Showing papers in "Journal of Neurology, Neurosurgery, and Psychiatry in 1998"

CLOX: an executive clock drawing task

Abstract: Objective—To describe a clock drawing task (CLOX) designed to elicit executive impairment and discriminate it from non-executive constructional failure. Subjects—90 elderly subjects were studied (45 elderly and well persons from the independent living apartments of a continuing care retirement community and 45 patients with probable Alzheimer’s disease). The clock drawing performance of elderly patients was compared with that of 62 young adult controls. Methods—Subjects received the CLOX, an executive test (EXIT25), and the mini mental state examination (MMSE). The CLOX is divided into an unprompted task that is sensitive to executive control (CLOX1) and a copied version that is not (CLOX2). Between rater reliability (27 subjects) was high for both subtests. Results—In elderly subjects, CLOX subscores correlated strongly with cognitive severity (CLOX1: r=˛0.83 v the EXIT25; CLOX2:r=0.85vthe MMSE). EXIT25 and MMSE scores predicted CLOX1 scores independently of age or education (F(4,82)=50.7, p<0.001; R 2 =0.71). The EXIT25 accounted for 68% of CLOX1 variance. Only the MMSE significantly contributed to CLOX2 scores (F(4,72)= 57.2, p<0.001; R 2 =0.74). CLOX subscales discriminated between patients with Alzheimer’s disease and elderly controls (83.1% of cases correctly classified; Wilkes’ lambda=0.48, p<0.001), and between Alzheimer’s disease subgroups with and without constructional impairment (91.9% of cases correctly classified; Wilkes’ lambda=0.31, p<0.001). Conclusions—The CLOX is an internally consistent measure that is easy to administer and displays good inter-rater reliability. It is strongly associated with cognitive test scores.The pattern of CLOX failures may discriminate clinical dementia subgroups. (J Neurol Neurosurg Psychiatry 1998;64:588‐594)

Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia

Abstract: Objective—A pilot study of the density of dendritic spines on pyramidal neurons in layer III of human temporal and frontal cerebral neocortex in schizophrenia. Methods—Postmortem material from a group of eight prospectively diagnosed schizophrenic patients, five archive schizophrenic patients, 11 nonschizophrenic controls, and one patient with schizophrenia-like psychosis, thought to be due to substance misuse, was impregnated with a rapid Golgi method. Spines were counted on the dendrites of pyramidal neurons in temporal and frontal association areas, of which the soma was in layer III (which take part in corticocortical connectivity) and which met strict criteria for impregnation quality. Altogether 25 blocks were studied in the schizophrenic group and 21 in the controls. If more than one block was examined from a single area, the counts for that area were averaged. All measurements were made blind: diagnoses were only disclosed by a third party after measurements were completed. Possible confounding aVects of coexisiting Alzheimer’s disease were taken into account, as were the eVects of age at death and postmortem interval. Results—There was a significant (p<0.001) reduction in the numerical density of spines in schizophrenia (276/mm in control temporal cortex and 112/mm in schizophrenic patients, and 299 and 101 respectively in the frontal cortex). An analysis of variance, taking out eVects of age at death and postmortem interval, which might have explained the low spine density for some of the schizophrenic patients, did not aVect the significance of the results. Conclusion—The results support the concept of there being a defect in the fine structure of dendrites of pyramidal neurons, involving loss of spines, in schizophrenia and may help to explain the loss of cortical volume without loss of neurons in this condition, although the eVect of neuroleptic drugs cannot be ruled out. (J Neurol Neurosurg Psychiatry 1998;65:446‐453)

Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET

Abstract: Objectives—To measure the rate of progression in striatal [ 18 F]dopa metabolism in a large group (n=32) of patients with Parkinson’s disease, to estimate the average duration of preclinical period, and to examine the influence of the PET method on the assessment of rate of progression and preclinical period. Methods—Thirty two patients with Parkinson’s disease (mean age 58 (SD 13) years, mean duration 39 (SD 33) months) were assessed with [ 18 F]dopa PET and UPDRS scoring on two occasions a mean of 18 (SD 6) months apart. PET data were sampled with separate caudate and putamen and total striatal regions of interest, and both graphical (Ki) and ratio methods of analysis. Results—The mean annual rate of deterioration in [ 18 F]dopa uptake varied according to structure and method of analysis, with putamen Ki showing the most rapid mean rate of progression (4.7% of normal mean per year). The group showed a significant deterioration (p<0.0004, paired two tailed t test) in UPDRS and in the putamen (p=0.008) and total striatal (p=0.012) [ 18 F]dopa uptake measured using a graphical analysis, but no significant change in caudate or putamen uptake measured by a ratio approach. A study of sensitivity confirmed that putamen Ki was the most sensitive measure of disease progression, caudate ratio the least. Symptom onset in Parkinson’s disease was estimated at a mean putamen [

Functional magnetic resonance imaging of human brain activity in a verbal fluency task

Abstract: OBJECTIVES—Functional MRI (fMRI) holds the promise of non-invasive mapping of human brain function in both health and disease. Yet its sensitivity and reliability for mapping higher cognitive function are still being determined. Using verbal fluency as a task, the objective was to ascertain the consistency of fMRI on a conventional scanner for determining the anatomic substrate of language between subjects and between sexes. Comparison was made with previous PET studies. METHODS—Using a 1.5 Tesla magnet and an echoplanar pulse sequence, whole brain fMRI was obtained from 12 normal right handed subjects (6 males and 6 females) as they performed a verbal fluency task. RESULTS—A broadly consistent pattern of response was seen across subjects. Areas showing activation changes included the left prefrontal cortex and right cerebellum, in agreement with previous PET 15O-H2O studies. In addition, significantly decreased responses were seen in the posterior cingulate and over an extensive area of mesial and dorsolateral parietal and superior temporal cortices. The male cohort showed a slight asymmetry of parietal deactivation, with more involvement on the right, whereas the female cohort showed a small region of activation in the right orbitofrontal cortex. There were individual task related regional changes in all 12 subjects with the area showing the most significant change being the left prefrontal cortex in all cases. CONCLUSIONS—Magnetic resonance scanners of conventional field strength can provide functional brain mapping data with a sensitivity at least that of PET. Activation was seen in left prefrontal and right cerebellar regions, as with PET. However, decremental responses were seen over a much larger area of the posterior cortex than had been anticipated by prior studies. The ability to see a response in each subject individually suggests that fMRI may be useful in the preinterventional mapping of pathological states, and offers a non-invasive alternative to the Wada test for assessment of hemispheric dominance. There were no gross differences in the pattern of activation between male and female subjects.

Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination.

Abstract: OBJECTIVE—To analyse the natural history and survival of corticobasal degeneration by investigating the clinical features of 14 cases confirmed by postmortem examination. METHODS—Patients with definite corticobasal degeneration were selected from the research and clinical files of seven tertiary medical centres in Austria, the United Kingdom, and the United States. Clinical features were analysed in detail. RESULTS—The sample consisted of eight female and six male patients; mean age at symptom onset was 63 (SD 7.7) years, and mean disease duration was 7.9 (SD 2.6) years. The most commonly reported symptom at onset included asymmetric limb clumsiness with or without rigidity (50%) or tremor (21%). At the first neurological visit, on average 3.0 (SD 1.9) years after symptom onset, the most often encountered extrapyramidal features included unilateral limb rigidity (79%) or bradykinesia (71%), postural imbalance (45%), and unilateral limb dystonia (43%). Ideomotor apraxia (64%), and to a lesser extent cortical dementia (36%), were the most common cortical signs present at the first visit. During the course of the disease, virtually all patients developed asymmetric or unilateral akinetic rigid parkinsonism and a gait disorder. No patient had a dramatic response to levodopa therapy. Median survival time after onset of symptoms was 7.9 (SD 0.7) (range, 2.5-12.5) years, and, after the first clinic visit, 4.9 (SD 0.7) (range, 0.8-10) years. Early bilateral bradykinesia, frontal syndrome, or two out of tremor, rigidity, and bradykinesia, predicted a shorter survival. CONCLUSION—The results confirm that unilateral parkinsonism unresponsive to levodopa and limb ideomotor apraxia are the clinical hallmarks of corticobasal degeneration, and only a minority of patients with corticobasal degeneration present with dementia. The study also suggests that a focal cognitive and extrapyramidal motor syndrome is indicative of corticobasal degeneration. Survival in corticobasal degeneration was shortened by the early presence of (more) widespread parkinsonian features or frontal lobe syndrome.

A double blind, randomised, parallel group study to investigate the dose equivalence of Dysport® and Botox®in the treatment of cervical dystonia

Abstract: OBJECTIVE This study was designed to establish whether a ratio of three units of Dysport ® is equivalent to one unit of Botox ® for the treatment of cervical dystonia. METHODS Patients with predominantly rotational cervical dystonia, and a minimum of four previous Botox treatments, were randomised to receive either the clinically indicated dose of Botox or three times that dose in Dysport units. Study botulinum toxin was administered in a double blind fashion, to one or more clinically indicated muscles, at one or more sites per muscle. Patients returned for assessment two, four, eight, and 12 weeks after treatment. RESULTS A total of 73 patients (Dysport, 38; Botox, 35) were entered. The Dysport group received a mean (SD) dose of 477 (131) (range 240–720) Dysport units, and the Botox group received a mean (SD) dose of 152 (45) (range 70–240) Botox units. The mean (SEM) post-treatment Tsui scores for the Dysport group (4.8 (0.3)) and the Botox group (5.0 (0.3)) were not statistically different (p=0.66). The study had 91% power to detect a clinically significant difference of two points. Both groups showed substantial improvement in Tsui score by week 2 (mean (SD); Dysport, 46 (28)%; Botox, 37 (28)%), with a peak effect at week 4 (mean (SD); Dysport, 49 (29)%; Botox, 44 (28)%). A similar response profile was seen for other assessments of efficacy. The duration of effect, assessed by time to retreatment, was also similar (mean (SD); Dysport, 83.9 (13.6) days; Botox, 80.7 (14.4) days; p=0.85). During the study 22 of 38 (58%) Dysport patients reported 39 adverse events, and 24 of 35 (69%) Botox patients reported 56 adverse events (p=0.35). A global assessment of efficacy and safety considered that 29 of 38 (76%) Dysport patients and 23 of 35 (66%) Botox patients were treatment successes (p=0.32). CONCLUSION Patients with predominantly rotational cervical dystonia treated with the clinically indicated dose of Botox or three times that dose in Dysport units show similar improvements and do not have significantly different safety profiles.

Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis.

Abstract: The neurofilament protein is a major structural protein of neurons and a marker for axonal damage. The concentrations of the light subunit of the neurofilament triplet protein (NFL) in CSF were significantly increased in patients with relapsing-remitting multiple sclerosis compared with healthy controls (p<0.001). Seventy eight per cent of patients with multiple sclerosis showed increased NFL concentrations. Significant correlations between the NFL concentration in CSF and clinical indices were discerned for disability, exacerbation rate, and time from the start of the previous exacerbation to the time of the lumbar puncture. The results suggest that axonal damage occurs during relapsing-remitting multiple sclerosis and that the damage contributes to disability and the appearance of clinical exacerbations. The concentration of NFL in CSF is a potential marker of disease activity in multiple sclerosis and might be useful in future clinical trials of multiple sclerosis.

Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity

Abstract: OBJECTIVE To investigate whether the stiff limb syndrome may be separated from the stiff man syndrome and progressive encephalomyelitis with rigidity on simple clinical grounds, and whether such a distinction has implications for aetiology, treatment, and prognosis. METHODS Twenty three patients referred over a 10 year period with rigidity and spasms in association with continuous motor unit activity, but without evidence of neuromyotonia, extrapyramidal or pyramidal dysfunction or focal lesions of the spinal cord were reviewed. The patients were divided into those with an acute or subacute illness, leading to death within 1 year, and those with a chronic course. The latter were divided into those in whom rigidity and spasms dominated in the axial muscles, or in one or more distal limbs, at the time of their first assessment. RESULTS This simple division identified three distinct groups of patients. (1) Progressive encephalomyelitis with rigidity: two patients had a rapidly progressive condition characterised by widespread rigidity which resulted in death within 6 and 16 weeks. One patient had negative anti-GAD and anti-neuronal antibodies, but had markedly abnormal CSF and widespread denervation. The principal pathological findings in this case were a subacute encephalomyelitis which primarily affected the grey matter. In the remaining patient anti-GAD antibodies were not tested, and postmortem was refused. (2) Stiff man syndrome: eight patients had rigidity and painful spasms of the lumbar paraspinal, abdominal, and occasionally proximal leg muscles associated with a lumbar hyperlordosis. There was no involvement of the upper limbs, distal lower limbs, sphincters or cranial nerves. Seven had anti-GAD antibodies and most had additional evidence of autoimmune disease. Neurophysiologically there was continuous motor unit activity with abnormal exteroceptive reflexes, but a normal interference pattern during spasms. The patients all responded to baclofen/diazepam and remained ambulant. (3) Stiff limb syndrome: thirteen patients had rigidity, painful spasm, and abnormal postures of the distal limb, usually the leg. About half went on to develop sphincter or brainstem involvement. Generalised myoclonic jerks were not a feature. Only two had truncal rigidity, and another two had anti-GAD antibodies. Most had no evidence of autoimmune disease. Neurophysiologically they had continuous motor unit activity in the affected limb, abnormal exteroceptive reflexes, and abnormally segmented EMG activity during spasms. The disease ran a protracted course, and most patients had only a partial response to baclofen or diazepam. About half became wheelchair bound. CONCLUSIONS The stiff limb syndrome seems distinct from the stiff man syndrome or progressive encephalomyelitis with rigidity, and is an important cause of rigidity and spasm in the setting of continuous motor unit activity.

Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke

Abstract: Recent trials of plasminogen activators in acute ischaemic stroke underscore the delicate balance between promise of benefit and risk. Attempts to manage clinical outcome by systemic infusion of recombinant tissue plasminogen activator (rt-PA) have so far had mixed success.1 2 The benefits seen in the National Institutes of Neurological Diseases and Stroke (NINDS) trial of rt-PA in acute ischaemic stroke were a significant absolute improvement in disability outcome.2 3 However, the risks in that study and in the European Cooperative Acute Stroke Study (ECASS)1 included further disability and mortality associated with haemorrhagic consequences of the plasminogen activator (PA).1 2 Three recent studies of streptokinase in acute ischaemic stroke were terminated because of safety concerns.4-9 In all five trials, the risk of symptomatic haemorrhage associated with the PA was significantly increased over placebo (table 1). In addition, approaches which effect recanalisation of documented cerebral arterial thrombotic occlusions by intravenous or intra-arterial PA infusion have yet to be rigorously shown to promote overall benefit, although anecdotal evidence suggests that individual patients may improve clinically.10-24 The reasons are practical. The perceived risks, those of angiography and the interventional procedures required for intra-arterial PA delivery, have not been fully evaluated,25 although the relative risks of diagnostic angiography are low.26-28 Clearly, this assessment hides many important differences in PA behaviour, study design and conduct, patient populations, diagnostic and therapeutic procedures, disease severity, comorbidity, and a host of other potential contributors. None the less, concerns which may erode the promise of benefit of thrombolytic agents in acute ischaemic stroke include the accentuation of innate risks associated with the evolution of ischaemic injury after the stroke event itself.29-34 These include early mortality caused by severe brain oedema and the development of haemorrhagic transformation which causes clinical deterioration or …

Routine follow up after head injury: a second randomised controlled trial

Abstract: OBJECTIVE To confirm that patients admitted to hospital with a head injury benefit from a routinely offered early intervention service. PATIENTS AND METHODS A mixed rural and urban Health District of 560 000 people with two accident and emergency departments provided the setting. Existing routine services for most patients with head injury are minimal. All patients aged 16–65 years admitted to hospital after a head injury of any severity, with or without other injuries entered the trial. Prospective randomisation, with a block randomisation procedure was used to allocate all eligible patients to either: a group offered an additional service by a specialist team; or a group receiving existing standard services. Patients were assessed at follow up six months after injury. The primary outcome measure was the Rivermead head injury follow up questionnaire, a validated and reliable measure of social disability. The Rivermead post-concussion symptoms questionnaire was used to estimate severity of post-concussion symptoms. Each patient in the trial group was contacted 7–10 days after injury, and offered assessment and interventions as needed. These initially focused on the provision of information, support, and advice. Forty six per cent of patients in the trial group also received further outpatient intervention or additional support by telephone. RESULTS 314 patients were registered: 184 were randomised into the trial group, 130 into the control group. For prognostic data, the groups were comparable at randomisation, and remained comparable when assessed at six months. 132 trial and 86 control patients were followed up at six months after injury. Patients’ post-traumatic amnesia ranged from mild (n=79, 40%), and moderate (n=62, 32%), to severe (n=38, 19%) and very severe (n=17, 9%). The trial group patients had significantly less social disability (p=0.01) and significantly less severe post-concussion symptoms (p=0.02) at follow up at six months after injury than the control group patients. CONCLUSIONS The early interventions offered by a specialist service significantly reduced social morbidity and severity of post-concussion symptoms in trial group patients at six months after head injury. Recommendations about how specialist services should be targeted are made both in the light of these results and those from a previous randomised controlled trial.

Clinical usefulness of magnetic resonance imaging in multiple system atrophy

Abstract: OBJECTIVES To determine the sensitivity, specificity, and positive predictive values of a selection of abnormal findings in the putamen and infratentorial structures on routine magnetic resonance imaging for distinguishing between multiple system atrophy, idiopathic Parkinson’s disease, and age matched controls. PATIENTS AND METHODS Two neuroradiologists blindly and independently rated axial T2 weighted and proton density MRI of 44 patients with multiple system atrophy, 47 patients with idiopathic Parkinson’s disease, and 45 controls. High field (1.5 T) scans were available in 16 patients with multiple system atrophy, 15 patients with idiopathic Parkinson’s disease, and 16 controls. All other patients had 0.5 T scans. RESULTS On both 0.5 and 1.5 T scans the following items had high specificity but low sensitivity: putaminal atrophy, a hyperintense putaminal rim, and infratentorial signal change. Finding any infratentorial abnormality gave higher sensitivity but lower specificity. Putaminal isointensity or hypointensity relative to globus pallidus, absolute putaminal hypointensity, and altered size of the olives were not useful discriminators. The overall sensitivity was 73% on 0.5 T and 88% on 1.5 T scans. The specificities of these findings for multiple system atrophy in comparison to idiopathic Parkinson’s disease and controls on 0.5 T were 95% and 100% respectively, and on 1.5 T were 93% and 91% respectively. Finding any of the described abnormalities on MRI gave a positive predictive value of 93% on the 0.5 T machine, and 85% on the 1.5 T scanner.

