Brain 2006 129(9):2233-2237; doi:10.1093/brain/awl230
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From the Archives
(1) A form of familial presenile dementia with spastic paralysis
(including the pathological examination of a case).
By C. Worster-Drought,
J.G. Greenfield and W.H. McMenemey.
Brain 1940: 63; 237–254.
Plates VIII–XII.
With (2) A form of familial presenile
dementia with spastic paralysis.
By C. Worster-Drought, J.G.
Greenfield and W.H. McMenemey.
Brain 1944: 67; 37–43.
Plate 1.
With (3) Subacute spongiform encephalopathy—a
subacute form of encephalopathy attributable to vascular dysfunction
(spongiform cerebral atrophy).
By S. Nevin, W.H. McMenemey,
S. Behrman and D.P Jones (From Maida Vale Hospital for Nervous
Diseases and the Brook Hospital, London).
Brain 1960: 83; 521–564.
Plates LXXIX–LXXXIII.
With (4) Creutzfeldt–Jakob
disease. The neuropathology of a transmission experiment.
By Elisabeth Beck, P.M. Daniel, W.B. Matthews, D.L. Stevens, M.P.
Alpers, D.M. Asher, D.C. Gajdusek and C.J. Gibbs Jr (From the
Department of Neuropathology, Institute of Psychiatry, The Maudsley
Hospital, London, S.E.5, The Derbyshire Royal Infirmary, Derby,
and National Institutes of Health, Bethesda, MD, USA).
Brain 1969: 92; 699–716.
With (5) Subacute spongiform encephalopathy
(Creutzfeldt–Jakob disease). The nature and progression
of spongiform change.
By C.L. Masters and E.P Richardson Jr.
(From the Charles S. Kubik Laboratory for Neuropathology, Massachusetts
General Hospital, and the Departments of Neurology-Neuropathology,
Harvard Medical School, Boston).
Brain 1978: 101; 333–344.
With (6) Creutzfeldt–Jakob disease virus isolations from
the Gerstmann–Sträussler syndrome with an analysis
of the various forms of amyloid plaque deposition in the virus-induced
spongiform encephalopathies.
By Colin L. Masters, D. Carleton
Gajdusek and Clarence J. Gibbs Jr (From the Laboratory of Central
Nervous System Studies, National Institute of Neurological and
Communicative Disorders and Stroke, National Institutes of Health,
Bethesda, MD, USA).
Brain 1981: 104; 559–588.
‘In 1933, under the heading of familial presenile dementia with spastic paralysis two of us described a case showing an unusual combination of dementia and spastic paralysis’. Subsequently, it became clear that two siblings and eight other relatives in three generations were affected. Now, Worster-Drought and colleagues report the autopsy findings of their original proband and bring up to date the clinical course in one affected sister. Charles G, an engine driver, developed a speech disturbance and started to lose cognitive functions at age 47: initially he was inert and apathetic with loss of memory, and had spasticity affecting the bulbar and limb muscles; later, the dementia and spasticity progressed and he became ataxic; finally, he was monosyllabic, uttering ‘fine’ in response to all questions, unable to walk and doubly incontinent prior to his death in March 1936, aged 54. His younger sister (MB) presented in 1933, aged 44, with impaired memory and altered behaviour: later, her speech became slurred and her gait unsteady; by 1940, she was apathetic with spasticity affecting the bulbar and limb muscles, and ataxic. Both cases had a modest increase in cerebrospinal fluid protein; and the sister had evidence for cerebral atrophy on air encephalography. Of the 10 affected family members, 7 had presented with paralysis and dysarthria, and 3 with dementia; each manifested both symptoms as the illness evolved. Death was invariably in the 50s, and disease duration around 8 years from onset. The family recognized their plight, and had made the observations that women are more usually affected and inheritance also occurs through the female line.
