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Figure.
Pretherapy vs posttherapy average Short Form 36 sum scores.

Pretherapy vs posttherapy average Short Form 36 sum scores.

Table 1. 
Patient Characteristics
Patient Characteristics
Table 2. 
Disease Activity in the Year Before High-Dose Cyclophosphamide Treatment
Disease Activity in the Year Before High-Dose Cyclophosphamide Treatment
Table 3. 
Expanded Disability Severity Scale Scores Initially vs at Last Follow-up
Expanded Disability Severity Scale Scores Initially vs at Last Follow-up
Table 4. 
Magnetic Resonance Imaging Results Before Therapy vs at Last Follow-up
Magnetic Resonance Imaging Results Before Therapy vs at Last Follow-up
1.
Karp  CLvan Boxel-Dezaire  AHByrnes  AANagelkerken  L Interferon-beta in multiple sclerosis: altering the balance of interleukin-12 and interleukin-10? Curr Opin Neurol 2001;14361- 368
PubMedArticle
2.
Bjartmar  CTrapp  BD Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 2001;14271- 278
PubMedArticle
3.
Noseworthy  JHLucchinetti  CRodriguez  MWeinshenker  BG Multiple sclerosis. N Engl J Med 2000;343938- 952
PubMedArticle
4.
Goodin  DSFrohman  EMGarmany  GP  Jr  et alTherapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology200258169178 [erratum appears in Neurology. 2002;59:480].
PubMed
5.
Prestrud  AAGladstone  DE Quality of life after high-dose cyclophosphamide in patients with severe autoimmune diseases. J Eval Clin Pract 2005;11411- 416
PubMedArticle
6.
Gladstone  DEPrestrud  AABrannagan  TH  III  et al.  High-dose cyclophosphamide results in long-term disease remission with restoration of a normal quality of life in patients with severe refractory chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst 2005;1011- 16
PubMedArticle
7.
Gladstone  DEBrannagan  TH  IIISchwartzman  RJPrestrud  AABrodsky  I High dose cyclophosphamide for severe refractory myasthenia gravis. J Neurol Neurosurg Psychiatry 2004;75789- 791
PubMedArticle
8.
Gladstone  DEPrestrud  AAPradhan  A High-dose cyclophosphamide for severe systemic lupus erythematosus. Lupus 2002;11405- 410
PubMedArticle
9.
Brodsky  RASensenbrenner  LLSmith  BD  et al.  Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Ann Intern Med 2001;135477- 483
PubMedArticle
10.
Polman  CHReingold  SCEdan  G  et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58840- 846
PubMedArticle
11.
Ware  JE  JrSherbourne  CD The MOS 36-item short-form health survey (SF-36), I: conceptual framework and item selection. Med Care 1992;30473- 483
PubMedArticle
12.
Krupp  LBAlvarez  LALaRocca  NGScheinberg  LC Fatigue in multiple sclerosis. Arch Neurol 1988;45435- 437
PubMedArticle
13.
McDonald  WICompston  AEdan  G  et al.  Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50121- 127
PubMedArticle
14.
Saccardi  RMancardi  GLTyndall  A Autologous hematopoietic stem cell transplantation in multiple sclerosis.  In:A Report of the European Blood and Marrow Transplantation Group (EBMT). Atlanta, Ga: American Society of Hematology; 2005
15.
Cohen  BAMikol  DD Mitoxantrone treatment of multiple sclerosis: safety considerations. Neurology 2004;63S28- S32
PubMedArticle
16.
Openshaw  HStuve  OAntel  JP  et al.  Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor. Neurology 2000;542147- 2150
PubMedArticle
17.
Brodsky  RAPetri  MSmith  BD  et al.  Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease. Ann Intern Med 1998;1291031- 1035
PubMedArticle
18.
Hough  RESnowden  JAWulffraat  NM Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective. Br J Haematol 2005;128432- 459
PubMedArticle
19.
Burt  RKCohen  BRose  J  et al.  Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol 2005;62860- 864
PubMedArticle
20.
Samijn  JPte Boekhorst  PAMondria  T  et al.  Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry 2006;7746- 50
PubMedArticle
21.
Saccardi  RMancardi  GLSolari  A  et al.  Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood 2005;1052601- 2607
PubMedArticle
22.
Merkies  ISSchmitz  PIvan der Meche  FG  et al.  Quality of life complements traditional outcome measures in immune-mediated polyneuropathies. Neurology 2002;5984- 91
PubMedArticle
23.
Strand  VGladman  DIsenberg  DPetri  MSmolen  JTugwell  P Outcome measures to be used in clinical trials in systemic lupus erythematosus. J Rheumatol 1999;26490- 497
PubMed
24.
Lobentanz  ISAsenbaum  SVass  K  et al.  Factors influencing quality of life in multiple sclerosis patients: disability, depressive mood, fatigue and sleep quality. Acta Neurol Scand 2004;1106- 13
PubMedArticle
25.
Krupp  LBHyman  LGGrimson  R  et al.  Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;601923- 1930
PubMedArticle
Original Contribution
October 2006

