 |
|
Clinical Presentation and Pharmacological Therapy in Corticobasal Degeneration
K. Kompoliti, MD;
C. G. Goetz, MD;
B. F. Boeve, MD;
D. M. Maraganore, MD;
J. E. Ahlskog, PhD, MD;
C. D. Marsden, FRCP;
K. P. Bhatia, MD;
P. E. Greene, MD;
S. Przedborski, MD;
E. C. Seal, MD;
R. S. Burns, MD;
R. A. Hauser, MD;
L. L. Gauger, BA;
S. A. Factor, DO;
E. S. Molho, MD;
D. E. Riley, MD
Arch Neurol. 1998;55:957-961.
ABSTRACT
| |
Background To date, to our knowledge, there is no systematic presentation of treatment outcome in large series of patients clinically diagnosed as having corticobasal degeneration.
Objective To evaluate the clinical presentation and treatment outcome of patients clinically diagnosed as having corticobasal degeneration.
Subjects We gathered case patients seen in 8 major movement disorder clinics during the last 5 years who were diagnosed as having corticobasal ganglionic degeneration.
Methods Using a chart review method, we recorded the clinical presentation, medications used, response to medications, and adverse effects.
Results A total of 147 case patients were reviewed, 7 were autopsy proven. Parkinsonian features were present in all, other movement disorders in 89%, and higher cortical dysfunction in 93%. The most common parkinsonian sign was rigidity (92%), followed by bradykinesia (80%), gait disorder (80%), and tremor (55%). Other movement disorders were dystonia in 71% and myoclonus in 55%. Higher cortical dysfunction included dyspraxia (82%), alien limb (42%), cortical sensory loss (33%), and dementia (25%). Ninety-two percent of the case patients received dopaminergic drugs, which resulted in a beneficial effect for 24%. Parkinsonian signs were the elements improving the most and levodopa was the most effective drug. Benzodiazepines, primarily clonazepam, were administered to 47 case patients, which resulted in improvement of myoclonus in 23% and dystonia in 9%. The most frequent disabling adverse effects of drug trials in these case patients were somnolence (n=24), gastrointestinal complaints (n=23), confusion (n=16), dizziness (n=12), hallucinations (n=5), and dry mouth (n=5).
Conclusions Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.
INTRODUCTION
IN 1967 and 1968, Rebeiz et al1-2 described the clinical and pathologic findings in 3 patients who presented with slowness, awkwardness of volitional movement, and superimposed involuntary movements. All 3 were asymmetrically involved at onset with relatively preserved intellect until death. The duration of the illness until death was 6 to 8 years. Pathologic evaluation showed frontoparietal atrophy, asymmetrical in 2 cases, characterized histologically by neuronal loss, gliosis, and a distinctive neuronal change consisting of swelling of the cell body and resistance to staining methods (achromasia). They called the syndrome cortico-dentato-nigral degeneration with neuronal achromasia.
Following that initial description, the subject of corticobasal degeneration (CBD) was largely forgotten for almost 2 decades, until the second half of the 1980s. Since then, there has been a significant increase in recognition and reporting in varying degrees of detail, from case reports to small series of patients.3-24 However, to our knowledge, no study has assembled a large series of clinical cases. In 1995, an international congress was organized by the Movement Disorder Society to focus on CBD. As part of this effort, groups working with patients with CBD joined efforts to consolidate their small series into a larger sample. As a result, we describe the clinical presentation and review the pharmacological response of 147 case patients clinically diagnosed as having CBD by movement disorder experts.
PATIENTS AND METHODS
Movement disorder specialists from 8 centers gathered all case patients clinically diagnosed as having CBD, with or without autopsy confirmation, seen in their centers until 1995. There were no a priori entry criteria. The complete medical records were reviewed with respect to clinical history, pharmacological intervention, and adverse effects. Clinical signs and response to the use of medications were called present or absent based on the evaluating clinician's expert opinion as documented in the chart. The participating physicians were given a structured checklist with clinical signs, medications, and adverse effects to fill. The centers participating were the following: Mayo Clinic, Rochester, Minn, 38 case patients; the National Hospital for Neurology and Neurosurgery, Queen Square, London, England, 30 case patients; Columbia-Presbyterian Medical Center, New York, NY, 19 case patients; Cleveland Clinic, Cleveland, Ohio, 18 case patients; University of South Florida College of Medicine, Tampa, 13 case patients; Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill, 10 case patients; Albany Medical College, Albany, NY, 10 case patients; and Mt Sinai Medical Center, Cleveland, 9 case patients.
