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Multiple Sclerosis Therapeutics
Second edition
Multiple Sclerosis Therapeutics
Second edition
Edited by

Jeffrey A Cohen MD
Mellen Center for Multiple Sclerosis Treatment and Research
The Cleveland Clinic Foundation
Cleveland
Ohio
USARichard A Rudick MD
Mellen Center for Multiple Sclerosis Treatment and Research
The Cleveland Clinic Foundation
Cleveland
Ohio
USA
Prefaces written by

Henry McFarland MD
Chief, Immunology Branch
National Institute of Neurological
Disorders and Stroke
National Institute of Health
Bethesda MD
USA

LONDON AND NEW YORK

 © 1999, 2003, Martin Dunitz Ltd, a member of the Taylor & Francis Group
First edition published in the United Kingdom in 1999 by Martin Dunitz Ltd, The Livery House,
7–9 Pratt Street, London NW1 0AE Tel: +44 (0) 20 74822202 Fax: +44 (0) 20 72670159 E-mail:
[email protected] Website: http://www.dunitz.co.uk/
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Second edition 2003
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 Contents

Contributors x
Preface to first edition xxii
Preface to second edition xxv
Acknowledgements xxvii

I Introduction

1 Aspects of multiple sclerosis that relate to clinical trial design and treatment 3
Jeffrey A Cohen and Richard A Rudick

II Clinical trial methodology

2 Measures of neurologic impairment and disability in multiple sclerosis 23

Gary R Cutter
3 Assessment of neuropsychological function in multiple sclerosis 38
Jill S Fischer
4 Health-related quality of life assessment in multiple sclerosis 66
Deborah M Miller
5 Magnetic resonance imaging in multiple sclerosis: an overview 86
David H Miller
6 Measures of gadolinium enhancement in multiple sclerosis 103
Jack H Simon
7 Measures of magnetization transfer in multiple sclerosis 136
Massimo Filippi, Marco Rovaris, Joseph C McGowan and Carla Tortorella
8 Measures of T1 and T2 relaxation in multiple sclerosis 176
Marianne AA van Walderveen and Frederick Barkhof
9 Measurement of central nervous system atrophy in multiple sclerosis 197
Elizabeth Fisher and Richard A Rudick
10 Measures to quantify axonal damage in vivo based on magnetic resonance 220
spectroscopy in multiple sclerosis
Douglas L Arnold and Paul M Matthews
 11 Functional imaging in multiple sclerosis 235
Nancy L Sicotte
12 Use of cost analyses to improve our understanding of the therapeutic trade- 251
offs for multiple sclerosis
Elizabeth D Kulas and Kathryn Whetten-Goldstein
13 Ethical considerations in multiple sclerosis clinical trials 261
William Pryse-Phillips
14 The process of drug development and approval in the USA, the European 272
Union and Canada
Nadine Cohen, Ann Dodds-Frerichs, Tammy Phinney and John Watson
15 Sponsors, monitoring committees and investigators: the investigator’s 288
perspective
Fred D Lublin and Stephen C Reingold
16 Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: 292
reporting extended results from phase III clinical trials
Donald E Goodkin, Stephen C Reingold, William A Sibley, Jerry S
Wolinsky, Henry F McFarland, Diane L Cookfair and Fred D Lublin
17 The failed clinical trial in multiple sclerosis 297
Lael A Stone, Richard A Rudick and Nancy D Richert
18 The challenge of long-term studies in multiple sclerosis: use of pooled data, 308
historical controls, and observational studies to determine efficacy
John H Noseworthy
19 Emerging concepts of pathogenesis: relationship to MS therapies 321
Jorge R Oksenberg, Sergio E Baranzini and Stephen L Hauser

III Clinical trials of disease-modifying therapy

20 Interferons in relapsing-remitting multiple sclerosis 360

Ludwig Kappos
21 Interferons in secondary progressive multiple sclerosis 386
Ruth Ann Marrie and Jeffrey A Cohen
22 Biological responses to type I interferons: relationship to therapeutic effects 402
in multiple sclerosis
Richard M Ransohoff
23 Glatiramer acetate as therapy for multiple sclerosis 418
Corey C Ford
24 Use of mitoxantrone to treat multiple sclerosis 450
Gilles Edan, Sean Patrick Morrissey and Hans-Peter Hartung
25 Intravenous immunoglobulin to treat multiple sclerosis 478
Franz Fazekas, Siegrid Strasser-Fuchs, Ralf Gold and Otto R Hommes
26 Therapeutic plasma exchange for multiple sclerosis 495
Brian G Weinshenker and Mark Keegan
 27 Treatment of multiple sclerosis with methylprednisolone 512
Robert J Fox and R Philip Kinkel
28 Cyclophosphamide treatment of multiple sclerosis 536
Derek R Smith and Howard L Weiner
29 Treatment of multiple sclerosis by hematopoietic stem cell transplantation 558
Richard K Burt, Bruce Cohen, Lorri Lobeck, William H Burns and
Christopher Bredeson
30 Emerging disease-modifying therapies for multiple sclerosis 572
Karim Makhlouf and Samia J Khoury
31 Combination therapies in multiple sclerosis 581
Christian Confavreux
32 Sex hormones and other pregnancy-related factors with therapeutic 593
potential in multiple sclerosis
Rhonda R Voskuhl
33 Complementary and alternative treatments in multiple sclerosis 609
Vijayshree Yadav and Dennis N Bourdette

IV Disease-modifying drug therapy in clinical practice

34 Disease-modifying drug therapy for multiple sclerosis in clinical practice 624

Lawrence M Samkoff and Andrew D Goodman
35 Treatment for patients with primary progressive multiple sclerosis 646
Siobhan M Leary and Alan J Thompson
36 Fatigue in multiple sclerosis 657
Lauren B Krupp
37 Management of spasticity in multiple sclerosis 669
François A Bethoux
38 Management of bladder and sexual dysfunction in multiple sclerosis 682
Scott E Litwiller
39 Treatment of disorders of mood and affect in multiple sclerosis 717
Sarah L Minden, Melissa Frumin and Jane L Erb
40 Treatment of pain, paresthesias, and paroxysmal disorders in multiple 757
sclerosis
Marco A Rizzo
41 Treatment of tremor caused by multiple sclerosis 775
Anwar Ahmed, Jorge A Gonzalez-Martinez and Erwin B Montgomery
42 Management of cognitive impairment in multiple sclerosis 788
Steven R Schwid
43 Rehabilitation in multiple sclerosis patients 802
François A Bethoux
 Contributors
Anwar Ahmed MD
Movement Disorders Section
Department of Neurology
Cleveland Clinic Foundation
Cleveland OH
USA

Douglas L Arnold MD
MR Spectroscopy Unit
Montréal Neurological Institute and Hospital
Montréal PQ
Canada

Sergio E Baranzini PhD

Department of Neurology
University of California at San Francisco,
School of Medicine
San Francisco CA
USA

Frederick Barkhof MD
MR Center for MS Research
Vrije Universiteit Medical Center
Amsterdam
The Netherlands

François A Bethoux MD
Staff Physician
Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland Clinic Foundation
Cleveland OH
USA

Dennis N Bourdette MD
Interim Chair and Roy & Eulalia Eulalia Swank Family
Research Professor
Department of Neurology
Oregon Health & Sciences University
Portland OR
USA
 Christopher Bredeson MD
Bone Marrow Transplant Program
Department of Medicine
Medical College of Wisconsin
Milwaukee WI
USA

William H Burns MD
Professor of Medicine and Microbiology
Director, Bone Marrow Transplant Program
Medical College of Wisconsin
Milwaukee WI
USA

Richard K Burt MD
Assistant Professor of Medicine
Division of Immune Therapy and Autoimmune Disease
Northwestern University Medical School
Chicago IL
USA

Bruce Cohen MD
Department of Neurology
Northwestern University Medical School
Chicago IL
USA

Nadine Cohen PhD

Senior Vice President, Regulatory Affairs
Biogen, Inc.
Cambridge MA
USA

Christian Confavreux MD
Professor of Neurology
Head of Department, INSERM U 433
Service de Neurologie and
EDMUS Co-ordinating Center
Hôpital Neurologique
Lyon
France

Diane L Cookfair PhD

Department of Neurology
University at Buffalo, SUNY
Buffalo NY
USA

Gary R Cutter PhD

Professor of Medicine
Director, Center for Research, Design & Statistical Methods
Department of Internal Medicine
UNR School of Medicine
University of Nevada
Reno NV
USA

Ann Dodds-Frerichs MBA

Director, Regulatory Affairs Biogen, Inc.
Cambridge MA
USA

Gilles Edan
Department of Neurology
CHU Pontchaillou
Rennes
France

Jane L Erb MD
Department of Psychiatry
Brigham and Women’s Hospital
Boston MA
USA

Franz Fazekas MD
Professor of Neurology
Department of Neurology and
MRI Centre
Karl-Franzens-Universität Graz
Graz
Austria

Massimo Filippi MD
Head, Neuroimaging Research Unit
Department of Neuroscience
San Raffaele Institute
Milan
Italy

Jill S Fischer PhD

Consultant, Neuropsychological &
Health Outcomes Research
Chicago IL
USA

Elizabeth Fisher PhD

Department of Biomedical Engineering
Whitaker Biomedical Imaging Laboratory
Lerner Research Institute
Cleveland Clinic Foundation
Cleveland OH
USA

Corey C Ford MD PhD

Medical Director
Clinical and MR Research Center and Multiple Sclerosis Specialty Clinic
Albuquerque NM
USA

Robert J Fox MD
Associate Staff
Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland Clinic Foundation
Cleveland OH
USA

Melissa Frumin MD
Instructor in Psychiatry
Harvard Medical School and Neuropsychiatrist
Brigham Behavioral Neurology Group
Brigham and Women’s Hospital
Boston MA
USA

Ralf Gold MD
Department of Neurology
Julius-Maximilians-Universität
Würzburg
Germany

Jorge A Gonzalez-Martinez MD
Section of Stereotactic and Functional
Neurosurgery
Department of Neurosurgery
Cleveland Clinic Foundation
Cleveland OH
USA
 Donald E Goodkin MD
Director, Medical Affairs
Amgen Corporation
Seattle WA
USA

Andrew D Goodman MD
Department of Neurology
University of Rochester School of Medicine and Dentistry
Rochester NY
USA

Hans-Peter Hartung MD
Professor and Chairman
Department of Neurology
Karl-Franzens-Universität Graz
Graz
Austria

Stephen L Hauser MD
Professor and Chairman
Department of Neurology
University of California at San Francisco, School of Medicine
San Francisco
USA

Otto R Hommes MD
Chairman
European Charcot Foundation for MS Research
Nijmegen
The Netherlands

Ludwig Kappos
Outpatient Clinic Neurology-Neurosurgery
University Clinics/Kantonsspital
Basel
Switzerland

Mark Keegan MD FRCP(C)

Department of Neurology
Mayo Clinic and Foundation
Rochester MN
USA

Samia J Khoury MD
Associate Professor of Neurology
Co-Director, Partners MS Center
Director, Clinical Immunology Laboratory
Center for Neurologic Diseases
Brigham and Women’s Hospital
Boston MA
USA

R Philip Kinkel MD
Director, Multiple Sclerosis Center
Beth Israel Deaconess Medical Center
Boston MA
USA

Lauren B Krupp MD
Professor of Neurology
Director, Neuropsychology Research
Co-Director, MS Comprehensive Care Center
Department of Neurology
State University of New York at Stony Brook
Stony Brook NY
USA

Elizabeth D Kulas
Center for Health Economics Research
Waltham MA
USA

Siobhan M Leary MD MRCP

Institute of Neurology
University of London
National Hospital for Neurology and Neurosurgery
London
UK

Scott E Litwiller MD FACS

Urologic Specialists of Oklahoma
Tulsa OK
USA

Lorri Lobeck MD
Department of Neurology
Medical College of Wisconsin
Milwaukee WI
USA
 Fred D Lublin MD
Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Mount Sinai Medical Center
New York NY
USA

Karim Makhlouf MD
Department of Neurology
Odense University Hospital
Odense
Denmark

Ruth Ann Marrie MD

Department of Neurology
Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland Clinic Foundation
Cleveland OH
USA

Paul M Matthews MD
Centre for Functional Magnetic Research
Imaging of the Brain
Department of Clinical Neurology
University of Oxford
John Radcliffe Hospital
Oxford
UK

Henry F McFarland MD
Chief, Neuroimmunology Branch
National Institute of Neurological Disorders and Stroke
Bethesda MD
USA

Joseph C McGowan PhD

Department of Electrical Engineering
United States Naval Academy
Annapolis MD
USA

David H Miller MD FRCP

NMR Unit
The National Institute for Neurology
London
UK
 Deborah M Miller PhD LISW
Director, Comprehensive Care
Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland Clinic Foundation
Cleveland OH
USA

Sarah L Minden MD
Assistant Professor of Psychiatry
Harvard School of Medicine
Brigham and Women’s Hospital
Boston MA
USA

Erwin B Montgomery, Jr MD
Center for Functional and Restorative
Neuroscience
Departments of Neurology and Neuroscience
Lerner Research Institute
Cleveland Clinic Foundation
Cleveland OH
USA

Sean Patrick Morrissey MD

Abteilung für Psychiatrie
Universitätsklinikum Regensburg
Regensburg
Germany

John H Noseworthy MD FRCP(C)

Department of Neurology
Mayo Clinic and Foundation
Rochester MN
USA

Jorge R Oksenberg PhD

Assistant Professor
Department of Neurology
University of California at San Francisco
San Francisco CA
USA

Tammy Phinney MSc

Manager, Regulatory Affairs
Biogen, Inc.
Cambridge MA
USA

William Pryse-Phillips MD FRCP FRCP(C)

