Clinical trial NCT02282514
Conditions: Stiff-Person Syndrome
Keywords: Autoimmune Diseases Autologous Hematopoietic Stem Cell Transplantation
Sponsor: Northwestern University
Start date: 2014-10-01; Completion date: 2019-08-30
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Non-myeloablative regimens (as the investigators use herein) are designed to maximally suppress the immune system without destruction of the bone marrow stem cell compartment.

When using a non-myeloablative regimen recovery occurs without infusion of stem cells and the stem cells are autologous. While not necessary for recovery, stem cell infusion may shorten the interval of neutropenia and attendant complications. Thus in reality there is no transplant only an autologous supportive blood product.

Based on our encouraging results of non-myeloablative hematopoietic stem cell transplantation, for patients with multiple sclerosis and chronic inflammatory demyelinating polyneuropathy, the investigators will investigate the role of non-myeloablative hematopoietic stem cell transplantation for patients with SPS who require assistance to ambulate.

Detailed description:
Pre-study Testing

1. History and physical
2. Electrocardiogram (EKG)
3. Dobutamine stress echocardiogram
4. High-resolution computed tomography of the chest (HRCT)
5. Blood draw for laboratory tests- these tests will include a complete blood count, evaluating liver and kidney function, assessing immune system, tissue typing, and checking for certain germs that can cause infections, including a pregnancy test for females and prostate-specific antigen (PSA) for male as well as testing for HIV
6. Pulmonary Function Test (PFT)
7. Electromyography (EMG)
8. Magnetic Resonance Imaging (MRI) of the Abdomen and Pelvis
9. Magnetic Resonance Imaging (MRI) of the Spinal Cord
10. Magnetic Resonance Imaging (MRI) of the Brain with Gadolinium (only if PERM of cerebellar ataxia)
11. Colonoscopy
12. Mammogram (if female)
13. Timed ambulation
14. Quality of Life Questionnaires \[ Short Form (36) Health Survey (SF36) and Barthel Index\]
15. Chronic Pain Acceptance Questionnaire (CPAQ)
16. Rankin Functional Scale
17. Modified Ashworth Scale
18. Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1), Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2) antibody (only if cerebellar ataxia)
19. Spinocerebellar ataxia (SCA) 1, 2, 3, 4, 5, 6, 7, 8 genes (only if ataxia)

Study Treatment

Stem Cell Collection: Cyclophosphamide 2.0 gm/m2 will be given on day 0, G-CSF 5-10 mcg/kg/day subcutaneous (SQ) will start on day +5 and will continue until apheresis is discontinued. Apheresis will begin when the absolute neutrophil count (ANC) \> 1.0 x 109/L and continue until \>2.0 x 106 cluster of differentiation 34 (CD34)+ cells/kg patient weight are cryopreserved. A 10-15 liter apheresis will be performed unless stopped earlier for clinical judgment of toxicity (e.g., numbness, tetany). A maximum of four apheresis will be performed.

Arms: arm 1: The conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5, 1.0 mg/kg on days -4 and -3, and then 1.5 mg/kg on days -2 and -1. Methylprednisolone 1000 mg will be infused intravenously before each dose of rATG. Autologous hematopoietic stem cells will be infused intravenously on day 0. A granulocyte-colony stimulating factor (G-CSF) 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Intravenous Rituxan (500mg) will be administered on days -6 and +1.
Interventions: intervention 1: Autologous Hematopoietic Stem Cells intervention 2: Cyclophosphamide intervention 3: Mesna intervention 4: rATG intervention 5: Methylprednisolone intervention 6: G-CSF intervention 7: Rituxan
Intervention descriptions: intervention 1: The stem cells will be collected from patient's blood during mobilization. Then the patient will be given high dose chemotherapy in accordance with approved recommendations for use in conditioning regimens for stem cell transplant in autoimmune diseases. Autologous Hematopoietic Stem Cell Transplantation is to re-infuse immature cells that can re-establish blood production and patient's immune system. intervention 2: An alkylating agent which causes prevention of cell division by forming adducts with DNA intervention 3: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis intervention 4: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells intervention 5: Steroid intervention 6: Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream intervention 7: A chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders

Protocol documents:
Prot_SAP_000.pdf: 
 
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Non-myeloablative Hematopoietic Stem Cell Transplantation for Stiff 
Person Syndrome (SPS) and Anti-GAD Antibody Variants: 
Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM), 
and Adult Onset Autoimmune Anti-GAD Positive Cerebellar Ataxia 
 
 
 
Principal Investigator 
Richard Burt MD, Division of Immunotherapy 
 
 
Co-Principal investigators 
Senda Ajroud Driss MD, Department of Neurology 
Jeffrey Allen MD, Department of Neurology Robert 
Sufit MD, Department of Neurology 
Teepu Siddique PhD, MD, Department of 
Neurology Roumen Balabanov MD, Department of 
Neurology 
 
 
 
Investigators 
Paula Gozdziak RN, Division of Immunotherapy 
Amy Morgan NP, Division of Immunotherapy 
Allison Clendenan NP, Division of Immunotherapy 
 
 
Data Safety Board 
John Rose MD, Division Director, Neuroimmunology and Neurovirology, University of Utah 


 
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TABLE OF CONTENTS 
1.0 
Précis 
3 
2.0 
Objectives 
3 
3.0 
Background 
4 
4.0 
Diagnosis of SPS 
5 
5.0 
Rational and Scientific Justification 
6 
6.0 
Eligibility 
16 
7.0 
Study Parameters 
18 
8.0 
Treatment Plan 
19 
9.0 
Supportive Care Guidelines 
20 
10.0 
Hospital Discharge Guidelines 
21 
11.0 
Side Effects 
22 
12.0 
Drug Information 
22 
13.0 
Evaluation of Toxicity 
24 
14.0 
Adverse Event Reporting 
24 
15.0 
Evaluation of Response 
25 
16.0 
Biostatistical Considerations 
25 
17.0 
Criteria for Removal from Study 
25 
18.0 
Registration Procedure 
26 
19.0 
Records to be Kept 
26 
20.0 
References 
27 
 
 
 
APPENDICES: 
I 
Chronic Pain acceptance questionnaire (CPAQ) 
35 
II 
Activities of Daily Living (Barthel Index)) 
36 
III 
SF-36 
37 
IV 
Rankin Functional Scale 
43 
V 
Modified Ashworth Scale 
44 


 
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1.0 PRECIS 
 
Stiff Person Syndrome is a chronic disease manifest by truncal and limb rigidity and 
spasms that affects the extremities, back, abdomen, and respiratory muscles. SPS is an 
autoimmune disease associated with high titer anti-glutamic acid decarboxylase (anti- 
GAD) antibodies that prevent inhibitory pathway relaxation of antagonists muscles 
groups. Painful spasms and rigidity result from excessive and prolonged motor neuron 
firing. Despite symptomatic and immunotherapeutic treatments, the disease is 
progressive and most patients require assistance for ambulation (cane, walker, 
wheelchair), develop postural deformities, have chronic painful spasm, and are unable 
to continue employment. 
Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) is a part 
of the SPS spectrum with anti-GAD antibodies limb and truncal rigidity, 
muscle 
spasm, brain stem signs (gaze palsies, facial weakness, ptosis etc), and hyperekplexia 
(pronounced startle responses to tactile or acoustic stimuli) . Although rare, anti-GAD 
positive cerebellar ataxia without known spinal cerebellar atrophy mutations is also 
considered a variant of SPS. Based on our encouraging results of non-myeloablative 
hematopoietic stem cell transplantation, for patients with multiple sclerosis and chronic 
inflammatory demyelinating polyneuropathy, we will investigate the role of non- 
myeloablative hematopoietic stem cell transplantation for patients with SPS who require 
assistance to ambulate. 
 
2.1 OBJECTIVES 
 
We will assess the toxicity/efficacy (phase I/II) of cyclophosphamide, anti-thymocyte 
globulin and rituxan with autologous hematopoietic stem cell transplantation for SPS. 
There are no established criteria for complete remission (CR) or partial remission (PR). 
The primary (survival) and secondary (disease improvement) endpoints to be 
considered in this study are: 
 
2.2 Primary end point – Overall Survival 
2.3 Secondary endpoint -- Disease improvement 
 Decrease (50%) and complete discontinuation of muscle 
relaxation anti-spasmotic medications 
 Chronic Pain acceptance questionnaire (CPAQ) (appendix I) 
 Timed ambulation 
 Activities of Daily Living (appendix II) 
 SF-36 QOL (Appendix III) 
 Rankin Functional Scale (appendix IV) (Improvement for 
disability scales is defined in the same manner as for the SF-36 
QOL, that is whether or not there is a statistically significant 
change in the score / scale / dimension done by standard statistical 
methodology such as student t test or mixed method analysis. 


 
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3.0 BACKGROUND – STIFF PERSON SYNDROME 
 
Glutamic acid decarboxylase (GAD-65) catalyses glutamate conversion into γ- 
aminobutyric acid (GABA) in the central nervous system and in the pancreatic β cells 
(1, 2). Neurons that produce GABA have predominately inhibitory effects on neuronal 
firing. Antibodies targeting GAD-65 occur in stiff person syndrome, cerebellar ataxia, 
epilepsy, limbic encephalitis, combinations thereof, and diabetes mellitus (3, 4). While 
patients with type I diabetes generally have low titer antibodies to GAD-65, patients 
with SPS may have high titer antibodies against GAD-65 (5, 6). However anti-GAD 
antibodies are insufficient to make the diagnosis and only 60-80% of SPS patients have 
anti-GAD antibodies (6, 7). Possible etiologies for SPS in patients without anti-GAD 
antibodies include antibodies to GABA-A receptor associated protein, synaptophysin, 
gephyrin, and GABA-transaminase (7-12). It may be that differences in recognition of 
presynaptic  GAD epitopes or post synaptic pathways may explain the various 
manifestations, i.e. stiffness, spasms, rigidity, cerebellar ataxia (dysmetria, nystagmus, 
dysarthria, ataxia, oculomotor dysfunction), epilepsy, limbic encephalitis, diabetes, or 
combinations thereof (14-19). 
 