The data were compiled by the primary investigator. Signs were categorized into the following domains: parkinsonian features, other movement disorders, and higher cortical dysfunction. Recording of medication response was based on the reporting investigator's rating, and amelioration of at least one clinical area of disability was considered as clinical improvement. In all instances drug response was defined as associated with objective improvement. Because reporting investigators did not collect the corresponding data in a standardized manner we were comfortable assessing the presence but not the degree of improvement. Information on medication initiation with respect to onset of disease and precise duration of benefit, when present, was not documented, secondary to methodological limitations. Data analysis was performed using descriptive statistics. Subgroup analyses were performed using the 2-sided Fisher exact test. Comparisons were done for tables with marginal total of 5 or more. Bonferroni adjustment was used to correct for multiple comparisons.
RESULTS
CLINICAL MANIFESTATIONS
We reviewed 147 case patients, 7 of them with autopsy-proven CBD. Fifty-nine percent were women. Parkinsonian features occurred in all. Ninety-five percent of the case patients had at least 2 parkinsonian signs, and 8 had 1 each (gait disorder only, 4; rigidity only, 2; bradykinesia only, 1; and tremor only, 1). Other movement disorders occurred in 89% and higher cortical dysfunction in 93%. The most common parkinsonian sign was rigidity, which was present in 92%, followed by bradykinesia (80%), gait disorder (80%), and tremor (55%). The prototypic findings of combined parkinsonian signs, other movement disorders, and higher cortical dysfunction were found in 78% of case patients; 20% had only 2 of the features and 2 case patients had only 1 of the features. Of the 7 autopsy-confirmed cases, 6 had the prototypic triad of cardinal features and 1 had only parkinsonism and other movement disorders but no higher cortical dysfunction. Table 1 summarizes the clinical presentation of the autopsy-confirmed case patients.
|
|
|
|
Table 1. Clinical Presentation
|
|
|
Other movement disorders observed among the 147 case patients were dystonia (71%) and myoclonus (55%). Five case patients had athetosis and 1 had orolingual dyskinesias. Higher cortical dysfunction included dyspraxia (82%), involving the limbs (80%), ocular (18%), and orofacial muscles (3%), alien limb (42%), cortical sensory loss (33%), dementia (25%), and aphasia (10%).
Miscellaneous neurologic manifestations were recorded in 81% of the case patients. These included pyramidal signs (57%), supranuclear gaze abnormalities (33%), dysarthria (29%), and cerebellar signs (5%). In 3%, pain was a prominent symptom, always associated with limb dystonia.
MEDICATIONS
Ninety-two percent of the case patients received some kind of dopaminergic medication (Table 2). Eighty-seven percent received levodopa with a peripheral decarboxylase inhibitor; 25%, either bromocriptine or pergolide mesylate; 20%, selegiline hydrochoride; and 16%, amantadine hydrochoride. Other medications used were benzodiazepines (32%), anticholinergics (27%), baclofen (19%), antidepressants (11%), anticonvulsants (9%), propranolol hydrochoride (8%), and neuroleptics (4%). Botulinum toxin injections were given to 6% of the case patients.
|
|
|
|
Table 2. Specific Areas of Improvement*
|
|
|
Clinical improvement occurred in 24% of case patients receiving dopaminergic medications, no improvement was noted in 71%, and 5% experienced drug-associated worsening of parkinsonian features, dystonia, myoclonus, or gait dysfunction. No case patient experienced drug-related worsening of higher cortical dysfunction. Median levodopa dose used was 300 mg (range, 100-2000 mg). A combination product of levodopa and carbidopa produced clinical improvement in 26%. Bradykinesia and rigidity were the disorders that improved the most.
