Asymmetric Cortical Degeneration Syndromes A
Proposed Clinical Classification Richard J. Caselli, MD, Clifford R. Jack, Jr, MD
\s=b\ Twenty-six patients presented with slowly progressive focal neurologic symptoms that conformed clinically to one of three categories: aphasia, perceptuomotor dysfunction, or neuropsychiatric dysfunction. Of 12 patients with progressive aphasia, seven were dysfluent and five were fluent. Nine patients had progressive perceptuomotor impairment due to bilateral parietal lobe atrophy, which also included frontal lobe signs in seven patients and occipital lobe signs in three patients. The right hemisphere was more severely involved in five patients and the left hemisphere in four. Five patients had a progressive neuropsychiatric syndrome, and there was also generalized spasticity in three patients due to frontal lobe atrophy. The clinically suspected anatomic localization of cortical atrophy or hypoperfusion in all three categories was confirmed with neuroimaging techniques. A brain biopsy specimen from one patient showed mild, nonspecific degenerative changes. A clinical classification scheme incorporating our observations as well as the observations of others is presented to aid in the recognition of these syndromes. (Arch Neurol. 1992;49:770-780)
result from focal neurologie deficits circumscribed degenerative process, Progressi v e relatively with his Pick1 can
a
as
emphasized in original report on a patient progressive aphasia and dementia due to asymmetric at¬ rophy of the left temporal lobe. Since then, other clinical permutations of focal cerebral degenerative processes have been described, including isolated progressive aphasia without dementia,2 progressive frontal lobe syndromes,3"5 progressive apraxia,6 progressive parietal lobe syn¬ dromes,7-8 and progressive prosopagnosia.9 The neuro¬ pathologic substrates, which differ among patients, in¬
clude increased neuronal lipofuscin,210 severe gliosis,8 spongiform atrophy,11 Pick's disease,12 Alzheimer's dis¬ ease,1314 and an unusual combination of pathologic fea¬ tures.15 Corticobasal ganglionic degeneration with neu-
for publication March 11, 1992. From the Section of Neurology, Mayo Clinic Scottsdale (Ariz) (Dr Caselli); and the Section of Neurologic Radiology, Mayo Clinic and Mayo Foundation, Rochester, Minn (Dr Jack). Presented, in part, at the 42nd annual meeting of the American Academy of Neurology, Miami Beach, Fla, May 2, 1990. Reprint requests to Section of Neurology, Mayo Clinic Scottsdale, 13400 Shea Blvd, Scottsdale, AZ 85259 (Dr Caselli).
Accepted
roñal achromasia produces relatively focal parietofrontal atrophy and changes in certain subcortical nuclei (most consistently, the substantia nigra).16"18 However, neuronal achromasia has also been associated with progressive is occasionally accompa¬ aphasia.19 Motor neuron disease nied by clinically distinctive dementia syndromes, includ¬ ing frontal lobe features20 and progressive aphasia.21 Different clinical disorders do not appear to have distinctive histopathologic features; thus, clinical symp¬ toms may be determined solely by the neuroanatomic lo¬ cation of the degenerative process.10 This point is of diag¬ nostic importance because modern neuroimaging techniques can reveal focal areas of atrophy and help to distinguish focal cerebral degenerative processes from one another and from clinically typical cases of Alzheimer's disease. Despite increasing clinical awareness in the last decade about focal cerebral degenerative diseases, they remain underrecognized. In part, this is the result of uncertainty about nosologie relationships between the variously de¬ scribed pathologic entities underlying these conditions. It also reflects an inveterate, but imprecise, tendency to regard dementia as a "diffuse" cognitive disturbance,22-23 implying a certain pathophysiologic and clinical homoge¬ neity among patients with different dementing illnesses. Hence, patients with unusual cognitive asymmetries and who perform imperfectly in cognitively disparate areas are considered to have a "diffuse" disturbance, which, by in¬ ference, is generally equated with Alzheimer's disease. This is true in some instances.24 However, it has been shown that appreciation of the sometimes subtle clinical distinctions between typical Alzheimer's disease and other forms of dementia in patients with a clinical diagnosis of "diffuse dementia" or Alzheimer's disease may occasion¬ ally lead to an alternative diagnosis and even occasional recognition of a treatable condition.25-26 Because there is unequivocal evidence that some patients with relatively focal degenerative syndromes have more diffuse clinical and pathologic abnormalities, we use the term asymmetric cerebral degeneration syndrome (ACDS) to refer to patients whose clinical condition is dominated by a focal syndrome but whose neuropsychologic profile may reveal dispro¬ portionately milder impairment in other cognitive do¬ mains. Increased clinical recognition of ACDS is an important early step in further elucidating the nosologie relationships
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Table
1.—Demographics of 26
Characteristics No. of
patients
M:F ratio
Sex, Age at onset of disease, y Time to study, y Education, No. of y Handedness, R:L ratio *Right lobe more involved than left. tLeft lobe more involved than right.