High-Dose Cyclophosphamide for Moderate to Severe Refractory Multiple Sclerosis

Author Affiliations

Author Affiliations: Departments of Medicine (Drs Gladstone and Zamkoff and Ms Locher), Neurology (Drs Krupp, Christodoulou, and Coyle), Radiology (Dr Peyster), and Ophthalmology (Dr Sibony), State University of New York at Stony Brook.

Arch Neurol. 2006;63(10):1388-1393. doi:10.1001/archneur.63.10.noc60076
Abstract

Background  High-dose cyclophosphamide is active in immune-mediated illnesses.

Objective  To describe the effects of high-dose cyclophosphamide on severe refractory multiple sclerosis.

Design, Setting, and Patients  Patients with multiple sclerosis with an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after 2 or more Food and Drug Administration–approved disease-modifying therapy regimens were evaluated.

Interventions  Patients received 200 mg/kg of cyclophosphamide over 4 days.

Main Outcome Measures  Patients had brain magnetic resonance imaging and neuro-ophthalmologic evaluations every 6 months and quarterly EDSS and quality-of-life evaluations for 2 years.

Results  Twelve patients were evaluated for clinical response (median follow-up, 15.0 months; follow-up range, 6-24 months). During follow-up, no patients increased their baseline EDSS scores by more than 1.0. Five patients decreased their EDSS scores by 1.0 or more (EDSS score decrease range, 1.0-5.0). Two of 11 patients had a single enhancing lesion at baseline; these lesions resolved after high-dose cyclophosphamide treatment. At 12 months, 1 patient showed 1 new enhancing lesion without a corresponding high-intensity T2-weighted or fluid-attenuated inversion recovery signal. Patients reported improvement in all of the quality-of-life parameters measured. Neurologic improvement involved changes in gait, bladder control, and visual function. Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. Patient quality-of-life improvement occurred independently of EDSS score changes. In this small group of patients with treatment-refractory multiple sclerosis, high-dose cyclophosphamide was associated with minimal morbidity and improved clinical outcomes.

Conclusions  High-dose cyclophosphamide treatment in patients with severe refractory multiple sclerosis can result in disease stabilization, improved functionality, and improved quality of life. Further studies are necessary to determine the most appropriate patients for this treatment.Published online August 14, 2006 (doi:10.1001/archneur.63.10.noc60076).

