HaemoPREF: Further evaluation of patient perception and preference for treatment in a real world setting.

INTRODUCTION: Adherence to haemophilia A (HA) treatment may be influenced by patients' beliefs about their condition and treatment. Furthermore, difficulties administering treatment may lead to poor adherence. New treatment strategies aim to reduce the burden associated with administration and to improve patient perception of treatment, which, in turn, increase adherence levels. AIMS: This study aimed to examine patient perception of HA treatment and related factors using patient-reported outcome (PRO) questionnaires and to confirm the psychometric properties of a recently developed questionnaire, the HaemoPREF. METHODS: A non-interventional, cross-sectional, questionnaire study was conducted with adult HA patients in Spain (n=31), Germany (n=10) and Italy (n=48), who were using ReFacto AF with the FuseNGo administration device. Patients completed the HaemoPREF and other questionnaires measuring related constructs: treatment adherence, satisfaction and well-being, online at two time points. Correlational, regression and psychometric analyses were conducted. RESULTS: PRO scores indicated that patients are satisfied with and adherent to their treatment. Multivariate regression of the HaemoPREF global score identified a number of significant predictors (P≤.05). The HaemoPREF Global Score had a moderate relationship with subscales on the related questionnaires (mean correlation=0.43; range=0.39-0.48). The HaemoPREF demonstrated good test-retest reliability (intraclass correlation coefficient=0.82), internal consistency reliability (Cronbach's alpha range=0.69-0.82) and convergent validity with measures of treatment satisfaction (Spearman correlation coefficient, r=.48) and well-being (r=.41). CONCLUSION: The findings suggest that patients using ReFacto AF with FuseNGo were satisfied with and adherent to their treatment. The HaemoPREF can identify important concepts relating to patient treatment experience in HA.

Sudeck atrophy.

This paper reviews the contribution of Sudeck to the understanding of the condition commonly referred to as 'Sudeck's atrophy' and which is commonly used as a synonym for a condition variously called reflex sympathetic dystrophy, causalgia, algodystrophy and others. Sudeck came to show in his later papers that the so-called atrophy was, in the majority of cases, a normal inflammatory process of bone change in the course of healing after an inflammatory/infective or traumatic insult. Contrary to the views of much current literature, the vast majority of such cases had a good prognosis. In those cases which became pathological and had a correspondingly poorer prognosis, the characteristic clinical picture becomes associated with radiological and pathological changes, which, uniquely, are described by Sudeck. A knowledge of such radiological and pathological substrate for clinical symptomatology is important in the analysis of pain following trauma.

Gender and the integration of acoustic dimensions of prosody: implications for clinical studies.

This study was conducted to detect the existence of a relationship between spectral and temporal prosodic cues and to examine gender differences in any such relationship. The rationale for the investigation was to gain a greater understanding of normal prosody and the requirements for control groups in clinical studies of prosody. Ten male and 10 female speakers with no known speech or neurological deficits participated in the study. They performed a reading task which involved delivering 10 sentences first with a declarative and then repeated with an interrogative intonation (20 sentences per speaker). Intrasubject and intersubject analyses of the speech data revealed a dependence of pitch on duration that differed between male and female speakers. Significant differences between the genders were also found in speech rate, pitch range, and pitch slope. The findings suggest that an integrated treatment of acoustic cues may provide a more invariant feature of normal prosody against which clinical groups may be compared. The data also imply that in clinical studies of the production of prosody gender should be carefully controlled.

Neuronal hypertrophy in the neocortex of patients with temporal lobe epilepsy.

The underlying cause of neocortical involvement in temporal lobe epilepsy (TLE) remains a fundamental and unanswered question. Magnetic resonance imaging has shown a significant loss in temporal lobe volume, and it has been proposed that neocortical circuits are disturbed functionally because neurons are lost. The present study used design-based stereology to estimate the volume and cell number of Brodmann's area 38, a region commonly resected in anterior temporal lobectomy. Studies were conducted on the neocortex of patients with or without hippocampal sclerosis (HS). Results provide the surprising finding that TLE patients have significant atrophy of neocortical gray matter but no loss of neurons. Neurons are also significantly larger, dendritic trees appear sparser, and spine density is noticeably reduced in TLE specimens compared with controls. The increase in neuronal density we found in TLE patients is therefore attributable to large neurons occupying a much smaller volume than in normal brain. Neurons in the underlying white matter are also increased in size but, in contrast to other reports, are not significantly elevated in number or density. Neuronal hypertrophy affects HS and non-HS brains similarly. The reduction in neuropil and its associated elements therefore appears to be a primary feature of TLE, which is not secondary to cell loss. In both gray and white matter, neuronal hypertrophy means more perikaryal surface area is exposed for synaptic contacts and emerges as a hallmark of this disease.

