Download The Pathology of the Spinal Cord in Progressive

Journal of Neuropathology and Experimental Neurology
Copyright q 2002 by the American Association of Neuropathologists
Vol. 61, No. 3
March, 2002
pp. 268 274
The Pathology of the Spinal Cord in Progressive Supranuclear Palsy
ROBERTA VITALIANI, MD, TOMASO SCARAVILLI, MD, EDUARD EGARTER-VIGL, MD, BRUNO GIOMETTO, MD,
CHRISTINE KLEIN, MD, FRANCESCO SCARAVILLI, MD, FRCPATH, SHU F. AN, MD, PHD, AND
PETER P. PRAMSTALLER, MD
Abstract. We describe the results of a study of the spinal cord of 5 patients with progressive supranuclear palsy (PSP).
Examination of the 6th cervical, 7th thoracic, and 5th lumbar segments revealed variable degree of gliosis and density of neuropil
threads (NTs), nerve cell loss, and tau-positive cytoplasmic staining of neurons, some of which was reminiscent of neurofibrillary tangles (NFT). Tau-positive neurons were seen at each spinal level and in the 3 zones in which each level was
subdivided. Cells with the appearance of NFT predominated in the intermediate zone. Morphometric study revealed 47%,
52%, and 32% decrease in cell numbers in the motor area (lamina IX) at the 3 spinal levels, respectively, and 39% in the
intermedio-lateral column.
This is the first report describing severe neuronal loss throughout the whole spinal cord in patients with PSP and its results
are in keeping with a previous study of the nucleus of Onufrowicz. The reasons why cell loss fails to produce clinical
symptoms are analyzed and the clinico-pathological correlations between anatomical changes and dystonia are considered.
On the basis of existing data, we conclude that previous suggestions implicating spinal interneurons in the pathogenesis of
neck dystonia should not be supported.
Key Words:
Cell loss; Dystonia; Progressive supranuclear palsy (PSP); Spinal cord; Tau.
INTRODUCTION
Progressive supranuclear palsy (PSP) was defined as a
clinical entity in 1964 by Steele, Richardson, and Olszewski (1), who described its clinical presentation and
pathological features. In the past, patients with PSP had
probably been diagnosed as suffering from post-encephalitic Parkinsonism. Conversely, cases previously interpreted as early reports of PSP (2–4) were subsequently
shown to be due to a mesencephalic tumor (5) and Whipple’s disease (6), respectively.
PSP is classified as a ‘‘parkinsonian-plus’’ syndrome
and is the most common form of parkinsonism after Parkinson disease. Recent studies have revealed a prevalence
of 6.4/100,000 individuals and an incidence of 5.3/
100,000. A recently observed increase in the diagnosis
of PSP may not be due to an actual increased incidence,
but probably to greater attention paid by the physicians
and to improved clinical criteria for its diagnosis (7). The
clinical diagnosis can be of possible or probable PSP;
diagnosis of definite PSP requires neuropathological confirmation.
Clinica Neurologica 2a (RV, TS, BG), Università degli Studi di Padova, Padua, Italy; Dipartimenti di Patologia (EE-V) and Neurologia
(PPP), Ospedale Regionale di Bolzano-Bozen, Italy; Department of Molecular Pathogenesis, Division of Neurology (CK), Medical University
of Lübeck, Lübeck, Germany; Department of Neuropathology (FS,
SFA), Institute of Neurology, UCL, London, United Kingdom.
Correspondence to: Professor Francesco Scaravilli, Department of
Neuropathology, Institute of Neurology, University College London,
Queen Square, London WC1N 3BG United Kingdom.
This study was supported by the Progressive Supranuclear Palsy (PSP
Europe) Association.
Abnormalities of the spinal cord were considered uncommon in PSP (8), and related symptoms were not included among those characteristic of the disease. However, recently we reported 3 patients with pathologically
proven PSP, who complained of urinary disturbances.