Agonist dose was 0.82 mg of pergolide mesylate equivalent (1 mg of pergolide mesylate=10 mg of bromocriptine; range, 0.15-3.0 mg). Only 6% of the case patients experienced clinical improvement of their parkinsonism. Selegiline was used in 30 case patients and produced improvement in 3 (10%), with parkinsonian features improving the most. Similarly, amantadine had a beneficial effect in 13% of case patients, with rigidity, tremor, and gait being the disorders that improved the most.
Clinical improvement occurred in 40% of case patients receiving benzodiazepines. Clonazepam was the most frequently used agent and was particularly helpful in controlling myoclonus (23%). Anticholinergics and baclofen were variously used, but with infrequent clinical improvement. Anticonvulsants and propranolol were used to treat tremor and were occasionally successful. Antidepressants were not effective in treating depression and no therapy helped higher cortical dysfunction.
Of 9 case patients given botulinum toxin injections, 6 experienced improvement of their dystonia. Neuroleptics were given to 6 case patients with improvement in 4. Two case patients experienced nonspecific improvement, 1 improvement of the myoclonus and 1 of the dysarthria.
MEDICAL ADVERSE EFFECTS
The most frequent adverse effect from using levodopa was gastrointestinal complaints (15%), followed by confusion (4%), somnolence (4%), dizziness (4%), and hallucinations (2%). Agonist use resulted in confusion in 14%, gastrointestinal complaints in 11%, and dizziness in 11% of the case patients. Dyskinesias did not occur even in case patients who received high doses of dopaminergic drugs. Benzodiazepines and anticonvulsants produced somnolence in 26% and 15% of the case patients, respectively.
SUBGROUP ANALYSIS
Three subgroup comparisons were made and no significant differences were detected for any of the following comparisons: autopsy-proven case patients (n=7) vs other case patients (n=140) for clinical signs and medication responses; patients responding with clinical improvement to levodopa (n=33) vs other case patients (n=95) for clinical signs and medication responses; clinically prototypic case patients who had the triad of parkinsonism, other movement disorders, and higher cortical dysfunction (n=115) vs other patients (n=32) for medication responses.
COMMENT
CLINICAL MANIFESTATIONS
The aim of our study was to define the clinical spectrum of the condition movement disorder experts consider to be CBD. No predetermined diagnostic criteria were set for the participants, but all enrolling investigators were active academic investigators at major treatment centers. Based on this material, CBD is predominantly a motor disorder. Whereas parkinsonian features were always found, the overall clinical presentation was distinctive because of the additional presence of other movement disorders and higher cortical dysfunction. It is not clear to what extent the universal finding of parkinsonian signs represents a selection bias among specialists of movement disorders. Alternatively, the fact that most case patients with CBD are eventually referred to a specialist of movement disorders may reflect this fact.
Tremor in individuals with CBD does not resemble tremor in those with Parkinson disease and occurs in only 55% of the case patients. In Parkinson disease, this sign is reported to occur more frequently25 and can be the predominant motor sign. In their study of autopsy-proven case patients with CBD and case patients with Parkinson disease, Goetz and al26 found that tremor dominance was a significant discriminating factor between the 2 conditions.
Supranuclear gaze palsy was present in one third of our case patients, and ocular dyspraxia in 18%. In their recording of eye movements in 10 subjects with CBD, Vidailhet et al24 concluded that patients can generate saccades spontaneously or as part of the opticokinetic nystagmus testing, but are unable to reproduce them on command. Other early abnormalities are saccadic pursuit and saccadic hypometria. Horizontal and vertical eye movements are equally affected. Vidailhet et al24 suggested that these findings can be valuable in differentiating CBD from progressive supranuclear palsy, at least in the beginning, since the eye movement abnormalities tend to be similar in advanced disease.
