Movement Disorders Vol. 5 , No. 2, 1990, pp. 17%183 0 1990 Movement Disorder Society
Letters to the Editor ma1 dominant multiple system degenerations and consolidates the clinical reports of Fletcher and colleagues.
Dystonia and Cerebellar Ataxia To the Editor: Fletcher and colleagues (Degenerative cerebellar ataxia and focal dystonia, Movement Disorders 1988;3:336-342) reported eight patients with a variety of cerebellar ataxias in whom focal dystonia was a prominent presenting feature. I wish to report a further case in which there is neuropathological confirmation of a diagnosis of multiple system atrophy without autonomic involvement in the proband’s mother. The proband is a 36-year-old novelist who presented in July 1987 with neck pain followed a few weeks later by involuntary deviation of her chin to the left. This was treated unsuccessfully with pimozide and anticholinergic drugs; she was admitted to the National Hospital for Nervous Diseases in May 1988 when she was noted to have a severe torticollis with marked overactivity, particularly of the left splenius, left trapezius, and sternomastoid muscles. In addition, she had a mild cerebellar dysarthria. The following investigations were normal: serum copper studies, serum thyroxine, urea and electrolytes, serum calcium, blood glucose, and full blood count. There were no acanthocytes seen on three wet blood films, and serological tests for syphilis were negative. A magnetic resonance imaging scan of the brain showed significant brainstem atrophy with mild cerebellar atrophy. Her spasmodic torticollis was treated with moderate success with botulinus toxin. The family history suggested an autosomal dominantly inherited condition. Her maternal aunt had an ataxic disorder and died in her 50s and her maternal grandfather may also have been affected; he also died in his mid-50s. Her mother developed a cerebellar ataxia with dysarthria in her 30s and died in a nursing home with muscle wasting and weakness at the age of 50 from bronchopneumonia. A postmortem, carried out by Dr. Trevor Hughes in Oxford, revealed a fixed brain weight of 1,094 g with a hind brain weighing 95.7 g with marked cerebellar and brainstem atrophy. There was a marked degeneration of the cerebellum, and the Purkinje cells were severely degenerated with only about 10% of the neuronal cell bodies surviving. The white matter of the Cerebellum was also degenerated, and there was severe depletion of neurones in the dentate nucleus. There was marked atrophy of the superior cerebellar peduncles, the inferior olives had lost neucones and showed gliosis, and there was degeneration of the oculomotor, facial, and hypoglossal nerve nuclei. The corticospinal tracts in the mid-brain, pons, and medulla were also degenerated. In the spinal cord there was some degeneration in the posterior columns and complete and severe degeneration of the spinocerebellar tracts. Clarke’s column was severely degenerated and there was depletion of the anterior horns at all spinal cord segmental levels. This report supports the heterogeneity of autoso-
Andrew Lees The National Hospital for Nervous Diseases Queen Square, London
Parkinson’s Disease: A Reduced Ability to Shift to a New Grouping If Not Prompted or Guided To the Editor: In a recent article in Movement Disorders (I), Brown and Marsden provided data suggesting that patients with Parkinson’s disease are impaired on tasks when they have to rely on internal control for the regulation of behavior, but are relatively unimpaired on tasks when external cues are available. Both their data and their suggestions are fully in agreement with those reported by us (2) and others (3,4). Nevertheless, they claim that their findings fail to support our previously reported hypothesis that patients with Parkinsons’s disease suffer from an impaired shifting aptitude. Unfortunately, our hypothesis has been incorrectly reported by them. In 1984 we hypothesized that patients with Parkinson’s disease “should