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Frontotemporal Dementia/Pick's Disease

Frontotemporal Dementia/Pick's Disease It has now been more than 110 years since Arnold Pick described the first of a series of cases separating focal atrophies from what at that time was called senile atrophy. The title of that article, "On the Relationship Between Senile Cerebral Atrophy and Aphasia,"reflects the essence of the case report, that of progressive aphasia, focal, temporal atrophy.THE CLINICAL SYNDROMEA 71-year-old man called August H. (not to be confused with Auguste D. who was Alzheimer's first case in 1906 and who was also aphasic) had episodes of "confusion" and "loss of consciousness," as well as behavioral symptoms that were probably related to frontal lobe degeneration. Nevertheless, Pick emphasized the temporal development of aphasia and, citing Chiari's autopsy report, the relationship of the aphasia to circumscribed temporal atrophy without evidence of strokes:The history suggests that the speech disturbance developed gradually. . . . There was pronounced atrophy of the gyri of the left hemisphere particularly on the left temporal lobe. No focal disease was established. . . . It seems right to state that a more or less sharply circumscribed type of aphasia may exist at a particular point in time and be related to circumscribed, perhaps simple brain changes.Another of Pick's cases represented the behavioral syndrome of frontotemporal dementia and is cited in "Über primäre progressive Demenz bei Erwachsenen"("On primary progressive dementia of adults"):A 41 year old housewife changed gradually. She became careless, clumsy, . . . did not carry out her usual work, did not take care of her children, did not change her clothes or the bedding, and stopped combing her hair. She left work unfinished and laid about idly. She did not initiate conversation, repeated questions, tended to give stereotypical answers, and often perseverated. Her only concern was her body, she was complaining of fleas and hunger and was always asking for food. She had unusual fits of anger, verbally abused and hit her children or whatever was nearby, including cattle.Pick's other cases concerned progressive aphasia and apraxia and another case description that today would be called semantic dementia.The eponymic term Pick's diseasewas suggested by Gans,a pupil of Pick, who thought that the phylogenetically younger frontal and temporal lobes were more vulnerable to degeneration due to abiotrophy, a concept that became popular around that time, much as apoptosis is now. Many subsequent articles on Pick's disease emphasized the behavioral disturbance.HISTOPATHOLOGIC FEATURESOnari and Spatzwere responsible for defining Pick's disease on the basis of histologic features, the characteristic involvement of the second and third cortical layers, the status spongiosis, swollen neurons, and the argyrophilic round inclusions, first described by Alzheimer.Later these inclusions were called Pick bodies. Onari and Spatz said:The main intention of these lines is to direct renewed attention to a disease picture which until now has been paid too little attention. We are convinced that Pick's disease is not an extreme rarity; though it is today still often unknown to clinicians or anatomists, because even when it is observed, it is not considered as such. From the anatomical point of view, it can be said that the substrate of Pick's disease in its two subgroups, comprising the frontal and temporal atrophies, is quite characteristic.Microscopically, they described the major features:The shrinkage affects the first and second layer of the cortical grey matter . . . occasionally resulting in the disappearance of the ground substance producing status spongiosis. . . .The remaining nerve cells are shrunken and just like the glial cells, more pigmented here and there. Swollen nerve cells can also be observed in the pattern of primary irritation. . . .Alzheimer's silver balls (bullets) appear both in the temporal and frontal horns but also can be entirely absent without altering the total picture.Later, some pathologists restricted the term Pick's diseaseto the finding of the silver-staining round inclusions, although the above description defining the histologic features made it clear that this feature was not necessary.Others have also included cases without these inclusions in the definition of the disease. After reviewing a large series of their own, Constantinidis et alclassified Pick's disease: (A) with Pick bodies, (B) only with swollen neurons, and (C) only with gliosis. They felt:. . . in spite of the dissimilarities between these forms, considering the absence of sufficient knowledge about pathogenesis, it seems prudent at present to maintain the uniqueness of Pick's entity.MODERN REFORMULATION AND HISTOCHEMICAL FEATURESThe disease was renamed frontal lobe dementia, then frontotemporal degenerationin a series of articles.The clinical features used today as diagnostic