- Email: [email protected]
Predicting the future in idiopathic rapid-eye movement sleep behaviour disorder
Reflection and Reaction
results: there, the ABCD³-I score holds up. Modification of the ABCD² score to include a new clinical variable of prior recent TIA was not validated, and thus should not be used clinically, as noted by the investigators. While this study was being prepared for publication, another study was published that included many of the same cohorts and proposed a different prediction score for stroke risk after TIA.7 This other study describes the ABCD²-I score, which in its ideal form adds three points to the ABCD² score for acute infarction on brain CT or MRI. Because the score was derived and validated in the same set of cohorts, some would argue that it has not been independently validated, but it improved stroke-risk prediction in 14 of 16 cohorts; it is therefore difficult to argue that the ABCD²-I score does not work in various settings. Unfortunately, the timing of these studies creates a new problem: we now have two competing scores incorporating imaging into ABCD², and no data to tell us which score is superior. Overall, the pooled C statistic for ABCD2-I was 0·80 (95% CI 0·74–0·86) for predicting stroke risk at 90 days,7 whereas that for ABCD³-I (which adds carotid stenosis) was 0·79 (0·66–0·90) in the derivation cohorts and 0·71 (0·64–0·77) in the validation cohorts.1 Although these findings might make the scores seem indistinguishable, this indirect comparison is problematic because different groups were tested, and noise in recording of predictors or outcomes in either study would reduce the predictive value of the score in that group. We
will have to wait for a head-to-head comparison and, for now, confusion and uncertainty will probably reduce the use of both scores. It is difficult to imagine that carotid stenosis will not remain an important component in a score that includes imaging data, but it is to be hoped that the comparative study will emerge quickly so we can avoid an alphabet soup of potential scores. S Claiborne Johnston University of California, Department of Neurology, San Francisco, CA 94143-0114, USA [email protected] I have no conflicts of interest. 1
2
3
4
5
6
7
Merwick A, Albers GW, Amarenco P, et al. Addition of brain and carotid imaging to the ABCD² score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study. Lancet Neurol 2010; published online Oct 8. DOI:10.1016/S1474-4422(10)70240-4 Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369: 283–92. Douglas VC, Johnston CM, Elkins J, Sidney S, Gress DR, Johnston SC. Head computed tomography findings predict short-term stroke risk after transient ischemic attack. Stroke 2003; 34: 2894–98. Coutts SB, Simon JE, Eliasziw M, et al. Triaging transient ischemic attack and minor stroke patients using acute magnetic resonance imaging. Ann Neurol 2005; 57: 848–54. Coutts SB, Eliasziw M, Hill MD, et al, for the VISION study group. An improved scoring system for identifying patients at high early risk of stroke and functional impairment after an acute transient ischemic attack or minor stroke. Int J Stroke 2008; 3: 3–10. Ay H, Arsava EM, Johnston SC, et al. Clinical- and imaging-based prediction of stroke risk after transient ischemic attack: the CIP model. Stroke 2009; 40: 181–86. Giles MF, Albers GW, Amarenco P, et al. Addition of brain infarction to the ABCD2 score (ABCD2I): a collaborative analysis of unpublished data on 4574 patients. Stroke 2010; 41: 1907–13.
