2018

P. CHAND ET AL.

muscle is involved.7 Third, the discharge frequency of
the EMG activity during the involuntary contractions
was 40 to 50 Hz. Discharge rates in cramps are typically
around 150 Hz.6 Last but not least, our polymyographic
recordings showed that massive electric muscle activity
was not limited to one muscle. It extended over different
leg muscles, even more or less simultaneously in both
legs. The latter directed us to consider this mass activity
as muscle spasms.
As already stated, spasms are ill defined.10 That there
were no clinical signs of pyramidal tract lesion provides
an important argument that the involuntary painful contractions in this patient are not “conventional” spasms. In
healthy subjects, motor units usually fire at 6 to 10 Hz
when first recruited and at 15 to 60 Hz during maximal
voluntary contractions.15 Thomas and Ross showed with
needle EMG studies of motor unit activity in patients after
spinal cord injury that, during spasms, the motor unit firing
frequencies show mean peak firing rates of 18 ⫾ 9 Hz.12
Rate coding for many motor units appears to be similar
whether descending motor input is intact or whether it has
been reduced severely by spinal cord injury.
In 1978, Satoyoshi already described that, during the
involuntary contractions in his patients, needle EMG recordings revealed synchronized motor unit discharges of 40
to 50 Hz and of 4 to 10 mV amplitude. He suggested that
abnormal discharge of anterior horn cells is responsible for
the mass activity.1 The HD-sEMG recordings showed a
stable spatial extension of such synchronized activity
throughout the vastus lateralis muscle during the contractions. This finding supports and provides additional arguments for this hypothesis of massive hyperactivity or disinhibition at the alpha motor neuron level. In conclusion,
although a more proximal origin cannot be excluded, the
surface EMG findings strongly suggest a deregulation at the
alpha motor neuron level leading to involuntary muscle
contractions in Satoyoshi syndrome.
Acknowledgment: We thank Henny Janssen, technician, for assisting in the EMG measurements and the anonymous reviewers for their
useful comments.

REFERENCES
1. Satoyoshi E. A syndrome of progressive muscle spasm, alopecia,
and diarrhea. Neurology 1978;28:458 – 471.
2. Satoh A, Tsujihata M, Yoshimura T, Nagataki S. Myasthenia
gravis associated with Satoyoshi syndrome: muscle cramps, alopecia and diarrhea. Neurology 1983;33:1209 –1211.
3. Drost G, Verrips A, Hooijkaas H, Zwarts MJ. Glutamic acid
decarboxylase antibodies in Satoyoshi syndrome. Ann Neurol
2004;55:450 – 451.
4. Endo K, Yamamoto T, Nakamura K, et al. Improvement of Satoyoshi syndrome with tacrolimus and corticosteroids. Neurology
2002;2:2014 –1215.
5. Satoyoshi E, Yamada K. Recurrent muscle spasms of central
origin. Arch Neurol 1967;16:254 –264.

Movement Disorders, Vol. 21, No. 11, 2006

6. Miller TM, Layzer RB. Muscle cramps. Muscle Nerve 2005;32:
431– 422.
7. Roeleveld K, van Engelen BG, Stegeman DF. Possible mechanisms of muscle cramp from temporal and spatial surface EMG
characteristics. J Appl Physiol 2000;88:1698 –1706.
8. Blok JH, van Dijk JP, Drost G, Zwarts MJ, Stegeman DF. A high-density
multichannel surface electromyography system for the characterization of single motor units. Rev Sci Instrum 2002;73:1887–1897.
9. Zwarts MJ, Stegeman DF. Multichannel surface EMG: basic aspects and clinical utility. Muscle Nerve 2003;28:1–17.
10. Young RR. Spasticity: a review. Neurology 1994;44(Suppl. 9):
S12–S20.
11. Zijdewind I, Thomas CK. Motor unit firing during and after voluntary contractions of human thenar muscles weakened by spinal
cord injury. J Neurophysiol 2003;89:2065–2071.
12. Thomas CK, Ross BH. Distinct patterns of motor unit behaviour
during muscle spasms in spinal cord injured subjects. J Neurophysiol 1997;77:2847–2850.
13. Drost G, Blok JH, Stegeman DF, van Dijk JP, van Engelen BGM,
Zwarts MJ. Propagation disturbance of motor unit action potentials
during transient paresis in generalized myotonia: a high density
surface EMG study. Brain 2001;124:352–360.
14. Ross BH, Thomas CK. Human motor unit activity during induced
muscle cramp. Brain 1995;188:983–993.
15. Monster AW, Chan H. Isometric force production by motor units
of extensor digitorum communis muscle in man. J Neurophysiol
1977;40:1432–1443.

