Abstract
Objective: To evaluate the clinical presentations and dominant symptoms of patients with postmortem proven cortical–basal ganglionic degeneration (CBGD) from one neuropathology center.
Background: CBGD is a rare but increasingly recognized condition with clinical and pathologic features that continue to evolve. Attempts have been made to develop clinical criteria to enhance the specificity of diagnosis, but it is not clear what proportion of patients harboring CBGD disease present in the “classical” fashion versus other presentations. Previous large-case series that emphasize a parietal/perceptual-motor presentation may be biased because the cases mainly originate from movement disorder centers.
Methods: Thirteen cases of pathologically confirmed CBGD with sufficient clinical data were identified from a single neuropathology center between 1981 and 1996.
Results: Before death, only 4 of the 13 patients had a clinical diagnosis of CBGD, 6 had a clinical diagnosis of Alzheimer’s disease (AD), 1 had AD and parkinsonism, and 2 had an atypical dementia of the frontotemporal type. Nine of 13 cases had early dementia.
Conclusions: Dementia was the most common presentation of CBGD in this study. Despite the best efforts to define criteria to enhance the specificity of a diagnosis of CBGD, it is becoming clear that the clinical syndrome that accompanies this disease is quite varied. Unfortunately, patients fulfilling classical diagnostic criteria may represent a minority of those with this pathologic diagnosis.
Cortical-basal ganglionic degeneration (CBGD), or corticobasal degeneration, was originally described as a late adult-onset, progressive neurodegenerative disorder. It presents as a distinctive levodopa-resistant asymmetric akinetic-rigid syndrome associated with “cortical” features such as apraxia, cortical sensory loss, and alien limb phenomenon but with a relatively intact intellectual capacity.1 Clinical presentations consisting of speech disturbances or dementia have been recognized2 but have been thought to represent the minority of cases. Large clinical series that have had pathologic confirmation in only a minority of cases3,4 have stressed a parietal/perceptual-motor type of presentation. However, these have originated from movement disorder centers that would not commonly see patients with dementia. Not surprisingly, a recent multi-institutional clinicopathologic study drawn predominantly from movement disorders clinic referrals5 found that the most common presentation of CBGD was an asymmetric parkinsonism syndrome. Conversely, recent pathologic case reports of CBGD have often demonstrated “atypical” clinical features. However, many of the available pathology series have lacked clinical details and have been largely drawn from a dementia clinic referral base.6-8 Thus, it is not clear what proportion of all patients harboring CBGD pathology present in the “typical” fashion versus other presentations.
Materials and methods.
Case selection.
We reviewed the archives of the Division of Neuropathology at the Toronto Hospital between 1981 and 1996 in search of CBGD cases. The material collected in the archives is derived from multiple sources including The Toronto Hospital autopsy service, neuropathology referrals from other hospitals, The Toronto Hospital Movement Disorder and Dementia Clinics, and the Canadian Brain Tissue Bank (CBTB). The brain specimens were fixed in neutral-buffered formalin solution for at least 2 weeks before examination. Multiple tissue blocks were sampled from the cerebral cortex, basal ganglia, brain stem, and cerebellum of each brain. The tissue blocks were embedded in paraffin, and 5-μm-thick sections were obtained. All sections were stained with hematoxylin–eosin/Luxol fast-blue and Bielschowsky’s modified silver stain. All cases with cortical neuronal loss, gliosis, and swollen neurons were retained and immunostained for the presence of tau. Selected neocortical and subcortical sections were used for immunocytochemistry for phosphorylated neurofilament (SMI-34, Sternberger Monoclonal, 1:1000), phosphorylated tau (clone AT8, Innogenetics, 1:1000), and ubiquitin (Dako cat no. Z-458, 1:600). Antibody binding was detected using a biotin–streptavidin detection system using 3,3′-diaminobenzidine as the chromogenic substrate.
The CBGD cases were characterized by cortical neuronal loss, gliosis, swollen “achromatic” neurons with substantia nigra degeneration, and “corticobasal inclusions” with widespread cortical and subcortical tau-positive neuronal and glial inclusions. Cases with these characteristic pathologic and immunohistochemical features of CBGD9,10 with sufficient clinical data were included. The clinical characteristics of these patients were obtained by a retrospective review of their medical charts. All patients were institutionalized before death and died as a result of their having a debilitating neurodegenerative condition. This case series may reflect the large number of dementia cases seen at the CBTB; however, movement disorder patients seen at The Toronto Hospital Movement Disorder Clinic are also strongly encouraged to donate their brains to the CBTB.