have a diminished shifting aptitude as to behaviour not directed by currently available sensory information” (2). On the basis of our data, we reached the conclusion that “this diminished shifting aptitude is manifest in motor behaviour that is triggered and guided by self-generated information” (2). In addition, we purposely pointed out that an organism with decreased striatal activity “remains able to rearrange behaviour programmes with the help of currently available sensory information” (2). Thus, both we and Brown and Marsden fully agree that patients with Parkinson’s disease do not inevitably show a deficit in switching set in all cognitive tasks but, instead suffer from a difficulty in switching in tasks in which external cues cannot be used for controlling the required switching. Contrary to the position of Brown and Marsden (l),our hypothesis was not generated as a result of the post-hoc interpretation of test results but was formulated on the basis of human and animal observations (2). For that reason, we selected and designed shifting aptitude tests in which external cues could not be used. Let us illustrate this. In the modified Wisconsin Card Sorting Test, viz., our block sorting test, for instance, the subject must sort a deck of blocks, each bearing a variable size of one of three different shapes in one of three different colors. The subject must sort the blocks according to one of the three stimulus attributes-shape, color, and size-until told to
178
LETTERS TO THE EDITOR stop. They must then switch to a new attribute as the basis for the sorting and continue until told to switch again. This switching continues throughout the task. Apart from the different ways in which the difficulty on this task may be manifested ( l ) , we only presented data on the first phase, viz., data reflecting the ability to abstract the stimulus attribute, and data on the second phase, viz., data reflecting the ability to switch without the help of external cues. We did not present data on the third phase, viz., data reflecting the ability to switch to the remaining stimulus attribute. Since the latter switch could be made by subtracting the already selected stimulus attributes of shape and color from the given stimulus attributes (shape, color, and size), we considered the last part of this test as switching with the help of external cues. Indeed, analyzing this part of the task according to previously reported procedures (2) reveals that our patients with Parkinson’s disease did not differ from our control subjects. Anyhow, all the available data collected by different researchers point in the direction of a very similar deficit in patients with Parkinson’s disease, viz., a reduced ability to switch in tasks in which external cues cannot be used. Finally, the findings of Brown and Marsden are especially welcome, for they help to draw renewed attention to the almost forgotten idea of Andre Barbeau that patients with Parkinson’s disease are unable to shift to a new grouping if not prompted or guided (5). A. R. Cools *J. H. L. van den Bercken tM. W. I. Horstink SK.P. M. van Spaendonck SH. J. C. Berger Department of Pharmacology, Faculty of Medicine, Departments of *Special Education, iNeurology, and $Medical Psychology University of Nijmegen Nijmegen, The Netherlands
REFERENCES 1 . Brown RG, Marsden CD. An investigation of the phenomenon of “set” in Parkinson’s disease. Movement Dis 1988; 3:152-161. 2. Cools AR, van den Bercken JHL, Horstink MWI, van Spaendonck KPM, Berger HJC. Cognitive and motor shifting aptitude disorders in Parkinson’s disease. J Neuroi Neurosurg Psychiatry 1984;47:443-453. 3. Lees AJ, Smit E. Cognitive deficits in the early stages of Parkinson’s disease. Brain 1983;106:257-270. 4. Taylor AE, Saint-Cyr JA, Lang AE. Frontal lobe dysfunction in Parkinson’s disease. Brain 1986;109:845-883. 5. Barbeau A. Biology of the striatum. In: Gall GE, ed. Biology and brain dysfunction. Vol. 2. New York: Plenum Press, 1973:333-350.