Anti-GAD antibodies do not correlate with disease severity, diversity of 
symptomatology or response to therapies (20). Anti-GAD antibodies define a novel 
group of syndromes, collectively viewed as 'hyperexcitability disorders' but historically 
SPS is termed according to the most common manifestation as Stiff Person Syndrome 
(20). Other than an autoimmune etiology, Stiff Person Syndrome may have be a 
paraneoplastic manifestation of an underlying malignancy (20). Paraneoplastic SPS 
antibodies may be associated with antibodies to amphiphysin in patients with breast 
cancer or small cell lung cancer (21, 22) 
 
Stiff Person Syndrome is rare with an incidence of 1 person per million and a 2; 1 female 
/ male ratio (1, 23). There is no cure for Stiff person syndrome. No positive controlled 
clinical trials to establish standard optimal therapy have been reported. Current 
treatment consists of benzodiazepines (diazepam, clonazepam) intrathecal baclofen (24-
27), anticonvulsants (28), and immune modulation with steroids (29), plasma exchange 
(30), IVIG (31-33), and rituximab (34). The natural history of Stiff Person Syndrome is 
axial, limb, and paraspinal muscle spasms leading to gait disability and progressive 
disability and inability to walk without assistance. Emotion stress, or unexpected sounds 
or touch can lead to a sudden attack (35). The fear of sudden unexpected attacks results 
in fear of leaving the house and being stranded if an attack occurs ultimately leading to 
loss of independence, assistance in ambulation, and inability to bend at the waist (36). 
Sudden death due to autonomic dysfunction (hyperpyrexia, diaphoresis, tachypnea, 
tachycardia, pupillary dilation, and arterial hypertension) may also occur (37). 


 
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4.1 DIAGNOSIS OF SPS 
 
4.2 Differential clinical diagnosis for SPS (38) 
 
 
Myelopathy: compressive, ischaemic, haemorrhagic and inflammatory 
(including multiple sclerosis and infectious causes) 
 
Myopathy: channelopathies, inflammatory, myotonic dystrophy, paramyotonia 
 
Neuropathic: neuromyotonia, Isaac's syndrome 
 
Parkinson's disease or Parkinson-plus syndromes (e.g., progressive 
supranuclear palsy, multiple system atrophy) 
 
Primary lateral sclerosis 
 
Dystonia (generalised and focal) 
 
Ankylosing spondylitis 
 
Neuroleptic malignant syndrome, malignant hyperthermia and 
serotonin syndrome 
 
Tetanus 
 
Psychogenic 
 
Hereditary spastic paraparesis 
 
Leukodystrophies 
 
Drug-induced and toxicity: monoamine oxidase inhibitors, phenothiazines, 
amphetamines, 5,6-methylenedioxy-N-methyl-2-aminoindane, 1-methyl-4- 
phenyl-1,2,3,6-tetrahydropyridine, carbon monoxide 
 
Spinal interneuronitis with rigidity 
 
 
4.3 Dalakas criteria for the diagnosis of typical stiff person syndrome (38-40) 
 
 
Stiffness in the axial muscles, prominently in the abdominal and 
thoracolumbar paraspinal muscle leading to a fixed deformity (hyperlordosis) 
 
Superimposed painful spasms precipitated by unexpected noises, emotional 
stress, tactile stimuli 
 
Confirmation of the continuous motor unit activity in agonist and 
antagonist muscles by electromyography 
 
Absence of neurological or cognitive impairments that could explain the stiffness 
 
Positive serology for GAD65 (or amphiphysin or other) autoantibodies, 
assessed by immunocytochemistry, western blot or radioimmunoassay 
 
Response to diazepam 


 
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5.1 RATIONALE  AND SCIENTIFIC JUSTIFICATION: 
 
“If we are uncritical we shall always find what we want: we shall look away 
from, and not see, whatever might be dangerous to our pet theories.”—The 
Poverty of Historicism - Karl Popper 
 
There are many misconceptions about hematopoietic stem cell transplant for autoimmune 
diseases. 
 
First, generally speaking, conditioning may be non-myeloablative or myeloablative. 
Myeloablative regimens are based on myeloablative cancer drugs and/or total body 
irradiation. These extreme regimens cause irreversible bone marrow failure, thus 
requiring HSC reinfusion to recover. Toxicity, cost, and late complications (e.g., 
infertility, secondary myelodysplasia, leukemia, and solid tumors) can be substantial 
with this approach. In contrast, non-myeloablative regimens (as we use herein) are 
designed to maximally suppress the immune system without destruction of the bone 
marrow stem cell compartment. 
 
Second, when using a non-myeloablative regimen recovery occurs without infusion of 
stem cells and the stem cells are autologous. While not necessary for recovery, stem cell 
infusion may shorten the interval of neutropenia and attendant complications. Thus in 
reality there is no transplant only an autologous supportive blood product. 
 
What follows is mostly unpublished data from our own experience in transplant of 
neurologic disease (MS and CIDP) in order to demonstrate the safety and efficacy of 
this type of treatment. Most of the following data is in the process of being written or 
already under peer review and needs to be treated as propriety and confidential. 
 
 
EXPERIENCE OF NON-MYELOABLATIVE HEMATOPOIETIC STEM CELL 
TRANSPLANT (HSCT) FOR OTHER NEUROLOGIC AUTOIMMUNE 
DISEASES: MULTIPLE SCLEROSIS AND CHRONIC INFLAMMATORY 
DEMYELINATING POLYNEUROPATHY 
5.2 MULTIPLE 
SCLEROSIS Introduction 
Multiple sclerosis (MS) is an immune mediated disorder of the central nervous system 
that in most patients begins as an inflammatory relapsing remitting (RR) disease. 
Subsequently and despite standard therapies, the majority of patients eventually enter a 
secondary progressive (SP) phase for which no therapy has demonstrated efficacy. Fifty 
percent of patients are unable to continue employment, require assistance to ambulate, 
or are unable to walk by 10, 15, and 25 years from diagnosis, respectively. Despite an 
annual cost of treating MS that is approximately $47,000 USD per patient (41, 42), no 


 
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FDA approved therapy has been demonstrated to significantly reverse neurologic 
disability or improve quality of life (43-49). 
 
Between July 2003 and June 2013, 129 patients underwent HSCT for MS at 
Northwestern University (Chicago). Three patients who remain alive (by phone contact) 
are not included in the analysis because two failed to return for neurologic evaluation 
and one had inconsistent neurologic findings. The remaining 126 patients returned for 
follow- up and are included in this analysis. All patients were treated at Northwestern 
University (Chicago, Illinois, USA) on either an Institutional Review Board (IRB) 
approved study (n=50) or on a compassionate basis (n=76). Patients treated on a 
compassionate basis signed consent forms and were treated and followed before and 
after transplant in an identical manner to those on study and are reported with 
retrospective IRB approval. 
 
The reasons and number of patients treated on a compassionate basis were: entering 
SPMS (n=22), insurance refused coverage (n=15), a single prior brainstem or visual 
relapse or cognitive impairment such that further attacks or disease progression would 
be deemed to render them para- or quadriplegic, blind, cognitively impaired, or unable 
to continue employment (n=14), EDSS greater than 6.0 (n=10), failed all available 
FDA approved treatments (n=8), other coexisting autoimmune or neurologic diseases 
(n=4) and one each for age over 55, allergy to gadolinium, and tumefactive MS. 
 
Study end points 
The primary end-points were safety, relapse-free survival (no acute relapses), 
progression free survival (no increase in EDSS) and event free survival (no acute 
relapses, no progression and no new gadolinium enhancing or T 2 lesions on MRI). 
Secondary endpoints were disability and impairment defined by the EDSS and NRS 
scores. Tertiary endpoints consisted of the MSFC, quality of life short-form 36 (SF-36) 
questionnaire, and MRI enhancing and total brain T2 lesion volume (T2LV). 
 
Results 
 
Demographics 
All patients were followed from 6 months to 5 years (mean 32 months). The patients’ 
median age was 36 years (range 18 to 58 years old), with a female to male ratio of 1.4, 
and predominately Caucasian ethnic origin (107 Caucasian, 9 African American, 6 
Asian, and 4 Hispanic). The mean duration of disease from time of diagnosis was 79 
months (range 9 to 264 months). Mean EDSS was 4.05 (range 1.5 to 8). 
 
Engraftment and toxicity 
After stem cell infusion, the median day of white blood cell engraftment (absolute 
neutrophil count > 1000 / ul) and hospital discharge were day 9 and 10, respectively. 
The mean number of platelet and red blood cell transfusions were 2.6 and 2.1, 
respectively. 
 
Admission rectal surveillance cultures were positive for vancomycin resistant 
enterococcus in 12 patients, while admission nasal cultures were positive for 
methicillin- resistant Staphylococcus aureus (MRSA) in 2 subjects. Fever > 380 Celsius 
(100.4 Fahrenheit) occurred in 63 patients (50%) all of whom were blood culture 
negative except one who had coagulase-negative staphylococcus thought to be a 


 
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contaminant. Diarrhea positive for Clostridium difficile occurred in four patients. 
 
There was no treatment related mortality and no early or late fungal, Pneumocystis 
jirovecii, cytomegalovirus, Epstein Barr, or JC virus infections. Four patients 
developed late reactivation of dermatomal zoster treated with oral acyclovir. Immune-
mediated thrombocytopenia (ITP) developed in (3 of 17) (17%) patients treated with 
alemtuzumab compared to 2 of 109 (1.8%) patients treated with ATG (P = 0.02). Drug 
free remission of ITP occurred in all cases after transient treatment with corticosteroids 
and intravenous immunoglobulin, and / or rituximab. 
 