criteria include:Insidious onset and slow progression, early loss of personal awareness (neglect of personal hygiene and grooming), early loss of social awareness (lack of social tact, misdemeanours such as shoplifting), early signs of disinhibition (such as unrestrained sexuality, violent behaviour, inappropriate jocularity, restless pacing), mental rigidity and inflexibility, hyperorality (oral/dietary changes, overeating, food fads, excessive smoking and alcohol consumption, oral exploration of objects), stereotyped and perseverative behaviour (wandering, mannerisms such as clapping, singing, dancing, ritualistic preoccupation such as hoarding, toileting, and dressing), utilisation behaviour (unrestrained exploration of objects in the environment), distractibility, impulsivity, and impersistence.Though language deterioration was also included in this description, the aphasic presentation was aptly named primary progressive aphasiaby Mesulamand for a while was considered to be a separate entity. The extrapyramidal variety of Pick's disease was described in the 1930s and is likely the same condition as corticobasal degeneration, first described as corticodentatonigral degenerationby Rebeiz et al,who recognized the resemblance to the pathologic features of Pick's disease. The association of ubiquinated inclusions with the frontotemporal dementia syndrome, with or without clinical motor neuron involvement, has been recognized also, and it is becoming increasingly evident that this pathologic finding occurs frequently in typical cases of frontotemporal dementia.Frontotemporal degeneration covers a pathologic spectrum that includes the typical histology of Pick's disease, as well as corticobasal degeneration and dementia lacking distinctive histologic features, which refers to cases without typical inclusions. This last term will be used less because most of the cases may be found to have ubiquinated, tau negative inclusions of the motor neuron disease type, which have an appearance and location similar to Pick bodies. The term Pick complexwas also suggested for the whole syndrome including frontotemporal dementia, primary progressive aphasia, and corticobasal degeneration and the spectrum of underlying pathologic features, so that frontotemporal dementia can be used for the behavioral presentation only.We propose the concept of Pick Complex to include neurodegenerative diseases such as primary progressive aphasia, frontal lobe dementia, amyotrophic lateral sclerosis (with the above), and corticonigral and corticobasal degenerations.GENETIC DISCOVERIESThe recent discovery of chromosome 17 linked frontotemporal dementia (FTDP-17) has created a genetic and biological confirmation of the cohesion among various manifestations of frontotemporal dementia/Pick's disease. Wilhelmsen,who linked the first family to chromosome 17, wrote:. . . the region in common to all the chromosome 17q21-22-linked dementias contains the gene for the microtubule-associated protein tau (MAPtau). . . . It would be very satisfying to finally identify disease phenotypes for mutations in MAPtau, a molecule intensely studied because of the histology of AD [Alzheimer's disease], but never previously shown to cause disease.True to prediction, this discovery was followed by the finding of tau mutations. Hutton et al,with no less than 50 coauthors, wrote:Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10.Since then, more than 20 mutations in more than 50 families have been described, encompassing the whole clinical and pathologic spectrum of frontotemporal dementia/Pick's disease (Pick complex). It also became evident that only 30% to 50% of families with dominantly inherited disease have tau mutations, and more loci are being sought, especially for those families with motor neuron disease type of inclusions, who may fail to express tau. Common tau haplotypes and mutations have further confirmed that corticobasal degeneration and progressive supranuclear palsy also belong to Pick complex, although there are many defenders of their distinctiveness. Even though subcortical pathologic features are more prominent, cortical involvement frequently manifests as frontotemporal dementia and primary progressive aphasia. While the search for the genetic and biochemical etiology continues, recognition of the relatedness of these variants will improve diagnosis and awareness of the relatively high frequency of the disease, especially in the presenile age group.APickÜber die Beziehungen der senilen Hirnatrophie zur Aphasie.Prag Med Wochenschr.1892;17:165-167.APickÜber primäre progressive Demenz bei Erwachsenen.Prag Med Wochenschr.1904;29:417-420.AGansPick Betrachtungen über Art und Ausbreitung des krankhaften Prozesses in einem Fall von Pickscher Atrophie des Stirnhirns.Ztschr f d ges Neurol U Psychiatr.1922;80:10-28.KOnariHSpatzAnatomische Beitrage zur Lehre von der Pickschen umschriebenen Grosshirnrinden-Atrophie ("Picksche Krankheit").Z Gesamte Neurol Psychiatr.1926;101:470-511.AAlzheimerÜber eigenartige Krankheitsfälle des späteren Alters.Z Gesamte Neurol Psychiatr.1911;4:356-385.JConstantinidisJRichardRTissotPick's disease: histological and clinical correlations.Eur Neurol.1974;11:208-217.