Patients' aims for epilepsy surgery: desires beyond seizure freedom.

PURPOSE: To evaluate prospectively patient's aims for epilepsy surgery as previously outlined theoretically by Taylor et al. (Epilepsia 1997;3:625-30). METHODS: Ninety-three consecutive patients were interviewed by a psychiatrist as part of their evaluation for epilepsy surgery. Open-ended questions about the patient were asked, and carers' aims or ambitions for change as a result of putative relief of seizures were elicited. The interviewer aimed to obtain a maximum of five aims for later follow-up purposes. These questions were part of an extensive psychiatric interview that is described. RESULTS: The aims of 69 patients or carers were analyzed. The 204 statements of aims were grouped into 59 categories initially. The five most frequently cited constituted 50% of all the aims listed. These aims were desire for work, driving of motor vehicles, independence, socializing, and freedom from drugs. The patients rarely identified a desire for improvement in cognitive functioning as an aim for epilepsy surgery. A final analysis into six categories showed that changes in social process predominated, even over changes in personal behavior. CONCLUSIONS: The social and personal aims to accompany relief of epilepsy identified by patients are consistent with the literature on psychosocial adjustment to epilepsy.

The function of dreaming.

Theories on the function of REM sleep and dreaming, with which it has a contingent relationship, remain diverse. They include facilitation of memory storage, reverse learning, anatomical and functional brain maturation, catecholamine restoration, psychoanalytical (wish fulfilment or otherwise). It is possible that one function is grafted onto another as the personality develops. Given a close relationship between REM sleep and dreaming, and given that the neonate spends 18 hours asleep per day, of which 12 hours are spent in REM sleep, it is logical to look in the neonate for a primary function of dreaming. The two constants in the dreaming process are: 1) the dreamer is always present as first person observer; 2) there is always a topographical setting. Based on the foregoing, it is proposed that a major function of REM sleep is the development and maintenance of a sense of personal identity, through creating a 'being there' environment at regular intervals during prolonged periods of absence from a waking state in topographical surrounds. The infant cannot forget who he/she is. Thus, he/she develops a clear sense of his/her own identity, or the 'I'ness of me', and a sense of his/her separateness from the topographical world. At the same time, by largely forgetting the dreams, he/she is not burdened by the need for an elaborate method of storage of the vicarious and bizarre experiences.

Accuracy and validity of stereology as a quantitative method for assessment of human temporal lobe volumes acquired by magnetic resonance imaging.

The object of this study was to compare the accuracy and validity of stereology as a method for determining whole temporal lobe volume with the more established technique of semi-automated thresholding and tracing. Ten, fixed, post-mortem human brains, were imaged using a three dimensional (3D) acquisition protocol. The volume of the left temporal lobe, dissected from each brain, was determined by fluid displacement. Each volume was compared to measurements obtained from magnetic resonance images (MRI) of the post-mortem brain using each of the two segmentation methods. Post-acquisition processing was performed using MEASURE software. Three investigators performed each measurement three times using each method, yielding a total of 180 measurements. Stereology took, on average, half the time of thresholding/tracing. Using a clinically acceptable variation for 95% of repeat measures; both intra-observer and inter-observer variation were acceptable for each technique. However, validity, as demonstrated by graphs of agreement against water displacement showed that the "limits of agreement" using stereology were within the acceptable range, while those using the thresholding/tracing technique were not. Quantitative estimates of variation and a graphical representation of the limits of agreement show that stereology is at least as precise as the thresholding/tracing method but is superior in terms of speed and validity. This has broad implications for published estimates of brain region volumes in human diseases such as epilepsy, dementia and other neurodegenerative disorders.

Acute demyelination, neuropathological diagnosis, and clinical evolution.