There are no validated, universally accepted criteria for the diagnosis of CBD. Litvan et al27 compared clinical diagnoses made by neurologists who were blinded when the case patients were presented to them as clinical vignettes with clinicopathologic diagnoses and concluded that there is a low sensitivity for the clinical diagnosis of CBD, suggesting that this disorder is underdiagnosed. Mayo Clinic physicians28-29 have developed their own criteria for the diagnostic classification of CBD. Boeve et al28 presented 9 case patients clinically diagnosed as having CBD who underwent autopsy. They concluded that
a variety of different pathological substrates may result in a similar clinical profile and that the classical CBGD syndrome can occur in the absence of neuronal achromasia, basal ganglia degeneration, and nigral degeneration. The one invariable pathologic abnormality in that series, however, was asymmetric parietal ± frontal cortical degeneration.28
MEDICATIONS
Most case patients in this population received a dopaminergic medication, in most instances a combination product of levodopa and carbidopa. Twenty-four percent of the case patients experienced clinical improvement and in most instances the improvement was ascribed to the use of levodopa. The other dopaminergic agents (dopaminergic agonists, selegiline, or amantadine) were used less frequently and produced less consistent improvement. Given the retrospective design of this study, there is no information available on the magnitude or the duration of the response, although in most cases it was a modest improvement. After performing Bonferroni correction for multiple comparisons, there were no statistically significant differences between responders and nonresponders receiving levodopa with regard to clinical presentation and response to the use of other medications.
Anticonvulsants and propranolol were used more than anticipated and were often helpful in ameliorating tremor. Tremors in individuals with CBD can be rest, postural, or dystonic. Although each center's experience with these drugs was small, and this was not a blinded, placebo-controlled assessment, the combined series permits a conclusion that these drugs are worth trying in patients with CBD with tremors. Likewise, botulinum toxin injections, although not tested in a large number of patients at any one center, were effective in alleviating dystonic spasms and the pain associated with them. These combined data suggest that botulinum toxin may be used more widely in the future.
Finally, approaching specific areas of impairment with traditionally used empirical medications had some limited success, the most remarkable being the response of myoclonus to clonazepam. These data suggest that focused therapies for myoclonus (clonazepam), dystonic signs (clonazepam, anticholinergics, or baclofen), or pyramidal signs (baclofen) should be tried with patients in whom such signs predominate in the clinical picture.
To our knowledge, our study represents the first attempt to present the clinical manifestations of a large number of case patients with the diagnosis of CBD, and to summarize the combined experience of the therapeutic outcome of drug trials in this case patient population. Advantages of the study are the large number of case patients presented and the fact that they were assessed by physicians specializing in the diagnosis and treatment of parkinsonian disorders. Because there was no specific drug protocol, the data represent patterns of clinical practice in large university-based centers where these case patients are generally referred. The study is limited because the data were collected retrospectively and there was no specific data collection methodology other than complete chart review. The medication responses were obtained in an open-label fashion and it is impossible to assess the contribution of placebo effect. The series forms a cohort that can now be followed up prospectively with attention to eventual autopsy confirmation.
AUTHOR INFORMATION
Accepted for publication November 25, 1997.
Dr Factor is supported by the Riley Family Chair in Parkinson's Disease, Albany, NY.
Reprints: Katie Kompoliti, MD, Department of Neurological Sciences, Rush-Presbyterian-St Luke's Medical Center, 1725 W Harrison St, Suite 1106, Chicago, IL 60612 (e-mail: kkompoli{at}rpslmc.edu).
From Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Drs Kompoliti and Goetz); Mayo Clinic, Rochester, Minn (Drs Boeve, Maraganore, and Ahlskog); National Hospital for Neurology and Neurosurgery, Queen Square, London, England (Drs Marsden and Bhatia); Columbia University, New York, NY (Drs Greene and Przedborski); Cleveland Clinic Foundation, Cleveland, Ohio (Drs Seal and Burns); University of South Florida, Tampa (Dr Hauser and Ms Gauger); Albany Medical College, Albany, NY (Drs Factor and Molho); and Mt Sinai Medical Center, Cleveland (Dr Riley).