Predicting the future in idiopathic rapid-eye movement sleep behaviour disorder Published Online September 23, 2010 DOI:10.1016/S14744422(10)70221-0 See Articles page 1070
1040
Some of the views on rapid-eye-movement sleep behaviour disorder (RBD) have changed greatly during the 25 years since the disease was first characterised in human beings.1 Initially RBD was regarded as an intriguing and supposedly rare parasomnia. This notion has expanded into the appreciation that RBD might be an early clinical manifestation of an evolving neurodegenerative disorder.2–9 Ample evidence now exists to show that RBD is often associated with neurodegenerative disorders, particularly the synucleinopathies—Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. Furthermore, RBD often precedes development of cognitive, neuropsychiatric,
motor, and autonomic features of these syndromes by years or decades.2–9 Interest in RBD is growing— justifiably—since any intervention for neurodegenerative disorders will more likely affect the progression of neurodegeneration and rate of clinical progression if it is started early. However, many questions remain, as the clinical implications and prospects of early intervention are considered for patients with idiopathic RBD (IRBD), which is the term applied when RBD is not associated with any obvious signs or symptoms of another neurologic disorder. Some of the key questions and concepts relating to IRBD are depicted in the figure. The risk of development www.thelancet.com/neurology Vol 9 November 2010
Reflection and Reaction
www.thelancet.com/neurology Vol 9 November 2010
Question 1
Idiopathic RBD
Question 2
Neurodegenerative disorder
Non-neurodegenerative disorder
Question 3
Synucleinopathy
Non-synucleinopathy
Parkinson’s disease
Dementia with Lewy bodies
Multiple system atrophy
Pure autonomic failure
Incidental Lewy body disease
Question 4 Test Cognitive, motor, or autonomic functioning
of cognitive or motor impairment as manifestations of a probable synucleinopathy 12 years after RBD onset is about 50%.6 Some individuals might have a seemingly indolent variant of neurodegenerative disease, with development of cognitive, motor, or autonomic impairment occurring as many as 50 years after onset of RBD.7 Although it is apparently fortunate to have a slow rate of evolution of the disorder, the concomitant inability to accurately predict the future course and eventual symptoms and syndromes poses challenges for patients in preparation for their futures, and for scientists to plan for assessing the efficacy of future disease-modifying therapies. Key recent studies5,8,9 are providing insights into some of these questions and some of the most impressive predictive data are reported in this issue of The Lancet Neurology. Iranzo and colleagues10 undertook two neuroimaging studies: dopamine transporter imaging with ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) SPECT and transcranial sonography (TCS)—both suggest nigral or strital dysfunction when findings are abnormal, and hence are suggestive of an underlying neurodegenerative disorder associated with nigrostriatal dysfunction. The investigators examined 43 patients with IRBD (mean duration of RBD was about 9·5 years) with ¹²³I-FP-CIT SPECT and TCS at baseline, and then followed them longitudinally with clinical assessments. 27 (63%) patients had decreased striatal ¹²³I-FP-CIT binding or substantia nigra hyperechogenicity at baseline. By the follow-up assessment about 2·5 years after neuroimaging, eight (19%) patients (reduced ¹²³I-FP-CIT uptake was noted in six, substantia nigra hyperechogenicity in five, and a combination in three), developed clinicallydefined Parkinson’s disease (five), dementia with Lewy bodies (two), or multiple system atrophy (one). These eight individuals had shown features of RBD for at least 10 years (median of 11 years range of 10–21 years) at neuroimaging. Iranzo and colleagues suggest that decreased binding of ¹²³I-FP-CIT in the striatum and substantia nigra hyperechogenicity might be useful markers for identification of individuals with IRBD who are at increased short-term risk for development of the synucleinopathies—Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. These findings therefore suggest possible answers to some of the key questions described here (figure). Any
Onset of RBD
A
B
C
Age Figure: Key questions and concepts relating to idiopathic RBD Clinical researchers aim to identify patients with apparent idiopathic RBD (IRBD) and commence disease-modifying therapies that could delay onset, slow down the course, and prevent additional manifestations of an evolving neurodegenerative disorder. However, several questions remain. First, among those who have polysomnographicallyconfirmed IRBD, it is not currently possible to identify with confidence those who have an underlying neurodegenerative disorder (question 1). Although synucleinopathies are the most common proteinopathies associated with RBD, other disorders within the spectrum of tauopathies and trinucleotide repeat disorders have been reported.5 For individuals who are exhibiting RBD as a manifestation of an early neurodegenerative disorder, it is not currently possible to determine an underlying proteinopathy (question 2). Prediction of the clinical syndrome and its associated features, that will later become manifest, is not possible either(question 3); finally, we cannot predict when other features will evolve (question 4; cognitive impairment, parkinsonism, or autonomic dysfunction might arise after a few years [A], many years [B], or never[C]). Tests or biomarkers (represented by “Test” in this figure) that could predict development of cognitive impairment, parkinsonism, or autonomic dysfunction would be highly desirable. RBD=rapid-eye-movement sleep behaviour disorder.
