Handbook of Clinical Neurology, Vol.

82 (3rd series)
Motor Neuron Disorders and Related Diseases
A.A. Eisen, P.J. Shaw, Editors
© 2007 Elsevier B.V. All rights reserved

Chapter 1

Historical aspects of motor neuron diseases

ANDREW A. EISEN*
Vancouver General Hospital, Vancouver, BC, Canada

Systematic, statistical classification of diseases dates in the work of some of his well-known students, amongst
back to the 19th century. Groundwork was done by early them Alfred Binet, Pierre Janet and Sigmund Freud
medical statisticians William Farr (1807–1883) and (Ekbom, 1992). He was a professor at the University of
Jacques Bertillon (1851–1922). Nevertheless, these clas- Paris for 33 years, and in 1862 he began an association
sifications largely ignored many neuromuscular diseases with Paris’s Salpêtrière Hospital that lasted throughout
which were lumped together in what today would be his life, ultimately becoming director of the hospital. In
regarded as a confused fashion. It was not until the 1882, his focus turned to neurology, and he has been
International Health Conference held in New York City called by some the founder of modern neurology. He
in 1946 entrusted the Interim Commission of the World established a neurological clinic at the Salpêtrière that was
Health Organization with the responsibility of preparing unique in Europe, and in so doing established the
a sixth revision of the International Lists of Diseases and bases for a neurological classification which have endured
Causes of Death that a semblance of neuromuscular clas- (see Fig. 1.2). He described multiple sclerosis [The
sification evolved. combination of nystagmus, intention tremor and
This can be contrasted with knowledge about move-
ment disorders, and in particular Parkinson’s disease
which was clearly recognized in ancient times with
descriptions to be found in the Bible, and the ancient
writings of Atreya and Susruta. In addition, classic texts
provide information on historical personages, including
the dystonia of Alexander the Great (Hornykiewicz, 1977;
Keppel Hesselink, 1983; Garcia-Ruiz, 2000). On the other
hand Alzheimer’s disease was only recognized as such in
1911 (compared to ALS in 1865), when Alois Alzheimer
published a detailed report on a peculiar case of the
disease that had been named after him by Emil Kraepelin
in 1910 (Alzheimer, 1991; Alzheimer et al., 1991, 1995).
Achucarro, who had studied with Alois Alzheimer at his
Nervenklinik in Munich, Germany described the first
American case of Alzheimer’s in a 77-year-old in 1910
(Schwartz and Stark, 1992; Graeber et al., 1997).

1.1. Charcot and early descriptions of amyotrophic

lateral sclerosis (ALS)

Jean-Martin Charcot was born in Paris, France, late in

1825 (Fig. 1.1). Although he was a 19th century scientist,
his influence carried on into the next century, especially Fig. 1.1. Jean-Martin Charcot 1825–1893.

*Correspondence to: Andrew Eisen, Professor Emeritus, ALS Clinic, Vancouver General Hospital #322 Willow Pavilion, 805 West
12th Avenue, Vancouver, BC V5Z 1M9, Canada. E-mail: [email protected], Tel: +1(604)-875-4405, Fax: +1(604)-875-5867.
2 A. A. EISEN
scanning or staccato speech, Charcot’s triad, is some- In his time, he was both highly respected and chastized
times but not always associated with multiple sclerosis] as a third-rate show-off. His scientific career was a
(Charcot, 1879). He attributed progressive and acute continuous mixture of rigorous clinical neurology
muscular atrophy to lesions of the anterior horns of the (including detailed descriptions of amyotrophic lateral
spinal cord and locomotor ataxia to the posterior horn sclerosis, Parkinson’s disease, brain anatomy, etc.) and
and spinal root. He gathered together the data leading to uncontrolled, controversial and sometimes even theatri-
the description of amyotrophic lateral sclerosis as is dis- cal experiments in the field of hysteria. Charcot’s fame
cussed below. was as much the result of the unquestionable quality of
In 1873 he replaced Dr Alfred Vulpian (see Fig. 1.3) his scientific work as that of his theatrical presentations.
as the Chair of Pathological Anatomy which he held for In the arts as in politics, he was more of a conservative
a decade. He added histology to macroscopic anatomy than an opportunist; authoritarian, shy, and brusque,
and undertook the exploration of the enormous gloomy and taciturn, he nonetheless had a remarkable
resources in pathology at Salpêtrière (Bonduelle, 1994, power to attract.
