مرکزی صفحہ Journal of the History of the Neurosciences Origins of the Creutzfeldt and Jakob Concept

Origins of the Creutzfeldt and Jakob Concept

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Journal of the History of the Neurosciences
DOI:
10.1076/jhin.8.1.21.1771
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April, 1999
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Origins of the Creutzfeldt and Jakob Concept
Serge Duckett & Jan Stern
Published online: 09 Aug 2010.

To cite this article: Serge Duckett & Jan Stern (1999) Origins of the Creutzfeldt and Jakob Concept, Journal of the History
of the Neurosciences: Basic and Clinical Perspectives, 8:1, 21-34, DOI: 10.1076/jhin.8.1.21.1771
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Journal of the History of the Neurosciences
1999, Vol. 8, No. 1, pp. 21–34

0964-704X/99/0801-021$15.00
© Swets & Zeitlinger

Origins of the Creutzfeldt and Jakob Concept*
Serge Duckett1 and Jan Stern2
1Jefferson Medical
2

College of the Thomas Jefferson University, Philadelphia, PA
Queen Mary’s Hospital for Children, Carshalton, Surrey, UK

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‘Tout a été écrit mais pas tout a été lu’ (Raymond Garcin)
(Everything has been written but not everything has been read)

ABSTRACT
A review of the publications of Hans Creutzfeldt and Alfons Jakob pertaining to the concept which bears
their name (CJD) reveals that they described a neuropathological syndrome and were opposed to its classification as a neurological disease. The evidence on which Creutzfeldt and Jakob based their view is reevaluated, and studies by other workers are cited in which a range of environmental and genetic factors
generated the CJ syndrome, challenging the proposition that CJD is a disease with a single cause.
Key words: Creutzfeldt-Jakob disease, polioencephalopathy, cortical laminar necrosis, spongiosis.

INTRODUCTION
‘When an eponym such as Jakob-Creutzfedt is
given to a disease of unknown nature, it is essential that the clinical and pathological findings
in cases so designated must correspond exactly
with what these authors have described: to add
or detract will render their definition imprecise,
create confusion, hinder the spread of knowledge and delay the progress of research’. This
advice given by Nevin et al. (1967, p. 7) is relevant because the nosological entity described by
Hans Creutzfeldt (1920, 1921a) and Alfons
Jakob (1921 a,b,c, 1923, 1925) has given rise to
at least 84 different names (Masters, 1989),
from Creutzfeldt-Jakob disease (CJD), to further
names created recently for prion variants, and to
several different anatomical and clinical classifications (Kirschbaum, 1968; Rossum, 1968). It
has generated over 2500 publications, led to the
award of two Nobel prizes and attracted over a
40-year period an estimated $100 million in research funding. The bulk of this massive re*

search enterprise has been based on the proposition that the Creutzfeldt-Jakob concept relates to
a single disease with a single cause. Viruses and
abnormal prion proteins have been indicted.
This work has produced important biological
data and thought-provoking circumstantial evidence, but so far no cause has gained universal
acceptance.

BACKGROUND INFORMATION
Hans Gerhard Creutzfeldt (1887–1964) was a
clinician trained in neuropathology by Ludwig
Edlinger in 1912. From 1912 to1914 he worked
with Alois Alzheimer (1864–1915) at the University of Breslau (now Wroclaw, Poland).
From 1914–1919 he was a medical officer in the
German navy in the North Sea. During
1919–1920 he worked with Walther Spielmeyer
(1879–1935) in the Psychiatry Research Institute in Munich. He was appointed director of the
psychiatry and neurology clinic at the Christian-

Address correspondence to: S. Duckett MD, Laboratoire R. Escourolle, 47-83 Boulevard de l’Hôpital, 75651
PARIS Cedex 13, France. Tel.: +33 1 42 16 18 81, or +33 1 44 07 24 45. Fax: +33 1 42 17 60 61.

Downloaded by [New York University] at 09:34 04 August 2015

22

S. DUCKETT AND J. STERN

Albrechts University in Kiel (1938–1945), and
rector of its research institute in 1948. Creutzfeldt was a vocal anti-Nazi, intimately associated with the neuropsychiatrist Karl Bonhoeffer
(1868–1948), whose two sons and two sons-inlaw were executed by the Nazis. He refused to
join the Nazi party at his university, one of only
two, and is said to have denounced in the classroom Hitler and his associates as murderers. His
wife was sent to jail for the same offence. His
son Harald defected from the German navy and
joined the Dutch underground resistance. The
secret of Creutzfeldt’s survival was that during
WW II he served again as a medical consultant
to the navy in Kiel surrounded by WW I naval
companions now in high positions. Thus he was
protected by the ‘old boys’ naval club and remained in his function as director of the department of neurology and psychiatry where incidentally not one of his patients, mentally incapacitated or of a minority, was ever removed or
harmed (Lifton,1986; W. Creutzfeldt, private
communication, 1997).
Alfons Jakob (1884–1931) was a neuropathologist trained by Alzheimer in Munich in
1911–1912. He served as a medical officer in
the German army from 1914–1918. In 1918
Jakob was appointed director of the neuropathology laboratory at Hamburg University, a
position he held until his death, at age 47, in
1931. His laboratory had an international reputation. According to Bernard J. Alpers, Jakob’s
pupil and penultimate predecessor of one of us
(SD) as head of the neuropathology laboratory at
Jefferson Medical College, Jakob was a very
private and disciplined individual, an excellent
and knowledgeable teacher and charismatic
leader.
The head of the Munich clinic where Creutzfeldt and Jakob trained was Emil Kraepelin
(1856–1926), the leading German psychiatrist of
his day, appointed to that position in 1903.
Kraepelin’s great interest was dementia. Oscar
Vogt (1870–1959) and Cécile Vogt (1875–1962)
convinced Kraepelin that neurohistology would
be of great help in determining the aetiology of
dementia and that consequently he, Kraepelin,
should establish a neuropathological laboratory
with full-time staff, neuropathologists, techni-

cians, photographer etc, with adequate funding.
Kraepelin appointed his associate, Alzheimer, a
psychiatrist trained in neuropathology by Franz
Nissl (1860–1919), as its director. Nissl and
Korbinian Brodmann (1860–1918) were on the
staff at one time or other. In 1912 Alzheimer
took the chair of psychiatry at the University of
Breslau and he was replaced by Spielmeyer who
directed the laboratory until he was ousted by
the Nazis in 1935. He died that year and his
widow emigrated to England, invited there by
her husband’s pupils, where she committed suicide shortly afterwards.

