Symptomatic intracranial haemorrhage after intra-arterial thrombolysis in acute ischaemic stroke: assessment of 294 patients treated with urokinase

Background

The PROACT II trial showed that intra‐arterial thrombolysis (IAT) is effective for treatment of acute ischaemic stroke attributable to M1 and M2 segment occlusions. Incidence of symptomatic intracranial haemorrhage (sICH) was 10%.

Objective

: To evaluate the risk and predictors of sICH after IAT by using urokinase in a large number of patients presenting with the whole spectrum of cerebral vessel occlusions.

Methods

294 patients with stroke treated with intra‐arterial urokinase were retrospectively analysed. The risk of sICH as well as bleeding characteristics were assessed. Demographic and radiological data, time to treatment, urokinase dose, recanalisation rates, stroke aetiology and severity were analysed for predictors.

Results

sICH occurred in 14 of 294 (4.8%) patients. The median National Institute of Health Stroke Scale score of all patients was 15. All but one sICH were located in the infarcted brain tissue, and no sICH occurred in patients with peripheral vessel occlusions (M3 or M4 segments of the middle cerebral artery). Poor collaterals (p = 0.001), early signs of ischaemia on computed tomography (p = 0.003), higher urokinase dose (p = 0.019), lower recanalisation rate (p = 0.02) and higher diastolic blood pressure on admission (p = 0.04) were found to be correlated with sICH on univariate analysis. On multivariate analysis, poor collaterals (p = 0.004), urokinase dose (p = 0.021) and early signs on computed tomography (p = 0.026) remained predictors of sICH.

Conclusions

With regard to the whole spectrum of cerebral vessel occlusions, an incidence of <5% sICH after IAT is distinctly low. This result underlines the important role of IAT in the treatment of acute stroke.The aim of treatment in acute ischaemic stroke is revascularisation as fast as possible. For this purpose, both intravenous thrombolysis (IVT) and intra‐arterial thrombolysis (IAT) have proved to be effective.^1,2,3,4,5 The most devastating complication of both treatments is intracranial haemorrhage (ICH). ICH is categorised into haemorrhagic transformation, which is usually petechial and asymptomatic, and parenchymal haematomas without deterioration and those with clinical deterioration. Those with clinical deterioration are referred to as symptomatic ICH (sICH), which is associated with an increased mortality and occurs spontaneously in 0.6–4% of patients with ischaemic strokes. Thrombolysis increases the risk of sICH. Current literature reports wide ranges of incidence—for example, 3.3–21.2% for IVT and 0–14.3% for IAT.^{1,3,6,7,8,9,10,11,12,13,14}The largest IAT series was the PROACT II trial reporting on a defined subgroup of patients with stroke (n = 180) exclusively with M1 and M2 segment occlusions of the middle cerebral artery (MCA).³This study was conducted to evaluate the risk of sICH in the whole spectrum of patients with large cerebral artery occlusions treated with IAT. Characteristics of patients with sICH were assessed and predictors analysed.     

Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis

Background

To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS).

Methods

Patients referred to our clinic during 2001–2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case–control study (132 patients and 220 healthy controls). A food‐frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking).

Results

A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B₂, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS.

Conclusion

A high intake of PUFAs and vitamin E is associated with a 50–60% decreased risk of developing ALS, and these nutrients appear to act synergistically.Sporadic amyotrophic lateral sclerosis (ALS) probably develops through the combined effects of several modifying genes and environmental factors.¹ Despite several studies that investigated environmental exposures in relation to ALS, age, gender and smoking are the only established risk factors.² Several, not mutually exclusive, pathological processes may contribute to motor neurone death in ALS in a so‐called convergence model,³ including oxidative stress, mitochondrial dysfunction, protein misfolding, axonal strangulation, apoptosis, inflammation, glutamate excitotoxicity and defects in neurotrophin biology. Nutrients are factors that could influence these processes and thereby the risk of developing ALS or its clinical expression.ALS was previously found to be positively associated with intake of glutamate,⁴ fat,⁴ fish⁵ and milk,^6,7 and inversely associated with intake of lycopene,⁸ dietary fibre,⁴ bread and pasta.⁹ Two other studies, however, failed to establish the relationship with milk.^10,11 Several of these studies included only small samples of patients (<25),^5,6,9 or investigated nutrition as one of many environmental factors, thus increasing the likelihood of chance findings.^{5,6,7,9,10,11} Furthermore, most studies did not account for the possible influence of clinical onset preceding the diagnosis^{5,6,7,8,9,10,11} or adjust for possible confounders including total energy intake, body mass index (BMI), sex, smoking and education.^{5,6,7,9,10,11}One study found an association between intake of total fat and ALS, although this was not hypothesised beforehand.⁴ This finding is of interest considering the observed associations of intake of saturated and unsaturated fatty acids and cholesterol with other neurodegenerative diseases.¹² In this case–control study, therefore, we examined the possible association between premorbid dietary intake of fatty acids, cholesterol, glutamate, phytoestrogens, calcium and anti‐oxidants and the risk of developing ALS, adjusting for confounding factors.     

Cerebral venous thrombosis and plasma concentrations of factor VIII and von Willebrand factor: a case control study

Background

High plasma concentrations of factor VIII (FVIII) and von Willebrand factor (VWF) have been recently associated with a moderately increased risk of venous thrombosis, but their roles in cerebral sinus and venous thrombosis (CSVT) have not been addressed. To determine whether elevation of FVIII and VWF is more frequent in CSVT, we analysed plasma levels of FVIII and VWF in a case control study.

Methods

The study population consisted of 25 consecutive patients (of whom nine were excluded) admitted for CSVT to the Department of Neurology, Amiens University Hospital, France, from January 1997 to December 2002, for a general screening for thrombophilia. Sixty‐four healthy subjects matched for age and sex formed the group control.

Results

Mean FVIII (CSVT: 167.3 (SD 48.8) IU/dl; control group: 117.9 (39.8) IU/dl; p = 0.001) and VWF levels (CSVT: 165.4 (76.5)%; control group: 108.5 (27.8)%; p = 0.01) were significantly higher in the CSVT group. Using the 95th percentile of the control group as the cut off value, elevated FVIII (>190 IU/dl) occurred in 25% (4/16) (p = 0.005) and elevated VWF (>168%) in 37.5% (6/16) of patients with CSVT (p<0.001). Using previously reported cut off values (>150 IU/dl or >150%) showed the same results (FVIII: p = 0.005; VWF: p = 0.009).

Conclusion

Our study suggests that elevation of plasma factor VIII levels is the most common prothrombotic risk factor for CSVT. Elevation of VWF is also associated with an increased risk of CSVT but its effect seems to be partly mediated through FVIII.Cerebral sinus and vein thrombosis (CSVT) is a rare localisation of venous thromboembolic disease. It generally occurs in young or middle‐aged adults and accounts for approximately 1% of strokes.¹ Many coagulation disorders have been associated with CSVT.^2,3,4Several prospective studies showed that high concentrations of factor VIII (FVIII) are associated with a moderately increased risk of venous thromboembolism (VTE).^5,6 The role of increased levels of von Willebrand Factor (VWF) in VTE remains unclear.^5,7 Recent studies suggest that the effect of VWF is fully explained by FVIII concentrations.⁵ Indeed, the ABO blood group, which regulates plasma concentrations of both FVIII and VWF, may also play a role in susceptibility to thrombosis.^8,9,10The increased risk of VTE with elevated levels of FVIII or VWF has been observed in previous studies.^5,6,7,11 However, they did not specifically include patients with CSVT^7,9 or they were incomplete.¹²The aim of our study was to assess plasma levels of FVIII, VWF and other thrombophilic factors in patients with CSVT in a case control study.     

