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Treatment of Corticosteroid-Resistant Neurosarcoidosis With a Short-Course Cyclophosphamide Regimen

^* From the Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology (Drs. Doty and Judson), and Department of Pharmacy Services, College of Pharmacy (Dr. Mazur), Medical University of South Carolina Charleston, SC.

Correspondence to: Marc A. Judson, MD, FCCP, Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, Medical University of South Carolina, 96 Jonathan Lucas St, Suite 812-CSB, PO Box 250623, Charleston, SC 29425; e-mail: judsonma{at}musc.edu

	Abstract

TOP Abstract Introduction Patients and Methods Results Discussion References

 
Background/objectives: Many patients with neurosarcoidosis have disease that is refractory to corticosteroids or they are unable to tolerate high-dose corticosteroids because of detrimental side effects. We examined a short-course, pulse-dose regimen using cyclophosphamide to treat such patients.

Methods: We identified a population of patients with neurosarcoidosis refractory to standard therapy with corticosteroids. Patients who were unable to tolerate corticosteroid therapy due to side effects were also included. Alternative therapy for these patients was initiated using IV cyclophosphamide.

Results: Seven patients were identified for treatment with our cyclophosphamide regimen. The mean duration of therapy was 5.4 months. Four of the seven patients reported symptomatic improvement on therapy, and all seven patients demonstrated objective improvement in either MRI or cerebrospinal fluid abnormalities. Mean corticosteroid dose of the group was reduced from 42 mg/d before therapy to 18 mg/d after therapy. Relapse of neurologic symptoms was noted in one patient after the completion of therapy. One patient acquired an opportunistic infection, and a second patient required hospitalization for a central venous catheter infection.

Conclusion: Short-course cyclophosphamide appears to be a reasonable, steroid-sparing treatment option for patients with corticosteroid-refractory neurosarcoidosis.

Key Words: CNS • corticosteroids • cyclophosphamide • neurosarcoidosis • sarcoidosis • steroid sparing • therapy

	Introduction

TOP Abstract Introduction Patients and Methods Results Discussion References

 
Neurologic manifestations of sarcoidosis are seen in only 5 to 15% of patients with sarcoidosis^{1 2} ; however, they account for a disproportionately large percentage of the morbidity and mortality attributed to the disease. Neurosarcoidosis has a variable presentation, with symptoms ranging from peripheral and cranial neuropathies to myopathy to more serious CNS manifestations such as meningitis, seizures, mass lesions, and encephalopathy.^{1 2 3 4 5} No standard treatment of neurosarcoidosis has been established, but corticosteroids have been the traditional cornerstone of therapy. Unfortunately, patients with refractory neurosarcoidosis often require high doses of steroids for long periods of time, which leads to additional morbidity.⁵ Previous studies^{2 5 6 7 8} have reported the use of corticosteroid-sparing agents, both cytotoxic and noncytotoxic, for treatment of neurosarcoidosis. We present here our experience with the use of a short-course, pulse-dose regimen of cyclophosphamide for the treatment of neurosarcoidosis. Patients with disease refractory to corticosteroids or in whom there was significant morbidity related to corticosteroid therapy were specifically chosen for our cyclophosphamide regimen.

	Patients and Methods

TOP Abstract Introduction Patients and Methods Results Discussion References

 
Patients were selected from those followed up at the Sarcoidosis Center at the Medical University of South Carolina. Between September 1998 and June 2002, 451 patients were seen at our center. Thirty-seven patients met either definite or probable criteria by the Case Control Etiologic Study of Sarcoidosis⁹ instrument for the diagnosis of neurosarcoidosis. We identified patients whose neurosarcoidosis was refractory to conventional therapy with corticosteroids or who were unable to tolerate conventional therapy due to corticosteroid side effects. Patients were treated with IV cyclophosphamide using an intermittent dosing regimen similar to that employed by Lower et al.² Cyclophosphamide was administered approximately every 3 weeks at an outpatient chemotherapy facility. The initial dose was 500 mg with escalation to 750 mg, and then to a maintenance dose of 1,000 mg. Patients were monitored for neutropenia, azotemia, hematuria, and other side effects during therapy. Generally, after five doses of cyclophosphamide were administered, each patient was reevaluated and a decision was then made to continue therapy or stop based on symptomatic or objective improvement or worsening.