These symptoms were neurophysiologically documented
and correlated with a profound cell loss in the nucleus of
Onufrowicz (NO) in the sacral cord (9) and widespread
presence of neurofibrillary tangles (NFT) in all nerve cell
types, including motor neurons. Previously, Kikuchi et al
(10) described gliosis, decreased reactivity for microtubule-associated protein 2 (MAP2) antibody, presence of
NFT, and axonal swelling in the gray matter of the spinal
cord. The changes appeared to decrease in severity following a cranio-caudal axis and did not include nerve
cell loss; however, no nerve cell counts were performed.
We were surprised by the discrepancy between the severity of the pathology in the sacral spinal cord and the
cell loss in the NO described by ourselves and the mild
involvement of the lower spinal levels in the cases of the
previous authors. The rationale behind the present investigation was to ascertain whether the findings of the NO
were localized to this region or were representative of a
diffuse neuronal loss throughout the whole spinal cord.
MATERIALS AND METHODS
Patients
Patient 1: This man presented at the age of 58 with akinetic
rigid syndrome, backward falls, and bulbar symptoms within 1
yr from the onset, soon followed by echolalia, palilalia, and
pseudobulbar affect. Urinary symptoms included urgency and
frequency and, 3 yr later, urinary incontinence. By the age of
62 the patient presented the typical supranuclear gaze palsy
accompanied by a masked facies, extensor posturing of the
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neck, hypophonia, and brisk tendon reflexes. An MRI of the
brain showed cortical and brainstem atrophy; sphincter EMG
(sEMG) showed denervation of the anal sphincter muscle, and
an EMG of the left tibialis anterior revealed signs of denervation. The patient died at the age of 66.
Patient 2: At the age of 58 this woman began suffering frequent falls, followed 2 yr later by right-sided rigidity and gait
difficulties caused by dragging of the right foot and slow movements. At the age of 62, neurological examination revealed supranuclear gaze palsy, increased tone both in the limbs and
trunk, severe postural instability, and fine tremor in the upper
limbs; the patient was hypophonic and complained of dysphagia. MRI brain scan showed cortical atrophy and suggested
mild periventricular ischemic changes, while the sEMG was
normal. The patient died 1 yr later of pneumonia.
Patient 3: This man presented at the age of 68 with urinary
incontinence, and 2 yr later developed abnormal gait and balance. Neurological examination 4 yr later revealed amimic facies with supranuclear gaze palsy, slurred speech, pseudobulbar
affect, parkinsonism with left-sided rest tremor, and apraxia. An
MRI detected both cortical and subcortical atrophy accompanied by periventricular ischemic changes. The sEMG showed
signs of denervation. The patient died at the age of 73.
Patient 4: A 52-yr-old man complained of deterioration of
his mental status with loss of interest, slowness, and self-neglect. Neurological examination showed expressionless face,
monosyllabic speech, akathisia, and fine tremor. Later, he presented with difficulty of the balance, frequent falls, unsteadiness
and dysarthria, flat affect, parkinsonian rigidity with no volitional upward gaze, nuchal rigidity, paucity of finger movement, intermittent parkinsonian tremor of the right hand, spasticity of the fingers with weakness in the upper limbs, stiff legs
and brisk reflexes with bilateral extensor plantar and slow gait.
No CT scan was performed. He died at the age of 65.
Patient 5: This woman presented at the age of 54 with forgetfulness and pseudobulbar affect. Neurological examination
revealed expressionless facies, slow gait and failing to swing
the left arm when walking, rigidity of left arm and loss of dexterity in the left hand. It was also queried whether she could
raise her eyes. CT scan showed mild ventricular dilatation and
cerebral cortical atrophy. Subsequently she became incontinent
with an almost inaudible speech and with her neck held in extension. The facies was staring and immobile, the left arm held
flexed at the elbow and wrist, and the left foot fixed in plantar
flexion. Eye movements showed no vertical and only minimal
horizontal movement. Oculocephalic movements were intact
and there was no apraxia for eye opening and closing. Palilalia
and impairment of strength in limbs on the left were noted. She
died at the age of 57.