Hypothyroidism was present in seven patients (5.5%) before transplant. After 
transplant, seven additional patients developed thyroid abnormalities with 
hypothyroidism or hyperthyroidism occurring in 2 and 5 patients, respectively. For the 
119 patients who did not have pre HSCT thyroid abnormalities, thyroid dysfunction 
subsequently developed in 14% (2 of 14) treated with alemtuzumab and 4.8% (5 of 
105) treated with ATG (P = 0.19). No patient developed leukemia or myelodysplasia. 
During transplant hospitalization, one patient was incidentally found to have a pre-
existing adrenal mass that upon resection was localized adrenal carcinoma. Three years 
after transplant, one patient developed breast ductal carcinoma in situ. 
 
Overall survival, relapse free survival, progression free survival, disease activity free 
survival 
Treatment related mortality was 0% and overall survival 99.2%. One death occurred 30 
months after HSCT related to hypertensive cardiovascular disease. The Kaplan-Meier 
estimated 5-year relapse-free survival (no acute relapses), progression free survival (no 
increase in EDSS), and disease activity free survival (no acute relapses, no progression, 
and no new gadolinium enhancing or T 2 lesions on MRI) are 93%, 88%, and 78%, 
respectively. 
 
EDSS and NRS 
The EDSS and NRS scores improved significantly at all post-transplant evaluations 
(P<0.001). For all patients, the mean EDSS scores improved from 4.05 pre-transplant to 
3.32 at 6 months, 3.1 at 12 months, 3.03 at 24 months, and then remained relatively 
stable with values at 36, 48, and 60 months of 3.12, 2.89, and 2.94, respectively. 
Similarly, the NRS scores improved from a mean pre-transplant value of 72.1 to post 
HSCT scores of 80.3, 81.9, and 83.8 at 6, 12 and 24 months, respectively, and thereafter 
remained relatively stable at 84.2, 84.7, and 83.1 at 36, 48, and 60 months, respectively. 
 
On multivariate analysis, EDSS outcome was influenced by pre-transplant disease 
duration (P = 0.003) and clinical disease course (RR versus SP). NRS outcome was 
affected by pre-transplant disease duration, pre-transplant clinical disease course, and 
fever during transplant. Gender and age had no independent effect on EDSS or NRS 
scores. 
 
MSFC 
Based on comparison with the means and standard deviations from pre-HSCT baseline, 
the MSFC score and its component Z-scores for the 25-foot walk, 9-hole peg test, and 
PASAT 3 second improved significantly at 6, 12, 24, 36, 48, and 60 months after 
transplant. 
 


 
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MRI metrics 
The number of enhancing lesions on brain MRI decreased significantly at all post- 
transplant time points. The percentage of patients with at least one enhancing lesion 
from 6 to 3 months before HSCT, within 3 months of HSCT, and at 6, 12, 24, 36, 48, 
and 60 months after transplant were 30%, 56%, 0.8%, 2%, 3.8%, 3.7%, 11%, and 8%, 
respectively. The mean number of enhancing lesions was 3.22 at 3 to 6 months before 
HSCT, 2.57 within 3 months of HSCT, 0.01 at 6 months, 0.13 at 12 months, 0.07 at 24 
months, 0.24 at 36 months, 0.67 at 48 months, and 0.08 at 60 months post-transplant. 
Brain T2 lesion volume (T2LV) decreased significantly between pre transplant MRI 
scan and most recent post-transplant MRI scan. With a mean follow-up of 2.6 years, 
the mean T2LV decreased by 31% from 16.36 cm3 (SD 18.65, median 8.8, range 84.5 – 
0.23) to 11.32 cm3 (SD 12.92, median 5.66, range 55.2-0.09) (P < 0.0001). 
 
Quality of Life 
Between pre-transplant and last evaluation, patients’ quality of life as measured by 
the SF-36 improved significantly in all scales (P< 0.002) and dimensions (P< 0.001) 
and in total score (P < 0.001) . 
 
Discussion of HSCT for MS 
 
HSCT in patients with RRMS using a non-myeloablative immune-specific regimen and 
unselected peripheral blood stem cells had no treatment-related mortality and little 
infectious toxicity including no late opportunistic infections other than reactivation of 
dermatomal zoster. Specifically, there was no CMV-related disease or JC virus induced 
progressive multifocal encephalopathy (PML). To date, our results compare favorably 
with reports of natalizumab related PML (50) or fingolimod related cardiovascular 
events and herpes encephalomyelitis (51). 
 
In patients with MS, this report shows that ITP is a significantly more frequent 
complication after treatment with a regimen containing alemtuzumab compared to ATG. 
This is consistent with an earlier report that alemtuzumab containing transplant 
regimens for autoimmune diseases are associated with an increased risk of immune 
mediated cytopenias independent of the autoimmune disorder being transplanted (52). 
However, thyroid dysfunction appears to be a relatively more unique complication of 
immune based therapies for MS. Without transplant, thyroid dysfunction has been 
reported to occur in 34% of patients treated with alemtuzumab and 6.5% of patients 
treated with interferon beta-1a (53). Of patients referred to us for HSCT, 5.5% already 
had thyroid dysfunction. Following HSCT with either alemtuzumab or ATG another 
14% and 4.8%, respectively, developed thyroid dysfunction. 


 
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A correlation between T2 lesion load and EDSS progression has been demonstrated in 
RRMS, where change in lesion load in the first 5 years correlates with late EDSS 
disability (54). Herein, we demonstrate that a sustained improvement in EDSS scores 
following HSCT is accompanied by a decrease in MRI T2LV. Decreased T2LV may be 
related to resolution of inflammation and edema. However, the rate of lesion growth for 
RRMS has been reported to be on average+ 0.80 cm3 / year, that is an expected increase 
of approximately +2.0 cm in 2.6 years (55). In comparison, during the same time 
interval, the mean T2LV in the transplant cohort decreased by -5.04 cm3. In a similar 
manner, improvement in the MSFC score is consistent with improvement in EDSS (56). 
 
Patient selection is important in determining outcome since the EDSS disability and 
NRS impairment scores did not improve in patients with SPMS or in those with disease 
duration longer than 10 years. These factors, in multivariate analysis, were independent 
prognostic variables. In our study, older age, per se, did not have a worse outcome 
although older patients with an established diagnosis of SPMS were excluded from 
transplant. Nevertheless our data suggest that older patients, if they still have 
inflammatory MS, improve after transplant. 
 
Heat stress can affect neuron metabolism and brain function (57), and fever has been 
reported as an unfavorable prognostic factor for neurologic recovery in other types of 
neuronal injury such as cardiopulmonary bypass, cardiac arrest, cerebral vascular 
accidents, traumatic closed head injury, and subarachnoid hemorrhage (58-62). For MS, 
environmental heat is associated with pseudo-relapses and or severe fatigue (63, 64). In 
our study, maximum body temperature during transplant hospitalization correlated with 
higher EDSS scores (worse disability) in univariate but not multivariate analysis. 
Transplant fever and final neurologic outcome may be linked to the clinical course of 
MS and or disease duration since brain temperature has been reported to be higher in 
MS patients with higher disability (65). Unlike EDSS scores, the effect of fever was 
significant (P < 0.05) in multivariate analysis for post-transplant NRS impairment. This 
difference might be due to the fact that the EDSS and NRS are different outcome 
measures. EDSS is non-linear and biased towards locomotor function, while the NRS 
has a wider range of scores and is more sensitive to non-ambulatory changes in the 
clinical statues (66). 
 
In this cohort of 126 MS patients, a non-myeloablative reduced intensity conditioning 
regimen followed by infusion of unselected autologous peripheral blood stem cells 
significantly improved neurologic disability and impairment (NRS and EDSS) as well 
as quality of life, MSFC, and T2 MRI lesion burden. HSCT using a non-myeloablative 
regimen should be considered in patients with frequent relapses. 


 
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5.2 CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY 
(CIDP) 
 
Introduction 
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune- mediated 
demyelinating disease of the peripheral nervous system that may present acutely or 
insidiously with either a progressive, stepwise, or relapsing clinical course (67). 
“Typical” CIDP as defined by the European Federation of Neurological 
Societies/Peripheral Nerve Society (EFNS/PNS) affects proximal and distal motor and 
sensory function, results in diminished deep tendon reflexes, and evolves over at least 2 
months (68, 69). “Atypical” CIDP variants have heterogeneous phenotypic patterns 
that may be multifocal (Lewis-Sumner Syndrome), distally accentuated (distal acquired 
demyelinating symmetric or DADS), purely motor, or purely sensory (68, 69). The 
pathogenesis of CIDP and atypical variants has yet to be well characterized but is 
likely to involve multiple immune pathways that contribute to chronic neural 
dysfunction (70). Advances in our understanding of CIDP immunopathology have 
highlighted the importance of both T cells and antibodies (71), even though in the 
majority of CIDP patients the cryptic antigenic target(s) is unknown (70). 
 
CIDP remains one of the few peripheral neuropathies for which effective therapy exists 
(72, 73). Corticosteroids (74, 75), intravenous immunoglobulin (IVIG) (76, 77), and 
plasmapheresis (78) have each been shown to be effective in randomized clinical trials. 
Retrospective studies have shown that when more than one of these conventional 
therapies are utilized approximately 80% of CIDP patients respond (79, 80). However, 
some individuals do not respond to first-line treatments (81), or become refractory or 
intolerant to conventional intervention (82). Furthermore, side effect profiles, quality of 
life restrictions, and financial burdens can limit the use of corticosteroids, intravenous 
immunoglobulins (IVIG), and plasma exchange (83- 85). These limitations are 
especially relevant when treatment is chronic, as is often the case in those with CIDP. 
Herein, we report the results of non-myeloablative hematopoietic stem cell 
transplantation (HSCT) for patients with CIDP refractory to conventional treatment 
options. 
 
Methods 
 
Patients 
Patients were treated at Northwestern Memorial Hospital (Chicago, Illinois, USA) on an 
IRB and FDA approved protocol (www.clinicaltrials.gov NCT00278629). The trial was 
initially designed to include 40 patients but given the results herein has been extended 
to eighty patients and to allow longer follow-up. Eligible patients met European 
Federation of Neurological Societies and the Peripheral Nerve Society (EFNS / EPS) 
electromyography (EMG) criteria for definite CIDP and failed corticosteroids and either 
IVIG or plasmapheresis. Failure was defined as persistent MRC grade 3/5 or worse 
weakness in at least one muscle or grade 4/5 in at least two muscles, or dysphagia, or 
persistent incapacitating sensory loss (e.g. gait ataxia). Patients dependent on IVIG or 
plasmapheresis had to be documented to deteriorate upon stopping or delaying 


 
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treatment or decreasing dose. 
 
