.11,12 At high concentrations, THC also binds to CB1 receptors in the hypothalamus, which is responsible for integrating satiety, thirst, digestive function, and thermoregulation.13-15 This causes hypothalamic dysregulation that may be temporarily relieved by hot showers.2
Possible causes of our patient’s signs and symptoms included appendicitis, pyelonephritis, nephrolithiasis, ectopic pregnancy, and pelvic inflammatory disease. Our patient’s normal laboratory and imaging studies made these diagnoses less likely. Her lack of a fallopian tube or ovary on the right side prompted us to quickly rule out a right-sided ectopic implantation.
We considered our patient’s chlamydial infection as the source of her symptoms. However, she had experienced no vaginal discharge or bleeding, and her nausea and abdominal pain did not improve with a therapeutic dose of azithromycin. Imaging showed no evidence of chlamydia-associated complications, such as pelvic inflammatory disease or tubo-ovarian abscess, both of which are uncommon in pregnancy.
THE TAKEAWAY
Consider cannabinoid hyperemesis in patients who are experiencing vomiting and abdominal pain that are temporarily relieved by bathing in hot water. Ask such patients about their cannabis use, and strongly encourage them to discontinue the drug. Counsel pregnant women about the maternal and fetal risks of cannabis use and the potential teratogenicity of hot water bathing. Provide IV fluids to ensure adequate hydration and a benzodiazepine as appropriate for anxiety and cannabis withdrawal symptoms.16 Advise patients that their symptoms may return within weeks to months if they resume using cannabis.2,17
1. ACOG Committee on Obstetric Practice. ACOG Committee Opinion. Number 299, September 2004 (replaces No. 158, September 1995). Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol. 2004;104:647-651.
2. Allen JH, de Moore GM, Heddle R, et al. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut. 2004;53:1566-1570.
3. Sontineni SP, Chaudhary S, Sontineni V, et al. Cannabinoid hyperemesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World J Gastroenterol. 2009;15:1264-1266.
4. de Moore GM, Baker J, Bui T. Psychogenic vomiting complicated by marijuana abuse and spontaneous pneumomediastinum. Aust N Z J Psychiatry. 1996;30:290-294.
5. Smith DW, Clarren SK, Harvey MA. Hyperthermia as a possible teratogenic agent. J Pediatr. 1978;92:878-883.
6. Shiota K. Neural tube defects and maternal hyperthermia in early pregnancy: epidemiology in a human embryo population. Am J Med Genet. 1982;12:281-288.
7. Milunsky A, Ulcickas M, Rothman K, et al. Maternal heat exposure and neural tube defects. JAMA. 1992;268:882-885.
8. Miller P, Smith DW, Shepard TH. Maternal hyperthermia as a possible cause of anencephaly. Lancet. 1978;11:1519-1521.
9. Substance Abuse and Mental Health Services Administration Web site. Results from the 2008 National Survey on Drug Use and Health: national findings. Available at: http://www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed December 15, 2011.
10. Gray TR, Eiden RD, Leonard KD, et al. Identifying prenatal cannabis exposure and effects of concurrent tobacco exposure on neonatal growth. Clin Chem. 2010;56:1442-1450.
11. Izzo AA, Coutts AA. Cannabinoids and the digestive tract. Handb Exp Pharmacol. 2005;(168):573-598.
12. McCallum RW, Soykan I, Sridhar KR, et al. Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther. 1999;13:77-80.
13. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74:129-180.
14. Childers SR, Breivogel CS. Cannabis and endogenous cannabinoid systems. Drug Alcohol Dependence. 1998;51:173-187.
15. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci. 1990;87:1932-1936.
16. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzodiazepine during fetal life. Lancet. 1992;340:694-696.
17. Wallace D, Martin AL, Park B. Cannabinoid hyperemesis: marijuana puts patients in hot water. Australas Psychiatry. 2007;15:156-158.
THE CASE
A 33-year-old multiparous pregnant woman at 7 weeks gestation came to our clinic after 3 days of vomiting. She had been vomiting up to 7 times a day and had right lower quadrant pain radiating into her flank. She described the pain as continuous, severe, and “crampy” in nature. The patient also complained of a loss of appetite, nonbloody diarrhea, fever, chills, night sweats, and urinary urgency. She’d tried acetaminophen without relief and repeatedly took hot showers—for up to 6 hours each day—which she said temporarily improved her symptoms.
At presentation, the patient’s vital signs were normal, with no orthostatic changes in blood pressure or heart rate. A physical and pelvic examination revealed tenderness in her right lower quadrant and flank and a mildly tender uterus. Chlamydia culture was positive. Pelvic ultrasound showed a normal intrauterine pregnancy, a surgically absent right ovary and tube, and a normal left ovary and tube. Her appendix was not visualized. Laboratory results, including a basic metabolic panel, complete blood count, liver function tests, amylase test, lipase test, and urinalysis were normal.
On admission, the patient received intravenous (IV) fluids, oral ondansetron 4 mg every 6 hours and IV hydromorphone 2 mg every 3 to 6 hours. Because her symptoms did not respond to initial therapy, we administered IV metoclopramide 10 mg every 6 to 8 hours and promethazine 12.5 mg rectally 3 times daily. After a discussion of the risks associated with benzodiazepine use during pregnancy, the patient agreed to treatment with IV lorazepam 2 mg. She was also informed of the risks of radiation during pregnancy,1 and opted to undergo an abdominal computed tomography (CT) scan and ultrasound. No abnormalities were found.
The patient said that in prior pregnancies, she had experienced nausea and vomiting during the first trimester, but that her current symptoms were much worse. She also said she’d been smoking cannabis twice a day for a year.
THE DIAGNOSIS
Based on our patient’s symptoms, her history of daily cannabis use, and the lack of improvement from antiemetics and analgesics, we concluded that she was suffering from cannabinoid hyperemesis. By Day 3, her symptoms improved and she could tolerate oral fluids. We advised her to stop using cannabis and discharged her.