Influence of cognitive impairment on the institutionalisation rate 3 years after a stroke

Background and purpose

Pre‐existing cognitive decline and new‐onset dementia are common in patients with stroke, but their influence on institutionalisation rates is unknown.

Objective

To evaluate the influence of cognitive impairment on the institutionalisation rate 3 years after a stroke.

Design

(1) The previous cognitive state of 192 consecutive patients with stroke living at home before the stroke (with the Informant Questionnaire on COgnitive Decline in the Elderly (IQCODE)), (2) new‐onset dementia occurring within 3 years and (3) institutionalisation rates within 3 years in the 165 patients who were discharged alive after the acute stage were prospectively evaluated.

Results

Independent predictors of institutionalisation over a 3‐year period that were available at admission were age (adjusted odds ratio (adjOR) for 1‐year increase  = 1.08; 95% confidence interval (CI) 1.03 to 1.15), severity of the neurological deficit (adjOR for 1‐point increase in Orgogozo score = 0.97; 95% CI 0.96 to 0.99) and severity of cognitive impairment (adjOR for 1‐point increase in IQCODE score = 1.03; 95% CI 1 to 1.06). Factors associated with institutionalisation at 3 years that were present at admission or occurred during the follow‐up were age (adjOR for 1‐year increase = 1.17; 95% CI 1.07 to 1.27) and any (pre‐existing or new) dementia (adjOR = 5.85; 95% CI 1.59 to 21.59), but not the severity of the deficit of the neurological deficit.

Conclusion

Age and cognitive impairment are more important predictors of institutionalisation 3 years after a stroke than the severity of the physical disability.Institutionalisation after a stroke increases with the severity of the neurological deficit, increasing age, female gender, low socioeconomic level, marital status and poor social environment.^1,2,3,4,5,6Dementia is common after a stroke,⁷ leading to autonomy loss.⁸ Pre‐existing dementia is present in up to 16% of patients with stroke,^9,10,11,12 and post‐stroke de mentia (PSD) occurs in up to one third.⁷ Several studies have found a link between cognitive impairment and institutionalisation after a stroke,^1,2,3,4,5 but they had several methodological limitations: (1) cross‐sectional studies were performed in long‐term stroke survivors and did not take into account patients who had been institutionalised but died before the study⁶; (2) there was no systematic cognitive assessment¹³ or only a Mini Mental State Examination,¹⁴ which is not appropriate for patients with stroke; and (3) most studies included only patients recruited in rehabilitation centres, leading to selection bias.^1,2,3,4,5 To our knowledge, no study has prospectively evaluated the influence of pre‐existing cognitive impairment and PSD on the institutionalisation rate after a stroke.The aim of this study was to evaluate the influence of the previous cognitive state and new‐onset dementia on the institutionalisation rate 3 years after a stroke.     

Axonal damage and outcome in subarachnoid haemorrhage

Background

On the basis of preliminary evidence from patients with subarachnoid haemorrhage (SAH), axonal degeneration is thought to be an underestimated pathological feature.

Methods

A longitudinal study in 17 patients with aneurysmal SAH. Ventricular CSF was collected daily for up to 14 days. The neurofilament heavy chain^SMI35 (NfH^SMI35, a biomarker for axonal damage) was quantified using a standard ELISA (upper limit of normal 0.73 ng/ml). The primary outcome measure was the Glasgow Outcome Score (GOS) at 3 months.

Results

Of 148 samples from patients with SAH, pathologically high NfH levels in the CSF were found in 78 (52.7%) samples, compared with 20 (5%) of 416 samples from the reference population (p<0.0001). A pathological increase in NfH was observed in all patients with a bad outcome (GOS 1–3) compared with 8% of those with a good outcome (GOS 4–5, p<0.0001). This increase typically became significant 7 days after the haemorrhage (p<0.01). The result was confirmed by analysing the individual mean NfH concentrations in the CSF (3.45 v 0.37 ng/ml, p<0.01), and was reinforced by the inverse correlation of NfH in the CSF with the GOS (r = −0.65, p<0.01). Severity of injury was found to be correlated to NfH^SMI35 levels in the CSF (World Federation of Neurological Surgeons, r = 0.63, p<0.01 and Glasgow Coma Score, r = −0.61, p<0.01).

Conclusion

Patients with SAH thus have secondary axonal degeneration, which may adversely affect their outcome.The presence of axonal degeneration in patients with subarachnoid haemorrhage (SAH) has recently been suggested in a longitudinal study.¹ One important finding was that damage to axons may continue after the primary injury and extend into the period of delayed cerebral ischaemia.^1,2,3,4Presence of secondary axonal degeneration in patients with SAH may be relevant to the outcome because, despite the high mortality (32–67%) during the hyperacute phase,^2,5 a considerable proportion of mostly young and otherwise healthy patients has the potential for good recovery from a limited degree of primary injury. In these patients, it is well known that secondary brain damage caused by delayed cerebral ischaemia adversely affects the potential for recovery.^2,3,4 About 50% of patients who survive do not return to their previous level of employment.^6,7,8In this longitudinal study, we monitored the development of axonal degeneration indirectly by measuring a biomarker for axonal degeneration (neurofilaments, reviewed by Petzold⁹). Firstly, we investigated whether neurofilaments would be increased early on (eg, a single peak, indicative of primary axonal injury) or rise late (eg, secondary peaks, suggestive of secondary axonal damage) in the disease course. Secondly, we tested whether the pattern of an anticipated¹ increase in neurofilament levels over time would be related to the degree of recovery.     

Treatment of shoulder pain in spastic hemiplegia by reducing spasticity of the subscapular muscle: a randomised, double blind, placebo controlled study of botulinum toxin A

Objective

This randomised, double blind, placebo controlled, two parallel group study was conducted to assess the beneficial effect of injection of botulinum toxin A (Dysport) into the subscapularis muscle on shoulder pain in stroke patients with spastic hemiplegia.

Methods

A single dose of botulinum toxin A (500 Speywood units) or placebo was injected into the subcapularis muscle. Pain was assessed using a 10 point verbal scale. Subscapularis spasticity was assessed by the change in passive shoulder lateral rotation and abduction. Upper limb spasticity was assessed using the Modified Ashworth Scale for shoulder medial rotators, and elbow, wrist and finger flexors. Assessments were carried out at baseline and at weeks 1, 2 and 4.

Results

Twenty patients (10 patients per group), 11 with ischaemic stroke and 9 with haemorrhagic stroke, completed the study. Pain improvement with botulinum toxin A was observed from week 1; score difference from baseline at week 4 was 4 points versus 1 point with placebo (p = 0.025). Lateral rotation was also improved, with a statistically significant difference compared with placebo at week 2 (p = 0.05) and week 4 (p = 0.018). A general improvement in upper limb spasticity was observed; it was significant for finger flexors at week 4 (p = 0.025).