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4137107&dopt=AbstractLGustafsonFrontal lobe degeneration of non-Alzheimer type, II: clinical picture and differential diagnosis.Arch Gerontol Geriatr.1987;6:209-223.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3689054&dopt=AbstractDNearyJSSnowdenBNorthernPJGouldingDementia of the frontal lobe type.J Neurol Neurosurg Psychiatry.1988;51:353-361.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3258902&dopt=AbstractABrunBEnglundLGustafsonClinical and neuropathological criteria for frontotemporal dementia.J Neurol Neurosurg Psychiatry.1994;57:416-418.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8163988&dopt=AbstractMMMesulamPrimary progressive aphasia: differentiation from Alzheimer's disease.Ann Neurol.1987;22:533-534.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3324947&dopt=AbstractJJRebeizEHKolodnyEPRichardson JrCorticodentatonigral degeneration with neuronal achromasia.Arch Neurol.1968;18:20-33.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=5634369&dopt=AbstractAKerteszLHudsonIRAMackenzieDGMunozThe pathology and nosology of primary progressive aphasia.Neurology.1994;44:2065-2072.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7969961&dopt=AbstractKWilhelmsenFrontotemporal dementia is on the MAPt.Ann Neurol.1997;41:139-140.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9029060&dopt=AbstractMHuttonCLLendonPRizzuAssociation of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.Nature.1998;393:702-705.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9641683&dopt=AbstractCorresponding author: Andrew Kertesz, MD, FRCPC, Department of Clinical Neurological Sciences, St Joseph's Hospital, University of Western Ontario, 268 Grosvenor St, London, Ontario N6A 4V2 Canada (e-mail: andrew.kertesz@sjhc.london.on.ca).Accepted for publication June 17, 2003.I thank Marybelle Lozanski and Bonita Stevenson for help with the references and the production of the manuscript. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Neurology American Medical Association

Frontotemporal Dementia/Pick's Disease

Kertesz, Andrew
JAMA Neurology , Volume 61 (6) – Jun 1, 2004
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American Medical Association
Copyright
Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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2168-6149
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2168-6157
DOI
10.1001/archneur.61.6.969
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15210543
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Abstract

It has now been more than 110 years since Arnold Pick described the first of a series of cases separating focal atrophies from what at that time was called senile atrophy. The title of that article, "On the Relationship Between Senile Cerebral Atrophy and Aphasia,"reflects the essence of the case report, that of progressive aphasia, focal, temporal atrophy.THE CLINICAL SYNDROMEA 71-year-old man called August H. (not to be confused with Auguste D. who was Alzheimer's first case in 1906 and who was also aphasic) had episodes of "confusion" and "loss of consciousness," as well as behavioral symptoms that were probably related to frontal lobe degeneration. Nevertheless, Pick emphasized the temporal development of aphasia and, citing Chiari's autopsy report, the relationship of the aphasia to circumscribed temporal atrophy without evidence of strokes:The history suggests that the speech disturbance developed gradually. . . . There was pronounced atrophy of the gyri of the left hemisphere particularly on the left temporal lobe. No focal disease was established. . . . It seems right to state that a more or less sharply circumscribed type of aphasia may exist at a particular point in time and be related to circumscribed, perhaps simple brain changes.Another of Pick's cases represented the behavioral syndrome of frontotemporal dementia and is cited in "Über primäre progressive Demenz bei Erwachsenen"("On primary progressive dementia of adults"):A 41 year old housewife changed gradually. She became careless, clumsy, . . . did not carry out her usual work, did not take care of her children, did not change her clothes or the bedding, and stopped combing her hair. She left work unfinished and laid about idly. She did not initiate conversation, repeated questions, tended to give stereotypical answers, and often perseverated. Her only concern was her body, she was complaining of fleas and hunger and was always asking for food. She had unusual fits of anger, verbally abused and hit her children or whatever was nearby, including cattle.Pick's other cases concerned progressive aphasia and apraxia and another case description that today would be called semantic dementia.The eponymic term