One week later, the patient reported that she had not smoked cannabis since she’d been admitted to the hospital and that her symptoms, including her compulsive bathing, continued to improve. The patient subsequently delivered a healthy newborn at term.
DISCUSSION
A drug sometimes used to relieve nausea may make it much worse
First described in 2004, cannabinoid hyperemesis is a triad of vomiting, abdominal pain, and compulsive bathing in patients with chronic cannabis use.2 Other symptoms include subjective fevers, chills, and diaphoresis. Symptoms of cannabinoid hyperemesis may persist for weeks and spontaneously remit for weeks to months. The syndrome can lead to serious complications, including volume depletion, weight loss of 5 to 10 kg per episode, burns caused by frequent hot showers, and esophageal rupture.2-4 The frequent hot baths or showers associated with cannabinoid hyperemesis are potentially harmful to the fetus—hyperthermia during early gestation can cause fetal mental deficiency, seizures, and neural tube defects.5-8
The association between cannabinoid hyperemesis and pregnancy is unknown. However, because 11% of pregnant women use cannabis,9 many women may be at risk for the condition. Pregnant women may use cannabis recreationally or to combat morning sickness. The high rate of cannabis use in this population may be due in part to a lack of perceived risk to the fetus, although prenatal cannabis exposure is associated with reduced fetal growth.10
Active component of cannabis may trigger vomiting, pain
While chronic cannabis use causes cannabinoid hyperemesis, the pathogenesis and pathophysiology of the disease remain unknown. Delta-9-tetrahydrocannabinol (THC), the active ingredient in cannabis, appears to be to blame.11-15
THC is lipophilic and accumulates in the body with chronic cannabis use. At higher accumulated levels, THC binds to cannabinoid receptors in the intestinal nerve plexus, causing lower esophageal sphincter relaxation and gastrointestinal motility inhibition.11,12 At high concentrations, THC also binds to CB1 receptors in the hypothalamus, which is responsible for integrating satiety, thirst, digestive function, and thermoregulation.13-15 This causes hypothalamic dysregulation that may be temporarily relieved by hot showers.2
Possible causes of our patient’s signs and symptoms included appendicitis, pyelonephritis, nephrolithiasis, ectopic pregnancy, and pelvic inflammatory disease. Our patient’s normal laboratory and imaging studies made these diagnoses less likely. Her lack of a fallopian tube or ovary on the right side prompted us to quickly rule out a right-sided ectopic implantation.
We considered our patient’s chlamydial infection as the source of her symptoms. However, she had experienced no vaginal discharge or bleeding, and her nausea and abdominal pain did not improve with a therapeutic dose of azithromycin. Imaging showed no evidence of chlamydia-associated complications, such as pelvic inflammatory disease or tubo-ovarian abscess, both of which are uncommon in pregnancy.
THE TAKEAWAY
Consider cannabinoid hyperemesis in patients who are experiencing vomiting and abdominal pain that are temporarily relieved by bathing in hot water. Ask such patients about their cannabis use, and strongly encourage them to discontinue the drug. Counsel pregnant women about the maternal and fetal risks of cannabis use and the potential teratogenicity of hot water bathing. Provide IV fluids to ensure adequate hydration and a benzodiazepine as appropriate for anxiety and cannabis withdrawal symptoms.16 Advise patients that their symptoms may return within weeks to months if they resume using cannabis.2,17
THE CASE
A 33-year-old multiparous pregnant woman at 7 weeks gestation came to our clinic after 3 days of vomiting. She had been vomiting up to 7 times a day and had right lower quadrant pain radiating into her flank. She described the pain as continuous, severe, and “crampy” in nature. The patient also complained of a loss of appetite, nonbloody diarrhea, fever, chills, night sweats, and urinary urgency. She’d tried acetaminophen without relief and repeatedly took hot showers—for up to 6 hours each day—which she said temporarily improved her symptoms.
At presentation, the patient’s vital signs were normal, with no orthostatic changes in blood pressure or heart rate. A physical and pelvic examination revealed tenderness in her right lower quadrant and flank and a mildly tender uterus. Chlamydia culture was positive. Pelvic ultrasound showed a normal intrauterine pregnancy, a surgically absent right ovary and tube, and a normal left ovary and tube. Her appendix was not visualized. Laboratory results, including a basic metabolic panel, complete blood count, liver function tests, amylase test, lipase test, and urinalysis were normal.
On admission, the patient received intravenous (IV) fluids, oral ondansetron 4 mg every 6 hours and IV hydromorphone 2 mg every 3 to 6 hours. Because her symptoms did not respond to initial therapy, we administered IV metoclopramide 10 mg every 6 to 8 hours and promethazine 12.5 mg rectally 3 times daily. After a discussion of the risks associated with benzodiazepine use during pregnancy, the patient agreed to treatment with IV lorazepam 2 mg. She was also informed of the risks of radiation during pregnancy,1 and opted to undergo an abdominal computed tomography (CT) scan and ultrasound. No abnormalities were found.
The patient said that in prior pregnancies, she had experienced nausea and vomiting during the first trimester, but that her current symptoms were much worse. She also said she’d been smoking cannabis twice a day for a year.
THE DIAGNOSIS
Based on our patient’s symptoms, her history of daily cannabis use, and the lack of improvement from antiemetics and analgesics, we concluded that she was suffering from cannabinoid hyperemesis. By Day 3, her symptoms improved and she could tolerate oral fluids. We advised her to stop using cannabis and discharged her.
One week later, the patient reported that she had not smoked cannabis since she’d been admitted to the hospital and that her symptoms, including her compulsive bathing, continued to improve. The patient subsequently delivered a healthy newborn at term.