Conclusions

Subscapularis injection of botulinum toxin A appears to be of value in the management of shoulder pain in spastic hemiplegic patients. The results confirm the role of spasticity in post‐stroke shoulder pain.Pain and spastic shoulder are frequent in hemiplegia following a stroke. Shoulder pain is a major problem for these patients, interfering with physiotherapy, sleep and daily activities. It is usually due to local causes: algoneurodystrophy (shoulder–hand syndrome), capsulitis, gleno‐humeral subluxation and also spasticity because of the prolonged muscular contracture and possible tendinopathies.^1,2,3,4 These causes can be associated, especially spasticity and algoneurodystrophy in severe hemiplegia, and patients exhibit the typical arm posture: adduction and medial rotation of the shoulder, and flexion of the elbow, wrist and finger.Different approaches are used for treatment of pain in such patients, depending on the mechanism involved. Oral medications for pain, as those for spasticity, are usually ineffective or insufficient. Treatment of algoneurodystrophy and capsulitis mainly consists of corticosteroids, systemic treatment being more effective than local administration.^3,5 To treat spasticity or its consequences, transection of the subscapularis tendon^6,7 or subcapularis nerve block^8,9 has been reported, but these treatments are not in common use. Botulinum toxin A has been shown to be effective in reducing spasticity and increasing the passive range of motion of the spastic upper limb in hemiplegic patients^{10,11,12,13,14} with a real functional benefit.¹⁵ The effect of botulinum toxin A on shoulder pain after a stroke has not been systematically studied. However, improvement of pain by the toxin has been reported in a placebo controlled study, although pain was not the main objective of the study.¹⁵ A beneficial effect has also been observed in an open study.¹⁶ Other controlled studies in which upper limb pain was assessed failed to show a significant reduction in pain.^10,11,12No specific treatment of the spastic shoulder muscles has been studied. Suprasupinator and infrasupinator muscles are not involved in painful contracted shoulder,¹⁷ and among the muscles implicated in medial rotation, the subscapularis and pectoralis muscles undoubtedly play a major role,¹⁸ with apparent pre‐eminence of the subscapularis muscle.¹⁹ In a recent study of three cases, injection of botulinum toxin A into the subscapularis muscle was shown to reduce pain and improve the passive range of motion.¹⁸Based on these observations, we formed the hypothesis that shoulder pain occurring in patients with spastic hemiplegia, even with limited range of motion compatible with capsulitis, can be relieved by reducing the spasticity of the main medial rotator muscle (ie, the subscapularis muscle). Therefore, we conducted the present study to further assess the beneficial effect of injection of botulinum toxin A (Dysport) into the subscapularis muscle on shoulder pain. An improvement in the passive range of motion was expected as a parameter of the efficacy of botulinum toxin on spasticity and as a possible secondary benefit.     

Trunk performance after stroke: an eye catching predictor of functional outcome

Background and aim

Trunk performance is an important predictor of functional outcome after stroke. However, the percentage of explained variance varies considerably between studies. This may be explained by the stroke population examined, the different scales used to assess trunk performance and the time points used to measure outcome. The aim of this multicentre study was to examine the predictive validity of the Trunk Impairment Scale (TIS) and its subscales when predicting the Barthel Index score at 6 months after stroke.

Methods

A total of 102 subjects were recruited in three European rehabilitation centres. Participants were assessed on admission (median time since stroke onset 20 days) and 6 months after stroke. Correlation analysis and forward stepwise multiple regression analysis were used to model outcome.

Results

The best predictors of the Barthel Index scores at 6 months after stroke were total TIS score (partial R² = 0.52, p<.0001) and static sitting balance subscale score (partial R² = 0.50, p<.0001) on admission. The TIS score on admission and its static sitting balance subscale were stronger predictors of the Barthel Index score at 6 months than the Barthel Index score itself on admission.

Conclusions

This study emphasises the importance of trunk performance, especially static sitting balance, when predicting functional outcome after stroke. The TIS is recommended as a prediction instrument in the rehabilitation setting when considering the prognosis of stroke patients. Future studies should address the evolution of trunk performance over time and the evaluation of treatment interventions to improve trunk performance.Although the age specific incidence of major stroke has fallen over the past few years,¹ it is still the main cause of long term disability in adults, with a growing number of survivors being dependent for activities of daily living (ADL).^2,3 Frequently identified variables predicting ADL after stroke are age and initial severity of motor and functional deficits.⁴ Trunk performance has also been identified as an important independent predictor of ADL after stroke.^5,6,7,8,9 However, based on multiple regression analyses, the reported variance of functional outcome after stroke explained by trunk performance ranges from 9% to 71%.^5,6,7,8,9 Differences in reported variance could be explained by the stroke population included, the various scales used to measure trunk performance and the time points used to measure outcome.Previous studies evaluating the predictive validity of trunk performance after stroke were performed in a single rehabilitation setting, warranting caution when generalising results.^5,6,7,8,9,10 Clinical tools used to assess trunk performance are the Trunk Control Test,^5,6,10 trunk control items of the Postural Assessment Scale for Stroke patients^7,8 and trunk assessment of Fujiwara et al.⁹ A limitation of the first two tests is that they both have a ceiling effect, which makes their use less suitable in long term outcome studies.^5,11,12,13 Furthermore, the trunk control items of the Trunk Control Test and Postural Assessment Scale for Stroke patients are largely comparable with the items of the trunk measure of Fujiwara et al.⁹ All previously mentioned clinical tools include items in the supine position which involve rolling as well as only basic balance movements in sitting. Finally, with the exception of the trunk control items of the Postural Assessment Scale for Stroke patients,⁸ no study has evaluated the prognostic value of trunk performance when predicting functional outcome at 6 months after stroke.The Trunk Impairment Scale (TIS) for patients after stroke was designed to measure ADL related selective trunk movements rather than participation of the trunk in gross transfer movements.¹⁴ The TIS assesses static and dynamic sitting balance and trunk coordination. Reliability, validity, measurement error, internal consistency and discriminant ability of the TIS have been reported elsewhere.^14,15 The TIS has no ceiling effect in subacute and chronic stroke patients and already appeared to be strongly related to measures of gait, balance and functional ability in a cross sectional study.¹² To the best of our knowledge, the predictive value of the TIS and its subscales has not been evaluated. Including age and other measures of motor and functional performance could provide a useful combination of variables predicting outcome after stroke. The Barthel Index score is a widely accepted measure in stroke rehabilitation research and assesses functional milestones in stroke recovery. Predicting Barthel Index scores at 6 months after stroke based on measurements taken on admission to a rehabilitation centre would further establish the importance of trunk performance when predicting long term outcome after stroke. Experts in the field of neurological rehabilitation have addressed the trunk as the central key point of the body.¹⁶ Proximal stability of the trunk is a prerequisite for distal head and limb movement and therefore expected to be related to functional ADL.In summary, there is still a lack of clarity regarding the importance of trunk performance in functional outcome after stroke. Scales which have been used in previous studies have important statistical limitations and are likely to be a comprehensive measure of motor performance of the trunk. Therefore, the aim of this multicentre study was to examine the predictive validity of the TIS and its subcomponents, together with other known predictors, in predicting functional outcome measured as a Barthel Index score at 6 months after stroke.     