Patients With
Progressive Aphasia Syndrome I Fluent Dysfluent
an
Asymmetric Cortical Degenerative Syndrome
Progressive Perceptuomotor
Progressive Neuropsychiatrie Syndromes Neuropsychiatrie Spastic
Syndromes
I-
I
R>L*
L>Rt
Overall
7
5
5
4
2
3
26
2:5
2:3
2:3
0:4
0:2
1:2
7:19
66
61
63
57
45
59
60
4
3.3
4
2.3
2.5
5.7
4
12
13
14
15
16
11
13
5:2
5:0
4:1
4:0
2:0
3:0
23:3
of the underlying degenerative diseases. Therefore, to fa¬ cilitate the clinical recognition of ACDS, we summarize our 29-month experience with patients whose clinical condi¬ tion was dominated by a slowly progressive neurologic syndrome that appeared readily localizable in the cere¬ brum. In most instances, the relative focality of the disease was supported by neuroimaging techniques. We also present a clinical classification scheme of ACDS that does not rely on pathologic data. PATIENTS AND METHODS All patients who presented with ACDS and who were exam¬ ined by the behavioral neurology service were selected consecu¬ tively between luly 1988 and December 1990. Asymmetric cortical degenerative syndrome was defined as a slowly progressive (ie, a period of years), localizable neurologic deficit or cortical syn¬ drome that was not caused by a focal structural lesion, such as tumor, vascular impairment or anomaly, demyelination, trauma, or infection. No patient had a history of neurologic disease, except for an unrelated pain syndrome. The demographic data are listed in Table 1. All patients underwent standard neurologic examination and detailed cognitive and radiologie evaluations. Most patients un¬ derwent neuropsychologic examination, and all were examined by a behavioral neurologist (RJ.C. in all but one case). Standard¬ ized neuropsychologic tests27"37 and clinical assessments were performed (Tables 2 and 3); however, not all patients received identical tests. Focal atrophy and hypoperfusion, although often subtle, were demonstrated radiographically with magnetic reso¬ nance imaging (MRI) and single-photon emission computed to¬
tenuation correction. Transaxial sections were generated from the collected data, and coronal and sagittal sections were recon¬ structed from the transaxial sections. In some patients, the decrease in perfusion apparent on SPECT may reflect loss of tis¬ sue volume because of local brain atrophy in addition to a decrease in cerebral blood flow per unit volume of brain tissue. Neither computed tomography (CT), MRI, nor SPECT was in¬ terpreted in a blinded fashion for the purposes of our study. Al¬ though focal areas of atrophy may be striking in some cases, they may be subtle and must often be looked for. The diagnosis of ACDS was suspected on a clinical basis, and neuroimaging, ob¬ tained in most cases as a clinically necessary part of the diagnos¬ tic evaluation, was used to specifically assess the brain areas in question. Nonspecific regions of increased T2 signal were occa¬ sionally encountered in asymptomatic brain regions to the mild degree that is commonly encountered in cognitively normal eld¬ erly patients, but in no instance was there evidence of an under¬ lying structural abnormality other than focal atrophy in symp¬ tomatic brain regions. No patient with ,-weighted MRI abnormalities other than cortical atrophy was included in the
study.