Patients were excluded if they had only possible or probable CIDP by EFNS/PNS 
criteria, or had other plausible explanations for neuropathy such as Charcot Marie 
Tooth neuropathy or a family history of neuropathy, drug or toxin exposure, Lyme 
disease, hepatitis or HIV, diabetes, plasma cell dyscrasias, hematologic malignancies, 
POEMS syndrome, amyloidosis, or presence of sphincter disturbances. Other presumed 
immune- mediated neuropathies that respond differently to standard immune based 
treatments such as Multifocal Motor Neuropathy (MMN), DADS with anti-MAG 
antibodies, or Chronic Ataxic Neuropathy, Ophthalmoplegia, Monoclonal IgM protein, 
cold Agglutinins and Disialosyl antibodies (CANOMAD) were excluded from this 
evaluation. Patients with MGUS underwent a skeletal survey and bone marrow biopsy 
and aspirate to rule out hematologic malignancies. General health exclusion criteria 
included age < 18 or > 65 years old, left ventricular ejection fraction < 40%, DLCO < 
40%, creatinine > 2.0 mg/dl, or hepatic transaminases or bilirubin greater than twice 
normal. After initiation, the protocol was amended to exclude patients with history of 
cancer, poorly controlled hypertension, or hypertension related end organ dysfunction. 
 
Results 
 
One hundred and thirty patients were referred for HSCT. The majority, 90 patients, 
were not candidates because they did not meet EFNS/PNS criteria for definitive CIDP. 
After evaluation, the most common reason for exclusion was diagnosis of another 
neurologic disorder (n=35) including length dependent neuropathy (n=5), motor neuron 
disease (n=4), Charcot Marie Tooth genetic neuropathy (n=3), multifocal motor 
neuropathy (n=4), DADS with anti-MAG antibody (n=4), small fiber neuropathy (n=3), 
idiopathic neuropathy (n=2), and one each for multiple mononeuropathies, autoimmune 
autonomic ganglionopathy, Parsonage Turner syndrome, Wartenberg migrant sensory 
neuropathy, lumbosacral radiculopathy, chronic inflammatory sensory polyneuropathy 
(CISP), Guillaine Barre Syndrome (GBS), cauda equine syndrome, and CANOMAD. 
 
The second largest group excluded from the study had possible or probable CIDP but 
were excluded because they did not meet EFNS/PNS criteria for definitive CIDP 
(n=24) or had received an inadequate trial of IVIG (n=5). Six patients had 
malignancies (plasmacytoma) (n=3), and one each for lymphoma, POEMS, and 
melanoma). Three patients were found to have myopathies: inclusion body myositis 
(n=2), limb-girdle syndrome (n=1). 
 
Other reasons for exclusion included other confounding medical explanations for 
neuropathy (n=8) (diabetes (n=3), and one each of prior high dose chemotherapy, 
lumbosacral plexus radiation, coronary artery disease, osteomyelitis, and age > 65 years 
old), awaiting or denied insurance approval (n=10). 
 
Demographics 
Forty patients have been followed from 6 months to 5 years after transplant (mean 24 
months). Two patients are alive but have not returned for follow-up. The patients’ mean 
age was 44 years (range 20 to 63 years old), with a male to female ratio of 2.1 and 
predominately Caucasian ethnic origin (32 Caucasian, 4 Hispanic, 2 African American, 
2 Asian). The mean duration of symptoms before undergoing HSCT was 91 months 
(range 14 to 360 months). Thirty-three patients had typical and 7 atypical CIDP. CIDP 


 
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presented as acute or insidious onset in 10 and 30 patients, respectively. Before HSCT 
all patient had received corticosteroids and IVIG and 20 patients (50%) had received 
plasmapheresis. 
 
Safety / survival 
There was no treatment related mortality. Overall survival is 95%, (38/40). One patient 
who had been treated for Hodgkin’s lymphoma twenty-five years earlier and before 
transplant had symptoms of stomach outlet obstruction died 1 year after transplant 
from metastatic signet cell stomach cancer that originated within the prior mantle field 
radiation portal. A second patient with poorly controlled chronic hypertension-related 
cardiac and renal end organ dysfunction died from a sudden cardiovascular death 3 
months after HSCT. Thereafter, enrollment criteria were tightened to exclude patients 
with comorbid diseases or any prior cancer. The mean red blood cell and platelet 
transfusions were 2.9 and 3.4, respectively. Before starting transplant rectal 
surveillance cultures were positive for vancomycin resistant enterococcus and 
extended-spectrum - lactamase resistance in 3 and 4 patients, respectively. During 
hospitalization 33% (13/40) remained afebrile while 45% (18/40) and 23% (9/40) 
developed a maximum fever greater or equal to 38.5oC and 39.0oC, respectively. Two 
patients had blood cultures positive for coagulase negative staphylococcus. Two 
patients had positive urine cultures, one for enterococcus faecalis, and one for 
escherichia coli. No patient became septic or hypotensive. The mean day of discharge 
was day 11 after stem cell infusion. 
 
There were no early or late post-transplant fungal, Pneumocystis jirovecii, 
cytomegalovirus, Epstein Barr, or JC virus infections. No patient has developed 
myelodysplasia or hematopoietic malignancies. One patient with an abnormal cervical 
pap smear declined medical intervention for more than 1 year. Subsequently, following 
surgery, radiation, and chemotherapy for cervical cancer, she has remained cancer free 
for 2 years. 
 
Medication free 
Eighty-three percent of patients were tapered off all immune modulating medications. 
Seventy-four percent (28/38) became medication free immediately after HSCT. Over 
4 to 18 months, three patients were tapered off IVIG and 1 patient each was tapered 
off prednisone and mycophenylate mofetil. Four patients, all within 8 months of 
transplant, are currently undergoing a gradual taper of IVIG (3 patients) or 
plasmapheresis (1 patient). Three patients who became medication free immediately 
following HSCT restarted IVIG at 1, 2, and 4 years following transplant. The percent 
of patients free of any immune modulating therapy at 6 months and 1, 2, 3, and 4 
years after transplant are 74%, 81%, 83%, 92%, and 75%, respectively (figure 1). 
 
Outcome measures 
The MRC improved significantly from 51.3 pre HSCT to 55 (P<0.001), 56.4 (P<0.001), 
55.5 (p=0.008), 55 (p=0.05), and 55.5 (p=0.04) at 6, 12, 24, 36, and 48 months after 
HSCT. Rankin functional score improved from 2.92 pre HSCT to 2.04 (p< 0.001), 1.78 
(p= 0.002), 1.9 (p=0.03), 1.75 (p=0.05), and 1.5 (p=0.03) at 6 months, 1, 2, 3, and 4 
years. The Barthel Index improved from 83.2 pre HSCT to 94.5 (p=0.003), 96.6 
(p<0.001), 96.7 (p=0.03), 96.3 (p=0.04), and 95.8 (p=0.05) at 6 months, 1, 2, 3, and 4 
years. The INCAT disability scale was added after the study began and consequently 
has shorter follow-up but improved from a pre-transplant value of 4.47 to 3.05 


 
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(p<0.001), 1.67 (p<0.001), and 2.8 (p=0.004) at 6 months, and 1 and 2 years after 
HSCT. 
 
Electrophysiology 
Demyelination as measured by both conduction blocks (CB) and nerve conduction 
velocity (NCV) improved significantly following transplant. The mean percent CB 
improved from 36.11 pre transplant to 26.35 (p=0.005), 23.84 (p=0.001), 27.15 
(p=0.18), 26.17 (p=0.01), and 10.6 (p=0.04) at 6 months and 1, 2, 3, and 4 years post 
HSCT. The number of nerves with greater than 50% CB was 1.18 pre HSCT compared 
to 0.61 (p=0.002), 0.41 (p=0.001), 0.58 (p=0.33), 0.36 (p=0.03), and 0.17 (P=0.10) at 6 
months, 1, 2, 3, and 4 years after transplant. The average NCV (in m/s) improved from 
24.82 pre- HSCT to 30.74 (p=0.001), 34.45 (p < 0.001), 34.35 (p=0.008), 36.77 
(p=0.004), and 42 (p=0.001) at 6 months, 1, 2, 3, and 4 years post-transplant (figure 3). 
The NCV (in m/s) of the most severely affected nerve improved from 20.04 pre-HSCT 
to 26.37 (p=0.004), 28.9 (p<0.001), 28.13 (P=0.02), 30.65 (p=0.005), and 35.32 
(p=0.001) at 6 months, 1, 2, 3, and 4 years post-transplant. 
 
The average CMAP amplitude (in millivolts) improved from 3.18 pre-transplant to 3.66 
(p=0.50), 4.55 (p=0.001), 4.3 (p=0.02), 4.99 (p=0.02), and 4.67 (p=0.02) at 6 months 
and 1, 2, 3, and 4 years after transplant. The CMAP (in millivolts) of the most severely 
affected nerve improved although not statistically significant from a pre-transplant 
mean of 0.64 to 0.79, 1.18, 1.16, 1.31, and 1.43 at 6 months, and 1, 2, 3, and 4 years 
after HSCT. 
 
Quality of Life 
Between pre-transplant and last evaluation, patients’ quality of life as measured by 
the SF-36 improved significantly in all scales except emotional role limitation and 
mental health (table 2). There was significant improvement in both physical and 
mental dimensions (P< 0.001) and in total score (P < 0.001). 
 