Multiple sclerosis (MS) is a major disabling neurologic disease of young adults 1 and represents the most common immune-mediated inflammatory and demyelinating disorder of the central nervous system. 2The disability that MS produces is underscored by nearly 50% of patients who will require ambulatory aids within 15 years after disease onset.3 Currently, there is no cure for MS. Therapy is targeted at changing the short-term natural history of MS to decrease relapse rates and to postpone long-term disability. 4

High-dose cyclophosphamide (HDC) is a chemotherapy treatment option for severe, refractory, immune-mediated illnesses. The goal of HDC is to eradicate B and T cells responsible for disease while sparing the pluripotent blood stem cells from any ill effect. Since 1996, multiple articles 59 on numerous immune-mediated illnesses have shown that HDC decreases disease activity and improves quality of life (QOL).

Here we describe our experience with HDC (investigational new drug No. 65863) for severe refractory MS. The treatment goal was to stop disease progression rather than to induce disease regression (ie, resolution of fixed neurologic deficits).

METHODS

All of the patients signed an informed consent form approved by the internal review board of Stony Brook University, Stony Brook, NY. Thirteen patients met the diagnosis of MS as outlined by the McDonald International Panel Diagnostic Criteria.10 All of the patients had an Expanded Disability Status Scale (EDSS) score of 3.5 or higher. They all had active disease despite a minimum of 2 Food and Drug Administration–approved disease-modifying therapies. For patients with relapsing-remitting disease, treatment failure was defined as 2 or more relapses during the prior year. For patients with secondary progressive disease, treatment failure was defined as objective deterioration on neurologic examination during the prior year. All of the remittive therapies except for steroids were stopped 3 weeks before the HDC treatment; given such active disease, a washout period was not ethical. All of the patients had preserved cardiac and renal function.

Patients received 200 mg/kg of cyclophosphamide based on adjusted ideal body weight over 4 days. Hemorrhagic cystitis prophylaxis consisted of mesna and forced diuresis. Patients received antibacterial, antiviral, and antifungal prophylaxis. Irradiated blood-product transfusions maintained a hemoglobin concentration greater than 8.5 g/dL and a platelet count greater than 10 × 109/L. Patients with febrile neutropenia received broad-spectrum antimicrobials. Starting on day 10, patients received 5 μg/kg of filgrastim per day until their absolute neutrophil count rose to 1.0 × 109/L for 2 consecutive days.

Baseline evaluation included EDSS score, brain magnetic resonance imaging (MRI) with and without contrast, and neuro-ophthalmic assessment. Patients had repeat MRI and neuro-ophthalmic assessments every 6 months and quarterly EDSS evaluations for 2 years. A sustained EDSS response was defined as a decrease of 1.0 or more on 2 sequential evaluations. Sustained EDSS score worsening was defined as an increase of 1.0 or more on 2 sequential evaluations. On brain MRI, the number of T2-weighted and enhancing lesions was classified into the following groups: 1 to 5, 6 to 10, 11 to 15, and more than 15 lesions.

Quality of life in 10 patients was measured by Short Form 36. 11 Data were analyzed using SF Health Outcomes Scoring Software (QualityMetric, Inc, Lincoln, RI) to create norm-based scoring using means and SDs from the 1998 US general population. The norm-based scores in the US general population have a mean of 50 and an SD of 10. Additional summary physical composite and mental composite scores were derived. Changes in fatigue were assessed in 8 patients using the Fatigue Severity Scale (FSS), a self-administered questionnaire. In this scale, scores range from 1 to 7; scores of 4 or higher represent significant clinical fatigue.12

RESULTS
PRETREATMENT EVALUATION

Patient characteristics and treatment histories are summarized in Table 1. The 13 patients had a median age of 41.0 years (range, 26-52 years), a median EDSS score of 6.5 (range, 4-8), and a median disease duration of 15.4 years (range, 3.1-29.0 years). Seven (54%) of the 13 patients had secondary progressive disease. Seven (54%) had previously received mitoxantrone hydrochloride. Eleven (85%) received therapy within 90 days of the first dose of cyclophosphamide. All of the patients had deterioration of their neurologic examination results during a 12-month period before the first HDC evaluation despite at least 2 standard MS disease-modifying therapies (Table 2).