Autoimmune Etiology for Cranial Dystonia To the Editor: Several studies have associated cranial dystonia with autoimmune disorders (1-5). In speculating on the causal
179
relationship of these two entities, Jankovic and Patten (5) invoked the role of shared common antigens in neural components and the lupus antigen in inducing an antibody response with subsequent interference of neural function in specific brain regions. The situation was felt to be analogous to paraneoplastic autoimmune central nervous system (CNS) disorders. We have explored this possibility by screening serum samples of patients with cranial dystonia for anti-CNS antibodies using the indirect immunoperoxidase technique. Serum samples were obtained from 11 patients. Nine had primarily blepharospasm, and the other two had involvement of lower facial muscles as well. Only one had associated autoimmune disorders, namely, hypothyroidism and pernicious anemia. Paraffin-embedded 6-pm sections of normal human cerebral and cerebellar cortex, midbrain, medulla, and spinal cord obtained within 12 h postmortem were used for the screening studies. The sections were immunoreacted with the patients’ serum samples at 1:250, 1:500, and 1:1,OOO dilution ranges employing biotinylated protein A in the avidin-biotin peroxidase method of indirect immunocytochemistry (6,7). A rabbit antiserum to human glial fibrillary acidic protein (8) served as a methodological and positive control. None of the antisera tested revealed positive staining of neuronal or other cellular elements or processes in any of the regions examined. Interestingly, the serum of a patient with CNS lupus (used as a disease control) demonstrated selective labeling of granule cells in the cerebellum. We are quite aware of the inherent problems of false negativity of staining in the immunocytochemical procedure (9). The extreme sensitivity of biotinylated proteinA in the ABC technique (6,7), however, makes this an unlikely possibility in this study. We conclude that the presence of serum anti-CNS antibodies are unlikely in cranial dystonia and thus find no support for an autoimmune etiology for these disorders by this approach. Gajanan Nilaver Sidney Whiting John G . Nutt Department of Neurology Oregon Health Sciences University Portland, Oregon
REFERENCES 1. Jankovic J, Ford J. Blepharospasm and orofacial-cervical dystonia: clinical and pharmacological findings in 100 patients. Ann Neurol 1983;13:402411. 2. Ashizawa T, Pattern BM, Jankovic J. Meige’s syndrome. South Med J 1980;73:863-866. 3. Massey EW, Allen NB, Cole TB. Essential blepharospasm and Sjogren‘s syndrome. Neurology 1984;34:148. 4. Nutt JG, Carter J, DeGarmo P, Hammerstad JP. Meige’s syndrome and thyroid dysfunction. Neurology 1984;34 (suppl 1):222. 5. Jankovic J, Patten BM. Blepharospasm and autoimmune diseases. Movement Dis 1987;2:159-163. 6. Nilaver G , Kozlowski GP. Comparison of the PAP and ABC immunocytochemical techniques. In: Bullock GR, Petrusz P, eds. Techniques in immunocytochemistry. Vol. 4. New York: Academic Press 1989:19%215. 7. Hsu S-M, Raine L, Fanger H. Use of avidin biotin peroxi-
Movement Disorders, Vol. 5 , No. 2 , 1990
180
LETTERS TO THE EDITOR
dase (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 1981 ;29:577-580. Latov N, Nilaver G, Zimmerman EA, et al. Fibrillary astrocytes proliferate in response to brain injury. A study combining immunoperoxidase technique for glial fibrillary acidic protein and radioautography of 3H-thymidine. Dev Biol 1979 ;72:381-384. Nilaver G . In situ hybridization histochemistry as a supplement to immunohistochemistry. In: Uhl GR, ed. In situ hybridization in brain. New York: Plenum Press, 1987:24% 252.
Hemichorea-hemiballism in AIDS To the Editor: An additional case of AIDS with hemichoreahemiballism has been published by Sanchez-Ramos et al. (1). 1 think that these authors have not had access to non-English literature and this is the purpose of this letter. In 1986 (2) we reported the case of a 30-year-old male heroin addict with left hemichorea-hemiballism and fever as presenting symptoms of AIDS. On admission a computed tomography (CT) scan showed only mild cerebral atrophy. There were 180 cells/mm3 (70% lymphocytes) in the cerebrospinal fluid (CSF), with raised protein and low glucose levels. A symptomatic therapeutic trial with increasing doses of haloperidol was unsuccessful. Finally, serologic tests (direct agglutination, indirect immunofluorescence assay) in blood and CSF were demonstrative of infection by Toxoplasma. The treatment with pyrimethamine and sulfadiazine improved the changes in the CSF, but there was only a modest clinical response. Two months after admission, a CT scan showed moderate brain atrophy and some small, hyperdense, poorly defined lesions scattered in the cerebral hemispheres. Several systemic complications, and a progressive encephalopathy with seizures, pseudobulbar palsy, and akinetic mutism were eventually present. The patient died 6 months after the onset of the disease. At autopsy, multiple necrotic lesions (
Letters to the Editor ma1 dominant multiple system degenerations and consolidates the clinical reports of Fletcher and colleagues.