Autopsy in Charles G showed regional brain atrophy. The white matter was mottled and grey with reticulation due to minute cavities. Microscopic examination indicated widespread partial demyelination, especially in the corpus callosum, with evidence for myelin breakdown; overgrowth of neuroglial fibres (demonstrated to be of microglial origin by Professor Pio del Rio Hortega, who had first described the cell); loss of ‘Purkinje’ cells in the cerebellum, and of basket fibres on surviving neurones; and, especially around blood vessels in Ammon's horn and the cerebellum (Fig. 1), the presence of an amorphous material or clear space outlined by an irregular layer of collagen fibres showing hyaline swelling of their media. Speculating on the nature of this familial disorder, Dr Worster-Drought and his two colleagues focus on the hitherto undescribed perivascular amorphous deposits: reminiscent but not typical of the senile plaques described by Alzheimer; with some similarities but no means typical of Binswanger's encephalitis subcortalis; and a bit like some cases of Schilder's diffuse sclerosis. ‘Kinnier Wilson, in his textbook published posthumously, has regarded the familial disorder which we have described (in 1933) as a possible variant of the so-called spastic pseudosclerosis of Creutzfeldt and Jakob’. But, aside from the lack of familial cases, Worster-Drought and his team do not consider the pathology seen in their cases (and not available to Kinnier Wilson when he opined) to reflect that of Creuzfeldt–Jakob syndrome. They discard this suggestion. Rather, they interpret the condition as due to deficiency of a specific substance, or an example of abiotrophy.
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Fig. 1 The cornu Ammonis, showing focal atrophy of the cortex and the presence of large plaque-like structures in relation to the fascia dentata. (Mallory's phosphotungstic acid haematoxylin). (From Worster-Drought et al., 1940).
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In 1944, Worster-Drought, Greenfield and McMenemey report the
autopsy findings in ‘MB’, the younger sister of
Charles G. Her condition had progressed through total apathy
and spasticity to an ‘inanimate’ state prior to
death in December 1941, 9 years after presentation. Widespread
but patchy and partial demyelination was present. Again, the
blood vessels showed hyaline thickening of the media. Around
many, especially in Ammon's horn and the cerebellum, were pink
plaque-like structures measuring 75–150 µ surrounded
by microglia and some astrocyte processes (
Fig. 2). These were
more abundant than in Charles G. So was the nature of these
lesions any more apparent with access to a second autopsy case?
Rounding up the same neuropathological suspects, our authors
remain mystified. They have observed a new disease but know
not what it is.
Writing in 1981, Colin Masters, Carleton Gajdusek and Clarence
Gibbs describe 7 cases of their own and 10 from the literature
that conform to a disorder recently described, and which they
now propose to designate the Gerstmann–Sträussler
syndrome. They suggest that this is caused by a variant of the
Creutzfeldt–Jakob disease ‘virus’ (
sic). By
now, neuropathology has moved on and ‘one distinctive
feature of the (Gerstmann–Sträussler syndrome) is
the deposition of large numbers of unusual forms of amyloid
plaques . . intermediate . . between the amyloid senile plaque
of Alzheimer's disease . . the kuru plaque of kuru, (Creutzfeldt–Jakob
disease) and . . . scrapie . . Since (Gerstmann–Sträussler
syndrome), a form of cerebellar ataxia with dementia and amyloid
plaques is not well described in the English literature . .
we present the historical background and a review of . . published
cases which fit this syndrome' (
Figs 3 and
4). Prominent on
the list are George G and MB from the 1933, 1940 and 1944 papers
of Worster-Drought and colleagues: ‘while certain differences
exist between this family and that described by Gerstmann (lack
of cerebellar signs and no tract degeneration in the spinal
cord), it is clear that the underlying pathological process
is very similar’.
Sifting material made available from various sources, Masters
and colleagues consider 34 cases of typical or atypical Creutzfeldt–Jakob
disease amongst whom 7 can be classified as Gerstmann–Sträussler
syndrome. Material from four has already been shown to transmit
spongiform encephalopathy to non-human primates (not described
in detail or illustrated in this paper): ‘the forms of
amyloid plaque deposited in the (Gerstmann–Sträussler
syndrome) are intermediate between the Kuru plaque and the amyloid
senile plaque . . the mean duration of illness of patients with
the (Gerstmann–Sträussler syndrome) . . (59.5 months)
is intermediate between (Creutzfeldt–Jakob disease) and
Alzheimer's disease . . we conclude that at least some cases
of the (Gerstmann–Sträussler syndrome) are variants
of transmissible (Creutzfeldt–Jakob disease), and that
the amyloid plaques of the (Gerstmann–Sträussler
syndrome), the Kuru plaques of the spongiform encephalopathies,
and the senile plaques of Alzheimer's disease share a common
pathogenesis.’