RESULTS On the basis of extensive neurologic, linguistic, and cognitive testing, three distinct clinical categories of ACDS were
identified:
progressive aphasia, progressive percep¬ and progressive neuropsychiatrie
dysfunction, syndromes. tuomotor
Of the 26
were men
patients studied, 19 were women and seven (mean age, 60 years). Three of the patients were
mography (SPECT) in most patients. Magnetic resonance imaging was performed at 1.5 (General
left-handed. Six patients had a family history of dementia in a first-, second-, or third-degree relation, and one patient had a son with Tourette's syndrome.
three-dimensional volumetric magnetic resonance data set was acquired initially. This was a volumetric gradient echo acquisition measuring 24x24x12 cm in three dimensions, with contiguous cubic 1-mm voxels. This data set was then moved by magnetic tape off line to a stand-alone Sun workstation (Sun Microsystems, Mountain View, Calif). The data were then subjected to a two-dimensional segmentation and edge-extraction operation. Finally, a surface-rendering step was performed. The surfacerendering method has been described previously.38-39 Single-photon emission computed tomography was performed with a tomographic scanning camera (General Electric Starcam). Image acquisition was initiated 1 hour after administration of the radiotracer, 20 mC of [technetium-99m] hexamethyl propylene amine oxime (99mTc-HM-PAO), to an antecubital vein. The patient was placed in the supine position with eyes closed, and 128 frames in a 360° elliptical orbit were obtained with 20 seconds per frame. Tomographic reconstruction was done after prefiltration and at-
Twelve patients (eight women and four men) presented with slowly progressive aphasia, which was dysfluent in seven patients and fluent in five. Mean age at onset of dis¬ ease was 63 years (range, 54 to 73 years). Patients with were slightly older than those with flu¬ dysfluent ent aphasia (Table 1). Ten of the patients were fully righthanded, and two (men with dysfluent aphasia) were fully left-handed. General neurologic examination revealed no evidence of sensorimotor disorders, ideomotor apraxia, pseudobulbar affect, or perseverative tendencies. Cere¬ brospinal fluid examination was performed in one patient with progressive aphasia (dysfluent), and the results were normal. Patients with dysfluent aphasia manifested orofacial
Electric, Milwaukee, Wis). To generate surface-rendered images,
Progressive Aphasia
a
aphasia
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Table 2.—Performance of 26 Patients With an Asymmetric Cortical Degenerative on the Complex Figure Test, WAIS-R, WMS, WMS-R, and AVLT*
Syndrome
Scores
Complex Figure Test27
Syndrome/
Patient No. (Date)
Progressive aphasia Dysfluent 1 1 2
(5/89) (2/90) (2/89) (4/90)
(1/89) (7/90)
I
Copy
1
Recall
35 36 34 36 32 35
19 9.5 15.5 13.5 17.5 22.5
32 28 34
17.5 13.5 16.5
36
16
34 28 35 34
21.5 7 16 11
91
VIQt
PIQ
81 86
99 90
(Peabody)
AVLT31
WMS-R30
WAIS-Rt28
WMS,30 MQ
Vel
Vil
86 80 85 93
68 71 54 82 92
81 99 83 89 108 80
Delayed
12
10
12
5
0
2
4 4 2
5 2 4
Recall
101 87
99
70 65 64 70
Short-term Recall
Trial 5
121
62
81
75
119
4 6 6
Fluent 8 9 9 10 11 12
(9/87) (5/89)
67
(Peabody)
68 79 59 72
10 1
86
110 83
94
69
78
52
7 7
Progressive perceptuomotor
syndromes R>L 13 13 14 15 16 16 17
L>R 18 18 19 19 20 21 21
(4/89) (4/90)
20 5
(2/89) (5/90)
13.5 10.5 2.5 1
(7/89) (7/90) (12/88) (10/90)
(1/89) (4/90) Progressive
neuropsychiatrie syndromes Neuropsychiatrie
0 0.5 3.5 1
32 35 20.5
24 25 26 26
0 0 12.5
(9/89) (8/90)
1.5
26.5 22
22 23 23
(10/89) (8/90) Spastic
10.5
11.5 1.5
50 6.5
92 96 97 83 78 72
65 80 67 71 59 63
108
82
104
83
68
64
84 88 82
78 59 61
70
Proposed Clinical Classification Richard J. Caselli, MD, Clifford R. Jack, Jr, MD
\s=b\ Twenty-six patients presented with slowly progressive focal neurologic symptoms that conformed clinically to one of three categories: aphasia, perceptuomotor dysfunction, or neuropsychiatric dysfunction. Of 12 patients with progressive aphasia, seven were dysfluent and five were fluent. Nine patients had progressive perceptuomotor impairment due to bilateral parietal lobe atrophy, which also included frontal lobe signs in seven patients and occipital lobe signs in three patients. The right hemisphere was more severely involved in five patients and the left hemisphere in four. Five patients had a progressive neuropsychiatric syndrome, and there was also generalized spasticity in three patients due to frontal lobe atrophy. The clinically suspected anatomic localization of cortical atrophy or hypoperfusion in all three categories was confirmed with neuroimaging techniques. A brain biopsy specimen from one patient showed mild, nonspecific degenerative changes. A clinical classification scheme incorporating our observations as well as the observations of others is presented to aid in the recognition of these syndromes. (Arch Neurol. 1992;49:770-780)