DISCUSSION
A drug sometimes used to relieve nausea may make it much worse
First described in 2004, cannabinoid hyperemesis is a triad of vomiting, abdominal pain, and compulsive bathing in patients with chronic cannabis use.2 Other symptoms include subjective fevers, chills, and diaphoresis. Symptoms of cannabinoid hyperemesis may persist for weeks and spontaneously remit for weeks to months. The syndrome can lead to serious complications, including volume depletion, weight loss of 5 to 10 kg per episode, burns caused by frequent hot showers, and esophageal rupture.2-4 The frequent hot baths or showers associated with cannabinoid hyperemesis are potentially harmful to the fetus—hyperthermia during early gestation can cause fetal mental deficiency, seizures, and neural tube defects.5-8
The association between cannabinoid hyperemesis and pregnancy is unknown. However, because 11% of pregnant women use cannabis,9 many women may be at risk for the condition. Pregnant women may use cannabis recreationally or to combat morning sickness. The high rate of cannabis use in this population may be due in part to a lack of perceived risk to the fetus, although prenatal cannabis exposure is associated with reduced fetal growth.10
Active component of cannabis may trigger vomiting, pain
While chronic cannabis use causes cannabinoid hyperemesis, the pathogenesis and pathophysiology of the disease remain unknown. Delta-9-tetrahydrocannabinol (THC), the active ingredient in cannabis, appears to be to blame.11-15
THC is lipophilic and accumulates in the body with chronic cannabis use. At higher accumulated levels, THC binds to cannabinoid receptors in the intestinal nerve plexus, causing lower esophageal sphincter relaxation and gastrointestinal motility inhibition.11,12 At high concentrations, THC also binds to CB1 receptors in the hypothalamus, which is responsible for integrating satiety, thirst, digestive function, and thermoregulation.13-15 This causes hypothalamic dysregulation that may be temporarily relieved by hot showers.2
Possible causes of our patient’s signs and symptoms included appendicitis, pyelonephritis, nephrolithiasis, ectopic pregnancy, and pelvic inflammatory disease. Our patient’s normal laboratory and imaging studies made these diagnoses less likely. Her lack of a fallopian tube or ovary on the right side prompted us to quickly rule out a right-sided ectopic implantation.
We considered our patient’s chlamydial infection as the source of her symptoms. However, she had experienced no vaginal discharge or bleeding, and her nausea and abdominal pain did not improve with a therapeutic dose of azithromycin. Imaging showed no evidence of chlamydia-associated complications, such as pelvic inflammatory disease or tubo-ovarian abscess, both of which are uncommon in pregnancy.
THE TAKEAWAY
Consider cannabinoid hyperemesis in patients who are experiencing vomiting and abdominal pain that are temporarily relieved by bathing in hot water. Ask such patients about their cannabis use, and strongly encourage them to discontinue the drug. Counsel pregnant women about the maternal and fetal risks of cannabis use and the potential teratogenicity of hot water bathing. Provide IV fluids to ensure adequate hydration and a benzodiazepine as appropriate for anxiety and cannabis withdrawal symptoms.16 Advise patients that their symptoms may return within weeks to months if they resume using cannabis.2,17
1. ACOG Committee on Obstetric Practice. ACOG Committee Opinion. Number 299, September 2004 (replaces No. 158, September 1995). Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol. 2004;104:647-651.
2. Allen JH, de Moore GM, Heddle R, et al. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut. 2004;53:1566-1570.
3. Sontineni SP, Chaudhary S, Sontineni V, et al. Cannabinoid hyperemesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World J Gastroenterol. 2009;15:1264-1266.
4. de Moore GM, Baker J, Bui T. Psychogenic vomiting complicated by marijuana abuse and spontaneous pneumomediastinum. Aust N Z J Psychiatry. 1996;30:290-294.
5. Smith DW, Clarren SK, Harvey MA. Hyperthermia as a possible teratogenic agent. J Pediatr. 1978;92:878-883.
6. Shiota K. Neural tube defects and maternal hyperthermia in early pregnancy: epidemiology in a human embryo population. Am J Med Genet. 1982;12:281-288.
7. Milunsky A, Ulcickas M, Rothman K, et al. Maternal heat exposure and neural tube defects. JAMA. 1992;268:882-885.
8. Miller P, Smith DW, Shepard TH. Maternal hyperthermia as a possible cause of anencephaly. Lancet. 1978;11:1519-1521.
9. Substance Abuse and Mental Health Services Administration Web site. Results from the 2008 National Survey on Drug Use and Health: national findings. Available at: http://www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed December 15, 2011.
10. Gray TR, Eiden RD, Leonard KD, et al. Identifying prenatal cannabis exposure and effects of concurrent tobacco exposure on neonatal growth. Clin Chem. 2010;56:1442-1450.
11. Izzo AA, Coutts AA. Cannabinoids and the digestive tract. Handb Exp Pharmacol. 2005;(168):573-598.
12. McCallum RW, Soykan I, Sridhar KR, et al. Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther. 1999;13:77-80.
13. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74:129-180.
14. Childers SR, Breivogel CS. Cannabis and endogenous cannabinoid systems. Drug Alcohol Dependence. 1998;51:173-187.
15. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci. 1990;87:1932-1936.
16. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzodiazepine during fetal life. Lancet. 1992;340:694-696.
17. Wallace D, Martin AL, Park B. Cannabinoid hyperemesis: marijuana puts patients in hot water. Australas Psychiatry. 2007;15:156-158.
1. ACOG Committee on Obstetric Practice. ACOG Committee Opinion. Number 299, September 2004 (replaces No. 158, September 1995). Guidelines for diagnostic imaging during pregnancy. Obstet Gynecol. 2004;104:647-651.
2. Allen JH, de Moore GM, Heddle R, et al. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut. 2004;53:1566-1570.
3. Sontineni SP, Chaudhary S, Sontineni V, et al. Cannabinoid hyperemesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World J Gastroenterol. 2009;15:1264-1266.
4. de Moore GM, Baker J, Bui T. Psychogenic vomiting complicated by marijuana abuse and spontaneous pneumomediastinum. Aust N Z J Psychiatry. 1996;30:290-294.
5. Smith DW, Clarren SK, Harvey MA. Hyperthermia as a possible teratogenic agent. J Pediatr. 1978;92:878-883.
6. Shiota K. Neural tube defects and maternal hyperthermia in early pregnancy: epidemiology in a human embryo population. Am J Med Genet. 1982;12:281-288.