IMMEDIATE CHEMOTHERAPY EFFECTS

Patients experienced absolute neutropenia for a median of 9 days (range, 6-12 days), received a median of 1.0 unit (range, 0-3 units) of packed red blood cells, and received a median of 1.0 single-unit donor platelet infusion (range, 0-3 single-unit donor platelet infusions). Patients tolerated the treatment well. Only expected toxicities were observed: 6 (46%) had febrile neutropenia, nausea controlled with antiemetics was common, and serum chemistry abnormalities were transient and corrected with fluids and electrolyte administration. No patient experienced long-term morbidity or required rehospitalization after discharge.

NEUROLOGIC ASSESSMENT

The median follow-up for the 12 clinically evaluated patients was 15.0 months (range, 6-24 months). The EDSS responses are shown in Table 3. Five patients (42%) met the study criteria for a sustained response, with a decrease of 1.0 or more in their EDSS scores (range of decrease, 1.0-5.0). No patient showed sustained worsening (EDSS increase >1.0).

All of the patients had bladder problems before HDC treatment. Nine (75%) of 12 patients reported improved bladder function after treatment. Before HDC treatment, patient 2 had marked urgency, weekly incontinence, and required oxybutynin chloride and intranasal desmopressin acetate. After treatment, his bowel and bladder function score remains at 2, but he stopped receiving all of the medications and has incontinence twice per month. Eight patients had decreased bowel and bladder function scores, and 6 (50%) experienced complete symptom resolution.

After 14 months, patient 4 withdrew from the study. Her EDSS score was stable throughout the observation period. Patient 6 showed an EDSS score decrease of 0.5 at 6 months. At 8.4 months after therapy, during active bronchitis, her EDSS score returned to 6.5 and she received a 3-day course of intravenous methylprednisolone without effect. She has received no further therapy and has not experienced further worsening. During a herpes zoster oticus infection 407 days after therapy, patient 5 had an abrupt return of her spasticity, reversing a reduction of 1.5 in her EDSS score. Treated with pulse steroids and currently on a steroid taper, her baseline gait has returned. No other patient is receiving any other form of remittive therapy.

RADIOGRAPHIC ASSESSMENT

The MRI results are provided in Table 4. All of the patients had abnormal baseline brain MRI results consistent with MS.ext-link ext-link-type="bibr" rid="REF-NOC60076-13"/ Eleven patients had imaging studies at a central location, allowing for more precise evaluations. Nine (82%) of 11 patients had 15 or more lesions. During the follow-up period, no patient had a significant change in the number of lesions. At 2 years, patient 2 had 1 new nonenhancing medullary lesion. Two (18%) of 11 patients had a single enhancing lesion at baseline; these lesions resolved after HDC treatment. At 12 months, patient 5 showed 1 new enhancing lesion without a corresponding high-intensity T2-weighted or fluid-attenuated inversion recovery signal.

NEURO-OPHTHALMIC ASSESSMENT

Baseline visual acuity in 2 patients was normal and remained stable. Visual acuity in 4 (44%) of 9 patients improved by 2 or more lines on Snellen eye chart examination; this included patient 7, whose visual acuity changed from 20/60 OD and 20/50 OS to 20/20 OU. Color perception improved in 5 patients as measured by American Optical Hardy-Rand-Rittler pseudoisochromatic plates. It improved by 1.5 plates in patients 4, 9, and 12, by more than 2 plates in patient 10, and by more than 3 plates in patient 1.

QOL ASSESSMENT

The patients reported a major improvement in QOL. Pre–Short Form 36 and post–Short Form 36 summary measure scores (by norm-based scoring) are provided (Figure). Before therapy, patients reported a poor QOL as compared with US norms in all of the measured parameters, with a mean physical composite score of 28.3 (score range, 11.6-39.5) and a mean mental composite score of 43.4 (score range, 26.1-57.7). The 1-year evaluation for 7 patients with a follow-up of 1 year or longer (data not shown) showed that their mean physical composite score rose to 38.0 (increase of 9.7; score range, 27.8-54.8), and their mean mental composite score rose to 51.9 (increase of 8.5; score range, 34.9-63.9).