Dystonia and Cerebellar Ataxia To the Editor: Fletcher and colleagues (Degenerative cerebellar ataxia and focal dystonia, Movement Disorders 1988;3:336-342) reported eight patients with a variety of cerebellar ataxias in whom focal dystonia was a prominent presenting feature. I wish to report a further case in which there is neuropathological confirmation of a diagnosis of multiple system atrophy without autonomic involvement in the proband’s mother. The proband is a 36-year-old novelist who presented in July 1987 with neck pain followed a few weeks later by involuntary deviation of her chin to the left. This was treated unsuccessfully with pimozide and anticholinergic drugs; she was admitted to the National Hospital for Nervous Diseases in May 1988 when she was noted to have a severe torticollis with marked overactivity, particularly of the left splenius, left trapezius, and sternomastoid muscles. In addition, she had a mild cerebellar dysarthria. The following investigations were normal: serum copper studies, serum thyroxine, urea and electrolytes, serum calcium, blood glucose, and full blood count. There were no acanthocytes seen on three wet blood films, and serological tests for syphilis were negative. A magnetic resonance imaging scan of the brain showed significant brainstem atrophy with mild cerebellar atrophy. Her spasmodic torticollis was treated with moderate success with botulinus toxin. The family history suggested an autosomal dominantly inherited condition. Her maternal aunt had an ataxic disorder and died in her 50s and her maternal grandfather may also have been affected; he also died in his mid-50s. Her mother developed a cerebellar ataxia with dysarthria in her 30s and died in a nursing home with muscle wasting and weakness at the age of 50 from bronchopneumonia. A postmortem, carried out by Dr. Trevor Hughes in Oxford, revealed a fixed brain weight of 1,094 g with a hind brain weighing 95.7 g with marked cerebellar and brainstem atrophy. There was a marked degeneration of the cerebellum, and the Purkinje cells were severely degenerated with only about 10% of the neuronal cell bodies surviving. The white matter of the Cerebellum was also degenerated, and there was severe depletion of neurones in the dentate nucleus. There was marked atrophy of the superior cerebellar peduncles, the inferior olives had lost neucones and showed gliosis, and there was degeneration of the oculomotor, facial, and hypoglossal nerve nuclei. The corticospinal tracts in the mid-brain, pons, and medulla were also degenerated. In the spinal cord there was some degeneration in the posterior columns and complete and severe degeneration of the spinocerebellar tracts. Clarke’s column was severely degenerated and there was depletion of the anterior horns at all spinal cord segmental levels. This report supports the heterogeneity of autoso-
Andrew Lees The National Hospital for Nervous Diseases Queen Square, London
Parkinson’s Disease: A Reduced Ability to Shift to a New Grouping If Not Prompted or Guided To the Editor: In a recent article in Movement Disorders (I), Brown and Marsden provided data suggesting that patients with Parkinson’s disease are impaired on tasks when they have to rely on internal control for the regulation of behavior, but are relatively unimpaired on tasks when external cues are available. Both their data and their suggestions are fully in agreement with those reported by us (2) and others (3,4). Nevertheless, they claim that their findings fail to support our previously reported hypothesis that patients with Parkinsons’s disease suffer from an impaired shifting aptitude. Unfortunately, our hypothesis has been incorrectly reported by them. In 1984 we hypothesized that patients with Parkinson’s disease “should have a diminished shifting aptitude as to behaviour not directed by currently available sensory information” (2). On