result from focal neurologie deficits circumscribed degenerative process, Progressi v e relatively with his Pick1 can
a
as
emphasized in original report on a patient progressive aphasia and dementia due to asymmetric at¬ rophy of the left temporal lobe. Since then, other clinical permutations of focal cerebral degenerative processes have been described, including isolated progressive aphasia without dementia,2 progressive frontal lobe syndromes,3"5 progressive apraxia,6 progressive parietal lobe syn¬ dromes,7-8 and progressive prosopagnosia.9 The neuro¬ pathologic substrates, which differ among patients, in¬
clude increased neuronal lipofuscin,210 severe gliosis,8 spongiform atrophy,11 Pick's disease,12 Alzheimer's dis¬ ease,1314 and an unusual combination of pathologic fea¬ tures.15 Corticobasal ganglionic degeneration with neu-
for publication March 11, 1992. From the Section of Neurology, Mayo Clinic Scottsdale (Ariz) (Dr Caselli); and the Section of Neurologic Radiology, Mayo Clinic and Mayo Foundation, Rochester, Minn (Dr Jack). Presented, in part, at the 42nd annual meeting of the American Academy of Neurology, Miami Beach, Fla, May 2, 1990. Reprint requests to Section of Neurology, Mayo Clinic Scottsdale, 13400 Shea Blvd, Scottsdale, AZ 85259 (Dr Caselli).
Accepted
roñal achromasia produces relatively focal parietofrontal atrophy and changes in certain subcortical nuclei (most consistently, the substantia nigra).16"18 However, neuronal achromasia has also been associated with progressive is occasionally accompa¬ aphasia.19 Motor neuron disease nied by clinically distinctive dementia syndromes, includ¬ ing frontal lobe features20 and progressive aphasia.21 Different clinical disorders do not appear to have distinctive histopathologic features; thus, clinical symp¬ toms may be determined solely by the neuroanatomic lo¬ cation of the degenerative process.10 This point is of diag¬ nostic importance because modern neuroimaging techniques can reveal focal areas of atrophy and help to distinguish focal cerebral degenerative processes from one another and from clinically typical cases of Alzheimer's disease. Despite increasing clinical awareness in the last decade about focal cerebral degenerative diseases, they remain underrecognized. In part, this is the result of uncertainty about nosologie relationships between the variously de¬ scribed pathologic entities underlying these conditions. It also reflects an inveterate, but imprecise, tendency to regard dementia as a "diffuse" cognitive disturbance,22-23 implying a certain pathophysiologic and clinical homoge¬ neity among patients with different dementing illnesses. Hence, patients with unusual cognitive asymmetries and who perform imperfectly in cognitively disparate areas are considered to have a "diffuse" disturbance, which, by in¬ ference, is generally equated with Alzheimer's disease. This is true in some instances.24 However, it has been shown that appreciation of the sometimes subtle clinical distinctions between typical Alzheimer's disease and other forms of dementia in patients with a clinical diagnosis of "diffuse dementia" or Alzheimer's disease may occasion¬ ally lead to an alternative diagnosis and even occasional recognition of a treatable condition.25-26 Because there is unequivocal evidence that some patients with relatively focal degenerative syndromes have more diffuse clinical and pathologic abnormalities, we use the term asymmetric cerebral degeneration syndrome (ACDS) to refer to patients whose clinical condition is dominated by a focal syndrome but whose neuropsychologic profile may reveal dispro¬ portionately milder impairment in other cognitive do¬ mains. Increased clinical recognition of ACDS is an important early step in further elucidating the nosologie relationships
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Table
1.—Demographics of 26
Characteristics No. of
patients
M:F ratio
Sex, Age at onset of disease, y Time to study, y Education, No. of y Handedness, R:L ratio *Right lobe more involved than left. tLeft lobe more involved than right.