IRBD patient with abnormal findings on ¹²³I-FP-CIT SPECT or TCS probably has an underlying neurodegenerative disorder (question 1), which is probably a synucleinopathy (question 2). Furthermore, a key point is the short-term risk that such abnormal findings suggest (ie, the onset of cognitive, motor, or autonomic dysfunction will probably occur sooner rather than later [follow the course as shown in curve “A” rather than “B” or “C” for question 4, with ¹²³I-FP-CIT SPECT or TCS the test in question]). These patients would be eligible for enrolment in comprehensive longitudinal assessments with various tests and biomarkers to characterise their course in the present era of no disease-modifying therapies, 1041
Reflection and Reaction
and especially for participation in eventual trials of disease-modifying treatments. Continued longitudinal assessment of those who remain free of other neurologic signs or symptoms (such as the 19 participants in this study), with eventual neuropathological assessment in all individuals, are warranted to establish outcomes and underlying substrates for well-characterised IRBD patients (ie, perhaps some or all of these 19 will follow a course as in curve B in the figure or have underlying incidental Lewy body disease and follow a course as in curve C). The data in this study do not provide insights into the particular neurodegenerative disease phenotype that these patients will probably develop (question 3), or on whether some patients with IRBD and abnormal findings on ¹²³I-FP-CIT SPECT or TCS might have a nonsynucleinopathy with inherent nigrostriatal degeneration (eg, progressive supranuclear palsy) and these issues clearly warrant further investigation. Iranzo and colleagues’s work underscores the usefulness of studying adequate numbers of patients longitudinally with a spectrum of clinical tests and potential biomarkers to assess the natural history of IRBD and prepare for future clinical trials. Patients with IRBD are expecting these future trials, and most of them are eager to contribute toward these efforts.
I served as an investigator for a clinical trial sponsored by Cephalon, and received royalties from Cambridge Medicine, honoraria from the American Academy of Neurology, and research support from the US National Institute on Aging (P50 AG16574 [co-investigator], U01 AG06786 [co-investigator], RO1 AG15866 [co-investigator], and U24 AG26395 [co-investigator]), the Alzheimer’s Association (IIRG-05–14560 [principal investigator]), and the Robert H and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Programme of the Mayo Foundation. 1
2
3
4
5
6
7
8
9
10
Bradley F Boeve Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA [email protected]
Schenck CH, Bundlie SR, Ettinger MG, Mahowald MW. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 1986; 9: 293–308. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 1996; 46: 388–93. Iranzo A, Molinuevo JL, Santamaría J, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol 2006; 5: 572–77. Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 2007; 130: 2770–88. Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci 2010; 1184: 15–54. Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Montplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 2009; 72: 1296–300. Claassen DO, Josephs KA, Ahlskog JE, Silber MH, Tippmann-Peikert M, Boeve BF. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 2010; 75: 494–99. Stiasny-Kolster K, Doerr Y, Möller J, et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005; 128: 126–37. Miyamoto T, Miyamoto M, Suzuki K, Nishibayashi M, Iwanami M, Hirata K. ¹²³I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder. Sleep 2008; 31: 717–23. Iranzo A, Lomeña F, Stockner H, et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol 2010; published online Sept 15. DOI:10.1016/S1474-4422(10)70216-7.