the basis of our data, we reached the conclusion that “this diminished shifting aptitude is manifest in motor behaviour that is triggered and guided by self-generated information” (2). In addition, we purposely pointed out that an organism with decreased striatal activity “remains able to rearrange behaviour programmes with the help of currently available sensory information” (2). Thus, both we and Brown and Marsden fully agree that patients with Parkinson’s disease do not inevitably show a deficit in switching set in all cognitive tasks but, instead suffer from a difficulty in switching in tasks in which external cues cannot be used for controlling the required switching. Contrary to the position of Brown and Marsden (l),our hypothesis was not generated as a result of the post-hoc interpretation of test results but was formulated on the basis of human and animal observations (2). For that reason, we selected and designed shifting aptitude tests in which external cues could not be used. Let us illustrate this. In the modified Wisconsin Card Sorting Test, viz., our block sorting test, for instance, the subject must sort a deck of blocks, each bearing a variable size of one of three different shapes in one of three different colors. The subject must sort the blocks according to one of the three stimulus attributes-shape, color, and size-until told to
178
LETTERS TO THE EDITOR stop. They must then switch to a new attribute as the basis for the sorting and continue until told to switch again. This switching continues throughout the task. Apart from the different ways in which the difficulty on this task may be manifested ( l ) , we only presented data on the first phase, viz., data reflecting the ability to abstract the stimulus attribute, and data on the second phase, viz., data reflecting the ability to switch without the help of external cues. We did not present data on the third phase, viz., data reflecting the ability to switch to the remaining stimulus attribute. Since the latter switch could be made by subtracting the already selected stimulus attributes of shape and color from the given stimulus attributes (shape, color, and size), we considered the last part of this test as switching with the help of external cues. Indeed, analyzing this part of the task according to previously reported procedures (2) reveals that our patients with Parkinson’s disease did not differ from our control subjects. Anyhow, all the available data collected by different researchers point in the direction of a very similar deficit in patients with Parkinson’s disease, viz., a reduced ability to switch in tasks in which external cues cannot be used. Finally, the findings of Brown and Marsden are especially welcome, for they help to draw renewed attention to the almost forgotten idea of Andre Barbeau that patients with Parkinson’s disease are unable to shift to a new grouping if not prompted or guided (5). A. R. Cools *J. H. L. van den Bercken tM. W. I. Horstink SK.P. M. van Spaendonck SH. J. C. Berger Department of Pharmacology, Faculty of Medicine, Departments of *Special Education, iNeurology, and $Medical Psychology University of Nijmegen Nijmegen, The Netherlands
REFERENCES 1 . Brown RG, Marsden CD. An investigation of the phenomenon of “set” in Parkinson’s disease. Movement Dis 1988; 3:152-161. 2. Cools AR, van den Bercken JHL, Horstink MWI, van Spaendonck KPM, Berger HJC. Cognitive and motor shifting aptitude disorders in Parkinson’s disease. J Neuroi Neurosurg Psychiatry 1984;47:443-453. 3. Lees AJ, Smit E. Cognitive deficits in the early stages of Parkinson’s disease. Brain 1983;106:257-270. 4. Taylor AE, Saint-Cyr JA, Lang AE. Frontal lobe dysfunction in Parkinson’s disease. Brain 1986;109:845-883. 5. Barbeau A. Biology of the striatum. In: Gall GE, ed. Biology and brain dysfunction. Vol. 2. New York: Plenum Press, 1973:333-350.