Patients With
Progressive Aphasia Syndrome I Fluent Dysfluent
an
Asymmetric Cortical Degenerative Syndrome
Progressive Perceptuomotor
Progressive Neuropsychiatrie Syndromes Neuropsychiatrie Spastic
Syndromes
I-
I
R>L*
L>Rt
Overall
7
5
5
4
2
3
26
2:5
2:3
2:3
0:4
0:2
1:2
7:19
66
61
63
57
45
59
60
4
3.3
4
2.3
2.5
5.7
4
12
13
14
15
16
11
13
5:2
5:0
4:1
4:0
2:0
3:0
23:3
of the underlying degenerative diseases. Therefore, to fa¬ cilitate the clinical recognition of ACDS, we summarize our 29-month experience with patients whose clinical condi¬ tion was dominated by a slowly progressive neurologic syndrome that appeared readily localizable in the cere¬ brum. In most instances, the relative focality of the disease was supported by neuroimaging techniques. We also present a clinical classification scheme of ACDS that does not rely on pathologic data. PATIENTS AND METHODS All patients who presented with ACDS and who were exam¬ ined by the behavioral neurology service were selected consecu¬ tively between luly 1988 and December 1990. Asymmetric cortical degenerative syndrome was defined as a slowly progressive (ie, a period of years), localizable neurologic deficit or cortical syn¬ drome that was not caused by a focal structural lesion, such as tumor, vascular impairment or anomaly, demyelination, trauma, or infection. No patient had a history of neurologic disease, except for an unrelated pain syndrome. The demographic data are listed in Table 1. All patients underwent standard neurologic examination and detailed cognitive and radiologie evaluations. Most patients un¬ derwent neuropsychologic examination, and all were examined by a behavioral neurologist (RJ.C. in all but one case). Standard¬ ized neuropsychologic tests27"37 and clinical assessments were performed (Tables 2 and 3); however, not all patients received identical tests. Focal atrophy and hypoperfusion, although often subtle, were demonstrated radiographically with magnetic reso¬ nance imaging (MRI) and single-photon emission computed to¬
tenuation correction. Transaxial sections were generated from the collected data, and coronal and sagittal sections were recon¬ structed from the transaxial sections. In some patients, the decrease in perfusion apparent on SPECT may reflect loss of tis¬ sue volume because of local brain atrophy in addition to a decrease in cerebral blood flow per unit volume of brain tissue. Neither computed tomography (CT), MRI, nor SPECT was in¬ terpreted in a blinded fashion for the purposes of our study. Al¬ though focal areas of atrophy may be striking in some cases, they may be subtle and must often be looked for. The diagnosis of ACDS was suspected on a clinical basis, and neuroimaging, ob¬ tained in most cases as a clinically necessary part of the diagnos¬ tic evaluation, was used to specifically assess the brain areas in question. Nonspecific regions of increased T2 signal were occa¬ sionally encountered in asymptomatic brain regions to the mild degree that is commonly encountered in cognitively normal eld¬ erly patients, but in no instance was there evidence of an under¬ lying structural abnormality other than focal atrophy in symp¬ tomatic brain regions. No patient with ,-weighted MRI abnormalities other than cortical atrophy was included in the
study.