Results.
Clinical features.
The major clinical features are summarized in table 1. Thirteen subjects (6 female, 7 male) with the typical pathology of CBGD in whom sufficient clinical data were present were identified. Disease duration ranged from 3 to 10 years (mean, 6.1 years) with age of death from 62 to 78 years (mean = 70.2 years). One patient diagnosed as having CBGD pathologically had insufficient clinical records and was not included in the study but had been diagnosed clinically as having AD. Five patients had been seen at The Toronto Hospital Movement Disorder Clinic. The clinical and pathologic features of cases 5, 7, 9, 10, and 12 have been reported elsewhere in detail.2,11
Clinical characteristics of pathologically proven cortical–basal ganglionic degeneration (CBGD)
Patients diagnosed with CBGD clinically.
Before death, only 4 of 13 patients had a clinical diagnosis of CBGD. They had an asymmetric onset of a chronic progressive illness involving at least one abnormality of higher cortical function (apraxia, cortical sensory loss, or alien limb) plus a movement disorder consisting of a levodopa-resistant rigid, akinetic syndrome. Patient 13 was typical except for her early cognitive involvement and partial, unsustained improvement with levodopa/carbidopa. Neuropsychological assessment 1 year into her illness was mildly abnormal and showed evidence of bilateral cortical dysfunction. She had mild difficulty with tasks of attention and concentration, modest difficulty with serial list learning and conditional associative learning, as well as impairment in tasks involving higher executive functions. Patient 10 presented with a pure speech disturbance and only 5 years later had apraxia of eyelid opening and buccolingual apraxia develop. Six years into his illness, he had a wandering right arm with spontaneous “paddling” movements of the right hand, right facial spontaneous and stimulus-sensitive myoclonus, right-sided bradykinesia, and rigidity with loss of vibration in the right foot. He was thought to have CBGD before death with an unusual presentation.2
Patients initially diagnosed with AD.
Nine patients had early cognitive impairment with six patients having the clinical diagnosis of AD before death. Of the patients with AD, three (Patients 1, 3, and 9) had atypical features that could have prompted an alternative diagnosis. Patient 1 (who died in 1982) had early, rapidly progressive global cognitive dysfunction. When she was seen in neurologic consultation 1 year after symptom onset, she was institutionalized, unable to feed or dress herself, and was incontinent of both stool and urine. On examination, she was totally mute, could not follow even simple commands, and had a striking pout and bilateral grasp reflexes. She had a moderate increase in axial and left greater than right-sided tone and required assistance to ambulate. Patients 3 and 9 had early difficulty with speech. Patient 3 had some memory difficulty; however, within 3 years of his cognitive decline, he was limited to a vocabulary consisting of “yes,” “no,” and “I don’t know.” His overall condition was progressing rapidly, and at that time, his global cognitive status was so poor, he required constant supervision. Patient 9 had evidence of a severe aphasia with deficiencies involving word generation, repetition, naming, and comprehension but also had severe global cognitive decline. The patients diagnosed as having AD did have a more rapid course than would normally be expected (mean, 5.5 years), and in three cases, early extrapyramidal signs were present.
Patients initially diagnosed with a non-AD dementia.Patient 8 was thought to have an atypical dementia by the physicians caring for her as she presented with prominent personality changes. She had become increasingly withdrawn, speaking rarely and unable or unwilling to attend to routine activities of daily living. She was alert, fully aware of her surroundings, with a preserved memory after 4 years of her initial symptoms. In retrospect, a diagnosis of Pick’s disease or a frontotemporal dementia would have been appropriate but was not mentioned by the physicians caring for her. Personality changes consisting of hypersexuality, increasing gregariousness, and marked irritability were the first symptoms described in Patient 12. Over the next 2 years, he experienced a decline in memory, decreasing concentration, and unusual behavior such as sitting and staring at the clock for several hours. He was diagnosed 3 years after symptom onset with a frontal–temporal degeneration because of the personality changes. Patient 11 is complicated because she was an alcoholic with liver cirrhosis. Early bouts of confusion were believed to be secondary to hepatic encephalopathy, and when her confusion persisted, she was thought to have a Wernicke’s encephalopathy. However, 1 year after the onset of her progressive dementia, a masked-like face with bilateral bradykinesia and shuffling gait developed. Within 11/2 years, she was not oriented to time or place and followed only simple commands. She had markedly restricted upward gaze, but she had relatively preserved down gaze. She had considerable difficulty initiating any movement, was extremely rigid, and was unable to rise from a chair. A trial of levodopa/carbidopa showed no clear response. Clinicians caring for her classified her as having “dementia with parkinsonism not yet diagnosed.”