Another mysterious disorder seen through a glass darkly features in the article by Sam Nevin and colleagues from 1960. They position this detailed clinical and neuropathological description of eight cases, and four previously reported in preliminary form, updating their 1954 account of two other examples, by linking the material to cases described by Adolf Heidenhain in 1928. Nosology in this area had not proved easy, some observers concluding that a particular case might be ‘differentiated absolutely from Creutzfeldt–Jakob disease’; and others that the ‘attempt to establish these as a sub-variety of (Creutzfeldt–Jakob disease) is justified’. But by 1958, Jacob had declared that ‘the morphological characteristics of . . subacute presenile spongiform cerebral atrophy with a dyskinetic end-stage . . separate it from Creutzfeldt–Jakob disease and the ground substance rather than the ganglion cells (are) primarily affected by the pathological process whatever be its nature'. Here, Nevin and colleagues unwittingly cause cacographic confusion that persists to this day. They cite the paper by H. Jacob, W. Hicke and H. Orthner (Zur Klinik und Neuropathologic der subakuten prasenilen spongiosen Atrophien mit dyskinetischem Endstadium. Deutsche Zeitschrift fur Nervenheilkunde 1958: 178; 330–357). This is their intention. But it has confused many spellers of ‘Mad Cow Disease’ thereafter, since our man (to whom they do not refer) is Dr Alfons Maria Jakob: his account, listed in Garrison and Morton (item 4722), appeared in 1921 (Jakob A. Über eigenartige Erkrankungen des Zentralnervensystems mit bemerkenswertem anatomischen Befunde (spastische Pseudosklerose-Encephalomyelopathie mit disseminierten Degenerationsherden). Zeitschrift für die gesamte Neurologie und Psychiatrie 1921: 64; 147–228).
Disturbingly, of the eight cases reported by Dr Nevin and colleagues, three had previously undergone neurosurgical procedures for unrelated conditions, two within the same month in 1952 at Maida Vale Hospital (London), each developing terminal dementia after an interval of 16–18 months. The clinical features and neuropathological findings in these 8, and 15 similar cases from the published literature, are remarkably stereotyped: ‘an ingravescent stage in which symptoms build up almost imperceptibly . . a phase in which gross disturbance of cerebral function is manifest . . and a terminal stage in which death supervenes or life may be prolonged in a vegetative state for many months’. The clinical manifestations are visual failure, motor paralysis, loss of speech, ataxia, dementia and (cortical) myoclonus leading to a state of mute bewilderment, decorticate posturing and coma; the electroencephalogram shows loss of the normal rhythms, slowing with sharp wave diphasic (sic) complexes interspersed with runs of lower voltage (Fig. 5). The pathology is equally stereotyped showing severe cortical neuronal loss, gliosis and ‘status spongiosus’ (Fig. 6). Whereas some authors regard this condition as a variant of Creutzfeldt–Jakob disease . . we consider that it is fundamentally different and propose to refer to it as subacute spongiform encephalopathy. The pathological differences are in the greater but random distribution of the cortical lesions albeit with a special predilection for the occipital lobes in subacute spongiform encephalopathy; the sparing of brainstem and spinal cord motor nuclei in that condition; the presence of shrunken neurones amongst survivors with a triangulated darkly stained nucleus; absence of the ‘Verödungsherde’ (axonal loss with tissue destruction) described by Jakob; the more widespread gliosis; and more apparent ‘status spongiosus’ in the cortex and basal ganglia. In short, ‘there are no pathological grounds on which subacute spongiform encephalopathy as described . . can be related to Creutzfeldt–Jakob disease’, an opinion not shared by Jacob (writing in the 1958 paper) that, despite differences in their pathological features, the clinical similarities of spongiform cortical atrophy and pseudosclerosis cannot be ignored. For Dr Nevin and colleagues, ‘status spongiosus’ might be seen in the neurodegenerative disorders named eponymously after Pick, Alzheimer, Alpers and Wilson, and in arteriosclerotic or embolic vascular disorders; and the ‘sponges’ occupy the ground substance (extracellular matrix), rather than representing deficiency of the network normally produced by astrocyte processes, or distended neurones. As for the cause, Nevin and colleagues trawl many possibilities including the effects of toxins, infections, metabolic processes, trauma and autoimmunity but leave vascular insufficiency as their preferred explanation on the basis of guilt by association in the 23 cases—hence the title of their paper.