Autoimmune Etiology for Cranial Dystonia To the Editor: Several studies have associated cranial dystonia with autoimmune disorders (1-5). In speculating on the causal
179
relationship of these two entities, Jankovic and Patten (5) invoked the role of shared common antigens in neural components and the lupus antigen in inducing an antibody response with subsequent interference of neural function in specific brain regions. The situation was felt to be analogous to paraneoplastic autoimmune central nervous system (CNS) disorders. We have explored this possibility by screening serum samples of patients with cranial dystonia for anti-CNS antibodies using the indirect immunoperoxidase technique. Serum samples were obtained from 11 patients. Nine had primarily blepharospasm, and the other two had involvement of lower facial muscles as well. Only one had associated autoimmune disorders, namely, hypothyroidism and pernicious anemia. Paraffin-embedded 6-pm sections of normal human cerebral and cerebellar cortex, midbrain, medulla, and spinal cord obtained within 12 h postmortem were used for the screening studies. The sections were immunoreacted with the patients’ serum samples at 1:250, 1:500, and 1:1,OOO dilution ranges employing biotinylated protein A in the avidin-biotin peroxidase method of indirect immunocytochemistry (6,7). A rabbit antiserum to human glial fibrillary acidic protein (8) served as a methodological and positive control. None of the antisera tested revealed positive staining of neuronal or other cellular elements or processes in any of the regions examined. Interestingly, the serum of a patient with CNS lupus (used as a disease control) demonstrated selective labeling of granule cells in the cerebellum. We are quite aware of the inherent problems of false negativity of staining in the immunocytochemical procedure (9). The extreme sensitivity of biotinylated proteinA in the ABC technique (6,7), however, makes this an unlikely possibility in this study. We conclude that the presence of serum anti-CNS antibodies are unlikely in cranial dystonia and thus find no support for an autoimmune etiology for these disorders by this approach. Gajanan Nilaver Sidney Whiting John G . Nutt Department of Neurology Oregon Health Sciences University Portland, Oregon
REFERENCES 1. Jankovic J, Ford J. Blepharospasm and orofacial-cervical dystonia: clinical and pharmacological findings in 100 patients. Ann Neurol 1983;13:402411. 2. Ashizawa T, Pattern BM, Jankovic J. Meige’s syndrome. South Med J 1980;73:863-866. 3. Massey EW, Allen NB, Cole TB. Essential blepharospasm and Sjogren‘s syndrome. Neurology 1984;34:148. 4. Nutt JG, Carter J, DeGarmo P, Hammerstad JP. Meige’s syndrome and thyroid dysfunction. Neurology 1984;34 (suppl 1):222. 5. Jankovic J, Patten BM. Blepharospasm and autoimmune diseases. Movement Dis 1987;2:159-163. 6. Nilaver G , Kozlowski GP. Comparison of the PAP and ABC immunocytochemical techniques. In: Bullock GR, Petrusz P, eds. Techniques in immunocytochemistry. Vol. 4. New York: Academic Press 1989:19%215. 7. Hsu S-M, Raine L, Fanger H. Use of avidin biotin peroxi-
Movement Disorders, Vol. 5 , No. 2 , 1990
180
LETTERS TO THE EDITOR
dase (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 1981 ;29:577-580. Latov N, Nilaver G, Zimmerman EA, et al. Fibrillary astrocytes proliferate in response to brain injury. A study combining immunoperoxidase technique for glial fibrillary acidic protein and radioautography of 3H-thymidine. Dev Biol 1979 ;72:381-384. Nilaver G . In situ hybridization histochemistry as a supplement to immunohistochemistry. In: Uhl GR, ed. In situ hybridization in brain. New York: Plenum Press, 1987:24% 252.
Hemichorea-hemiballism in AIDS To the Editor: An additional case of AIDS with hemichoreahemiballism has been published by Sanchez-Ramos et al. (1). 1 think that these authors have not had access to non-English literature and this is the purpose of this letter. In 1986 (2) we reported the case of a 30-year-old male heroin addict with left hemichorea-hemiballism and fever as presenting symptoms of AIDS. On admission a computed tomography (CT) scan showed only mild cerebral atrophy. There were 180 cells/mm3 (70% lymphocytes) in the cerebrospinal fluid (CSF), with raised protein and low glucose levels. A symptomatic therapeutic trial with increasing doses of haloperidol was unsuccessful. Finally, serologic tests (direct agglutination, indirect immunofluorescence assay) in blood and CSF were demonstrative of infection by Toxoplasma. The treatment with pyrimethamine and sulfadiazine improved the changes in the CSF, but there was only a modest clinical response. Two months after admission, a CT scan showed moderate brain atrophy and some small, hyperdense, poorly defined lesions scattered in the cerebral hemispheres. Several systemic complications, and a progressive encephalopathy with seizures, pseudobulbar palsy, and akinetic mutism were eventually present. The patient died 6 months after the onset of the disease. At autopsy, multiple necrotic lesions (