Professor of Medicine (Neurology)
Memorial University of Newfoundland
Health Sciences Centre
St John’s
Newfoundland
Canada

Richard M Ransohoff MD
Department of Neurosciences
Lerner Research Institute
Cleveland Clinic Foundation
Cleveland OH
USA

Stephen C Reingold PhD

Research Programs
National Multiple Sclerosis Society
New York NY
USA

Nancy D Richert MD PhD

Staff Clinician, Neuroimmunology Branch
National Institutes of Neurological Disorders and Stroke (NINDS)
NIH, Bethesda MD
USA

Marco A Rizzo MD PhD

Associate Director
Yale Center for Multiple Sclerosis Treatment and Research
Yale University School of Medicine
New Haven CT
USA

Marco Rovaris MD
Neuroimaging Research Unit
Department of Neuroscience
San Raffaele Institute
Milan
Italy

Lawrence M Samkoff MD
Department of Neurology
University of Rochester School of Medicine and Dentistry
Rochester NY
USA

Steven R Schwid MD
Assistant Professor of Neurology
University of Rochester School of Medicine
Department of Neurology
Rochester NY
USA

William A Sibley MD
Professor of Neurology
Arizona Health Sciences Center
Tucson AZ
USA

Nancy L Sicotte MD
Assistant Professor of Neurology
Division of Brain Mapping
Department of Neurology
UCLA School of Medicine
Los Angeles CA
USA

Jack H Simon MD PhD

Professor of Radiology, Neurology and Neurosurgery
Director of Neuroradiology and MRI
University of Colorado Health Sciences Center
Denver CO
USA

Derek R Smith MD
MS Center, Brigham and Women’s Hospital
Boston MA
USA

Lael A Stone MD
Staff Neurologist
Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland Clinic Foundation
Cleveland OH
USA

Siegrid Strasser-Fuchs MD
Department of Neurology
Karl-Franzens-University Graz
Graz
Austria

Alan J Thompson MD FRCP FRCPI

Garfield Weston Professor of Clinical Neurology and Neurorehabilitation
Institute of Neurology
University of London
National Hospital for Neurology and Neurosurgery
London
UK

Carla Tortorella MD
Neuroimaging Research Unit
Department of Neuroscience
San Raffaele Scientific Institute
Milan
Italy

Rhonda R Voskuhl MD
Associate Professor
Department of Neurology
University of California, Los Angeles
Los Angeles CA
USA

Marianne AA van Walderveen MD

MR Center for MS Research
Vrije Universiteit Medical Center
Amsterdam
The Netherlands

John Watson BSc

Director, Regulatory Affairs
Biogen, Ltd.
Maidenhead, Berks
UK

Howard L Weiner MD
MS Center, Brigham and Women’s Hospital
Boston MA
USA

Brian G Weinshenker MD FRCP(C)

Professor of Neurology
Mayo Clinic and Foundation
Rochester MN
USA

Kathryn Whetten-Goldstein MPH PhD

Duke University Center for Health Policy,
Law and Management and the Terry Sanford Institute of Public Policy
Duke University
Durham NC
USA

Jerry S Wolinsky MD
Department of Neurology
The University of Texas at Houston Medical School
Houston TX
USA

Vijayshree Yadav MD
Fellow, Neuroimmunology
Oregon Health & Sciences University
Portland VA Medical Center
Portland OR
USA
 Preface to first edition

A little over 20 years ago it was thought by many that research into experimental
therapies in multiple sclerosis (MS) was, at best, unlikely to provide valid or reproducible
information relating to the treatment of the disease. This pessimistic opinion was
reflected at the First International Conference on Therapeutics in Multiple Sclerosis, held
in 1982. The concerns were based on many unsubstantial claims for efficacy for
treatments that could not be confirmed and on the failure to identify a significant
treatment effect in the many trials that had been done prior to the meeting. While the
failures were due in part to a highly variable and unpredictable clinical course, which is
the clinical hallmark of the disease, there was also concern that a higher level of scientific
quality was needed in experimental therapeutic research in MS. Today, research on new
therapies in MS has become increasingly efficient and effective in identifying the effect
of these therapies on the course of the disease. In fact, research into the treatment of MS
can be considered an example of excellence in experimental therapeutics in neurological
disease. The change is evidenced by the approval in the USA of three therapies for the
relapsing-remitting phase of the disease.
The change can be related to several factors. Certainly, demonstration that magnetic
resonance imaging (MRI) can provide an objective means for monitoring MS, at least in
some phases of the disease course, has provided a very powerful tool in experimental
therapeutics in MS. Most important, however, has been the growth of expertise in clinical
research in MS. Impressive advances in the attention given to the design of clinical trials
in MS ranging from early phase 1 or 2 studies to pivotal phase 3 studies are now evident.
Examples of clinical trials with severe or fatal flaws in trials design, common in the past,
are now unusual. These advances reflect the growing importance given to clinical
research in MS.
Despite these advances, many unresolved questions relating to the study of new
therapies in MS persist. Beginning with an important meeting focusing on clinical
outcomes in MS research sponsored by the National Multiple Sclerosis Society and held
in 1994, use of both clinical and MRI outcomes has been carefully studied. New
approaches to the assessment of clinical disease progression have been described and are
now beginning to be used in clinical trials. Further, use of MRI as an outcome measure
has been and continues to be carefully evaluated. Thus, summary of the advances in MS
experimental therapeutics, including detailed assessment of clinical and MRI outcomes,
is especially timely.
Early in the use of MRI as an outcome measure, many investigators were convinced
that measure of disease activity on MRI could replace clinical outcome measures
completely. It was hoped that MRI was a direct measure of the disease activity occurring
in MS and that monitoring changes in disease activity as seen on MRI during the use of a
new treatment could establish the effectiveness of that treatment. It is now clear that,
although MRI is a very powerful tool, the ability to translate changes in disease activity
seen using conventional MR imaging directly to clinical outcomes is not perfect. It is
becoming increasingly evident that the evolution of the MS lesion is complex and
probably variable among patients. Further, the evolution of the pathological processes
involved in the disease probably does not represent a continuum of a single process, but,
instead, various components each contributing in different ways to damage of the myelin
sheath and the axon. Thus, it is likely that the correlation between various MRI
modalities differs during various stages of the disease process. For example, the level of
disease activity as measured on T2-weighted images or on post-contrast T1-weighted
images early in the course of the disease may be helpful in predicting the severity of
future disease. These same measures of disease activity, when examined later in the
course of the disease, may have little relationship to the level of disability existing at the
time of study or to the future progression of the disease. It is likely that progression is
closely related to irreversible damage to the myelin sheath and to axonal damage, neither
of which are specifically reflected on T2-weighted images. Further, the level of new
activity seen in contrast-enhanced T1-weighted images may only have a small impact on
the overall level of disease once a large degree of diseased brain exists. Thus, it is hoped
that imaging sequences, which have greater pathological specificity for the events
contributing most directly to progression, will provide a more useful tool for monitoring
new therapies in clinical trials.
The chapters incorporated in the first section of this book, written by individuals with
particular expertise in their respective areas, will provide an up-to-date review of the
assessment of clinical and MRI outcomes measures that are and that will be used in
clinical trials in MS. Overall, the reader will develop an understanding of the problems in
experimental therapeutics that are unique to MS, knowledge about clinical outcomes that
form the heart of clinical trials, and a solid foundation regarding the strengths and
weaknesses of imaging as an outcome measure in clinical trials in MS. The interest is
experimental therapeutics in MS is growing rapidly as advances in immunology and
genetics point to therapies that may have potential for modifying the disease process. The
issues discussed will provide the reader with the information necessary to assess and to
participate in this exciting area of clinical research.
Following this basic foundation, subsequent chapters examine the results of the most
important symptomatic and disease-modifying therapies in MS. As one reviews current
understanding of many of these therapies, one can understand the importance of well-
designed clinical studies. Unfortunately, in many cases, the effectiveness of these
therapies is incompletely resolved. More importantly, the ability of many of the therapies
to have a truly modifying effect on the course of the disease is uncertain. As implied
above, it is likely that the effect of some of these therapies will differ among patients and
with respect to the stage of the disease process when they are administered. As the reader
evaluates the results obtained with therapies that have been tested in MS, the need for
continued improvement in trial design will become apparent. The decision as to whether
and when to treat is dependent upon both the physician and the patient having a complete
understanding of the effect of the therapy in relation to the stage of the disease and in
relation to side effects. In many cases, considerable uncertainty still exists and assessment
by both physician and patient of the risks in relation to the benefit is difficult.
 It is hoped that careful attention to future trial design and the use of new imaging
modalities to define better the effect of the therapies will lead not only to new, effective
treatments but also to improved understanding of the disease process.
Henry McFarland MD
National Institutes of Health, Bethesda, USA
 Preface to second edition

Progress in our understanding of multiple sclerosis or in our ability to treat the disease
was remarkably small until the beginning of the 1990s. In contrast, during the 1990s
progress both in the identification of therapies and in the understanding of the
pathophysiology of the illness progressed rapidly. The first edition of Multiple Sclerosis
Therapeutics presented an excellent state-of-the-art review of the results of advances in
the understanding of the mechanisms and treatment of the disease. Fortunately, progress
in MS research seen during the early 1990s has continued and over the past 3 years
important new findings have emerged and observations made in previous years have been
refined and focused.
With respect to our understanding of the biology of the disease, the past 3 years have
seen a continued focus on the events occurring in the MS lesion and important new
information on the heterogeneity of the pathological processes leading to myelin
destruction has been described. The importance of damage to the axon, even early in the
disease process, has been further defined and new information on repair processes or,
more accurately, the failure of repair processes has been studied.
The implications of heterogeneity in the pathological processes producing myelin
damage are great with respect to the probable impact of therapies; therapies that target an
inflammatory component to the disease may have limited value in patients in whom
myelin damage occurs in the absence of an important inflammatory component. Although
the ability to determine which patient will or will not benefit from a particular therapy is
not yet known, progress has been made over the past 3 years in understanding some of
the mechanisms of the approved therapies and, slowly, the longer term value of these
treatments is becoming better understood. Probably most important the results of recent
clinical trials have made the value of treatment early in the disease course clearer.
Imaging continues to be an important tool for helping to establish the benefit of new
therapies and for understanding the disease process. Formal guidelines for the use of MRI
as a diagnostic tool have been developed and the value of MRI in selecting patients for
early therapy is now generally accepted. The application of functional imaging to MS has
increased, as has the focus on the cognitive changes caused by the disease.
Finally, a new emphasis is being placed on the management of the disease using
approaches that can be an adjunct to disease modifying therapies. The role of
rehabilitative strategies is being actively studied, as are other symptomatic therapies
designed to improve the quality of life for individuals with the illness.
This new edition of Multiple Sclerosis Therapeutics has both updated prior chapters
and added new chapters to reflect advances over the past few years. Because of the
importance of new information which has appeared over the past three years on both
approved and emerging therapies, chapters dealing with approved therapies such as beta
interferon, glatiramer acetate and mitoxantrone, non-approved therapies used clinically
such as IVIg and plasma exchange and new or evolving strategies such as stem cell
transplantation and the combination of multiple therapies have been extensively revised.
Further, new chapters have been added to review topics that have received attention since
the publication of the first edition. These include chapters on sex hormones and
pregnancy-related factors as well as a discussion of complementary and alternative
therapies. Finally, a discussion on cost-benefit analyses has been included.
It is fortunate that a second edition is needed as it reflects the continued progress in
helping to alleviate disease activity and the resulting symptoms of MS. Hopefully a third
edition will be needed within a few years.
Henry McFarland MD
National Institutes of Health, Bethesda, USA
 Acknowledgements

Our thanks are due to the many authors who contributed towards this book. The
publishers have been a pleasure to work with: our thanks to Martin Dunitz for providing
early advice, and to Alan Burgess and Charlotte Mossop for all their efforts in co-
ordinating the project and ensuring the expeditious publication of this book. Dr Bruce
Trapp generously provided the beautiful micrograph on the cover. Finally, this book is
dedicated to Sally, Jennifer, Joshua, Marilyn, Brian and Jamie.
 I
Introduction
 1
Aspects of multiple sclerosis that relate to
clinical trial design and treatment
Jeffrey A Cohen and Richard A Rudick

INTRODUCTION

The past decade has witnessed substantial progress in our understanding of the
pathogenesis of multiple sclerosis (MS), improvement in our ability to diagnose the
disease and monitor its course, and the emergence of MS as a treatable neurologic
disease. Nevertheless, the development of effective treatments for MS has been impeded
by several characteristics of the disease. The purpose of this chapter is to discuss the
aspects of MS that have an impact on the design of clinical trials, the development of new
disease therapies, and patient care. These aspects include heterogeneity in disease course,
in severity, and in manifestations; the presence of subclinical disease activity early in the
disease; and the complexity of pathogenic mechanisms.