A retrospective analysis of 14 patients who presented with a progressively expanding mass lesion(s) shown at biopsy/autopsy to represent acute demyelination was carried out. The aims of this study were to determine the optimal neuropathological approach to diagnosis and to determine the clinical evolution of this condition. Subsequent investigations and clinical outcome studies confirmed MS in 10 cases. Two patients had received an incorrect neuropathologic diagnosis of astrocytoma resulting in cranial irradiation. Key histologic parameters in establishing a diagnosis of acute demyelination were a predominance of lipid filled macrophages, macrophage alignment along axons, and an absence of oligodendroglial inclusions. Axonal injury was present in all cases and a lymphocytic/plasma cell infiltrate was sparse in areas of demyelination. Neuroimaging revealed single lesions in 10 patients and multiple lesions in 4 patients. Two patients were lost to follow-up, 3 died within 18 months of diagnosis, 8 had a relapsing remitting clinical course, and 1 patient had a chronic progressive course. In conclusion, a dense lymphocytic and plasma cell infiltrate is unusual in acute human demyelination. Although axonal injury is a frequent histologic finding in acute demyelination, it does not preclude a favorable clinical outcome.

Deterioration of giant cell arteritis with corticosteroid therapy.

BACKGROUND: Failure of response of giant cell arteritis (GCA) to corticosteroid therapy has invariably been attributed to the delay in diagnosing the disease or the use of inadequate corticosteroid dosage. Following our observation of progressive deterioration following the introduction of prednisolone use in a patient, we examined the possibility that worsening of the condition might be due to corticosteroid therapy rather than coincidence. OBJECTIVE: To determine whether corticosteroid therapy may exacerbate GCA. DESLGN: Case report and an analysis of similar cases reported in the medical literature. PATIENT: A 64-year-old man had a 3-month history of headache, night sweats, malaise and general weakness, and anorexia and weight loss and a more recent history of jaw claudication, dysphagia, and hoarseness. Clinical findings included prominent temporal arteries with absent pulsation, abnormal saccades to the right, and eyelid retraction. Laboratory findings included an elevated erythrocyte sedimentation rate and platelet count. Results of a biopsy of the temporal artery confirmed GCA. Magnetic resonance imaging scans showed ischemic cerebellar lesions and a mature infarct in the left anterior occipital, posteroparietal region. Following corticosteroid therapy commencement, the patient's condition deteriorated steadily for 5 days with clinical signs suggestive of an evolving vertebrobasilar stroke. Following treatment with high-dose intravenous dexamethasone sodium phosphate and heparin sodium, his symptoms improved. DATA SOURCES: The review included analysis of autopsy-based reports in which clinical details are provided and clinical reports in which major visual or cerebral complications are described. Significant complications occurred in many cases shortly following the introduction of corticosteroid therapy. In many of these cases, the symptoms indicated that GCA had been present for a significant period prior to corticosteroid therapy. CONCLUSIONS: Progressively evolving occlusive strokes may occur following corticosteroid therapy in patients with GCA. In cerebrovascular complications, vascular occlusion occurs at sites of active vasculitis, usually within the vertebrobasilar system. It is not certain that the worsening of the condition following corticosteroid therapy is always coincidental, and an alternative possibility, namely a functional relationship between the initiation of corticosteroid therapy and clinical deterioration, should be borne in mind.

An international survey of long-term video/EEG services.

To determine current practices in the provision of video-EEG services, the authors conducted an international survey by post. The aim of the survey was to evaluate, by reference to other centres, how and why certain things are done, be assured that their own center is providing a quality service, identify weaknesses in their service, and from this, set improvement goals and objectives. A purposive sampling method was used by sending questionnaires to 78 hospitals where it was believed a long-term video-EEG monitoring service existed. Completed survey questionnaires were returned from 42 centers. Although the survey mechanism may have resulted in self-selection bias, evaluation of the responses provides information on patient management, staffing levels, equipment, and equipment management. Ultimately, these data may aid in identifying a minimum set of requirements for the provision of a video-EEG telemetry service.

Radiological determination of the posterior limits of the temporal lobe for volumetric analysis.

