Diego Kaski

Variant CJD in an individual heterozygous for PRNP codon 129

A 30-year-old man was admitted to hospital in June, 2008, with a 13-month history of personality change, progres sive unsteadiness, and intellectual decline. He complained of severe leg pain and poor memory. 2 months later he developed visual hallucinations and falsely believed he had an abdominal tumour. Symptoms worsened over the next 3 months. In October, 2008, his score on the mini mental state examination was 26/30. Pursuit eye movements were saccadic. He had a pout refl ex. There was mild ataxia in the arms. His legs were severely ataxic with brisk tendon refl exes and a left extensor plantar response. He needed two crutches to walk. Medical history included tonsil lectomy and removal of a cervical lymph node 15 years previously but he had never had a blood transfusion or received implantation of other human tissues. EEG showed slow wave activity. CSF protein, glucose, and cell count were normal but the 14-3-3 protein was positive. MRI of the brain was consistent with the pulvinar sign (fi gure A). Although not all neuroradiologists consulted considered the pulvinar sign positive, quantitative assessment showed symmetrical higher signal in the pulvinar nuclei than the caudate nuclei (fi gure B). Extensive screens for genetic, metabolic, and autoimmune diseases, including those induced by neoplasia, were negative. PRNP analysis did not show any known disease-associated mutations; codon 129 was heterozygous. A clinical diagnosis of variant Creutzfeldt-Jakob disease (vCJD) was made on the basis of a characteristic clinical onset and progression, exclusion of other diagnoses, and MRI fi ndings. Sporadic CJD was judged unlikely given the com bination of young age, clinical features, MRI fi ndings, and absence of pseudoperiodic complexes on EEG. His carers did not want further investigation. His condition deteri orated and he died in January, 2009. Autopsy was not done. Human prion diseases have acquired, sporadic, and inherited aetiologies, show wide phenotypic heterogeneity, and are associated with propagation of infectious prions of many distinct strain types. Since 1994, about 200 cases of vCJD, causally related to exposure to bovine spongiform encephal opathy (BSE) prions, have been identifi ed worldwide. vCJD is generally seen in young adults, has characteristic neuropathological features and tissue distribution of infectivity, and a distinctive type 4 (London classifi cation) molecular strain type. A polymorphism at codon 129 (encoding methionine or valine) of the human prion protein gene (PRNP), constitutes a powerful susceptibility factor in all types of prion disease. In vCJD, every case genotyped to date has been methionine homozygous. In the other acquired prion diseases, cases have occurred in all genotypes but with diff erent mean incubation periods, which can span decades; PRNP codon 129 heterozygotes gen er ally have the longest incubation periods. There is a report of a recipient of a blood transfusion from a donor incubating vCJD who died of unrelated causes but showed signs of prion infection at autopsy and was PRNP codon 129 hetero zygous. Animal studies have suggested that diff erent clinicopathological phenotypes could occur in people with various PRNP codon 129 genotypes. The majority of the UK population have potentially been exposed to BSE prions but the extent of clinically silent infection remains unclear. About a third of the UK population are PRNP codon 129 methionine homozygous. If individuals with other geno types are similarly susceptible to developing prion disease after BSE prion exposure, but with longer incubation periods, further cases, which may or may not meet diagnostic criteria for vCJD, would be expected in these PRNP codon 129 genotypes. However, prion disease susceptibility and incubation periods are also aff ected by other genetic loci, and the possibility remains that cases of vCJD to date may have unusual combinations of geno types at these loci, yet to be fully characterised.

Revision: Is Visual Perception a Requisite for Visual Imagery?

Vision is the most highly developed sense in man and represents the doorway through which most of our knowledge of the external world arises. Visual imagery can be defined as the representation of perceptual information in the absence of visual input. Visual imagery has been shown to complement vision in this acquisition of knowledge—it is used in memory retrieval, problem solving, and the recognition of properties of objects. The processes underlying visual imagery have been assimilated to those of the visual system and are believed to share a neural substrate. However, results from studies in congenitally and cortically blind subjects have opposed this hypothesis. Here I review the currently available evidence.

Vestibular Perception following Acute Unilateral Vestibular Lesions

Little is known about the vestibulo-perceptual (VP) system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO) and VP function in 25 patients with vestibular neuritis (VN) acutely (2 days after onset) and after compensation (recovery phase, 10 weeks). Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5°/s2 and velocity steps of 90°/s (acceleration 180°/s2). We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any ‘perceptual noise’ added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced – asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of perceptual processes (ultimately cortical) participating in vestibular compensation, suppressing asymmetry acutely in unilateral vestibular lesions.

