CASE REPORT REPORT
CYCLOPHOSPHAMIDE
Treatment of hemorrhagic acute disseminated encephalomyelitis with cyclophosphamide Jaclyn M. Jaskowiak, Pharm.D., BCPS, UC San Diego Health System, San Diego, CA.
Purpose. Improvements in hemorrhagic and clinical symptoms in a patient with hemorrhagic acute disseminated encephalomyelitis (ADEM) treated with i.v. cyclophosphamide are reported. Summary. A 49-year-old woman was hospitalized with progressively worsening left-sided weakness, dysphagia, diplopia, and vertigo. Shortly before hospital admission, the patient had been treated at another facility with corticosteroids and plasma exchanges. Brain magnetic resonance imaging (MRI) studies conducted at the time of admission showed demyelinating lesions of the pons consistent with ADEM; rapid progression of the patient’s symptoms also suggested an autoimmune, demyelinating process, and viral studies ruled out an infectious etiology. Despite initial treatment with i.v. immune globulin and additional corticosteroid courses, the patient’s condition continued to deteriorate over the next few weeks, with development of respiratory distress requiring intubation. Repeat MRI revealed a new brain lesion in the splenial region of the corpus callosum, prompting the initiation of i.v. cyclophosphamide therapy (180 mg daily). Approximately 19 days after cyclophosphamide therapy was initiated, an MRI scan revealed substantial reduction of the pontine hemorrhage and a normal splenium appearance, with no new lesion development. The use of cyclophosphamide for hemorrhagic ADEM refractory to other treatments has been previously reported. Conclusion. After approximately three weeks of daily i.v. cyclophosphamide therapy, a patient with hemorrhagic ADEM was noted to have stable to improved brain MRI findings along with limited improvement of mental status and movement symptoms. Am J Health-Syst Pharm. 2016; 73:202-5
A
Address correspondence to Dr. Jaskowiak ([email protected]). Copyright © 2016, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/16/0202-0202. DOI 10.2146/ajhp150079
202
cute disseminated encephalomyelitis (ADEM) is a rare demyelinating disorder of the central nervous system for which there are few treatment options.1,2 Corticosteroids, plasma exchange, and immunomodulatory therapies have been used to treat ADEM. The overall prognosis for complete recovery from ADEM is 50–75%. The hemorrhagic variant of ADEM occurs in approximately 2% of patients with ADEM and can be fatal; a 70% mortality rate within the first week after diagnosis has been reported.3 Although the pathophysiology of ADEM is unknown, an autoimmune response to myelin basic protein
AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 4 | FEBRUARY 15, 2016
triggered by infection or immunization is one possible etiology.2 ADEM has no gender predominance and occurs more frequently in children.4 The clinical presentation is variable, and presenting features of ADEM can include rapidly developing encephalopathy, acute hemiparesis, ataxia, cranial neuropathies, and impaired vision.5 No reports of randomized controlled trials related to the treatment of ADEM have been published, and specific therapeutic approaches are controversial. Cyclophosphamide is an alkylating agent that is used in the treatment of various neoplastic diseases
CASE REPORT
CYCLOPHOSPHAMIDE
and autoimmune disorders.3 Cyclophosphamide is a treatment option for hemorrhagic ADEM when other treatment modalities are ineffective. Limited data on the use of cyclophosphamide in hemorrhagic ADEM have been published, particularly with regard to the dose, duration, and frequency of use and monitoring requirements.6 This case report describes a patient with hemorrhagic ADEM, also known as acute hemorrhagic leukoencephalitis, who received cyclophosphamide 180 mg i.v. daily for 21 days.