Alzheimer’s Disease Presenting as
Corticobasal Syndrome
Pratap Chand, DM, FRCP,1 Jordan Grafman, PhD,2
Dennis Dickson, MD,3 Keisuke Ishizawa, MD,3
and Irene Litvan, MD1*
1

Department of Neurology, University of Louisville School of
Medicine, Louisville, Kentucky, USA; 2Cognitive
Neuroscience Section, National Institute of Neurological
Disorders and Stroke, Bethesda, Maryland, USA;
3
Department of Pathology, Mayo Clinic Jacksonville,
Jacksonville, Florida, USA

Abstract: A 60-year-old man presented with slowly progressive left hemi-Parkinsonism, left hand apraxia, myoclonus,
dystonia, visuospatial disturbances, and alien limb phenomenon, resembling corticobasal syndrome. Eight years later,

This article includes Supplementary Video, available online at http://
www.interscience.wiley.com/jpages/0885-3185/suppmat
*Correspondence to: Dr. Irene Litvan, Raymond Lee Lebby Professor
of Parkinson Disease Research, Department of Neurology, University of
Louisville School of Medicine, 500, South Preston Street, A Building,
HSC#113, Louisville, KY 40202. E-mail: i.litvan@louisville.edu
Received 14 February 2005; Revised 7 October 2005; Accepted 12
October 2005
Published online 14 September 2006 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.21055

AD PRESENTING AS CORTICOBASAL SYNDROME
neuropathology revealed features of Alzheimer’s disease,
with asymmetrical (right more than left) cortical tau burden with image analysis. The videotaped clinical features,
neuropsychological aspects, and neuropathological correlates are presented and discussed. © 2006 Movement Disorder Society
Key words: Alzheimer’s disease; corticobasal degeneration;
corticobasal syndrome; myoclonus; alien limb phenomenon;
neuropathology

Alzheimer’s disease (AD) is the most common form
of primary degenerative dementia and is characterized by
a progressive amnestic disorder with subsequent involvement of other cognitive functions and personality alterations. However, AD can present with various other
clinical profiles of a focal cortical degenerative syndrome with features dependent on the areas of the brain
affected. Some of these syndromes include progressive
aphasia, apraxia, visuospatial disturbances, and motor
disturbances.1 Motor disturbances in the form of Parkinsonism (i.e., bradykinesia, rigidity, postural instability,
and abnormal gait) and myoclonus are well documented
in AD, and their occurrence correlates with the disease
duration and progression as well as with the functional
and cognitive decline.1 Corticobasal degeneration (CBD)
is a disease with slowly progressive cognitive and motor
disturbances that classically has been described to
present in the sixth to seventh decade of life with an
asymmetrical akinetic–rigid syndrome, myoclonus, and
apraxic limb (held in a fixed dystonic position resembling the alien limb phenomenon).2 Due to considerable
overlap in the clinical phenotypes between CBD and
other neurodegenerative disorders, such as progressive
supranuclear palsy (PSP), and frontotemporal dementia
(FTD), and the various underlying pathologies presenting with the classic clinical phenotype, there is a view
that patients with this phenotype should be diagnosed as
having corticobasal syndrome (CBS) and that neuropathology should be the only criteria to make a definitive
diagnosis of CBD.2
There have been a few reports of patients with a
CBS presentation who turned out to have AD at postmortem examination.3–5 We present the video and
clinical profiles, neuropsychological evaluation, and
neuropathological features of a patient who presented
with CBS and postmortem asymmetrical AD pathological involvement.
CASE REPORT
A 60-year-old, right-handed male high school teacher
presented with slow loss of function in his left arm.
Initial evaluation by a neurologist documented a left