Epidemiological study of Guillain-Barré syndrome in south east England

Abstract: Objectives—To determine the incidence, treatment,and outcome of Guillain-Barre syndrome in south east England. Methods—Patients presenting with confirmed Guillain-Barre syndrome between 1 July 1993 and 30 June 1994 were recruited via a voluntary reporting scheme coordinated by the British Neurological Surveillance Unit, hospital activity data collected from acute admitting hospitals within the South East and South West Thames Regional Health Authorities, death certificates, and a contemporary research study of Guillain-Barre syndrome and Campylobacter jejuni infection. All patients were followed up for one year to determine outcome. Results—Seventy nine patients were recruited, 35 (44%) male, 44 (56%) female, including three children (two boys, one girl). The crude (95% confidence interval (95% CI)) annual incidence was 1.2 (0.9‐ 1.4) cases/100 000 population and 1.5 (1.3‐ 1.8)/100 000 when adjusted for undetected cases. Twenty (25%) patients required ventilation for an average (SD) of 42 (64) days. Thirty six (46%) patients received intravenous human immunoglobulin, five (6%) received plasma exchange, 11 (14%) both treatments, three (4%) steroids, and 25 (32%) no immunomodulatory treatment.One year later,six patients (8%) had died, all of whom were older than 60, three (4%) remained bedbound or ventilator dependent,seven (9%) were unable to walk unaided, 14 (17%) were unable to run, and 49 (62%) had made a complete or almost complete recovery. Increasing age was significantly associated with a poorer outcome at one year. Conclusions—Despite the frequent use of modern immunomodulatory treatments Guillain-Barre syndrome still carries considerable morbidity and mortality. (J Neurol Neurosurg Psychiatry 1998;64:74‐77)

Interstitial glycerol as a marker for membrane phospholipid degradation in the acutely injured human brain

Abstract: OBJECTIVE Brain interstitial glycerol was studied as a potential marker for membrane phospholipid degradation in acute human brain injury. METHODS Glycerol was measured in microdialysis samples from the frontal lobe cortex in four patients in the neurointensive care unit, during the acute phase after severe aneurysmal subarachnoid haemorrhage. Microdialysis probes were inserted in conjunction with a ventriculostomy used for routine intracranial pressure monitoring. Clinical events involving hypoxia/ischaemia were diagnosed by neurological signs, neuroimaging (CT and PET), and neurochemical changes of the dialysate—for example, lactate/pyruvate ratios and hypoxanthine concentrations. RESULTS Altogether 1554 chemical analyses on 518 microdialysis samples were performed. Clinical events involving secondary hypoxia/ischaemia were generally associated with pronounced increases (up to 15-fold) of the dialysate glycerol concentration. In a patient with a stable condition and no signs of secondary hypoxia/ischaemia the glycerol concentration remained low. Simultaneous determination of glycerol in arterial plasma samples showed that the changes in brain interstitial glycerol could not be attributed to systemic changes and an injured blood brain barrier. CONCLUSIONS This study suggests that membrane phospholipid degradation occurs in human cerebral ischaemia. Interstitial glycerol harvested by microdialysis seems to be a promising tool for monitoring of membrane lipolysis in acute brain injury. The marker may be useful for studies on cell membrane injury mechanisms mediated by for example, Ca 2+ disturbances, excitatory amino acids, and reactive oxygen species; and in the evaluation of new neuroprotective therapeutic strategies.

Transient epileptic amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature

Abstract: OBJECTIVES To clarify the clinical and neuropsychological aspects of transient epileptic amnesia (TEA) based on 10 personally studied cases as well as review of 21 previously published cases; and to propose tentative diagnostic criteria for the diagnosis of TEA. METHODS All 10 patients and informants underwent a standardised clinical interview. The radiological and neurophysiological (EEG) data were also reviewed in all cases. The diagnosis of transient epileptic amnesia was made on the basis of the following criteria: (1) there was a history of recurrent witnessed episodes of transient amnesia; (2) cognitive functions other than memory were judged to be intact during typical episodes by a reliable witness; (3) there was evidence for a diagnosis of epilepsy. This evidence was provided by either ( a ) wake or sleep EEG, or ( b ) the co-occurrence of other seizure types (if their roughly concurrent onset or close association with episodes of transient amnesia suggested a connection), or ( c ) a clear cut response to anticonvulsant therapy, or by a combination of these three factors. In addition all patients were administered a comprehensive neuropsychological test battery designed to assess verbal and non-verbal anterograde memory and retrograde memory for famous personalities and personal events. Their results were compared with those of 25 age and IQ matched normal controls. RESULTS TEA usually begins in later life, with a mean age of 65 years in this series. Episodes are typically brief, lasting less than one hour, and recurrent, with a mean frequency of three a year. Attacks on waking are characteristic. Repetitive questioning occurs commonly during attacks. The anterograde amnesia during episodes is, however, often incomplete so that patients may later be able to “remember not being able to remember”. The extent of the retrograde amnesia during attacks varies from days to years. Most patients experience other seizure types compatible with an origin in the temporal lobes, but transient amnesia is the only manifestation of epilepsy in about one third of patients. Epileptiform abnormalities arising from the temporal lobes are most often detected on interictal sleep EEG. Despite normal performance on tests of anterograde memory, many patients complain of persistent interictal disturbance of autobiographical memory, involving a significant but variable loss of recall for salient personal episodes. The epochs affected may predate the onset of epilepsy by many years. CONCLUSIONS TEA is an identifiable syndrome and comprises episodic transient amnesia with an epileptic basis, without impairment of other aspects of cognitive function. Future studies should consider the question of whether TEA reflects ictal activity or a postictal state, and the mechanism of the persistent autobiographical amnesia. It is hypothesised that the latter may result in part from impairment of very long term memory consolidation as a result of epileptic activity in mesial temporal structures.