RESULTS On the basis of extensive neurologic, linguistic, and cognitive testing, three distinct clinical categories of ACDS were
identified:
progressive aphasia, progressive percep¬ and progressive neuropsychiatrie
dysfunction, syndromes. tuomotor
Of the 26
were men
patients studied, 19 were women and seven (mean age, 60 years). Three of the patients were
mography (SPECT) in most patients. Magnetic resonance imaging was performed at 1.5 (General
left-handed. Six patients had a family history of dementia in a first-, second-, or third-degree relation, and one patient had a son with Tourette's syndrome.
three-dimensional volumetric magnetic resonance data set was acquired initially. This was a volumetric gradient echo acquisition measuring 24x24x12 cm in three dimensions, with contiguous cubic 1-mm voxels. This data set was then moved by magnetic tape off line to a stand-alone Sun workstation (Sun Microsystems, Mountain View, Calif). The data were then subjected to a two-dimensional segmentation and edge-extraction operation. Finally, a surface-rendering step was performed. The surfacerendering method has been described previously.38-39 Single-photon emission computed tomography was performed with a tomographic scanning camera (General Electric Starcam). Image acquisition was initiated 1 hour after administration of the radiotracer, 20 mC of [technetium-99m] hexamethyl propylene amine oxime (99mTc-HM-PAO), to an antecubital vein. The patient was placed in the supine position with eyes closed, and 128 frames in a 360° elliptical orbit were obtained with 20 seconds per frame. Tomographic reconstruction was done after prefiltration and at-
Twelve patients (eight women and four men) presented with slowly progressive aphasia, which was dysfluent in seven patients and fluent in five. Mean age at onset of dis¬ ease was 63 years (range, 54 to 73 years). Patients with were slightly older than those with flu¬ dysfluent ent aphasia (Table 1). Ten of the patients were fully righthanded, and two (men with dysfluent aphasia) were fully left-handed. General neurologic examination revealed no evidence of sensorimotor disorders, ideomotor apraxia, pseudobulbar affect, or perseverative tendencies. Cere¬ brospinal fluid examination was performed in one patient with progressive aphasia (dysfluent), and the results were normal. Patients with dysfluent aphasia manifested orofacial
Electric, Milwaukee, Wis). To generate surface-rendered images,
Progressive Aphasia
a
aphasia
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 06/19/2015
Table 2.—Performance of 26 Patients With an Asymmetric Cortical Degenerative on the Complex Figure Test, WAIS-R, WMS, WMS-R, and AVLT*
Syndrome
Scores
Complex Figure Test27
Syndrome/
Patient No. (Date)
Progressive aphasia Dysfluent 1 1 2
(5/89) (2/90) (2/89) (4/90)
(1/89) (7/90)
I
Copy
1
Recall
35 36 34 36 32 35
19 9.5 15.5 13.5 17.5 22.5
32 28 34
17.5 13.5 16.5
36
16
34 28 35 34
21.5 7 16 11
91
VIQt
PIQ
81 86
99 90
(Peabody)
AVLT31
WMS-R30
WAIS-Rt28
WMS,30 MQ
Vel
Vil
86 80 85 93
68 71 54 82 92
81 99 83 89 108 80
Delayed
12
10
12
5
0
2
4 4 2
5 2 4
Recall
101 87
99
70 65 64 70
Short-term Recall
Trial 5
121
62
81
75
119
4 6 6
Fluent 8 9 9 10 11 12
(9/87) (5/89)
67
(Peabody)
68 79 59 72
10 1
86
110 83
94
69
78
52
7 7
Progressive perceptuomotor
syndromes R>L 13 13 14 15 16 16 17
L>R 18 18 19 19 20 21 21
(4/89) (4/90)
20 5
(2/89) (5/90)
13.5 10.5 2.5 1
(7/89) (7/90) (12/88) (10/90)
(1/89) (4/90) Progressive
neuropsychiatrie syndromes Neuropsychiatrie
0 0.5 3.5 1
32 35 20.5
24 25 26 26
0 0 12.5
(9/89) (8/90)
1.5
26.5 22
22 23 23
(10/89) (8/90) Spastic
10.5
11.5 1.5
50 6.5
92 96 97 83 78 72
65 80 67 71 59 63
108
82
104
83
68
64
84 88 82
78 59 61
70
