Brain

Griffiths, T, D;Sigmundsson,, T;Takei,, N;Rowe,, D;Murray, R, M

doi: 10.1093/brain/121.2.191pmid: 9549499

Abstract Neurological assessment was carried out on patients with schizophrenia from multiply and singly affected families, their relatives, and a normal control group (214 subjects). A systematic examination was used in which abnormal signs were divided into 'primary' and 'integrative' signs. Primary signs were elicited by a standard clinical neurological examination and included signs of focal damage to nuclei and tracts, whilst integrative signs were selected as reflecting distributed brain function. The assessments were carried out to test the hypotheses that (i) neurological abnormalities are present in schizophrenia, (ii) the pattern of abnormality is different in familial and sporadic schizophrenic subjects, and (iii) the well relatives of familial (but not sporadic) schizophrenic subjects will show neurological abnormalities. An excess of primary signs compared with the controls was demonstrated in the sporadic schizophrenic group only. Both the familial schizophrenics and their first-degree relatives (but not their sporadic counterparts) showed an increase in integrative signs. The results support the existence of different mechanisms of underlying brain dysfunction in familial and sporadic schizophrenia. This content is only available as a PDF.

Oldani,, A;Zucconi,, M;Asselta,, R;Modugno,, M;Bonati, M, T;Dalprà,, L;Malcovati,, M;Tenchini, M, L;Smirne,, S;Ferini-Strambi,, L

doi: 10.1093/brain/121.2.205pmid: 9549500

Abstract A number of clinical and aetiological studies have been performed, during the last 30 years, on patients with abnormal nocturnal motor and behavioural phenomena. The aetiological conclusions of these studies were often conflicting, suggesting either an epileptic or a non-epileptic origin. Among the clinical characteristics of these patients, the familial clustering was one thoroughly accepted. A nocturnal familial form of frontal lobe epilepsy (autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE), often misdiagnosed as parasomnia, has been recently described in some families. In one large Australian kindred, a missense mutation in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) gene, located on chromosome 20 q13.2-13.3, has been reported to be associated with nocturnal frontal lobe epilepsy. We performed an extensive clinical and video-polysomnographic study in 40 patients complaining of repeated abnormal nocturnal motor and/or behavioural phenomena, from 30 unrelated Italian families. Thirty-eight patients had an electroclinical picture strongly suggesting the diagnosis of ADNFLE. They had a wide clinical spectrum, ranging from nocturnal enuresis to sleep-related violent behaviour, thus including all the main features of the so-called 'typical' parasomnias. The video-polysomnographic recording confirmed the wide spectrum of abnormal manifestations, including sudden awakenings with dystonic/ dyskinetic movements (in 42.1% of patients), complex behaviours (13.2%) and sleep-related violent behaviour (5.3%). The EEG findings showed ictal epileptiform abnormalities predominantly over frontal areas in 31.6% of patients. In another 47.4% of patients the EEG showed ictal rhythmic slow activity over anterior areas. Only 18.4% of the patients had already received a correct diagnosis of epilepsy. In 73.3% of the patients treated with anti-epileptic drugs the seizures were readily controlled. Pedigree analysis on 28 of the families was consistent with autosomal dominant transmission with reduced penetrance (81%). DNAs from 20 representative affected individuals were sequenced in order to check for the presence of the missense mutation in the CHRNA4 gene found in the Australian kindred affected by ADNFLE. Nucleotide sequence analysis did not reveal the presence of this mutation, but it did confirm the presence of two other base substitutions, not leading to amino acid changes. These two intragenic polymorphisms, together with a closely linked restriction fragment length polymorphism at the D20S20 locus, have been used for linkage analysis of ADNFLE to the terminal region of the long arm of chromosome 20 in five compliant families. The results allowed us to exclude linkage of ADNFLE to this chromosomal region in these families, thus confirming the locus heterogeneity of the disorder. Large and full video-polysomnographical studies are of the utmost importance in order to clarify the real prevalence of both nocturnal frontal lobe epilepsy and parasomnias, and to provide a correct therapy. This content is only available as a PDF.

Tubridy,, N;Coles, A, J;Molyneux,, P;Compston, D, A;Barkhof,, F;Thompson, A, J;McDonald, W, I;Miller, D, H