All patients eventually had at least some cognitive dysfunction, except Patient 5, who was thought not to have a dementia despite a 10-year course. Five patients (Cases 1, 3, 8, 9, and 10) had early language dysfunction that included reduced speech output. Four of these patients had accompanying early memory loss but in one patient (Patient 10), speech dysfunction progressed rapidly to mutism without cognitive changes followed after a delay of 5 years by more typical motor features of CBGD.
Neuropathologic findings.
The main findings on pathologic examination are summarized in table 2 to aid in correlating the patients with their pathologic findings. Detailed neuropathologic findings have been reported previously on all patients except one (Case 13).2,11,12 On macroscopic examination, cortical atrophy was generally most marked in the frontal lobe, where it was usually moderate to severe (but not “knife-like”) with significant loss of nigral pigmentation in all cases except Case 9. On microscopic examination, the severity of neocortical neuronal loss and gliosis reflected the pattern of cortical atrophy seen on gross examination and varied from mild neuronal loss and gliosis of the superficial layers with microvacuolation to severe pancortical neuronal loss with loss of the cytoarchitecture. Swollen neurons were most abundant in the frontal cortex; however, in one patient (Case 8), they were more numerous in the parietal lobe. Subcortical neuronal loss and gliosis were consistently observed and at least moderate to severe in the substantia nigra of all patients. Corticobasal inclusions (fibrillary homogeneous basophilic inclusions) were always present.
Neuropathologic findings of patients with cortical–basal ganglionic degeneration (CBGD)
Table 2 lists the tau immunodeposits observed in the middle frontal gyrus where their density was maximal. The most frequent findings consisted of granular neuronal deposits, neuropil threads, immunoreactive white matter profiles, and glial inclusions (glial coils and thorn-shaped astrocytes), which were abundant in all cases. Neurofibrillary tangles were also present in all cases, but were fewer in number than the granular neuronal deposits and of variable morphology, including coiled forms and small tangles in interneurons. Pick bodies were observed in seven patients but were usually few in number and were never seen in the hippocampus or dentate fascia. Concentric or annular astrocytic plaques were seen in all patients.
Discussion.
Dementia as an early feature of CBGD has been thought to be uncommon, and in the original description of three cases by Rebeiz et al.,1 the lack of significant early cognitive changes was emphasized. Clinical studies accompanied by a small number of pathologically confirmed cases were thought to support that original impression.3,11 However, in pathologically diagnosed patients, dementia has been recognized even as the sole manifestation of the disease. Older pathologic studies had used a variety of terms to describe cases of dementia with histologic changes now thought to likely represent those of CBGD. These included Pick’s disease type b,13 cortical degeneration with swollen chromatolytic neurons,14 primary progressive dementia with swollen chromatolytic neurons,15 and corticonigral degeneration with neuronal achromasia and basal neurofibrillary tangles.16
Feaney et al.6 examined seven cases of CBGD pathologically and found that most patients presented with behavioral changes and cognitive impairment. They also found aphasia to be present in six cases, but in only one case was aphasia documented in the absence of significant intellectual impairment. However, these cases were largely derived from dementia clinics (D. Dickson, personal communication), making it impossible to draw any conclusion about the relative frequency of a presentation with dementia versus a movement disorder. Schneider et al.17 found an early dementia in 6 of their 11 cases with all eventually having some cognitive decline; however, many of these patients had overlapping neuropathologic features, including AD, progressive supranuclear palsy, Parkinson’s disease, and hippocampal sclerosis. A review of the neuropathology of 50 patients with the clinical diagnosis of a frontotemporal dementia identified 4 patients with CBGD pathology. A clinicopathologic study of five autopsy cases of CBGD from Japan found that three patients presented with behavioral changes and eventually all patients became demented.8 In our pathologic series, 9 of 13 patients presented with and 12 of 13 patients eventually had dementia develop.