THE STUDIES OF HANS CREUTZFELDT
AND ALFONS JAKOB
Creutzfeldt’s Case
Creutzfeldt was Alzheimer’s assistant in Breslau
when they first met a 22-year-old woman,
Bertha Elschker, hospitalized June 13, 1913,
with a rapidly deteriorating mental and neurological disorder the likes of which they had
never seen. They studied her clinically in the
greatest detail. She died August 11, 1913 and
following the postmortem examination Creutzfeldt with Alzheimer’s directorial approval decided to publish the case. However, in 1914
Creutzfeldt went to war, and a year later Alzheimer died. In 1919 Creutzfeldt joined Spielmeyer
in Munich as a visiting scientist and spent the
year preparing his two studies concerning B.
Elschker, both titled ‘‘On a Particular Focal
Disease of the Central Nervous System’’ and
delivered for publication on January 20, 1920
(Creutzfeldt, 1920, 1921a). Spielmeyer reviewed the neuropathological material and as
the director of the laboratory approved the publication. He graciously consented that the publications should indicate that they had emanated
from Alzheimer’s clinic in Breslau. These publications cautiously convey Creutzfeldt’s sentiment that he had possibly identified a hitherto
unknown medical entity. The introductory
phrase reads: ‘The present case report lays no
claim to giving a fully complete picture of a disease state’, followed by ‘the purpose of this publication, therefore, is merely to call attention to

ORIGINS OF THE CREUTZFELDT AND JAKOB CONCEPT

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a peculiar picture of a disease state’ (p. 1). The
reader is invited to consult the excellent translations published by Richardson (1989a,b) of
Creutzfeldt’s (1920) full original paper and of
Jakob’s (1921c) résumé of his cases.
Case history
The report concerned Bertha Elschker, born
on December 8, 1890, the youngest of five
children, two of whom were mentally retarded and institutionalized. Bertha had been
placed in a convent in 1899. In 1910 her gait
was remarkably awkward. She had been
treated at a dermatology clinic from June to
August 1912 for ‘hysterical exfoliative dermatitis’ affecting her hands, feet, face and
perianal region. It was noted that she had
spastic legs, patellar and ankle clonus responses, a positive Babinski response and a
generalized tremor. During the examination
she had a major hysterical attack with a ‘cautious’ fall, leg stiffness and opisthotonos. After the attack the stiffness of gait and spasticity could be made to disappear by ‘energetic’
prodding. In May 1913 her gait became increasingly unsteady and she showed signs of
dementia. She was admitted to Alzheimer’s
neurology clinic at the University of Breslau
in June 1913, where she was examined by
Creutzfeldt who noted paresis, spasticity, hypertonia, hyperreflexivity, bilateral Babinski
response, intention tremor, facial hyperkinesia and nystagmus. She was demented, incoherent with variable mood changes, echopraxis and echolalia.
The following paragraph is the translation
by Richardson (1989a) of the record of the
final days of this patient: ‘On August 6 a genuine epileptic attack occurs , beginning with
clonic jerking in the right arm, then involving
the right half of the face; on the left, relatively less severe contractions in the musculature of the shoulder, chest and face are the
only signs of involvement; towards evening,
a second attack, exactly similar to the first. In
the ensuing days, the patient lies in a severely
obtunded state, with constant cortical
twitchings which at times occur only on the
right and at times are bilateral; now and again

23

the twitchings appear to be more generalized,
quite like those seen in the epileptic attacks.
At about the same time, an erythema
multiforme bullosum makes its appearance in
the vicinity of the left ear, in an area closely
corresponding to the territory of the third division of the trigeminal nerve, the first signs
of which appear as herpetiform small vesicles
in the last hours, stupor deepens, swallowing
is impaired; death ensues on August 11, in
status epilepticus’ (p. 1).
According to Creutzfeldt’s résumé (1920)
the progression of the disease was as follows.
The first attack at age 20 consisted of mental
problems. In the second episode which occurred when she was 21, the patient presented
spastic symptoms and hysterical behaviour.
The last attack led to her admission and demise. There was considerable recovery between these attacks.
At autopsy there was bronchopneumonia,
diffuse bronchitis, gall stones, ovarian cyst
and erythema bullosum in and around the left
ear. The brain weighed 1375 g; the meninges
were moderately opaque, the lateral ventricles moderately dilated and small cortical
foci of degeneration were present in the preand postcentral gyri. The neuropathological
diagnosis was that of a poliencephalopathy
characterized by neuronal pathology and loss,
and tissue reaction particularly in the cerebral
cortex where the changes were focal and generalized, laminar in distribution affecting especially the third and deeper layers, with gliosis also affecting the basal ganglia, thalamus, cerebellum, brainstem and spinal cord.
In the words of Creutzfeldt: ‘‘With higher
magnification one recognizes that the transition from sound to diseased tissue is not always abrupt as the survey view leads us to
suppose. Instead, one finds here pathologic
changes in the tissue elements in this region
which suggest the possibility of determining
how the lesions arise.’’ ‘‘The pyramidal cells
in the third layer (Brodmann) are diseased’
(p. 19). The neuronal pathology is most apparent in the frontal lobe, less so in the other
lobes and grey tissue areas. There follows
here and later a lengthy description of the