Measuring vibration threshold with a graduated tuning fork in normal aging and in patients with polyneuropathy. European Inflammatory Neuropathy Cause and Treatment (INCAT) group

Abstract: OBJECTIVE—To provide clinically useful vibration threshold normal values. METHODS—The graduated Rydel-Seiffer tuning fork was evaluated in 198 healthy controls and 59 patients with a polyneuropathy. The measures were done in triplicate at four locations: the distal interphalangeal joint of the index finger, ulnar styloid process, interphalangeal joint of the hallux, and internal malleolus. The values obtained with this tuning fork in healthy controls and patients with polyneuropathy were compared with the values of an electronic device, the Vibrameter. RESULTS—Vibration sense was better perceived in the arms compared with the legs. There was a significant age related decline of vibration sense at all locations. The values from the Rydel-Seiffer tuning fork and the Vibrameter were significantly correlated in both groups. The sensitivity of these two instruments for the four sites examined in the polyneuropathy group ranged from 29-76% and 31-73%, respectively and was the highest at the hallux for both instruments. CONCLUSION—This study provides clinical useful normal values of vibration threshold for the Rydel-Seiffer tuning fork. This is a simple and easily applicable instrument that assesses vibration sense semiquantitatively and should therefore have a place in routine neurological examination.

Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache.

Abstract: One third of patients with aneurysmal subarachnoid haemorrhage (ASAH) present with headache only. A prompt diagnosis is crucial, but these patients must be distinguished from patients with non-haemorrhagic benign thunderclap headache (BTH). The headache characteristics and associated features at onset in subarachnoid haemorrhage and benign thunderclap headache were studied to delineate the range of early features in these conditions. In this prospective study, one of two observers interviewed 102 patients with acute severe headache by means of a standard questionnaire. The patients were alert on admission and had no focal deficits. ASAH was subsequently diagnosed in 42 patients, non-aneurysmal perimesencephalic haemorrhage (PMH) in 23 patients, and BTH in 37 patients. Headache developed almost instantaneously in 50% of patients with ASAH, 35% of patients with PMH, and 68% of patients with BTH and within 1 to 5 minutes in 19%, 35%, and 19%, respectively. Loss of consciousness was reported in 26% of patients with ASAH, 4% of patients with PMH and 16% of patients with BTH, and transient focal symptoms in 33%, 9%, and 22% respectively. Seizures and double vision had occurred only in ASAH. Vomiting and physical exertion preceding the onset of headache were more frequent in patients with ASAH (69% and 50%) and those with PMH (83% and 39%) than in those with BTH (43% and 22%). Headache developed almost instantaneously in only half the patients with aneurysmal rupture and in two thirds of patients with benign thunderclap headache. In patients with acute severe headache, female sex, the presence of seizures, a history of loss of consciousness or focal symptoms, vomiting, or exertion increases the probability of ASAH, but these characteristics are of limited value in distinguishing ASAH from BTH. Aneurysmal rupture should be considered even if focal signs are absent and the headache starts within minutes.

Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late surgery

Abstract: Background—A retrospective study of patients with low grade astrocytoma was carried out because the best management of such patients remains controversial. Prognostic factors were identified by multivariate analysis. Special attention was paid to the eVect of extent and timing of surgery. Methods—Ninety patients with low grade astrocytoma were studied. Seventy two patients had resective surgery, 15 had a diagnostic biopsy only, and three patients had resective surgery after initial biopsy. Results—Significant prognostic factors for survival were age, preoperative neurological condition, epilepsy as the single sign, extent of surgery, and histology. The extent of surgery was highly significant on univariate analysis (p=0.002); however, after correction for age and preoperative symptoms this was considerably reduced (p=0.04). A subgroup of 30 patients with epilepsy as their single presenting symptom was identified. Thirteen of these patients were treated immediately after diagnosis, whereas the other 17 patients were initially followed up and treated only after clinical or radiological progression. Survival in both groups was identical (63% survival rate after five years) and much better than survival for the whole group (27% survival rate after five years). Malignant dediVerentiation was observed in 25 (70%) of 36 patients who were reoperated, after a median period of 37 months. This period was 41 months for the subgroup of patients with epilepsy only and 28 months for the remaining patients. Conclusions—Due to the retrospective nature of the study only restricted conclusions can be drawn. Low grade glioma with epilepsy as the single symptom has a much better prognosis than if accompanied by other symptoms. This prognosis is not influenced by the timing of surgery. It seems, therefore, safe to defer surgery until clinical or radiological progression in low grade glioma with epilepsy only. (J Neurol Neurosurg Psychiatry 1998;64:581‐587)

Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer’s disease: a community based follow up study