7. Milunsky A, Ulcickas M, Rothman K, et al. Maternal heat exposure and neural tube defects. JAMA. 1992;268:882-885.
8. Miller P, Smith DW, Shepard TH. Maternal hyperthermia as a possible cause of anencephaly. Lancet. 1978;11:1519-1521.
9. Substance Abuse and Mental Health Services Administration Web site. Results from the 2008 National Survey on Drug Use and Health: national findings. Available at: http://www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed December 15, 2011.
10. Gray TR, Eiden RD, Leonard KD, et al. Identifying prenatal cannabis exposure and effects of concurrent tobacco exposure on neonatal growth. Clin Chem. 2010;56:1442-1450.
11. Izzo AA, Coutts AA. Cannabinoids and the digestive tract. Handb Exp Pharmacol. 2005;(168):573-598.
12. McCallum RW, Soykan I, Sridhar KR, et al. Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther. 1999;13:77-80.
13. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74:129-180.
14. Childers SR, Breivogel CS. Cannabis and endogenous cannabinoid systems. Drug Alcohol Dependence. 1998;51:173-187.
15. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci. 1990;87:1932-1936.
16. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzodiazepine during fetal life. Lancet. 1992;340:694-696.
17. Wallace D, Martin AL, Park B. Cannabinoid hyperemesis: marijuana puts patients in hot water. Australas Psychiatry. 2007;15:156-158.
Case Report: Headache in a Postpartum Patient With Essential Thrombocytosis
Case
At presentation, the patient was in no apparent distress and had normal vital signs, including normal blood pressure. On physical examination, she was alert and oriented, with unremarkable head, neck, fundoscopic, cardiac, pulmonary, skin, and neurological examinations. Laboratory results were only notable for a platelet count of 677 x 109/L. The remainder of the complete blood count, chemistry, and coagulation panels was all within normal limits. A noncontrast computed tomography (CT) of the brain was unremarkable. She was treated symptomatically with ketorolac, diphenhydramine, and metoclopramide, but received no relief.
Based on the patient’s history of ET and postpartum state, there was a high suspicion for cerebral venous thrombosis (CVT). Magnetic resonance imaging/magnetic resonance venography (MRI/MRV) of the brain was obtained, which revealed near-complete thrombosis of the vein of Galen and straight sinus (Figure). Neurology and hematology services were consulted emergently, and the patient was started on a heparin drip and admitted to the neurosurgical intensive care unit. Hydroxyurea was also given for cytoreduction, and platelets normalized to 305 x 109/L within 1 day of treatment. The patient’s neurological examination remained nonfocal, her headache gradually resolved, and she was discharged on hospital day 3 on oral anticoagulants.
Discussion
Essential thrombocytosis is a chronic myeloproliferative disorder characterized by clonal proliferation of the megakaryocyte cell line due to a defect in a pluripotent hematopoietic stem cell.1 The estimated annual incidence is 2.5 per 100,000 individuals.2 It affects patients of both genders, most commonly between ages 50 to 70 years.3
Up to 25% of patients with ET experience neurological complications, mainly occlusive strokes, chronic headache, and dizziness.4 Since pregnancy also increases thrombogenicity, and CVT occurs in 12 per 100,000 deliveries,5 it should be considered in any pregnant or postpartum patient with neurological symptoms.
Diagnosis of ET
Essential thrombocytosis is a diagnosis of exclusion, and no clinical or laboratory finding is diagnostic.1 Although patients with ET are at increased risk for bleeding, these events usually involve mucosal and cutaneous sites and are clinically insignificant. Thrombotic complications account for the majority of the morbidity and mortality associated with ET and can be both arterial and venous. In one case series, roughly 50% patients with ET experienced a thrombotic event within 9 years from diagnosis.6 Thrombotic complications are seen most commonly in patients younger than age 55 years at diagnosis. Common sites of thrombosis include the deep veins of the lower extremities, pulmonary vessels, hepatic vein, portal vein, digital microvasculature, and placenta.1
Despite the high rate of thrombotic complications in ET, there is little data on neurological complications and few reports of CVT in patients with ET.7-9 In one chart review of 70 patients with ET, researchers identified 18 patients who developed neurological complications,4 the most common of which was cerebrovascular accident/transient ischemic attack. Only one patient in the series had a CVT. The majority of patients with neurological events were female and no clinical or laboratory parameter predicted the risk of neurological event.
Thrombocytosis
Thrombocytosis is classified as either primary/essential or secondary/reactive. The majority of thrombocytosis is secondary/reactive and is caused by a variety of inflammatory conditions, such as infection and malignancy. Unlike ET, secondary thrombocytosis is not associated with any bleeding or thrombotic complications and does not require direct treatment.1
Treatment of ET
The decision to treat ET is based on clinical parameters and is usually reserved for patients at high-risk of thrombosis, including those with history of thrombosis or platelets >1,500 x 109/L.1 The first-line agent for treatment of essential thrombocytosis, hydroxyurea has been shown to decrease thrombotic episodes.10 Other cytoreductive agents include anagrilide and interferon-α, the use of which is considered safe in pregnancy.1
Cerebral Venous Thrombosis
Cerebral venous thrombosis is a rare but potentially fatal condition. Patients may present with headache (95%), seizures (47%), and vision changes (41%), and may or may not have focal or generalized neurological deficits.11 Thrombosis can lead to venous obstruction, resulting in increased intracranial pressure and ultimately cerebral herniation and death. Predisposing risk factors for CVT include thrombophilic and procoagulant disorders, maxillofacial infections, trauma, malignancy, and vasculitides. Among female patients with CVT, studies show approximately 50% were on oral contraceptives and 20% were pregnant or in the postpartum period at the time of the event. Nearly half of patients with CVT have multiple risk factors.12
Diagnosis of CVT
Diagnosis of CVT requires a high clinical suspicion. Lumbar puncture usually reveals high opening pressure with normal cerebrospinal fluid analysis.13 The classic finding of CVT on a contrast-enhanced CT scan is the “empty delta sign,” which is a central hypointensity within the superior sagittal sinus secondary due to slow/absent flow surrounded by contrast enhancement in a triangular shape. An ischemic infarction crossing arterial boundaries or near a venous sinus—with or without a hemorrhagic component—is also suggestive of CVT. However, CT scans are read as normal or indeterminate in up to 30% patients.14 Moreover, while CT venography may visualize the cerebral venous system, there is a false-negative rate of 25%.15 Therefore, MRI with MRV is the gold standard for diagnosis.