1997). In the study of ‘Localizations of diseases of the Charcot’s understanding of ALS evolved over a
spinal cord (1873–74)’ he specified the anatomy and decade and was based on amazingly few patients (Goetz,
physiology of the cord and subsequently cerebral locali- 2000; Pearce, 2002). At the time of Charcot’s descrip-
zations of motor activities, both integral to his and tions of ALS, primarily 1850 to 1874, clinical diagnosis
our understanding of amyotrophic lateral sclerosis was rudimentary and the distinction between upper and
(known as Charcot’s disease before it popularly became lower motor neurons had not yet been made, and there
Lou Gehrig’s disease) (Bonduelle, 1994, 1997; Goetz, was no understanding of the role of the corticospinal
1994, 2000). tract in connecting them (Goetz et al., 1995). The earli-
An eminent scientist, Charcot was recognized as one est description of ALS (1865) was that of a young
of the world’s most prominent professors of neurology. woman whose deficit was restricted to the upper motor

Fig. 1.2. Saltpêtrière in 1882, the year that Charcot turned his thoughts to neurology.
 HISTORICAL ASPECTS OF MOTOR NEURON DISEASES 3
occurred independently of each other, which is the
general consensus. Eisen and Krieger (1998), however,
have adduced physiologic evidence that reinforced
Charcot’s ideas about the significance of upper and
lower motor neuron pathology.
His clinico-pathological observations led Charcot to
believe there was a two-part motor system organization.
Anterior horn cell disease resulted in weakness with
atrophy, and sclerosis of the lateral columns produced
spasticity with contractures (Charcot, 1880). Charcot
was not the first to describe cases of ALS, but did coin
the term amyotrophic lateral sclerosis (Rowland, 2001).
Charles Bell and others reported cases as early as 1824.
Having distinguished the motor functions of anterior
spinal nerve roots and the sensory functions of the
posterior roots, Bell was interested in finding patients
with purely motor disorders (Goldblatt, 1968). By mid-
century there were fiery debates among famous neurol-
ogists. Among the syndromes characterized by limb
weakness and muscle atrophy, they ultimately came to
separate neurogenic and myopathic diseases. It was not
clear whether some syndromes were variants of the
same condition or totally different disorders; this puzzle
included progressive muscular atrophy, progressive
bulbar palsy, primary lateral sclerosis and ALS.
Fortunately Charcot’s thoughts were also recorded
Fig. 1.3. Alfred Vulpian who preceded Charcot as Professor in English translations of the Tuesday Lectures at the
of Anatomy at Saltpêtrière. Hôpital de la Salpêtrière (references cited by Rowland
(2001)) and in translation by George Sigerson, who
included the essential concepts of Charcot’s ALS lec-
neurons (in fact more likely primary lateral sclerosis). tures in English and Goetz has brought the translations
She had been thought to be suffering from hysteria. up-to-date (Goetz, 2000). The Tuesday Lectures also
Autopsy showed ‘sclerotic changes limited to the lateral exemplified Charcot’s zest for theatrical performance.
columns of the spinal cord’ (Charcot, 1865). Four years For example, during one lecture of 1888, Charcot said:
later (1869), in a series of papers written together with ‘(To the patient): Give me your left arm. (Using a pin,
Joffroy, Charcot reported cases of infantile and juvenile M. CHARCOT pricks at different points the arm and
spinal muscular atrophy in whom the lesions were the hand...).’ Charcot followed this performance with
restricted to the anterior horn cells (Charcot and Joffroy, another test, explaining to the audience as he did so
1869a,b,c). Further clinical studies revealed a combina- that: ‘You see that I am pulling the patient’s finger, even
tion of upper and lower motor neuron signs which led a little brutally perhaps, without her suffering at all
Charcot to coin the term ‘amyotrophic lateral sclerosis’ [sans qu’elle éprouve rien]... .’ Turning to his subject, he
(Charcot, 1874, 1880). ‘We encountered several patients asked: ‘What am I doing to you?’ She replied: ‘I feel
with the following conditions: paralysis with spasms of nothing.’ The reality and authority of Charcot’s lecture
the arms and principally the legs (without any loss of demonstrations was largely guaranteed by the fact
sensation), together with progressive amyotrophy, which that they unfolded in real time before the audience
was confined mostly to the upper limbs and trunk’ (Goetz, 1987).