HETEROGENEITY IN MS

Disease course
The clinical course of MS presents challenges because the disease has strikingly
heterogeneous clinical manifestations that evolve over decades in most patients. A
classification of disease course has been developed by consensus (Table 1.1).[1] During
the relapsing-remitting stage, periodic relapses occur at irregular and unpredictable
intervals, averaging approximately one per year. The episodic attacks of neurologic
dysfunction are followed by partial or complete recovery, and individual relapses are
separated by a clinically stable phase. Relapses tend to become less conspicuous over the
years, and the majority of patients (approximately 75%) ultimately evolve into a pattern
of gradual neurologic deterioration, termed secondary progression. During this stage,
physical, cognitive, emotional, social, and economic decline is the rule, and the illness
seems more refractory to treatment. This stage of the disease is also difficult to study,
because deterioration typically occurs slowly over the course of years, and the significant
individual variability persists. The transition from relapsing-remitting MS to secondary
progressive MS does not occur at a precise point in time. Rather, clinical relapses become
less distinct episodes, recovery becomes less robust, and the relapsing-remitting stage
blends into the secondary progressive stage, typically 10–20 years after the onset of
symptoms. The transition to the secondary progressive stage can be dated only in
retrospect, once it is clear that the patient has continuously worsened for months or years.
 Multiple sclerosis therapeutics 4

Eighty-five percent of patients have relapsing

Table 1.1 Clinical categories of multiple sclerosis
Disease Description
category
Relapsing- Episodic relapses with recovery and a stable phase between
remitting relapses. MS begins as relapsing-remitting MS in
MS approximately 85% of cases. Clinical relapses imply that the
disease is active, but clinical remission does not mean the
disease is quiescent. MRI studies have shown that the
disease may be active when the disease is clinically inactive.
Secondary Gradual neurologic deterioration with or without
progressive superimposed acute relapses in a patient who previously had
MS relapsing-remitting MS. Over 75% of patients with
relapsing-remitting MS will develop secondary progressive
MS. A major goal of disease therapy in relapsing-remitting
MS patients is to prevent evolution to secondary progressive
MS.
Primary Gradual, nearly continuous neurologic deterioration from the
progressive onset of symptoms. Some patients with primary progressive
MS MS have onset in middle age and MRI and CSF findings
identical to patients with secondary progressive MS. These
patients probably have secondary progressive MS, but
without evident clinical relapses during the early stage of
disease. Other primary progressive MS patients appear to
have a degenerative process with minimal evidence of
inflammation. These patients present with a gradually
worsening gait disorder and often have minimal cranial
disease by MRI scans.
Progressive Gradual neurologic deterioration from onset but with
relapsing subsequent superimposed relapses. This is an unusual
MS clinical pattern that may also be analogous to secondary
progressive MS without an initial relapsing-remitting course.
Adapted from Lublin and Reingold.[1]

forms of MS, either relapsing-remitting MS or secondary progressive MS. Approximately

10–15% of patients have so-called primary progressive MS, in which continuous clinical
deterioration occurs from the onset of disease (see chapter 34). Patients with primary
progressive MS tend to have symptom onset at a later age (typically between the ages of
40 and 60 years), and the female preponderance seen with relapsing forms of MS is not
evident. Patients with primary progressive MS present clinically with insidiously
progressive spastic weakness, imbalance, and sphincter dysfunction; diffuse and less
nodular T2 lesions on magnetic resonance imaging (MRI); fewer or no gadolinium-
enhancing lesions; and little inflammatory change in the cerebrospinal fluid (CSF).[2]
These cases may represent a type of MS that is less dependent on inflammation and that
may be primarily degenerative. A consensus has emerged that primary progressive MS
should be considered separately from the other groups for the purpose of controlled
clinical trials, in part because of uncertainty about the etiologic relationship between this
 Aspects of multiple sclerosis 5

form and the other categories. Some patients with primary progressive MS exhibit
clinical features, MRI findings, and a CSF profile similar to those of patients with
secondary progressive MS and probably have the same disease as secondary progressive
MS, but without clinically distinct relapses during the early stage. This is probably also
true of progressive relapsing MS. Thus, studies in primary progressive MS are
problematic because these cases are relatively uncommon, and because the primary
progressive MS category probably comprises a combination of secondary progressive MS
patients who did not have a symptomatic relapsing-remitting stage and patients with a
less inflammatory central nervous system (CNS) disease that is less responsive to
immunomodulatory treatment approaches.
Common practice has been to attempt to select relatively homogeneous patient groups
for inclusion in clinical trials, typically by defining disability limits using the Kurtzke
Expanded Disability Status Scale (EDSS)[3] and by entering patients within specified
disease categories. This strategy aims at reducing between-patient variability and
increasing the power to show therapeutic effects with a given sample size. This explains
why separate trials have been conducted for patients with relapsing-remitting MS,
secondary progressive MS, and primary progressive MS.
There are several caveats to restricting trials to certain types of patients. First,
excessively narrow entry criteria may impede recruitment. Second, it may not be clear
whether the results of a trial enrolling a selected cohort of patients can be extrapolated to
other groups of MS patients. Third, the distinction between clinical disease categories is
not precise, and the reliability of classifying patients into these categories has never been
tested. In all likelihood, there is an admixture of patients in MS trials. This point is well
illustrated by the European and North American trials of interferon beta-1b in secondary
progressive MS, in which two trials with very similar entry criteria enrolled different
patient populations and yielded different results with the same therapeutic agent. The
problems of classifying patients are most intense at the interface between relapsing-
remitting MS and secondary progressive MS. As disease duration and EDSS increase, the
patient is more likely to be categorized as having secondary progressive MS, and the cut-
off point appears to be around EDSS 4.0. At this level and above, the large majority of
patients would be classified as secondary progressive MS. Finally, it must be recognized
that clinical disease categories are defined empirically—biologic markers for the
categories are not available.
Table 1.2 lists characteristics of patients entered into several large MS clinical trials.
Despite overlap, disease duration and disability level are clearly different in trials in
relapsing-remitting MS from trials in secondary progressive MS. Because the reliability
and utility of restricting entry by disease category is unclear, some trials allowed entry of
patients based only on disability criteria (e.g. the studies of sulfasalazine[4] and
linomide[5]). Patients in these trials were intermediate between the populations in trials
restricted to relapsing-remitting MS or secondary progressive MS in terms of disability
score and disease duration.
 Multiple sclerosis therapeutics 6

Clinical manifestations
The potential clinical manifestations of MS are myriad and can include, among others,
cognitive impairments of a variety of types, loss of vision or abnormalities of eye
movements, weakness, spasticity, cerebellar dysfunction, sensory loss or positive sensory
phenomena, bowel and bladder
Table 1.2 Patient characteristics in selected
controlled clinical trials
Agent tested by clinical n Age Duration of EDSS
trial (years) disease (years)
Trials with entry restricted to relapsing-remitting MS
Interferon beta-1b[8] 372 35 4.4 2.9
Interferon beta-1a[10] 301 37 6.5 2.4
Interferon beta-1a[11] 560 35* 5.3* 2.5
Glatiramer acetate[9] 251 34 6.9 2.6
Mean 35.2 5.6 2.6
Trials with entry restricted to secondary progressive MS
Interferon beta-1b 718 41 13.1 5.1
(European)[83]
Interferon beta-1b (North 939 47 14.7 5.1
American)[84]
Interferon beta-1a 618 43 13.3 5.4
(SPECTRIMS)[85]
lnterferon beta-1a 436 47 14.2 5.2
(IMPACT)[27]
Mean 44.5 14.3 5.2
Trials with entry not restricted by disease category
Sulfasalazine[4] 199 28 5.5 2.5
Linomide[5] 715 46 15.3 5.2
Mean 42.1 13.2 4.6
*Median; all other values are mean.

dysfunction, fatigue, and paroxysmal phenomena.[6] Patients within a disease category

exhibit a wide range of clinical manifestations in varying combinations, and
manifestations typically change in individual patients over time. Even within multiply
affected families, there is striking clinical heterogeneity between affected family
members. Management of the wide variety of MS symptoms is a challenge to the
clinician. However, with the increased emphasis on disease-modifying therapies, one
needs to remember that identification and effective treatment of troublesome symptoms
of MS can have a major beneficial effect on the patient’s ability to function and quality of
life (see chapters 35–42).
The heterogeneity in potential clinical manifestations also presents significant
challenges for the design of clinical trials. Separate trials and treatment arms within a
given trial contain variable admixtures of clinical manifestations that are not necessarily
 Aspects of multiple sclerosis 7

evenly matched between studies. Outcome measures must be multidimensional to capture

the ways in which MS affects patients. Traditional clinical outcome measures are heavily
weighted towards motor impairment, particularly gait dysfunction. Common symptoms
such as sphincter disturbances, pain, and fatigue may have significant effects on quality
of life without affecting measures of physical impairment and disability. Finally,
symptomatic and disease-modifying therapies may have differing effects on different
disease manifestations (i.e. benefit for some with no effect on others, or even worsening).

Disease severity and prognostic factors

Because of pronounced variability, there is a need for accurate prognostic markers that
could be used both for treatment decisions concerning individual patients and for
selecting appropriate patients for clinical trials. Overall, 50% of patients are unable to
carry out household and employment responsibilities 10 years after disease onset, 50%
require an assistive device to walk after 15 years, and 50% are unable to walk after 25
years.[7] However, about 10% of patients have unusually bad disease and deteriorate to
severe irreversible disability in only a few years. Another 10% have benign disease, with
intermittent neurologic symptoms but little disease progression and minimal disability
decades after the initial symptoms.
Although the ultimate prognosis for MS is poor, it is a chronic disease that usually
changes slowly. During the time frame of a clinical trial, typically 2–3 years, clinical
evidence of disease activity is modest. For example, most patients in large-scale trials in
relapsing-remitting MS experienced no relapses or only one relapse.[8–11] Also, in these
studies, one-third or fewer of the placebo patients demonstrated worsening on traditional
measures of impairment or disability, such as the EDSS, over 2–3 years. Clinical stability
in the majority of placebo-treated patients results in the need for large sample sizes. One
approach to this problem has been to develop more sensitive outcome measures (see
below).
Another approach has been to attempt to enroll patients at risk of disease activity and
exclude patients who are not likely to change during the trial. In groups of patients,
benign disease has been associated with sensory symptoms or optic neuritis at onset,
good recovery from relapses, and infrequent relapses early in the disease course.[12–14]
Conversely, symptom onset at an older age, progressive disease from onset, or poor
recovery from relapses mark a relatively worse prognosis. However, clinical features are
only weak predictors of overall prognosis, and their value for assigning prognosis for the
purpose of informative enrollment in clinical trials has not been successful.[15] The
presence of multicentric white matter lesions at the time of first MS symptoms has been
associated with a higher risk of MRI and clinical disease progression in the subsequent 5
years.[16] The presence of gadolinium-enhancing lesions at baseline in a clinical trial
predicts the frequency of clinical relapses, increase in T2 lesion volume, and the risk of
brain atrophy progression over the subsequent 2 years.[17,18] Thus, most trials employ
some entry criteria, either clinical (e.g. relapses or progression over a specified time
period before the trial) or imaging (e.g. gadolinium-enhancing lesions on screening MRI
scans), to identify patients with increased likelihood of exhibiting disease activity during
the trial (so that they will be ‘informative’) and to exclude patients who are not likely to
change during the trial period. However, these criteria are only partially effective. Also,
 Multiple sclerosis therapeutics 8

as discussed above, it must be remembered that overly restrictive entry criteria aimed at
identifying active patients can make it difficult to find eligible patients and so impede
recruitment.

CLINICAL OUTCOME MEASURES FOR MS TRIALS

Traditional clinical outcome measures

Traditional clinical outcome measures for MS trials include enumerating relapses and
rating neurologic impairment or disability (see chapter 2). Relapses are defined as
neurologic symptoms lasting at least 48 hours accompanied by a change in the neurologic
examination that cannot be explained by infection or other intercurrent illness. Although
seemingly straightforward, relapses can be difficult to identify precisely in clinical trials.
Patients often report changes in their symptoms without clear-cut changes on neurologic
examination, or have changes recorded on their neurologic examination that are not
associated with a change in symptoms. Furthermore, different neurologists almost
certainly define relapses differently despite using the same broad definition above.
To address this inconsistency, investigators have attempted to create operational
definitions for relapses, including predefined changes on the examination or rating scales
required to confirm a relapse, but this creates different types of problems. Other
investigators have graded the severity of clinical relapses on the basis of the magnitude of
change on clinical rating scales or the extent of interference with functioning. These
definitions of severity are somewhat arbitrary, however, and have not been validated. The
relapse rate remains useful as an outcome measure in controlled trials, but it is critical to
mask the treatment from patients and evaluator effectively, because a relapse is in large
part patient-defined. It is also absolutely mandatory that the relapse data be analysed in
terms of impairment and disability data derived from the neurologic examination or
quantitative tests of neurologic function. This is particularly important because patients
typically experience fewer relapses while converting to steadily progressive neurologic
deterioration.
A sizeable number of MS clinical rating scales of impairment and disability have been
developed. Traditionally, the EDSS[3] has been the most frequently used scale in MS
trials. The EDSS is an ordinal scale that comprises 19 steps between 0 and 10 in 0.5-point
increments; increasing score represents increasing disability. Between 0 and 3.5, the
composite score is based on the scores assigned to eight functional system scales.
Between 4.0 and 5.5, the composite score represents the distance that the patient can
ambulate; 6.0 represents the use of unilateral assistance such as a cane to walk; 6.5
represents the need for bilateral assistance, such as a walker. Scores from 7.0 to 9.5
represent increasing degrees of immobility and dependence. Groups of patients progress
up the EDSS in a reasonably ordered and consistent way, and the EDSS has become well
accepted as the standard method for categorizing patients by disease severity.
The EDSS has been criticized because of several shortcomings related to its use as an
outcome measure for controlled clinical trials.[19] The main problems with the EDSS can
be summarized as follows:
 Aspects of multiple sclerosis 9

1 The standard neurologic examination is inherently subjective. In the lower range of the
EDSS, the definitions for scoring the functional system scales based on the
examination are vague and subjective. As a result, intra-rater and inter-rater reliability
of the EDSS are poor even with formal training of evaluators.
2 In the middle range of the scale, the EDSS is almost entirely an ambulation instrument.
Changes in other neurologic manifestations (e.g. arm function and vision) have no
impact on the score. Furthermore, the information about ambulation is truncated into a
small number of discrete categories, and so important information about change in
walking ability is discarded. For example, an individual patient may remain at the 6.5
level for several years, during which walking becomes increasingly limited. The
change may be apparent to both the patient and the evaluator, but the EDSS does not
reflect it.
3 Because it is based on the standard neurologic examination, the EDSS is insensitive to
cognitive impairment, a common and clinically important aspect of MS (see chapters 3
and 41).
4 In the upper range, the EDSS steps are so vague and stable as to be almost useless as a
rating scale for clinical trials.
5 The EDSS steps are non-linear, and so the rate at which patients progress through the
scale varies at different points.
These attributes make the EDSS relatively insensitive to change in neurologic function
and impair its ability to demonstrate treatment effects in clinical trials.