Small vessel childhood primary angiitis of the CNS: first steps toward a standardised treatment regimen Published Online October 4, 2010 DOI:10.1016/S14744422(10)70244-1 See Articles page 1078
1042
Childhood primary angiitis of the CNS is a rare, idiopathic inflammatory brain disorder that accounts for 2–6% of paediatric artheriopathies.1,2 The disorder is divided into medium-large vessel and small vessel disease, which each present with distinct clinical and radiological features. Initial case reports of small vessel disease in children were reported in the 1990s.3,4 Similar to adult small vessel primary angiitis of the CNS, the clinical presentation is usually subacute, with multifocal neurologic deficits, headaches, and neurobehavioural impairment. However, seizures and tumour-like
presentations are reported more frequently in children with small vessel disease than in adults with the disorder.5 Brain biopsy is generally required for diagnosis because angiography is frequently negative. Biopsies reveal segmental, non-granulomatous, intramural infiltration predominantly of T lymphocytes in the small arteries, arterioles, capillaries, or venules.6 Although small vessel childhood primary angiitis of the CNS is rare, early recognition and appropriate treatment is important for reduction of morbidity and mortality. The disorder should be considered in the differential www.thelancet.com/neurology Vol 9 November 2010
results: there, the ABCD³-I score holds up. Modification of the ABCD² score to include a new clinical variable of prior recent TIA was not validated, and thus should not be used clinically, as noted by the investigators. While this study was being prepared for publication, another study was published that included many of the same cohorts and proposed a different prediction score for stroke risk after TIA.7 This other study describes the ABCD²-I score, which in its ideal form adds three points to the ABCD² score for acute infarction on brain CT or MRI. Because the score was derived and validated in the same set of cohorts, some would argue that it has not been independently validated, but it improved stroke-risk prediction in 14 of 16 cohorts; it is therefore difficult to argue that the ABCD²-I score does not work in various settings. Unfortunately, the timing of these studies creates a new problem: we now have two competing scores incorporating imaging into ABCD², and no data to tell us which score is superior. Overall, the pooled C statistic for ABCD2-I was 0·80 (95% CI 0·74–0·86) for predicting stroke risk at 90 days,7 whereas that for ABCD³-I (which adds carotid stenosis) was 0·79 (0·66–0·90) in the derivation cohorts and 0·71 (0·64–0·77) in the validation cohorts.1 Although these findings might make the scores seem indistinguishable, this indirect comparison is problematic because different groups were tested, and noise in recording of predictors or outcomes in either study would reduce the predictive value of the score in that group. We
will have to wait for a head-to-head comparison and, for now, confusion and uncertainty will probably reduce the use of both scores. It is difficult to imagine that carotid stenosis will not remain an important component in a score that includes imaging data, but it is to be hoped that the comparative study will emerge quickly so we can avoid an alphabet soup of potential scores. S Claiborne Johnston University of California, Department of Neurology, San Francisco, CA 94143-0114, USA [email protected] I have no conflicts of interest. 1
2
3
4
5
6
7
Merwick A, Albers GW, Amarenco P, et al. Addition of brain and carotid imaging to the ABCD² score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study. Lancet Neurol 2010; published online Oct 8. DOI:10.1016/S1474-4422(10)70240-4 Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369: 283–92. Douglas VC, Johnston CM, Elkins J, Sidney S, Gress DR, Johnston SC. Head computed tomography findings predict short-term stroke risk after transient ischemic attack. Stroke 2003; 34: 2894–98. Coutts SB, Simon JE, Eliasziw M, et al. Triaging transient ischemic attack and minor stroke patients using acute magnetic resonance imaging. Ann Neurol 2005; 57: 848–54. Coutts SB, Eliasziw M, Hill MD, et al, for the VISION study group. An improved scoring system for identifying patients at high early risk of stroke and functional impairment after an acute transient ischemic attack or minor stroke. Int J Stroke 2008; 3: 3–10. Ay H, Arsava EM, Johnston SC, et al. Clinical- and imaging-based prediction of stroke risk after transient ischemic attack: the CIP model. Stroke 2009; 40: 181–86. Giles MF, Albers GW, Amarenco P, et al. Addition of brain infarction to the ABCD2 score (ABCD2I): a collaborative analysis of unpublished data on 4574 patients. Stroke 2010; 41: 1907–13.