(Charcot and Joffroy, 1869c). Even though Charcot is credited as describing the
He thought the anterior horn pathology followed pathology of ALS, Cruveilhier (1853a,b) made an
and was caused by disease of the lateral columns essential contribution earlier, when he noted atrophy of
and drew a parallel with anterior horn cell pathology the anterior roots and suspected malfunction of the ante-
in multiple sclerosis, a concept not now in favor. rior horn cells. Charcot knew of that work and compared
Gowers (1886) strongly contested Charcot’s notion that it with his own observations of anterior horn cell pathol-
ALS commenced in the descending motor tracts and ogy in infantile spinal muscular atrophy, poliomyelitis
argued that the upper and lower motor neuron lesions and other disorders characterized by muscular atrophy.
4 A. A. EISEN
The terminology of these cases was not clarified after the onset, all the symptoms have appeared and
for decades. Gowers (1886) is sometimes credited become worse. Death follows in 2 or 3 years, on
for introducing the term ‘motor neuron disease’ in average, from the onset of bulbar symptoms. This
1886–1888. However, that term must have come later is the rule but there are a few anomalies. Symptoms
because Gowers used only the terms chronic spinal may start in the legs or be limited to one side of the
muscular atrophy, ALS or chronic poliomyelitis. Brain body, a form of hemiplegia. In two cases, it started
(1933) may have been the first to use ‘motor neuron dis- with bulbar symptoms.
ease’; in the first edition of his textbook, published in
At present, the prognosis is grave. As far as I know,
1933. He gave ‘motor neuron disease’ as a synonym for
there is no case in which all the symptoms occurred and
ALS (without mentioning why he used the new name).
a cure followed. Is this an absolute block? Only the
It was 5 years after Charcot’s initial case report that
future will tell. Charcot, therefore, gave a complete pic-
he first used the term ‘amyotrophic lateral sclerosis,’
ture of ALS, emphasizing lower motor neuron signs in
which appeared in the title of the paper (http://clearx.
the arms and upper motor neuron signs in the legs. His
library.ubc.ca:2796/cgi/content/full/58/3/512-REF-
description of the natural history, lamentably, has not
NHN7430-1; Charcot, 1874). In part IV of that series,
changed much in ensuing years. He described the
he recorded more observations that have become stan-
bulbar syndrome in detail. He described clonus and he
dard teachings: Amyotrophic paralysis starts in the
may have been the first to use the term ‘primary lateral
upper limbs as a cervical paraplegia. After 4, 5, 6
sclerosis.’
months or more, the emaciation spreads and there is
Charcot’s own assessment of ALS was clearly
protopathic muscular atrophy, which advances for 2 or
stated: ‘I do not think that elsewhere in medicine, in
3 years. After a delay of 6 or 9 months, the legs are
pulmonary or cardiac pathology, greater precision can
affected…but the muscles are conserved and contrast
be achieved. The diagnosis as well as the anatomy and
singularly with the state of the upper limbs.
physiology of the condition “amyotrophic lateral scle-
There is no paralysis of the bladder. The patient has
rosis” is one of the most completely understood condi-
more difficulty walking and then cannot stand... After
tions in the realm of clinical neurology’ (Charcot,
some time, the patient has noticed that, in bed or sitting,
1874). Charcot died in 1893 in Morvan, France.
the legs sometimes extend or flex until a position is pro-
duced involuntarily …and the legs come to resemble a
rigid bar. The rigidity is exaggerated when the patient is 1.2. Notable names with ALS
held up by assistants who want to walk him. The feet
Because ALS is rare (an incidence of < 2 per 100,000)
take on a posture of equinus varus. This rigidity, often
the list of famous or household names of people that
extreme, affects all joints by a spasmodic action of
have or had the disease is rather short. Amongst these is
the muscle. The tremor interferes with standing and
David Niven, the English actor, Dimitri Shostakovich,
walking.
