Sean O’Riordan

Paroxysmal torticollis and blepharospasm following bilateral cerebellar infarction.

Sirs: Paroxysmal secondary dystonia is most frequently due to multiple sclerosis. We here present a case of paroxysmal cervical dystonia following bilateral cerebellar infarction; no similar syndrome has previously been reported. A 35 year-old woman developed sudden weakness of her legs associated with vertigo, vomiting and blindness. These symptoms resolved within 24 hours of hospital admission; examination revealed a left superior homonymous paracentral scotoma with mild symmetric upper limb and moderate truncal ataxia. Three days later she developed frequent paroxysmal episodes of rotational torticollis to the right side with simultaneous bilateral blepharospasm. These episodes occurred without warning, were stereotyped in nature, and lasted 20-30 seconds without alteration of consciousness; they stopped when she rested in bed but immediately began on sitting and were further increased in frequency by standing and by mental arithmetic. In between attacks at rest there was no dystonic posturing. Over 2 weeks the truncal ataxia and the movement disorder resolved. MRI (T2-weighted axial FLAIR-sequence) demonstrated areas of high signal in the cerebellar hemispheres in the territories of the right superior cerebellar artery (Fig. 1a) and the medial branch of the left posterior inferior cerebellar artery (Fig. 1b), and in the territory of the right posterior cerebral artery in the right occipital lobe and calcarine cortex (Fig. 1c); no abnormalities were evident on sagittal or axial MRI through the brainstem. A diagnosis of multiple posterior circulation cerebral infarcts was made. Trans-oesophageal echocardiography with bubble contrast showed no patent foramen ovale. MR angiography (not formal angiography) of the aortic arch, anterior cerebral circulation, and vertebrobasilar circulation showed no significant extracranial stenosis or dissection. EEG during the abnormal movement, CSF analysis and a thrombophilia screen were normal. There was no family history of dystonia, scoliosis, or tremor; there was no personal history of trauma, migraine with aura, perinatal distress or exposure to any potentially dystoniainciting drug. Risk factors for stroke included the oral contraceptive pill (OCP) and cigarette smoking; in view of these risk factors and the possibility of an occult source of thromboembolism the patient was treated with anticoagulation for 6 months and advised both to discontinue the OCP and not to smoke. One year later the only abnormality remaining was the visual field defect. Dystonia secondary to infarction in the cerebellum is rare. The anatomical site of infarction causing dystonia is usually in the lentiform nucleus [1] or ventromedial mesencephalon and red nucleus area affecting the substantia nigra, nigrostriatal and cerebellothalamic fibres;[2] however, a recent review of 25 cases of secondary cervical dystonia [3] included two patients in whom structural brain lesions (hemangioblastoma and cavernous angioma) were localized exclusively to the left and right cerebellar hemisphere respectively, resulting in left-sided torticollis in both cases. On the basis of this series the authors noted that co-lateralization of the anatomical site of the lesion with the dystonic syndrome was inconsistent, especially for lesions in the posterior cranial fossa, and hypothesized that the pathophysiology involved disruption of excitatory projections to the inferior olive. Our case is anatomically consistent with this theory; furthermore, blepharospasm has been reported in the context of bilateral cerebellar lesions,[4] and microinjection of kainic acid into the cerebellar vermis elicited reliable and reproducible dosedependent dystonic posturing in mice.[5] Both primary dystonia and post-stroke dystonia associated with lesions in the basal ganglia and thalamus have been associated with altered functioning of the cerebellum on fMRI.[6] Experimental evidence raises the possibility that the postural nature of the movement disorder may be due to vestibular dysfunction. In cats, bilateral vestibular neurectomy resulted in modulation of the firing rate of vestibular nucleus neurons by tilt K. O’Rourke, MRCPI Æ S. O’Riordan, MRCPI J. Gallagher, MRCPI M. Hutchinson, FRCP (&) Department of Neurology St. Vincent’s University Hospital Elm Park Dublin 4, Ireland Tel.: 353-1/269503 Fax: 353-1/2697949 E-Mail: mhutchin@iol.ie LETTER TO THE EDITORS J Neurol (2006) 253: 1644–1645 DOI 10.1007/s00415-006-0202-3

Cervical dystonia following peripheral trauma--a case-control study.