The Multiple Sclerosis Functional Composite

In response to these concerns, a workshop was held in Charleston, South Carolina, USA,
in 1994. The consensus from the workshop indicated that the majority of participants felt
that an improved clinical outcome measure was required for future clinical trials.[19] The
new clinical outcome measure was to retain the best elements of the EDSS but include
measure(s) of cognitive impairment and be quantitative, reproducible, and more useful in
monitoring treatment effects in controlled clinical trials. The National Multiple Sclerosis
Society’s Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis
appointed the Clinical Outcomes Assessment Task Force and charged them with making
specific recommendations for improved clinical outcome measures. The Task Force
articulated desirable attributes of a clinical outcome measure for MS trials:[20]
1 The measure should be quantitative, continuous, and linear to the extent possible.
2 The measure should have high intra-rater and inter-rater reliability or, for self-report
measures, should have high test-retest reproducibility.
3 The measure should be sensitive to clinical change over a relatively short time interval,
so that it could be reasonably expected to show therapeutic effects during a clinical
trial.
4 The measure should be valid.
5 The measure should be easy to administer, well tolerated by subjects, economical, and
time-efficient.
The need for increasingly sensitive clinical measures was considered of extreme
importance to allow progress in the field. Table 1.3 shows sample size calculations for
 Multiple sclerosis therapeutics 10

two clinical trials using EDSS worsening as the primary outcome. The first clinical trial
is placebo-controlled. The sample size calculation assumes that 40% of placebo recipients
will reach the clinical endpoint in 3 years. It is assumed that the active therapy will be
40% effective (i.e. only 24% of patients in the active treatment group will reach the
clinical endpoint). Such a trial would require 132 subjects per arm, or a total of 264
subjects. Assuming a 20% drop-out rate, the study would require 317 patients to achieve
a power of 80% to show the therapeutic effect at the required significance level of
p<0.05. The second study in the table incorporates an active arm comparison. That is,
treatment 1 was partially effective, and the second study compares treatment 2, a newer
promising therapy, with the ‘standard’ treatment 1. For the active arm comparison study,
624 patients would be required to show a further 40% benefit of treatment 2 over
treatment 1, assuming that the outcome measure and all other parameters remain
unchanged. Thus, as partially effective therapies are developed, demonstrating
effectiveness of better treatments will require longer trials, substantially increased sample
sizes, more sensitive clinical measures, or some combination of these approaches.
To arrive at its recommendations, the Task Force analysed informative data sets from
controlled clinical trials and natural history studies to assess potential measurement
techniques against the favorable attributes listed above.[21] Based on that analysis, the
Task Force recommended a three-part composite, termed the Multiple Sclerosis
Functional Composite (MSFC) for further testing and for use in controlled clinical
trials.[22] The MSFC includes quantitative functional tests of lower extremity function and
ambulation (the timed 25-foot walk[23]), upper extremity function (the nine-hole peg
test[24]), and cognitive function (the 3-second version of the Paced Auditory Serial
Addition Test[25]). Results from each of the component measured is transformed to a Z-
score, representing the number of standard deviation units away from the mean of a
reference population, and the individual Z-scores are averaged to create a single score.
The MSFC was used in the recently completed phase III study of interferon beta-1a in
secondary progressive MS, demonstrating the feasibility of using the MSFC in a large-
scale multinational study and confirming its excellent reproducibility.[26] In this study, the
MSFC was more sensitive to change in neurologic status over time than the EDSS and
was able to show a beneficial treatment effect when the EDSS failed (see chapter 20).[27]
This study was the first to use the MSFC as the predefined primary clinical outcome
measures. The MSFC is also being used as a secondary measure in a number of other
ongoing trials.
Studies supporting the validity of the MSFC are rapidly accumulating. Validation of a
new outcome measure is a complex process. Several aspects of validity are recognized. A
number of studies support the validity of the MSFC, showing correlation with the
EDSS,[21,26,28,29] and disease course.[28] The MSFC has been shown to correlate more
strongly with T2-hyper-
Table 1.3Number of study subjects required for
a placebo-controlled trial and an active arm
comparison trial
Placebo- Active arm
controlled trial comparison trial
Comparison Treatment 1 versus Treatment 2 versus
 Aspects of multiple sclerosis 11

Placebo Treatment 1
Rate of worsening in Placebo 40% Treatment 1 24%
control group
Rate of worsening in Treatment 1 24% Treatment 2 14.4%
comparison group
Treatment effect size 40% 40%
Sample size for 3-year 317 subjects required 624 subjects required
study*
*Assumes a 40% treatment effect; a two-tailed test of significance with
α=0.05 and 1−β=0.80 and a 20% drop-out rate. Adapted from Rudick et
al.[20]

intense lesion burden on cranial MRI[30–32] and whole brain atrophy[31,32] than the EDSS.
The clinical relevance of the MSFC was supported by its correlation with patient self-
reported MS symptoms and health-related quality of life.[29,33] In a long-term follow-up
study,[32] subjects enrolled in the phase III study of interferon beta-1a in relapsing-
remitting MS[10] were reassessed an average of 8.1 years after randomization. Baseline
MSFC and MSFC worsening over 2 years in the original trial were highly correlated with
requirement for assistance to walk, evolution from a relapsing-remitting to a secondary
progressive course, and severe whole brain atrophy at follow-up. The MSFC correlated
with these endpoints better than the EDSS did.

SURROGATE MARKERS FOR USE IN MS TRIALS

Ultimately, the goal of disease-modifying therapy in MS is to slow or prevent clinical

deterioration. However, as discussed above, clinically meaningful disability develops
over years in a typical patient with MS. Also, it has become increasingly clear that early
in the disease clinical manifestations bear a loose relationship with the ongoing
pathologic process. Thus, there is need for a surrogate marker that is sensitive (able to
detect subclinical disease activity) and meaningful (able to predict the future clinical
course). Although there have been reports of putative blood and CSF markers of immune
activity or CNS tissue damage, most efforts to date have focused on the use of MRI for
this purpose (see chapters 5–11).

Subclinical disease activity in MS

Although relapsing-remitting MS appears to have clinically active and quiescent periods,
inflammatory lesions are developing or evolving almost continuously. Gadolinium
enhancement represents the initial event (or at least a very early event) in the
development of a new T2 lesion[34] and marks sites of active brain inflammation.[35–37]
Approximately 50% of patients with relapsing-remitting MS have one or more
gadolinium-enhancing lesions on a single cranial MRI scan obtained when the disease is
clinically inactive,[38,39] and over 70% have at least one gadolinium-enhancing lesion
evident on three successive monthly MRI scans. Serial MRI studies have shown that MRI
activity (the appearance of new or enlarging T2-hyperintense lesions, or gadolinium-
 Multiple sclerosis therapeutics 12

enhancing lesions) may exceed clinical relapses by 10–20 times.[40,41] The vast majority
of new gadolinium-enhancing lesions are clinically silent.[41]
Approximately 60–70% of patients have multiple brain lesions on MRI at the time of
their initial clinical event,[42,43] suggesting that subclinical inflammatory events predated
the clinical presentation. Once relapsing-remitting MS has been established, residual
clinical manifestations between relapses are often mild early in the disease, yet there is
ongoing tissue damage, reflected in the accrual of T2-hyperintense MRI lesions.[40]
Atrophy probably also represents an end-stage effect of a variety of destructive processes
in MS. Cerebral atrophy on MRI is a frequent finding in patients with severe, long-
standing disease. With sufficiently sensitive techniques, atrophy can be detected in
patients with early relapsing-remitting MS and only mild clinical disability.[18,44–46] Thus,
tissue damage is often accumulating in MS when the disease appears stable clinically.
Although accrual of T2-hyperintense lesions is the MRI hallmark of MS, the burden of
T2-hyperintense lesions and their rate of accumulation over time correlate only very
approximately with clinical disability. There are a number potential explanations for the
dissociation. One explanation is that these lesions are pathologically heterogeneous—that
is, inflammation, edema, demyelination, axonal damage, and gliosis all can have identical
appearance on standard T2-weighted images. Hypointensity on T1-weighted images (so-
called black holes),[47–49] reduced magnetization transfer (measured by the magnetization
transfer ratio),[47,50] abnormal water diffusion,[51,52] or decreased concentration of the
neuronal marker N-acetyl aspartate (NAA) on magnetic resonance spectroscopy[53–58] are
thought to represent lesions with more destructive pathology.
These techniques also suggest that recurrent brain inflammation damages axons. This
was directly confirmed through histologic analysis of MS lesions[37,48] in which axonal
transection at sites of active inflammation was demonstrated, regardless of the duration of
MS in the individual case. There is increasing evidence that accumulating axonal damage
accounts, to a great extent, for disability progression. This hypothesis is supported by the
finding that the burden of the more destructive MRI lesions with axonal damage tends to
correlate somewhat better with clinical disability than the total T2 lesion burden does.
Another potential reason for the poor correlation between T2 lesion burden and
disability may be the inability of standard T2-weighted MRI to detect significant
pathology ‘between’ lesions. Pathologic studies have shown inflammation,
demyelination, and axonal damage in areas outside visible plaques.[59,60] Imaging at
ultrahigh field strength (4.0–8.0 T) demonstrates lesions that are not visible at standard
field strength (1.0–1.5 T).[61] A variety of advanced imaging techniques have also shown
widespread abnormalities in normal-appearing white matter. These techniques include T1
and T2 relaxation times, [62] magnetic resonance spectroscopy,[55,63–67] magnetization
transfer imaging,[60,68,69] and diffusion tensor imaging imaging.[51,52] imaging.[51,52] The
severity and extent of these abnormalities correlates reasonably well with disability.
These observations suggest that imaging approaches that provide a global measure of
pathology could be useful in monitoring individual patients over time, both in clinical
practice and in clinical trials. Measures developed for this purpose include cerebral
atrophy,[44,70] whole-brain magnetization transfer ratio histograms,[71] total brain NAA,[72]
and whole-brain diffusion magnetic resonance histograms.[73] An alternative approach is
the use of functional imaging techniques such as functional MRI[74] and positron emission
tomography,[75] which can demonstrate neuronal dysfunction that is dissociated from
 Aspects of multiple sclerosis 13

lesions either anatomically or temporally (see chapter 11). The functional disturbance
may also identify regions that are compromised but not yet irreversibly damaged.
Thus, several lines of evidence indicate that active inflammation and resultant tissue
damage during the relapsing-remitting stage of MS is not accurately reflected by clinical
manifestations. One hypothesis holds that irreversible CNS tissue injury occurs
repeatedly in the inflammatory lesions during the relapsing-remitting stage.[76] This CNS
injury accumulates over the years, leading to progressive clinical deterioration in patients
with secondary progressive MS. Progressive disability develops only after the amount of
tissue loss has exceeded a threshold, beyond which compensatory mechanisms are
exhausted and functional decline ensues. MRI has the potential ability to provide a more
accurate window on the ongoing pathology than clinical assessment does. Nevertheless,
further studies are needed to confirm this putative advantage.

MRI as a surrogate marker of the disease process

The poor relationship between clinical manifestations and ongoing brain inflammation
(and the resultant tissue damage) also implies that more accurate and sensitive markers of
the pathologic process in relapsing-remitting MS will be required for use as a surrogate
marker. The Food and Drug Administration (FDA) in the USA defines a ‘surrogate
marker’ as any non-clinical measure that can reliably predict clinical changes ‘within a
reasonable amount of time’. Although certain conventional MRI parametes (see chapters
5 and 6) correlate with disease activity, and although MRI can be used to predict the risk
of conversion from clinically isolated syndromes suggestive of MS to clinically definite
MS,[16] no MRI measure has acceptable validity at present for predicting eventual
disability in MS.
Nevertheless, it is generally agreed that MRI has the greatest potential for meeting the
FDA definition of a surrogate marker. Neurologists already obtain cranial MRI scans
periodically to assess MS disease activity and progression, to help to determine the need
for disease-modifying therapy in patients with clinically mild disease, and to monitor the
response to such therapy. The Advisory Committee on Clinical Trials of New Agents in
Multiple Sclerosis of the United States National Multiple Sclerosis Society appointed a
Task Force, which made recommendations about using MRI in clinical trials (Table
1.4).[77] The Task Force report was generally optimistic about the potential for using MRI
parameters as surrogate markers, made initial recommendations based primarily on
analysing gadolinium-
Table 1.4 Recommendations of the Task Force
on Use of MRI in MS Clinical Trials
1 MRI is a highly sensitive marker of pathologic activity in relapsing-
remitting and secondary progressive MS
2 There are significant correlations emerging between a number of
magnetic resonance and clinical parameters, although in established MS
the relationship between short-term MRI activity and long-term
disability is uncertain
3 High sensitivity makes MRI an excellent tool for rapid screening of
therapies aimed at suppressing new pathologic activity in relapsing-
 Multiple sclerosis therapeutics 14

remitting and secondary progressive MS. Because the long-term

relationship between MRI and disability is still uncertain, MRI data
should not be the definitive determinant of therapeutic efficacy. A
clinically significant endpoint must be shown. MRI should be used to
select appropriate patients with clinically isolated syndrome for trials of
therapy aimed at delaying the evolution to definite MS.
4 There are evolving major improvements in the resolution and sensitivity
of MRI and in new techniques to monitor demyelination and neuronal
damage and to quantify lesion load. Further studies are needed in
ongoing treatment trials to determine whether these new techniques
(fluid-attenuated inversion recovery sequences, magnetization transfer
imaging, magnetic resonance spectroscopic imaging, and diffusion-
weighted imaging) will prove to be strongly predictive of clinical
outcome.