Deglutitive laryngeal closure in stroke patients

Background

Dysphagia has been reported in up to 70% of patients with stroke, predisposing them to aspiration and pneumonia. Despite this, the mechanism for aspiration remains unclear.

Aims

To determine the relationship between bolus flow and laryngeal closure during swallowing in patients with stroke and to examine the sensorimotor mechanisms leading to aspiration.

Methods

Measures of swallowing and bolus flow were taken from digital videofluoroscopic images in 90 patients with stroke and 50 healthy adults, after repeated volitional swallows of controlled volumes of thin liquid. Aspiration was assessed using a validated Penetration–Aspiration Scale. Oral sensation was also measured by electrical stimulation at the faucial pillars.

Results

After stroke, laryngeal ascent was delayed (mean (standard deviation (SD)) 0.31 (0.06) s, p<0.001), resulting in prolongation of pharyngeal transit time (1.17 (0.07) s, p<0.001) without a concomitant increase in laryngeal closure duration (0.84 (0.04) s, p = 0.9). The delay in laryngeal elevation correlated with both the severity of aspiration (r = 0.5, p<0.001) and oral sensation (r = 0.5, p<0.001).

Conclusions

After stroke, duration of laryngeal delay and degree of sensory deficit are associated with the severity of aspiration. These findings indicate a role for sensorimotor interactions in control of swallowing and have implications for the assessment and management of dysphagia after stroke.Dysphagia has been reported in up to 70% of patients with stroke, with the major clinical complication being deglutitive aspiration.¹ Historically, the prevailing belief has been that for most patients, aspiration resolves spontaneously within days.² In fact, aspiration is now known to persist well beyond 6 months in up to 50% of patients with stroke,³ and the incidence of pneumonia remains unacceptably high.⁴ Despite this, objective measurements of relationships between bolus flow and laryngeal closure, factors that might predict patients at risk of aspiration, have never been systematically determined in a cohort of patients with pure stroke.Patients with hemispheric stroke are described as presenting with “difficulty initiating coordinated movement”,⁵ “delayed pharyngeal response”⁶ and “delayed or absent swallow reflex”.⁷ It has been speculated that these features are associated with a breakdown in the descending efferent outputs from the cortex, which initiate the brain stem‐mediated pharyngeal response and laryngeal protection.⁸ However, the neural control of swallowing integrates peripheral afferent inputs from the oropharynx with descending efferent outputs.⁹ Recent work by Aviv et al¹⁰ has suggested that patients with stroke and dysphagia also have impairments in pharyngeal sensation. Despite these observations, whether such sensory deficits specifically affect deglutitive laryngeal function remains unknown.The protective mechanism that guards against aspiration is laryngeal closure, which is achieved by a sequence of events, beginning with cessation of respiration, approximation of the arytenoids and adduction of the vocal cords. Complete closure is achieved by a combination of laryngeal ascent and epiglottic descent.^11,12 Laryngeal closure duration (LCD) modulates to accommodate bolus characteristics¹³; however, whether the timing of laryngeal ascent is fixed or responsive to bolus characteristics is not known.^14,15Studies on swallowing in humans have implicated the faucial pillar, an area innervated by the glossopharyngeal nerve, as a “trigger” for the onset of laryngeal ascent.^14,16,17 Studies on patients with aspirating stroke have suggested that delayed onset of laryngeal ascent can be shortened by stimulation at the faucial pillar.¹⁸ Stimulation at the faucial pillar has been considered beneficial because it stimulates mechanoreceptors at the head of the hypopharynx, which relay information to the brain stem and cortex to initiate laryngeal closure. The evidence to support this contention is, however, controversial, with some authors suggesting that higher cortical functions are more important.¹⁹ Furthermore, some studies have suggested that the important receptive sensory fields for triggering swallowing do not include the faucial pillar region.²⁰ Thus, although the faucial pillar is the anatomical gateway to the hypopharynx, it may have no role in the onset of laryngeal ascent. A systematic examination of this relationship in health and stroke is, however, lacking.The aims of this study were therefore to examine the temporal linkage of bolus transit and laryngeal closure in healthy adults and to compare our findings with those obtained from patients after hemispheric stroke. We hypothesised that in healthy participants, both the initiation and duration of laryngeal closure would be modulated by sensory input, and that this relationship would be impaired in patients with stroke. We also postulated that altered oral sensation would relate to the severity of aspiration in patients with stroke.     

Abnormal breathing patterns in stroke: relationship with location of acute stroke lesion and prior cerebrovascular disease

Objective

To determine whether central periodic breathing (CPB) is associated with acute involvement of any particular part of the brain, or the extent of total damage in patients with acute stroke.

Methods

CPB was identified using portable monitoring equipment in patients with stroke on admission. A neuroradiologist classified acute stroke lesions and prior cerebrovascular disease on brain images.

Results

Among 134 patients with acute stroke, those with CPB were more likely to have a large acute stroke lesion in a cerebral hemisphere (p = 0.01) and more mass effect (p = 0.03). There was no association between CPB and severe prior cerebrovascular disease on imaging (p = 0.76).

Conclusion

CPB is related to the acute (not old) lesions, particularly large acute cerebral hemispheric lesions with mass effect. A relationship between lesions in any discrete brain location (unilateral or bilateral) and CPB could not be shown.Central periodic breathing (CPB), including Cheynes–Stokes respiration, during wakefulness has been reported to occur in 53% of patients with acute stroke.¹ Limited information suggests a possible relationship between the site and size of the stroke lesion and the presence of CPB. Previous studies suggested that the presence of bilateral hemispheric or brain stem stroke lesions might be crucial for the presence of CPB after stroke.^2,3 However, these were small studies (n = 28, n = 49) predating computed tomography, which found that hospitalised patients with intermittent CPB during wakefulness had bilateral hemispheric or brain stem lesions on autopsy. More recent studies have failed to find any association between the location of brain lesion on imaging and CPB while patients were awake¹ (n = 32) or asleep^4,5 (n = 93, n = 39).We reported previously that CPB was associated with a poor functional outcome at 3 months after stroke, even after accounting for clinical stroke severity, but the mechanism linking CPB with poor outcome was unclear.⁶ Therefore, we aimed to determine, using data from the same cohort, whether CPB was related to features of the acute stroke lesion on brain imaging or to prior cerebrovascular disease (ie, previous infarcts, haemorrhages and/or periventricular white matter lesions (PVWML)/leucoaraiosis).     

Diffusion anisotropy of the cervical cord is strictly associated with disability in amyotrophic lateral sclerosis

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water‐filled spaces in biological tissues.

Methods

Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age‐matched and sex‐matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross‐sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.

Results

Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross‐sectional area (p<0.001). Mean diffusivity histogram‐derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p<0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).