At last follow-up, improvement occurred for all of the 10 patients in each of the 8 measured components. Moreover, an increase of 10 or more points (or a 1-SD increase) occurred in 4 (50%) of 8 measured Short Form 36 scales, including role physical, general health, vitality, and social functioning. The groups' mean physical composite score rose to 40.2 (increase of 11.9; score range, 27.8-65.4), and their mean mental composite score rose to 50.2 (increase of 6.8; score range, 28.6-64.8).

Seven (88%) of 8 patients reported a fatigue reduction. Before therapy, the groups' median FSS score was 6.3 (score range, 1.7-7.0). At last follow-up, the groups' median FSS score was 4.3 (decrease of 2.0; score range, 2.8-7.0). Five patients experienced an FSS score reduction of 1 or more.

COMMENT

The rationale for using HDC in MS is based on treating other refractory immune-mediated neurologic diseases. 6,7 Cyclophosphamide, dosed at 200 mg/kg, eradicates lymphocytes but allows for spontaneous hematopoietic recovery. Thus, lymphocyte immune-mediated illnesses should be responsive to HDC.

This study demonstrated that HDC is well tolerated and that patients with MS do not experience a unique toxicity profile. 68 All of the patients experienced full and spontaneous hematopoietic recovery.

All of the patients in this trial had moderate to severe MS with a median EDSS score of 6.5. Seven patients had secondary progressive disease, an MS subtype less responsive to therapies. 3 After HDC treatment, no patient met study criteria for disease progression. Further, 5 (42%) of the patients showed a decrease of 1 or greater in their EDSS scores. Subset analysis of the EDSS score changes revealed improvement in 3 general areas: for ambulation (the major determinant of the EDSS score), 3 patients improved to full ambulatory status, walking without an aid or rest for 500 m; for urinary function, 5 patients (including 2 patients with previous incontinence) experienced full resolution of urinary symptoms; and for visual function, patients' performance improved in separately measured parameters of visual acuity and color perception.

Baseline radiographic imaging revealed a high number of lesions consistent with this cohort's disease severity. Clinical improvement was not limited to those with baseline enhancing lesions. This finding differs from the current hematopoietic stem cell transplantation (HSCT) trial in Europe. 14 During follow-up, only 1 patient developed 1 new enhancing lesion that was not associated with a T2-enhanced or fluid-attenuated inversion recovery signal.

Currently, the only Food and Drug Administration–approved chemotherapy for MS is mitoxantrone. Neutropenia 10 days after infusion is common. During this time, patients with MS are at increased risk for urinary infections and pneumonia. There is a 14% incidence of permanent amenorrhea for women older than 35 years. Clinically significant heart failure is rare, with an estimated prevalence of 0.15%. At 30 months' follow-up, asymptomatic cardiac dysfunction is more common at 2% and rises to 5% when doses of mitoxantrone hydrochloride exceed 100 mg/mm. However, patients with adverse cardiac history, prior radiation, or chemotherapy use may experience heart dysfunction earlier. Mitoxantrone rarely causes acute myeloid leukemia. These leukemias often develop within 2 years of treatment. 15

Comparatively, HDC requires central access, and nausea and vomiting are common. The incidence of hemorrhagic cystitis is 2%. The incidence of a transient dilated cardiomyopathy is 1%. High-dose cyclophosphamide always results in neutropenia. Overall, the incidence of mortality secondary to HDC is approximately 1%. These risks are comparable to those encountered with HSCT.