Discussion 
 
Since the first report of HSCT for CIDP was published in 2002 (86) several case reports 
and small retrospective case series have followed (87-92). In the largest series, 8 of 11 
patients with CIDP treated with HSCT were in drug free remission at the time of 
publication (median follow-up duration 28 months) (87). We prospectively evaluated 
the safety and efficacy of HSCT in a population of well- defined EFNS/PNS “definite” 
CIDP patients refractory to at least 2 of 3 conventional immunotherapy treatments. 
Similar to the smaller retrospective series (87), 66% received no additional 
immunotherapy after HSCT, and an additional 13% tapered off immunotherapy within 
18 months of HSCT. These patients, comprising nearly 80% of the total cohort, were 
relapse-free for the duration of the available follow- up. Interval improvement in 
strength (MRC sum score), disability (Rankin functional score, Barthel index, INCAT), 
quality of life (SF-36), and electrophysiology evidence of demyelination (mean nerve 
conduction velocity, conduction velocity of most severely affected nerve, mean 
conduction block, and number of nerves with > 50% conduction block), and 
electrophysiology evidence of neuronal regeneration (mean CMAP) were concurrently 
observed to improve during the follow-up period. 
 
From a clinical perspective, there are little long-term outcome data in CIDP using 


 
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conventional therapy. The landmark IVIG CIDP Efficacy (ICE) and pulsed high-dose 
dexamethasone versus standard prednisolone treatment for chronic inflammatory 
demyelinating polyradiculoneuropathy (PREDICT) trials reported 6 month drug free 
remission in 55% (ICE) and 40% (PREDICT) of patients (77, 93). A subsequent 
PREDICT analysis with a median follow up of 4.5 years revealed that only 26% of the 
initial cohort had a sustained remission (94). Similar to the follow-up PREDICT 
result, other retrospective series of IVIG (95) or heterogeneously (96) treated CIDP 
patients with at least 4 years of median follow have reported long term drug free 
remission in 25% and 31% of patients, respectively. 
 
Our results with a median follow up of 24 months are thus far favorable to prior 
observations, especially since we selected IVIG and or plasmapheresis failures of whom 
only 7 (18%) relapsed after HSCT, while only 1 patient showed no definite 
improvement. When relapse occurred, most (5 of 7) did so within 6 months of HSCT. 
The relapsed group demonstrated no statistically significant differences in age, gender, 
duration of CIDP, MGUS status, baseline nerve conduction studies, or baseline strength 
examination compared to the drug-free remission group (data not shown). 
 
Minimization of diagnostic errors was accomplished by strict adherence to EFNS/PNS 
CIDP diagnostic criteria and by exclusion of patients lacking an unequivocal diagnostic 
evaluation or those with a potential alternative neuropathy etiology. The threshold for 
re-initiation of immunotherapy after HSCT, i.e. relapse, was low since any patient could 
have immunotherapy restarted at the discretion of the study team or the independent 
local neurologist’s clinical judgment. In order to avoid selecting patients with long-term 
inactive disease, patients dependent on conventional therapy with chronic stable deficits 
required documentation of clinical decline following dose reduction or delay in standard 
therapy prior to study inclusion. Furthermore, should our results simply been a 
consequence of getting patients with inactive disease off unneeded immunotherapy we 
would not have expected interval improvements in strength (MRC sum score), 
electrophysiology (nerve conduction velocity, conduction block, mean CMAP), and 
disability (Barthel index, Rankin score, and INCAT scale). 
 
Given the durability of medication free outcome, HSCT may be cost effective compared 
to maintenance IVIG or plasmapheresis. Non-myeloablative HSCT is a onetime 
intervention that results in clinically relevant reversal of disability, improvement in 
CMAP amplitude, NCV, CB, quality of life, and in most cases long- term independence 
from conventional therapies. 
 
5.3 Summary of HSCT for Multiple Sclerosis and CIDP 
 
HSCT, using non-myeloablative regimens (i.e. not cancer regimens), was performed 
safely and achieved sustainable prolonged medication free reversal of disability and 
improvement in quality of life. Unique aspects of each neurological disease impact the 
outcome of HSCT. For MS, patients need to be selected during the inflammatory stage 
of disease and fever needs to be avoided by using corticosteroids during HSCT. For 
CIDP, strict EFNS/PNS criteria need to be used to avoid treating non-CIDP causes of 
peripheral neuropathy. 


 
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6.1 Eligibility Criteria for HSCT of Stiff person Syndrome (SPS) 
 
6.2 Inclusion Criteria (must meet criteria of A or B or C) 
 
A) Diagnosis of Stiff-person Syndrome and 
 
1. Age between 18 and 60 years old 
2. Failure of medically tolerable doses (20-40 mg/day) of diazepam 
3. Failure of either IVIG and or plasmapheresis 
4. Stiffness in the axial muscles, prominently in the abdominal and 
thoracolumbar paraspinal muscle leading to a fixed deformity (hyperlordosis) 
5. Superimposed painful spasms precipitated by unexpected noises, emotional 
stress, tactile stimuli 
6. Confirmation of the continuous motor unit activity in agonist and antagonist 
muscles by electromyography when off diazepam and anti-spasmotic 
medications 
7. Absence of neurological or cognitive impairments that could explain the stiffness 
 
B) Diagnosis of a SPS variant— Progressive Encephalomyelitis with Rigidity 
and Myoclonus (PERM) defined as: 
1. Acute onset of painful rigidity and muscle spasms in the limbs and trunk 
2. Brainstem dysfunction (nystagmus, opsoclonus, ophthalmoparesis, deafness, 
dysarthria, dysphagia) 
3. Profound autonomic disturbance. 
4. Positive serology for GAD65 autoantibodies, assessed by immunocytochemistry, 
western blot or radioimmunoassay (>1000 u/ml) 
5. MRI may show increased signal intensity throughout the spinal cord and the 
brainstem 
 
C) Diagnosis of a SPS variant - anti-GAD positive cerebellar ataxia 
 
1. Subacute or chronic onset of cerebellar symptoms—gait or limb 
ataxia, dysarthria, nystagmus 
2. Positive serology for GAD65 autoantibodies, assessed by 
immunocytochemistry, western blot or radioimmunoassay (>1000 u/ml) 
3. Anti-GAD antibody in cerebrospinal fluid 
4. Abnormal MRI imaging of brainstem or cerebellum other than cerebellar atrophy 
5. Negative history of toxin or alcohol 
6. Absence of Vitamin B12 or Vitamin E deficiency 
7. Absence of positive HIV, syphilis or whipple disease 
8. Absence of consanguity, positive family history for ataxia or positive 
genetic screen for SCA1, SCA2, SCA3, SCA6, SCA 7 or SCA8 mutation 


 
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6.3 Exclusion criteria for HSCT of Stiff person Syndrome (SPS) and variants 
 
1. Current or prior history of a malignancy or paraneoplastic syndrome 
2. Inability to sign and understand consent and be compliant with treatment 
3. Positive pregnancy test 
4. Inability to or comprehend irreversible sterility as a possible side effect 
5. Amphiphysin antibody positive 
6. LVEF < 45% or ischemic coronary artery disease on dobutamine 
stress echocardiogram 
7. DLCO < 60% predicted 
8. Serum creatinine > 2.0 mg/dl 
9. Bilirubin >2.0 mg/dl 
10. Platelet count < 100,000 / ul, WBC < 1,500 cells/mm3 
11. History of toxin or alcohol abuse 
12. History of Vitamin B12 or Vitamin E deficiency 
13. Positive HIV, syphilis, or whipple disease 
14. Consanguity, positive family history for ataxia or positive genetic screen 
for SCA1, SCA2, SCA3, SCA6, SCA 7 or SCA8 mutation (if ataxia 
present) 
15. Absence of at least one SPS associated antibody such as anti-GAD, or GABA-
A receptor associated protein, or synaptophysin, or gephyrin, or GABA- 
transaminase 
16. Life expectancy less than 1 year 


 
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7.0 Study Parameters 
 
Parameter 
Pre-HSCT 
During 
hospitalizatio
6 month, 1, 2, 3, 4, 
5 years 
History and physical 
X 
daily 
X 
CBC 
X 
X 
X 
Chemistry and creatinine 
X 
X 
X 
LFT 
X 
X (TIW) 
X 
Dobutamine stress test 
X 
EKG 
X 
PFT 
X 
AntiGAD antibody 
X 
X 
Amphiphysin antibody@ 
X 
X (Only if positive 
pre HSCT) 
EMG 
X 
X (optional) 
Mammogram@ 
X (optional) 
HRCT@ 
X 
Abdomen pelvis CT or MRI @ 
X 
Colonoscopy@ 
X (optional) 
Anti-Hu@ 
X 
CEA, CA-125, (PSA -if male)@ 
X 
HIV, RPR 
X 
PCA-1 PCA-2 antibody 
X (Only if 
cerebellar 
MRI brain with gad 
X (Only if PERM 
or cerebellar 
MRI of spine 
X 
SCA1,2,3,6,7,8 genes 
X (optional) 
Dose diazepam or baclofen 
X 
X 
SF-36 
X 
X 
Timed ambulation 
X 
X 
Chronic Pain 
Acceptance 
X 
X 
Activities of Daily Living 
Questionnaire (Barthel 
X 
X 
Rankin Functional Scale 
X 
X 
Modified Ashworth Scale 
X (optional) 
X (optional) 
 
@ preformed to rule out malignancy 


 
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8.1 
TREATMENT PLAN 
 
8.2 Mobilization and Peripheral Blood Stem Cell Harvest 
 
The mobilization schedule is outlined in below: 
 
MOBILIZATION AND PBSC HARVEST 
PROCEDURE\DAY 
0 
1 
2 
3 
4 
5 
10+ 
ANC 
> 1000 
Cyclophosphamide 
2.0 gm/m2 
X 
 
G-CSF 
5-10 mcg/kg/day SQ 
X 
X 
 
X* 
Prophylaxis Antifungal 
and Antibiotic (such as 
fluconazole and 
amoxicillin/clavulanate) 
X 
 
Apheresis 
X* 
 
*Apheresis will begin when the ANC > 1.0 x 109/L and continue until >2.0 x 106 
CD34+ cells/kg patient weight are cryopreserved. A 10-15 liter apheresis will be 
performed unless stopped earlier for clinical judgment of toxicity (e.g., 
numbness, tetany). A maximum of four apheresis will be performed. The G-CSF 
will continue until apheresis is discontinued 
 
8.3 Conditioning regimen 
 
DAY 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
+5 
Hydration 
X 
X 
X 
X 
X 
Cyclophosphamid
e 50 mg/kg/day 
X 
X 
X 
X 
MESNA 50 
mg/kg/day 
X 
X 
X 
X 
ATG 
(rabbit) 
0.5 
1.0 
1.0 
1.5 
1.5 
Methylprednisolone 
1 gram/day 
X 
X 
X 
X 
X 
Stem cell reinfusion 
X 
G-CSF 5 
mcg/kg/day 
X 
Rituxan 500 mg IV 
(not weight, height 
adjusted) 
X 
X 
 


 
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Cyclophosphamide 50 mg/kg/day will be given IV over 1 hour in 250 cc of normal saline on 
day –5, -4, -3, and -2. If actual weight is < ideal weight, cyclophosphamide will be given 
based on actual weight. If actual weight is > ideal weight, cyclophosphamide will be given as 
adjusted ideal weight. Adjusted ideal weight = ideal weight + 40% x actual weight minus ideal 
weight. 
 