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24

S. DUCKETT AND J. STERN

variety of abnormal presentations of the neurons, their nuclei and processes, including
ballooning, atrophy, intracytoplasmic and
intranuclear bodies and other features. ‘‘This
alteration of the ganglion cells is accompanied by progressive changes in the glia.’’
There follows a full description of the pathological glia. ‘‘Later the ganglion cell disappears, and in its place there remains a star- or
rosette-shaped syncytium.’’ The pathology of
neuronal processes is varied and includes
‘‘fusiform enlargements’’ (torpedoes). At this
point, ‘‘one may say that in the lesions the
neural parenchyma has disappeared in its entirety.’’ An extraordinary number of rod cells
appear ‘‘in all these lesions’’. Finally, ‘‘in
lesions which I should like to describe as old
scars’’ he describes the regressive changes,
the nuclear changes, the mitoses, ‘‘the phenomena of shrinkage and dissolution, retrograde degeneration’’ (pp. 19-21). He also
noted the important vascular contribution to
the reparative process lesions, and the neuronal pathology in the sensory nucleus of the
trigeminal nerve (Creutzfeldt, 1921a, Figs.
10, 11). Accumulations of small inclusion
bodies about 0.5-:m in diameter are illustrated in the cytoplasm of a cortical neuron
(Creutzfeldt, 1921a, Fig. 21), of a neuron in a
sensory ganglion (Creutzfeldt, 1921a, Fig.
26), of a thalamic neuron (Creutzfeldt, 1921a,
Fig. 30) without explanation. Spongiosis is
not described in the text.
In discussing the aetiology, Creutzfeldt excluded
infectious or toxic causes or ‘a hereditary affection in the narrower sense’, and yet he singled
out the recent appearance of the herpes zosterlike infection noted above. Herpes zoster infections of the nervous system had been recorded
since 1876 (Hardy, 1876; Rose et al., 1964) but
a zoster encephalopathy had not by 1920. We
suggest that there is evidence that Creutzfeldt’s
case, discussed here, may be the first such report. Since then there have been reports of zoster encephalopathy, the findings including cortical laminar necrosis and disseminated necrotic
foci throughout the CNS (McCormick et al.,
1969; Ruppenthal, 1980). In his summary

Creutzfeldt writes: ‘I have restricted myself to a
simple statement of the findings because I believe that in a single case all of the possible
manifestations of the disease group to which it
belongs cannot be developed, and primarily I do
not want, by ill-based attempts at interpretation,
to lead similar cases into all too narrow a track’
(p. 25). This ‘simple statement’ concerning the
discovery and the realization of the importance
of a major neuropathological syndrome amply
justifies its acceptance as an original and seminal masterpiece of pathological observation.
Creutzfeldt’s second publication (Creutzfeldt,
1921a) is an amplification of the first report. It
contains a daily journal of the last days of the
patient’s life and a remarkable dialogue between
a dying demented woman and a compassionate
physician.
Jakob’s Cases (Jakob, 1921a,b,c, 1923, 1925)
Jakob recognized at once the importance of
Creutzfeldt’s (1920) report and shortly afterwards he reported four similar cases (Jakob,
1921a,b,c,) and he gave the disorder afflicting
them a neuropathological rather than a clinical
name: ‘Spastic pseudosclerosis encephalopathy
with disseminated foci of degeneration’ (Jakob,
1921a). For our present study, this overlong title
is abbreviated to ‘spastic pseudosclerosis’. He
used this appellation because he believed that
this disorder, which clinically resembled multiple sclerosis and amyotrophic lateral sclerosis,
was in fact an extrapyramidal disorder similar to
Wilson’s disease (alias Westphal-Strümpell disease). In his second article, Jakob (1921b) described the same three cases in greater detail,
and this account was reviewed by Creutzfeldt
(1921b), see below.
Clinical presentations, cases 1,2,3
Case 1: Heinemann (1867–1919) a 51-yearold housewife was admitted to hospital in the
spring of 1918 for cramps, pain and weakness
of the legs, particularly the feet which had
troubled her for many years. She had lost her
son in April of that year and since then had
become very tired, forgetful, depressed and
dizzy. She had attempted suicide with carbon
monoxide (Kirschbaum, 1968, p. 36). After a

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ORIGINS OF THE CREUTZFELDT AND JAKOB CONCEPT

remission the problems in the legs recurred, a
spastic ataxic gait developed, arm and knee
tendon reflexes were exaggerated, ankle jerks
and abdominal reflexes absent. The blood and
CSF gave positive Wassermann reactions for
syphilis. The diagnosis was syphilis. In early
1919 her neurological and mental problems
increased. She was depressed, ataxic, hypotonic and eventually unable to walk. She had
aphonia, dysphasia, hemiparesis with bilateral positive Babinski responses. Clinically
and radiologically a syphilitic aortitis was
diagnosed. Again the blood Wassermann reaction was positive. Treatment with a mercury ointment was begun. Her condition
worsened rapidly. She became delirious, demented, disoriented, incontinent, restless,
drowsy. The diagnosis before her death in
May 1919 was depression with taboparalysis,
see below. The post mortem diagnosis was
syphilis, see below.
Case 2: Jendrosek (1886–1920), a 34-yearold female factory worker was transferred
from a general hospital in Hamburg (Eppendorf) to a state institution (Friedrichsberg),
May 7, 1920 with a diagnosis of dementia
praecox. She was an alcoholic and presumably had syphilis in earlier days. The patient
had been hospitalized three times in recent
months, the first time on February 28, for the
accentuation of a digestive illness, bowel and
bladder incontinence, gait disorder, dizziness
which she had experienced for a long time,
and the recent weight loss of 50 kg. She was
sent home on March 3. She was
rehospitalized ten days later on March 15 for
two weeks, because of the diagnosis of a gastric tumour, for which she refused surgery.
She was hospitalized again on April 12 for
eczema. At this time she presented with echolalia, auditory hallucinations, restlessness.
The diagnosis was dementia praecox and she
was transferred on May 7 to a state asylum as
noted above. She weighed 42 kg. Condylomata were present in genital and anal regions.
She had a broad-based gait, walked only with
assistance, had rigidity of the lower limbs, a
left positive Babinski response without spastic reflexes, a tendency to fall to the left. Ab-