Spinal Cord Motor Neurons: They are located in Rexed’s
lamina IX (12), which occupies part of the anterior horn of the
cord. The overall structure of the lamina varies according to
the different levels examined; its size is larger in the cervical
and lumbar enlargements and smaller throughout the whole thoracic cord in which the horn has a dorso-ventral orientation. At
both cervical and lumbar levels, lamina IX is divided by lamina
VIII into areas: 1 median, containing cells for the muscles of
the trunk, and others lateral, containing several cells innervating
the muscles of the extremities (13). Motor cells include groups
of large a- and small g-neurons, which are more obvious in the
enlargements than at thoracic level. Both types of neurons are
identified by polyhedral shape, large central and vesicular nuclei, 1 obvious nucleolus, coarse Nissl bodies, and several dendrites.
Intermedio-Lateral Column: The intermedio-lateral column is
one of the several nuclei of neurons forming Rexed’s lamina
VII and is laterally located in the spinal gray matter between
the posterior and anterior horns. The column is present throughout the whole thoracic cord and in the upper 2 lumbar segments
(14) and consists of small polygonal or spindle-shaped nerve
cells with vesicular nuclei, inconspicuous nucleoli, and scanty
cytoplasm containing only finely dispersed Nissl granules.
Postmortem Examination
Morphometry
All patients underwent full postmortem examination. Their
brains and spinal cords were removed and placed in 10% buffered formalin for 3 wk. Representative blocks of the cerebral
and cerebellar hemispheres, including the deep gray nuclei,
midbrain, pons, and medulla were embedded in paraffin for the
histological diagnosis of PSP (11). Staining included routine
and immunohistochemical methods. The latter were carried out
with the following antibodies: anti-tau (A024, Dako, UK, 1:
For quantitative evaluation of tau-positive neurons and of
neuropil threads (NTs), sections of cervical, thoracic, and lumbar spinal cord of patients 1–4 were stained with the AT8 antibody. Immunostaining of the cord of patient 5 failed due to
the prolonged fixation in non-buffered formalin. For the purpose of this study, the spinal gray matter was subdivided in 3
regions (Fig. 1): 1) ventral, including Rexed’s laminae VIII and
IX and corresponding to the areas labeled lateral division of
Fig. 1. Diagrams of the cervical (a), thoracic (b), and lumbar (c) spinal cord showing the subdivisions into ventral (V),
intermediate (I), and dorsal (D) regions applied in the present
study.
150), anti-GFAP (Dako, UK, 1:400), anti-bA4 peptide (Dako,
UK, 6F/D3, 1:60), and a-synuclein (gift of Dr Diane Hanger,
Institute of Psychiatry, London, UK, 1:1,000). For the purpose
of this study, blocks of the 6th cervical, 7th thoracic, and 5th
lumbar spinal segments of the patients and 3 age-matched control individuals were also embedded. Forty consecutive 20-mmthick paraffin sections were stained with Luxol fast blue/cresyl
violet (LFB/CV) and used for morphometric studies. Other consecutive 5-mm-thick sections were immunostained with the antitau antibody AT8 (Immunogenetics, UK, 1:100).
Anatomical Definition
J Neuropathol Exp Neurol, Vol 61, March, 2002
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VITALIANI ET AL
TABLE 1
Semi-quantitative Evaluation of NTs and Gliosis in the
3 Levels of the Cord and in the 3 Zones
Patients
Cervical
Ventral
Interm.
Dorsal
Thoracic
Ventral
Interm.
Dorsal
Lumbar
Ventral
Interm.