Conclusions

Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neurone disease, characterised by a progressive and simultaneous degeneration of upper and lower motor neurones.^1,2 In its typical form, the disease begins either in one limb or with a combination of bulbar and corticobulbar symptoms, and continues with progressive weakness of the bulbar, limb, thoracic and abdominal musculature.^1,2 By using a variety of conventional magnetic resonance imaging (MRI) sequences, several studies^{3,4,5,6,7,8,9,10,11,12,13,14,15} have shown changes in signal intensity along the brain portion of the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles, varying between 25% and 80%. Reduced magnetisation transfer ratios in the internal capsule^8,11 and N‐acetylaspartate levels in the motor cortex^13,16,17 of patients with ALS have also been observed. However, none of these studies has reported a correlation between such magnetic resonance abnormalities and the degree of disability.^{8,11,13,16,17}Diffusion‐tensor magnetic resonance imaging (DT MRI) enables the random diffusional motion of water molecules to be measured and thus provides quantitative indices of the structural and orientational features of the central nervous system (CNS).¹⁸ DT MRI has been used to assess quantitatively the tissue damage of the brain portion of the corticospinal tracts in ALS,^{12,19,20,21,22,23} and all studies have shown increased mean diffusivity (indicating a loss of structural barriers limiting the motion of water molecules) and decreased fractional anisotropy (indicating a loss of tissue organisation). However, brain DT MRI studies also resulted in heterogeneous clinicopathological correlations, as some authors found a moderate correlation between brain DT MRI metrics and the severity of disability,^12,21,23 but others did not.¹⁹ In the past few years, DT MRI has also been used successfully to grade the extent of cervical cord damage associated with demyelinating conditions.^24,25,26Considering that the cervical cord in ALS is one of the most affected portions of the CNS (owing to the combined presence of neuronal loss in the anterior horns of the grey matter and degeneration of the corticospinal tracts), we obtained mean diffusivity and fractional anisotropy histograms of the cervical cord from patients with ALS with the following aims: (1) to quantify the extent of tissue damage in this critical CNS region; and (2) to investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts.     

Stroke in patients with human immunodeficiency virus infection

Objective

To report the nature of stroke in patients infected with human immunodeficiency virus (HIV) in a region with high HIV seroprevalence and describe HIV associated vasculopathy.

Methods

Patients with first ever stroke, infected with HIV and prospectively included in the stroke register of the Groote Schuur Hospital/University of Cape Town stroke unit were identified and reviewed.

Results

Between 2000 and 2006, 67 of the 1087 (6,1%) stroke patients were HIV infected. Of these, 91% (n = 61) were younger than 46 years. Cerebral infarction occurred in 96% (n = 64) of the HIV positive patients and intracerebral haemorrhage in 4% (n = 3). HIV infected young stroke patients did not demonstrate hypertension, diabetes, hyperlipidaemia or smoking as significant risk factors for ischaemic stroke. Infection as a risk factor for stroke was significantly more common in HIV positive patients (p = 0.018, OR 6.4, CI 3.1 to 13.2). In 52 (81%) patients with ischaemic stroke, an aetiology was determined. Primary aetiologies comprised infectious meningitides/vasculitides in 18 (28%) patients, coagulopathy in 12 (19%) patients and cardioembolism in nine (14%) patients. Multiple aetiologies were present in seven (11%) patients with ischaemic stroke. HIV associated vasculopathy was identified in 13 (20%) patients. The HIV associated vasculopathy manifested either extracranially (seven patients) as total or significant carotid occlusion or intracranially (six patients) as medium vessel occlusion, with or without fusiform aneurysmal dilation, stenosis and vessel calibre variation.

Conclusion

Investigation of HIV infected patients presenting with stroke will determine an aetiology in the majority of patients. In our cohort, 20% of patients demonstrated evidence of an HIV associated vasculopathy.Infection with the human immunodeficiency virus (HIV) contributes to an increased risk of stroke.^1,2,3,4 In South Africa, 5.4 million people out of a total population of nearly 48 million South Africans are infected with HIV, giving a total prevalence of approximately 11% in 2006.⁵ Isolated reports have identified vasculopathy as a cause of stroke in HIV infected patients.^{6,7,8,9,10,11,12}We report the largest clinical cohort of HIV associated strokes prospectively admitted and investigated by the only tertiary stoke unit in Sub‐Saharan Africa. Groote Schuur Hospital is a university teaching hospital serving an open population of approximately 2.9 million persons. The selection bias of our Stroke Unit favours patients from low socioeconomic income groups (more affluent patients with health insurance tend to seek medical care in the private sector), young stroke patients under the age of 46 years (24% of the sample because of referral from other hospitals) and more severe strokes.Our objective was to describe the nature of stroke in HIV infected patients in clinical practice in a region with a high seroprevalence in the general population and further define HIV associated vasculopathy.     

Autonomic dysfunction in dementia

Background

There are no studies of autonomic function comparing Alzheimer''s disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson''s disease dementia (PDD).

Aims

To assess cardiovascular autonomic function in 39 patients with AD, 30 with VAD, 30 with DLB, 40 with PDD and 38 elderly controls by Ewing''s battery of autonomic function tests and power spectral analysis of heart rate variability. To determine the prevalence of orthostatic hypotension and autonomic neuropathies by Ewing''s classification.

Results

There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. PDD showed consistent impairment of both parasympathetic and sympathetic function tests in comparison with controls (all p<0.001) and AD (all p<0.03). DLB showed impairment of parasympathetic function (all p<0.05) and one of the sympathetic tests in comparison with controls (orthostasis; p = 0.02). PDD had significantly more impairment than DLB in some autonomic parameters (Valsalva ratio: p = 0.024; response to isometric exercise: p = 0.002). Patients with VAD showed impairment in two parasympathetic tests (orthostasis: p = 0.02; Valsalva ratio: p = 0.08) and one sympathetic test (orthostasis: p = 0.04). These results were in contrast with AD patients who only showed impairment in one sympathetic response (orthostasis: p = 0.004). The prevalence of orthostatic hypotension and autonomic neuropathies was higher in all dementias than in controls (all p<0.05).

Conclusion

Autonomic dysfunction occurs in all common dementias but is especially prominent in PDD with important treatment implications.Patients with autonomic failure experience disabling postural dizziness, syncope, falls, constipation and incontinence.¹ There is a need to identify symptomatic dysautonomia in dementia in order to ensure appropriate management and reduce risk of falls, which is particularly important as falls are a major cause of increased morbidity, institutionalisation and mortality in these individuals.²There are no previous prospective studies of autonomic function comparing the most common dementia subtypes in the elderly; Alzheimer''s disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson''s disease dementia (PDD). A generalised deficit in cholinergic function would be expected to lead to autonomic dysfunction, and the common dementias have all been associated with underactivity of the cholinergic nervous systems.³ The Braak staging of Parkinson''s disease⁴ emphasises early involvement of the brainstem, including the dorsal vagal nucleus, and autonomic failure is a feature of Parkinson''s disease.⁵The only previous studies using standard bedside clinical autonomic tests have mainly included patients with AD only,^6,7,8,9,10 although two have included patients with multi‐infarct dementia or Binswanger''s encephalopathy,^11,12 and there is one retrospective report of clinical autonomic dysfunction in DLB patients.¹³ Studies using bedside tests require a level of cooperation by the subject which may not be possible in dementia. These data can be enhanced by measurements of heart rate variability,¹⁴ which requires less cooperation from the subject than other autonomic function tests and is suitable for use in patients with dementia.¹⁵We examined autonomic function using a combination of standardised bedside clinical testing and heart rate variability techniques, in an unselected series of patients with a range of dementia subtypes, diagnosed according to well validated diagnostic criteria, in comparison with appropriately matched elderly controls. Given the evidence of the retrospective study of DLB patients and data regarding autonomic dysfunction in Parkinson''s disease (PD),⁵ we hypothesised that autonomic dysfunction would be more severely impaired in DLB and PDD than in AD, and that the most severe impairment would be present in PDD because of the length of illness and severity of neurodegenerative disease.     