25

dominal reflexes were absent. Her speech
was slow and monotonous. She had a rigid
facial expression, echolalia and a poor memory. She was confused and hallucinated. The
Wassermann reaction was negative in blood
but positive in the CSF. Towards the end of
her life she had epileptic attacks, and died on
May 27. The clinical diagnosis was dementia
praecox, then multiple sclerosis, and the post
mortem diagnosis was syphilis, see below.
Case 3: Ernst Kahn (1876–1919) a territorial army serviceman, age 43,was transferred
to a state psychiatry centre (Friedrichsberg)
on January 28, 1919 with the diagnosis of
taboparesis. His past medical history was
unremakable until early 1918, when he became ill while on military service in Rumania, with rheumatic symptoms, dizziness, attacks of weakness, digestive ailments. In May
1918 he presented with aching legs which
became weaker, vertigo, unsteady gait, illegible hand writing and loss of memory of recent events. He was confused and on neurological examination he presented with ocular
paralysis, ataxia, dysarthria, positive tendon
reflexes and bilateral Babinski responses. In
the three months which followed his hospitalization in January 1919 his neurological and
mental state deteriorated, he became more
anxious, confused and hallucinated and had a
speech disorder. Abdominal and tendon reflexes were absent. There appeared a muscle
atrophy of the lower limbs. The Wassermann
reaction was negative in blood, weakly positive in the CSF. He died of a myocardial infarct in March, 1919. At autopsy there was
found bronchopneumonia, an enlarged liver
and spleen. Jakob’s proposed diagnosis was
malaria, confirmed as follows: ‘‘Professor
Rocha-Lima looked at the spleen and liver
preparations and confirmed the diagnosis of
malaria’’ (Jakob, 1921b, p. 200), see below.
Neuropathology
The description of the neuropathological findings of the first three cases is similar to that of
cases 4 (Jacobsen) and 5 (Hoffert) discussed
below.

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S. DUCKETT AND J. STERN

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Jakob’s clinical presentation of his fourth case
(Jakob, 1921c)
Jakob’s third study on the subject contained a
résumé of his original three cases plus a fourth
case and his clinical and pathological conclusions. It is primarily an exposition of his interpretation of the ailments which affected his and
Creutzfeldt’s patients, namely, that it was an
extrapyramidal disorder similar to Wilson’s disease.
Case 4: Jacobsen (1869–1912) a mason was
admitted to a psychiatric hospital on January
13, 1912 with a diagnosis of bronchopneumonia and possible catatonia. He died 10 days
later. Jakob’s résumé of the medical history
of this case is described as follows (Richardson, 1989b): ‘‘Thus in this patient’s case we
are dealing with a 43-year-old man who, as
the son of a heavy drinker, was in earlier
years subject to alcohol abuse. In later years
he drank less and was reported not to have
drunk any alcohol at all in the last six months
before his illness. The disease began with
digestive disturbances, increasing weakness
of the legs, stiffness of the legs and an odd
disturbance of gait. The patient was unable to
mobilize his legs for walking, although there
was no actual paralysis. After a transitory
improvement (remission) in the neurologic
symptoms, he began having nocturnal states
of anxious dreams and in the hospital the outstanding features were the rigid facial expression, a periodic restlessness of the facial musculature, each definite evidence of paralysis.
At the same time there were pronounced pyramidal tract symptoms with absent abdominal reflexes. Periods during which the patient
lay quietly and rigidly in bed and returned to
behave more or less appropriately, alternated
with others that were characterized by anxious hallucinatory states of confusion. The
lability of the mental symptoms was striking.
Amid increasing restlessness and evidence of
fever and bronchopneumonia, death occurred
after a three-month period of evolution of the
more severe nervous and mental symptoms’’
(p. 44). The final diagnosis was possible
chronic alcoholism, see below.

Jakob’s clinical presentation of his fifth case
(Jakob, 1923)
In 1923 Jakob published a monograph on extrapyramidal diseases in which ‘spastic pseudosclerosis’ was prominently discussed. He
reported another case of ‘spastic pseudosclerosis’ (Hoffert).
Case 5: A. Hoffert was A 38-year-old
woman, who in December 1920 became confused, inattentive, restless and deluded at
about the same time that she suffered a severe
psychological trauma. Her previous medical
history was unknown. The diagnosis had at
one time been chronic epidemic encephalitis.
She then developed dysarthria, slow speech
and facial twitches. She was admitted to a
psychiatric unit in May 1921. Her neurological and mental state deteriorated. There was a
tremor of the head and the upper half of the
body, rigidity, loss of associated movements
and adiodokokinesia of the left arm. She had a
rigid facial expression, increased deep tendon
reflexes, positive Babinski and Oppenheim
reflexes. Blood and CSF Wassermann were
negative, but there was opacity in the CSF in
Phase I. The disease progressed, the tremor,
the muscular incoordination worsened, there
were myoclonic jerks and the patient was demented. She died on January 30, 1922.
Neuropathology of Jakob’s five cases (Jakob,
1923)
All five cases and Creutzfeldt’s case (1921a)
presented, according to Jakob, a similar neuropathological picture. This was a polioencephalopathy with preferential localisations in certain
gray areas characterised by its neuronal pathology, gliosis and, in the most severe cases, spongiosis. The morphology of the degenerating neurons was variable, from distended to atrophic.
The principal localization of this process was
found in the frontal lobes and in the anterior precentral gyrus with more or less severe changes
in the rest of the cortex affecting particularly the
deeper cortical layers. Other gray areas affected
were the striatum, the thalamus (medioventral
nuclear region, lateral nucleus), substantia nigra
and tegmentum of the pons, cerebellum, brainstem and spinal cord.