2019

hemi-Parkinsonism and a left upper extremity myoclonus. His family history revealed that his mother had a
3-year history of dementia and died at 83 years of age.
Brain computed tomography and magnetic resonance
image (MRI) scans were normal for his age. During the
first year, the patient noted progressive difficulties in
dressing, reading a map, mental slowness, writing, and
recognizing where his left hand was in space. A neuropsychological evaluation revealed mild deficits in attention, complex reasoning, visual perception, and visual
constructive skills, as well as moderate to severe visual
memory impairment. His performance and full-scale IQ
scores were considered below expectation given his premorbid functioning (Table 1; Year 1). Three years after
symptom onset, the patient was examined for the first
time at the National Institutes of Health (NIH). He was
alert and oriented with immediate memory 3/3, delayed
recall 2/3, ability to follow three-step commands and
anomia with a good interpretation of proverbs and social
situations. He had left visual field neglect, left ideomotor
apraxia, and an alien limb phenomenon manifested as
intermanual conflict and inability to differentiate his limb
from the examiner’s limb. Cranial nerves were normal.
He had bilateral bradykinesia and rigidity, more evident
on the left; stooped posture; and decreased associated
movements when walking. He had a left upper extremity
and occasionally right upper extremity action and stimulus sensitive myoclonus. There was a left pronator drift
and a positive left Babinski sign. There was a palmomental reflex, but no grasp or snout. MRI of the brain
showed asymmetrical cerebral cortical and subcortical
atrophy, more pronounced on the right (Fig. 1). An
electroencephalogram (EEG) showed mild background
disorganization but no focal abnormalities or periodic
discharges. The sensory evoked potentials confirmed the
presence of cortical originated myoclonic movements.
Neuropsychological tests showed impairment in multiple
cognitive domains consistent with mild dementia (Table
1; Year 3). He was markedly impaired on the Benton
Visual Form Discrimination and Judgment of Line Orientation Tests. His drawings were remarkable for their
dramatic neglect of the left visual hemi-field. Five years
from symptom onset, he started to drag his left foot and
myoclonus spread to all extremities. His posture became
more stooped, and he required assistance for activities of
daily living. On examination, the degree of his cognitive
impairment and aphasia had worsened (Table 1; Year 5).
He showed a bilateral ideomotor apraxia, more evident
on the left, for both transitive and intransitive actions. He
had a dystonic posturing of the left hand and difficulty in
finding and controlling the left hand that seemed to move
on its own (see video Segment 1, alien limb phenome-

Movement Disorders, Vol. 21, No. 11, 2006

2020

P. CHAND ET AL.
TABLE 1. Neuropsychological evaluation
Neuropsychological test
Wechsler Adult Intelligence Scale-Revised
Score (Percentile)
Full Scale IQ
Verbal IQ
Information
Digit Span
Vocabulary
Arithmetic
Comprehension
Similarities
Performance IQ
Picture Completion
Picture Arrangement
Block Design
Object Assembly
Digit Symbol
Wechsler Memory Scale-Revised Raw
Score (Percentile)
General Memory Index
Delayed Recall
Digit Span Forward
Visual Memory Span Forward
Visual memory Span Backward
Logical Memory I
Logical memory II
Visual reproduction I
Visual reproduction II
Mattis Dementia Rating Scale
Total Raw Score
Attention
Initiation/Perseveration
Construction
Conceptualization
Memory
Benton Judgment of Line Orientation
Benton Facial Recognition Test
Benton Visual Form Discrimination
Western Aphasia Battery

Year 1 evaluation

Year 3 evaluation

Year 5 evaluation

96a (40)
113 (81)

80 (9)
94 (34)
11
5
11
5
12
10
61 (1)
4
2
2
2
1

Untestable
76 (5)
7
2
9
2
10
7
Untestable

⬍50
81
4 (⬍5%)
1 (⬍1%)
1 (⬍1%)
8 (⬍3%)
7 (⬍9%)
10 (2%)
17 (17%)

Untestable

118
30
31
3
37
17
25/60
35/54 (⬍37)
6/16

71
25
14
0
26
6

78 (7)

Untestable
6/16
60/100

a
A premorbid-full scale IQ of 116/117 was estimated, based on familiarity with terms and concepts and demographic
variables. Untestable: Test was attempted but discontinued due to multiple errors.

non). He also showed a stimulus-sensitive myoclonus
(see video Segment 1). Seven years after symptom onset,
he developed severe difficulties ambulating and eventu-

ally became bedridden; his left arm became severely
dystonic and contracted. His speech became almost incomprehensible, and he was mute a few months before

FIG. 1. Coronal and axial T1-weighted sequence of magnetic resonance imaging scan of
the brain, showing diffuse cerebral atrophy and
ventriculomegaly, being more prominent on the
right fronto-temporo-parietal area.