doi: 10.1093/brain/121.2.225pmid: 9549501

Abstract We report the findings in 60 patients with secondary progressive multiple sclerosis who had monthly brain MRI studies for 4 months (one baseline and three follow-up scans). The purpose was to define the short-term MRI natural history in a large cohort with secondary progressive disease and to ascertain its relationship with other clinical and MRI features. The patients were participating in either a natural history study or the placebo arm or non-treatment phase of a therapeutic trial. The cohort had clinical features typical of secondary progressive disease: thus, all had moderate or severe locomotor disabilities [Expanded Disability Status Scale (EDSS), score 3.5-8], with a median disease duration of 12 years. There was equal representation of males and females. During the 3 months of follow-up there was a total of 362 new enhancing lesions seen in 42 patients, and there were 24 relapses in 20 patients. There was no correlation between new enhancing lesions and age at study entry, age of disease onset, gender disease duration or EDSS, but there was a strong correlation with the number of enhancing lesions on the baseline scan (r = 0.65, P < 0.0001) and subsequent activity. There was a non-significant trend for higher numbers of new enhancing lesions in those having relapses during the 3 months of scanning (P = 0.14) or in the preceding 6 months (P = 0.06). The 34 patients who did not relapse in either period had significantly fewer new active lesions (P = 0.02) than those who relapsed at some stage during the 9 months. Nevertheless, considerable activity was seen in the non-relapsing cohorts: there was a mean of 3.5 (median 2) new enhancing lesions in those not relapsing during the 3 month study, and 5.5 (median 2) in those not relapsing in the previous 6 months. We conclude that short-term MRI activity is generally high in secondary progressive disease, confirming a useful role for the technique in exploratory trials. Further work should concentrate on elucidating the mechanisms of secondary progression by longer term follow-up studies of larger cohorts using multiple MRI and clinical measurements. This content is only available as a PDF.

Afra,, J;Cecchini, A, P;, De Pasqua, V;Albert,, A;Schoenen,, J

doi: 10.1093/brain/121.2.233pmid: 9549502

Abstract We have previously shown that during repetitive pattern-reversal stimulation, lasting 2 min, the amplitude of the visual evoked potential (PR-VEP) increases in migraineurs when tested interictally whereas it decreases in healthy control subjects. According to Sappey-Marinier et al. (J Cereb Blood Flow Metab 1992; 12: 584-92) habituation of the PR-VEP in normal subjects is maxima after 12 min, at a time when there is a decrease of stimulation-enhanced lactate levels in the occipital cortex. We have therefore compared PR-VEP during long periods of repetitive stimulation in healthy control subjects (n = 25) and in patients suffering from migraine without (n = 25) and with aura (n = 15) between attacks. During uninterrupted stimulation at 3.1 Hz VEPs were sequentially averaged in blocks of 100 responses for a total duration of 15 min and analysed in terms of latencies and peak-to-peak amplitudes of N1-P1 and P1-N2 peaks. Amplitude changes from the baseline were calculated for each block, by comparison with the first block, and analysed statistically using Zerbe's method. The N1-P1 and P1-N2 amplitudes in the first block tended to be lower in migraineurs than in healthy control subjects. During the 15 min of stimulation, amplitudes of both components progressively decreased in control subjects, but remained stable in both groups of patients. The difference between patients and control subjects proved to be significant (P < 0.05). The neurophysiological data were not correlated with clinical features such as attack frequency or duration of illness. These results are yet another demonstration in migraine of an interictal habituation deficit in cortical information processing, which might favour lactate accumulation in sensory cortices during sustained activation. This content is only available as a PDF.

Manji,, H;Howard, R, S;Miller, D, H;Hirsch, N, P;Carr,, L;Bhatia,, K;Quinn,, N;Marsden, C, D;Bahtia,, K

doi: 10.1093/brain/121.2.243pmid: 9549503

Abstract Patients with dystonic syndromes sometimes develop increasingly frequent and relentless episodes of devastating generalized dystonia which we call status dystonicus. Twelve cases of status dystonicus, of various underlying aetiologies, are presented. Possible precipitating factors were identified in only five cases: intercurrent infection (one); discontinuation of lithium (one) and tetrabenazine (one); and the introduction of clonazepam (two). Nine patients required mechanical ventilation and three others were sedated with intravenous chlormethiazole. Drug therapy used included benzhexol, tetrabenazine, pimozide, baclofen, chlorpromazine, haloperidol, carbamazepine and acetozolamide. Two patients underwent thalamotomies, one of whom improved. Two patients died, five returned to their pre-status dystonicus condition, two eventually made a full recovery and three were worse. Patients with status dystonicus should be managed on an intensive care unit as they may develop bulbar and respiratory complications which may require ventilation. Metabolic problems encountered can include rhabdomyolysis with acute renal failure. Drug therapy with benzhexol, tetrabenazine and pimozide or haloperidol may be beneficial in some cases. This content is only available as a PDF.

Catalan, M, J;Honda,, M;Weeks, R, A;Cohen, L, G;Hallett,, M

doi: 10.1093/brain/121.2.253pmid: 9549504

Abstract The brain regions activated by simple repetitive and sequential finger movements of different length were localized by measuring regional cerebral blood flow (rCBF) with PET. The experimental design consisted of finger movements cued by auditory pacing at 0.5 Hz. In all conditions of different sequence length the contralateral primary sensorimotor and premotor cortex, supplementary motor area and ipsilateral cerebellar cortex were activated. These areas showed a large increase in activation from rest to simple repetitive movement, and a further increase with the shortest sequence, suggesting an executive role in running sequences. The ipsilateral premotor area (Brodmann area 6), bilateral posterior parietal areas (Brodmann area 7) and precuneus showed an increase in rCBF related only to the length of the sequences, without any change from rest to simple repetitive movement. These areas are more selectively related to sequence performance. This finding is consistent with the hypothesis that these areas function in the storage of motor sequences in spatial working memory. Our results suggest that sequential finger movements recruit discrete sets of brain areas with different functions. This content is only available as a PDF.