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ORIGINS OF THE CREUTZFELDT AND JAKOB CONCEPT

In his conclusion, Jakob acknowledged for
the first time that the term ‘spastic pseudosclerosis’ did not pertain to a single disorder as he had
originally proposed, but that it was an embracive
term to cover many diseases. ‘It is for the time
being undecided if these cases, histologically of
the same kind, belong aetiologically-nosologically together, and are perhaps somehow related
to encephalitis. For the time being they shall be
combined under the nonprejudicial designation
of spastic pseudosclerosis of uncertain aetiology. A symptomatically similar disease evolution is also found in the group of disorders Wilson-pseudosclerosis, and in disease processes
with severe changes in the blood vessels of an
arteriosclerotic or syphilitic origin. These cases
are demarcated from the above by the characteristics of the anatomical process (p. 245)’.
Diagnosis of Jakob’s five cases
As noted above the diagnosis in the first two
cases was syphilis, worded as follows: ‘Therefore we have perhaps to assume an earlier syphilitic infection in both cases.’ (Jakob, 1921b, p.
185). (‘So müssen wir in beiden Fällen vielleicht
eine frühere syphilitische Infektion annehmen.’)
The diagnosis in the third case (Ernst K) was
originally syphilis and it became malaria after
the post-mortem examination (Jakob,1921b,
p. 200). Later Jakob (1921c) worded his proposed diagnosis for Cases 1 to 4 as follows: ‘‘In
den ersten beiden Fällen sind gewisse ätiologische Hinweise auf eine eventuelle syphilitische Infektion gegeben. Im dritten Falle ist vielleicht mit einer chronischen latenten Malariainfektion zu rechnen. In meinem neuen Falle
muss ätiologisch der chronische Alkoholmissbrauch berücksichtigt werden.’ (‘In the first
two cases some indications of a possible syphilitic infection are given. In the third case one
may perhaps have to consider a chronic latent
malarial infection. In my new case chronic
abuse of alcohol must be taken into aetiologic
consideration.’) (see Jakob (1921c, p. 376) and,
in translation, Richardson (1989b, p. 45)).
The aetiology of the cases described by Jakob
The reader may well ask at this point – what was
the cause of the disorders afflicting these pa-

27

tients? Was it syphilis, malaria or chronic alcoholism? According to Jakob it was, his point
being that these diseases caused a similar neuropathological syndrome – ‘spastic pseudosclerosis’. His theory was that the bulk of the pathology in these different cases fell upon the extrapyramidal system (Jakob, 1927). To illustrate
his proposition he related in detail in his second
publication (Jakob, 1921b) the case of Dau, a
44-year-old merchant who had presented with
syphilis and amyotrophic lateral sclerosis
(ALS). ‘In this case (Dau) syphilis is established
and the only question is to what extent the later
occurring ALS is connected with the syphilitic
infection’. (‘In unserem Falle ist die Lues
sichergestellt, und es fragt sich nur, inwieweit
die später auftretende amyotrophische Lateralsklerose mit der syphilitischen Infection zusammenhängt.’) The interested reader is invited to
read this theoretical proposition set out in seven
pages of small print (Jakob, 1921b, pp. 202209).
Objections to Jakob’s Views
Creutzfeldt (1921b) reviewed Jakob’s second
article (Jakob, 1921b). He agreed with Jakob
that the neuropathological picture of their cases
was similar, but declared that now that he had
read Jakob’s more detailed descriptions and
analysis, he considered ‘spastic pseudosclerosis’
to be a non-specific neuropathological syndrome. He discarded Jakob’s evaluation and emphasis on the diagnostic importance of the clinical signs of their cases. Jakob was first and foremost a neuropathologist, not a clinician. Creutzfeldt states:
There are also serious reservations about the
expression pseudosclerosis spastica. The term
dates from a time when pseudosclerosis did
not have an anatomically secure basis, and as
a transfer of an anatomically closely delineated disease process to a clinically similar
disease pattern it is a not very attractive example of producing medical analogies and
names. Today we recognize pseudosclerosis
histopathologically and it is therefore no longer permissible to ascribe to it a fundamentally different disease process which histolog-