enhancing lesions, and indicated the rapid developments in the field that can be expected
to result in future more specific recommendations. The current status of MRI as a
technique to monitor the MS disease process was recently reviewed.[78]
Analysis of MRI lesions faces a number of important challenges as a surrogate marker
for controlled clinical trials:
1 There are a number of candidate measures. For example, T2-hyperinten lesion lesion
burden, T1-hypointense lesion burden, number or volume of gadolinium-enhancing
lesions, number of new or enlarging T2-hyperintense lesions, magnetization transfer
ratios in lesions, spectroscopic data applied to lesions, and lesion evolution are all
potentially informative. However, these measures are interrelated, and it is not clear
which should be used or how they should combined.
2 MRI lesions are highly dynamic with substantial variability within individual patients
in longitudinal studies. This leads to potential for sampling error. For example, if a
patient is tested during a burst of disease activity, lesion analysis may suggest that the
pathology is increasing when the overall trend is actually decreasing. Also, there is
substantial between-subject variability in MRI lesion burden. These two factors result
in the need for large sample sizes or frequent MRI scans.
3 The processes that lead to loss of the blood-brain barrier resulting in increased
permeability to gadolinium are not the cause of the accumulation of inflammatory
cells in the CNS but rather the result of it. Furthermore, although the presence of
gadolinium enhancement in MS is probably a marker of inflammation, inflammation
and resultant tissue damage can probably proceed under some circumstances without
gadolinium enhancement, at least as detected by conventional imaging techniques.
4 T2-hyperintense lesions comprise a variety of histopathologic substrates. Thus, T2-
hyperintense lesions, although a characteristic finding in MS, are not a very specific
one. Standard T2-weighted MRI is also not sensitive to all pathology in MS. Newer
techniques such as magnetization transfer imaging, magentic resonance spectroscopy,
and diffusion tensor imaging demonstrate abnormalities extending beyond the lesions
visualized with conventional MRI techniques and may be more sensitive to clinically
relevant pathology. However, these techniques are difficult to standardize across
institutions. Thus, their use in multicenter trials raises complex practical issues.
 Aspects of multiple sclerosis 15

5 Global measures of the pathologic process, such as a whole-brain atrophy, whole-brain

magnetization transfer ratio histograms, and total brain NAA, are appealing, since they
are likely to reflect the net effect of various pathologic processes, and the outcome is
likely to be meaningful. However, such global measures may not be sensitive to
disease activity over short time intervals, and they do not provide insights into the
mechanisms of tissue loss or the mechanisms of therapeutic responses.
6 Because therapeutic agents differ in their mechanisms of action, it is likely that they
have differing effects on lesion formation, evolution, or repair. Thus, MRI endpoints
need to be tailored to the agent under study.
7 Analysis of MRI lesions has not yet been shown to predict subsequent clinical
deterioration reliably, although few studies so far have incorporated adequate
methodology to establish predictive validity.
In summary, although MRI lesion analysis is promising, further studies are needed to
define precisely how MRI should be used as a surrogate marker in clinical trials and to
validate its use.

FUTURE CONSIDERATIONS FOR THERAPEUTICS IN MS

Placebo control groups and active arm comparison studies

Placebo-controlled trials in relapsing-remitting MS are now impractical, because
effective therapies are available in most regions of the world. More importantly, placebo-
controlled trials are ethically questionable (see chapter 12) given the convincing evidence
for meaningful therapeutic benefits from the available treatments. The use of a placebo
control group in studies of secondary progressive MS is also becoming increasingly
problematic, with emerging reports of effective therapies (see chapters 20, 23, and 27).
However, current therapies for both relapsing-remitting MS and secondary progressive
MS are only partly effective; potentially better therapies need to be developed and tested.
Therefore, it will be necessary to define a methodology for active arm comparison studies
and for studies of drugs given in combination (see chapter 30). This will substantially
increase the complexity and cost of controlled clinical trials unless more sensitive clinical
measures or reliable surrogate markers can be identified.

Early treatment
There is an increasing consensus that diseasemodifying therapy should be started early in
patients with relapsing-remitting MS to delay or prevent subsequent neurologic disability,
rather than withheld until after disability has become manifest (see chapter 33).[79] The
rationale for this recommendation is supported by the observation that subjects with
relapsing-remitting MS in the placebo control arms in phase III studies who are then
switched to active treatment during open-label follow-up studies continue to fare less
well than subjects on active treatment from the beginning of the study.[80,81] Once a
specific neurologic impairment has persisted for longer than 6 months, spontaneous
recovery is uncommon and no therapies are known that promote recovery. There also is a
trend to increasing willingness to consider more aggressive therapies (see chapters 23, 27,
 Multiple sclerosis therapeutics 16

and 28) for patients who have continued disease activity despite standard treatments and
for patients with worrying clinical or MRI features. These therapies have the potential for
greater efficacy but carry the risk of greater toxicity.

Quality of life and cost-benefit analyses

With the trend in the direction of proactive preventive therapy designed to delay or
prevent evolution to secondary progressive MS, the potential medical, economic, and
societal benefits of effective therapy in the early disease stage may not be immediately
evident. At early stages of the disease, many patients feel reasonably well and are
working. How will we demonstrate the need for and the benefits of aggressive early
treatment used to prevent the devastating later effects of MS? The use of more sensitive
clinical endpoints that are able to detect smaller short-term changes in clinical status only
exacerbates the issue of the clinical meaning of those changes. Increasingly, patient self-
reports of health status and quality of life will be needed to address the clinical relevance
of the results (see chapter 4). In addition, follow-up studies are needed to confirm that
agents shown to be of benefit in the relatively short time period encompassed by
controlled clinical trials continue to be effective and well tolerated and that the benefit
shown in the short term translates into more clearly meaningful effects in the long term
(see chapters 15 and 17). The methodologic issues in long-term studies are substantial.
Finally, investigators and society at large are increasingly faced with the difficult issue of
weighing the short- and long-term benefits of therapies against their cost (see chapter 12).

Rationally designed interventions

Most contemporary clinical trials are based on the concept that MS is caused by
autoreactive T cells that injure the CNS. Interventions have ranged from highly specific
inhibition of the trimolecular complex to global immune suppression. However, based on
recent pathology studies,82 concepts of MS pathogenesis have substantially changed (see
chapter 19). There is increased recognition that the pathogenic mechanisms in MS are
more complex than was originally thought and involve not only cell-mediated
mechanisms but also humoral mechanisms. Reports of benefit of therapeutic approaches
likely to be directed to humoral mechanisms supports this concept (see chapters 25 and
26). There may also be a degenerative component, particularly at later stages of the
disease. The pathologic process is probably heterogeneous; it may vary significantly
between patients and in individual patients over time. The implication is that novel
therapeutic approaches targeted at a variety of steps in the pathogenic process are needed
(see chapters 30, 32, and 33).
The other implication is that individual patients may respond to different therapies.
Once therapy is started, how do we distinguish responders from partial responders and
non-responders? What are the most appropriate treatment options (switching agents or
combination therapy) for patients demonstrating a suboptimal response? Is rational
polypharmacy with agents aimed at different aspects of the disease process possible? Will
we eventually develop adequate information related to pathogenic mechanisms,
immunogenetics, and mechanisms of action of the therapies to design in a rational way
 Aspects of multiple sclerosis 17

therapeutic interventions, or will development of MS therapeutics be predominantly a

trial-and-error process?

Neuronal pathology
Axonal damage and neuronal pathology are now recognized to be prominent features of
MS and major contributors to permanent disability, providing a rationale for
neuroprotective factors in future clinical trials. However, understanding of the
mechanisms leading to axonal degeneration, strategies to interrupt these processes, and
methods to monitor this aspect of treatment in trials are lacking.

Regenerative strategies
Treatments aimed at augmenting repair processes, both remyelination and axonal
regeneration, are greatly needed. Studies of these agents will require development of new
methods to monitor repair and restoration of function.

Application of clinical trial results to clinical practice

Extrapolating from controlled clinical trials to clinical practice is an imprecise art.
Neurologists are required to make decisions for individual patients based on limited data
from clinical trials. By necessity, entry criteria for clinical trials are restricted to reduce
heterogeneity and to focus the question for the trial. But in clinical practice only a tiny
fraction of the patients have the same characteristics as the clinical trial population.
Additionally, methods for monitoring individual patients during open-label therapy are
lacking. Can we develop methods to address a common clinical question: ‘Is this drug
working in this patient?’ This issue applies not only to disease-modifying therapies but
also to symptomatic medications and non-pharmacologic therapeutic approaches. A valid
definition of therapeutic response is needed for individual treatment decisions. Clinical
studies at the interface between controlled clinical trials and clinical practice will be
critical for optimizing therapy for individual MS patients.

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Exploring the Variety of Random
Documents with Different Content
 35 2 THE GENEALOGY OF THE vi. Mary Elizabeth, b. 3 Oct.,
1846 ; d. 10 Feb., 1848. And a twin who lived only a few days. 654.
CALEB 7 CUSHING (John Newmarch0 Benjamin '" Caleb 4"3 John 2
Matthew ' ) was born in Salisbury, Mass., 17 Jan., 1800. He married,
23 Nov., 1824, Caroline Elizabeth, daughter of the Hon. Samuel S.
Wilde, Judge of the Supreme Court of Mass. She was born 26 April,
1802, and died without issue, 28 Aug., 1832. Caleb Cushiug did not
marry again. Graduated in 18 17 from Harvard College, where he
was a tutor, 1820 to 1821. He was admitted to the bar in 1822 and
practised law in Newburyport, Mass., until 1829. He was
representative from Newburyport to the State Legislature, 1825, '26,
'33, '34, '50, '58 and '59 ; senator from Essex County in 1826. and
elected to Congress in 1835. He was thrice re-elected to Congress
and sat in the House of Representatives until 1843, when he was
appointed Envoy Extraordinary and Minister Plenipotentiary to China,
whither he proceeded in July of the same year by way of the
Mediterranean, Egypt and India. He negotiated the famous treaty
with China and returned through Mexico in 1844. On the 1 5th of
January, 1847, ne was commissioned Colonel of the Massachusetts
Regiment and led it to Mexico. While serving there, 14 April, 1847,
he was made a Brigadier-General and held the office through the
war until July, 1848. He was the first mayor of Newburyport, 1851
and '52 ; and in the latter year was appointed Commander of the
Ancient and Honorable Artillery Company of Massachusetts. From
1852 to 1853, ne was Judge of the Supreme Judicial Court of
Massachusetts, and from 1853 to 1857, Attorne}rGeneral of the
United States. In 1866, he was appointed one of three eminent
lawyers to revise and codify the laws
The text on this page is estimated to be only 15.33%
accurate