the Russian composer and Mao Tse Tung, the revolu-
He summarized the features of amyotrophic lateral
tionary leader of China. Nelson Butters was one of
sclerosis:
America’s most distinguished neuropsychologists of
(1) Paralysis without loss of sensation of the upper the last 25 years. He died from ALS in 1995 at age 58.
limbs, accompanied by rapid emaciation of the Like Stephen Hawking (see below), Dr Butters, toward
muscles... At a certain time, spasmodic rigidity the end made use of computers to communicate and
always takes over with the paralyzed and atrophic work. This permitted him to edit a major journal in
muscles, resulting in permanent deformation by neuropsychology, even when he could move only one
contracture. finger and then only one toe. With these small movements
(2) The legs are affected in turn. Shortly, standing and he used Email to write to colleagues everywhere –
walking are impossible. Spasms of rigidity are first usually on professional matters, but also to transmit
intermittent, then permanent and complicated at amusing academic gossip. However, the two names that
times by tonic spinal epilepsy. The muscles of the have had the most impact are Lou Gehrig (Figs. 1.4 and
paralyzed limb do not atrophy to the same degree 1.5) and Stephen Hawking (Fig. 1.6).
as the arms and hands. The bladder and rectum are Of all the players in baseball history, none possessed
not affected. There is no tendency to the formation as much talent and humility as Lou (Henry Louis)
of bedsores. Gehrig. It seems that Lou Gehrig demonstrated the
(3) In the third period, the preceding symptoms worsen characteristic ‘nice personality’ of so many patients
and bulbar symptoms appear. These three phases with ALS. His accomplishments on the field made him
happen in rapid succession – 6 months to 1 year an authentic American hero, and his tragic early death
 HISTORICAL ASPECTS OF MOTOR NEURON DISEASES 5
cooking, cleaning houses and taking in laundry to make
ends meet. His father, Heinrich, often had trouble find-
ing work and had poor health.
Gehrig’s consecutive game streak of 2,130 games
(a record that stood until Cal Ripken, Jr. broke it in
1995) did not come easily. He played well every day
despite a broken thumb, a broken toe and back spasms.
Later in his career Gehrig’s hands were X-rayed and
doctors were able to spot 17 different fractures that had
‘healed’ while Gehrig continued to play. Despite having
pain from lumbago one day, he was listed as the short-
stop and leadoff hitter. He singled and was promptly
replaced but kept the streak intact. His endurance and
strength earned him the nickname ‘Iron Horse.’ In 1938,
Gehrig fell below 0.300 average for the first time since
1925 and it was clear that something was wrong. He
lacked his usual strength. Teammate, Wes Ferrell noticed
Fig. 1.4. Lou Gehrig’s farewell speech.
that on the golf course, instead of wearing golf cleats,
Gehrig was wearing tennis shoes and sliding his feet
along the ground. Gehrig played the first eight games of
made him a legend. Gehrig’s later glory came from the 1939 season, but he managed only four hits. On a ball
humble beginnings. He was born on June 19, 1903 in hit back to pitcher Johnny Murphy, Gehrig had trouble
New York City. The son of German immigrants, Gehrig getting to first in time for the throw. On June 2, 1941, Lou
was the only one of four children to survive. Is it there- Gehrig succumbed to ALS and the country mourned.
fore possible that Lou Gehrig had hereditary ALS, but Eleanor, his wife, received over 1,500 notes and telegrams
that his siblings never survived long enough to develop of condolence at their home in Riverdale, New York.
the disease? His mother, Christina, worked tirelessly, President Franklin Delano Roosevelt even sent her
flowers. Gehrig was cremated and his ashes were buried
at Kensico Cemetery in Valhalla, New York.
Stephen Hawking was born on the 300th anniversary
of Galileo’s death. He has come to be thought of as the
greatest mind in physics since Albert Einstein. With
similar interests – discovering the deepest workings of

Fig. 1.5. Lou Gehrig. Fig. 1.6. Stephen Hawking.