28

S. DUCKETT AND J. STERN

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ically has nothing to do with pseudosclerosis
(p. 321).
The name ‘spastic pseudosclerosis’ with its clinical implications, he said, was unfortunate and
anyhow the name was a conjunction of conflicting terms, an oxymoron. He concludes: ‘It is
best to do without a clinical label altogether as
the comparative diversity of the picture makes a
singular symptomatological name more difficult, while on the other hand the knowledge of
the characteristic histological findings guide us
securely and unambiguously’ (p. 322). He
named the neuropathological syndrome ‘degeneratio grisei focularis et diffusa progressiva’.
This was the last remark he ever published on
the matter that we could find in the literature,
during his life that would last for a further 43
years.
Creutzfeldt’s objections to Jakob’s shortlived attempted conceptualisation of ‘spastic
pseudosclerosis’ as a distinct nosological entity
were echoed by his clinical colleagues, particularly in England and France. There was no disagreement with the neuropathological assessment, but it was felt that there were too many
and varied clinical presentations for ‘spastic
pseudosclerosis’ to be considered a clinical entity. Thus, Jean Lhermitte and Douglas McAlpine (1926) wrote: ‘Undoubtedly the syndrome of
Creutzfeldt and Jakob possesses features, both
clinical and pathological which lend it considerable interest, but it is questionable whether one
can accept it as a definite clinical entity’ (p.
173).
Kinnier Wilson, Director of the Neuropathology Laboratory and Dean of the Institute of
Neurology, Queen Square, strongly objected in
meetings and in print to Jakob’s concept of
‘Wilson’s spastic pseudosclerosis’, to his persistent predilection for associating it with the disease that bore his name, and even to the name
‘spastic pseudosclerosis’. In both editions of his
textbook on neurology published in 1940 and
posthumously in 1955 he wrote:
A peculiar syndrome (spastic pseudosclerosis) on which cortical, pyramidal and extrapyramidal features seem to be conjoined has

been recorded on a few occasions during recent years. The clinical picture has varied
considerably and the underlying pathological
change also; in some examples the former has
edged off in the direction of amyotrophic lateral sclerosis, while now and again symptoms
referable to basal ganglia have been mild or
absent. For these and other reasons the status
of the syndrome is still sub judice and its recognition as an entity impracticable. The indeterminate character of the syndrome is not
such as to preclude its being reckoned a type
more or less sui generis, but at the same time
makes nomenclature difficult. As shown elsewhere, pseudosclerosis itself is a worthless
term, having nothing to commend it; hence
the addition of the adjective spastic merely
adds to the confusion, for it irrationally mixes
clinical and pathological notions (under no
circumstances can a sclerotic be spastic) apart
from the fact that the syndrome has nothing
whatever to do with hepatolenticular degeneration. (Wilson, 1955, p. 1044).
Wilson had voiced these views in the 1920’s,
Jakob (1925) pithily replied: ‘I agree with most
authors, especially S.A.K Wilson, that nearly all
problems in connection with it (‘‘spastic pseudosclerosis’’) are still unsolved’ (p. 596).
William McMenemey (1941), later director of
the pathology laboratory at the National Hospitals for Nervous Diseases, Maida Vale, wrote
that the ‘so-called CJD’ was a doubtful entity
which should be regarded as a syndrome rather
than a disease. He wrote: ‘It remains at present
a convenient dumping ground for several instances of atypical presenile dementias which
run a rapid course and have for their histology a
parenchymatous degeneration of the brain with
some glial hyperplasia’ (p. 60). This view was
shared by Alfred Meyer and colleagues (1954)
and considered justified by Jakob’s pupil
Kirschbaum (1968, p. 36).
The origin of the term CJD
Spielmeyer (1922) coined the term CreutzfeldtJakob disease. The phraseology he used to introduce that eponym and justify the term ‘disease’
was unusual:

ORIGINS OF THE CREUTZFELDT AND JAKOB CONCEPT

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The peculiar focal disorder of the cerebral
cortex reported by Creutzfeldt has not remained solitary. Clinically it is above all
characterised by spasms, hyperalgesias and
psychiatric symptoms. In his material studied
with exceptional care A. Jakob has discovered a whole series of cases of this disease.
Thus we may hope that the clinical and anatomical characteristics of Creutzfeldt-Jakob
disease (Jakob’s spastic pseudosclerosis) will
be well demarcated (p. 1818).
It is not possible to justify the use of the term
‘disease’ as Spielmeyer did on the basis of
‘hope’. Why did Spielmeyer, the dean of German neuropathology, a man of international renown authoritatively declare a neuropathological syndrome to be a disease when there was no
scientific reason to do so? The explanation may
be that there was a strong rivalry between the
neuropathological schools of Spielmeyer and
Jakob. Spielmeyer was promoting Creutzfeldt’s
original contribution to this concept, effected in
his department, because Jakob and his pupils
were clamouring that he, Jakob, had discovered
the syndrome, and that Creutzfeldt’s work was
anecdotal and published after he, Jakob, had
‘finished his studies’ (Jakob, 1921c). Spielmeyer’s generous gesture in creating this ‘disease’ was unfortunate because of his stature and
the confusion it eventually caused. Neither
Creutzfeldt nor Jakob ever used or permitted
their pupils to use the eponyms CreutzfeldtJakob disease or Jakob-Creutzfeldt disease
while they were alive.

JAKOB’S FINAL YEARS (1925–1931)
In April and May, 1924, Jakob visited New
York and Philadelphia where he gave the same
lecture (Jakob, 1925) on diseases of the extrapyramidal system with the same conclusions for
‘spastic pseudosclerosis’ as expressed in his
monograph (Jakob, 1923): ‘It is still an open
question whether these histologically similar
cases form a uniform etiologic-nosologic entity.
I have therefore put them into one group under