The posterior peri-Sylvian area is the most highly lateralized part of the human brain due to its specialised role in language. Currently, there is no clearly defined posterior boundary of the temporal lobe which takes account of language lateralization and which can be reliably determined radiologically. However, there have been a number of recent advances in magnetic resonance technology including volume visualisation techniques which have as their goal the realistic three-dimensional representation of the brain which is acquired in two-dimensional slices. These have enabled the identification of precise macroanatomical and cytoarchitectural boundaries from which an efficient and reproducible posterior limit may be demarcated. Such limit standardisation is important for volumetric investigations of both neurological and psychiatric disease. Magnetic resonance imaging (MRI) scans of 20 normal subjects (10 male and 10 female), aged between 18 and 42 years, were acquired as part of a study of normal temporal lobe volume variation. In order to demonstrate the method of posterior limit placement, a thin slice (1.5 mm) 3D spoiled gradient magnetic resonance image of the brain of a 30 year-old right-handed male, without neurological disease, was acquired on a 1.5 tesla GE magnetic resonance machine. The data set was transferred via network to the hard disk of a 166 MHz Pentium processor PC. A software package called MEASURE allowed reformation of the data set in all three orthogonal planes. Then, using a high resolution algorithm, the brain was aligned along the newly proposed posterior plane which runs from the limit of the Sylvian fissure, identified on a 3D rendering, to the posterior/inferior splenium. It is hoped that this procedure will be utilised as a standard method for radiological determination of the limit of the posterior temporal lobe in order to allow volumetric measurements of this structure to be compared in a meaningful way.

Discrimination of prosody and music by normal children.

Prosody or the melody of speech is the process used to alter the meaning (linguistic prosody) or emotional force (affective prosody) of a sentence. The components of prosody are rhythm, pitch, tone and stress and they are articulated by modulation of the acoustic correlates of prosody; frequency, duration and amplitude. Little is known about the development of prosody in normal children other than that it appears to be a precursor to the further acquisition of normal language. In order to examine the development of the perception of prosody in normal children, a group of 40 neurologically normal children aged between 5 and 9 years were subjected to a number of prosodic recognition tasks. The objective was to modify a number of existing tasks and to devise a number of new ones to test both linguistic and affective prosody and the appreciation of affective cues in music. The results indicate a step-wise improvement in perceptual contours up to 8.5 years old. However the perception of emotion in music appears highly developed early on in development. This study provides normative data and is the first report of a comparison between the development of prosodic and musical appreciation in this age group of normal children.

Prosodic preservation in Landau-Kleffner syndrome: a case report.

Landau-Kleffner syndrome (LKS) is a rare acquired condition of auditory verbal agnosia and convulsive disorder in children. It has been proposed that there is a functional relationship between electrical disturbance and the speech defect. Prosody or the melody of language, as described by Monrad-Krohn (1947), is one aspect of non-verbal communication which is distributed bilaterally in the brain. Prosodic parameters of expression and perception in one 7.5-year-old child were tested to see if they were preserved as a means of communication. The child was observed during video-electroencephalogram (EEG) monitoring over a 48-hour period. All utterances were recorded and subject to analysis for the salience and variation of acoustic correlates of prosody. Prosodic comprehension was measured using specific perceptual tasks previously presented to normal children between the ages of 5.5 and 8.5. Despite being unable to meaningfully use or perceive phonemes, the child was able to use variations in fundamental frequency, duration and intensity of utterances, to convey both emotional and propositional intent. Similarly, the child was able to discriminate prosodic contours of a male adult voice to an age equivalent to 5.5 to 6.5 years. This argues in favour of the notion for educating such children not only through the visual channel but also through the auditory channel.

MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study.

Chemokines are low molecular weight chemotactic cytokines that have been shown to play a central role in the perivascular transmigration and accumulation of specific subsets of leukocytes at sites of tissue damage. Two major families have been defined depending on the positioning of four conserved cysteines. The CXC chemokines predominantly attract neutrophils, whereas the CC chemokines predominantly attract monocytes and other leukocyte cell types. Members of the monocyte chemotactic protein (MCP)-1 family form a major component of the CC family of chemokines and are considered the principal chemokines involved in the recruitment of monocytes/macrophages and activated lymphocytes. In this study we addressed the expression and distribution of MCP-1, -2 and -3 in multiple sclerosis (MS) lesions of differing ages and levels of inflammatory activity using immunohistochemistry and in situ hybridization. In acute and chronic-active MS lesions immunoreactivity for MCP-1, -2 and -3 was prominent throughout the lesion center with reactivity diminishing abruptly at the lesion edge. Hypertrophic astrocytes were strongly reactive and inflammatory cells showed variable reactivity. Outside of the lesion only hypertrophic astrocytes were reactive. The results obtained by in situ hybridization for MCP-1 were in agreement with those obtained by immunostaining. In more chronic lesions immunoreactivity for MCP-1, -2 and -3 was considerably diminished, and in chronic-silent lesions immunoreactivity was restricted to a few scattered reactive astrocytes. Normal control brains showed no immunoreactivity for MCP-1, -2 and -3. Although the cellular distribution of all three members of this family was similar, antibodies to MCP-3 gave prominent staining of the extracellular matrix that was not noted for MCP-1 and -2. These results support the conclusion that members of the MCP family of chemokines are involved in the development of MS lesions in the central nervous system.