Changes in optic nerve head blood flow in children with cerebral malaria and acute papilloedema

Objective

To investigate capillary blood flow in the optic nerve head (ONH) of children with cerebral malaria.

Methods

Malawian children with cerebral malaria admitted to a paediatric research ward were examined by direct and indirect ophthalmoscopy. ONH blood flow was measured using laser Doppler flowmetry (LDF) in suitable patients. Mean blood volume and velocity were obtained from 30 to 60 s recordings from the temporal ONH and used to calculate blood flow. These were compared with admission variables, funduscopic findings and disease outcomes.

Results

45 children with cerebral malaria had LDF recordings; 6 subsequently died and 5 survivors had neurological sequelae. 12 (27%) had papilloedema. The mean microvascular blood volume was higher in patients with papilloedema (3.28 v 2.54 arbitrary units, p = 0.002). The blood velocity correlated directly with haematocrit (r = 0.46, p = 0.001) and inversely with blood glucose (r = −0.49, p = 0.001).

Conclusion

The increase in ONH microvascular blood volume in papilloedema measured by LDF is consistent with current theories of pathogenesis of papilloedema. LDF has potential as a tool to distinguish papilloedema from pseudopapilloedematous disc swellings. The relationship between blood velocity and haematocrit may relate to levels of sequestration in cerebral malaria.Cerebral malaria, caused by Plasmodium falciparum, primarily affects children in sub‐Saharan Africa with mortality ranging from 15% to 50%. The characteristic histological feature of malaria caused by P falciparum is sequestration of parasitised erythrocytes within the microvasculature by cytoadherence. This occurs in the brain^1,2,3 and other organs, including the retina.⁴ Sequestration in small vessels is implicated in the pathogenesis of coma in cerebral malaria, although the mechanism remains unclear.⁵Papilloedema occurs in 10–15% of patients with cerebral malaria, increasing the risk of death by 4.5‐fold.^6,7 Other ocular fundus features associated with cerebral malaria are retinal whitening, orange or white vessels, and retinal haemorrhage.^6,7,8,9 As in other neurological conditions, papilloedema is associated with raised intracranial pressure.⁵ The pathogenesis of papilloedema is associated with increased pressure within the optic nerve sheath, a compartment in contact with the subarachnoid space. This leads to interruption of axoplasmic flow in the optic nerve fibres, resulting in swelling of their prelaminar portion.^10,11 The exact mechanism of this restriction and the importance of vascular changes remain unclear.¹²The optic nerve head (ONH) is an accessible element of the central nervous system (CNS), and measuring blood flow in the ONH could illuminate the pathogenic mechanisms in cerebral malaria. Laser Doppler flowmetry (LDF) is a non‐invasive method of measuring blood flow in the ONH using the Doppler shift in laser light scattered by moving erythrocytes. By directing the laser away from visible blood vessels the microcirculation can be sampled. The mean relative blood velocity and volume are computed from the spectrum of Doppler frequency shifts. The volume is derived from the width of the Doppler shift spectrum, and the velocity from the magnitude of Doppler shifts. LDF has proved useful in physiological studies of ONH blood flow^13,14,15,16 and of glaucoma.¹⁷ A feasibility study of LDF in cerebral malaria produced promising results.¹⁸We report a study of ONH microcirculation in children with cerebral malaria in relation to clinical parameters, particularly papilloedema.     

Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors

Background and objective

Non‐infectious causes of fever are often considered in critical neurological patients but their true significance has not been formally studied. The aim of this study was to evaluate the incidence, causes and predictors of fever in patients with acute neurological/neurosurgical disease and no documented infection.

Methods

Prospective data collection of consecutive patients admitted to the neurological intensive care unit (NICU) of an academic medical centre for more than 48 h was carried out. Fever was defined as body temperature ⩾101°F (38.3°C) documented on at least one measurement for 2 consecutive days. Patients were enrolled only if a diagnostic workup, including cultures of ⩾2 body samples, was performed before antibiotic use. Febrile patients with no proven evidence of infection were considered to have non‐infectious fever.

Results

93 patients were included in the final analysis. Fever was non‐infectious in 31 patients (33%). There were no differences between the infectious and non‐infectious fever groups in terms of age, use and duration of invasive catheters, daily duration of fever and number of days with fever. Documented infections tended to be more common among febrile patients with traumatic brain injury (52% vs 36%; p = 0.06). Non‐infectious fever was more frequent among patients with subarachnoid haemorrhage (48% vs 18%; p = 0.01) in whom it was associated with vasospasm (p = 0.03) and symptomatic vasospasm (p = 0.05). Non‐infectious fever started earlier (mean 2.6 vs 4 days; p = 0.007) and onset of fever within the first 72 h of admission predicted negative evaluation for infection (p = 0.01). Subarachnoid haemorrhage and fever onset within the first 72 h were independent predictors of non‐infectious fever on multivariable analysis.

Conclusions

Fever in the absence of documented infections occurs commonly in the NICU, especially among patients with subarachnoid haemorrhage and vasospasm. Early onset of fever predicts a non‐infectious cause.Between one‐quarter¹ and more than one‐half^2,3,4 of patients admitted to the neurological intensive care unit (NICU) develop fever. The cause of fever in these patients often remains unexplained. As hyperthermia is strongly detrimental for the recovery of the acutely injured brain^5,6,7,8,9 and contributes to an increase in the length of stay in the NICU,^4,10 timely and accurate diagnosis of the cause of fever in the NICU is crucial.Infections are the most common causes of fever in the NICU population but they are only documented in half of all febrile patients.¹ Central fever related to loss of the physiological regulation of body temperature by the hypothalamus is often proposed as a possible cause for persistent fever in acute neurological patients with no evidence of infection. There are no current means to confirm the diagnosis of central fever. Thus we can only assess its frequency by studying patients in whom fever remains unexplained after thorough investigations for infectious and other non‐infectious causes.The objective of this study was to determine the incidence, causes and predictors of non‐infectious fever in patients with acute neurological disease.     

Assessing "occult" cervical cord damage in patients with neuropsychiatric systemic lupus erythematosus using diffusion tensor MRI

Background

Whereas focal and diffuse brain damage on conventional MRI is seen in patients with neuropsychiatric systemic lupus erythematosus (NSLE), the spinal cord seems to be rarely involved. Diffusion tensor (DT) MRI provides information on the patterns of tissue disruption of the central nervous system, which may go undetected by conventional MRI.

Objective

To quantify the extent of otherwise “occult” injury of the cervical cord in NSLE, and to improve our understanding of its nature.