Dorsal
1
2
3
4
NTs
Gliosis
NTs
Gliosis
NTs
Gliosis
111
1
111
1
2
6
111
1
111
1
6
2
111
1
111
1
6
2
1
1
1
1
2
2
NTs
Gliosis
NTs
Gliosis
NTs
Gliosis
11
1
11
1
6
6
111
1
11
1
1
1
11
1
111
1
1
1
1
6
1
6
2
2
NTs
Gliosis
NTs
Gliosis
NTs
Gliosis
11
1
11
1
6
2
11
1
111
1
1
2
1
1
11
1
1
6
6
1
1
1
2
2
Abbreviations: NTs, neuropil threads; interm, intermediate.
the anterior gray horn (LAG) and medial division of the anterior
gray horn (MAG) (for cervical and lumbar levels) and anterior
gray horn (AG) and ventral intermediate gray (IG) (for the thoracic level) by Kikuchi et al (10); 2) intermediate, including
Rexed’s laminae V, VI, VII (including the Clarke’s and intermedio-lateral nuclei at thoracic level) and X, corresponding to
the residual IG (10); and 3) dorsal, including Rexed’s laminae
I, II, III, and IV and corresponding to posterior gray (PG) and
substantia gelatinosa (SG) (10).
Two counts of tau-positive neurons were made: one included
all the cells that could be identified as neurons by their size and
morphological features; the other took into account only cells
with cytoplasmic features reminiscent of NFTs.
With regard to the density of NTs and gliosis, a semi-quantitative system that takes into account the density of immunostaining was adopted, ranging from 2 (no staining) to 111
(strong) immunostaining. With regard to the assessment of gliosis, the density of immunostained glial fibers revealed to be a
more reliable criterion than counting astrocytic cell bodies. Glial inclusions in PSP included tuft-shaped astrocytes (15, 16)
and coiled oligodendrocytes (16). Their presence in the various
regions was noted but not quantified.
The values of a semi-quantitative evaluation of NTs and gliosis are given in Table 1. Values for the quantitative assessment
of tau-positive cells and for those with appearances suggestive
of NFT are given in Table 2. Table 2 also shows the separate
mean values of tau-positive cells and of those with NFT appearances at each level and in each region in which the cord
was subdivided. For morphometric analysis, alternate 20-mmthick sections of the C6, T7, and L5 were stained with LFB/
CV.
J Neuropathol Exp Neurol, Vol 61, March, 2002
TABLE 2
Numbers of Tau-Positive Neurons and Numbers of
Those with NFTs (brackets) at the 3 Levels of the Cord
and in the 3 Zones in 4 Patients
Patient
Level
Ventral
Column
Intermediate
1
Cervical
Thoracic
Lumbar
Total
Cervical
Thoracic
Lumbar
Total
Cervical
Thoracic
Lumbar
Total
Cervical
Thoracic
Lumbar
Total
26(1)
8(3)
23(3)
57(7)
6(2)
8(0)
1(1)
15(3)
13(6)
6(1)
0(0)
19(7)
11(1)
3(1)
2(1)
16(3)
15(6)
17(6)
25(6)
57(18)
7(4)
6(5)
3(2)
16(11)
10(5)
10(4)
2(0)
22(9)
10(3)
7(1)
13(6)
30(10)
2
3
4
Dorsal
21(5)
6(2)
7(4)
34(11)
11(6)
4(1)
1(1)
16(8)
4(2)
3(2)
5(2)
12(6)
10(4)
1(1)
4(1)
15(6)
Total
62(12)
31(11)
55(13)
148(36)
24(12)
18(6)
5(4)
47(22)
27(13)
19(7)
7(2)
53(22)
31(8)
11(3)
19(8)
61(19)
TABLE 3
Mean Cell Count and SD of Motor Neurons Per Section
at the 3 Spinal Levels and of Neurons in the
Intermedio-Lateral Column
Control
Cervical
Thoracic
Lumbar
Interm. Lat.