However, HDC is strikingly different from HSCT. First, stem cell mobilization is unnecessary, avoiding MS exacerbations associated with filgrastim 16 and removing the risk of autoreactive lymphocyte reinfusion, likely the cause of the disappointing results seen with HSCT. 17,18 Second, posttransplantation antilymphocyte therapy, shown to increase the procedure's mortality and morbidity, is unnecessary. 19,20 Saccardi et al 21 described such an approach. Stem cell mobilization required 4 g/mm of cyclophosphamide and daily filgrastim. As a conditioning regimen, patients received carmustine, cytosine arabinoside, etoposide, and melphalan. Posttransplantation therapy included rabbit antithymocyte, prednisone, intravenous cyclosporine, and weekly intravenous immunoglobulin. Five nonfatal events occurred during the mobilization period. During the early transplantation period, fever, sepsis, symptomatic cytomegalovirus reactivation, and urinary tract infections occurred. Between 2 and 4 months, 2 documented herpes zoster infections occurred. In comparison, the toxicity profile encountered with HDC was much less severe and no chemotherapy toxic effects occurred between 2 and 4 months. Another study of intense T-cell depletion followed by HSCT concluded that there were serious toxic effects without clinical disease progression prevention: “ . . . of [their] 9 patients who deteriorated, 7 became worse within the first 6 months . . . of transplantation.” 20

When describing the effects of a new therapy, disability scale analyses are insufficient endpoints, as they do not always parallel disease activity. 22,23 Here we provide longitudinal data on the long-term QOL effect of HDC. Our patients' baseline data support previous reports that patients with MS have a reduced QOL. 24 Although this is an open-labeled trial that may potentially confound QOL assessment, after this single intervention, these patients reported improvement in multiple QOL parameters as measured in this group's physical and mental composite health averages of score changes. The analyses at 1 year and last follow-up indicate that HDC's effects are durable and unrelated to the transient chemotherapy-induced anti-inflammatory state associated with neutropenia. Importantly, increases in QOL parameters were not limited to those who had a decrease in their EDSS scores. Additionally, a clinically significant reduction in the FSS score 25 was achieved in the majority of measured patients.

For many patients with MS, current therapy does not stop disease progression. These patients with advanced refractory MS of long duration underwent a single intervention, HDC. This 4-day infusion was extremely well tolerated. This group not only had EDSS score stabilization but overall had both increased functionality independent of further remittive therapy and QOL improvement. Further studies are necessary to determine the most appropriate patients for this treatment.

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Article Information

Correspondence: Douglas E. Gladstone, MD, Division of Oncology, Stony Brook University Health Sciences Center, T17-080, Stony Brook, NY 11794 (dgladstone@notes.cc.sunysb.edu).

Accepted for Publication: May 24, 2006.

Published Online: August 14, 2006 (doi:10.1001/archneur.63.10.noc60076).

Author Contributions:Study concept and design: Gladstone. Acquisition of data: Gladstone, Zamkoff, Krupp, Peyster, Sibony, Christodoulou, Locher, and Coyle. Analysis and interpretation of data: Gladstone, Krupp, Peyster, Christodoulou, and Coyle. Drafting of the manuscript: Gladstone, Krupp, Peyster, Sibony, Christodoulou, Locher, and Coyle. Critical revision of the manuscript for important intellectual content: Gladstone, Locher, and Coyle. Statistical analysis: Gladstone and Coyle. Obtained funding: Gladstone. Administrative, technical, and material support: Gladstone and Locher. Study supervision: Gladstone, Krupp, Peyster, and Coyle.

Acknowledgment: We give special thanks to Ann Prestrud, MPH, for help in obtaining the investigational new drug and to June Giardelli, NP, for help in maintaining the investigational new drug.