29

‘spastic pseudosclerosis’ of uncertain etiology.’
(Jakob, 1925, p. 601).
Jakob’s (1927) Study of Cortical Laminar
Necrosis (CLN)
Creutzfeldt (1920, 1921a) and Jakob (1923) had
described the presence of CLN in their six cases.
CLN is also present in cases listed by Kirschbaum (1968). Creutzfeldt and Jakob proposed
that the primary target in their neuropathological
syndrome was the neuron. Jakob (1927) wrote a
pivotal article on CLN in which he underlined
the presence of CLN in association with the CJtype polioencephalopathy of ‘spastic pseudosclerosis’ in a variety of infectious’, vascular
and genetic disorders, such as Huntington’s chorea and Wilson’s disease. Thus was suggested
the possibility that the same non-specific CJtype polioencephalopathy with CLN could be
caused by hypoxia, carbon monoxide intoxication, hypoglycaemia, metabolic diseases, cardiopulmonary deficiencies, epilepsy, and other adverse factors. CLN affects one or more laminae,
preferentially but not exclusively the third and
deeper layers, in one or more lobes of the cerebral cortex. Courville (1958) proposed a scenario for the progressive destruction of tissue in
CLN, similar to that proposed by Creutzfeldt
(1920) and Jakob (1921c). They agreed that the
pathological process begins with a loss of neurons, followed by gliosis and sometimes spongy
changes in late stages, and later on by softening
of tissue with residual vascular scar, finally by
total necrosis and destruction of tissue. The
quality and the extent of the necrosis in the cortex as in other gray areas depends on the intensity, identity, speed and localisation of the insult
and thus governs the variability of the clinical
manifestations. CLN is a pathological process
presenting a succession of variable morphological pictures each of which represents an instant
event in the advancing necrotic process
(Creutzfeldt, 1920; Jakob, 1923; Courville,
1958). Thus the morphology of CLN seen by an
observer varies from case to case and depends
on the chronological and histological stage of
the necrotic process examined. CLN was described in a 13-year-old girl by Weir Mitchell

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30

S. DUCKETT AND J. STERN

(1860), reported in the syphilitic brain by Lissauer (1892) and first systematically studied in
a variety of diseases by Köppen (1896, 1898).
CLN has a variety of German, English and
French names. The history of the evolution of
the CLN concept is recounted by Courville
(1958). Two theories were eventually proposed
to explain the characteristic laminar distribution
of the lesion in the cerebral cortex. Proponents
of the vascular theory (Spielmeyer, 1925;
Scholz, 1926) opined that the laminar distribution of pathology corresponded to the pattern of
the capillary distribution in the cortex, and that
it represented morphological anomalies or a
functional disturbance in capillaries, which impeded the transport of blood, and thus oxygen to
neural tissues. Thus was enunciated the view
that the destruction of the neurons in CLN was
caused by ischaemia and this was supported by
an important body of clinical observations (for a
review see Courville, 1958). The ‘pathoclisis
theory’ proposed by Vogt & Vogt (1922), discarded at one time but recently resuscitated,
stated that different types of neurons in diverse
areas of grey matter have disparate chemical
constitutions, receptors, transmitters which respond differently to other agents such as excitatory amino acids (Graham, 1992; Auer &
Benveniste, 1997). It now appears that both theories play a role in the pathogenesis of CLN.
Experimental and clinico-pathological studies
of human and animal cases brought support to
the theory that a CJ-type polioencephalopathy
including CLN could be caused by hypoxia.
Gildea & Cobb (1930) produced ‘mad cats’ with
varied clinical presentations and an ischaemic
polioencephalopathy including CLN by partially
strangling the cats. Lhermitte and Barrelet
(1934) and Alajouanine et al. (1936) reported
human cases with a polioencephalopathy, CLN,
dementia and assorted neurological manifestations caused by air embolisms during surgery
and vascular pathology. Courville (1958) cited
some 30 cases of polioencephalopathy with
CLN caused by hypoxia, drugs, respiratory and
cardiovascular problems, epilepsy, anaesthetics,
asthma and other agents. The first neuropathology reports to identify by name cases of the CJ
syndrome as caused by trauma, renal disease

and vasculopathies were published many years
later (Behrmann et al., 1962; McMenemey &
Pallis, 1962; Crompton, 1963; McMenemey et
al., 1965). This revolutionary proposition that
the CJ syndrome might not be a ‘single disease
with a single cause’ was short-lived because at
that time the proposition that CJD was caused by
a ‘slow virus’ became dominant.
The importance of CLN has been underlined
in the last decade by radiologists who with magnetic resonance imaging identified CLN, sometimes clinically unsuspected, in a variety of diseases afflicting all ages, such as CJD (Falcone et
al., 1992; Iwasaki et al., 1994), genetic and metabolic disorders (Knaap et al., 1993; Kinoshita
et al., 1996; Valanne et al., 1996) and hypoxia
(Takahashi et al., 1993). Concurrently, physiologists and biochemists established that the cause
of CLN could be any impediment to the delivery
of oxygen and/or glucose to the CNS and/or a
genetic or acquired defect in the energy metabolism of the brain.
‘Alpers’ Disease’ (Progressive Infantile Poliodystrophy)
This disease is briefly mentioned here because it
was described in children by Jakob (1930) and
his pupils (Freedom, 1927; Alpers, 1931), and
because the pathological picture resembles that
seen in the CJ syndrome to the extent that
Crompton (1968) proposed that Alpers’ disease
is CJD in children. The currently accepted view
is that Alpers’ disease is a mitochondrial disorder (Swick, 1989).
Spongiosis, Status Spongiosus, Spongiform
State
The terms spongiosis, spongiform change, status
spongiosus (Spielmeyer, 1920) are metaphors
used in neuropathology to describe distended
usually empty holes, cysts, spaces measuring >1
to 20:m in diameter, some say larger, closely
packed or dispersed in normal or pathological
gray or white matter. These holes may be extraor intracellular, in neurones, glial or other cells,
and in myelin (Jellinger 1970). Most neuropathology reports on their localisation are by electron microscopists who have observed that the
spongiosis in the CJ brain consists of focal dila-