17.5
4.4
20.5
4.0
PSP patients
(63.57)
(61.0)
(62.67)
(62.7)
9.2
2.1
13.9
2.4
(61.6)
(60.7)
(63.0)
(61.0)
%
reduction
47
52
32
39
The neuronal cells of the anterior horns and of the intermediolateral nucleus were counted using an oil immersion objective (3100) with a numerical aperture of 1.32 (depth of field
5 0.24 mm) and applying the principle of the optical disector
(9). Separate cell counts were carried out on the left and right
sides. The microscope was also equipped with a gauge to measure the movements on the Z-axis. This allows accurate monitoring of the depth of the plane of focus inside the 20-mm sections. The cells were counted if their nucleoli were clearly
visible and contained in a 10-mm volume at 5 mm below the
top and 5 mm above the bottom of the section. As alternate
sections were used for the cell counts, the total counting volume
was of 10 mm for every 40 mm (the thickness of 2 consecutive
sections). The cell counts from the left and right sides were
pooled to form a single group.
For statistical analysis, Windows Excel software was used to
perform the 2-tailed Student t-test (Table 3). The mean diameters of motor cells of PSP patients and controls at various
levels of the cord are shown in Table 4.
RESULTS
The macroscopic appearance of the brains of the 5 patients was unremarkable. The spinal cord was of normal
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SPINAL CORD PATHOLOGY IN PSP
TABLE 4
Mean Diameters and SD of Motor Neurons (mm) at the
3 Spinal Levels and of Neurons of Intermedio-Lateral
Column
Cervical
Control
1 31.2
2 32.6
3 33.1
Patient
1 42.6
2 40.1
3 36.9
4 33.2
5 27.1
Thoracic
Lumbar
Interm. Lat.
(65.5)
(66.8)
(66.1)
19.7 (63.7)
20.4 (64.9)
20.2 (64.7)
46.9 (67.6)
37.9 (67.3)
48.1 (68.3)
24.3 (64.8)
25.5 (64.8)
28.5 (66.7)
(66.3)
(66.9)
(66.8)
(67.3)
(65.9)
26.9
26.5
25.3
23.6
15.5
49.7
44.1
49.5
45.0
39.8
32.2
37.2
32.5
30.1
30.1
(65.2)
(64.5)
(65.3)
(65.4)
(63.6)
(68.3)
(65.7)
(67.8)
(69.3)
(69.1)
(65.5)
(65.7)
(67.1)
(67.6)
(64.2)
size in 4 patients; in patient 1 the bulk of the gray matter
was considerably reduced at all levels.
All 5 patients shared similar microscopic findings in
the cerebral and cerebellar hemispheres and brainstem;
these included moderate to severe degrees of neuronal
loss and reactive astrocytic gliosis. Immunohistochemistry revealed presence of NFTs, NTs, and argyrophilic and
tau-positive inclusions in astrocytes and oligodendrocytes. Histological and immunohistochemical appearance
as well as the localization of the changes fulfilled the
criteria for the diagnosis of PSP (11). There were no substantial differences in severity of the pathological changes
among the 5 patients. Furthermore, no changes suggestive of any other tau- or synuclein-related pathology were
seen: only occasional NFT in CA1 in 3/5 patients without
senile plaques and no Lewy bodies.
In the spinal cord of all the patients, the laminar distribution of the gray matter was easily identifiable at all
levels. Nerve cells did not show obvious signs of degeneration or vacuolation, but there was a variable degree of
glial reaction, involving both gray (Table 1) and white
matter.
Immunostaining with tau antibody showed mild (Fig.
2a) to marked (Fig. 2b) density of NTs (Table 1) and tau
deposition in the cytoplasm of nerve cells. The distribution of tau-positive cells in the cord is shown in Table 2.
Their appearance varied from sparsely to densely granular. The former, consistent with the pre-tangle stage of
NFT formation (17), was seen predominantly in the largest neurons, including motor neurons in lamina IX (Fig.
3a). The more densely granular pattern appeared to involve smaller nerve cells (Fig. 3b). In some of the most
densely stained cells, the appearance of the immune reaction was reminiscent of NFTs (Fig. 4), as seen in routine preparations. In lamina VII of the thoracic cord,
stained cells included a number of neurons of the intermedio-lateral (Fig. 5) and, less frequently, of the Clarke’s
columns. The density of the different types of tau-positive cells appeared to be higher in the intermediate zone
and anterior zone in 2 patients, than posteriorly and decreased cranio-caudally (Table 2). However, when only
cells with tau-positive cytoplasm reminiscent of NFT
were taken into consideration, the intermediate, posterior
and anterior regions were involved in descending order,
with the cervical level more affected than the thoracic
and lumbar (Table 2). Density was diffusely high in patient 1, but was similar in the other 3 patients.
