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

Treatment of CorticosteroidResistant Neurosarcoidosis With a Short-Course Cyclophosphamide Regimen John D. Doty, MD; Joseph E. Mazur, PharmD; and Marc A. Judson, MD, FCCP

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. (CHEST 2003; 124:2023–2026) Key words: CNS; corticosteroids; cyclophosphamide; neurosarcoidosis; sarcoidosis; steroid sparing; therapy Abbreviation: CSF ⫽ cerebrospinal fluid

manifestations of sarcoidosis are seen in N eurologic only 5 to 15% of patients with sarcoidosis ; however, 1,2

they account for a disproportionately large percentage of the morbidity and mortality attributed to the disease.

*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. Manuscript received December 27, 2002; revision accepted May 27, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). 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: [email protected] www.chestjournal.org

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.1–5 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 studies2,5– 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 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 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. The clinical course is summarized in Table 3. All patients were receiving corticosteroids at the time of cyclophosphamide initiation, with an average dose of CHEST / 124 / 5 / NOVEMBER, 2003

2023

Table 1—Baseline Characteristics* Characteristics Female/male gender Age, yr Years since diagnosis before starting cyclophosphamide Site of initial organ involvement CNS Eye Lung Peripheral nervous system Sinus Skin Site of diagnostic biopsy Lung Skin Lacrimal gland Sinus None Other involved organs Lung Skin Eye Liver Sinuses

Data 4/3 47.7 (41–62) 3.9 (0–10)

2 1 1 1 1 1 2 2 1 1 1 6 3 1 1 1

*Data are presented as mean (range) or No.

42 mg/d. The duration of therapy with corticosteroids prior to starting cyclophosphamide was variable. Four of the seven treated patients reported symptomatic improvement, including patient 1 who experienced complete remission. All seven patients improved objectively with either decreased MRI enhancement or improvement in CSF abnormalities, including the three patients who did not demonstrate symptomatic improvement. Five patients had other organs involved at the time of cyclophosphamide therapy; of these, two patients were noted to have improvement in other organ symptoms. The corticosteroid dose was successfully reduced in six of the seven patients with the mean dose decreasing to 18 mg/d. 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 2024

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 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 Selected Reports

Table 2—Neurosarcoidosis Diagnostic Criteria and Symptomatology* Definite Criteria

Patient No.

MRI With Meningeal or Brain Biopsy Stem Enhancement

1

2

Probable Criteria

CSF Lymphocytosis or Increased Protein

Bell Palsy or Other Cranial Other Nerve MRI Unexplained Dysfunction Abnormality Neuropathy

Yes

Yes

3

Yes

Yes

Yes

Yes

Yes

Yes

4

5

Yes

Yes

Yes

Yes

Yes

6

Yes

Yes

7

Neurologic Manifestations Headache, right facial numbness, MRI with abnormal dural enhancement Cranial nerve V1 palsy, CSF WBC 111 cells/␮L (81% lymphocytes) and protein 102 mg/dL New-onset scizure, MRI with abnormal enhancement around right lateral and third ventricles, CSF WBC 6 cells/ ␮L (99% lymphocytes) and protein 160 mg/dL Lower-extremity weakness, numbness, fecal incontinence, MRI with abnormal signal about spinal cord from T1 to T6 Lower-extremity weakness, numbness, CSF WBC 26 cells/ ␮L (83% lymphocytes) and protein 231 mg/dL Headache, dizziness, tinnitus, MRI with diffuse meningeal enhancement, CSF WBC 8 cells/␮L (69% lymphocytes) and protein 184 mg/dL Lower-extremity numbness, MRI with abnormal signal throughout cervical spine

*From Judson et al.9

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 – 8 This article describes our experience with a short-course regi-

Table 3—Clinical Course* Patient No.

Initial Prednisone Dose, mg/d

1 2

10 40

3 4 5 6

10 60‡ 40 20

7

107§

Time Course of Therapy, mo

Final Prednisone Dose, mg/d

Osteoporosis, weight gain Poor glycemic control

15 4

5 20

Yes No

Yes, MRI Yes, MRI

No N/A†

None Weight gain Weight gain Poor glycemic control, carpal tunnel syndrome New-onset diabetes

2 5 3 5

10 20 20 15

Yes Yes Yes No

Yes, MRI Yes, MRI Yes, CSF Yes, MRI

N/A† Yes (liver) No No

No Yes, see text No No No No

4

40§

No

Yes, MRI

Yes (skin)

No

Reported Side Effects of Prednisone Therapy

Relapse of Symptomatic MRI, CSF Other Organ Neurologic Improvement Improvement Improvement Symptoms

*NA ⫽ not applicable. †Patients 2 and 3 had no active disease in other organs at the time of therapy. ‡Patient 4 was receiving azathioprine until the initiation of cyclophosphamide therapy. §Listed doses for patient 7 are given as the prednisone equivalent of dexamethasone. www.chestjournal.org

CHEST / 124 / 5 / NOVEMBER, 2003

2025

men 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 – 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 2026

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.

References 1 Chapelon K, Ziza JM, Piette JC, et al. Neurosarcoidosis: signs, course and treatment in 35 confirmed cases. Medicine 1990; 69:261–276 2 Lower EE, Broderick JP, Brott TG, et al. Diagnosis and management of neurological sarcoidosis. Arch Intern Med 1997; 157:1864 –1868 3 Stern BJ, Krumholz A, Johns C, et al. Sarcoidosis and its neurologic manifestations. Arch Neurol 1985; 42:909 –917 4 Sharma OP. Neurosarcoidosis: a personal perspective based on the study of 37 patients. Chest 1997; 112:220 –228 5 Agbogu BN, Stern BJ, Sewell C, et al. Therapeutic considerations in patients with refractory neurosarcoidosis. Arch Neurol 1995; 52:875– 879 6 Stern BJ, Schonfeld SA, Sewell C, et al. The treatment of neurosarcoidosis with cyclosporine. Arch Neurol 1992; 49: 1065–1071 7 Zuber M, Defer G, Cesaro P, et al. Efficacy of cyclophosphamide in sarcoid radiculomyelitis. J Neurol Neurosurg Psychiatry 1992; 55:166 –167 8 Kavanaugh AF, Andrew SL, Cooper B, et al. Cyclosporine therapy of central nervous system sarcoidosis [letter]. Am J Med 1987; 82:387 9 Judson MA, Baughman RP, Teirstein AS, et al. Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16:75– 86 10 Hargreaves MR, Mowat AG, Benson MK. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports. Thorax 1992; 139:18 –21 11 Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener’s granulomatosis. Ann Intern Med 1996; 124:477– 484 12 Stillwell TJ, Benson RC Jr. Cyclophosphamide-induced hemorrhagic cystitis: a review of 100 patients. Cancer 1988; 61:451– 457 13 Fauci AS, Barton FH, Katz P, et al. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98:76 – 85 14 Haubitz M, Schellong S, Gobel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibodyassociated vasculitis and renal involvement: a prospective, randomized study. Arthritis Rheum 1998; 41:1835–1844 Selected Reports