Pregnancy and CVT
As previously noted, pregnant or postpartum patients are at an increased risk of developing CVT. During pregnancy, decreased levels of protein S inhibitors and increased levels of fibrinogen, clotting factors, and protein C inhibitors lead to increased thrombogenicity.16 Older maternal age, pregnancy-related hypertension, peripartum infections, and cesarean delivery also increase the risk of CVT.16
Patients with CVT associated with pregnancy have more acute onset of symptoms and neurological findings, and 2% to 10% less mortality than patients with CVT secondary to other etiologies. Cerebral venous thrombosis should be considered in the differential diagnosis of any pregnant or postpartum patient presenting with neurological symptoms.
Treatment of CVT
Regardless of underlying etiology or symptom duration, all patients with CVT should receive anticoagulation therapy. Unfractionated or low-molecular weight heparin has been shown to decrease thrombus propagation, increase the rate of recanalization, and improve long-term outcomes—even in the presence of intracranial hemorrhage.17 In the 30% to 40% of patients with CVT who present with intracranial hemorrhage, anticoagulation decreases mortality and is not associated with new or enlarged bleeding.17-19 Patients who continue to deteriorate despite anticoagulation therapy may benefit from endovascular thrombolysis or decompressive hemicraniectomy.20 In a study of patients with CVT, 80% had full recovery, 6% had minor disability, and 14% had a poor outcome.12
Conclusion
This case describes a patient with two risk factors for CVT, a life-threatening condition. It should be considered in patients with ET and/or pregnant and postpartum patients presenting with headache or other neurological symptoms. Magnetic resonance venography is the diagnostic imaging of choice as the CVT may not be visible on CT. All patients with thrombosis and ET should receive anticoagulation therapy and hydroxyurea to prevent cerebral herniation and death.
Dr Canders is a resident, department of emergency medicine, David Geffen School of Medicine, University of California, Los Angeles. Dr Taira is a clinical assistant professor, department of emergency medicine, Los Angeles County Hospital/University of Southern California, Los Angeles.
Disclosure: The authors report no financial disclosures or conflicts of interests related to this article.
- Schafer AI. Thrombocytosis and thrombocythemia. Blood Rev. 2001;15(4):159-166.
- Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol. 1999;61():10-15.
- Tefferi A. Recent progress in the pathogenesis and management of essential thrombocythemia. Leuk Res. 2001;25(5):369-377.
- Kesler A, Ellis MH, Manor Y, Gadoth N, Lishner M. Neurological complications of essential thrombocytosis (ET). Acta Neurol Scand. 2000;102(5):299-302.
- Cantú C, Barinagarrementeria F. Cerebral venous thrombosis associated with pregnancy and puerperium: Review of 67 cases. Stroke. 1993;24(12):1880-1884.
- Bazzan M, Tamponi G, Schinco P, Vaccarino A, Foli C, Gallone G, et al. Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Hematol. 1999;78(12):539-543.
- Walther EU, Tiecks FP, Haberl RL. Cranial sinus thrombosis associated with essential thrombocythemia followed by heparin-associated thrombocytopenia. Neurology. 1996;47(1):300-301.
- McDonald TD, Tatemichi TK, Kranzler SJ, Chi L, Hilal SK, Mohr JP. Thrombosis of the superior sagittal sinus associated with essential thrombocytosis followed by MRI during anticoagulant therapy. Neurology. 1989;39(11):1554-1555.
- Iob I, Scanarini M, Andrioli GC, Pardatscher K. Thrombosis of the superior sagittal sinus associated with idiopathic thrombocytosis. Surg Neurol. 1979;11(6):439-41.
- Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995;332(17):1132-1136.
- de Bruijn SF, de Haan RJ, Stam J. Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients. For The Cerebral Venous Sinus Thrombosis Study Group. J Neurol Neurosurg Psychiatry. 2001;70(1):105-108.
- Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F; ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35(3):664-670.
- DeLashaw MR, Vizioli TL, Jr, Counselman FL. Headache and seizure in a young woman postpartum. J Emerg Med. 2005;29(3):289-293.
- Bousser MG. Cerebral venous thrombosis: diagnosis and management. J Neurol. 2000;247(4):252-258.
- Grover M. Cerebral venous thrombosis as a cause of acute headache. J Am Board Fam Pract. 2004;17(4):295-298.
- Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral venous thrombosis in carriers of prothrombic-gene mutation and in users of oral contraceptives. N Engl J Med. 1988;338(25):1793-1797.
- Star M, Flaster M. Advances and controversies in the management of cerebral venous thrombosis. Neurol Clin. 2013;31(3):765-783.
- Einhäupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338(8767):597-600.
- Preter M, Tzourio C, Ameri A, Bousser MG. Long-term prognosis in cerebral venous thrombosis: follow-up of 77 patients. Stroke 1996;27(2):243-246.
- Coutinho JM, Stam J. How to treat cerebral venous and sinus thrombosis. J Thromb Haemost. 2010;8(5):877-883.
Case
At presentation, the patient was in no apparent distress and had normal vital signs, including normal blood pressure. On physical examination, she was alert and oriented, with unremarkable head, neck, fundoscopic, cardiac, pulmonary, skin, and neurological examinations. Laboratory results were only notable for a platelet count of 677 x 109/L. The remainder of the complete blood count, chemistry, and coagulation panels was all within normal limits. A noncontrast computed tomography (CT) of the brain was unremarkable. She was treated symptomatically with ketorolac, diphenhydramine, and metoclopramide, but received no relief.
