Erik Vandenbussche

Cognitive changes in patients with Huntington's disease (HD) and asymptomatic carriers of the HD mutation--a longitudinal follow-up study.

Abstract.ObjectiveObjective information about the onset and progression of cognitive impairment in Huntington’s disease (HD) is very important in the light of appropriate outcome measures when conducting clinical trials. Therefore, we evaluated the progression of cognitive functions in HD patients and asymptomatic carriers of the HD mutation (AC) over a 2.5–year period.We also sought to detect the earliest markers of cognitive impairment in AC.MethodsA prospective study comparing HD patients, clinically asymptomatic HD mutation–carriers (AC) and non–carriers (NC). These groups were examined three times during a period of 2.5 years. At baseline the study sample consisted of 49 subjects. Forty–two subjects (19 HD patients, 12 AC and 11 NC) completed three assessments. A battery of neuropsychological tests measuring intelligence, attention, memory, language, visuospatial perception, and executive functions was performed.ResultsThe performance of HD patients deteriorated on the following cognitive tests: Symbol Digit Modalities Test (SDMT), Stroop Colour and Word, Boston Naming Test (BNT), Object and Space Perception and Trail Making Test–B. Longitudinal comparison of AC and NC revealed that performances on SDMT, Block Span, Digit Span Backwards, Hopkins Verbal Learning Test (learning and delayed recall) and Conditional Associative Learning Test are impaired in AC.ConclusionsTasks measuring mainly attention, object and space perception and executive functions adequately assess the progression of HD disease. Other cognitive functions do not significantly deteriorate. Furthermore, problems in attention, working memory, verbal learning, verbal long–term memory and learning of random associations are the earliest cognitive manifestations in AC.

Psychophysical evidence for a general temporal processing deficit in children with dyslexia

The hypothesis of a general (i.e. cross-modal) temporal processing deficit in dyslexia was tested by examining rapid processing in both the auditory and the visual system in the same children with dyslexia. Participants were 10- to 12-year-old dyslexic readers and age-matched normal reading controls. Psychophysical thresholds were estimated for auditory gap and visual double flash detection, using a two-interval, two-alternative forced-choice paradigm. Significant group differ- ences were found for the auditory and the visual test. Furthermore, temporal processing measures were significantly related to word and pseudo-word reading skills. As 70% of the dyslexic readers had significantly higher thresholds than controls for both auditory and visual temporal processing, the evidence tends to support the hypothesis of a general temporal processing deficit in children with dyslexia.

Attention and information processing in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.

Omitting radiotherapy for central nervous system (CNS) prophylaxis has improved the overall quality of life for long‐term survivors of childhood acute lymphoblastic leukemia (ALL). However, recent reports suggest minor cognitive impairment in survivors who received chemotherapy only.

Visual-perceptual impairment in a random sample of children with cerebral palsy

Several studies have tried to establish the prevalence of visual-perceptual impairment in children with physical disabilities, particularly in those with cerebral palsy (CP), but failed to take into account the selective impairment of non-verbal intelligence that is frequent in these children. This has resulted in the confounding of visual-perceptual and non-verbal intelligence impairment. In the present study we aimed to determine how widespread visual-perceptual impairment is in children with CP by evaluating perceptual ability together with the performance level on non-verbal intelligence subtests. All children (n=96; 44 females, 52 males) who attended an institute for children with physical disabilities were included (age ranged from 4 years 11 months to 21 years 5 months) who had a non-verbal mental age between 3 and 7 years; Total IQ was <85 in 91% of participants. They were given a grating acuity task and the visual-perceptual battery L94, comprising six visual object recognition and two visuoconstruction tasks. Relative to their performance level on non-verbal intelligence subtests, 37.5% of the children were impaired on at least one task, and 18.7% on two or more tasks. No child was impaired on the visuoconstruction tasks. Visual-perceptual impairment was highest among six children with brain malformation (67%), followed by spastic CP (40%), and brain damage acquired after the first year of life (38%). There was no difference in visual-perceptual impairment between the subtypes of spastic CP. Results are not secondary to visual acuity deficits, as only one L94 task was significantly correlated with acuity impairment. We conclude that visual-perceptual impairment is frequent in children with physical disabilities, and not restricted to children with CP of hypoxic-ischaemic origin.

Lesions of the Superior Temporal Cortical Motion Areas Impair Speed Discrimination in the Macaque Monkey

The effects of circumscribed lesions of the superior temporal cortical motion areas on speed discrimination were tested in three macaque monkeys using both moving random‐textured patterns and moving bars. The lesions, which included the middle temporal visual area, the adjacent medial superior temporal visual area and the fundus superior temporal visual area, produced a severe and lasting deficit in speed discrimination when tested with the random patterns. In contrast, deficits were smaller when tested with moving bars. Control lesions of the inferior temporal cortex in two monkeys had little effect on speed discrimination. There was no clear deficit following inferior temporal or superior temporal sulcus lesions on a vernier acuity task. These experiments indicate that the middle temporal and adjacent areas play a crucial role in speed discrimination and that lesion effects depend on the cues available to the animals.