Case report A 49-year-old woman was hospitalized with progressively worsening left-sided weakness, dysphagia, diplopia, and vertigo. Prior to admission, the patient had completed a seven-day course of i.v. methylprednisolone 1 g daily and seven cycles of plasma exchange, without response, at another facility. After the patient’s admission to the neurology service, imaging studies showed demyelinating lesions of the pons, the area of the brain responsible for relaying information to various parts of the nervous system.7 The leading suspected diagnosis from the neurology service at the time of admission was ADEM. The primary reason for this diagnosis was the relatively rapid progression of the patient’s symptoms, which suggested an autoimmune, demyelinating process rather than an infectious etiology. Pertinent laboratory test values included a white blood cell count of 14.9 × 103 cells per mL, an erythrocyte sedimentation rate of 48 mm/hr, and a negative cerebrospinal fluid (CSF) oligoclonal band profile. The patient had a medical history of fibromyalgia, migraine headaches, endometriosis, type 2 diabetes mellitus, and hypertension, with no history of smoking or substance abuse. She reported no other recent illnesses and no recent immunizations or travel. Extensive cultures and viral studies (via polymerase chain reaction methods) were negative.
KEY POINTS • Cyclophosphamide is a treatment option for hemorrhagic acute disseminated encephalomyelitis (ADEM) when other treatment modalities are ineffective. • This case report provides novel documentation of using low-dose cyclophosphamide (180 mg per day) for 21 consecutive days for hemorrhagic ADEM. • The use of i.v. cyclophosphamide 180 mg per day for 21 consecutive days is a reasonable treatment option for a patient with a diagnosis of hemorrhagic ADEM.
The patient was started on i.v. immune globulin (IVIG) 0.4 mg/kg per day for five days and i.v. methylprednisolone sodium succinate (1 g of methylprednisolone per day) for seven days, but no improvement was noted. Those treatments were followed by an oral prednisone taper (initially 1 g/kg/day, with the dosage tapered over 3.5 weeks). The patient became more lethargic, and her level of consciousness progressively deteriorated during the hospital stay. Magnetic resonance imaging (MRI) revealed the presence of a pontine hemorrhage measuring 1.9 × 2.2 cm, and hemorrhagic ADEM was diagnosed. Subsequently, the patient decompensated, could no longer follow commands, and developed respiratory distress requiring rapid sequence intubation. She was transferred to the intensive care unit, where she received a repeat course of i.v. methylprednisolone sodium succinate (1 g of methylprednisolone per day for seven days, without a taper) and plasma exchange every other day for six treatments, with a subsequent course of IVIG 0.4 mg/kg/
day for five days. After the patient’s respiratory status improved over the next 10 days, she was extubated and transferred to a step-down unit; after extubation, the patient was found to have an Escherichia coli urinary tract infection (UTI). A tracheostomy tube was eventually placed due to worsening dysphagia and the patient’s inability to speak. A repeat MRI demonstrated a new brain lesion in the splenium, an area of the corpus callosum that aids in synchronizing communication between the hemispheres of the brain.8 This finding prompted the initiation of cyclophosphamide therapy. The patient was initiated on cyclophosphamide i.v. 180 mg daily. The patient’s renal function was stable, with a serum creatinine concentration of 0.45 mg/dL and an estimated glomerular filtration rate of >60 mL/ min per 1.73 m2 of body surface area. The patient’s absolute neutrophil count and platelet count were 6.4 × 103 cells/mL and 238 × 103 cells/ mL, respectively. Intravenous mesna 100 mg, i.v. ondansetron 4 mg, and prehydration were ordered daily to augment the cyclophosphamide regimen. Also, due to the patient’s recent UTI episode (urinalysis had shown greater than 50 red blood cells per high-power field and a large amount of blood), a urinary dipstick test was performed weekly to ensure that the patient was being appropriately monitored for hemorrhagic cystitis; subsequent urinary dipstick test results were negative. Approximately 19 days after cyclophosphamide was initiated, an MRI revealed stable to improved findings with regard to the pontine hemorrhage. The hemorrhage had decreased in size from 1.9 × 2.2 cm to 1.9 × 1.4 cm, and the splenium was normal in appearance. The patient also slowly improved clinically. Her mental status gradually improved to a point where she was able to follow commands again and was alert, oriented, and interactive. Her commu-
AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 4 | FEBRUARY 15, 2016 203
CASE REPORT nication improved as she was able to mouth words and use her tracheostomy speaking valve. She also had improved movements on the left side of her body. The patient completed 21 consecutive days of cyclophosphamide therapy. Approximately 41 days after cyclophosphamide was initiated, a repeat MRI showed no new lesions and further reduction of the pontine hemorrhage to a size of 1.8 × 1.1 cm. However, despite physical therapy and some clinical improvement, the patient was unable to perform activities of daily living on her own. Sixty days after the initiation of cyclophosphamide therapy, the patient was discharged to a long-term acute care facility. At that time it was decided that rather than resuming daily cyclophosphamide therapy, monthly cyclophosphamide maintenance therapy, administered on an outpatient basis, was more feasible for the patient. Other than monthly maintenance cyclophosphamide therapy, no further treatments for ADEM were noted in the patient’s record.