Mesna 50mg/kg/day will be given IV over 24 hours in 250 cc of normal saline or D5W. 
Weight base is calculated same as cyclophosphamide as above. 
 
ATG (rabbit) 0.5 mg/kg on day –5; 1mg/kg on day –4 and -3; 1.5 mg/kg on day -2 and -
1 (total 5.5mg/kg) will be given IV over 10 hours in 250 cc of normal saline beginning 
at least 1 hour after infusion of cyclophosphamide. If actual weight is less than ideal 
weight, rATG will be given based on actual weight.  If actual weight is greater than 
ideal weight, rATG will be given as adjusted weight. Adjusted weight = ideal weight + 
25% of [actual weight - ideal weight]. Premedicate with acetaminophen 650 mg po and 
diphenhydramine 25 mg po/IV 30 minutes before the infusion. An in-line 0.22 µm filter 
should be used for ATG administration. 
 
Methylprednisolone A suggested dose of 250mg IV should be administered 30 minutes 
before each ATG infusion. 
 
Hydration A suggested rate of 125 cc/hr NS should be given starting 6 hours before 
cyclophosphamide and continue until 24 hours after the last cyclophosphamide dose. 
The rate of hydration will be aggressively adjusted in order to avoid fluid overload. BID 
weights will be obtained. Amount of fluid can be modified based on patient's fluid 
status. Minimum target urine output is 2 liters/m2/day 
 
G-CSF 5 mcg/kg/day SQ will be continued until the absolute neutrophil counts reach at 
least 500/µl. 
 
Rituxan 500 mg will be given IV on the day before the first dose of ATG and the day 
after stem cell infusion. 
 
9.0 
SUPPORTIVE CARE GUIDELINES (may vary according to institutional 
guidelines) 
 
9.1 
Infection Prophylaxis Guidelines -These are guidelines for autoimmune 
disease (not cancer) and are consistent with all our FDA approved phase 
I, II, and III (randomized) studies for HSCT of autoimmune diseases 
 
All prophylactic antibiotics may be changed or discontinued according to clinical 
circumstances (such as patient’s allergy) as determined by attending physician(s). 
 
9.11 
Bacterial infection prophylaxis. When WBC/ANC drops, or on day 0, a 
broad spectrum intravenous antibiotic such as piperacillin/tazobactam or 
cefepime (pseudomonal coverage is needed) will be initiated regardless of 
temperature until the ANC returns to > 500/µl. If fever occurs or patient has a 
history of surgical hardware or other risk for infection, antibiotic coverage will 
be expanded to include vancomycin (unless allergy). Patients with a history of 
allergy to penicillin or cephalosporin must be evaluated by an allergist for   


 
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testing prior to stem cell transplant. Once the WBC engraft and patient is 
without sign of infection and/or fever, intravenous antibiotics will be stopped. 
Administration of antibiotics will be done according to the institutional standard 
of practice of the participating center. 
 
9.12 
Pneumocystis prophylaxis. Upon admission, pentamidine nebulizer 
300mg will be given. Bactrim DS one tablet q.a.m on Monday, Wednesday, and 
Friday will be started after complete engraftment and will be continued as long 
as patient is on immunosuppressive medicine or 6 months, whichever comes 
later. If patient has sulfa allergy or poor engraftment, aerosolized pentamidine 
inhalation 300 mg/month will be performed for same duration. 
 
9.13 
Antifungal prophylaxis. Isavuconazole 372 mg by mouth daily will 
start on day +2 and continued until discharge from hospital. At discharge, 
antifungal will be switched to fluconazole 400 mg PO daily for six months 
post-transplant. Other antifungals such as voriconazole or posaconazole may 
be used. Antifungal medications may be held, discontinued, or switched for 
adverse side effects, for elevated transaminases, or to change coverage of 
fungal organism depending on clinical situation. 
 
9.14 
Antiviral prophylaxis. Valtrex 500 mg po BID (or equivalent antiviral 
drugs that have activity to HSV & VZV with equivalent dosage) will be started 
on day admission and continued for 12 months. 
 
9.15 
Signs of infection. If patient has signs of infection, choice and duration of 
antibiotics will be decided by attending physician's discretion. Dosage adjustment 
is required if patient has organ dysfunction. 
 
9.2 
Transfusion Guidelines 
 
All blood products need to be leukoreduced, irradiated and, preferably, CMV compatible. 
 
9.21 
Platelet counts. Will be kept 10,000 or more throughout 
transplant period. 
 
9.22 
RBC counts. Threshold to RBC transfusion will be determined 
by patient’s condition; in general, hemoglobin level >8.0 is 
preferable. 
 
9.3 
Other Supportive Care Guidelines 
 
9.31 
Respiratory care. Incentive spirometry will be performed 
several times/day to prevent atelectasis. 
 
9.32 
Nutrition. If patient cannot take oral intake, TPN is recommended during 
the peri-transplant period. During neutropenia, a low bacterial diet will be 
provided. 
 
10.1 HOSPITAL DISCHARGE GUIDELINES 
 


 
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1. Afebrile. 
2. Platelet transfusion independent. 
3. Neutrophil count greater than 500/ul. 
 
11.0 
SIDE EFFECTS 
 
Risk of hematopoietic stem cell transplantation. The major hazard of this protocol 
is transplant-related morbidity and mortality. The marrow ablative regimen of 
cyclophosphamide and ATG and rituximab and methylprednisolone will suppress the 
hematopoietic ability of the patient's marrow, and leave the patient susceptible to a 
wide variety of infections and bleeding complications until the re-infused marrow 
engrafts. 
 
Aggressive supportive care as described above will be used to prevent all avoidable 
risk. However, a small percentage of patients may die as a direct result of transplant 
related complications. Transplant related mortality is directly related to a patient's age, 
general medical condition, prior exposure to prolonged or aggressive chemotherapy 
regimens, conditioning regimen, source of stem cells and type of graft. Transplant 
related complications include infections, bleeding, veno-occlusive disease of the liver, 
and failure to engraft. This protocol is designed to minimize all these complications. 
 
Risk of PICC line and apheresis catheter. Placement of an external central line 
catheter device is a routine procedure which may be done under local or general 
anesthesia. Potential complications include bleeding, pneumothorax, hemothorax, or 
arrhythmia. Like all artificial devices, lines may become infected and require treatment 
with antibiotics and/or removal. 
 
Risk of PBSC collection. This procedure requires 4-6 hours and will be performed 
through an apheresis catheter or a 16-gauge catheter introduced into the antecubital 
vein. The total volume outside the body at any time does not exceed 450 ml. The most 
common complication is hypocalcemia arising from citrate anticoagulation, which is 
usually mild or rarely severe with nausea, vomiting or arrhythmias. Symptoms are 
avoided with replacement solutions added during apheresis, slowing the flow rate, 
and/or supplemental oral antacids containing calcium. Other complications are 
infrequent, but include hypotension, vasovagal syncope and infection. 
 
Drug/chemotherapy side effects. See Section 12 - Drug Information. 
 
12.0 
DRUG INFORMATION 
 
12.1 
ATG (rabbit) 
 
12.11 
Other names: thymoglobulin. 
12.12 
Description: A rabbit polyclonal antibody to lymphocytes. 
12.13 
Drug administration: Diluted in 250 NS and infused over 10 hours. 
12.13 
Storage and Stability: 50mg/ml (5 ml ample) vial stored in refrigerator. 
12.14 
Toxicity: Side effects of ATG are serum sickness and/or anaphylaxis: 
chills, arthralgias, headache, myalgias, nausea, vomiting, diarrhea, 
chest-pain, hypotension, dyspnea, pulmonary edema, abdominal pain. 
Other side effects include abnormal liver function tests (SGOT, 


 
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SGPT) abnormal renal function, and thrombocytopenia. 


 
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12.2 Cyclophosphamide 
 
12.21 
Other names: Cytoxan, Neosar 
12.22 
Chemical: 2-bis (2-chloroethyl) amino tetrahydro-2H-1, 3, 
2- oxazaphosphorine-2-oxide monohydrate. 
12.23 
Classification: Alkylating agent. 
12.24 
Action: Causes prevention of cell division by forming adducts 
with DNA. 
12.25 
Metabolism: Metabolized to active compounds by microsomal 
enzymes in the liver. Excreted by the kidney in both the original 
form and as metabolites. 
12.26 
Availability: 25 mg and 50 mg tablets (tablets cannot be split); 100 
mg, 200 mg, 500mg, 2000 mg vials Mead Johnson and Adria. 
12.27 
Storage: Stable at room temperature indefinitely before reconstitution. 
After reconstitution, stable for 6 days upon refrigeration or for 24 
hours at room temperature. 
12.28 
Administration: Dissolved in 250 cc 0.9%NS and administered over 
60 minutes IV. Must be aggressively hydrated before, during, and for 
24 hours after cyclophosphamide. If the rate of required hydration is 
not tolerated in a patient, bladder irrigation may need to be 
substituted. 
12.29 
Side effects: Myelosuppression, leukopenia (nadir 8-14 days), 
hemorrhagic cystitis, syndrome of inappropriate secretion of 
antidiuretic hormone (SIADH), bladder carcinoma, cellular 
dysplasia, mucositis, rash, alopecia, anorexia, nausea, vomiting, 
sterile phlebitis, rare pulmonary toxicity, teratogenicity, hemorrhage, 
myocarditis, infertility, secondary leukemia; with rapid IV push, 
oropharyngeal tingling, metallic taste, headache, urticaria, facial 
swelling. Metabolic abnormalities following cyclophosphamide 
induced cell lysis can require dialysis in patients with underlying 
renal insufficiency. 
 