References
1.
Karp  CLvan Boxel-Dezaire  AHByrnes  AANagelkerken  L Interferon-beta in multiple sclerosis: altering the balance of interleukin-12 and interleukin-10? Curr Opin Neurol 2001;14361- 368
PubMedArticle
2.
Bjartmar  CTrapp  BD Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol 2001;14271- 278
PubMedArticle
3.
Noseworthy  JHLucchinetti  CRodriguez  MWeinshenker  BG Multiple sclerosis. N Engl J Med 2000;343938- 952
PubMedArticle
4.
Goodin  DSFrohman  EMGarmany  GP  Jr  et alTherapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology200258169178 [erratum appears in Neurology. 2002;59:480].
PubMed
5.
Prestrud  AAGladstone  DE Quality of life after high-dose cyclophosphamide in patients with severe autoimmune diseases. J Eval Clin Pract 2005;11411- 416
PubMedArticle
6.
Gladstone  DEPrestrud  AABrannagan  TH  III  et al.  High-dose cyclophosphamide results in long-term disease remission with restoration of a normal quality of life in patients with severe refractory chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst 2005;1011- 16
PubMedArticle
7.
Gladstone  DEBrannagan  TH  IIISchwartzman  RJPrestrud  AABrodsky  I High dose cyclophosphamide for severe refractory myasthenia gravis. J Neurol Neurosurg Psychiatry 2004;75789- 791
PubMedArticle
8.
Gladstone  DEPrestrud  AAPradhan  A High-dose cyclophosphamide for severe systemic lupus erythematosus. Lupus 2002;11405- 410
PubMedArticle
9.
Brodsky  RASensenbrenner  LLSmith  BD  et al.  Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Ann Intern Med 2001;135477- 483
PubMedArticle
10.
Polman  CHReingold  SCEdan  G  et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58840- 846
PubMedArticle
11.
Ware  JE  JrSherbourne  CD The MOS 36-item short-form health survey (SF-36), I: conceptual framework and item selection. Med Care 1992;30473- 483
PubMedArticle
12.
Krupp  LBAlvarez  LALaRocca  NGScheinberg  LC Fatigue in multiple sclerosis. Arch Neurol 1988;45435- 437
PubMedArticle
13.
McDonald  WICompston  AEdan  G  et al.  Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50121- 127
PubMedArticle
14.
Saccardi  RMancardi  GLTyndall  A Autologous hematopoietic stem cell transplantation in multiple sclerosis.  In:A Report of the European Blood and Marrow Transplantation Group (EBMT). Atlanta, Ga: American Society of Hematology; 2005
15.
Cohen  BAMikol  DD Mitoxantrone treatment of multiple sclerosis: safety considerations. Neurology 2004;63S28- S32
PubMedArticle
16.
Openshaw  HStuve  OAntel  JP  et al.  Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor. Neurology 2000;542147- 2150
PubMedArticle
17.
Brodsky  RAPetri  MSmith  BD  et al.  Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease. Ann Intern Med 1998;1291031- 1035
PubMedArticle
18.
Hough  RESnowden  JAWulffraat  NM Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective. Br J Haematol 2005;128432- 459
PubMedArticle
19.
Burt  RKCohen  BRose  J  et al.  Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol 2005;62860- 864
PubMedArticle
20.
Samijn  JPte Boekhorst  PAMondria  T  et al.  Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry 2006;7746- 50
PubMedArticle
21.
Saccardi  RMancardi  GLSolari  A  et al.  Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood 2005;1052601- 2607
PubMedArticle
22.
Merkies  ISSchmitz  PIvan der Meche  FG  et al.  Quality of life complements traditional outcome measures in immune-mediated polyneuropathies. Neurology 2002;5984- 91
PubMedArticle
23.
Strand  VGladman  DIsenberg  DPetri  MSmolen  JTugwell  P Outcome measures to be used in clinical trials in systemic lupus erythematosus. J Rheumatol 1999;26490- 497
PubMed
24.
Lobentanz  ISAsenbaum  SVass  K  et al.  Factors influencing quality of life in multiple sclerosis patients: disability, depressive mood, fatigue and sleep quality. Acta Neurol Scand 2004;1106- 13
PubMedArticle
25.
Krupp  LBHyman  LGGrimson  R  et al.  Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;601923- 1930
PubMedArticle
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