Discussion Treatment options for ADEM include the use of high-dose corticosteroids, plasma exchange, and IVIG.1 The patient received repeated courses of all three treatments. However, a pontine hemorrhage occurred after these treatments were completed. This additional finding prompted the initiation of therapy with cyclophosphamide daily for 21 consecutive days. Cyclophosphamide is an antineoplastic agent that is used in multiple disorders, including leukemias, lymphomas, and other malignancies. It is also used for the treatment of various immune-mediated disorders, such as multiple sclerosis. Cyclophosphamide has antiinflammatory and immunosuppressive effects. It increases levels of the antiinflammatory cytokines interleukin (IL)-4, IL-5, and IL-10 and transforming growth factor b and inhibits the proinflammatory
204
CYCLOPHOSPHAMIDE
cytokine IL-12.9 Cyclophosphamide produces immunosuppression by suppressing cell-mediated and humoral immunity through its action on T and B cells.10 It also reduces CSF myelin basic protein,11 which might be considered imperative in the context of ADEM management given that the disorder’s etiology is thought to involve an autoimmune response to myelin basic protein.3 There are currently no published data on the use of cyclophosphamide for hemorrhagic ADEM as detailed as the data provided here. Articles in the primary literature list cyclophosphamide as a treatment option for ADEM, but none lists complete regimen details, including the dose, the duration and frequency of use, and the monitoring parameters. Schwarz et al.12 conducted a follow-up study of 40 patients with ADEM, and the authors mentioned the use of i.v. cyclophosphamide 1 g in the study patients. However, no information on the duration and frequency of therapy, or monitoring guidance, was provided. Only one published report on a case of ADEM, by Seales and Greer,6 listed the dose of cyclophosphamide (180 mg given on hospital days 8–10 and 12–24, with the dose tapered over 7 hospital days). A potentially appropriate regimen and duration of cyclophosphamide use for treatment of hemorrhagic ADEM may be inferred from published data on use of the drug for the treatment of multiple sclerosis. Weiner and Cohen13 discussed regimens involving outpatient i.v. pulse therapy with cyclophosphamide every four to eight weeks for patients with multiple sclerosis, and Girard et al.14 described the use of cyclophosphamide 200 mg/day for four to six weeks in patients with that disorder. In the case described here, the duration of daily cyclophosphamide therapy for ADEM (21 days) was determined by a neurooncologist, who noted that daily use of the drug for at least four weeks has been documented in patients with multiple sclerosis.
AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 4 | FEBRUARY 15, 2016
Given similarities in the two disorders (ADEM is included in the differential diagnosis of multiple sclerosis), it can be inferred that using a similar regimen for the treatment of ADEM may be appropriate. ADEM is an acute demyelinating disorder that develops rapidly, whereas multiple sclerosis involves chronic demyelination. The presence of encephalopathy is a requirement for the diagnosis of ADEM but rare in the early stages of multiple sclerosis.5 In the case described here, the patient’s symptoms progressed rapidly and her level of consciousness deteriorated during the hospital stay. In differentiating between ADEM and multiple sclerosis in this case, a discerning finding was the presence of intrathecal synthesis of oligoclonal bands in the CSF.4 Oligoclonal bands in the CSF are present in 48–95% of patients with multiple sclerosis but in only 0–29% of those with ADEM; these bands were not present in the patient described here. Moreover, inflammatory markers are usually increased in ADEM but normal in multiple sclerosis.15 The patient described here had an elevated white blood cell count and erythrocyte sedimentation rate and was therefore diagnosed with ADEM. Cyclophosphamide has been used in the treatment of inflammatory, nonmalignant diseases,7 and the use of cyclophosphamide as a treatment for ADEM is warranted. Due to a lack of follow-up information, it is difficult to determine whether or not further improvement with (presumably administered) subsequent treatments with cyclophosphamide occurred after the patient was discharged from the hospital (the plan was for outpatient monthly maintenance therapy to continue for one year). It can be deduced that daily i.v. cyclophosphamide at a low dose (180 mg) is a reasonable treatment option for a patient with diagnosed hemorrhagic ADEM when other treatment strategies are unsuccessful. However, whether improve-
CASE REPORT
CYCLOPHOSPHAMIDE
ment in the patient’s status during the hospital stay was solely due to cyclophosphamide therapy is unknown.
Conclusion After approximately three weeks of daily i.v. cyclophosphamide therapy, a patient with hemorrhagic ADEM was noted to have stable to improved brain MRI findings along with limited improvement of mental status and movement symptoms.
Disclosures The author has declared no potential conflicts of interest.
References 1. Greer DM, Chow FC, Deuel TA, Venna N, eds. Pocket neurology. Philadelphia: Lippincott Williams & Wilkins; 2012:198-9. 2. Storch-Hagenlocher B, Griffin D. Acute disseminated encephalomyelitis (parainfectious and postvaccinal encephalitis). In: Hacke W, Stanley D, Bleck T, Diringer M, eds. Neurocritical care. Berlin: Springer; 1994:493-9.
3. Cyclophosphamide [monograph]. In: Clinical Pharmacology Online [online database]. Tampa, FL: Elsevier Gold Standard (accessed 2014 Jan 19). 4. Dale RC, Branson JA. Acute disseminated encephalomyelitis or multiple sclerosis: can the initial presentation help in establishing a correct diagnosis? Arch Dis Child. 2005; 90:636-9. 5. Transverse Myelitis Association. Acute disseminated encephalomyelitis (2012). http://myelitis.org/symptomsconditions/acute-disseminatedencephalomyelitis (accessed 2015 Jan 14). 6. Seales D, Greer M. Acute hemorrhagic leukocephalitis: a successful recovery. Arch Neurol. 1991; 48:1086-8. 7. Purves D, Augustine GJ, Fitzpatrick D et al., eds. Neuroscience. 3rd ed. Sunderland, MA: Sinauer Associates; 2004:38. 8. Knyazeva MG. Splenium of corpus callosum: patterns of interhemispheric interaction in children and adults. Neural Plast. 2013; 13:1-12. 9. Smith DR, Balashov KE, Hafler DA et al. Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: increased interleukin-4 production and associ-
ated eosinophilia. Ann Neurol. 1997; 42:313-8. 10. Kim YH, Choi BK, Oh SH et al. Mechanisms involved in synergistic anti-cancer effects of anti 4-1-BB and cyclophosphamide therapy. Mol Cancer Ther. 2009; 8:469-78. 11. Wender M, Tokarz E, Michalowska G, Wajgt A. Therapeutic trials of multiple sclerosis and intrathecal IgG production. Ital J Neurol Sci. 1986; 7:205-8. 12. Schwarz S, Mohr A, Khauth M et al. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology. 2001; 56:1313-8. 13. Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler. 2002; 8:142-54. 14. Girard PF, Aimard G, Pellet H. Therapeutique immuno-depressive en neurologie. Presse Med. 1967; 75:9678. In French. 15. Dale RC, de Sousa C, Chong WK et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain. 2000; 123, Pt. 12:2407-22.
AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 4 | FEBRUARY 15, 2016 205
CYCLOPHOSPHAMIDE
Treatment of hemorrhagic acute disseminated encephalomyelitis with cyclophosphamide Jaclyn M. Jaskowiak, Pharm.D., BCPS, UC San Diego Health System, San Diego, CA.
Purpose. Improvements in hemorrhagic and clinical symptoms in a patient with hemorrhagic acute disseminated encephalomyelitis (ADEM) treated with i.v. cyclophosphamide are reported. Summary. A 49-year-old woman was hospitalized with progressively worsening left-sided weakness, dysphagia, diplopia, and vertigo. Shortly before hospital admission, the patient had been treated at another facility with corticosteroids and plasma exchanges. Brain magnetic resonance imaging (MRI) studies conducted at the time of admission showed demyelinating lesions of the pons consistent with ADEM; rapid progression of the patient’s symptoms also suggested an autoimmune, demyelinating process, and viral studies ruled out an infectious etiology. Despite initial treatment with i.v. immune globulin and additional corticosteroid courses, the patient’s condition continued to deteriorate over the next few weeks, with development of respiratory distress requiring intubation. Repeat MRI revealed a new brain lesion in the splenial region of the corpus callosum, prompting the initiation of i.v. cyclophosphamide therapy (180 mg daily). Approximately 19 days after cyclophosphamide therapy was initiated, an MRI scan revealed substantial reduction of the pontine hemorrhage and a normal splenium appearance, with no new lesion development. The use of cyclophosphamide for hemorrhagic ADEM refractory to other treatments has been previously reported. Conclusion. After approximately three weeks of daily i.v. cyclophosphamide therapy, a patient with hemorrhagic ADEM was noted to have stable to improved brain MRI findings along with limited improvement of mental status and movement symptoms. Am J Health-Syst Pharm. 2016; 73:202-5
A
Address correspondence to Dr. Jaskowiak ([email protected]). Copyright © 2016, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/16/0202-0202. DOI 10.2146/ajhp150079
202
cute disseminated encephalomyelitis (ADEM) is a rare demyelinating disorder of the central nervous system for which there are few treatment options.1,2 Corticosteroids, plasma exchange, and immunomodulatory therapies have been used to treat ADEM. The overall prognosis for complete recovery from ADEM is 50–75%. The hemorrhagic variant of ADEM occurs in approximately 2% of patients with ADEM and can be fatal; a 70% mortality rate within the first week after diagnosis has been reported.3 Although the pathophysiology of ADEM is unknown, an autoimmune response to myelin basic protein
AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 4 | FEBRUARY 15, 2016
triggered by infection or immunization is one possible etiology.2 ADEM has no gender predominance and occurs more frequently in children.4 The clinical presentation is variable, and presenting features of ADEM can include rapidly developing encephalopathy, acute hemiparesis, ataxia, cranial neuropathies, and impaired vision.5 No reports of randomized controlled trials related to the treatment of ADEM have been published, and specific therapeutic approaches are controversial. Cyclophosphamide is an alkylating agent that is used in the treatment of various neoplastic diseases
CASE REPORT
CYCLOPHOSPHAMIDE
and autoimmune disorders.3 Cyclophosphamide is a treatment option for hemorrhagic ADEM when other treatment modalities are ineffective. Limited data on the use of cyclophosphamide in hemorrhagic ADEM have been published, particularly with regard to the dose, duration, and frequency of use and monitoring requirements.6 This case report describes a patient with hemorrhagic ADEM, also known as acute hemorrhagic leukoencephalitis, who received cyclophosphamide 180 mg i.v. daily for 21 days.