Patients with neurologic symptoms underwent individualized clinical testing. All patients underwent serial physical examinations performed by the same examiner (M.A.J.) both at neurologic symptom onset and throughout the treatment course. Clinical tests included MRI with gadolinium contrast and cerebrospinal fluid (CSF) analysis performed as indicated. Patients with improvement in reported symptoms or improvement in neurologic examination were classified as having symptomatic improvement. Patients with reductions in CSF lymphocytic pleocytosis or protein levels or decreased meningeal enhancement on MRI were classified as having objective improvement.

	Results

TOP Abstract Introduction Patients and Methods Results Discussion References

 
Seven patients with refractory neurosarcoidosis were selected for cyclophosphamide therapy. The baseline characteristics of the patients receiving cyclophosphamide are summarized in Table 1 . Table 2 describes the diagnostic criteria met by each patient and the specific neurologic manifestations.

After patient 1 had been receiving therapy for approximately 9 months, her prednisone was stopped after a gradual taper. Within 2 months, she had worsening of her headaches, and MRI showed increased enhancement of the meninges. She was treated by increasing prednisone to 40 mg/d and tapering back to 10 mg/d over the next several weeks, while continuing the cyclophosphamide doses at 1,000 mg every 3 weeks. MRI performed 3 months later was improved, and she reported subjective improvement as well. After completion of a 15-month course of cyclophosphamide, her symptoms have remitted and her corticosteroids have been tapered completely.

Patient 2 had a difficult course. After receiving her first dose of cyclophosphamide, she was unavailable for follow-up for 3 months and was restarted on therapy. An MRI done 3 months later showed mild improvement in meningeal enhancement, and therapy was continued 2 additional months and then stopped because she showed no symptomatic improvement at any time. Two months after discontinuing cyclophosphamide, an MRI showed worsening of meningeal enhancement, and she received one additional dose. Mental status changes developed, including encephalopathy, depression, anhedonia, and suicidal ideation, which necessitated nursing home placement. She died of sepsis from necrotizing fasciitis secondary to a decubitus ulcer.

Patient 3 is somewhat unusual, in that neurosarcoidosis was probably not responsible for all of his neurologic symptoms. His initial MRI, done to evaluate new-onset seizures, showed diffuse meningeal enhancement. After results of a skin biopsy were consistent with sarcoidosis, he received one dose of cyclophosphamide and was unavailable for follow-up. He presented to medical attention nearly 2 years later with persistence of his seizures, headaches, and facial numbness. An MRI again showed meningeal enhancement, but also hydrocephalus with obstruction presumed to be at the foramen of Monro. He was restarted on cyclophosphamide, and underwent neurosurgical evaluation leading to the placement of a ventriculoperitoneal shunt. At surgery, he was noted to have a congenital abnormality that was believed to be responsible for the hydrocephalus. No evidence of sarcoidosis was noted on surgical pathology. Follow-up MRI 1 year later showed persistent ventriculomegaly, but resolution of the meningeal enhancement. His seizure frequency had decreased dramatically.

The successful course of patient 4 should also be mentioned. She was treated with azathioprine for lower extremity weakness that was attributed to neurosarcoidosis. Her weakness progressed over the next 2 months and she had bowel and bladder incontinence. Azathioprine was discontinued, cyclophosphamide was initiated, and she noted an almost immediate improvement in strength. Within 6 weeks, she was ambulatory with a walker; by the conclusion of therapy 6 months later, she could walk with a cane. She experienced a flare of uveitis 2 months after discontinuing cyclophosphamide, which her ophthalmologist treated by increasing her prednisone dose to 100 mg/d. She has since been tapered back to her baseline dose of 20 mg/d and is without symptoms.

Serious side effects related to cyclophosphamide therapy were noted in patient 7, who acquired an opportunistic pulmonary infection with Nocardia asteroides. One episode of hematuria was observed in patient 5, but this was associated with a urinary tract infection and resolved with therapy. Complications indirectly related to the cyclophosphamide therapy were noted in patient 1, who was hospitalized with a central venous catheter infection, necessitating antibiotic therapy and insertion of a new catheter. Since completion of therapy, two patients have died. The death of patient 2 has been previously discussed, and patient 5 died unexpectedly of unknown cause 5 months after his last cyclophosphamide dose.