The mean numbers of neurons in the lamina IX at cervical, thoracic, and lumbar levels and in the intermediolateral column of patients and controls are shown in Table
3. Results show a reduction of 47%, 52%, and 32% in
the different motor areas and 39% in the intermedio-lateral column. These differences are statistically significant
(p , 0.001).
The mean neuronal cell diameters in PSP patients and
in controls are shown in Table 4. These differences are
not statistically significant. The distribution of motor cell
diameters was also calculated to investigate whether cell
loss involved any particular cell size. Results (diagrams
not shown) showed that cells of all sizes took part in the
loss.
DISCUSSION
This study shows nerve cell loss and tau pathology in
the spinal cord of 5 patients with PSP. Neuronal loss in
the motor neuronal pool in lamina IX and in the intermedio-lateral column is in keeping with the results of a
previous work describing severe neuronal loss in the NO
in patients with PSP (9). In lamina IX the loss was severe
at all levels, but more so in the cervical and thoracic
segments, where it involved approximately 50% of the
cells. In lumbar segments, only one third of the cells had
disappeared. Tau pathology consisted of NFTs, NTs, and
glial inclusions, morphologically similar to those observed in the brain of patients with this disease.
Changes in the spinal cord of patients with PSP have
seldom been investigated and are considered a minor
event in this disorder (8) despite the fact that NFTs in
the spinal cord were already described by Steele et al (1).
Bugiani et al (18) reported loss of spinal neurons in 2 of
their 5 patients; however, they did not provide data concerning the segmental and laminar distribution of the lesions. Nerve cell loss in the anterior horns was described
by Blumenthal and Miller (19), Ishino et al (20), and
Powell et al (21). Kurihara et al (22) mentioned loss of
neurons and gliosis in the anterior horn without giving
further details, and Tomonaga (23) described neurofibrillary tangles in the intermedio-lateral column.
The combined morphological and morphometric approach used by Kato et al (24) provides a better opportunity to compare data. Their salient findings, in the only
patient in whom the whole spinal cord was investigated,
included NFTs, predominantly in the posterior horns and
with a cranio-caudal gradient of decreasing severity;
J Neuropathol Exp Neurol, Vol 61, March, 2002
272
VITALIANI ET AL
Fig. 2. Tau immunostaining reveals the density of the NTs in the spinal cord of PSP patients. The density is mild (1) in 2a
and marked (111) in 2b. Scale bar 5 10 mm.
Fig. 3. Photomicrograph showing the sparsely granular distribution of tau immunostaining in a large (motor) neuron (a),
contrasting with one more densely stained small nerve cell in the Clarke’s column (b).
Fig. 4. The arrangement of the tau immunostaining in this neuron located in intermediate region of the cord is reminiscent
of the appearances of the globose tangles seen with routine staining.
Fig. 5. Tau immunostaining is seen also in a number of neurons in the intermedio-lateral column. Scale bar: Figures 3–5 5
10 mm.
evidence of atrophy and chromatolysis in anterior horn
cells without obvious cell loss; and mild gliosis only in
the cervical gray matter.
Kikuchi et al (10) studied the spinal cord of 6 patients
with PSP. They found decreased immunoreactivity for
microtubule-associated protein-2 (MAP2) in the cervical
J Neuropathol Exp Neurol, Vol 61, March, 2002
cord of 3 of patients, whereas both thoracic and lumbar
levels were unaffected. Loss of small neurons was described in the intermediate gray region, whereas motor
neurons were unaffected both in number and MAP2 content. NFTs were more numerous at cervical and lumbar
than thoracic levels and glial inclusions were definitely
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SPINAL CORD PATHOLOGY IN PSP
more numerous at cervical levels and poorly represented
in the thoracic and lumbar levels.