Case report A 49-year-old woman was hospitalized with progressively worsening left-sided weakness, dysphagia, diplopia, and vertigo. Prior to admission, the patient had completed a seven-day course of i.v. methylprednisolone 1 g daily and seven cycles of plasma exchange, without response, at another facility. After the patient’s admission to the neurology service, imaging studies showed demyelinating lesions of the pons, the area of the brain responsible for relaying information to various parts of the nervous system.7 The leading suspected diagnosis from the neurology service at the time of admission was ADEM. The primary reason for this diagnosis was the relatively rapid progression of the patient’s symptoms, which suggested an autoimmune, demyelinating process rather than an infectious etiology. Pertinent laboratory test values included a white blood cell count of 14.9 × 103 cells per mL, an erythrocyte sedimentation rate of 48 mm/hr, and a negative cerebrospinal fluid (CSF) oligoclonal band profile. The patient had a medical history of fibromyalgia, migraine headaches, endometriosis, type 2 diabetes mellitus, and hypertension, with no history of smoking or substance abuse. She reported no other recent illnesses and no recent immunizations or travel. Extensive cultures and viral studies (via polymerase chain reaction methods) were negative.
KEY POINTS • Cyclophosphamide is a treatment option for hemorrhagic acute disseminated encephalomyelitis (ADEM) when other treatment modalities are ineffective. • This case report provides novel documentation of using low-dose cyclophosphamide (180 mg per day) for 21 consecutive days for hemorrhagic ADEM. • The use of i.v. cyclophosphamide 180 mg per day for 21 consecutive days is a reasonable treatment option for a patient with a diagnosis of hemorrhagic ADEM.
The patient was started on i.v. immune globulin (IVIG) 0.4 mg/kg per day for five days and i.v. methylprednisolone sodium succinate (1 g of methylprednisolone per day) for seven days, but no improvement was noted. Those treatments were followed by an oral prednisone taper (initially 1 g/kg/day, with the dosage tapered over 3.5 weeks). The patient became more lethargic, and her level of consciousness progressively deteriorated during the hospital stay. Magnetic resonance imaging (MRI) revealed the presence of a pontine hemorrhage measuring 1.9 × 2.2 cm, and hemorrhagic ADEM was diagnosed. Subsequently, the patient decompensated, could no longer follow commands, and developed respiratory distress requiring rapid sequence intubation. She was transferred to the intensive care unit, where she received a repeat course of i.v. methylprednisolone sodium succinate (1 g of methylprednisolone per day for seven days, without a taper) and plasma exchange every other day for six treatments, with a subsequent course of IVIG 0.4 mg/kg/
day for five days. After the patient’s respiratory status improved over the next 10 days, she was extubated and transferred to a step-down unit; after extubation, the patient was found to have an Escherichia coli urinary tract infection (UTI). A tracheostomy tube was eventually placed due to worsening dysphagia and the patient’s inability to speak. A repeat MRI demonstrated a new brain lesion in the splenium, an area of the corpus callosum that aids in synchronizing communication between the hemispheres of the brain.8 This finding prompted the initiation of cyclophosphamide therapy. The patient was initiated on cyclophosphamide i.v. 180 mg daily. The patient’s renal function was stable, with a serum creatinine concentration of 0.45 mg/dL and an estimated glomerular filtration rate of >60 mL/ min per 1.73 m2 of body surface area. The patient’s absolute neutrophil count and platelet count were 6.4 × 103 cells/mL and 238 × 103 cells/ mL, respectively. Intravenous mesna 100 mg, i.v. ondansetron 4 mg, and prehydration were ordered daily to augment the cyclophosphamide regimen. Also, due to the patient’s recent UTI episode (urinalysis had shown greater than 50 red blood cells per high-power field and a large amount of blood), a urinary dipstick test was performed weekly to ensure that the patient was being appropriately monitored for hemorrhagic cystitis; subsequent urinary dipstick test results were negative. Approximately 19 days after cyclophosphamide was initiated, an MRI revealed stable to improved findings with regard to the pontine hemorrhage. The hemorrhage had decreased in size from 1.9 × 2.2 cm to 1.9 × 1.4 cm, and the splenium was normal in appearance. The patient also slowly improved clinically. Her mental status gradually improved to a point where she was able to follow commands again and was alert, oriented, and interactive. Her commu-
AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 4 | FEBRUARY 15, 2016 203
CASE REPORT nication improved as she was able to mouth words and use her tracheostomy speaking valve. She also had improved movements on the left side of her body. The patient completed 21 consecutive days of cyclophosphamide therapy. Approximately 41 days after cyclophosphamide was initiated, a repeat MRI showed no new lesions and further reduction of the pontine hemorrhage to a size of 1.8 × 1.1 cm. However, despite physical therapy and some clinical improvement, the patient was unable to perform activities of daily living on her own. Sixty days after the initiation of cyclophosphamide therapy, the patient was discharged to a long-term acute care facility. At that time it was decided that rather than resuming daily cyclophosphamide therapy, monthly cyclophosphamide maintenance therapy, administered on an outpatient basis, was more feasible for the patient. Other than monthly maintenance cyclophosphamide therapy, no further treatments for ADEM were noted in the patient’s record.