Predicting the future in idiopathic rapid-eye movement sleep behaviour disorder Published Online September 23, 2010 DOI:10.1016/S14744422(10)70221-0 See Articles page 1070
1040
Some of the views on rapid-eye-movement sleep behaviour disorder (RBD) have changed greatly during the 25 years since the disease was first characterised in human beings.1 Initially RBD was regarded as an intriguing and supposedly rare parasomnia. This notion has expanded into the appreciation that RBD might be an early clinical manifestation of an evolving neurodegenerative disorder.2–9 Ample evidence now exists to show that RBD is often associated with neurodegenerative disorders, particularly the synucleinopathies—Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. Furthermore, RBD often precedes development of cognitive, neuropsychiatric,
motor, and autonomic features of these syndromes by years or decades.2–9 Interest in RBD is growing— justifiably—since any intervention for neurodegenerative disorders will more likely affect the progression of neurodegeneration and rate of clinical progression if it is started early. However, many questions remain, as the clinical implications and prospects of early intervention are considered for patients with idiopathic RBD (IRBD), which is the term applied when RBD is not associated with any obvious signs or symptoms of another neurologic disorder. Some of the key questions and concepts relating to IRBD are depicted in the figure. The risk of development www.thelancet.com/neurology Vol 9 November 2010
Reflection and Reaction
www.thelancet.com/neurology Vol 9 November 2010
Question 1
Idiopathic RBD
Question 2
Neurodegenerative disorder
Non-neurodegenerative disorder
Question 3
Synucleinopathy
Non-synucleinopathy
Parkinson’s disease
Dementia with Lewy bodies
Multiple system atrophy
Pure autonomic failure
Incidental Lewy body disease
Question 4 Test Cognitive, motor, or autonomic functioning
of cognitive or motor impairment as manifestations of a probable synucleinopathy 12 years after RBD onset is about 50%.6 Some individuals might have a seemingly indolent variant of neurodegenerative disease, with development of cognitive, motor, or autonomic impairment occurring as many as 50 years after onset of RBD.7 Although it is apparently fortunate to have a slow rate of evolution of the disorder, the concomitant inability to accurately predict the future course and eventual symptoms and syndromes poses challenges for patients in preparation for their futures, and for scientists to plan for assessing the efficacy of future disease-modifying therapies. Key recent studies5,8,9 are providing insights into some of these questions and some of the most impressive predictive data are reported in this issue of The Lancet Neurology. Iranzo and colleagues10 undertook two neuroimaging studies: dopamine transporter imaging with ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) SPECT and transcranial sonography (TCS)—both suggest nigral or strital dysfunction when findings are abnormal, and hence are suggestive of an underlying neurodegenerative disorder associated with nigrostriatal dysfunction. The investigators examined 43 patients with IRBD (mean duration of RBD was about 9·5 years) with ¹²³I-FP-CIT SPECT and TCS at baseline, and then followed them longitudinally with clinical assessments. 27 (63%) patients had decreased striatal ¹²³I-FP-CIT binding or substantia nigra hyperechogenicity at baseline. By the follow-up assessment about 2·5 years after neuroimaging, eight (19%) patients (reduced ¹²³I-FP-CIT uptake was noted in six, substantia nigra hyperechogenicity in five, and a combination in three), developed clinicallydefined Parkinson’s disease (five), dementia with Lewy bodies (two), or multiple system atrophy (one). These eight individuals had shown features of RBD for at least 10 years (median of 11 years range of 10–21 years) at neuroimaging. Iranzo and colleagues suggest that decreased binding of ¹²³I-FP-CIT in the striatum and substantia nigra hyperechogenicity might be useful markers for identification of individuals with IRBD who are at increased short-term risk for development of the synucleinopathies—Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. These findings therefore suggest possible answers to some of the key questions described here (figure). Any
Onset of RBD
A
B
C
Age Figure: Key questions and concepts relating to idiopathic RBD Clinical researchers aim to identify patients with apparent idiopathic RBD (IRBD) and commence disease-modifying therapies that could delay onset, slow down the course, and prevent additional manifestations of an evolving neurodegenerative disorder. However, several questions remain. First, among those who have polysomnographicallyconfirmed IRBD, it is not currently possible to identify with confidence those who have an underlying neurodegenerative disorder (question 1). Although synucleinopathies are the most common proteinopathies associated with RBD, other disorders within the spectrum of tauopathies and trinucleotide repeat disorders have been reported.5 For individuals who are exhibiting RBD as a manifestation of an early neurodegenerative disorder, it is not currently possible to determine an underlying proteinopathy (question 2). Prediction of the clinical syndrome and its associated features, that will later become manifest, is not possible either(question 3); finally, we cannot predict when other features will evolve (question 4; cognitive impairment, parkinsonism, or autonomic dysfunction might arise after a few years [A], many years [B], or never[C]). Tests or biomarkers (represented by “Test” in this figure) that could predict development of cognitive impairment, parkinsonism, or autonomic dysfunction would be highly desirable. RBD=rapid-eye-movement sleep behaviour disorder.