Based on the patient’s history of ET and postpartum state, there was a high suspicion for cerebral venous thrombosis (CVT). Magnetic resonance imaging/magnetic resonance venography (MRI/MRV) of the brain was obtained, which revealed near-complete thrombosis of the vein of Galen and straight sinus (Figure). Neurology and hematology services were consulted emergently, and the patient was started on a heparin drip and admitted to the neurosurgical intensive care unit. Hydroxyurea was also given for cytoreduction, and platelets normalized to 305 x 109/L within 1 day of treatment. The patient’s neurological examination remained nonfocal, her headache gradually resolved, and she was discharged on hospital day 3 on oral anticoagulants.
Discussion
Essential thrombocytosis is a chronic myeloproliferative disorder characterized by clonal proliferation of the megakaryocyte cell line due to a defect in a pluripotent hematopoietic stem cell.1 The estimated annual incidence is 2.5 per 100,000 individuals.2 It affects patients of both genders, most commonly between ages 50 to 70 years.3
Up to 25% of patients with ET experience neurological complications, mainly occlusive strokes, chronic headache, and dizziness.4 Since pregnancy also increases thrombogenicity, and CVT occurs in 12 per 100,000 deliveries,5 it should be considered in any pregnant or postpartum patient with neurological symptoms.
Diagnosis of ET
Essential thrombocytosis is a diagnosis of exclusion, and no clinical or laboratory finding is diagnostic.1 Although patients with ET are at increased risk for bleeding, these events usually involve mucosal and cutaneous sites and are clinically insignificant. Thrombotic complications account for the majority of the morbidity and mortality associated with ET and can be both arterial and venous. In one case series, roughly 50% patients with ET experienced a thrombotic event within 9 years from diagnosis.6 Thrombotic complications are seen most commonly in patients younger than age 55 years at diagnosis. Common sites of thrombosis include the deep veins of the lower extremities, pulmonary vessels, hepatic vein, portal vein, digital microvasculature, and placenta.1
Despite the high rate of thrombotic complications in ET, there is little data on neurological complications and few reports of CVT in patients with ET.7-9 In one chart review of 70 patients with ET, researchers identified 18 patients who developed neurological complications,4 the most common of which was cerebrovascular accident/transient ischemic attack. Only one patient in the series had a CVT. The majority of patients with neurological events were female and no clinical or laboratory parameter predicted the risk of neurological event.
Thrombocytosis
Thrombocytosis is classified as either primary/essential or secondary/reactive. The majority of thrombocytosis is secondary/reactive and is caused by a variety of inflammatory conditions, such as infection and malignancy. Unlike ET, secondary thrombocytosis is not associated with any bleeding or thrombotic complications and does not require direct treatment.1
Treatment of ET
The decision to treat ET is based on clinical parameters and is usually reserved for patients at high-risk of thrombosis, including those with history of thrombosis or platelets >1,500 x 109/L.1 The first-line agent for treatment of essential thrombocytosis, hydroxyurea has been shown to decrease thrombotic episodes.10 Other cytoreductive agents include anagrilide and interferon-α, the use of which is considered safe in pregnancy.1
Cerebral Venous Thrombosis
Cerebral venous thrombosis is a rare but potentially fatal condition. Patients may present with headache (95%), seizures (47%), and vision changes (41%), and may or may not have focal or generalized neurological deficits.11 Thrombosis can lead to venous obstruction, resulting in increased intracranial pressure and ultimately cerebral herniation and death. Predisposing risk factors for CVT include thrombophilic and procoagulant disorders, maxillofacial infections, trauma, malignancy, and vasculitides. Among female patients with CVT, studies show approximately 50% were on oral contraceptives and 20% were pregnant or in the postpartum period at the time of the event. Nearly half of patients with CVT have multiple risk factors.12
Diagnosis of CVT
Diagnosis of CVT requires a high clinical suspicion. Lumbar puncture usually reveals high opening pressure with normal cerebrospinal fluid analysis.13 The classic finding of CVT on a contrast-enhanced CT scan is the “empty delta sign,” which is a central hypointensity within the superior sagittal sinus secondary due to slow/absent flow surrounded by contrast enhancement in a triangular shape. An ischemic infarction crossing arterial boundaries or near a venous sinus—with or without a hemorrhagic component—is also suggestive of CVT. However, CT scans are read as normal or indeterminate in up to 30% patients.14 Moreover, while CT venography may visualize the cerebral venous system, there is a false-negative rate of 25%.15 Therefore, MRI with MRV is the gold standard for diagnosis.
Pregnancy and CVT
As previously noted, pregnant or postpartum patients are at an increased risk of developing CVT. During pregnancy, decreased levels of protein S inhibitors and increased levels of fibrinogen, clotting factors, and protein C inhibitors lead to increased thrombogenicity.16 Older maternal age, pregnancy-related hypertension, peripartum infections, and cesarean delivery also increase the risk of CVT.16
Patients with CVT associated with pregnancy have more acute onset of symptoms and neurological findings, and 2% to 10% less mortality than patients with CVT secondary to other etiologies. Cerebral venous thrombosis should be considered in the differential diagnosis of any pregnant or postpartum patient presenting with neurological symptoms.
Treatment of CVT
Regardless of underlying etiology or symptom duration, all patients with CVT should receive anticoagulation therapy. Unfractionated or low-molecular weight heparin has been shown to decrease thrombus propagation, increase the rate of recanalization, and improve long-term outcomes—even in the presence of intracranial hemorrhage.17 In the 30% to 40% of patients with CVT who present with intracranial hemorrhage, anticoagulation decreases mortality and is not associated with new or enlarged bleeding.17-19 Patients who continue to deteriorate despite anticoagulation therapy may benefit from endovascular thrombolysis or decompressive hemicraniectomy.20 In a study of patients with CVT, 80% had full recovery, 6% had minor disability, and 14% had a poor outcome.12
Conclusion
This case describes a patient with two risk factors for CVT, a life-threatening condition. It should be considered in patients with ET and/or pregnant and postpartum patients presenting with headache or other neurological symptoms. Magnetic resonance venography is the diagnostic imaging of choice as the CVT may not be visible on CT. All patients with thrombosis and ET should receive anticoagulation therapy and hydroxyurea to prevent cerebral herniation and death.