12.3 G-CSF 
 
12.31 Other name: Neupogen. 
12.32 Description: hematopoietic growth factor. 
12.33 Drug administration: subcutaneous administration 5-15 mcg/kg/day. 
12.34 Storage and Stability: 300 mcg and 480 mcg vials stored in refrigerator. 
12.35 Toxicity: myalgias, headache, flu-like symptoms, fever, bone pain 
in approximately 20% of patients, possible elevation of uric acid, 
transaminases, and LDH. 
 
12.4 Mesna 
 
12.40 Other name: Mesnex 
12.41 Description: detoxifying agent inhibit the hemorrhagic cystitis 


 
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induced by cyclophosphamide. 
12.42 Drug administration: intravenous infusion over 24-hour period. 
Dosagewill be equivalent to 60-100% of total cyclophosphamide dosage. 
12.43 Storage and Stability: Stored at room temperature 15-30°C. Dilute 
with D5W or normal saline at final concentration of 20mg/ml. The 
diluted solution is chemically and physiologically stable 24 hours at 
25°C 
12.44 Toxicity: bad taste in the mouth, soft stool, headache, fatigue, 
nausea, diarrhea, limb pain, hypotension and allergy. 
 
12.5 Rituximab 
 
12.50 Other name: rituxan 
12.51 12.51 Description: is a chimeric monoclonal antibody used in the 
treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, 
and some autoimmune disorders. 
12.52 Drug administration: The recommended dosage for patients with low 
grade or follicular NHL is 375 mg/m2 infused intravenously. In 
autoimmune diseases the standard dosing for adults is usually 500 mg 
not adjusted for weight or height. The infusion is given at weekly 
intervals for four total dosages. Acetaminophen and diphenhydramine 
hydrochloride are given 30-60 minutes before the infusion to help 
reduce side effects. If given as a retreatment the dosage is the same. 
Clinical trials were ongoing in 2001 to help clarify the ideal dosage 
and treatment schedule for this drug. Generally, decrease in symptoms 
occurs at an average of 55 days after the last administration of the 
antibody. 
12.53 Side effects: The majority of side effects occur after or during the 
first infusion of the drug. Some common side effects include 
dizziness, feeling of swelling of tongue or throat, fever and chills, 
flushing of face, headache, itching, nausea and vomiting, runny nose, 
shortness of breath, skin rash, and unusual fatigue. 
 
13.0 
EVALUATION OF TOXICITY (Daily while hospitalized and on 
return evaluations) 
 
Daily assessment will be made with regards to toxicity by one of the protocol 
investigators. National Cancer Institute Common Toxicity Criteria will be used to 
grade all non-hematologic toxicities. 
 
14.1 ADVERSE EVENT REPORTING 
 
Any serious unexpected event or any death within 30 days of study treatment must be 
immediately reported, regardless of the cause, to Richard Burt MD (312-695-4960). 
 
14.1 To be reported by phone (312-695-4960) or FAX (312-695-4961) to 
Richard  Burt MD: 


 
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a) All life-threatening and lethal (Grade 4 and 5) unanticipated reactions. Grade 
4 myelosuppression is an anticipated reaction of HSCT. The spectrum of SPS 
includes insulin dependent diabetes often with poorly controlled blood sugars 
and spasms of abdominal pain. In patients with SPS, light touch such as a blood 
pressure cuff or noise such as conversation can precipitate skeletal or abdominal 
spasms with pain, nausea, and diarrhea. Therefore, transient Grade 4 
hyperglycemia is an anticipated reaction in patients with a comorbidity of 
diabetes. Grade 4 vomiting and anorexia are also anticipated reactions. 
 
14.2 To be reported in writing within 10 working days: 
 
a) Life-threatening and lethal (Grade 4 and 5) unexpected reactions (Grade 
4 myelosuppression is expected with HSCT). Grade 4 hyperglycemia is 
expected in SPS patients with SPS-related diabetes. In patients with SPS, 
light touch such as a blood pressure cuff or noise such as conversation 
can precipitate skeletal or abdominal spasms with pain, nausea, and 
diarrhea. Grade 4 vomiting and anorexia is expected due to 
complications of SPS causing spasms of abdominal pain.) 
b) Any death within 30 days of study treatment. 
 
15.0 
EVALUATION OF RESPONSE - To be performed at 6 and 12 months 
post- transplant, and annually thereafter for 5 years. 
 
1 Primary end point – Overall Survival 
2. Disease improvement -- Disease improvement 
 Decrease (50%) and complete discontinuation of muscle relaxation 
anti- spasmotic medications 
 Chronic Pain acceptance questionnaire (CPAQ) (appendix I) 
 Timed ambulation 
 Activities of Daily Living (appendix II) 
 SF-36 QOL (Appendix III) 
 Rankin Functional Scale (appendix IV) (Improvement for disability scales is 
defined in the same manner as for the SF-36 QOL, that is whether or not 
there is a statistically significant change in the score / scale / dimension done 
by standard statistical methodology such as student t test or mixed method 
analysis. 
 
16.1 
BIOSTATISTICAL CONSIDERATIONS 
 
This is a phase I/II study of 40 patients. Statistical considerations and safety 
rules for the protocol are as follows: 
 
16.2 Stopping rules for transplant-related regimen-related toxicity. 
Regimen- related toxicity within the first 28 days after transplant will be 
determined as follows: non-hematological grade 4 toxicity that fails to 


 
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resolve in 10 days; and hematological grade 4 toxicity that fails to resolve in 
28 days. Operationally sufficient evidence of any ratio of regimen-related toxicity 
will occur when any of the following ratios is observed: any 2/10, 4/20, 8/40. 
 
16.3 Stopping rules for transplant-related mortality (TRM). TRM will be 
defined as death within the first 100 days of transplant due to transplant- 
related complications. Operationally, this will occur with any 2 of 10 
deaths. 
 
16.4 Any death within the first 100 days will result in halting the study 
until reviewed and the IRB and FDA notified. 
 
17.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
1. Pregnancy prior to starting therapy. 
 
2. Patient withdrawal - before beginning conditioning regimen or 
after successful recovery of hematopoiesis. 
 
3. Disease progression making travel and follow-up studies of such 
inconvenience that they impose a significant risk or burden to the 
patient. 
 
 
18.0 
REGISTRATION PROCEDURE 
 
Patients must not start protocol treatment prior to registration. When eligibility is 
confirmed by the physician and nurse, and the protocol checklist is initialed and 
signed by the physician and nurse, the patient will be entered. 
 
 
19.1 
RECORDS TO BE KEPT 
 
Records will be kept in the office of the Division of Immunotherapy. 
 
 


 
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S,  Matà S, Mazzeo A, Sabatelli M, Nobile-Orazio E; Italian Network for CIDP  
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in patients with chronic inflammatory demyelinating polyradiculoneuropathy. 
Eur J Neurol. 2010; 17(2):289-94. 
80. Viala K, Maisonobe T, Stojkovic T, Koutlidis R, Ayrignac X, Musset L, 
Fournier E, Léger JM, Buche P. A current view of the diagnosis, clinical 
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demyelinating  polyradiculoneuropathy. J Peripher Nerv Syst. 2010; 15(1):50-6. 
81. Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating 
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82. Kuitwaard K, van Doorn PA. Newer therapeutic options for chronic 
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83. Mahdi-Rogers M, McCrone P, Hughes RA. Economic costs and quality of life in 
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D, Chalk C, Levine M, Goeree R. Cost-utility of Intravenous 
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APPENDIX I 
Chronic Pain Acceptance Questionnaire (CPAQ) 
 
Below you will find a list of statements. Please rate the truth of each statement as it applies to you. 
 
Use the following rating scale to make your choices. For instance, if you believe a statement is ‘Always 
True,’ you would write a 6 in the blank next to that statement 
 
0 
1 
2 
3 
4 
5 
6 
Never 
Very 
Seldom 
Sometimes 
Often 
Almost 
Always 
True 
Rarely 
True 
True 
True 
Always 
True 
True 
True 
 
1. I am getting on with the business of living no matter what my level of pain is   
 
 
2. My life is going well, even though I have chronic pain   
 
 
3. It’s OK to experience pain   
 
 
4. I would gladly sacrifice important things in my life to control this pain better   
 
 
5. It’s not necessary for me to control my pain in order to handle my life well   
 
 
6. Although things have changed, I am living a normal life despite my chronic pain   
 
 
7. I need to concentrate on getting rid of my pain   
 
 
8. There are many activities I do when I feel pain   
 
 
9. I lead a full life even though I have chronic pain  
 
 
10. Controlling pain is less important than any other goals in my life   
 
 
11. My thoughts and feelings about pain must change before I can take important steps in my life   
 
 
12. Despite the pain, I am now sticking to a certain course in my life   
 
 
13. Keeping my pain level under control takes first priority whenever I’m doing something   
 
 
14. Before I can make any serious plans, I have to get some control over my pain   
 
 
15. When my pain increases, I can still take care of my responsibilities   
 
 
16. I will have better control over my life if I can control my negative thoughts about pain   
 
 
17. I avoid putting myself in situations where my pain might increase   
 
 
18. My worries and fears about what pain will do to me are true   
 
 
19. It’s a relief to realize that I don’t have to change my pain to get on with my life   
 
 
20. I have to struggle to do things when I have pain   
 
 
 
REFERENCE- McCracken LM, Vowles KE, Eccleston C, Pain 107, 2004, 159-166 


 
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APPENDIX II 
 
Activities of Daily Living (Barthel 
Index) 
 
 


 
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APPENDIX III 
 
Short Form- 36 Health Survey (SF-36) 
 
INSTRUCTIONS: The survey asks for your views about your health. This 
information will help keep track of how you feel and how well you are able to 
do your usual activities. 
 