Five of our patients presented with prominent speech difficulties. Many cases of CBGD have been described in which marked speech disturbances occurred early in the course, exemplifying the early focal distribution of the disease process.3,17-19 Cases with histologic changes typical of CBGD presenting with language difficulties have been reported in the literature as primary progressive aphasia.10,20 Thus, CBGD needs to be considered in the differential diagnosis of progressive language disorders.
As our clinical conceptualization of this disorder is evolving, so is the understanding of its pathology. Seven of the 13 patients originally had an alternative pathologic diagnosis consisting of either atypical Pick’s disease or an unclassified dementia. The original histologic features of cortical neuronal loss, gliosis, and swollen neurons have been found to be neither distinctive nor specific. Swollen (or ballooned) neurons, once thought unique to Pick’s disease and then CBGD, are increasingly recognized in a variety of neurodegenerative conditions,21,22 and therefore it is understandable why some patients in this series had been misdiagnosed, especially early on. As the pathologic characterization of CBGD has improved, these cases can be separated more easily. The characteristic “knife-edge” lobar atrophy of Pick’s disease is only rarely seen in patients with CBGD. Pick bodies are far fewer in the neocortex and absent in the hippocampus of CBGD cases in contrast to Pick’s disease, in which they are more numerous in the neocortex and massive in number in the hippocampus.23 Despite both Pick’s disease and CBGD having widespread tau-immunoreactive lesions, the relative proportion and distribution of the different morphologic glial and neuronal inclusions differ.6,23 In CBGD, “astrocytic plaques,” which are annular clusters of thick, short, tau-positive deposits within distal processes of cortical astrocytes, frequently are identified, but cases have been described that lack these inclusions.12,17 These astrocytic plaques have been thought to be highly specific for CBGD; however, rare exceptions have been reported.24,25
There are no universally accepted standard criteria for the diagnosis of CBGD. Lowe et al.7,22,26 recently suggested the following pathologic criteria for the diagnosis of CBGD: cortical degeneration with swollen neurons, neuronal loss in the substantia nigra pars compacta with corticobasal inclusions, variable involvement of subcortical structures, and extensive neuronal and glial tau immunodeposits. All of our 13 patients met these criteria.
Clearly, there are limitations to any autopsy series of this size, and referral bias will affect the relative frequencies of how patients present. But with the known inaccuracies of diagnosing patients on clinical grounds, this series, drawing from both dementia and movement disorder referrals, probably is more representative of the true clinical picture of CBGD than studies arising exclusively from one source or predominantly from one type of practice. This may account for the different conclusion of a recent multi-institutional report that described 14 cases of pathologically proven CBGD.5 This study found that cognitive problems were a rare presenting feature (21%) and dementia was evident in only 36% at first visit, increasing to only 46% at last visit. However, almost all of the cases in this series were obtained from movement disorder referral centers, and patients with a primary clinical diagnosis of dementia would have been less likely to be included.
The heterogeneous clinical presentations of CBGD reflect the variability in the distribution and severity of lesions seen on histologic examination.2,8 The “classical” clinical presentation of CBGD (a parietal/perceptual-motor syndrome) may be seen in only a minority of patients, and this syndrome may be caused by other disorders diagnosed only on pathologic examination,27,28. Most patients with CBGD (11 of our 13 cases) eventually exhibit both a cognitive deficit and movement disorder. Better antemortem diagnostic tests are needed to differentiate the large number of neurodegenerative diseases capable of causing these clinical features. Until these tests are available, there will be major limitations to any large-scale, prospective, epidemiologic study (e.g., case–control studies) attempting to evaluate factors that predispose to the development of CBGD.
Acknowledgments
Supported in part by a Center of Excellence Grant to A.E.L. from the National Parkinson Foundation (Miami).
- Received March 26, 1999.
- Accepted July 21, 1999.
References
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