6 A. A. EISEN
the universe – he has been able to communicate arcane 1.3. The first ALS gene
matters not just to other physicists but to the general
public. Charcot claimed that ALS was never hereditary. He
He grew up outside London in an intellectual family. clearly overlooked Aran’s (1850) cases published 20
His father was a physician and specialist in tropical dis- years earlier. As highlighted by Andersen (2003),
eases; his mother was active in the Liberal Party. He amongst Aran’s patients was a 43-year-old sea captain
was an awkward schoolboy, but knew from an early age presenting with cramps in the upper limb muscles and
that he wanted to study science. He became increas- subsequent wasting and weakness. He died within
ingly skilled in mathematics and in 1958 he and some 2 years of onset of his disease and most likely had ALS.
friends built a primitive computer that actually worked. Aran reports that one of the patient’s three sisters and
In 1959 he won a scholarship to Oxford University and two maternal uncles had died of a similar disease. It
in 1962 he got his degree with honors and went to seems that this was the first hereditary case of ALS. It
Cambridge University to pursue a PhD in cosmology. took another 143 years before the superoxide dismutase
There he became intrigued with black holes (first pro- gene (SOD1) was discovered to be associated with famil-
posed by Robert Oppenheimer) and ‘space-time singu- ial ALS (Rosen et al., 1993). Eleven missence mutations
larities’ or events in which the laws of physics seem to were found in 13 of 18 familial ALS (FALS) pedigrees.
break down. After receiving his PhD, he stayed at
Cambridge, becoming known even in his 20s for his 1.4. Western Pacific ALS
pioneering ideas and use of Einstein’s formulae, as
well as his questioning of older, established physicists. It is not the role of this chapter to discuss similarities
In 1968 he joined the staff of the Institute of Astronomy and differences between Western Pacific ALS and the
in Cambridge and began to apply the laws of thermo- disease elsewhere. However, the differences may be
dynamics to black holes by means of very complicated more apparent than real. Evidence indicates that ALS
mathematics. was prevalent on the island of Guam at least since 1815,
At the remarkably young age of 32, he was named a some 50 years before Charcot’s first descriptions
fellow of the Royal Society. He received the Albert (Lavine et al., 1991). Had Charcot been able to visit
Einstein Award, the most prestigious in theoretical Guam one wonders what he would have made of the
physics. And in 1979, he was appointed Lucasian disease. Although he described the pathology and
Professor of Mathematics at Cambridge, the same post clinical picture so accurately it seems strange that there
held by Sir Isaac Newton 300 years earlier. In 1988 was little reference if any as to its possible cause.
Hawking wrote A Brief History of Time: From the Big During the early years of American occupation of
Bang to Black Holes, explaining the evolution of his Guam (1898–1920) death certificates were written in
thinking about the cosmos for a general audience. It Spanish and there were frequent deaths attributed to
became a best-seller of long standing and established “paralytico” or “lytico” terms the Chamorro used for
his reputation as an accessible genius. ALS. The term ‘rayput’ or ‘bodig’ (slowness or lazi-
He remains extremely busy, his work hardly slowed ness) was used for Parkinsonism-dementia. The
by amyotrophic lateral sclerosis. “My goal is simple. It Western Pacific form of ALS has been of interest for
is complete understanding of the universe, why it is as over 50 years because its incidence, prevalence and
it is and why it exists at all.” mortality rates were initially 50 to 100 times those of
It is worthy and appropriate to mention one other ALS elsewhere. The male:female ratio approximated
name, that of Professor Richard Olney, who, at the time 2:1, the median age at onset was 44 years, familial
of writing, is in the terminal stages of ALS. It is impos- aggregation was recognized and ALS was associated
sible to imagine the nightmare of a neurologist, dedi- frequently with a Parkinsonism/dementia complex
cated to ALS developing the disease that has occupied (PDC) (Armon, 2003). Recently, the frequency of
his career. Richard, a personal friend of mine and many Western Pacific ALS has declined, implying a tempo-
of the contributors of this volume, started the ALS rary exposure to an environmental risk factor, possibly
Clinic at the University of California (San Francisco) in in a genetically susceptible population. This has fueled