There are obvious similarities and differences between
our findings and those of Kato et al (24) and Kikuchi et
al (10). Some of these differences may reflect the different methods used. All 3 groups seem to agree that the
spinal cord harbors NFTs. However, only in 1 of the patients reported by Kikuchi et al (10) were they seen at
lumbar level. Conversely, they were present in this location in all our patients. These findings correlate with
the neuronal loss that, although showing some regional
variation, was present at all spinal levels. With regard to
the laminar distribution of the changes, Kato et al (24)
and Kikuchi et al (10) found that the dorsal and intermediate gray area was more severely affected than the
anterior. We found higher densities of tau-positivity anteriorly and in the intermediate zone. However, if only
neurons with mature tau-positive NFTs are considered,
our figures compare with those of the 2 previous groups.
The main difference between these groups and ours is
that neither of them found any cell loss in the motor area.
The reasons for this discrepancy probably reside in the
fact that neither group made use of the morphometric
approach employed in the present investigation. Similar
considerations apply to the cell loss described by Kikuchi
et al (10) in the intermediate gray region, which probably
includes the intermedio-lateral column. Finally, our results show that, with regard to the motor cells, neurons
of all diameters are involved in the cell loss.
Some of the pathological findings in our patients need
to be correlated with their clinical presentation. Four of
them, including the 3 previously described by Scaravilli
et al (9), in whom morphometric analysis of the nucleus
of Onufrowicz revealed nerve cell loss of 64% presented
with urinary disturbances. However, no other signs of
autonomic failure were noted in them, despite a 39%
nerve cell loss in the intermedio-lateral columns. The correlation between autonomic symptoms and cell loss in
the intermedio-lateral column was studied by Kennedy
and Duchen (25); they found cell loss of 70% in patients
with multiple system atrophy and autonomic disturbances. It is therefore possible that the cell loss has to reach
higher levels of severity than those observed in our study
before clinical symptoms appear. This conclusion is supported by the observations by Fearnley and Lees (26),
who calculated that the overall cell loss in the substantia
nigra must reach 50% before symptoms of Parkinson disease appear. Similar considerations may be made for the
lack of correlation between the 50% loss of spinal motor
neurons and the absence of muscle weakness and fibrillation at cervical level. Indeed, McComas et al (27) came
to the conclusion that muscles may still be able to develop twitch tensions within the normal range despite an
80% decrease in motor units.
In their paper, Kikuchi et al (10) discuss the possible
anatomical correlation for the dystonia that affects PSP
patients, including ours. Among the various possible localizations considered, they take into account the role of
spinal cord interneurons, in particular those of the intermediate region of the spinal cord. These were abnormal
in their patients. However, the abnormalities referred to
by Kikuchi et al regard only MAP2 content in neurons,
whereas cell loss was not morphometrically assessed.
Moreover, Hedreen et al (28) conclude that whereas it is
impossible to implicate any specific region of the nervous
system in the pathogenesis of dystonia, the most likely
site would appear to be the striatum, a region commonly
affected in PSP. This view is supported by neuroimaging
studies (29–31). Therefore, on the basis of these findings
and the present knowledge of the physio-pathological
mechanisms leading to dystonia, we think it is at least
premature to refer to spinal interneurons as the possible
cause of neck dystonia in PSP patients.
In conclusion, we describe for the first time the severe
loss of neurons in the motor and intermedio-lateral columns of the spinal cord. These results confirm our previous study of the NO (9) and indicate that the spinal
cord is extensively involved in PSP. We comment on the
clinical implications of our results and the possible reasons why this loss may not produce clinical symptoms.
We also briefly discuss the correlations between anatomical lesions and dystonia and conclude that previous suggestions implicating spinal interneurons should, at present, not be supported.
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Received September 24, 2001
Revision received November 5, 2001
Accepted November 19, 2001