Discussion Treatment options for ADEM include the use of high-dose corticosteroids, plasma exchange, and IVIG.1 The patient received repeated courses of all three treatments. However, a pontine hemorrhage occurred after these treatments were completed. This additional finding prompted the initiation of therapy with cyclophosphamide daily for 21 consecutive days. Cyclophosphamide is an antineoplastic agent that is used in multiple disorders, including leukemias, lymphomas, and other malignancies. It is also used for the treatment of various immune-mediated disorders, such as multiple sclerosis. Cyclophosphamide has antiinflammatory and immunosuppressive effects. It increases levels of the antiinflammatory cytokines interleukin (IL)-4, IL-5, and IL-10 and transforming growth factor b and inhibits the proinflammatory
204
CYCLOPHOSPHAMIDE
cytokine IL-12.9 Cyclophosphamide produces immunosuppression by suppressing cell-mediated and humoral immunity through its action on T and B cells.10 It also reduces CSF myelin basic protein,11 which might be considered imperative in the context of ADEM management given that the disorder’s etiology is thought to involve an autoimmune response to myelin basic protein.3 There are currently no published data on the use of cyclophosphamide for hemorrhagic ADEM as detailed as the data provided here. Articles in the primary literature list cyclophosphamide as a treatment option for ADEM, but none lists complete regimen details, including the dose, the duration and frequency of use, and the monitoring parameters. Schwarz et al.12 conducted a follow-up study of 40 patients with ADEM, and the authors mentioned the use of i.v. cyclophosphamide 1 g in the study patients. However, no information on the duration and frequency of therapy, or monitoring guidance, was provided. Only one published report on a case of ADEM, by Seales and Greer,6 listed the dose of cyclophosphamide (180 mg given on hospital days 8–10 and 12–24, with the dose tapered over 7 hospital days). A potentially appropriate regimen and duration of cyclophosphamide use for treatment of hemorrhagic ADEM may be inferred from published data on use of the drug for the treatment of multiple sclerosis. Weiner and Cohen13 discussed regimens involving outpatient i.v. pulse therapy with cyclophosphamide every four to eight weeks for patients with multiple sclerosis, and Girard et al.14 described the use of cyclophosphamide 200 mg/day for four to six weeks in patients with that disorder. In the case described here, the duration of daily cyclophosphamide therapy for ADEM (21 days) was determined by a neurooncologist, who noted that daily use of the drug for at least four weeks has been documented in patients with multiple sclerosis.
AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 4 | FEBRUARY 15, 2016
Given similarities in the two disorders (ADEM is included in the differential diagnosis of multiple sclerosis), it can be inferred that using a similar regimen for the treatment of ADEM may be appropriate. ADEM is an acute demyelinating disorder that develops rapidly, whereas multiple sclerosis involves chronic demyelination. The presence of encephalopathy is a requirement for the diagnosis of ADEM but rare in the early stages of multiple sclerosis.5 In the case described here, the patient’s symptoms progressed rapidly and her level of consciousness deteriorated during the hospital stay. In differentiating between ADEM and multiple sclerosis in this case, a discerning finding was the presence of intrathecal synthesis of oligoclonal bands in the CSF.4 Oligoclonal bands in the CSF are present in 48–95% of patients with multiple sclerosis but in only 0–29% of those with ADEM; these bands were not present in the patient described here. Moreover, inflammatory markers are usually increased in ADEM but normal in multiple sclerosis.15 The patient described here had an elevated white blood cell count and erythrocyte sedimentation rate and was therefore diagnosed with ADEM. Cyclophosphamide has been used in the treatment of inflammatory, nonmalignant diseases,7 and the use of cyclophosphamide as a treatment for ADEM is warranted. Due to a lack of follow-up information, it is difficult to determine whether or not further improvement with (presumably administered) subsequent treatments with cyclophosphamide occurred after the patient was discharged from the hospital (the plan was for outpatient monthly maintenance therapy to continue for one year). It can be deduced that daily i.v. cyclophosphamide at a low dose (180 mg) is a reasonable treatment option for a patient with diagnosed hemorrhagic ADEM when other treatment strategies are unsuccessful. However, whether improve-
CASE REPORT
CYCLOPHOSPHAMIDE
ment in the patient’s status during the hospital stay was solely due to cyclophosphamide therapy is unknown.
Conclusion After approximately three weeks of daily i.v. cyclophosphamide therapy, a patient with hemorrhagic ADEM was noted to have stable to improved brain MRI findings along with limited improvement of mental status and movement symptoms.
Disclosures The author has declared no potential conflicts of interest.
References 1. Greer DM, Chow FC, Deuel TA, Venna N, eds. Pocket neurology. Philadelphia: Lippincott Williams & Wilkins; 2012:198-9. 2. Storch-Hagenlocher B, Griffin D. Acute disseminated encephalomyelitis (parainfectious and postvaccinal encephalitis). In: Hacke W, Stanley D, Bleck T, Diringer M, eds. Neurocritical care. Berlin: Springer; 1994:493-9.
3. Cyclophosphamide [monograph]. In: Clinical Pharmacology Online [online database]. Tampa, FL: Elsevier Gold Standard (accessed 2014 Jan 19). 4. Dale RC, Branson JA. Acute disseminated encephalomyelitis or multiple sclerosis: can the initial presentation help in establishing a correct diagnosis? Arch Dis Child. 2005; 90:636-9. 5. Transverse Myelitis Association. Acute disseminated encephalomyelitis (2012). http://myelitis.org/symptomsconditions/acute-disseminatedencephalomyelitis (accessed 2015 Jan 14). 6. Seales D, Greer M. Acute hemorrhagic leukocephalitis: a successful recovery. Arch Neurol. 1991; 48:1086-8. 7. Purves D, Augustine GJ, Fitzpatrick D et al., eds. Neuroscience. 3rd ed. Sunderland, MA: Sinauer Associates; 2004:38. 8. Knyazeva MG. Splenium of corpus callosum: patterns of interhemispheric interaction in children and adults. Neural Plast. 2013; 13:1-12. 9. Smith DR, Balashov KE, Hafler DA et al. Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: increased interleukin-4 production and associ-
ated eosinophilia. Ann Neurol. 1997; 42:313-8. 10. Kim YH, Choi BK, Oh SH et al. Mechanisms involved in synergistic anti-cancer effects of anti 4-1-BB and cyclophosphamide therapy. Mol Cancer Ther. 2009; 8:469-78. 11. Wender M, Tokarz E, Michalowska G, Wajgt A. Therapeutic trials of multiple sclerosis and intrathecal IgG production. Ital J Neurol Sci. 1986; 7:205-8. 12. Schwarz S, Mohr A, Khauth M et al. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology. 2001; 56:1313-8. 13. Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler. 2002; 8:142-54. 14. Girard PF, Aimard G, Pellet H. Therapeutique immuno-depressive en neurologie. Presse Med. 1967; 75:9678. In French. 15. Dale RC, de Sousa C, Chong WK et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain. 2000; 123, Pt. 12:2407-22.
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