REFERENCES
| |
1. Rebeiz JJ, Kolodny EH, Richardson EP Jr. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol. 1968;18:20-33.
ISI
| PUBMED
2. Rebeiz JJ, Kolodny EH, Richardson EP Jr. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc. 1967;92:23-26.
PUBMED
3. Hauser RA, Murtaugh FR, Akhter K, Gold M, Olanow CW. Magnetic resonance imaging of corticobasal degeneration. J Neuroimaging. 1996;6:222-226.
ISI
| PUBMED
4. Feany MB, Ksiezak-Reding H, Liu WK, Vincent I, Yen SH, Dickson DW. Epitope expression and hyperphosphorylation of tau protein in corticobasal degeneration: differentiation from progressive supranuclear palsy. Acta Neuropathol (Berl). 1995;90:37-43.
PUBMED
5. Feany MB, Dickson DW. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol. 1995;146:1388-1396.
ABSTRACT
6. Feany MB, Mattiace LA, Dickson DW. Neuropathologic overlap of progressive supranuclear palsy, Pick's disease and corticobasal degeneration. J Neuropathol Exp Neurol. 1996;55:53-67.
ISI
| PUBMED
7. Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain. 1989;112:1171-1192.
FREE FULL TEXT
8. Gibb WR, Luthert PJ, Marsden CD. Clinical and pathological features of corticobasal degeneration. Adv Neurol. 1990;53:51-54.
PUBMED
9. Gimenez-Roldan S, Mateo D, Benito C, Grandas F, Perez-Gilabert Y. Progressive supranuclear palsy and corticobasal ganglionic degeneration: differentiation by clinical features and neuroimaging techniques. J Neural Transm Suppl. 1994;42:79-90.
PUBMED
10. Greene PE, Fahn S, Lang AE, Watts RL, Eidelberg D, Powers JM. What is it? case 1, 1990: progressive unilateral rigidity, bradykinesia, tremulousness, and apraxia, leading to fixed postural deformity of the involved limb. Mov Disord. 1990;5:341-351.
FULL TEXT
|
ISI
| PUBMED
11. Eidelberg D, Dhawan V, Moeller JR, et al. The metabolic landscape of cortico-basal ganglionic degeneration: regional asymmetries studied with positron emission tomography. J Neurol Neurosurg Psychiatry. 1991;54:856-862.
ABSTRACT
12. Dickson DW, Yen SH, Suzuki KI, Davies P, Garcia JH, Hirano A. Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes. Acta Neuropathol (Berl). 1986;71:216-223.
FULL TEXT
| PUBMED
13. Brunt ER, van Weerden TW, Pruim J, Lakke JW. Unique myoclonic pattern in corticobasal degeneration. Mov Disord. 1995;10:132-142.
FULL TEXT
|
ISI
| PUBMED
14. Jendroska K, Rossor MN, Mathias CJ, Daniel SE. Morphological overlap between corticobasal degeneration and Pick's disease: a clinicopathological report. Mov Disord. 1995;10:111-114.
FULL TEXT
|
ISI
| PUBMED
15. Lang AE, Bergeron C, Pollanen MS, Ashby P. Parietal Pick's disease mimicking cortical-basal ganglionic degeneration. Neurology. 1994;44:1436-1440.
FREE FULL TEXT
16. Lippa CF, Smith TW, Fontneau N. Corticonigral degeneration with neuronal achromasia: a clinicopathologic study of two cases. J Neurol Sci. 1990;98:301-310.
FULL TEXT
|
ISI
| PUBMED
17. Mori H, Nishimura M, Namba Y, Oda M. Corticobasal degeneration: a disease with widespread appearance of abnormal tau and neurofibrillary tangles, and its relation to progressive supranuclear palsy. Acta Neuropathol (Berl). 1994;88:113-121.
PUBMED
18. Pillon B, Blin J, Vidailhet M, et al. The neuropsychological pattern of corticobasal degeneration: comparison with progressive supranuclear palsy and Alzheimer's disease. Neurology. 1995;45:1477-1483.
FREE FULL TEXT
19. Paulus W, Selim M. Corticonigral degeneration with neuronal achromasia and basal neurofibrillary tangles. Acta Neuropathol (Berl). 1990;81:89-94.