Hon. Caleb Cushing

 CUSHING FAMILY 3 5 3 of the United States, and in 1872,
was one of the Counsel for the United States at the Geneva
Conference for the settlement of the Alabama claims. • ' In the
death of Mr. dishing, not only his native state, but the nation will feel
the loss of a man who for more than half a century has been
distinguished for his learning and eloquence as a lawyer and judge,
as a legislator and diplomatist and as a man of letters, contributing
largely, by state papers and contributions to various periodicals, to
the literature of his time. He was also noted for his conversational
and forensic talents, and for his knowledge of foreign languages.
Probably no other man that ever held office in this country, with the
exception of John Quincy Adams, ever brought so much real
knowledge to the transaction of business, while his versatility and
readiness were equal to his attainments." 655. JOHN" NEWMARCH 7
CUSHING (John Newmarch" Benjamin "J Caleb4"3 John - Matthew ' )
was born in Newburyport, Mass., 21 Oct., 1820. He married, 16 May,
1843, Mary Lawrence, daughter of Capt. Lawrence Brown. She died
2 Aug., 1898. He was a ship-owner and merchant of Newburyport.
Children : 1061. i. Mary Anna, b. 3 March, 1844. ii. Lawrence Brown,
b. 9 Nov., 184=5. Resides in Newburyport, Mass. 1062. iii. Elizabeth
Johnson, b. 30 Sept , 1S50. iv. Margaret Woodbridge, b. 9 Feb.,
1855. v. John Newmarch, b. 24 Jan., 1862. Graduated from Harvard
College, 1S87, and Harvard Law School, 1890. Died 22 Dec, 1890.
656. WILLIAM7 CUSHING (John Newmarch" Benjamin 5 Caleb4-'*
John 2 Matthew ' ) was born in Newburyport,
 354 THE GENEALOGY OF THE Mass., 10 Aug., 1823. He
married, first, 23 Sept., 1847, Sarah Moody, daughter of Ebenezer
Stone, of Newbury poit. She died 26 June, 1863. He married,
secondly, 29 May, 1866, Ellen M. Holbrook, of Jamaica Plain, Mass.
Died 16 Oct., 1875. Graduated from Harvard College in 1843. He
then went to Oregon, where he remained about three years,
attending to mercantile business for his father. On his return in 1846,
he engaged with his father in the shipping business. He was Mayor
of Newburyport for the yeais J856, '57 and '58, and Representative
to the Legislature in 1872. He was for some years President and
Director of the Ocean National Bank of Newburyport and connected
with various charitable organizations. He was largely interested with
his brother John Newmarch in navigation, and the owner of several
fine ships. " He was a kind hearted man, affable to all, and one < f
the most even-tempered persons that ever lived, being extremely
popular with all classes — a man of large and generous impulses."
— Boston Journal. Children, by his first wife : 1063. i. William Philip,
b. 10 June, 1849. 1064. ii. Sarah Moody, b. 26 May, 1852. iii. Caleb,
b. 20 April, 1856 ; d. 24 Dec, 1874. iv. Fanny Elizabeth, b. 1 June,
1863. 657. SARAH7 CUSHING (Caleb0"5 James4 Caleb3 John1'
Matthew1) was born in Salisbury, Mass., 15 June, 1793. She married,
1 Feb., 1816, Dr. Benjamin Flint. He died 26 Sept., 1838. Resided in
Bangor, Me. Children : i. Ambrose C (Flint), b. 4 June, 1819. Lived in
Bangor, Me. ii. John C, b. 3 Aug., 1821. Lived in Sioux City, Iowa.
 C USHING FAMILY 3 5 5 658. HARRIET BYRON 7 CUSHING
(Caleb « James 4 Caleb3 John2 Matthew1) was born iS June, 1798.
She married, 16 July, 1S1S, Dr. Samuel Hoskins. He was born at
Grafton, N.H., 22 Jan., 1795, and died at Chelsea, Mass., 12 Jan.,
1873. Children : i. John Church Cushing (.Hoskins), b. iS Jan., 1820;
m. Clarissa Virginia Bennett. Was Postmaster at Sioux City, Iowa, ii.
William H., b. 30 Dec, 1821. iii. Samuhl W , b. 31 Jan., 1824. Lived in
Oldtown, Me. iv. Mary, b. 14 Feb., 1826. Lived in Chelsea, Mass. v.
Lois A. R-, b. 31 May, 1828. Lived in Chicago, 111. vi. James D., b. 9
Oct., 1830, Lived in Sioux City, Iowa. vii. Caleb Allen, b. 3 Feb., 1S33.
Was a civil engineer on the Baltimore & Ohio Railroad. viii. Harriet S.,
b. 5 March, 1S37 ; d. 26 June, 1S73. 659. THOMAS JEFFERSON 7
CUSHING (Caleb « James4 Caleb3 John2 Matthew1) was born 7
Feb., 1801. He married, 21 Dee., 1826, Sophia Gallison. She was
born in 1806, and died in 1852. He died 26 June, 1841. Child : i.
HELEN M. b. 27 Jan., 1829 ; in. C. H. Coy. Lived in Boston. 660.
JONATHAN AMBROSE7 CUSHING (Caleb8-5 James4 Caleb3 John 2
Matthew l ) was born 12 May, 1806. He married, 8 June, 1843,
Nancy W. Hill. Died in Washington, D.C., 3 July, 1873. Children : i.
Mary A., b. 22 April, 1848. ii. Henry D., b. 24 Dec, 1849. 661. JAMES
MADISON7 CUSHING (Caleb""' James4 Caleb3 John 2 Matthew l )
was born 19 Sept., 1808. He married, 5 June, 1S50, Maacha T. Miller.
Died in Boston, Mass., 26 March, 1883.
 3 5 6 THE GENEALOGY OF THE Child : i. Sarah Mildred, b.
17 June, 1851. 662. AMANDA M. 7 CUSHING (Caleb 6'5 James 4
Caleb 3 John 2 Matthew 1 ) was born 15 May, 1813. She married, 24
Aug., 1837, Elihu R. Averill. Lived in Dover, Me. Children : i. George
B. (Averill), b. 4 June, 1838. ii. Frank W., b. 14 July, 1840. iii. Anna
B., b. 24 Oct., 1S44. iv. Mary C, b. 24 Oct., 1844. v. WlLLARD C, b.
12 May, 1847. vi. Florence M., b. 29 Jan., 1852. vii. Ambrose H., b.
19 March, 1854. viii. Alice M., b. 21 Nov., 1856. 663. SAMUEL7
CUSHING (Theodore "Caleb5 James4 Caleb I John 2 Matthew l ) was
born in Salisbury, N. H., 23 Jan., 1799. He married, first, at Parma,
N.Y., 14 Feb., 1828, Rebecca H. Lee. She died 13 Aug., 1836. He
married, secondly, 23 May, 1838, Elizabeth, daughter of Elias Stone,
a Revolutionary soldier. Samuel- died 8 Jan., 1882. He removed to
Vermont with his parents and learned the trade of chair-maker with
his father, and removed to Monroe Co., N. Y., in 1838, with his
family. He was actively connected [with the "Underground Railway".
A true bill for " harboring slaves " was found against him in Oct.,
1843, and he was arrested, but was subsequently released. He was
a deacon in the church. Children, by his first wife : 1065. i. Henry
Theodore, b. 8 Nov., 1828. 1066. ii. Charles Samuel, b. 11 Sept.,
1830. Children, by his second wife : iii. Tirzah Rebecca, b. 23 Sept.,
1839 ; d. 1 Feb., 1856. iv. James Royal, b. 20 Dec, 1840; d. 15 Feb.,
1846.
 CUSHING FAMILY 35 7 v. William Wilberforce, b. 5 Dec,
1841 ; d. 10 Feb., 1846. vi. Emily Arabella, b. 29 Aug., 1844; d. 21
Feb., 1846. vii. James William, b. 4 Aug., 1848 ; d. 29 Nov., 1848.
664. JAMES ROYAL7 CUSHING (Theodore ° Caleb 5 James 4 Caleb 3
John - Matthew ' ) was born in Salisbury, N. H., 24 Nov., 1800. He
married, first, 15 Sept., 1829, Hannah Lawrence, daughter of Dea.
Joseph, of Woburn, Mass. She died 24 June, 1843. He married,
secondly, 14 Xov., 1844, Unity Myra Daniels. She was born 17 Aug.,
1800. James died at Tilton's Corner, East Haverhill, Mass., 11 June,'
1 88 1. Graduated from Bangor Theological Seminary in 1828. After
closing his studies at Bangor, he was employed for a few months in
Boston as a City Missionary, when he accepted a call from the
Congregational Church in Boxboro, Mass. Four years later he became
an agent of the American Tract Society. Subsequently, from 1835 to
1844, he was pastor of the Congregational Church in the East Parish
of Haverhill, Mass. ; and from 1844 to 1854, pastor at Wells, Me.
From 1854 to 1861, he was pastor at East Taunton, Mass., and for
seven years more he served in the same capacity at Rochester,
Mass. After 1875, he lived at East Haverhill, in the family of his son,
James R. dishing, Jr., where he died. Children, by his first wife : i.
Hannah Abigail, b. 14 July, 1831 ; m. 27 July, 1862, Jeremy Lake, ii.
Ann Maria, b. 11 Aug., 1832 ; d. 16 Oct., 1S43. iii. Joseph Lawrence,
b. 17 Tan., 1835 ; in. Mary West. No children. Lived near St. Louis,
Mo. 1067. iv. James Royal, b. 17 Dec , 1837. v. MillicentRosanna, b.
27 Feb., 1839 ; d. 22 Sept., 1842. 665. NATHANIEL SAWYER 7
CUSHING ( Theodore e Caleb 5 James 4 Caleb 3 John 2 Matthew J )
was born in Salisbury, N.H, 7 Dec, 1804. He married, first, 7 Sept.,
1830,
 358 THE GENEALOGY OF THE Melissa, daughter of Samuel
Wright, of Hebron, Conn. She was born 24 Sept., 1809, and died 30
May, 1857. He married, secondly, 6 Dec., 1S60, Elizabeth B. Smith.
She died 28 April, 1904. He died 13 May, 1889. In 1827, he removed
to Monroe Co., N. Y., and in 1837, ne settled in Lombard, 111. In
1840, he took up his residence at Chicago, where for 35 years he
was a large wholesale paint and plaster dealer. Children, by his first
wife : i. Walter Nathaniel, b. in Brockport, Monroe Co., N.Y., 2 June,
1835 ; d. 16 July, 1835. 1068. i. Martha Abigail, b. in Du Page, Will
Co., 111., 26 Feb., 1840. iii. Harriet Melissa, b. in Chicago, 111., 6
Feb-, 1842 ; m. ?6 Nov., 1865, Christopher B.Bouton ; d. 17 Sept.,
1868. iv. Thomas Clarkson, b. in Chicago, 111., 1 June, 1844; d. 9
Oct., 1844. 1069. v. Kdward Theodore, b. in Chicago, 111., 2 Sept.,
1845. vi. Rva Cordelia, b. in Chicago, 111., 12 Dec, 1852 ; m. 10
April, 1878, Walter Tod ; d. 26 June, 1886. One child, Elizabeth
Cushing, b. 19 Dec, 1884, 666. EMILY MORRILX7 CUSHING
(Theodore "! Caleb5 James4 Caleb"' John 2 Matthew ' ) was born in
Thetford, Vt., 9 July, 1809. She married, 8 Oct., 1837, Rev. Samuel
Porter, of Avon Springs, N.Y. Died 14 Feb., 1895. Settled in Michigan,
near Detroit. Children lived later mostly in Chicago, 111. Children : i.
Theodore Arthur (Porter), b. 29 July, 1838. ii. Eliza Maria, b. 27 Oct.,
1841 ; d. 11 Sept., 1843. iii. Ellen Myra, b. 5 April, 1844. iv. Sarah
Arabella, b. 5 Sept., 1846. v. Julia Melissa, b. 21 Jan., 1850. vi.
Bertha Evangeline, b. 3 Dec, 1853. vii. Mary Arzabah F., b. 28 March,
1855 ; d. 17 Oct., 1861.
 CUSHING FAMILY 359 667. WILLIAM THEODORE7
CUSHING (Theodore" Caleb"' James4 Caleb :i John- Matthew1) was
born in Thetforcl, Vt., 28 Jan., 18 16. He married, 22 Feb., 1844,
Susan Arabella Granger. Died 14 March, 1898. He was a lay preacher
and bible student. Removed to Western N. Y. in 1830. Studied for a
physician ; spent the year 1840 in Chicago, then a place of less than
5,000 inhabitants, and in the fall of that year removed to Rochester,
N. Y., where he was engaged in mercantile pursuits for 37 years. He
was a member of the City Council there, In 1877, ne removed to
Atlantic City, Iowa. Children : 1070. i. Theodore, b. 1 June, 1847.
1071. ii. Ffancis John, b. 23 Jan., 1849. 1072. iii. William Granger, b.
1 March, 1855. iv. Susan Myra, b. 14 Jan., 1861 ; d. 17 Sept, 1861.
668. JOSEPH WAINWRIGHT 7 CUSHING (John Wainwright ° Caleb 5
James 4 Caleb 3 John 2 Matthew l). He married, 26 Nov., 1840,
Anna, daughter of John Morrill, of Sebec, Me. Lived in Milo and
Sebec, Me. Children : i°73Wainwright, b. 12 Aug., 1841. Sarah
Martha, b. 28 May, 1843. Caleb, b. 17 Jan., 1845. Enlisted in the
Maine Volunteers, and was killed at the battle of Wilderness, 5 May,
1864. iv. Celia Ann, b. 17 March, 1847 ; m. 25 June, 1869, Edwin C.
Prentiss, a printer of Boston. Two children : (1) Mabel Anna, b. 1
June, 1871, d. 29 March, 1873, and (2) Caleb Arthur, b. 23 April,
1875, d. 13 July, 1876. v. Maria Josephine, b. 17 June, 1850 ; d. 1
Feb., 1851. 1074. vi. Clara Elizabeth, b. 19 Nov., 1854. vii. William
Edwin, b. in Sebec, Me., 3 July, 1856 ; m. in 1886, Ida Iv. Perry.
Resides in Somerville, Mass. One child, Raymond E., b. 1887.
 360 THE GENEALOGY OF THE 669. RUFUS 7
CUSHINGQohn "^ Caleb 3 John 2 Matthew x ) was born in Freeport,
Me., 19 Jan., 1794. He married in Freeport, 22 March, 1815, Sarah
Hooper of Greene. She died 19 Dec., 1870. He died in Freeport, 23
Nov., 1884. Served one year in the War of 181 2. Children, born in
Freeport : 1075. i. David Story, b. 28 June, 1816. ii. RuFUS Monroe,
b. 21 May, 1819 ; drowned at Apilachicola, 11 June, 1849 iii. MoSES
Harris, b. 26 Jan., 1821 ; d. in St. Thomas, 27 May, 1843. 1076. iv.
Hosea Ballou, b. 21 May, 1823. 1077. v. James Sullivan, b. 3 Sept.,
1827. 1078. vi. Laura Ellen, b. 17 Dec, 1833. vii. Sarah Jane, b. 30
July, 1836; d. in Freeport, 16 Feb., 1842. 670. DOROTHEA 7
CUSHING (John ti5-4 Caleb 3 John 2 Matthew1) was born in
Freeport, Me. She married, first, Mann ; and secondly, Dennis Soule.
Children, born in Freeport ; by her second husband : i. Delia Ann
(Soule) ; m. John Osgood, ii. Elizabeth, b. 1829. iii. Pomeroy Cutler,
b. 1830 ; in. in 1859, Martha Osgood ; d. in Freeport, Dec, 1890. iv.
Abbie Parsons, b. 1834; in. in 1856, Ezekiel W. Mitchell ; d. 18 Dec,
1877. 671. JOHN 7 CUSHING (John w Caleb 3 John 2 Matthew1) was
bom in Freeport, Me., 18 April, 1802. He married, 27 Sept., 1831,
Ducretia B. Shaw of Cumberland. He died 3 Jan., 1894. Children,
first two born in Pownal, and the rest in Lewiston : i. EmmelinE, b. 9
May, 1833 ; in. 28 Oct., 1858, Jacob M. Shaw, of Cumberland, ii.
Laura, b. 30 March, 1835.
 CUSHING FAMILY 36 1 iii. Olive A., b, 27 Nov., 1837 ; d. in
Lewiston, 17 April, 1859. iv. Joseph, b. 21 Dec, 1839; d. m Lewiston,
1 Sept., 1S61. 1079. v. Elizabeth, b. 18 July, 1842. vi. John M., b. 12
Feb., 1S45 ; d. in New York, 5 Oct., 1868. Served six years in the
regular army. vii. Cornelia A., b. 24 Feb., 184S ; d. in Lewiston, 31
May, 1864. viii. Prentice M., b. 24 Nov., 1S50 ; d. in Lewiston, 3 Aug.,
1S54. 672. JAMES SULLIVAN 7 CUSHING (John •** Caleb 3 John -
Matthew l ) was born in Freeport, Me., April, 1807. He married, first,
in 1836, Abigail Thorts Parsons. She died in Nov., 1838. He married,
secondly, Dec, 184.0, Rachel Griffin Hayes. She died 30 Nov., 1885.
He died 6 Nov., 1846. Was styled "Captain ". Children, by his second
wife : 1080. i. Charles Sullivan, b. 29 April, 1S42. 1081. ii. James
Henderson, b. 3 Feb., 1845. 673. JANE 7 CUSHING (John G"5-4
Caleb 3 John 2 Matthew1) was born in Marshfield. She married in
1828, Bradbury Dennison of Freeport. Children, born in Freeport : i.
Azelia (Dennison), b. Dec., 1829; m. in 1846, Samuel Soule. ii.
GEORGE W., b. 1833 ; m. in 1858, Charlotte P. Ward. iii. Melissa
Jane, b. 4 June, 1838 ; m.in 1856, H. Litchfield, iv. Parmenas, b. 30
July, 1840 ; m. Evelyn Litchfield. v. John Cushing, b. 14 Nov., 1845 ;
m. in 1877, Lucy Joslyn. 674. EDWARD 7 CUSHING (John **+ Caleb
3 John Matthew T ) was born in Marshfield, 8 March, 1809. He