Longitudinal study evaluating neuropsychological changes in so‐called asymptomatic carriers of the Huntington's disease mutation after 1 year

Objectives– To determine (1) whether the battery of neuropsychological tests was sufficiently sensitive to find differences between symptomatic patients with Huntingtons disease (HD) and clinically asymptomatic individuals carrying the HD gene (AGC) and individuals without the HD gene (NGC) and (2) whether increasing cognitive impairment is found in AGC as compared with NGC. Methods– A case–control, single‐blind study comparing subjects with clinically manifest HD (n=21), AGC (n=12) or NGC (n=11) and a 1‐year follow‐up of AGC and NGC. Genotype for the HD gene was determined by molecular testing. A large battery of neuropsychological tests measuring several cognitive domains was performed. Results– On most neuropsychological tasks, HD patients perform significantly worse than AGC and NGC. At baseline and follow‐up examination, compared with NGC, AGC had lower scores on the symbol digit modalities test. Scores on a block span task declined more rapidly among AGC than among NGC. Conclusion– Cognitive impairments in HD patients are found when compared with clinically asymptomatic individuals carrying the HD mutation. Furthermore, our results suggest that subtle cognitive deficits are present in asymptomatic persons who have inherited the HD gene.

Visuoperceptual impairment in multiple sclerosis patients diagnosed with neuropsychological tasks.

A comprehensive set of 31 binocular neuropsychological tasks assessing a series of spatial and non-spatial visuoperceptual abilities was used to study visuoperceptual impairment in a representative group of 49 MS-clinic patients exhibiting neither diagnosed ophthalmological afflictions nor major psychiatric diagnoses. Among these patients, true frequency rate of visuoperceptual impairment, i.e. of subjects failing four or more tasks, was estimated at 26%. The pattern of visuoperceptual impairment was non-uniform, non-selective, restricted and idiosyncratic. Only four tasks yielded significant rates of impairment. They concerned colour discrimination, the perception of the Müller-Lyer illusion and object recognition in two separate conditions. Each of the four factors identified by factor analysis had an important representative (with factor loading 40.35) among these four tasks. Failures on these tasks correlated poorly. Together, the four tasks satisfactorily predicted visuoperceptual impairment as defined by the comprehensive set of tasks (sensitivity 86.7%; specificity 81.3%), but with regard to an uncontaminated criterion, their aggregate sensitivity and specificity was only 75 and 56% respectively. Visuoperceptual neuropsychological task performance related significantly but weakly to cognitive status, physical disability and to pyramidal, cerebellar and brain stem neurological signs, and did not correlate with other clinical neurological signs, disease duration, type of MS, a history of optic neuritis, depression or medication status.

The variety of visual perceptual impairments in pre-school children with perinatal brain damage

To study the selectivity of visual perceptual impairment in children with early brain injury, eight visual perceptual tasks (L94), were administered to congenitally disabled children both with and without risk for cerebral visual impairment (CVI). The battery comprised six object-recognition and two visuoconstructive tasks. Seven tasks were newly designed. For these normative data are presented (age 2.75-6.50 years). Because the recognition tasks required object naming, each item included a canonical control drawing and visual perceptual ability was evaluated relative to the non-verbal intelligence level, instead of chronological age. In 22 multiple disabled children with no indications of CVI, the frequency of impairment did not exceed that in the reference sample for any L94 task. In contrast, in 57 5-year-old children who were at risk for CVI due to pre-maturity or birth asphyxia, a significant increase in the frequency of impairment was seen on six L94 tasks (range 12-38%). However, only five children had more than two impairments, indicating that the deficits were selective, not pervasive. We conclude that early brain lesions interfere with the functioning of particular visual subsystems, yet leave other subsystems intact and functioning within the normal range.

Relation between visual perceptual impairment and neonatal ultrasound diagnosis of haemorrhagic-ischaemic brain lesions in 5-year-old children

Visual‐perceptual abilities were assessed in 5‐year‐old children with the following neonatal neurological conditions: born preterm with normal ultrasound scan (NL, n=17); born preterm with ultrasound diagnosis of intraventricular haemorrhage (IVH, n=17); born preterm with ultrasound diagnosis of periventricular leukomalacia (PVL, n=12); born term with hypoxic‐ischaemic encephalopathy (HIE, n=11). Visual‐perceptual ability was evaluated with the L94: eight visual‐perceptual tasks designed to evaluate different aspects of visual perception at the preschool level in children with multiple disabilities. Impairment was established in comparison to the performance age obtained on non‐verbal intelligence subtests, instead of chronological age. Frequency of L94 impairment was highest in children with PVL, while children with IVH did not differ from the NL control group. Impairment rates were increased also in children with transient periventricular echodensities, and in children with HIE. Impairments were only moderately related to the delay of visual acuity maturation in infancy.