Subjects and methods

Conventional and DT MRI scans of the cervical cord and brain were acquired from 11 patients with NSLE and 10 healthy controls. Histograms of mean diffusivity (MD) and fractional anisotropy (FA) of the cervical cord and brain were analysed. Measures of cervical cord and brain atrophy and focal lesion loads were computed.

Results

Only one patient had a single focal lesion of the cord whereas all had multiple brain lesions on conventional MRI scans. Cord and brain volumes did not differ between patients and controls. Mean peak height of the cervical cord MD histogram (p = 0.0001) and average brain FA (p = 0.001) were significantly lower in patients than in controls. Average cord MD was correlated with average brain MD (r = 0.69, p = 0.01) and FA (r = −0.81, p = 0.002).

Conclusion

DT MRI shows mild and otherwise “occult” cord damage in NSLE, which might be secondary to Wallerian degeneration of long tract fibres passing trough damaged areas of the brain.Systemic lupus erythematosus (SLE) frequently affects the central nervous system (CNS), leading to a condition which is termed neuropsychiatric SLE (NSLE).¹ Diffuse immune mediated tissue damage, focal ischaemic lesions and vasculitis are all potential pathological substrates underlying CNS dysfunction in NSLE. However, in contrast with other “diffuse” CNS disorders, cord damage seems to be a relatively rare feature of NSLE,² outside the context of acute myelitis.³Diffusion tensor (DT) MRI provides quantitative indices of the structural and orientational features of the CNS tissues.⁴ The increased sensitivity of DT MRI over conventional MRI in detecting tissue changes associated with demyelinating⁴ and ischaemic vascular disease⁵ has prompted the use of DT MRI to define the actual extent of brain damage associated with NSLE.^6,7,8 However, to date, no DT MRI study has investigated the features of NSLE pathology in the spinal cord. Using a DT MRI sequence tailored to cervical cord imaging,⁹ the present study was performed to assess the overall extent of otherwise “occult” damage of the cervical cord in patients with NSLE. We also assessed the correlation between the extent of such cord damage with that present in the brain in an attempt to improve our understanding of its nature.     

Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study

Background

Evoked potentials are used in the functional assessment of sensory and motor pathways. Their usefulness in monitoring the evolution of multiple sclerosis has not been fully clarified.

Objective

The aim of this longitudinal study was to examine the usefulness of multimodal evoked potential in predicting paraclinical outcomes of disease severity and as a prognostic marker in multiple sclerosis.

Methods

Eighty four patients with clinically definite multiple sclerosis underwent Expanded Disability Status Scale (EDSS) and functional system scoring at study entry and after a mean (standard deviation) follow‐up of 30.5 (11.7) months. Sensory and motor evoked potentials were obtained in all patients at study entry and at follow‐up in 64 of them, and quantified according to a conventional score.

Results

Cross‐sectionally, the severity of each evoked potential score significantly correlated with the corresponding functional system (0.32ConclusionsThese results suggest that evoked potential is a good marker of the severity of nervous damage in multiple sclerosis and may have a predictive value regarding the evolution of disability.Evoked potentials have been used for more than 20 years in multiple sclerosis to objectify the involvement of sensory and motor pathways in patients with vague and indefinite disturbances, or to disclose clinically silent lesions.¹ Although evoked potentials allow functional assessment of nervous conduction along clinically eloquent pathways, the pathophysiology of their abnormalities in multiple sclerosis is quite complex and not completely understood. The pathological substrates of functional deficits in multiple sclerosis are mainly represented by demyelination and axonal loss.^2,3 Demyelination may determine slowing of conduction, failure to transmit impulses at high frequency, partial or complete conduction block and secondary axonal degeneration.⁴ The combination of all these phenomena may account for the pattern of evoked potential abnormalities found in individual patients. The value of evoked potentials in the diagnosis of multiple sclerosis has been greatly reduced after the advent of magnetic resonance imaging (MRI), because of the higher sensitivity of MRI to subclinical lesions.¹ As a matter of fact, although the McDonald criteria for multiple sclerosis diagnosis,⁵ largely based on MRI findings, have been criticised,⁶ only visual evoked potentials are viewed as contributing to the diagnosis of multiple sclerosis.⁵Although there is a general agreement that evoked potentials correlate with function in somatosensory,^7,8 visual⁹ or motor pathways¹⁰ and the combination of evoked potential abnormalities correlates with disability,^11,12 the usefulness of multimodal evoked potentials in monitoring the evolution of multiple sclerosis has not been yet clarified. Conflicting results have been reported on the correlation between clinical and evoked potential changes, which were absent or mild in some studies^{13,14,15,16,17} carried out on small samples and with short follow‐up. A better relationship has been found in other studies,^{11,18,19,20,21} mainly because of a higher number of patients studied and longer follow‐up duration. Moreover, the use of conventional scores to quantify the severity of neurophysiological abnormalities allows us to combine the results of multimodal evoked potential in a global score, reflecting the global impairment of function.¹² The responsiveness of these scales during the various phases of the disease has yet to be defined. The aim of this study was to evaluate whether neurophysiological abnormalities may parallel the clinical disease evolution in a cohort of patients with established multiple sclerosis, by means of multimodal evoked potentials quantified using a conventional score.     

Cognitive outcome in adults after bacterial meningitis

Objective

To evaluate cognitive outcome in adult survivors of bacterial meningitis.

Methods

Data from three prospective multicentre studies were pooled and reanalysed, involving 155 adults surviving bacterial meningitis (79 after pneumococcal and 76 after meningococcal meningitis) and 72 healthy controls.

Results

Cognitive impairment was found in 32% of patients and this proportion was similar for survivors of pneumococcal and meningococcal meningitis. Survivors of pneumococcal meningitis performed worse on memory tasks (p<0.001) and tended to be cognitively slower than survivors of meningococcal meningitis (p = 0.08). We found a diffuse pattern of cognitive impairment in which cognitive speed played the most important role. Cognitive performance was not related to time since meningitis; however, there was a positive association between time since meningitis and self‐reported physical impairment (p<0.01). The frequency of cognitive impairment and the numbers of abnormal test results for patients with and without adjunctive dexamethasone were similar.

Conclusions

Adult survivors of bacterial meningitis are at risk of cognitive impairment, which consists mainly of cognitive slowness. The loss of cognitive speed is stable over time after bacterial meningitis; however, there is a significant improvement in subjective physical impairment in the years after bacterial meningitis. The use of dexamethasone was not associated with cognitive impairment.The estimated annual incidence of bacterial meningitis is 4–6 per 100 000 adults and Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) are the causative bacteria in 80% of cases.^1,2 Fatality rates in patients with pneumococcal meningitis (26%) and meningococcal meningitis (7%) are significant.^1,2,3 Even in patients with apparent good recovery, cognitive impairment occurs frequently,⁴ especially after pneumococcal meningitis.^4,5,6 The cognitive functions affected by bacterial meningitis differ between studies, most likely because of the limited numbers of patients examined, and the lack of uniformity across studies in assessment methods and in the definition of cognitive impairment.^{4,5,6,7,8,9,10} We therefore pooled data on cognitive outcome after bacterial meningitis from three of our previous studies to more clearly determine which cognitive functions are affected by bacterial meningitis and to identify which patients are at risk of developing cognitive impairment.     