Abstract: OBJECTIVES Biochemical markers for Alzheimer’s disease would be of great value, especially to help in diagnosis early in the course of the disease. A pronounced increase in CSF tau protein (CSF-tau) is found in most patients with Alzheimer’s disease. However, the specificity has to be further studied, as an increase in CSF-tau has also been found in other dementias, especially in vascular dementia. As most previous CSF studies have been based on selected inpatients, it was considered of special interest to examine the diagnostic potential of CSF-tau in a community population based sample of consecutive patients with dementia. Such patient material has been examined at the Pitea River Valley Hospital in Northern Sweden since 1986, and includes all those with memory disturbances in the community. The aim was also to study if an increase in CSF-tau is found early in the disease process, and whether CSF-tau changes during the progression of disease. METHODS Participants: Community population based sample of 75 demented patients (43 with Alzheimer’s disease, 21 with vascular dementia, and 11 with mixed Alzheimer’s disease/vascular dementia), 18 healthy subjects, and 18 neurological controls. A follow up investigation (including analysis of a new CSF sample) was performed in all patients after about one year. MAIN OUTCOME MEASURES Concentrations of total (both normal tau and PHF-tau) tau in CSF, clinical measures (duration and severity of dementia), and apoE polymorphism. RESULTS CSF-tau was markedly increased in Alzheimer’s disease, 41/43 (95%) patients had values above the cut off level (mean+2 SD) in controls (306 pg/ml). High CSF-tau concentrations were also found in most patients with vascular dementia, preferentially in patients with vascular dementia without progressive leukoaraiosis on CT, whereas patients with vascular dementia with progressive leukoaraiosis had normal CSF-tau. Concentrations of CSF-tau were stable at one year follow up in both patients with Alzheimer’s disease and patients with vascular dementia, and there was no correlation between CSF-tau and either duration or severity of dementia. CONCLUSIONS The findings confirm the high sensitivity of CSF-tau for the diagnosis of Alzheimer’s disease, but high CSF-tau was also found in vascular dementia, resulting in a lower specificity. However, high CSF-tau is preferentially found in patients with vascular dementia without progressive leukoaraiosis, which may constitute a group with concomitant Alzheimer’s disease pathology. High CSF-tau may be present during the whole course of the disease in Alzheimer’s disease. Possibly, therefore, the same high CSF-tau concentrations may be present before the onset of clinical dementia. Follow up studies on such patients will tell whether analysis of CSF-tau is useful as a biochemical marker for early Alzheimer’s disease.

Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease

Abstract: OBJECTIVES—To determine whether continous waking day dopaminergic stimulation with the dopamine agonist apomorphine can reduce levodopa induced dyskinesias in Parkinson's disease METHODS—19 patients with severe unpredictable refractory motor fluctuations and functionally disabling levodopa induced dyskinesias were treated with continuous subcutaneoius apomorphine monotherapy for a minimum duration of 2.7 years RESULTS—A mean 65% reduction in dyskinetic severity and a mean 85% reduction in frequency and duration occurred. On discontinuing levodopa a concomitant reduction in off period time was also seen (35% of waking day "off" reduced to 10%) CONCLUSION—Continuous waking day dopaminergic stimulation with apomorphine reset the threshold for dyskinesias and led to a pronounced reduction in their frequency. Apomorphine should be considered as a less invasive alternative to pallidotomy or deep cerebral stimulation in controlling levodopa induced interdose dose dyskinesias.

Neuropsychological prediction of dementia in Parkinson's disease.

Abstract: OBJECTIVE—To identify neuropsychological characteristics predictive of later dementia in Parkinson's disease. METHODS—A comprehensive neuropsychological test battery was administered to a cohort of 89 initially non-demented patients with Parkinson's disease consecutively enrolled at a specialised Parkinson's disease clinic. They were reassessed after a mean of 3.5 years for the diagnosis of dementia. The Cox proportional hazards model was used to identify baseline characteristics predictive of dementia. RESULTS—Only four of the baseline clinical characteristics of Parkinson's disease and neuropsychological variables remained independently linked to subsequent development of dementia: the age of onset of Parkinson's disease (>60 years; relative risk (RR) 4.1, 95% confidence interval (95% CI) 1.8-24.0, p<0.03), the picture completion subtest of the Wechsler adult intelligence scale (score<10; RR 4.9, 95% CI 1.0-24.1, p<0.02), the interference section of the Stroop test (score<21; RR 3.8, p=0.08), and a verbal fluency task (score<9; RR 2.7, 95% CI 0.8-9.1, p=0.09). Depressive symptoms and the severity of motor impairment were not predictive of dementia. CONCLUSION—These features are different from the neuropsychological characteristics predictive of Alzheimer's dementia in healthy elderly people (mainly memory and language performance). They are in keeping with the well known specificity of the impairments in Parkinson's disease for visuospatial abilities and difficulties in inhibiting irrelevant stimuli. It is postulated that the composite nature of the picture completion subtest, involving several cognitive abilities impaired in Parkinson's disease, explains its sensitivity.

Spinal epidural abscess: the importance of early diagnosis and treatment

Abstract: OBJECTIVES To remind clinicians of the dangers of delayed diagnosis and the importance of early treatment of spinal epidural abscess. METHODS A review of the literature on spinal epidural abscess and a comparison of the published literature with local experience. RESULTS Imaging with MRI or CT enables early diagnosis of spinal epidural abcess and optimal therapy is surgical evacuation combined with 6–12 weeks (median 8 weeks) of antimicrobial chemotherapy. Clinical features are fever, pain, and focal neurological signs and may be associated with preceding and pre-existing bone or joint disease. The commonest aetiological organism is S aureus . CONCLUSION Early diagnosis and appropriate early antimicrobial chemotherapy with surgery is associated with an excellent prognosis.

Prevalence of Alzheimer plaques in AIDS

Abstract: OBJECTIVES—Both genetic and environmental risk factors for Alzheimer's disease have been identified. The best established environmental risk factor, head trauma, is thought to act through the triggering of an inflammatory response. Another stimulus to an inflammatory response in the brain is AIDS. Whether there is an increased prevalence of β/A4 amyloid deposits in the form of argyrophilic plaques in the brains of patients with AIDS has therefore been investigated. METHODS—The prevalence of argyrophilic amyloid plaques in the cerebral cortex of frontal and temporal lobes was compared in 97 cases of AIDS dying at ages 30-69 years with that in 125 age matched, non-HIV infected controls. RESULTS—In the control group, and in AIDS, the prevalence of plaques increased with age (p=0.005 and 0.048 respectively). There was a significantly greater prevalence of argyrophilic plaques in the AIDS group as a whole (29%) (p< 0.004) and in those in the fourth decade (18%) (p<0.014) than in control subjects (13% and 0% respectively). CONCLUSION—There is a predisposition to argyrophilic plaque formation in the brain in AIDS. The findings support the view that a stimulus to an inflammatory response in the brain favours argyrophilic plaque formation. The clinical relevance of our findings is, as yet, unclear.

Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings

Abstract: OBJECTIVE Vitamin B 12 deficiency is a systemic disease that often affects the nervous system. One of the most prevalent manifestations is subacute combined degeneration (SCD) of the spinal cord. To access the clinical, electrophysiological, and structural abnormalities associated with SCD, a study was conducted in nine patients. METHODS Clinical, electrophysiological (electroneurography, somatosensory and motor evoked potentials), and MRI evaluations were performed in patients before and after treatment. RESULTS The most prominent clinical and electrophysiological findings in all patients were dysfunctions of the posterior column. Corresponding hyperintense lesions in the posterior column of the spinal cord were found in two patients by T2 weighted MRI. Damage to the central motor pathway was identified in four patients. Demyelinating neuropathy was present in one patient and axonal neuropathy in four. All patients showed improvement of their symptoms after treatment with cobalamin. Abnormalities of the spinal cord on MRI disappeared early in recovery. Motor evoked potentials and median somatosensory evoked potentials typically normalised after treatment, whereas tibial somatosensory evoked potentials remained abnormal in most patients. CONCLUSIONS Clinical, electrophysiological, and MRI findings associated with SCD in vitamin B 12 deficiency are diverse. Thus vitamin B 12 deficiency should be considered in the differential diagnosis of all spinal cord, peripheral nerve, and neuropsychiatric disorders.

Cognitive complaints in patients after whiplash injury: the impact of malingering

Abstract: Objectives—The validity of memory and concentration complaints that are often reported after a whiplash trauma is controversial. The prevalence of malingering or underperformance in postwhiplash patients, and its impact on their cognitive test results were studied. Methods—The Amsterdam short term memory (ASTM) test, a recently developed malingering test, was used as well as a series of conventional memory and concentration tests. The study sample was a highly selected group of patients, who were examined either as part of a litigation procedure (n=36) or in the normal routine of an outpatient clinic (n=72). Results—The prevalence of underperformance, as defined by a positive score on the malingering test, was 61% (95% CI: 45‐77) in the context of litigation, and 29% (95% CI: 18‐40) in the outpatient clinic (p=0.003). Furthermore, the scores on the memory and concentration test of malingering post-whiplash patients (n=43) and non-malingering post-whiplash patients (n=65) were compared with the scores of patients with closed head injury (n=20) and normal controls (n=46). The malingering post-whiplash patients scored as low as the patients with closed head injury on most tests. Conclusions—The prevalence of malingering or cognitive underperformance in late post-whiplash patients is substantial, particularly in litigation contexts. It is not warranted to explain the mild cognitive disorders of whiplash patients in terms of brain damage,as some authors have done. The cognitive complaints of nonmalingering post-whiplash patients are more likely a result of chronic pain, chronic fatigue, or depression. (J Neurol Neurosurg Psychiatry 1998;64:339‐343)

What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo controlled, dose ranging study using Dysport

Abstract: OBJECTIVES—Botulinum toxin injections have become a first line therapeutic approach in cervical dystonia. Nevertheless, published dosing schedules, responder rates, and frequency of adverse events vary widely. The present prospective multicentre placebo controlled double blind dose ranging study was performed in a homogenous group of previously untreated patients with rotational torticollis to obtain objective data on dose-response relations. METHODS—Seventy five patients were randomly assigned to receive treatment with placebo or total doses of 250, 500, and 1000 Dysport® units divided between one splenius capitis (0, 175, 350, 700 units) and the contralateral sternocleidomastoid (0, 75, 150, 300 units) muscle. Assessments were obtained at baseline and weeks 2, 4,and 8 after treatment and comprised a modified Tsui scale, a four point pain scale, a checklist of adverse events, global assessment of improvement, and a global rating taking into account efficacy and adverse events. At week 8 the need for retreatment was assessed and then the code was unblinded. For those still responding, there was an open follow up until retreatment to assess the duration of effect. RESULTS—seventy nine per cent reported subjective improvement at one or more follow up visits. Decreases in the modified Tsui score were significant at week 4 for the 500 and 1000 unit groups versus placebo (p<0.05). Additionally positive dose-response relations were found for the degree of subjective improvement, duration of improvement, improvement on clinical global rating, and need for reinjection at eight weeks. A significant dose relation was also established for the number of adverse events overall and for the incidence of neck muscle weakness and voice changes. CONCLUSION—Magnitude and duration of improvement was greatest after injections of 1000 units Dysport®; however, at the cost of significantly more adverse events. Therefore a lower starting dose of 500 units Dysport® is recommended in patients with cervical dystonia, with upward titration at subsequent injection sessions if clinically necessary.

Neurology and the kidney

Abstract: Renal failure is relatively common, but except in association with spina bifida or paraplegia it is unlikely to occur as a result of disease of the CNS. Renal failure, however, commonly affects the nervous system. The effects of kidney failure on the nervous system are more pronounced when failure is acute. In addition to the important problems related to renal failure there are both acquired and genetically determined diseases which may affect the kidney and the brain. Those acquired diseases include the vasculitides, the paraproteinaemias, and various granulomatous conditions (considered in other chapters of Neurology and Medicine). In two of the most commonly encountered genetically determined diseases, Von Hippel-Lindau disease and polycystic kidney disease, location of pathogenic mutations will provide improved screening programmes and, possibly, allow therapeutic intervention. Uraemia may affect both the central and peripheral nervous systems. Whereas the clinical features of uraemia are well documented, the pathophysiology is less well understood and probably multifactorial. Uraemic encephalopathy, which classically fluctuates, is associated with problems in cognition and memory and may progress to delirium, convulsions, and coma. The encephalopathy may initially worsen with periods of dialysis and almost certainly relates to altered metabolic states in association with ionic changes and possibly impaired synaptic function. Renal failure may affect the peripheral nervous system, resulting in a neuropathy which shows a predilection for large diameter axons. This may be reversed by dialysis and transplantation. The myopathy seen in renal failure, often associated with bone pain and tenderness, is similar to that encountered in primary hyperparathyroidism and osteomalacia. Dialysis itself is associated with neurological syndromes including the dysequilibrium syndrome, subdural haematoma, and Wernicke's encephalopathy. Dialysis dementia, which was prevalent during the 1970s, has reduced in frequency with the use of aluminium free dialysate. With the introduction of transplantation and the concomitant use of powerful immunosuppressive drugs, the pattern of neurological problems encountered in renal replacement therapy has shifted. Five per cent of patients develop nerve injuries during renal transplantation, and up to 40% of patients experience neurological side effects from cyclosporine. Furthermore, CNS infections, often fungal in type, have been reported in up to 45% of transplant patients coming to postmortem. The nature of the involvement of neurologists with their nephrology colleagues is therefore evolving.

Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up

Abstract: OBJECTIVES—Despite the recent introduction of new peroral drugs as well as neurosurgical methods for Parkinson's disease, treatment of late stage parkinsonian patients remains difficult and many patients become severely handicapped because of fluctuations in their motor status. Injections and infusions of apomorphine has been suggested as an alternative in the treatment of these patients, but the number of studies describing the effects of such a treatment over longer time periods is still limited. The objective was to investigate the therapeutic response and range of side effects during long term treatment with apomorphine in advanced Parkinson's disease. METHODS—Forty nine patients (30 men, 19 women; age range 42-80 years) with Parkinson's disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuous infusions of apomorphine. RESULTS—Most of the patients experienced a long term symptomatic improvement. The time spent in "off" was significantly reduced from 50 to 29.5% with injections and from 50 to 25% with infusions of apomorphine. The quality of the remaining "off" periods was improved with infusion treatment, but was relatively unaffected by apomorphine injections. The overall frequency and intensity of dyskinesias did not change. The therapeutic effects of apomorphine were stable over time. The most common side effect was local inflammation at the subcutaneous infusion site, whereas the most severe were psychiatric side effects occurring in 44% of the infusion and 12% of the injection treated patients. CONCLUSION—Subcutaneous apomorphine is a highly effective treatment which can substantially improve the symptomatology in patients with advanced stage Parkinson's disease over a prolonged period of time.

Dural arteriovenous fistulas as a cause of intracranial hypertension due to impairment of cranial venous outflow

Abstract: OBJECTIVES A retrospective study was carried out on 13 patients with intracranial dural arteriovenous fistulas (DAVFs) who presented with isolated or associated signs of intracranial hypertension. METHODS Nine patients presented with symptoms of intracranial hypertension at the time of diagnosis. Ocular fundoscopy available in 12 patients showed bilateral papilloedema in eight and optic disk atrophy in four. Clinical evolution was particularly noticeable in five patients because of chronic (two patients) or acute (after lumbar shunting or puncture: three patients, one death) tonsillar herniation. RESULTS Two patients had a type I fistula (drainage into a sinus, with a normal antegrade flow direction). The remaining 11 had type II fistulas (drainage into a sinus, with abnormal retrograde venous drainage into sinuses or cortical veins). Stenosis or thrombosis of the sinus(es) distal to the fistula was present in five patients. The cerebral venous drainage was abnormal in all patients. CONCLUSION Type II (and some type I) DAVFs may present as isolated intracranial hypertension mimicking benign intracranial hypertension. Normal cerebral angiography should be added as a fifth criterion of benign intracranial hypertension. The cerebral venous drainage pattern must be carefully studied by contralateral carotid and vertebral artery injections to correctly evaluate the impairment of the cerebral venous outflow. Lumbar CSF diversion (puncture or shunting) may induce acute tonsillar herniation and should be avoided absolutely. DAVF may induce intracranial hypertension, which has a poor long term prognosis and may lead to an important loss of visual acuity and chronic tonsillar herniation. Consequently, patients with intracranial hypertension must be treated, even agressively, to obliterate the fistula or at least to reduce the arterial flow and to restore a normal cerebral venous drainage. The endovascular treatment may associate arterial or transvenous embolisation and /or surgery. Patients in whom the fistula is not obliterated after an endovascular therapeutic procedure, need continous clinical and angiographical follow up.

Pallidal activity during dystonia: somatosensory reorganisation and changes with severity.

Abstract: A woman with progressive, medically intractable right upper limb dystonia underwent a pallidotomy with only transient improvement. During the procedure her dystonia became more severe as she repeatedly made a fist to command in order to provoke dystonia transiently (movement provoked dystonia). Comparisons within cells in the internal segment of the globus pallidus (Gpi) disclosed that the firing rate was the same at rest, with making a fist, and during movement provoked dystonia. However, the firing rate compared between cells decreased significantly throughout the procedure as the patient made a fist repeatedly. During the second half of the procedure the firing rate of cells in the Gpi was similar to that in hemiballismus. The proportion of cells in the GPi which responded to sensory stimulation was significantly higher in dystonia (53%) than in hemiballismus (13%). These results suggest that pallidal activity can correlate inversely with the severity of dystonia, perhaps due to activity dependent changes in neuronal function resulting from repeated voluntary movement.

Meta-analysis of the ACE gene in ischaemic stroke

Abstract: OBJECTIVES The angiotensin-1 converting enzyme (ACE) gene is known to have two polymorphic alleles I/D People with the DD genotype have been shown to be at greater risk of myocardial infarction, but only in some studies Similar studies in stroke patients also show inconsistent results, but most of these studies have been underpowered to detect a small contribution to stroke risk from the ACE gene A meta-analysis was undertaken using all known publications of the ACE polymorphism in ischaemic stroke METHODS Two computerised databases were searched for all publications relating to case-control studies using the ACE I/D variant in human ischaemic stroke Seven association studies were identified and a meta-analysis was conducted using the Mantel-Haenszel estimate for odds ratio (OR) to determine whether the DD genotype predicted outcome in either a genetically dominant or recessive model RESULTS 1918 white subjects (1196 cases and 722 controls) were used in the meta-analysis There was no difference in ACE genotype (χ 2 =292, p>005) or I/D allele frequency (χ 2 =328, p>005) in cases or controls The overall OR for the D allele as an independent risk factor in ischaemic stroke was 131 (95% confidence interval (95% CI): 106–162, p=001) under a recessive model, and 114 (95% CI: 091–144, p=026) under a dominant model CONCLUSIONS This meta-analysis shows that the the D allele, acting recessively, is a modest but independent risk factor for ischaemic stroke onset Meta-analysis may usefully be employed in allelic association studies for detecting small attributable risks of candidate genes in polygenic disorders