Dr Canders is a resident, department of emergency medicine, David Geffen School of Medicine, University of California, Los Angeles. Dr Taira is a clinical assistant professor, department of emergency medicine, Los Angeles County Hospital/University of Southern California, Los Angeles.
Disclosure: The authors report no financial disclosures or conflicts of interests related to this article.
Case
At presentation, the patient was in no apparent distress and had normal vital signs, including normal blood pressure. On physical examination, she was alert and oriented, with unremarkable head, neck, fundoscopic, cardiac, pulmonary, skin, and neurological examinations. Laboratory results were only notable for a platelet count of 677 x 109/L. The remainder of the complete blood count, chemistry, and coagulation panels was all within normal limits. A noncontrast computed tomography (CT) of the brain was unremarkable. She was treated symptomatically with ketorolac, diphenhydramine, and metoclopramide, but received no relief.
Based on the patient’s history of ET and postpartum state, there was a high suspicion for cerebral venous thrombosis (CVT). Magnetic resonance imaging/magnetic resonance venography (MRI/MRV) of the brain was obtained, which revealed near-complete thrombosis of the vein of Galen and straight sinus (Figure). Neurology and hematology services were consulted emergently, and the patient was started on a heparin drip and admitted to the neurosurgical intensive care unit. Hydroxyurea was also given for cytoreduction, and platelets normalized to 305 x 109/L within 1 day of treatment. The patient’s neurological examination remained nonfocal, her headache gradually resolved, and she was discharged on hospital day 3 on oral anticoagulants.
Discussion
Essential thrombocytosis is a chronic myeloproliferative disorder characterized by clonal proliferation of the megakaryocyte cell line due to a defect in a pluripotent hematopoietic stem cell.1 The estimated annual incidence is 2.5 per 100,000 individuals.2 It affects patients of both genders, most commonly between ages 50 to 70 years.3
Up to 25% of patients with ET experience neurological complications, mainly occlusive strokes, chronic headache, and dizziness.4 Since pregnancy also increases thrombogenicity, and CVT occurs in 12 per 100,000 deliveries,5 it should be considered in any pregnant or postpartum patient with neurological symptoms.
Diagnosis of ET
Essential thrombocytosis is a diagnosis of exclusion, and no clinical or laboratory finding is diagnostic.1 Although patients with ET are at increased risk for bleeding, these events usually involve mucosal and cutaneous sites and are clinically insignificant. Thrombotic complications account for the majority of the morbidity and mortality associated with ET and can be both arterial and venous. In one case series, roughly 50% patients with ET experienced a thrombotic event within 9 years from diagnosis.6 Thrombotic complications are seen most commonly in patients younger than age 55 years at diagnosis. Common sites of thrombosis include the deep veins of the lower extremities, pulmonary vessels, hepatic vein, portal vein, digital microvasculature, and placenta.1
Despite the high rate of thrombotic complications in ET, there is little data on neurological complications and few reports of CVT in patients with ET.7-9 In one chart review of 70 patients with ET, researchers identified 18 patients who developed neurological complications,4 the most common of which was cerebrovascular accident/transient ischemic attack. Only one patient in the series had a CVT. The majority of patients with neurological events were female and no clinical or laboratory parameter predicted the risk of neurological event.
Thrombocytosis
Thrombocytosis is classified as either primary/essential or secondary/reactive. The majority of thrombocytosis is secondary/reactive and is caused by a variety of inflammatory conditions, such as infection and malignancy. Unlike ET, secondary thrombocytosis is not associated with any bleeding or thrombotic complications and does not require direct treatment.1
Treatment of ET
The decision to treat ET is based on clinical parameters and is usually reserved for patients at high-risk of thrombosis, including those with history of thrombosis or platelets >1,500 x 109/L.1 The first-line agent for treatment of essential thrombocytosis, hydroxyurea has been shown to decrease thrombotic episodes.10 Other cytoreductive agents include anagrilide and interferon-α, the use of which is considered safe in pregnancy.1
Cerebral Venous Thrombosis
Cerebral venous thrombosis is a rare but potentially fatal condition. Patients may present with headache (95%), seizures (47%), and vision changes (41%), and may or may not have focal or generalized neurological deficits.11 Thrombosis can lead to venous obstruction, resulting in increased intracranial pressure and ultimately cerebral herniation and death. Predisposing risk factors for CVT include thrombophilic and procoagulant disorders, maxillofacial infections, trauma, malignancy, and vasculitides. Among female patients with CVT, studies show approximately 50% were on oral contraceptives and 20% were pregnant or in the postpartum period at the time of the event. Nearly half of patients with CVT have multiple risk factors.12
Diagnosis of CVT
Diagnosis of CVT requires a high clinical suspicion. Lumbar puncture usually reveals high opening pressure with normal cerebrospinal fluid analysis.13 The classic finding of CVT on a contrast-enhanced CT scan is the “empty delta sign,” which is a central hypointensity within the superior sagittal sinus secondary due to slow/absent flow surrounded by contrast enhancement in a triangular shape. An ischemic infarction crossing arterial boundaries or near a venous sinus—with or without a hemorrhagic component—is also suggestive of CVT. However, CT scans are read as normal or indeterminate in up to 30% patients.14 Moreover, while CT venography may visualize the cerebral venous system, there is a false-negative rate of 25%.15 Therefore, MRI with MRV is the gold standard for diagnosis.