Abstract.Post-traumatic cervical dystonia as a diagnostic entity remains a subject of debate. Patients with cervical dystonia (CD) were asked to identify any significant illness prior to the onset of their CD. Sixteen patients of 95 respondents reported a history of injury in the four-week period prior to onset of their dystonia. A retrospective study of the clinical characteristics of the 16 patients with early post-traumatic CD (CD-PT) in comparison with the 52 patients reporting no antecedent trauma (CD-NT) was performed. In this comparison the CD-PT group had a significantly increased frequency of laterocollis, significantly more reported pain and more reported depression. Non-significant trends were noted for less responsiveness to botulinum toxin and less use of gestes antagonistes in the CD-PT group. There were no group differences in the presence of a family history of dystonia. Eleven of the CD-PT group had been or were currently involved in litigation. A sub-group of seven CD-PT patients had laterocollis, six of whom conformed to a clinical pattern of persistent non-spasmodic laterocollis with marked pain; all seven had been involved in litigation. This form of CD-PT is a distinct clinical entity and has an onset within hours or a few days of the trauma. In contrast, no significant differences were noted between patients with CD-NT and the eight patients with later onset of CD between 4 weeks and one year after peripheral trauma.

Cervical dystonia: a disorder of the midbrain network for covert attentional orienting

While the pathogenesis of cervical dystonia remains unknown, recent animal and clinical experimental studies have indicated its probable mechanisms. Abnormal temporal discrimination is a mediational endophenotype of cervical dystonia and informs new concepts of disease pathogenesis. Our hypothesis is that both abnormal temporal discrimination and cervical dystonia are due to a disorder of the midbrain network for covert attentional orienting caused by reduced gamma-aminobutyric acid (GABA) inhibition, resulting, in turn, from as yet undetermined, genetic mutations. Such disinhibition is (a) subclinically manifested by abnormal temporal discrimination due to prolonged duration firing of the visual sensory neurons in the superficial laminae of the superior colliculus and (b) clinically manifested by cervical dystonia due to disinhibited burst activity of the cephalomotor neurons of the intermediate and deep laminae of the superior colliculus. Abnormal temporal discrimination in unaffected first-degree relatives of patients with cervical dystonia represents a subclinical manifestation of defective GABA activity both within the superior colliculus and from the substantia nigra pars reticulata. A number of experiments are required to prove or disprove this hypothesis.

Young Women do it Better: Sexual Dimorphism in Temporal Discrimination

The temporal discrimination threshold (TDT) is the shortest time interval at which two sensory stimuli presented sequentially are detected as asynchronous by the observer. TDTs are known to increase with age. Having previously observed shorter thresholds in young women than in men, in this work we sought to systematically examine the effect of sex and age on temporal discrimination. The aims of this study were to examine, in a large group of men and women aged 20–65 years, the distribution of TDTs with an analysis of the individual participant’s responses, assessing the “point of subjective equality” and the “just noticeable difference” (JND). These respectively assess sensitivity and accuracy of an individual’s response. In 175 participants (88 women) aged 20–65 years, temporal discrimination was faster in women than in men under the age of 40 years by a mean of approximately 13 ms. However, age-related decline in temporal discrimination was three times faster in women so that, in the age group of 40–65 years, the female superiority was reversed. The point of subjective equality showed a similar advantage in younger women and more marked age-related decline in women than men, as the TDT. JND values declined equally in both sexes, showing no sexual dimorphism. This observed sexual dimorphism in temporal discrimination is important for both (a) future clinical research assessing disordered mid-brain covert attention in basal-ganglia disorders, and (b) understanding the biology of this sexual dimorphism which may be genetic or hormonal.

Familial adolescent-onset scoliosis and later segmental dystonia in an Irish family

Abstract.Adolescent-onset scoliosis occurs more frequently than expected in primary adult-onset cervical dystonia and a genetic association between the conditions has been postulated. The authors report a family in which four members have adult-onset cervical and/or brachial dystonia, two of whom have coexistent scoliosis. Four other individuals have isolated childhood- or adolescent-onset scoliosis. Adolescent-onset scoliosis may represent part of the dystonia phenotype in this family.