1993. He was dedicated to the disease and care of decades of research and speculation.
patients suffering from it. He contributed considerably Marjorie Whiting, a nutritionist who lived with the
to the advancement of understanding ALS, especially Chamorros in Guam, became convinced that the disease
physiological aspects. He self-diagnosed the disease resulted from ingestion of the cycad nut used to prepare
about 2 years ago when on vacation he began stum- flour (Whiting, 1963). During the Japanese occupation
bling. There is no other recorded precedent of an ALS of Guam during World War II, many Chamorros fled
specialist developing the disease. into the forests and may have eaten more cycad flour
 HISTORICAL ASPECTS OF MOTOR NEURON DISEASES 7
than usual. However, there is at least one well recorded (Van den Berg-Vos et al., 2003). The issue is further
case of chronic cycad intake, without apparent harm, in complicated by early descriptions of primary muscle
Sergeant Soichi Yokoi of the Japanese Imperial Army. disease, especially Duchenne muscular dystrophy,
He was captured after 28 years as a fugitive in the jun- which were being published about the same time as the
gles of Guam and was wearing clothes that he had made first descriptions of spinal muscular atrophy. Tyler
himself from fibers he had peeled from the bark of a (2003) has recently reviewed the historical roots of
Pago tree. Such was the astonishing level of his self- Duchenne muscular dystrophy in the 19th century,
sufficiency that he was met with total disbelief until he citing early papers by Conte, Bell, Partridge and
explained to his captors how he was able to survive for Meryon through to the classic monographs of Duchenne
over a quarter of a century by living off the natural and Gowers. It is clear that a number of these cases
resources of the land. A principal part of his diet was turned out to be anterior horn cell disease and not
fadang. Remarkably, Sergeant Yokoi not only discov- primary muscle disease.
ered that fadang was edible but, astonishingly, devised a In 1850, Francois-Amilcar Aran described cases
way to prepare the nuts properly before cooking. He using the name “progressive spinal muscular atrophy”
lived to be 82, dying in 1997. (Aran, 1850). However, there had not been an autopsy
The cycad hypothesis was abandoned because two study of these patients and there was no clinical distinc-
similar clusters of neurodegenerative disease were tion between neurogenic and myopathic diseases,
found in remote indigenous populations in Japan and a notion that was yet to come. Aran was born in
Papua New Guinea, neither of whom seemed to eat Bordeaux, where he commenced his medical studies
cycad nuts. Also a good animal model never really but graduated in Paris. He published his first paper even
evolved (see Chapter 18). However, the cycad story before he had become MD, for which honor he deliv-
may have come back to life. It has now been suggested ered an inaugural thesis entitled Des palpitations
that the answer may lie in the Chamorro’s favorite du coeur, considérées principalement dans leur nature
entree: flying fox bats boiled in coconut cream (Cox et leur traitement (Aran, 1843).
and Sacks, 2002). The bats have been especially desir- He was active in the publishing of several journals,
able food items to the Chamorro, possibly because the among them Archives générales de médecine and the
tradition is one of few retained from older times before Union médicale, to which he was one of the most pro-
four centuries of upheaval and cultural oppression lific contributors, publishing both his own papers as
which began with Spanish colonial rule in 1565. They well as analyses of English works. As professor agrégé,
were served at weddings, fiestas, birthdays and the like. he held private courses of therapy at the École pratique.
The etiquette of bat-eating and preparation involves At the Hôtel-Dieu, as deputy to Léon Louis Rostand
rinsing off the outside of the animal like you would a (1790–1866), Aran’s clinical lectures were tremen-
cucumber and tossing it in boiling water. The animals dously successful. In the final years Aran preferably
are then served whole in coconut milk and are con- concerned himself with studies of materia medica,
sumed in their entirety. Meat, internal organs, fur, eyes while still a prolific writer. One of his papers was on
and wing membranes are all eaten. acute rheumatism, from which he himself had suffered
So why the dramatic decrease in incidence of ALS on repeatedly, and which caused his premature death on
Guam? Flying foxes are slow breeders, with females February 22, 1861, at the age of only 44 years. He left
needing to be 3 years old before they can successfully a large number of unfinished works, one of them a
give birth and rear babies. Then they rear only one young- Dictionnaire de thérapeutique, of which only the first
ster each year. Add this to the high death rate that is letters had been put on paper.
common in any young wild animal. In fact, numbers of Duchenne (Fig. 1.7) claimed equal priority to
flying foxes has dropped alarmingly towards extinction. describing spinal muscular atrophy. He had studied all
of Aran’s patients with electrical stimulation (Duchenne
1.5. Spinal muscular atrophies de Boulogne, 1851). However, it is not clear whether
Aran described Duchenne’s patients or vice versa.