IRBD patient with abnormal findings on ¹²³I-FP-CIT SPECT or TCS probably has an underlying neurodegenerative disorder (question 1), which is probably a synucleinopathy (question 2). Furthermore, a key point is the short-term risk that such abnormal findings suggest (ie, the onset of cognitive, motor, or autonomic dysfunction will probably occur sooner rather than later [follow the course as shown in curve “A” rather than “B” or “C” for question 4, with ¹²³I-FP-CIT SPECT or TCS the test in question]). These patients would be eligible for enrolment in comprehensive longitudinal assessments with various tests and biomarkers to characterise their course in the present era of no disease-modifying therapies, 1041
Reflection and Reaction
and especially for participation in eventual trials of disease-modifying treatments. Continued longitudinal assessment of those who remain free of other neurologic signs or symptoms (such as the 19 participants in this study), with eventual neuropathological assessment in all individuals, are warranted to establish outcomes and underlying substrates for well-characterised IRBD patients (ie, perhaps some or all of these 19 will follow a course as in curve B in the figure or have underlying incidental Lewy body disease and follow a course as in curve C). The data in this study do not provide insights into the particular neurodegenerative disease phenotype that these patients will probably develop (question 3), or on whether some patients with IRBD and abnormal findings on ¹²³I-FP-CIT SPECT or TCS might have a nonsynucleinopathy with inherent nigrostriatal degeneration (eg, progressive supranuclear palsy) and these issues clearly warrant further investigation. Iranzo and colleagues’s work underscores the usefulness of studying adequate numbers of patients longitudinally with a spectrum of clinical tests and potential biomarkers to assess the natural history of IRBD and prepare for future clinical trials. Patients with IRBD are expecting these future trials, and most of them are eager to contribute toward these efforts.
I served as an investigator for a clinical trial sponsored by Cephalon, and received royalties from Cambridge Medicine, honoraria from the American Academy of Neurology, and research support from the US National Institute on Aging (P50 AG16574 [co-investigator], U01 AG06786 [co-investigator], RO1 AG15866 [co-investigator], and U24 AG26395 [co-investigator]), the Alzheimer’s Association (IIRG-05–14560 [principal investigator]), and the Robert H and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Programme of the Mayo Foundation. 1
2
3
4
5
6
7
8
9
10
Bradley F Boeve Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA [email protected]
Schenck CH, Bundlie SR, Ettinger MG, Mahowald MW. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 1986; 9: 293–308. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 1996; 46: 388–93. Iranzo A, Molinuevo JL, Santamaría J, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol 2006; 5: 572–77. Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 2007; 130: 2770–88. Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci 2010; 1184: 15–54. Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Montplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 2009; 72: 1296–300. Claassen DO, Josephs KA, Ahlskog JE, Silber MH, Tippmann-Peikert M, Boeve BF. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 2010; 75: 494–99. Stiasny-Kolster K, Doerr Y, Möller J, et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005; 128: 126–37. Miyamoto T, Miyamoto M, Suzuki K, Nishibayashi M, Iwanami M, Hirata K. ¹²³I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder. Sleep 2008; 31: 717–23. Iranzo A, Lomeña F, Stockner H, et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol 2010; published online Sept 15. DOI:10.1016/S1474-4422(10)70216-7.
Small vessel childhood primary angiitis of the CNS: first steps toward a standardised treatment regimen Published Online October 4, 2010 DOI:10.1016/S14744422(10)70244-1 See Articles page 1078
1042
Childhood primary angiitis of the CNS is a rare, idiopathic inflammatory brain disorder that accounts for 2–6% of paediatric artheriopathies.1,2 The disorder is divided into medium-large vessel and small vessel disease, which each present with distinct clinical and radiological features. Initial case reports of small vessel disease in children were reported in the 1990s.3,4 Similar to adult small vessel primary angiitis of the CNS, the clinical presentation is usually subacute, with multifocal neurologic deficits, headaches, and neurobehavioural impairment. However, seizures and tumour-like
presentations are reported more frequently in children with small vessel disease than in adults with the disorder.5 Brain biopsy is generally required for diagnosis because angiography is frequently negative. Biopsies reveal segmental, non-granulomatous, intramural infiltration predominantly of T lymphocytes in the small arteries, arterioles, capillaries, or venules.6 Although small vessel childhood primary angiitis of the CNS is rare, early recognition and appropriate treatment is important for reduction of morbidity and mortality. The disorder should be considered in the differential www.thelancet.com/neurology Vol 9 November 2010