married, 29 Nov., 1838, Louisa G. Soule. She died at Pownal, 3 Ma}-,
1885. He died in 1896. Children, born in Pownal : 1082. i. Samuel
Edward, b. 4 Jan., 1840. 1083. ii. Moses Harris, b. 11 July, 1844.
 36 2 THE GENEALOGY OF THE iii. George Dana, b. 1 6
June, 1847; drowned at New Sharon, 5 May, 1867. iv. John Clement,
b. 8 March, 1849; m. 15 Feb., i88d, Martha York Libby. She was b. 6
Feb., 1857. He d. in Lewiston, 12 Oct., 1883. 1084. v. Henry Herbert,
b. 29 May, 1853. vi. Emma Louisa, b. 14 March, 1857 ; d. 16 March,
185S. vii. Minerva A., b. 29 June, 1859 ; in. 3 March, 1885, Lester
Tuttle. 675. GEORGE AMMI 7 CUSHING (John *** Caleb 3 John 2
Matthew 1 ) was born in Freeport, Me., 2 Jan., 1816. He married,
first, in Freeport, 11 March, 1841, Mehitable Soule. She died in
Freeport, 10 April, 1853. He married, secondly, 20 Oct., 1859, Abbie
Goodrich. Died in Portland, Me., 28 Feb., 1887. Children, born in
Portland, by his first wife : i. Georgiana, b. 6 Sept., 1843 ; d. in
Portland, 19 April, 1872. ii. Clara Ellen, b. 14 March, 1849 ; d. in
Portland, 30 March, 1865. iii. Abbie Emeline, b. 16 Oct., 1852 ; d. in
Freeport, 19 March, 1853. Child, born in Portland, by his second wife
: iv. ShailER Goodrich, b, 18 Nov., i860. A crayon artist. 676.
EDWARD MARTYN 7 CUSHING (Jonathan ° John rw Caleb a John 2
Matthew l ) was born in Freeport, Me., 6 Aug., 1802. He married, 5
Nov., 1826, Hannah, daughter of William and Elizabeth (dishing)
Hoyt. She was born 12 Nov., 1802, and died in Freeport, Me., 20
March, 1874. He died 7 Nov., 1870. Lived in Freeport on part of the
estate owned by his grandfather John Cushing. Children : i. Esther,
b. 12 Nov., 1832 ; d. unm., 6 Aug., 1850. 1085. ii. Elizabeth, b. 9
Oct., 1836. 1086. iii. James Edward, b. 8 Jan., 1839.
 CUSHING FAMILY 3 6 3 677. CHARLES 7 CUSHING
(Jonathan "John 3"4 Caleb 3 John - Matthew l ) was born in
Freeport, Me., 23 May, 1818. He married, first, 9 March, 1842,
Martha C. Brewer. She died 21 Xov., 1875. He married, secondly, 25
Oct., 18S2, Arsenath J. Skillin. He died 6 May, 1891. Wasone of the
most prominent ship-builders in the days of wooden ships. Children,
by his first wife : Juua Maria, b. 1 Jan., 1843. Albert Henry, b. 19
Feb., 1845. Mary Alice, b. 7 July, 1847 ; d. 27 June, 18S7. Charles
Augustus, b. 7 Feb., 1850. Esther, b. 17 Nov., 1851. Martha Ella, b.
30 July, 1854. Statira Koopman, b. 17 Dec, 1856; d. 2 Feb., 1862.
Horace Brewfr, b. 20 March, 1859 ; d. 2 Oct., 1865. Harry Munroe, b.
14 Nov., i860. Kate McClellan, b. 10 Feb., 1864. 678. GEORGE KING7
CUSHING (George^ JosephsJohn- Matthew1) was born in Boston,
Mass., 29 Nov., 1806. He married, 18 Oct., 1832, Eucretia Bean. She
died 8 Dec, 185 1. He died 2 Feb., 1898. Children : 1094. i. George,
b. 19 Nov., 1834. ii. Samuel Dearborn, b. 14 Dec, 1836 ; d. 1 March,
1837. iii. Thomas, b. 2 March, 1838; d. 11 April, 1838. 1095. iv.
Roswell Dearborn, b. 16 Aug., 1839. 1096. v. Otis, b. 1 March, 1842.
679. ANDREW 7 CUSHING (George °-5 Joseph 4"3 John Matthew1)
was born in Scituate, Mass., 24 Sept., 1814. He married, 1 Nov.,
1842, Chastine Lincoln. Died 7 Nov., 1892. He was for 50 years
connected with the Citj- Missionary Society of Boston, of which he
was for a long time superintendent : he was also President of the
Home for 1087. i. 10SS. ii. iii. 1089. iv. 1090. v. I09T. VI. Vll. vm.
1092. ix. i°93X.
 36 4 THE GENEALOGY OF THE Aged Women, on Revere
St., and one of the Vice-Presidents of the Howard Benevolent
Society. Children : i. Chastine Lincoln, b. 12 Oct., 1844. ii. Andrew
Lincoln, b. 1 Dec, 1848 ; d. 20 Aug., 1850. 680. CHRISTOPHER7
CUSHING (George05 Joseph4"3 John - Matthew ] ) was born in
Scituate, Mass., 3 May, 1820. He married, 23 Sept., 1847, Mary
Frances, daughter of William Choate, of Derry, N.H. She was born 5
Dec, 1822, and died 31 July, 1882. Dr. Cushing died at Cambridge,
Mass., 23 Oct., 1881. Graduated from Yale University in 1844, and
from Andover Theological College in 1847. Ordained 27 Feb., 1849,
as pastor of the Edwards Church in Boston, where he remained two
years. He then went to the Congregational Church in North
Brookfield, Mass., where he remained until 1868. Then became
Boston Secretary of the American Congregational Union until 1877.
In 1874, he became owner and editor of the ' ' Congregational
Quarterly ", which publication ceased in 1878. In 1879, he was
Treasurer of the Massachusetts Home Missionary Society in Boston.
Children : i. Christopher Choate, b. in Boston, 13 July, 1848 ; d. in
Cambridge, 26 April, 1869. ii. Mary Francis, b. in Derry, N. FL, 2 Nov.,
1851 ; m. in July, 1889, Rev. H. H. Haynes. iii. William Choate, b. in
No. Brookfield, 17 July, 1853 ; d. 30 Sept., 1853. 681. STEPHEN 7
CUSHING (Joseph u Pickels 5 Joseph M John2 Matthew1 ) was born
in Scituate, Mass., 17 Jan., 1797. He married, 1 Feb., 1824, Ethalinda
Edwards. Settled in Uowell, Mass.
 CUSHING FAMILY 3 6 5 Children : i. Minerva, b. 16 Nov.,
1S24; m. in 1872, Alvah Crocker, of Fitchburg, Mass. ii. Willard, b. 14
Dec, 1826 ; d. 26 May, 1S28. 1097. iii. Oliver Edwards, b. 12 March,
1829. 1098. iv. Akgeline, b. 10 Jan., 1832. 1099. v. Ethalinda, b. 14
Aug., 1834. vi. Dezia Howlitt, b. 20 Nov., 1S40 ; d. 2 July, 1855. vii.
Helen, b. 15 July, 1843. 682. MATILDA 7 CUSHING (Joseph 6 Pickels
5 Joseph4-3 John2 Matthew1) was born in Scituate, Mass., 29 Nov.,
1 80 1. She married, 7 Nov., 1824, David, son of David and Mary
(Fearing) Burr, He died 21 June, 1852. Matilda died in Hingham, 18
Aug., 1884. David wras a cooper and farmer. Resided on Deavitt St.,
Hingham. Children • i. David (Burr), b. 26 Dec, 1825 ; m. 23 Nov.,
1847, Sarah A. Colbath. ii. Joseph, b. 1 Aug., 1827. iii. Matilda
Cushing, b. 4 Nov., 1S31 ; m. 14 Nov., 1858, David B. Burbank, of
Candia, N. H. iv. Elisha, b. 15 May, 1839 ; m. 21 Feb., i860, Mary
J.Pratt, of Cohasset, Mass. 683. ANNA7 CUSHING (Joseph 'J Pickels'
Joseph4"3 John2 Matthew ' ) was born in Scituate, Mass , 20 Jan.,
1809. She married, in 1828, Nichols Litchfield, of Hingham. He was
born 18 July, 1805, and died 23 April, 1879. He was a shipwright by
occupation. Removed to East Boston, and thence to Holliston, Mass.,
where he died. Children, born in Hingham : i. Lawrence (Litchfield).
ii. Mary Cressv ; in. Donald McKay, of East Boston, iii. Abigail S. iv.
Allyne Cushing, b. 15 July, 1S35. Served in the Civil War. In 1871,
was consul-general at Calcutta. v. Myra Howe ; in. George S. Merrill.
 36 6 THE GENEALOGY OF THE 684. MARTIN7 CUSHING
(Joseph6 Pickels5 Joseph4"3 John2 Matthew1) was born in Scituate,
Mass., 9 July, 1810. He married Laura Holt. Child, born in Lowell,
Mass : i. Laura A., b. 3 Nov., 1841 ; m. in So. Scituate, 27 April,
1862, Henry Turner, who was b. 29 Jul}1, 1836. 685. AIXYNE7
CUSHING (Joseph6 Pickels5 Joseph4-' John2 Matthew1) was born in
Scituate, Mass., 9 Dec, 1812. He married, first, 15 Jan., 1835, Sarah,
daughter of Elijah Damon, of Scituate. She was born in Scituate, 15
Oct., 1814, and died in Hingham, 20 March, 1872. He married,
secondly, 30 Aug., 1874, Mrs. Mary B. (Gilman) Nichols, widow of
Alfred Nichols. Allyne dishing died 14 Aug., 1884. He was a
carpenter, and resided on Water St., Hingham. Children, all by his
first wife : i. Sarah Ann, b. 27 Oct., 1836 ; m. 1 Nov., 1869, William
H. Seale. Had a son, William, b. 14 Dec, 1S70; d. same day. ii.
Maria, b. 29 Jan., 1838. iii. Henry, b. 19 Feb., 1839 ; d. at So.
Scituate, 20 April, 1854. iv. ELLEN, b. 17 March, 1840; m. William
Fillebrown. v. Abby Iv., b. 6 July, 1842 ; m. Samuel L. Groce, of
Cohasset, Mass. vi. Irene, b. 10 March, 1844 , d. 9 Jan., 1845. vii.
Irene, b. 14 April, 1845 ; d. at Boston, 14 May, 1872. viii. Hosea, b.
20 Sept., 1846; d. 21 Aug., 1847. ix. Hosea, b. 21 Dec, 1847. x.
Elijah D., b. 30 Sept., 1850 ; m. (1) 18 June, 1874, Abbie F.,
daughter of Thomas and Elmira R. (Reed) King. She d. 15 Nov.,
1876. He m. (2) 5 July, 18S0, Josephine Estella, daughter of
Nathaniel Scott and Sybil (Gardner) Sylvester. She was b. in
Hingham, Aug., 1858. Elijah Cushing d. 5 Oct., 1888.
 CUSHLNG FAMILY 36 7 noo. xi. Martin, b. 24 Feb., 1852. xii.
Joseph, b. 18 Jan., 1854 ; d. 25 Oct., 1854. xiii. Josephine, b. 7
March, 1855 ; d. 5 Sept., 1855. xiv. Euyilla Josephine, b. 10 March,
1856 ; d. 1 April, 1857. xv. Euyjlla Josephine, b. 21 July, 1858 ; d. at
Somerville, iS Jan., 1877. 686. ELIZA ~ CUSHING (Pickels « Joseph
*"3 John Matthew ' ) was born 1 May, 1813. She married, 5 Nov.,
1834, Josiah, son of Isaac Bowen and Elizabeth (Torrey) Barker of
Hanson, Mass. He was a deacon in the church. She died 20 April,
1893. Children : i. Elizabeth (Parker), b. 28 Aug., 1835 ; d. 30 April,
1837. ii. Eliza Cushing, b. 5 Nov., 1S37 ; m. Rev. Josiah Ripley
Goddard, of Wingpo, China, iii. Isaac Bowen, b. 25 Nov., 1S39 ; d.
22 March, 1875. iv. Albert Smith, b. 31 March, 1843. v. Mary
Elizabeth, b. 26 Jan., 1847 ; m. Rev. Joseph Brown Reed, vi. William
Torrey, b. 14 Feb., 1S51. vii. Lydia Holmes, b. 12 March, 1S57 ; m.
Arthur H. Olmsted. 687. LYDIA KING 7 CUSHIXG (Pickels '- Joseph 4;
John -' Matthew ' ) was born 22 April, 18 16. She married, 18 July,
1841, Rev. Lewis Holmes, son of Peter and Mary (Harlon) Holmes, of
Plymouth, Mass. She died 3 Oct., 1892. Children : i. Robert Cushing
(Holmes), b. iS Feb., 1S44 ; d.6Sept., 1844. ii. Lydia King, b. 5 Nov.,
1853 ; d. 1 March, 1854. 688. DEBORAH JACOBS8 CUSHIXG (Peter
Hawkes7 John ° Peter "' Stephen 4 Peter 3 Daniel 2 Matthew l ) was
born 25 Sept., 1823. She married, 3 Nov., 1844, William King Baker
of Litchfield, Me.
 3 6 8 THE GENEALOGY OF THE Children, born in
Weymouth, Mass : i. Fanny Lincoln (Baker) ; m. Parkhurst Burrell. ii.
HELEN Cushing ; m. George Clarke Vickery Cushing. He was b. 31
Oct., 1846, and d. at North Weymouth, 12 • Oct., 1904. iii. Andrew
William ; m. Eva Hender. iv. Elizabeth Jacob ; m. Francis Drown, v.
KATE Stone ; m. Charles Stevens, vi. Sylvia. vii. Charles. viii. Frank.
ix. Grace Thaxter, b. 1865 ; m. Dr. Charles W. Garey, of Quincy,
Mass. 689. PETER 8 CUSHING (Peter Hawkes 7 John G Peter 5
Stephen 4 Peter 3 Daniel 2 Matthew l ) was born in Weymouth,
Mass., 7 July, 1827. He married, 2 Nov., 1854, Emma Shackford of
Boston. Lived in Weymouth. Children, born in Weymouth : 1101. i.
Frederick Herbert, b. 30 July, 1855. ii. Mary Emma, b. 30 Sept., 1S60
; m. 23 Feb., 1884, Wallace H. Allen, of Litchfield, Me. They have 4
children. 690. CHRISTOPHER8 CUSHING (Peter7 Christopher6 Peter
'" Stephen 4 Peter 3 Daniel 2 Matthew 1 ) was born 1 May, 181 8.
He married Mary E. Fletcher. Died 14 Nov., 1867. He was a merchant
in Bath, Me. Children, born in Bath : i. Nancy Lee, b. 27 Sept., 1851
; m. P. P. Buckman, of Bath, ii. Christopher Samuel, b. 5 May, 1857.
Painter. Lives in Bath, iii. Jane Woodard, b. 5 June, 1859 ; m. 30
Aug., 1881, J. P. Given. Oue child, Albert C. iv. Peter Loring, b. 18
Sept., 1861. Lives in Brunswick, Me. 1 102. v. Ada May, b. 16 June,
1866.
 CUSHING FAMILY 3 6 9 691. SAMUEL WOODARD 8
CUSHING (Peter 7 Christopher G Peter 5 Stephen 4 Peter 3 Daniel 2
Matthew ' ) was born 27 July, 182 1. He married, 26 Sept., 1848,
Mary Ann Mereen. Moved from Uee's Island, to Bath, Me., in 1854.
Merchant of Bath. Children : 1103. i, William Lee, b. 24 July, 1849.
1104, ii. John Mereen, b. 26 Feb., 1S5 r . iii. Samuel Dayton, b. 30
March, 1853. Organist, Toledo. O. iv. Eleanor Philbrook, b. 27 Sept.,
1856. Graduated from Smith College, A.B., in 1879. Professor of
Mathematics, Smith College. v. Charles ElbridgE, b. ii Aug., 1863.
Graduated from Yale University in 1885. Lawyer in New York City, vi.
Jane Delia, b. 27 May, 1866. Graduated from Smith College in 18S9.
Teacher in Orange, N. J. vii. Frank Delano, b. 5 Dec, 1S71.
Graduated fiom Yale University in 1895. Mariner, New York City. 692.
SAMUEL ANDREWS8 CUSHING (Samuel Andrews 7 Ned u Peter 5
Stephen 4 Peter 3 Daniel 2 Matthew ' ) was born in Boston, Mass.,
21 Oct., 1845. He married, at Dorchester, Mass., 9 June, 1873, Sarah
Austin, daughter of Lemuel Clapp. She was born in Dorchester, 18
Feb., 1848. Children, born in Dorchester ; i. Austin Andrews, b. 9
March, 1874. ii. Robert Parsons, b. 11 June, 1877. Graduated from
Harvard College, B.S., in 1899 ; m. at Brookline, Mass., 4 June, 1903,
Florence W. Turner, of Boston. 693. THOMAS HANSON 8 CUSHING (
Peter 7 Thomas n Pc-ter r' Jonathan 4 Peter 3 Daniel2 Matthew1)
was born 26 Feb., 1805. He married, 10 Jan., 1847, CarolineTorr.
Died 6 May, 1868. He was a noted contractor and builder of railroads
and railroad bridges. He was of the firm of Cushing & Blake and of
Cushing, Woods & Co., on the Margretta and
 3 70 THE GENEALOGY OP THE Cincinnati R.R. He built
bridges on most of the railroads in his day. Also of the firm of
Cushing & Collins, on the Portland and Rochester R.R., and the
European R.R., east of Bangor, Me. He was the first contractor that
built a railroad bridge in the state of Illinois under a contract from
the State. Children : i. Hannah Augusta, b. 23 Oct., 1S48 ; d. 8
March, 1850. 1 105. ii. Thomas Edgar, b. in Dover, N.H., 29 Jan.,
1853. iii. Caroline Emma, b. 28 July, 1854 ; m. 12 Sept., 1877 John
H. Neally. They live in Dover, N. H. No issue, iv. Sarah Abby, b. 23
Oct., 1856; m. 10 Feb., 1S80, Dr. Douglas Malcolm, of Baltimore, Md.
No issue. 694. AUGUSTUS 8 CUSHING (William 7 Thomas '' Peter 5
Jonathan 4 Peter :i Daniel 2 Matthew l ) was born 15 Jan., 1811. He
married, 6 May, 1834, Rachel Taylor, daughter of Rev. Clement and
Rachel (Taylor) Parker, formerly of York, Me. He died 3 July, 1868.
Lived in Somersworth, village of Great Falls, N. H. Children : 1106. i.
Thomas A., b. 19 May, 1835. 1107. ii. John P., b. 20 Nov., 1847. '
695. JARVIS 8 CUSHING (William 7 Thomas B Peter 5 Jonathan 4
Peter J Daniel 2 Matthew l ) was born 20 Sept., 1816. He married,
16 April, 1841, Delia B. Holbrook of Bath, Me. She was born 22 July,
1819, and died in 1894. He died in Cambridge, Mass., in 1900.
Children : i. Mary E., b. in Charlestown, Mass., 12 July, 1842 ; d.
Oct., 1896. ii. Georgr E., b. in Bath, Me., 1 Nov., 1843 ; d. Oct., 1846.
iii. Frkderic E., b. in Bath, 20 Dec, 1844. Served in the Civil War.
The text on this page is estimated to be only 26.70%
accurate