Pregnancy and CVT
As previously noted, pregnant or postpartum patients are at an increased risk of developing CVT. During pregnancy, decreased levels of protein S inhibitors and increased levels of fibrinogen, clotting factors, and protein C inhibitors lead to increased thrombogenicity.16 Older maternal age, pregnancy-related hypertension, peripartum infections, and cesarean delivery also increase the risk of CVT.16
Patients with CVT associated with pregnancy have more acute onset of symptoms and neurological findings, and 2% to 10% less mortality than patients with CVT secondary to other etiologies. Cerebral venous thrombosis should be considered in the differential diagnosis of any pregnant or postpartum patient presenting with neurological symptoms.
Treatment of CVT
Regardless of underlying etiology or symptom duration, all patients with CVT should receive anticoagulation therapy. Unfractionated or low-molecular weight heparin has been shown to decrease thrombus propagation, increase the rate of recanalization, and improve long-term outcomes—even in the presence of intracranial hemorrhage.17 In the 30% to 40% of patients with CVT who present with intracranial hemorrhage, anticoagulation decreases mortality and is not associated with new or enlarged bleeding.17-19 Patients who continue to deteriorate despite anticoagulation therapy may benefit from endovascular thrombolysis or decompressive hemicraniectomy.20 In a study of patients with CVT, 80% had full recovery, 6% had minor disability, and 14% had a poor outcome.12
Conclusion
This case describes a patient with two risk factors for CVT, a life-threatening condition. It should be considered in patients with ET and/or pregnant and postpartum patients presenting with headache or other neurological symptoms. Magnetic resonance venography is the diagnostic imaging of choice as the CVT may not be visible on CT. All patients with thrombosis and ET should receive anticoagulation therapy and hydroxyurea to prevent cerebral herniation and death.
Dr Canders is a resident, department of emergency medicine, David Geffen School of Medicine, University of California, Los Angeles. Dr Taira is a clinical assistant professor, department of emergency medicine, Los Angeles County Hospital/University of Southern California, Los Angeles.
Disclosure: The authors report no financial disclosures or conflicts of interests related to this article.
- Schafer AI. Thrombocytosis and thrombocythemia. Blood Rev. 2001;15(4):159-166.
- Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol. 1999;61():10-15.
- Tefferi A. Recent progress in the pathogenesis and management of essential thrombocythemia. Leuk Res. 2001;25(5):369-377.
- Kesler A, Ellis MH, Manor Y, Gadoth N, Lishner M. Neurological complications of essential thrombocytosis (ET). Acta Neurol Scand. 2000;102(5):299-302.
- Cantú C, Barinagarrementeria F. Cerebral venous thrombosis associated with pregnancy and puerperium: Review of 67 cases. Stroke. 1993;24(12):1880-1884.
- Bazzan M, Tamponi G, Schinco P, Vaccarino A, Foli C, Gallone G, et al. Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Hematol. 1999;78(12):539-543.
- Walther EU, Tiecks FP, Haberl RL. Cranial sinus thrombosis associated with essential thrombocythemia followed by heparin-associated thrombocytopenia. Neurology. 1996;47(1):300-301.
- McDonald TD, Tatemichi TK, Kranzler SJ, Chi L, Hilal SK, Mohr JP. Thrombosis of the superior sagittal sinus associated with essential thrombocytosis followed by MRI during anticoagulant therapy. Neurology. 1989;39(11):1554-1555.
- Iob I, Scanarini M, Andrioli GC, Pardatscher K. Thrombosis of the superior sagittal sinus associated with idiopathic thrombocytosis. Surg Neurol. 1979;11(6):439-41.
- Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995;332(17):1132-1136.
- de Bruijn SF, de Haan RJ, Stam J. Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients. For The Cerebral Venous Sinus Thrombosis Study Group. J Neurol Neurosurg Psychiatry. 2001;70(1):105-108.
- Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F; ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35(3):664-670.
- DeLashaw MR, Vizioli TL, Jr, Counselman FL. Headache and seizure in a young woman postpartum. J Emerg Med. 2005;29(3):289-293.
- Bousser MG. Cerebral venous thrombosis: diagnosis and management. J Neurol. 2000;247(4):252-258.
- Grover M. Cerebral venous thrombosis as a cause of acute headache. J Am Board Fam Pract. 2004;17(4):295-298.
- Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral venous thrombosis in carriers of prothrombic-gene mutation and in users of oral contraceptives. N Engl J Med. 1988;338(25):1793-1797.
- Star M, Flaster M. Advances and controversies in the management of cerebral venous thrombosis. Neurol Clin. 2013;31(3):765-783.
- Einhäupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338(8767):597-600.
- Preter M, Tzourio C, Ameri A, Bousser MG. Long-term prognosis in cerebral venous thrombosis: follow-up of 77 patients. Stroke 1996;27(2):243-246.
- Coutinho JM, Stam J. How to treat cerebral venous and sinus thrombosis. J Thromb Haemost. 2010;8(5):877-883.
- Schafer AI. Thrombocytosis and thrombocythemia. Blood Rev. 2001;15(4):159-166.
- Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol. 1999;61():10-15.
- Tefferi A. Recent progress in the pathogenesis and management of essential thrombocythemia. Leuk Res. 2001;25(5):369-377.
- Kesler A, Ellis MH, Manor Y, Gadoth N, Lishner M. Neurological complications of essential thrombocytosis (ET). Acta Neurol Scand. 2000;102(5):299-302.
- Cantú C, Barinagarrementeria F. Cerebral venous thrombosis associated with pregnancy and puerperium: Review of 67 cases. Stroke. 1993;24(12):1880-1884.
- Bazzan M, Tamponi G, Schinco P, Vaccarino A, Foli C, Gallone G, et al. Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Hematol. 1999;78(12):539-543.
- Walther EU, Tiecks FP, Haberl RL. Cranial sinus thrombosis associated with essential thrombocythemia followed by heparin-associated thrombocytopenia. Neurology. 1996;47(1):300-301.
- McDonald TD, Tatemichi TK, Kranzler SJ, Chi L, Hilal SK, Mohr JP. Thrombosis of the superior sagittal sinus associated with essential thrombocytosis followed by MRI during anticoagulant therapy. Neurology. 1989;39(11):1554-1555.
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An unusual presentation of an aggressive spindle cell skin cancer
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