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ORIGINS OF THE CREUTZFELDT AND JAKOB CONCEPT

tations in glial fibres (Marin et al., 1964; Gonatas et al., 1965) and/or dendritic fibres (Lampert,
1975) and vesicles, within which are sometimes
present membraneous debris (Bastian, 1991).
Gray (1986), on the other hand, produced experimental evidence to support his conclusion that
the spongiform changes he observed by electronmicroscopy in biopsies from four cases of
‘CJD’ were artefacts.
Spongiotic changes in the CNS were noted by
Probst (1903). Fischer (1911) was apparently
the first to use the term ‘spongiotic encephalopathy’, which he reported in cases of syphilis
(Lissauer type). Jakob (1923) described spongiosis in only one case (Hoffert). It is claimed by
Masters and Gajdusek (1982) that he missed
identifying spongiosis in Case 4 (Ernst Kahn)
but that it became evident when they destained
and restained his original histological sections.
Verification of this statement as well as a review
of Jakob’s material, histological slides, tissues
and photographs is now impossible. The entire
dossier of Jakob’s cases was borrowed in 1977
from Hamburg University and has not been returned (Professor D Stavrou, private communication, 1996). Because of the ubiquity of spongiosis in embedded tissues, interest then declined
but was rekindled decades later by the work of
‘the school of Maida Vale’ (Jones & Nevin,
1954; Nevin et al., 1960) and Jacob (1958) who
described disorders with polioencephalopathies,
CLN and extensive spongiotic changes in the
CNS similar to those in Heidenhain’s syndrome
(Heidenhain, 1929).
According to Kirschbaum (1971, p. 1414),
Lindenberg (1982) and others, histological spongiosis has no pathognomonic significance particularly in paraffin-embedded material. The
reasons are many. Artefactual spongiosis can be
caused by ‘post mortem ischaemic alterations’
the surgical act, improper and/or tardy handling
of tissues before and after fixation, lengthy
and/or inadequate fixation, the trauma and preparation of the tissue for histological examination. Brain has a water content of about 80 per
cent, higher in the grey matter than the white
matter. In the paraffin-embedding process, as
much water is removed as possible and replaced
by hot wax. After such treatment, some neuro-

31

pathologists question the significance of the
presence of ‘holes’, empty or not. Kirschbaum
(1968, p. 216) opines that status spongiosus is
reliably diagnosed in 10-15:m thick frozen and
celloidin sections stained with aniline dyes,
while artifacts caused by shrinkage make hazardous the distinction between sporadic holes in
thin paraffin sections. He asserts that status
spongiosus is incidental and exists in addition to
the basic pathology. It is a fact that in pathological tissue there is an ‘oedematous loosening of
the neuropil’, to use Lindenberg’s expression.
The problem is to separate conclusively real
from artefactual change in histological sections,
an important deontological and legal distinction
when diagnosing human material, but unattainable with present histological methods.
Kirschbaum’s Conclusions
Kirschbaum’s book (1968) is a detailed clinical
and neuropathological review of the first 150
purported cases of JCD, a term he preferred to
CJD because he felt that his mentor Jakob was
the major contributor to the elaboration of their
concept. Whatever the appellation, he states that
‘Jakob’s syndrome or disease is a neuropathological proposition’ (p. 210), and he concludes
that it is ‘still a doubtful nosologic category’ (p.
289).
In agreement with the original view of Creutzfeldt (1921b) referred to earlier (p. 7) and belatedly accepted by Jakob, Kirschbaum (1968, p.
228) concludes: ‘Multiple causative factors lead
to the particular changes of the JC type. The
available neuropathological information supports the conclusion that JC disease is not a unified disease concept. One is justified to subgroup tentatively, according to predominant
localisation with or without spongiosity.’
The last phrase of his book which concerns
the elucidation of the CJ concept, reads as follows: ‘The recognition of various clinical types,
transitions and histopathological characteristics
is only the first step in distinguishing the pathogenetic factors. The prospect of defining the
different causes and their therapy lies with clinical, microscopic, chemical and experimental
research’ (Kirschbaum, 1968, p. 289).

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S. DUCKETT AND J. STERN

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CONCLUSIONS
The merit of Creutzfeldt and Jakob was to have
recognized and singled out a particularly important neuropathological syndrome from the then
obscure mass of neuropathological observations,
as Charcot (1868) had done, when he singled out
multiple sclerosis from a mass of unidentified
demyelinating pathological presentations. In this
task they were aided and encouraged by their
mentors Alois Alzheimer and Walther Spielmeyer.
Creutzfeldt and Jakob concluded that they
had described a neuropathological syndrome
associated with many disorders, rather than a
disease, a concept subsequently discarded in
favour of the alternative explanation that their
syndrome concerned a disease with a single
cause, be it viruses or abnormal prions, both still
the subject of unresolved discussions (Aguzzi &
Weissmann, 1997; Chesebro, 1998). Modern
investigative techniques, such as in vivo neuroimaging, immunocytochemistry, transmissibility
studies and molecular genetic analysis have led
to a reappraisal of the CJ neuropathological syndrome. It soon became apparent that the syndrome can be generated by a number of pathogenetic mechanisms. Prions are involved in some
of these mechanisms but their role is as yet not
fully understood. However, the contention of
Creutzfeldt and Jakob that their concept does not
pertain to a disease with a single cause still appears vindicated.

ACKNOWLEDGEMENTS
We thank Arthur K. Asbury, Richard G. Berry, John
Cavanagh, Richard A. Chambers, W. Creutzfeldt,
Charles Duyckaerts, Reinhard Friede, Hans Goebel,
N. Gonatas, J. J. Hauw, Jean Lapresle, G. Pilkington,
Lucy Rorke, Gérard Said, J.G. Scadding, Danielle
Seilhean, M. Spranger, and Margaret Triggs, for comments, translations, corrections, help and advice (occasionally contradictory), also Mme V. LerouxHugon, Hôpital de la Salpetrière, Paris, and the staffs
of the Bibliothèque de la Faculté de Médicine, Paris,
and of the Royal Society of Medicine, London, for
patiently tracing rare publications essential for our
study.

A preliminary report of this study was presented at
the meeting of the British Neuropathological Society
held in London, January, 1998 (Duckett & Stern,
1998).

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