Movement Disorders, Vol. 21, No. 11, 2006

AD PRESENTING AS CORTICOBASAL SYNDROME

2021

TABLE 2. Neuropathology: lesion counts of senile plaques and neurofibrillary
tangles in cerebral cortical sections
Senile plaques

Neurofibrillary
tangles

Amyloid
angiopathy

Area

Left

Right

Left

Right

Left

Right

Frontal
Temporal
Parietal
CA4
CA2
Subiculum
Entorhinal cortex

50
50
50
11.5
1
19
20.5

50
50
50
12
6.5
40
41

9.5
8
2.5
5
13.5
11.5
19.5

11.5
16.5
11
4.5
14
27.5
22

3
0
0

3
1
2

The tau burden was based upon image analysis of PHF-1 immunostained sections. The
regions studied were from the superior frontal and superior parietal sections. The thickness
was 5 microns. The fields were chosen at random in the region of interest, and the analysis
was performed blinded to side. The senile plaques were counted and counts truncated at 50,
because this is more than twice the maximum needed for the Khachaturian criteria for AD.
The senile plaques were frequently neuritic in type with dense amyloid cores. Amyloid
angiopathy was noted in the frontal section and was scored by a three-point system as mild,
moderate, or severe, based upon the density of affected vessels in the leptomeninges and
parenchyma.

his death. Laboratory studies were always normal. He
died at age 68, 8 years after initial symptom onset.
Neuropathology
The brain weighed 1,225 grams and displayed moderate atrophy in the frontal, parietal, and superior temporal lobes. Minimal atherosclerosis was apparent in the
arteries of the circle of Willis and their major branches.
Microscopic sections of the neocortex, hippocampus,
basal ganglia, midbrain, pons, medulla, and cerebellum
were examined with hematoxylin and eosin (H&E), thioflavin-S fluorescent microscopy and all sections were
immunostained with tau antibodies (PHF-1) by standard
methods.6 The neocortex on H&E stain displayed neuronal loss, slight vacuolar change in the upper cortical
layers and gliosis. With thioflavin-S stains, many senile
plaques (SP) and neurofibrillary tangles (NFT) were
noted. Lesion counts are shown in Table 2. The tau
immunostaining showed extensive NFTs in the neocortex, including the primary visual cortex, and was thus
consistent with “Braak stage VI.”7 Patchy neuronal loss
in Sommer’s sector with NFT in residual neurons, SP in
the pyramidal cell and molecular layers of the dentate
fascia, and granulovacuolar degeneration or Hirano bodies were seen in the hippocampus, but there was no
hippocampal sclerosis. The entorhinal cortex had loss of
neurons in layer II with many NFT and SP (15–26 per
10⫻ field). NFT were present in both layer II (14 –25 per
40⫻ field) and the deeper cortical layers (10 –12 per 40⫻
field). The NFT lesion counts in the various cortical
sections (Fig. 2) showed a significantly greater increased
right side involvement in CA1 (P ⬍ 0.004) and subicu-

lum of the hippocampal sectors (P ⬍ 0.003) and the right
temporal (P ⬍ 0.048) and parietal (P ⬍ 0.008) areas
(Mann–Whitney rank sum test). However, the counts
were not adjusted for atrophy.
The case met the Consortium to Establish a Registry
for AD (CERAD) and NIA-Reagan criteria for “definite”
and “high likelihood AD,” respectively. The tau stains
showed Alzheimer’s type NFT in the expected distribution, but no evidence of ballooned neurons, astrocytic
plaques, or tau immunoreactivity in the white matter,
lower brainstem, or cerebellum, which are hallmarks of
CBD.8,9
The basal nucleus of Meynert was not available for
study, but the diagonal band of Broca had only a few

FIG. 2. Tau burden in frontal and parietal lobes with image analysis.
Sections from frontal and parietal cortices of right and left sides were
immunostained with a monoclonal antibody to tau (PHF-1). Thirty
nonoverlapping microscopic fields were photographed from each section, and the burden of tau immunoreactivity was determined from each
captured image using image analysis software (SigmaScan Plus). The
proportion of the area occupied by tau-immunoreactive neurons and
neuronal processes ranged from 2.7% to 22.7%. The tau burden was
significantly greater in frontal than parietal lobes for both sides. There
was a significantly greater tau burden in both frontal and parietal lobes
on the right compared with the left.