	Discussion

TOP Abstract Introduction Patients and Methods Results Discussion References

 
Traditionally, high-dose corticosteroids have been the standard of care for treatment of neurosarcoidosis. Unfortunately, a significant percentage of patients with neurosarcoidosis have disease refractory to corticosteroids or are unable to tolerate the high doses that are often required for effective treatment.² In recent years, attention has been turned to the use of cytotoxic and noncytotoxic agents as corticosteroid-sparing agents. Methotrexate, cyclosporine, chlorambucil, azathioprine, cranial irradiation, chloroquine, and hydroxychloroquine have all been described in the treatment of neurosarcoidosis.^{1 2 4 5 6 7 8} This article describes our experience with a short-course regimen of cyclophosphamide as adjunctive therapy, and it is the second largest case series using cyclophosphamide for neurosarcoidosis in the medical literature. Lower et al² reported a 10-patient series using cyclophosphamide for neurosarcoidosis treatment. Other reports in the literature have been limited to case studies.^{1 5 7} Although the cumulative toxicity of cyclophosphamide is substantial, the short duration of cyclophosphamide used in this series suggests that it may be less toxic than other therapies such as methotrexate, which has significant cumulative toxicity.¹⁰

Cyclophosphamide therapy resulted in reduction of the corticosteroid dose in six of the seven patients, with the mean dose reduction for the entire group being 58%. Only one patient required > 20 mg/d, which is a fairly low dose for the treatment of neurosarcoidosis. It is possible that the addition of agents such as hydroxychloroquine or methotrexate, which have been recommended for neurosarcoidosis, could have allowed the corticosteroid dose to be lowered further.^{2 4 5 6 7 8}

Four of the seven patients noted symptomatic improvement, and all seven patients were noted to improve objectively by either MRI or CSF findings. The MRI response occurred within 3 months after starting cyclophosphamide therapy. We believe that the MRI response was because of cyclophosphamide because no other change had been made in their therapy.

The improvement in MRI without concomitant improvement in neurologic symptoms in three patients deserves mention. We suspect that although the granulomatous inflammation of sarcoidosis was successfully abated by cyclophosphamide in these patients, permanent neurologic injury had already occurred.

Relapse of neurologic symptoms occurred in one patient (patient 2) after completion of cyclophosphamide therapy. Two of the five patients with other organ involvement had improvement in these symptoms, and no one noted worsening of other organ symptoms. Complications related to the therapy included a non–life-threatening opportunistic pulmonary infection in patient 7 who was not neutropenic at the time of the infection, and a central venous line infection in patient 1 requiring hospitalization for antibiotics and placement of a new line. Patient 2 died of sepsis that was thought to be related to necrotizing fasciitis secondary to a decubitus ulcer. Whether the use of cyclophosphamide increased the risk of sepsis in this patient is possible, but unknown. Hematuria was noted in patient 5, but this seems to have been secondary to a urinary tract infection.

Agbogu and coworkers⁵ described three patients with corticosteroid-refractory neurosarcoidosis who did not respond to cyclophosphamide; however, two of these patients received oral therapy. The third received 2 months of IV cyclophosphamide without a clinical response, and also received azathioprine, cyclosporine, and radiation therapy with clinical deterioration. Lower and colleagues² reported successful treatment of neurosarcoidosis in 9 of 10 patients. The mean duration of therapy was 21.5 months. Our experience with cyclophosphamide is unique in that our mean duration of therapy was significantly shorter at 5.4 months. The subjective and objective response rates are comparable between the two studies as are the relapse and complication rates, and the rates of other organ improvement. Certainly, a shorter duration of therapy is advantageous for compliance reasons. Additionally, the risk of hemorrhagic cystitis seems to increase with duration of therapy,¹¹ and development of cystitis correlates with the development of bladder cancer.¹² This risk is higher with the oral than IV route of cyclophosphamide.^{13 14}

In summary, short-course cyclophosphamide appears to have efficacy as an adjunctive therapy to corticosteroids and for patients with neurosarcoidosis. It appears to be steroid sparing. Toxicity was minimal in our patients, although the risk of infectious complications warrants close observation. Clinical improvement did not always occur despite MRI improvement in all patients. This is not surprising and suggests that the neurologic damage had become permanent. Our experience with an individualized short-course cyclophosphamide protocol demonstrates rates of response, complication, and relapse similar to those previously reported in the medical literature, and suggests that it is a reasonable treatment option.

	Footnotes

 
Abbreviation: CSF = cerebrospinal fluid

Received for publication December 27, 2002. Accepted for publication May 27, 2003.

	References

TOP Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Doty, J. D. Articles by Judson, M. A. Search for Related Content PubMed PubMed Citation Articles by Doty, J. D. Articles by Judson, M. A.