Wu,, G;Ekedahl,, R;Hallin, R, G

doi: 10.1093/brain/121.2.265pmid: 9549505

Abstract The intrafascicular organization of human peripheral nerves was studied with percutaneous microneurography in the median, radial and peroneal nerves with one-surface or two-surface thin diameter concentric needle electrodes. Data from 33 recording sites containing 47 slowly adapting type II (SAII) units were analysed. At many sites two, sometimes even three, neighbouring SAII units were recorded from the explored nerve fascicle and they had adjacent or even overlapping cutaneous receptive fields. Among pairs of SAII units found at the same site, one unit often had ongoing discharge, whereas the other was silent under resting conditions. The neighbouring SAII units were optimally activated by stretching the skin in different directions. Stretching the same skin area in different directions produced different unit recruitment. Clustered SAII units were often found in sites where Pacinian afferents and skin sympathetic activity were also recorded. No significant difference was observed in the degree of grouping of SAII units either between recordings obtained with one-surface versus two-surface electrodes or between glabrous and hairy skin. The data do not support the notion that myelinated fibres are randomly organized in peripheral nerve fascicles. Instead, the findings suggest that SAII units tend to be clustered in human peripheral nerves. Furthermore, the response of groups of SAII units to skin stretch suggests that they play a role in proprioception. Dual channel recordings with two-surface concentric needle electrodes may provide a novel approach to study fibre organization in human peripheral nerves and the behaviour of groups of nerve fibres. This content is only available as a PDF.

Miwa,, H;Nohara,, C;Hotta,, M;Shimo,, Y;Amemiya,, K

doi: 10.1093/brain/121.2.281pmid: 9549506

Abstract The somatosensory-evoked blink response (SBR) is a newly identified blink reflex elicited by electrical stimulation of peripheral nerves. The present study was performed to investigate the physiological mechanism underlying the SBR elicited by median nerve stimulation in normal subjects. The peripheral afferents responsible for the SBR included low-threshold cutaneous fibres. In the SBR-positive subjects, the late (R2) component of the blink reflex elicited by supraorbital nerve stimulation and the SBR facilitated each other when both responses were induced at the same time, but they each caused long-lasting inhibition in the other when one stimulus was given as a conditioning stimulus. The extent of inhibition was correlated with the size of the preceding SBR. In the SBR-negative subjects, simultaneous inhibition of R2 was observed when median nerve stimulation was applied as a conditioning stimulus. Brainstem excitability, as evaluated by blink-reflex recovery studies, did not differ between SBR-positive and SBR-negative subjects. Therefore, based on anatomical and physiological findings, it appears that the reflex pathways of the SBR and R2 converge within the brainstem and compete with each other, presumably by presynaptic inhibition at the premotor level, before entering the common blink-reflex pathway. The influence of median nerve stimulation upon tonic contraction of the orbicularis oculi muscle was studied to detect the latent SBR. There was not only a facilitatory period corresponding to the SBR but also an active inhibitory period (exteroceptive suppression), suggesting that the mechanism generating the SBR is not only influenced by blink-reflex volleys but also by active exteroceptive suppression. Thus, the SBR may appear as a result of integration of facilitatory and inhibitory mechanisms within the brainstem. This content is only available as a PDF.

Carroll, W, M;Jennings, A, R;Ironside, L, J

doi: 10.1093/brain/121.2.293pmid: 9549507

Abstract The new population of oligodendrocytes remyelinating an experimental demyelinating optic nerve lesion has been tracked backwards in time. Using autoradiography combined with electron microscopy and immunocytochemistry, serial sections of optic nerves from young adult cats were studied from 42 h (2 days) post-injection to 93 h (4 days) post-injection. The remyelinating oligodendrocyte lineage was found to commence with the single division of a resting progenitor cell residing in a central fascicular location outside the demyelinative lesion. The division of the founding progenitor cell occurs at 2 days post-lesion and results in two motile daughter cells. These cells, previously described by us as precursor cells, migrate to the lesion, closely appose demyelinated axons, produce axon wrapping processes and differentiate to become remyelinating oligodendrocytes. This study confirms that remyelinating oligodendrocytes originate from resting progenitor cells outside the lesion and not from mature oligodendrocytes, and implies that repeated demyelinative injury could exhaust the reparative capacity of such a region. This content is only available as a PDF.

Terwindt, G, M;Haan,, J;Ophoff, R, A;Groenen, S, M;Storimans, C, W;Lanser, J, B;Roos, R, A;Bleeker-Wagemakers, E, M;Frants, R, R;Ferrari, M, D

doi: 10.1093/brain/121.2.303pmid: 9549508