The clarity with which Charcot was able to describe Duchenne’s bid for priority was based on a notice of
ALS was not matched by early descriptions of diseases 50 words, not a scientific paper. The announcement
that appeared to be restricted to the lower motor stated that, at a weekly meeting of the Academy (French
neuron, manifesting primarily by limb weakness. Academy of Science), he presented a collection of
This is hardly surprising when one considers that as papers, which he called ‘Recherches Electro-
recently as 2003 classification of lower motor neuron Physiologiques’ and which he intended to be used as
syndromes (including diffuse, proximal, distal and evidence by future commission of authorities that never
monomelic) is still very much under discussion left a record, if it ever existed. The ultimate compromise
8 A. A. EISEN
influenced by Dupuytren, presented his Thèse de
médecine, a monograph on burns.
However, Duchenne’s early years in medicine were
undistinguished. His interest in “electropuncture,”
recently invented by Magendie and Jean-Baptiste
Sarlandière (1787–1838), enticed him back to Paris where
he was met with a rather cool reception, being ridiculed
for his provincial accent and his coarse manners.
Duchenne was never offered, and never applied for, an
appointment at a Paris teaching hospital or at the uni-
versity. He was known under the name of Duchenne de
Boulogne to avoid confusion with Édouard Adolphe
Duchesne (1894–1869), a fashionable society physician.
Nevertheless, Duchenne was a diligent investigator and
meticulous at recording clinical histories. When neces-
sary he would follow his patients from hospital to
hospital to complete his studies. In this way he achieved
an exceptionally rich and exquisite research material.
Toward the end of his life Duchenne became estab-
lished and popular, paradoxically Jean-Martin Charcot
was amongst his friends, and they held each other in
considerable esteem. His clinical ability was such that
the great Charcot dubbed him ‘The Master.’ At this
stage of his career he had become an international
celebrity. Every month he gave several dinner parties
for his colleagues (Charcot, Pierre Paul Broca, Auguste
Nélaton and Edmé Félix Alfred Vulpian). During
these get-togethers histological slides were projected
and discussed – mixed with funny pictures to please
Duchenne’s grandchild. These were the first attempts
at muscle pathology. Duchenne was probably the
Fig. 1.7. Duchenne de Boulogne. first person to use biopsy procedure to obtain tissue
from a living patient for microscopic examination.
This aroused a deal of controversial discussion in
was the eponym ‘Aran-Duchenne’ syndrome for what the lay press concerning the morality of examining
we now regard as the broader categories of spinal mus- living tissues. In order to perform histopathological
cular atrophies. diagnostics Duchenne constructed a biopsy needle, which
Guillaume Benjamin Amand Duchenne descended made possible percutaneous muscle biopsies without
from a family of fishermen, traders and sea captains anesthesia.
who had resided in the harbor city Boulogne-sur-Mer in
Northern France since the first half of the 18th century. 1.6. Spino-bulbar muscular atrophy
He was predestined for a career at sea, as his father was (SBMA) – Kennedy’s disease
the commander Jean Duchenne who had been a ship’s
captain during the Napoleonic wars and expected his [I am most grateful to my friend and colleague,
son to follow in his keel waters. Professor William Kennedy for much of what is tran-
Despite his father’s efforts to induce him to follow the scribed verbatim from his records.]
family seafaring tradition, his love of science prevailed. In 1966 William Kennedy (Fig. 1.8) and co-workers
Duchenne went to a local college at Douai, where he described an anterior horn cell disease characterized by
received his baccalauréat at the age of 19. From 1827, X-linked inheritance, onset in the 4th and 5th decades
aged 21, he studied medicine under teachers like René- and with slow progression with predominantly proxi-
Théophile-Hyacinthe Laënnec (1781–1826), Baron mal spinal and bulbar muscle involvement and tongue
Guillaume Dupuytren (1777–1835), François Magendie muscle furrowing. They commented on the associated
(1783–1855) and Léon Cruveilhier (1791–1874). He features of gynecomastia, diabetes and absence of long
graduated in medicine in Paris in 1831 and, probably tract signs (Kennedy et al., 1966).