Movement Disorders, Vol. 21, No. 11, 2006

2022

O. SITBURANA AND W.G. ONDO

NFT. The basal ganglia had many non-neuritic SP and
Alzheimer’s type II astrocytes. There were a few NFT in
the striatum, substantia nigra, dorsal raphe, and tectum, but
no significant neuronal loss or Lewy bodies. The locus
ceruleus and the central raphe had NFT. The lower brainstem and brainstem fiber tracts were unremarkable, except
for scattered NFT in the reticular formation. The cerebellum
had unremarkable Purkinje and internal granular cell layers,
no NFT, and many diffuse amyloid plaques.
DISCUSSION
The clinical CBS presentation in this case of an alien left
hand phenomenon, cortical myoclonus, Parkinsonism, bilateral parietal lobe dysfunction, and apraxia with preserved
initial language skills was highly suggestive of CBD, but at
autopsy, 8 years after symptom onset, the pathology was
that of AD together with some scattered ballooned pale
neurons in the cerebral cortex. The CBS-like presentation in
AD is rare,4,5 and the alien limb phenomenon has been
reported only once before in AD3 and is an illustration of
the clinical heterogeneity that may occur in AD. In retrospect, the early marked impairment of memory is unusual
for CBD and should raise the suspicion of AD with an
atypical presentation. Our patient showed the characteristic
findings reported in the neuropsychological testing in CBD
such as asymmetrical limb apraxia (usually ideomotor),
constructional and visuospatial difficulties, acalculia, a dysexecutive syndrome, and a nonfluent aphasia.10 He showed
impairment in multiple cognitive domains consistent with a
mild dementia.
Quantitative comparative neuropathologic studies
showed a predominance of lesions in the right frontoparietal region that could correlate with the signs of
apraxia, visual neglect, and alien limb phenomenon on
his left side. The tau stains showed AD-type NFT in the
expected distribution, but no evidence of the hallmarks
of CBD.9 The SP and NFT found in the striatum, substantia nigra, dorsal raphe, and even the midbrain tectum
are known to occur in advanced AD and are likely to
have contributed to the clinical signs of dystonia, Parkinsonism, and myoclonus in our patient, leading to the
CBS phenotype. It is interesting to note that AD and
CBD are now classified as tauopathies—as the main
proteinaceous component of NFTs is the abnormally
phosphorylated microtubule associated protein tau. The
extent to which the molecular structure of the tau aggregates varies in these diseases is just beginning to be
understood. Although the characteristic tau abnormality
and the sites of lesions vary among the tauopathies, there
may be considerable overlap in the clinical signs between them. One possible explanation for this clinical
diversity may be that the clinical profile is related to the

Movement Disorders, Vol. 21, No. 11, 2006

location of the tau neuropathology, which may vary
among patients with the same tauopathy as exemplified
in the present case. Except for this patient’s mother, there
were no other family members with a clinical diagnosis
of AD. Further research is needed to better understand
the reasons for the various underlying pathologic CBS
presentations and the diverse clinical AD phenotypic
presentations.
Acknowledgments: We thank Ann MacIntyre for her contributions to this case-report. Dr. Ishizqwa’s current address is
Department of Pathology, Saitama University, Saitama, Japan.

LEGEND TO THE VIDEO
The videotape shows the patient executing a series of
commands first with the right hand and then with the left
hand: (1) bang a gavel, (2) saw a board, (3) stir a gallon of
paint, (4) snap fingers, (5) dial a phone, and (6) tap a
telegraph. During the execution of these commands, the
patient displays considerable intermanual conflict, ideomotor apraxia, and action myoclonus. The left hand is held in
a dystonic posture. Despite the dystonia, he is able to
execute some commands, such as tapping a telegraph, but
he is unable to perform others, such as dial a phone or stir
paint. He is unable to snap fingers with the left hand and
says that he cannot find his hand (alien limb phenomenon).
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