Temporal Discrimination: Mechanisms and Relevance to Adult-Onset Dystonia

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test–retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis.

Non-parametric bootstrapping method for measuring the temporal discrimination threshold for movement disorders

OBJECTIVE Recent studies have proposed that the temporal discrimination threshold (TDT), the shortest detectable time period between two stimuli, is a possible endophenotype for adult onset idiopathic isolated focal dystonia (AOIFD). Patients with AOIFD, the third most common movement disorder, and their first-degree relatives have been shown to have abnormal visual and tactile TDTs. For this reason it is important to fully characterize each participants data. To date the TDT has only been reported as a single value. APPROACH Here, we fit individual participant data with a cumulative Gaussian to extract the mean and standard deviation of the distribution. The mean represents the point of subjective equality (PSE), the inter-stimulus interval at which participants are equally likely to respond that two stimuli are one stimulus (synchronous) or two different stimuli (asynchronous). The standard deviation represents the just noticeable difference (JND) which is how sensitive participants are to changes in temporal asynchrony around the PSE. We extended this method by submitting the data to a non-parametric bootstrapped analysis to get 95% confidence intervals on individual participant data. MAIN RESULTS Both the JND and PSE correlate with the TDT value but are independent of each other. Hence this suggests that they represent different facets of the TDT. Furthermore, we divided groups by age and compared the TDT, PSE, and JND values. The analysis revealed a statistical difference for the PSE which was only trending for the TDT. SIGNIFICANCE The analysis method will enable deeper analysis of the TDT to leverage subtle differences within and between control and patient groups, not apparent in the standard TDT measure.

Menstrual cycle and the temporal discrimination threshold

The temporal discrimination threshold (TDT) is a proposed pre-clinical biomarker (endophenotype) for adult onset isolated focal dystonia (AOIFD). Age- and sex-related effects on temporal discrimination demonstrate that women, before the age of 40 years, have faster temporal discrimination than men but their TDTs worsen with age at almost three times the rate of men. Thus after 40 years the TDT in women is progressively worse than in men. AOIFD is an increasingly female-predominant disorder after the age of 40; it is not clear whether this age-related sexually-dimorphic difference observed for both the TDT and sex ratio at disease onset in AOIFD is a hormonal or chromosomal effect. The aim of this study was to examine temporal discrimination at weekly intervals during two consecutive menstrual cycles in 14 healthy female volunteers to determine whether physiological hormonal changes affected temporal discrimination. We observed no significant differences in weekly temporal discrimination threshold values during the menstrual cycles and no significant correlation with the menstrual cycle stage. This observed stability of temporal discrimination during cyclical hormonal change raises interesting questions concerning the age-related sexually-dimorphic decline observed in temporal discrimination. Our findings pave the way for future studies exploring potential pathomechanisms for this age-related deterioration.

COMPARING STIMULUS-PRESENTATION METHODS IN TEMPORAL DISCRIMINTATION TESTING

Objective To investigate any differences in temporal discrimination using two methods of stimulus presentation. Background Temporal discrimination threshold (TDT) is a measure of the point at which an individual determines two sensory stimuli to be asynchronous (normal=30–50 ms). The classic approach involves presentation of progressively-asynchronous stimuli to an individual. The TDT is taken as the first of three consecutively-reported asynchronous stimuli. Due to the potential for a learned effect from this method of presentation, a method of constant stimuli with randomised presentation order was also employed. Methods Ten healthy volunteers were recruited to the study. Visual and tactile TDT testing using the classic and random method of presentation was carried out in a single session. The mean TDT score was calculated for each participant. The data was fitted to a cumulative Gaussian function from which the point of subjective equality (PSE) and the just noticeable difference (JND) was calculated. Results The mean values for the sequential method are as follows; TDT=32.03 ms, PSE=23.11 ms, JND=13.71 ms. The mean values for the random method are as follows; TDT 52.26 ms, PSE 33.35 ms, JND 28.58 ms. Conclusion Although a difference was observed in the results between stimulus presentation, there was a trending correlation between the PSE values for the two stimulus presentation types. This suggests that while the absolute values were different, the relative values were consistent. While our study is limited by number size and future research is required, preliminary results suggest the TDT is a robust measure.