FULL TEXT
| PUBMED
20. Riley DE, Lang AE, Lewis A, et al. Cortical-basal ganglionic degeneration. Neurology. 1990;40:1203-1212.
FREE FULL TEXT
21. Rinne JO, Lee MS, Thompson PD, Marsden CD. Corticobasal degeneration: a clinical study of 36 cases. Brain. 1994;117:1183-1196.
FREE FULL TEXT
22. Rey GJ, Tomer R, Levin BE, Sanchez-Ramos J, Bowen B, Bruce JH. Psychiatric symptoms, atypical dementia, and left visual field inattention in corticobasal ganglionic degeneration. Mov Disord. 1995;10:106-110.
FULL TEXT
|
ISI
| PUBMED
23. Sawle GV, Brooks DJ, Marsden CD, Frackowiak RS. Corticobasal degeneration: a unique pattern of regional cortical oxygen hypometabolism and striatal fluorodopa uptake demonstrated by positron emission tomography. Brain. 1991;114:541-556.
FREE FULL TEXT
24. Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Eye movements in parkinsonian syndromes. Ann Neurol. 1994;35:420-426.
FULL TEXT
|
ISI
| PUBMED
25. Rajput AH, Rozdilsky B, Ang L. Occurrence of resting tremor in Parkinson's disease. Neurology. 1991;41:1298-1299.
FREE FULL TEXT
26. Goetz CG, Litvan I, Stebbins GT, et al. The accuracy of clinical signs in separating autopsy-proven corticobasal ganglionic degeneration from Parkinson's disease: positive and negative predictive value analysis [abstract]. Neurology. 1996;46(suppl):A260-A261.
27. Litvan I, Agid Y, Goetz CG, et al. Validity of clinical diagnosis of corticobasal ganglionic degeneration. Mov Disord. 1996;11:354-355.
28. Boeve BF, Maraganore DM, Parisi JE, et al. Disorders mimicking the "classical" clinical syndrome of cortico-basal ganglionic degeneration: report of nine cases [abstract]. Mov Disord. 1996;11:351.
29. Maraganore DM, Ahlskog JE, Petersen RC. Progressive asymmetric rigidity with apraxia: a distinctive clinical entity [abstract]. Mov Disord. 1992;7:80.
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer's disease
Garbutt et al.
Brain 2008;131:1268-1281.
ABSTRACT
| FULL TEXT
Cognitive and motor assessment in autopsy-proven corticobasal degeneration
Murray et al.
Neurology 2007;68:1274-1283.
ABSTRACT
| FULL TEXT
Dissociation of numbers and objects in corticobasal degeneration and semantic dementia
Halpern et al.
Neurology 2004;62:1163-1169.
ABSTRACT
| FULL TEXT
What's in a name: voxel-based morphometric analyses of MRI and naming difficulty in Alzheimer's disease, frontotemporal dementia and corticobasal degeneration
Grossman et al.
Brain 2004;127:628-649.
ABSTRACT
| FULL TEXT
The Alien Hand: Cases, Categorizations, and Anatomical Correlates
Scepkowski and Cronin-Golomb
Behav Cogn Neurosci Rev 2003;2:261-277.
ABSTRACT
Progression of Dysarthria and Dysphagia in Postmortem-Confirmed Parkinsonian Disorders
Muller et al.
Arch Neurol 2001;58:259-264.
ABSTRACT
| FULL TEXT
The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia
Kertesz et al.
Neurology 2000;55:1368-1375.
ABSTRACT
| FULL TEXT
Corticobasal Ganglionic Degeneration With Balint's Syndrome
Mendez
J. Neuropsychiatry Clin. Neurosi. 2000;12:273-275.
ABSTRACT
| FULL TEXT
Dementia as the most common presentation of cortical-basal ganglionic degeneration
Grimes et al.
Neurology 1999;53:1969-1969.
ABSTRACT
| FULL TEXT
Pathologic heterogeneity in clinically diagnosed corticobasal degeneration
Boeve et al.
Neurology 1999;53:795-795.
ABSTRACT
| FULL TEXT
|