Pick's diseasewas suggested by Gans,a pupil of Pick, who thought that the phylogenetically younger frontal and temporal lobes were more vulnerable to degeneration due to abiotrophy, a concept that became popular around that time, much as apoptosis is now. Many subsequent articles on Pick's disease emphasized the behavioral disturbance.HISTOPATHOLOGIC FEATURESOnari and Spatzwere responsible for defining Pick's disease on the basis of histologic features, the characteristic involvement of the second and third cortical layers, the status spongiosis, swollen neurons, and the argyrophilic round inclusions, first described by Alzheimer.Later these inclusions were called Pick bodies. Onari and Spatz said:The main intention of these lines is to direct renewed attention to a disease picture which until now has been paid too little attention. We are convinced that Pick's disease is not an extreme rarity; though it is today still often unknown to clinicians or anatomists, because even when it is observed, it is not considered as such. From the anatomical point of view, it can be said that the substrate of Pick's disease in its two subgroups, comprising the frontal and temporal atrophies, is quite characteristic.Microscopically, they described the major features:The shrinkage affects the first and second layer of the cortical grey matter . . . occasionally resulting in the disappearance of the ground substance producing status spongiosis. . . .The remaining nerve cells are shrunken and just like the glial cells, more pigmented here and there. Swollen nerve cells can also be observed in the pattern of primary irritation. . . .Alzheimer's silver balls (bullets) appear both in the temporal and frontal horns but also can be entirely absent without altering the total picture.Later, some pathologists restricted the term Pick's diseaseto the finding of the silver-staining round inclusions, although the above description defining the histologic features made it clear that this feature was not necessary.Others have also included cases without these inclusions in the definition of the disease. After reviewing a large series of their own, Constantinidis et alclassified Pick's disease: (A) with Pick bodies, (B) only with swollen neurons, and (C) only with gliosis. They felt:. . . in spite of the dissimilarities between these forms, considering the absence of sufficient knowledge about pathogenesis, it seems prudent at present to maintain the uniqueness of Pick's entity.MODERN REFORMULATION AND HISTOCHEMICAL FEATURESThe disease was renamed frontal lobe dementia, then frontotemporal degenerationin a series of articles.The clinical features used today as diagnostic criteria include:Insidious onset and slow progression, early loss of personal awareness (neglect of personal hygiene and grooming), early loss of social awareness (lack of social tact, misdemeanours such as shoplifting), early signs of disinhibition (such as unrestrained sexuality, violent behaviour, inappropriate jocularity, restless pacing), mental rigidity and inflexibility, hyperorality (oral/dietary changes, overeating, food fads, excessive smoking and alcohol consumption, oral exploration of objects), stereotyped and perseverative behaviour (wandering, mannerisms such as clapping, singing, dancing, ritualistic preoccupation such as hoarding, toileting, and dressing), utilisation behaviour (unrestrained exploration of objects in the environment), distractibility, impulsivity, and impersistence.Though language deterioration was also included in this description, the aphasic presentation was aptly named primary progressive aphasiaby Mesulamand for a while was considered to be a separate entity. The extrapyramidal variety of Pick's disease was described in the 1930s and is likely the same condition as corticobasal degeneration, first described as corticodentatonigral degenerationby Rebeiz et al,who recognized the resemblance to the pathologic features of Pick's disease. The association of ubiquinated inclusions with the frontotemporal dementia syndrome, with or without clinical motor neuron involvement, has been recognized also, and it is becoming increasingly evident that this pathologic finding occurs frequently in typical cases of frontotemporal dementia.Frontotemporal degeneration covers a pathologic spectrum that includes the typical histology of Pick's disease, as well as corticobasal degeneration and dementia lacking distinctive histologic features, which refers to cases without typical inclusions. This last term will be used less because most of the cases may be found to have ubiquinated, tau negative inclusions of the motor neuron disease type, which have an appearance and location similar to Pick bodies. The term Pick complexwas also suggested for the whole syndrome including frontotemporal dementia, primary progressive aphasia, and corticobasal degeneration and the spectrum of underlying pathologic features, so that frontotemporal dementia can be used for the behavioral presentation