Answer every question by marking the answer as indicated. If you are unsure 
about how to answer a question, please give the best answer you can. 
 
1. 
In general, would you say your health is:  (circle one) 
 
Excellent 
1 
 
Very Good 
2 
 
Good 
3 
 
Fair 
4 
 
Poor 
5 
 
 
2. 
COMPARED TO ONE YEAR AGO, how would you rate your health 
in general NOW? 
 
Much better now than one year ago 
1 
 
Somewhat better now than one year ago 
2 
 
About the same as one year ago 
3 
 
Somewhat worse now than one year ago 
4 
 
Much worse now than one year ago 
5 


 
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3. 
The following items are about activities you might do during a typical 
day. Does your health now limit you in these activities? If so, how much? 
 
Circle one number on each item 
 
ACTIVITIES 
Yes, 
Yes, 
No 
Limited 
Not 
A Lot 
A Little
 Limi
ted At 
All 
 
 
a. Vigorous activities, such as running, lifting 
 
1 
2 
3 
heavy objects, participating in strenuous sports. 
 
b. Moderate activities, such as moving a table, 
 
1 
2 
3 
pushing a vacuum cleaner, bowling, or 
playing golf. 
 
c. Lifting or carrying groceries. 
1 
2 
3 
 
d. Climbing several flights of stairs. 
1 
2 
3 
 
e. Climbing one flight of stairs. 
1 
2 
3 
 
f. Bending, kneeling, or stooping. 
1 
2 
3 
 
g. Walking more than a mile. 
1 
2 
3 
 
h. Walking several blocks. 
1 
2 
3 
 
i. Walking one block. 
1 
2 
3 
 
j. Bathing or dressing yourself. 
1 
2 
3 


 
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4. 
During the past 4 weeks, have you had any of the following problems with 
your work or other regular daily activities as a result of your physical health? 
 
Circle one number on each line 
 
YES 
NO 
a. Cut down on the amount of time you spent on work or 
1 
2 
other activities. 
 
b. Accomplished less than you would like. 
1 
2 
 
c. Were limited in the kind of work or other activities. 
1 
2 
 
d. Had difficulty performing the work or other activities 
1 
2 
(for example, it took extra effort). 
 
 
 
5. 
During the past 4 weeks, have you had any of the following problems with your 
work or other regular daily activities as a result of any emotional problems 
(such as feeling depressed or anxious)? 
Circle one number on 
each line. 
 
YES 
NO 
 
a. Cut down on the amount of time you spent on work or 
1 
2 
other activities. 
 
b. Accomplished less than you would like. 
1 
2 
 
c. Don’t do work or other activities as carefully as usual. 
1 
2 


 
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6. 
During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Circle one 
Not at all 
 
1 
 
Slightly 
 
2 
 
Moderately 
 
3 
 
Quite a bit 
 
4 
 
Extremely 
 
5 
 
 
7. 
How much bodily pain have you had during the past 4 
weeks? 
 
Circle one 
 
None 
 
1 
 
Very mild 
 
2 
 
Mild 
 
3 
 
Moderate 
 
4 
 
Severe 
 
5 
 
Very Severe 
 
6 


 
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8. 
During the past 4 weeks, how much did pain interfere with your 
normal work (including both work outside the home and housework)? 
Circle 
one Not at all 
 
1 
Slightly 
 
2 
Moderately 
 
3 
Quite a bit 
 
4 
Extremely 
 
5 
9. 
These questions are about how you feel and how things have been with you 
during the past 4 weeks. For each question, please give the one answer that 
comes closest to the way you have been feeling. 
How much of the time during the past 4weeks -- 
A 
A 
All of   Most   Good   Some   Little   None the of 
the  Bit of  of the   of the   of the Time Time     
Time     Time     Time    Time 
a. Did you feel full of pep? 
1 
2 
3 
4 
5 
6 
b. Have you been a very nervous person? 
1 
2 
3 
4 
5 
6 
c. Have you felt so down in the dumps that 
1 
2 
3 
4 
5 
6 
nothing could cheer you up? 
d. Have you felt calm and peaceful? 
1 
2 
3 
4 
5 
6 
e. Did you have a lot of energy? 
1 
2 
3 
4 
5 
6 
f. Have you felt downhearted and blue? 
1 
2 
3 
4 
5 
6 
g. Did you feel worn out? 
1 
2 
3 
4 
5 
6 
h. Have you been a happy person? 
1 
2 
3 
4 
5 
6 
i. Did you feel tired? 
1 
2 
3 
4 
5 
6 


 
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10. 
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting friends, 
relatives, etc.)? 
Circle 
one All of the time 
1 
Most of the time 
2 
 
Some of the time 
3 
 
A little of the time 
4 
 
None of the time 
5 
 
 
11. 
How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
Mostly 
Don’t 
Mostly
 
Definitely (circle one number on each line) 
True
 
True 
Know 
False 
False 
 
a. I seem to get sick a little easier 
1 
2 
3 
4 
5 
than other people. 
 
b. I am healthy as anybody I know. 
1 
2 
3 
4 
5 
 
c. I expect my health to get worse. 
1 
2 
3 
4 
5 
 
d. My health is excellent. 
1 
2 
3 
4 
5 
 
 
 
Patient’s initials: 
Date: 
I confirm that the information on this survey is accurate. 
  
 
Staff initials: 
Date: 
 
 
 
 


 
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APPENDIX IV 
 
 
Rankin Functional 
Score 
 
0: 
Asymptomatic 
1: 
Nondisabling symptoms that do not interfere with life-style. 
2: 
Minor disability symptoms that lead to some restriction of life-style but 
do not interfere with the patients’ capacity to look after themselves. 
3: 
Moderate disability symptoms that significantly interfere with life-style 
or prevent totally independent existence. 
4: 
Moderately severe disability symptoms that clearly prevent independent 
existence, although patient does not need constant attention day and 
night. 
5: 
Severely disabled, totally dependent requiring constant attention day 
and night. 
 
Patient Name 
 
Date  
 


 
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APPENDIX V 
Modified Ashworth Scale 
The Modified Ashworth Scale (MAS) measures resistance during passive soft-tissue stretching. It is a quick and 
easy measure that can help assess the efficacy of treatment. The following conventions prevail: 
 
 
The MAS is performed in the supine position (this will garner the most accurate and the lowest score as any 
tension anywhere in the body will increase spasticity) 
 
Because spasticity is “velocity dependent” (the faster the limb is moved, the more spasticity is encountered), 
The MAS is performed while moving the limb at the “speed of gravity”’ this is defined as the same speed at 
which a non-spastic limb would naturally drop (fairly fast) 
 
The test is performed a maximum of three times for each joint; if more than three times, the short-term effect 
of a stretch can influence the score 
 
The MAS is performed prior to goniometric testing; goniometric testing provides a stretch, and the short-
term effect of a stretch can influence the score 
Scoring 
0 = Normal tone, no increase in tone 
1 = Slight increase in muscle tone, manifested by a catch and release or minimal resistance at the end of 
the range of motion (ROM) when the affected part(s) is moved in flexion or extension 
1+= Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the 
remainder (less than half) of the ROM 
2 = More marked increase in muscle tone through most of the ROM, but affected part(s) easily 
moved 3 = Considerable increase in muscle tone, passive movement difficult 
4 = Affected part(s) rigid in flexion or extension 
Positions 
The positions used for an MAS assessment are as follows: 
 
Score 
Elbow. Start position: Elbow fully flexed, forearm neutral. Movement: Extend elbow from 
maximum possible flexion to maximum possible extension. (Triceps would be in the same position, opposite 
direction.) 
 
Score 
Wrist. Start position: Elbow as straight as possible, forearm pronated. Movement: Extend 
the patient’s wrist from maximum possible flexion to maximum possible extension. 
 
Score 
Fingers. Start position: Elbow as straight as possible, forearm neutral. All fingers are done at 
once. Movement: Extend the patient’s fingers from maximum possible flexion to maximum possible 
extension. 
 
Score 
Thumb. Start position: Elbow as straight as possible, forearm neutral, wrist neutral. Movement: 
Extend the thumb from maximum possible flexion (thumb against index finger) to maximum possible 
extension (in anatomical position, “abducted”). 
 
Score 
Hamstrings. Start position: Prone so that ankle falls beyond end of the plinth, hip in neutral 
rotation. Movement: Extend the patient’s knee from maximum possible flexion to maximum possible extension 
 
Score 
Quadriceps. Start position: Prone so that ankle falls beyond end of the plinth, hip in neutral 
rotation. Movement: Flex the patient’s limb from maximum possible flexion to maximum possible extension 
 
Score 
Gastrocnemius. Start position: Supine, ankle plantarflexed, hip in neutral rotation and flexion. 
Movement: Dorsiflex the patient’s ankle from maximum possible plantarflexion to maximum possible 
dorsiflexion not more than three consecutive times and rate the muscle tone. 
 
Score 
Soleus. Start position: Supine, ankle plantarflexed, hip in neutral rotation and flexion and with the 
knee flexed to -150. Movement: Dorsiflex the patient’s ankle from maximum possible plantarflexion to 
maximum possible dorsiflexion 
 


 
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Reprinted from Bohannon R, et al. Interrater reliability of a Modified Ashworth Scale of muscle spasticity. Phys Ther. 1987; 67(7):206-207, with permission 
of the American Physical Therapy Association. This material is copyrighted, and any future reproduction or distribution requires written permission from 
APTA