Reversible posterior leucoencephalopathy during oral treatment with methotrexate

Sirs: Posterior reversible leucoencephalopathy (PRLE) is a wellknown complication of intravenous or intrathecal treatment with high doses of methotrexate [2–4, 6]. We report a case of PRLE following long-term low-dose administration via the oral route. A 49 year old woman experienced slowly progressive visual and motor disturbances for 5 months. She reported blurred vision, difficulty in recognizing faces or seeing objects as a whole, reading problems, as well as difficulties when reaching with her left arm. She had had psoriatic arthritis since the age of 35 years, type II diabetes mellitus since the age of 48, and was diagnosed with Hashimoto thyroiditis at the age of 48. Current medication consisted of oral methotrexate 7.5 mg once a week since the age of 42 (cumulative dose of 2730 mg), atorvastatine 10 mg three times a week, omeprazole 10 mg o.d. for 6 months, levothyroxine 50 μg o. d., propamide 125 mg bid, bromazepam 3 mg o. d., propranolol 80 mg o. d., and folic acid 1 mg o. d. Because the recent neurological problems were originally attributed to a cerebrovascular cause, her referring physician also started a combination of acetylsalicylate 25 mg bid and dipyridamol 200 mg bid. Prior treatment for psoriatic arthritis included oral gold between the age of 35 and 42 and steroids and non steroidal anti-inflammatory drugs around the age of 40. At the age of 43, liver function tests had been transiently and mildly elevated, which was attributed after liver biopsy to methotrexate therapy. During the past year she had experienced a 2 months period of cough and dyspnea interpreted as possible interstitial pulmonary disease after chest radiography and pulmonary function tests. This resolved spontaneously. There was no history of hypertension or substance abuse. On clinical neurological examination her speech was slow but wellarticulated. Visual fields were normal on confrontation testing. Visually guided saccades were within the normal range. Muscle strength and tone as well as tendon reflexes were intact, with plantar responses in flexion. She could not reach with her left hand for objects presented in left or right visual field. She could write but was unable to read her own writing (alexia without agraphia). She read words of more than 4 letters letter-by-letter. She could not draw from memory or copy a clock or a cube. Blood pressure was within the normal range. Neuropsychological examination, including among other tests the Visual Object and Space Perception Battery, the Birmingham Object Recognition battery [5] as well as Beery’s visuomotor integration test [1] confirmed the presence of severe visuoperceptual, visuospatial and visuoconstructional deficits. Magnetic resonance imaging (MRI) revealed extensive T2 and Fluid Attenuated Inversion Recovery (FLAIR) hyperintensities in the ventral occipitotemporal white matter bilaterally and in the right superior parietal lobule (see Fig. 1). MR angiography of the intraand extracranial vasculature was negative. CSF was normal (white blood cell count of 0.8 cells/μl, protein concentration of 545 g/l and a glucose level of 55 mg/dl – with a glucose serum level of 98 mg/dl – without intrathecal IgG synthesis). PCR for JC virus in CSF and urine were negative. Complete blood count revealed a mild pancytopenia with hemoglobin of 10.4 g/dl [12–16], mild macrocytosis (MCV 97.5 fl [76–96]), leucocytes of 3.1 109/l [4–10], and thrombocytes of 120 109/l [150–450]. A bone marrow puncture revealed mild erythroid hyperplasia and mild dysplastic features of the myeloid and megakaryocytic cell lineages, consistent with intake of methotrexate. Kidney function, lipidemia, sedimentation rate, ANF, lupus anticoagulans, ANCA, vitamin B12, thyroid function, and lactic acid were normal. Homocystein level was 14.5 μmol/l [6–13]. Thyroid peroxidase antibody levels were elevated (879 kU/l, with normal values between 0 and 100 kU/l). Serology of HIV, EBV, CMV and JC virus, Borrelia, and syphilis was negative. Electrocardiography, transesophagal echocardiography and 24-hours cardiac monitoring were normal. We stopped oral methotrexate while keeping the remaining medication. Over the following 6 months the clinical picture regressed almost entirely. Neuropsychological re-evaluation 5 months after stopping methotrexate using the same tests could no longer reveal any abnormalities. MRI examinations at 1, 4 and 12 months after stopping methotrexate showed regression of the ventral and the parietal lesions (see Fig. 1). To the best of our knowledge this is the first report of posterior leucoencephalopathy following oral treatment with methotrexate at a low dose given for a prolonged period of time with documented LETTER TO THE EDITORS