only.We propose the concept of Pick Complex to include neurodegenerative diseases such as primary progressive aphasia, frontal lobe dementia, amyotrophic lateral sclerosis (with the above), and corticonigral and corticobasal degenerations.GENETIC DISCOVERIESThe recent discovery of chromosome 17 linked frontotemporal dementia (FTDP-17) has created a genetic and biological confirmation of the cohesion among various manifestations of frontotemporal dementia/Pick's disease. Wilhelmsen,who linked the first family to chromosome 17, wrote:. . . the region in common to all the chromosome 17q21-22-linked dementias contains the gene for the microtubule-associated protein tau (MAPtau). . . . It would be very satisfying to finally identify disease phenotypes for mutations in MAPtau, a molecule intensely studied because of the histology of AD [Alzheimer's disease], but never previously shown to cause disease.True to prediction, this discovery was followed by the finding of tau mutations. Hutton et al,with no less than 50 coauthors, wrote:Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10.Since then, more than 20 mutations in more than 50 families have been described, encompassing the whole clinical and pathologic spectrum of frontotemporal dementia/Pick's disease (Pick complex). It also became evident that only 30% to 50% of families with dominantly inherited disease have tau mutations, and more loci are being sought, especially for those families with motor neuron disease type of inclusions, who may fail to express tau. Common tau haplotypes and mutations have further confirmed that corticobasal degeneration and progressive supranuclear palsy also belong to Pick complex, although there are many defenders of their distinctiveness. Even though subcortical pathologic features are more prominent, cortical involvement frequently manifests as frontotemporal dementia and primary progressive aphasia. While the search for the genetic and biochemical etiology continues, recognition of the relatedness of these variants will improve diagnosis and awareness of the relatively high frequency of the disease, especially in the presenile age group.APickÜber die Beziehungen der senilen Hirnatrophie zur Aphasie.Prag Med Wochenschr.1892;17:165-167.APickÜber primäre progressive Demenz bei Erwachsenen.Prag Med Wochenschr.1904;29:417-420.AGansPick Betrachtungen über Art und Ausbreitung des krankhaften Prozesses in einem Fall von Pickscher Atrophie des Stirnhirns.Ztschr f d ges Neurol U Psychiatr.1922;80:10-28.KOnariHSpatzAnatomische Beitrage zur Lehre von der Pickschen umschriebenen Grosshirnrinden-Atrophie ("Picksche Krankheit").Z Gesamte Neurol Psychiatr.1926;101:470-511.AAlzheimerÜber eigenartige Krankheitsfälle des späteren Alters.Z Gesamte Neurol Psychiatr.1911;4:356-385.JConstantinidisJRichardRTissotPick's disease: histological and clinical correlations.Eur Neurol.1974;11:208-217.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4137107&dopt=AbstractLGustafsonFrontal lobe degeneration of non-Alzheimer type, II: clinical picture and differential diagnosis.Arch Gerontol Geriatr.1987;6:209-223.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3689054&dopt=AbstractDNearyJSSnowdenBNorthernPJGouldingDementia of the frontal lobe type.J Neurol Neurosurg Psychiatry.1988;51:353-361.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3258902&dopt=AbstractABrunBEnglundLGustafsonClinical and neuropathological criteria for frontotemporal dementia.J Neurol Neurosurg Psychiatry.1994;57:416-418.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8163988&dopt=AbstractMMMesulamPrimary progressive aphasia: differentiation from Alzheimer's disease.Ann Neurol.1987;22:533-534.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3324947&dopt=AbstractJJRebeizEHKolodnyEPRichardson JrCorticodentatonigral degeneration with neuronal achromasia.Arch Neurol.1968;18:20-33.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=5634369&dopt=AbstractAKerteszLHudsonIRAMackenzieDGMunozThe pathology and nosology of primary progressive aphasia.Neurology.1994;44:2065-2072.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7969961&dopt=AbstractKWilhelmsenFrontotemporal dementia is on the MAPt.Ann Neurol.1997;41:139-140.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9029060&dopt=AbstractMHuttonCLLendonPRizzuAssociation of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.Nature.1998;393:702-705.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9641683&dopt=AbstractCorresponding author: Andrew Kertesz, MD, FRCPC, Department of Clinical Neurological Sciences, St Joseph's Hospital, University of Western Ontario, 268 Grosvenor St, London, Ontario N6A 4V2 Canada (e-mail: andrew.kertesz@sjhc.london.on.ca).Accepted for publication June 17, 2003.I thank Marybelle Lozanski and Bonita Stevenson for help with the references and the production of the manuscript.

Journal

JAMA Neurology – American Medical Association

Published: Jun 1, 2004

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