Short report and works by considering all possible recombinations of the data.14 The purpose of considering these recombinations or permutations is to attempt to account for ﬂuctuations in assessment scores which may occur over time, unrelated to the effects of treatment. First, the difference between the actual baseline and treatment means is calculated. Then, the mean difference for every other possible combination of data if the treatment had been intro- duced at different time points in the data set is computed. In other words, imagine that you were given the results without knowing when the patient was on or off a drug. One could look at all the different permutations of being on and off a drug and calculate the mean difference in performance for each of these permutations. If the difference between actual on- and off-treatment means is greater than that for any other combination, it is possible to calculate how often this would happen by chance. In general, the actual difference between means will be statistically signif- icant at the 5% level, if this difference falls in the 5% most extreme differences in the distribution of possible recombina- tions of the data.14 In this case, the total number of permutations for our three off- and ﬁve on-treatment observations is 56. Therefore, if the difference between actual on- and off-treatment means is greater than the mean difference for all the other possible recombina- tions of the dataset, the probability of this occurring purely by chance is 1/56¼0.018. This analysis revealed that rightward deviation on line bisec- tion reduced signiﬁcantly (ﬁgure 1B) after commencing guanfa- cine (p¼0.018), demonstrating clear amelioration of the spatial bias most characteristic of neglect. The number of items iden- tiﬁed on line cancellation also increased (ﬁgure 1C), although this did not reach statistical signiﬁcance (p¼0.071). On the other hand, accurate target detection (perceptual sensitivity) over the 8 min computerised sustained attention task was signiﬁcantly enhanced (p¼0.018, ﬁgure 1D), revealing that, in addition to ameliorating aspects of the spatial bias of neglect, guanfacine was able to improve the deﬁcit in sustained attention. Clinical observation was consistent with these data, with the patient’s general level of alertness and arousal improving following introduction of guanfacine. Furthermore, after a period of 6 months on the drug, his carers reported an ‘improvement in his awareness and conversation.’ to the extent that he was able to ‘.contribute signiﬁcantly to crossword puzzles and enjoy his music CDs.’ As a result of these persistent beneﬁts, the patient continues to take 2 mg guanfacine daily. DISCUSSION The case presented here demonstrated severe hemispatial neglect and impairments in sustained attention, associated with bilat- eral thalamic lesions caused by ADEM. Initiation of the norad- renergic agonist guanfacine led to an improvement of these deﬁcits, which persisted with continued guanfacine use. Thalamic lesions, especially those involving the medial nucleidincluding the medial pulvinardare most frequently associated with deﬁcits in arousal, which can be particularly severe following bilateral damage, as can occur following stroke.10 Hemispatial neglect is also often reported, again following strokes involving the medial thalamus and pulvinar, most frequently in the right hemisphere.10 11 15 In contrast, these impairments have rarely been referred to in the literature as a sequela of ADEM.3 Difﬁculty with arousal or maintaining alertness, so that attention can be sustained on current goals, is increasingly accepted as a component of the neglect syndrome, capable in fact of predicting the severity of the spatial bias.16 It has been proposed that arousal is dependent on noradrenergic input from the locus coeruleus to inferior parietal and frontal cortex, and indirectly to these regions via the thalamus.15 Damage to these regions can also be associated with neglect.11e13 Further evidence of the intimate link between arousal and the spatial orientation of attention comes from rehabilitation studies. Alertness training can improve neglect,17 while single doses of guanfacine have previously been shown to enhance sustained attention, in addition to ameliorating the spatial deﬁcit.6 Although continued guanfacine use has been demon- strated to be efﬁcacious in the treatment of inattentiveness in children and adolescents with attention-deﬁcit/hyperactivity disorder,5 this is the ﬁrst demonstration of a persistent amelio- ration of at least some components of the spatial deﬁcit of neglect with a noradrenergic agonist. Funding This research is supported by The Wellcome Trust and the NIHR CBRC at UCLH/UCL. Competing interests None. Ethics approval Ethics approval was provided by the UCLH/UCL. Provenance and peer review Not commissioned; externally peer reviewed. REFERENCES 1. Schwarz S, Mohr A, Knauth M, et al. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology 2001;56:1313e18. 2. Bernarding J, Braun J, Koennecke HC. 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