Following a preliminary report, the detailed account of the
brains of the one patient and the chimpanzee to whom Creutzfeldt–Jakob
disease was first transmitted is reported in 1969 by Elizabeth
Beck, physicians from Derbyshire, UK (Bryan Matthews and David
Stevens) who managed the patient, and those who performed the
transmission studies at the National Institutes of Health, USA.
‘RR’, at age 59, presented with a rapid dementing
disorder associated with visual involvement and myoclonus, becoming
mute and spastic in flexion prior to his death 7 months later.
Autopsy showed widespread neuronal loss, spongiform changes,
gliosis and fat-laden microglia but not much demyelination.
These changes affected the cerebral cortex, thalamic nuclei,
hypothalamo-neurohypophyseal axis, striatum, diencephalon and
cerebellum but spared the brainstem, cranial nerves and spinal
cord: ‘scattered throughout . . were unusual swollen cells
. . probably neurones . . with pale cytoplasm and an eccentric
nucleus . . such cells had a sharply defined, strongly PAS (periodic
acid shift) edge and often contained a small, central cluster
of PAS-positive granules’ (
Figs 7 and 9). Material from
a brain biopsy, taken with consent from relatives 5 months earlier,
was inoculated into a chimpanzee. After 13 months, he became
apathetic, appeared to have a visual field defect, and was ataxic
and weak in the legs over the 2 months prior to euthanasia.
Autopsy showed findings similar to ‘RR’ but with
a different pattern of distribution in the thalamic nuclei,
and more involvement of the pontine—especially the ventral
cochlear—nuclei with generally florid loss of neurones;
survivors ‘appeared ballooned with large, eccentric nuclei,
(and) a pale, homogenous (chromatolytic) cytoplasm which often
contained a dense, ill-defined central core’ (
Figs 8 and
10). By 1969, Elizabeth Beck and her colleagues conclude that
‘a study of the recent literature on Creutzfeldt–Jakob
disease makes it abundantly clear that the former tendency to
split the disease into several, though related, but otherwise
independent groups . . including ‘Nevin-Jones disease’
. . has lately been abandoned. Each shows the triad of neuronal
loss, swelling of surviving nerve cells, status spongiosus and
gliosis.
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Fig. 10 Chromatolytic nerve cells (‘primary irritation’). Chimpanzee A54: swollen neurone with peripherally placed nucleus from the fifth layer of the frontal cortex; note dense area in the centre and distended processes still attached to the cell body. H. and E. (From Beck et al., 1969).
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Nevin and his neuropathological colleagues and Beck and her
team refer to the ‘status spongiosus’ that characterizes
Creutzfeldt–Jakob disease. In their 1978 paper, Masters
and Richardson seek to clarify the nosology of spongiform changes
in the transmissible virus-induced (
sic) encephalopathies of
man. Amongst their 21 cases (transmission being observed in
all 6 where this was attempted) are spongiform changes defined
as ‘small vacuoles in the neuropil, usually round or ovoid,
occasionally confluent, and . . not within the cytoplasmic soma
of any of the cells . . (or) in a pericellular distribution’
(
Fig. 11). This is similar to the appearances, described as
subacute vascular encephalopathy by Nevin and colleagues in
1950 (and by Jones and Nevin in 1954), and seen in Case 5 of
Jakob's original series. Such changes occur in those with a
disease duration that is often <5 months, and this is pathognomic
of Creutzfeldt–Jakob disease. The second type is ‘status
spongiosus’: here, there is neuronal loss with cavitation
of the neuropil and surrounding dense gliosis (
Fig. 12). Although
each pathological type affects the cerebral cortex, thalamus,
parts of the striatum, hippocampus and cerebellum but not the
pons, brainstem or spinal cord, ‘status spongiosus’
is non-specific and merely a manifestation of end-stage gliosis.
Although the work by Charles Weissman, Stanley Prusiner and
others clarifying properties of the particle that captures normal
prion proteins and leads to spongiform encephalopathy lay ahead,
these six papers chart the long and arduous route taken by thorough
clinical and pathological description that fuelled debate on
the status, independent or otherwise, of these aggressive neurodegenerative
disorders—conflicts of classification and categorization
that, as papers in the current issue and our scientific commentary
reflect, have moved from microscopic to molecular analyses,
but are still not resolved to the mutual satisfaction of all
the experts.
Alastair Compston
Cambridge
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