Visual Dependency and Dizziness after Vestibular Neuritis

Symptomatic recovery after acute vestibular neuritis (VN) is variable, with around 50% of patients reporting long term vestibular symptoms; hence, it is essential to identify factors related to poor clinical outcome. Here we investigated whether excessive reliance on visual input for spatial orientation (visual dependence) was associated with long term vestibular symptoms following acute VN. Twenty-eight patients with VN and 25 normal control subjects were included. Patients were enrolled at least 6 months after acute illness. Recovery status was not a criterion for study entry, allowing recruitment of patients with a full range of persistent symptoms. We measured visual dependence with a laptop-based Rod-and-Disk Test and severity of symptoms with the Dizziness Handicap Inventory (DHI). The third of patients showing the worst clinical outcomes (mean DHI score 36–80) had significantly greater visual dependence than normal subjects (6.35° error vs. 3.39° respectively, p = 0.03). Asymptomatic patients and those with minor residual symptoms did not differ from controls. Visual dependence was associated with high levels of persistent vestibular symptoms after acute VN. Over-reliance on visual information for spatial orientation is one characteristic of poorly recovered vestibular neuritis patients. The finding may be clinically useful given that visual dependence may be modified through rehabilitation desensitization techniques.

Combining physical training with transcranial direct current stimulation to improve gait in Parkinson’s disease: a pilot randomized controlled study

Objective: To improve gait and balance in patients with Parkinson’s disease by combining anodal transcranial direct current stimulation with physical training. Design: In a double-blind design, one group (physical training; n = 8) underwent gait and balance training during transcranial direct current stimulation (tDCS; real/sham). Real stimulation consisted of 15 minutes of 2 mA transcranial direct current stimulation over primary motor and premotor cortex. For sham, the current was switched off after 30 seconds. Patients received the opposite stimulation (sham/real) with physical training one week later; the second group (No physical training; n = 8) received stimulation (real/sham) but no training, and also repeated a sequential transcranial direct current stimulation session one week later (sham/real). Setting: Hospital Srio Libanes, Buenos Aires, Argentina. Subjects: Sixteen community-dwelling patients with Parkinson’s disease. Interventions: Transcranial direct current stimulation with and without concomitant physical training. Main measures: Gait velocity (primary gait outcome), stride length, timed 6-minute walk test, Timed Up and Go Test (secondary outcomes), and performance on the pull test (primary balance outcome). Results: Transcranial direct current stimulation with physical training increased gait velocity (mean = 29.5%, SD = 13; p < 0.01) and improved balance (pull test: mean = 50.9%, SD = 37; p = 0.01) compared with transcranial direct current stimulation alone. There was no isolated benefit of transcranial direct current stimulation alone. Although physical training improved gait velocity (mean = 15.5%, SD = 12.3; p = 0.03), these effects were comparatively less than with combined tDCS + physical therapy (p < 0.025). Greater stimulation-related improvements were seen in patients with more advanced disease. Conclusions: Anodal transcranial direct current stimulation during physical training improves gait and balance in patients with Parkinson’s disease. Power calculations revealed that 14 patients per treatment arm (α = 0.05; power = 0.8) are required for a definitive trial.

Improving Gait and Balance in Patients With Leukoaraiosis Using Transcranial Direct Current Stimulation and Physical Training An Exploratory Study

Background. Leukoaraiosis describes ischemic white matter lesions, a leading cause of gait disturbance in the elderly. Objective. Our aim was to improve gait and balance in patients with leukoaraiosis by combining a single session of transcranial direct current stimulation (tDCS) and physical training (PT). Methods. We delivered anodal tDCS over midline motor and premotor areas in 9 patients with leukoaraiosis. Patients underwent gait and balance training during tDCS stimulation (real/sham). This was repeated 1 week later with the stimulation crossed-over (sham/real) in a double-blind design. Assessments included gait velocity, stride length, stride length variability (primary gait outcomes), and a quantitative retropulsion test (primary balance outcome). Results. Combining tDCS and PT improved gait velocity, stride length, stride length variability, and balance (all at P ≤ .05). Overall, training without tDCS showed no significant effects. Conclusions. Combined anodal tDCS and PT improves gait and balance in this patient group, suggesting that tDCS could be an effective adjunct to PT in patients with leukoaraiosis, for whom no treatment is currently available.