 HISTORICAL ASPECTS OF MOTOR NEURON DISEASES 9
marked and the lips protruded, but smiling was possible.
The voice was low pitched and gravelly. Word pro-
nunciation was poor. Sensation seemed normal.
Conduction hearing was decreased. There was bilateral
gynecomastia. The patient had been diagnosed with
diabetes at age 59.
Motor nerve conduction velocity was normal. EMG
showed scattered fibrillation potentials and giant motor
unit action potentials (MUAPs) in several muscles.
Muscle histology showed groups of atrophic muscle
fibers with small prominent groups of very large hyper-
trophic fibers with central nuclei and some basophilia.
He died of pneumonia at home at age 60. There was no
autopsy.
George’s father, Victor B, died at age 57. He had a
marked tremor at age 30. He was a farmhand until age
40 when he became too weak. He could ride a tractor
but could not mount or dismount alone. He needed a
railing to climb stairs. Rising from a chair required use
of his arms. George thought his father had had fascicu-
lations and a shrunken tongue. He was never hospital-
ized. There are no medical records. His possible
Fig. 1.8. Dr William Kennedy the year he described spinob-
involvement initially caused us much confusion.
ulbar muscular atrophy. On August 7, 1964, Robert G, age 68, of German
and Swiss descent, was referred for anterior horn cell
disease. Robert had generalized weakness, areflexia
“In July 1964, George B., age 57, entered my and the now familiar facies with fasciculations. NCV
(Dr Kennedy’s) office.” He was of French-Indian descent was normal. EMG showed very large MUAPs. Median
from a large family that lived on Grey Cloud island in the nerve sensory responses were absent. The patient and
Mississippi river. George complained of increasing gen- brother Alfred had been previously diagnosed by sev-
eralized weakness and pain, mainly in the neck and eral neurologists with primary muscular atrophy in
shoulders. As a youth he could run and work as well as 1951 and again in 1957. Alfred died in a university hos-
others. Since about age 35 he hadn’t felt strong. Muscle pital without autopsy. Brother William, with the same
cramps began in his chest, abdomen and calf and there disability, died of pneumonia in 1957. Robert died in
was twitching in his chin and shaking with his arms out- 1967. Robert’s wife requested that autopsy material be
stretched. Later he had definite weakness noticeable sent to me. There was marked reduction of anterior
when lifting objects over his head. Distal strength in his horn cells at all levels, but the cells of Clarke’s column
hands remained good. When George was 37, a neuropsy- and of the posterior horn were preserved. The anterior
chiatrist diagnosed primary muscular atrophy and com- spinal nerve roots contained fewer myelinated nerve
mented on the grooves in George’s tongue. Yet, from age fibers than expected as compared with the posterior
38 to 43 he worked in a slaughterhouse where he split spinal nerve roots. Muscle biopsy was identical to that
pigs down the back with a 16 lb cleaver. For about 20 of George B. Similar cases had been described earlier,
years cold weather had hampered fine motions such as but not fully appreciated (Kurland, 1957; Gross, 1966).
buttoning his shirt. At about age 54 he began to aid chew- It was not until the 1980s that the association of
ing by holding his chin up with his hands. At the same depressed or absent reflexes and small or absent sen-
time his voice changed pitch and began to be slurred. By sory potentials was described (Barkhaus et al., 1892;
1964 walking required great effort. Harding et al., 1982). In 1991 that genetic cause of
At examination muscle weakness was generalized, SBMA was identified by Albert La Spada and Kenneth
but more severe proximally. The gait was waddling. He Fischbeck as the expansion of a polymorphic CAG
could not walk on his toes, hop, squat or rise. Reaching repeat sequence in the first exon of the gene encoding
overhead and heelwalking were moderately weak. The the androgen receptor (La Spada et al., 1991).
biceps tendon reflex was depressed; all others were absent. Dr Kennedy was unaware that the disease he had
Large fasciculations were visible in the chin muscles. The discovered was given his name until it appeared as such
tongue was grooved and atrophic. Facial weakness was in a paper by Schoenen et al. (1979).
10 A. A. EISEN
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