Pathogen-free granulomatous diseases of the central nervous system.

Pathogen-free granulomatous diseases (PFGD) of the central nervous system (CNS) are a group of disorders with protean clinical and pathological findings. Failure to identify a causative organism leads to considerable diagnostic difficulty. The neuropathology records between 1985 and 1995 were retrospectively reviewed, and the medical records of all patients in whom a diagnosis of PFGD of the CNS was made were retrieved. Patients in whom an infective agent was shown either by culture, special staining techniques, or by immunohistochemical methods were excluded. We identified 11 patients (eight male, three female) who fulfilled the pathological criteria for this condition. Average age at diagnosis was 38.7 years (range, 17 to 78). Neurological symptoms were the presenting feature in nine patients. Neuroimaging findings included hydrocephalus (54.5%), meningeal enhancement (45.5%), and mass lesions (45.5%). Seven patients had antemortem CNS biopsies (brain/meninges [n = 6], spinal [n = 1]), which showed noncaseating granulomas. Eight patients died (mortality rate: 72.7%). Postmortem examination showed granulomatous involvement of the leptomeninges and cerebral parenchyma in all cases with systemic involvement in 50%, chiefly in the form of noncaseating granulomas of the hilar nodes. Six patients fulfilled the clinical, radiological, and pathological diagnostic criteria for neurosarcoidosis. The remaining five patients had an unclassifiable pathogen-free granulomatous disease of the CNS. PFGD of the CNS are associated with a poor prognosis. Although neurosarcoidosis may account for some of the cases, there remains an unclassifiable subgroup that continues to be a diagnostic and management challenge.

Contribution of medial versus lateral temporal-lobe structures to human odour identification.

To investigate possible distinct contributions of different temporal-lobe structures to odour identification, the University of Pennsylvania Smell Identification Test was administered monorhinally to seizure-free patients who had undergone one of three types of temporal-lobe resection practised in three different institutions for surgical treatment of epilepsy. The resections were neocorticectomy (Dublin), selective amygdalohippocampectomy (Zurich), or anterior temporal-lobe resection with encroachment on amygdala and hippocampus (Montreal). Resections, analysed from MRI scans, showed unexpected encroachment on medial structures in most patients of the neocorticectomy groups, and largest amygdala and hippocampal resections in the amygdalohippocampectomy groups. Impaired odour identification was observed in all patient groups, irrespective of surgical approach, with greatest impairment in the nostril ipsilateral to the resection. The finding of deficits in all three surgical groups suggests that damage in the anterior temporal area, perhaps in piriform cortex, is sufficient to disrupt performance on this task; it may be that function is disrupted in the medial temporal-lobe region by disconnection when the periamygdaloid area is damaged, even when amygdala and hippocampus are left intact. An alternative explanation for our results is that damage in any one of these areas disrupts a complex network involving several distinct temporal-lobe structures.

Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures.

We sought to elucidate the contributions of the amygdala, hippocampus and temporal neocortex to learning and memory for verbal and visuospatial material. Two matched learning tasks, using abstract words versus abstract designs, were administered to patients with unilateral neocorticectomy (NCE; Dublin), selective amygdalohippocampectomy (AHE; Zurich) or anterior temporal-lobe resection invading the amygdala and hippocampus (ATL; Montreal). Data were analysed according to side and type of resection. Learning and recall for words was impaired in groups with resection from the left temporal lobe, irrespective of whether mediobasal structures were spared or temporal neocortex was spared. All right-resection groups were unimpaired. Learning for abstract designs was impaired across all trials in the right AHE and NCE groups, and on the last two trials in the right ATL group. Restricted deficits of lower magnitude were observed on some trials in left-resection groups. These results show a partial dissociation between side of excision and type of material, but the finding of similar deficits in all resection types was unexpected. We propose that excision from either the hippocampal region or temporal neocortex may result in a disconnection, giving a similar functional outcome, as both types of resection interrupt a circuit likely to be essential for normal storage and retrieval of information.