The effect of trial number on the emergence of the ‘broken escalator’ locomotor aftereffect

Walking onto a stationary platform, which had been previously experienced as moving generates a locomotor aftereffect (LAE), which resembles the ‘broken escalator’ phenomenon. Experimentally, this is achieved by having subjects walk initially onto a stationary sled (BEFORE condition), then onto a moving sled (MOVING condition, or adaptation trials) and then again onto the stationary sled (AFTER condition). Subjects are always appropriately warned of the change in conditions. In this paper, we ask how many adaptation trials are needed to produce such a LAE. Thus, in two experiments, the number of MOVING trials was varied between 20 and 5 (Experiment 1) and between 8 and 1 (Experiment 2). Gait velocity, trunk position, foot contact timing and EMG of the ankle flexor-extensors muscles were measured. In comparison with BEFORE trials all groups in the AFTER trials walked inappropriately fast, experienced a large overshoot of the trunk and showed increased leg EMG, indicating that all groups showed a LAE. In each experiment, and for all variables, no significant difference between the groups (i.e. 20 down to one MOVING trials) was found. The study shows that this LAE, in contrast to other motor aftereffects reported in the literature, can be generated with only one or two adaptation trials and without requiring unexpected ‘catch’ trials. The fast aftereffect generation observed is likely to depend on two types of mechanisms: (1) the nature of the sensorimotor adaptation process, involving multiple sensory feedbacks (visual, vestibular and proprioceptive), anticipatory control and large initial task errors and (2) the involvement of two phylogenetically old neural mechanisms, namely locomotion and fear. Fear-relevant mechanisms, which are notably resistant to cognitive control, may be recruited during the adaptation trials and contribute to the release of this LAE.

The effect of single session bi-cephalic transcranial direct current stimulation on gait performance in sub-acute stroke: A pilot study

PURPOSE Non-invasive brain stimulation with transcranial direct current stimulation (tDCS) modulates cortical excitability and improves upper limb motor performance when applied to chronic stroke patients. The objective was to evaluate whether tDCS can influence gait function in sub-acute stroke patients. METHODS We assessed the effect of single session, bi-cephalic tDCS on gait performance in 14 subacute patients with stroke involving the cerebral hemisphere (2-8 weeks post-stroke) in a double-blinded, sham-controlled study. Patients were randomly allocated to receive either active (n = 7) or sham (n = 7) tDCS. The anodal electrode was placed on the scalp over the ipsilesional lower limb primary motor cortex and the cathode was placed over the contralesional leg motor cortex. Gait performance was measured using the Timed Up and Go test and the Performance Oriented Mobility Assessment before and after active or sham tDCS. RESULTS The tDCS group was significantly quicker in the Timed Up and Go test in the tDCS group, compared to the sham group (p = 0.018). The Performance Oriented Mobility Assessment was not different between groups (p = 0.897). CONCLUSIONS This is the first study to examine the effects of tDCS on gait in stroke patients in the sub-acute stage. Active tDCS improved gait performance (Timed Up and Go) in stroke patients, despite no changes to limb biomechanics of the hemiparetic side (Performance Oriented Mobility Assessment), as compared to sham stimulation. These results suggest that tDCS could be used as a therapeutic adjunct for gait rehabilitation following stroke.

Abnormal visual phenomena in posterior cortical atrophy

Individuals with posterior cortical atrophy (PCA) report a host of unusual and poorly explained visual disturbances. This preliminary report describes a single patient (CRO), and documents and investigates abnormally prolonged colour afterimages (concurrent and prolonged perception of colours complimentary to the colour of an observed stimulus), perceived motion of static stimuli, and better reading of small than large letters. We also evaluate CROs visual and vestibular functions in an effort to understand the origin of her experience of room tilt illusion, a disturbing phenomenon not previously observed in individuals with cortical degenerative disease. These visual symptoms are set in the context of a 4-year longitudinal neuropsychological and neuroimaging investigation of CROs visual and other cognitive skills. We hypothesise that prolonged colour after-images are attributable to relative sparing of V1 inhibitory interneurons; perceived motion of static stimuli reflects weak magnocellular function; better reading of small than large letters indicates a reduced effective field of vision; and room tilt illusion effects are caused by disordered integration of visual and vestibular information. This study contributes to the growing characterisation of PCA whose atypical early visual symptoms are often heterogeneous and frequently under-recognised.

Cranial functional (psychogenic) movement disorders

Functional (psychogenic) neurological symptoms are frequently encountered in neurological practice. Cranial movement disorders--affecting the eyes, face, jaw, tongue, or palate--are an under-recognised feature of patients with functional symptoms. They can present in isolation or in the context of other functional symptoms; in particular, for functional eye movements, positive clinical signs such as convergence spasms can be triggered by the clinical examination. Although the specialty of functional neurological disorders has expanded, appreciation of cranial functional movement disorders is still insufficient. Identification of the positive features of cranial functional movement disorders such as convergence and unilateral platysmal spasm might lend diagnostic weight to a suspected functional neurological disorder. Understanding of the differential diagnosis, which is broad and includes many organic causes (eg, stroke), is essential to make an early and accurate diagnosis to prevent complications and initiate appropriate management. Increased understanding of these disorders is also crucial to drive clinical trials and studies of individually tailored therapies.