CUSHING FAMILY 3 7 1 iv. Henrietta, b. in Cambridge,

Mass., 5 Jan., 1S46 ; d. April, 1S52. 1 108. v. Eli.kn I.., b. in
Cambridge, 9 July, 1847. 1109. vi. Aeonzo P>., b. in Cambridge, 3
Nov., 1S49. vii. Lena W., b. in Cambridge, 8 April, 1851. Lives in
Cambridge, Mass. ; unmarried, viii. Martha A., b. in Cambridge, 2
Dec, 1S52. Livesin Cambridge ; unmarried. 1 no. ix. Frankein P., b. in
Cambridge, 22 March, 1S57. x. EMMA J., b. in Somerville, Mass., 7
June, 1S62 ; d. Oct., 1S64. xi. Wiij.iam A., b. in Somerville, 8 July,
1S67 ; d. Oct., 1867. 696. NATHAN 8 CUSHING (William 7 Thomas'1
Peter"' Jonathan 4 Pe'.er ;i Daniel 2 Matthew l ) was boin 21 Feb.,
1818. He married Louisa Preseott of Dover, N. H. She was born
about 1822, and died about 1856. He died 25 July, 1854. Children :
i. Augustus Caeeb, b. Aug., 1S46 ; d. 1S62, in the Civil War. mi. ii.
Edwin F., b. 29 May, 1S48. 697. LUCY NELSON s CUSPIING
(Jonathan 7 Peter ""' Jonathan 4 Peter 3 Daniel - Matthew ' ) was
born 14 Ma}', 1828. She married in 1849, Hon. Francis D. Irving of
Cartersville, Va. Died 9 July, 1853. Children : i. Robert (Irving), b.
1851 ; d. in 1853. ii. Lucius Cushing, b. 30 June, 1853 ; d. unm. 7
Nov., 1889. 698. ELIZABETH HANSON 8 CUSHING (Jonathan Peter ~
Peter G"~' Jonathan 4 Peter 3 Daniel - Matthew 1 ) was born 14
Sept., 1831. vShe married at Fork of Willis, Va., 1 2 Jan., i860, Rev.
William C. Meredith of Winchester, Va. She died 14 Jan., 1865.
 3 7 2 THE GENEALOGY OF THE Children : i. Jonathan
Cushing (Meredith), b. 4 Jan., 1861. Is a lawyer in Kansas City, ii.
Lucy Page, b. 17 Sept., 1863 ; m. 9 Sept., 18S5, William C. Marshall,
of Fanquier Co., Va. 699. EMMELJNE 8 CUSHING (Elisha 7H5^ Daniel
3~2 Matthew1) was born in Hingham, Mass., 26 July, 1812. She
married, first, John Hollis of Braintree, Mass. ; and secondly, 3 Aug. ,
1845, John Adams Hollis of Braintree. He was born in Braintree, 14
Oct., 1805. She died 1 April, 1887. He was a boot-manufacturer.
Resided on Main St., corner of South St., Hingham. Children, by her
second husband, born in Braintree : i. John Cushing (Hollis), b. 14
Aug., 1846; m. 22 Oct., 1874, Mary G. Bassett. ii. Clara EmmeunE, b.
7 July, 1849. 700. JAMES H CUSHING (Elisha7^5"4 Daniel3"2
Matthew x ) was born in Andover, Mass., 26 June, 1818. He married,
15 March, 1849, Minerva Chaflin. Died 8 Sept., 1 884. He was of the
firm of ' ' Cushing & Bliss ' ' , Franklyn St., Boston. He had in his
possession the original family Bible of Matthew Cushing (No. 8)
printed in 1599. Child, born in Braintree, Mass. : i. Fannie M., b. 22
Oct., 1856. 701. ELIZABETH 8 CUSHING (Francis 7 Daniel Matthew1)
was born in Hingham, Mass., 18 June, 1816. She married in
Hingham, 12 Jan., 1834, John Pike. He was a rope-maker. Resided at
" Liberty Plain ", So. Hingham.
 GUSHING FAMILY 37 3 Children, born in Hinghatn : i. Sarah
Flizabeth (Pike), b. Aug., 1841 ; m. 21 Sept., i860, Melatiali Loring. ii.
Annie Frances ; m. 23 Sept., 1873, Webster H. Morey. 702. EDMUND
8 CUSHING (Francis 7 Daniel ^5"4-3-2 Matthew1) was born in
Hingham, Mass., 9 Feb., 1824. He married, 25 Nov., 1858, Sally S.,
daughter of Amos and Sally (L/tint) Poor. She was born in West
Newbury, 3 March, 1835. He was a harness-maker. Resided on Main
St., Hingham Centre. Children, born in Hingham : i. Lizzie Somerbv,
b. 16 June, 1863. ii. Fdmund Herbert, b. 18 Feb., 1865. 703. HENRY
s CUSHING (Francis7 Daniel ^-^ Matthew1) was born in Hingham,
Mass., 22 April, 1827. He married, 7 Dec, 1859, Almira, daughter of
Thomas and Almira B. (Reed) King. She was born in Hingham, 5
Sept. , 1 83 1 . He was a carriage-trimmer and harness-maker.
Resided on Main St., Hingham Centre. Children, born in Hingham : i.
Mira BELLE, b. 29 Nov., 1861. 1112. ii. Henry Francis, b. 24 Nov.,
1S63. iii. Carrie May, b. 19 Feb., 1868. 704. ELIZABETH LINCOLN 8
CUSHING (Samuel T Thomas 6 Ebenezer ' Daniel 4~3"2 Matthew l)
was born in Hingham, Mass., 1 May, 1818. She married, first,
Thomas, son of Bela and Olive (Wilder) Hobart. He was born in
Hingham, 9 March, 1817, and died 16 July, 1855. Was a setwork
cooper. She married, secondly, 4 April, 1858, Joseph Goold, widower.
She died 10 April, 1862. Resided on Main St., Hingham.
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