Perception of longitudinal body axis in patients with stroke: a pilot study

Background and aims

To investigate the hypothesis that patients with a hemisphere stroke may perceive their longitudinal body axis (LBA) rotated in the frontal plane. This error in an egocentric frame of reference could be detrimental to posture, as tilted LBA would imply an unequal distribution of body mass about the true vertical.

Method

26 healthy subjects matched in age with 18 patients living with stroke participated in the study. The 18 patients were tested on average 80 days after a first left (n = 8) or right (n = 10) hemisphere stroke. Participants perceived their LBA by adjustments of the orientation of a luminous rod pivoting around a dorsonavel axis to the subjective direction of LBA. Participants were studied in the supine position to dissociate somaesthetic cues from graviceptive cues.

Results

Patients with stroke perceived their LBA rotated to the contralesional side in comparison with controls (p = 0.004). For all controls and 10 patients with stroke, the perceived LBA was very close to true LBA (mean (SD) 0.24° (1.31°)). For eight patients with stroke (six right stroke, two left stroke), the perceived LBA was rotated from true body orientation in the direction opposite to the lesioned side (range 3–9.5°, mean 5.2°). These eight patients provided similar estimates by tactile manipulation of the rod (without vision). The rotation of perceived LBA was more pronounced for right‐hemisphere strokes. The magnitudes of perceptual rotations correlated with sensory loss, signs of spatial neglect and the degree of postural and gait disability.

Conclusion

This is the first study showing that certain patients with a hemisphere stroke perceive their LBA rotated to the contralesional side. The consequences for perceptuomotor coordination have implications for their postural disorders.Patients with cortical stroke may experience forms of spatial disorientation that can affect perception of the spatial organisation of the axes and planes of the body. The resulting distortions of the “egocentric frame of reference” may contribute to the impairment of sensorimotor coordination. A particularly important egocentric reference for the organisation of movement and balance is the longitudinal body axis (LBA)¹ and colinear sagittal plane.² Studies on patients with cortical lesions, particularly affecting the parietal lobe, have shown an ipsilesional shift in their perception of the sagittal plane.^3,4,5,6,7,8 When attempting to point “straight ahead”, their indication deviates to the side of the lesion. This ipsilesional deviation has been interpreted as a result of a rotation of the egocentric frame of reference^9,10 or as a result of a lateral shift of the egocentric frame of reference.^11,12 The phenomena of lateral postural inclination,¹³ lateral pushing¹⁴ and visual vertical tilt^15,16,17,18 in the frontal plane exhibited by some patients with stroke affecting the cerebral hemispheres suggest that cortical lesions may also cause patients to perceive that the LBA tilted from its true orientation. This is the hypothesis of this study. If it were true, this phenomenon would have clear consequences for balance, as tilted LBA and sagittal plane imply an unequal distribution of body mass about the true vertical.Perception of orientation of the sagittal plane is constructed from multisensory components, including visual, auditory, somatosensory and vestibular inputs, and also from information relating eye, head and trunk positions.¹⁹ However, the somatosensory basis of the sagittal plane alone has been shown to be sufficient and robust, as the supine observer is able to indicate his or her LBA and sagittal plane accurately in the absence of vision, even when otolithic and other graviceptive cues are minimised.^{20,21,22,23,24}The main objective of this study to assess the LBA in isolation from gravitoinertial and otolithic cues has not yet been investigated in patients with stroke. Our second aim was to relate any rotation of LBA perception to clinical deficits and the site of the lesion, with the idea that tilted perceived LBA, if present, could be associated with clinical deficits (such as somatosensory loss or spatial neglect) or lesion location (such as the parietal cortex) involved in disorders of body‐sheme construction.²⁵ Our third aim was to analyse the relationship between potential rotation of LBA perception and postural disability.     

Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease

Aim

To assess the long‐term cognitive and behavioural outcome after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients affected by Parkinson''s disease, with a 5‐year follow‐up after surgery.

Methods

11 patients with Parkinson''s disease treated by bilateral DBS of STN underwent cognitive and behavioural assessments before implantation, and 1 and 5 years after surgery. Postoperative cognitive assessments were carried out with stimulators turned on.

Results

A year after surgery, there was a marginally significant decline on a letter verbal fluency task (p = 0.045) and a significant improvement on Mini‐Mental State Examination (p = 0.009). 5 years after surgery, a significant decline was observed on a letter verbal fluency task (p = 0.007) and an abstract reasoning task (p = 0.009), namely Raven''s Progressive Matrices 1947. No significant postoperative change was observed on other cognitive variables. No patient developed dementia 5 years after surgery. A few days after the implantation, two patients developed transient manic symptoms with hypersexuality and one patient developed persistent apathy.

Conclusion

The decline of verbal fluency observed 5 years after implantation for DBS in STN did not have a clinically meaningful effect on daily living activities in our patients with Parkinson''s disease. As no patient developed global cognitive deterioration in our sample, these findings suggest that DBS of STN is associated with a low cognitive and behavioural morbidity over a 5‐year follow‐up, when selection criteria for neurosurgery are strict.Chronic bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective neurosurgical procedure for treatment of motor symptoms in patients with advanced Parkinson''s disease, who cannot be satisfactorily treated with pharmacological treatments. The safety of this procedure has been investigated by several studies, which have assessed the effects of STN DBS on cognition and behaviour.^1,2,3 Some investigations have also attempted to distinguish between the cognitive effects of surgical intervention and those of DBS of STN in itself.^4,5,6,7All neuropsychological investigations in patients treated by STN DBS showed a postoperative decline of verbal fluency, whereas less consistent effects have been reported on other cognitive tasks in different studies. A postoperative decline of episodic verbal memory, which was detectable 3 months after surgery, has been reported in some investigations.^6,8Different effects of STN DBS on various frontal cognitive functions have been described. STN stimulation may impair response‐inhibition performance on the interference task of the Stroop test, as compared with the off‐stimulation condition.^5,7,9 A positron emission tomography study showed that such impaired performance on the Stroop test in the on‐stimulation condition is associated with decreased activation in both the right anterior cingulate cortex and the right ventral striatum.⁹ Conversely, short‐term STN stimulation may improve performance on cognitive flexibility tasks, including random number generation⁷ and the Modified Wisconsin Card Sorting Test (MWCST).⁵Various behavioural effects have been described in patients with Parkinson''s disease treated by STN DBS. Some studies reported cases of depression¹⁰ or increased apathy,¹¹ whereas cases of mania were described in other studies^12,13,14 and an improvement of depression¹ or apathy¹⁵ was also found.The long‐term cognitive and behavioural effects of bilateral STN DBS were investigated in 70 patients with Parkinson''s disease followed up for 3 years.¹¹ In this study, a decline of verbal fluency, an improvement of depression and an increased apathy were observed 3 years after surgery. Some patients showed behavioural changes (aggressive behaviour, hypomania, depression and psychosis), which were mostly transient. Recently, the long‐term outcome of bilateral DBS of STN was investigated in a multicentre study conducted in 49 patients with Parkinson''s disease followed up for 3 or 4 years.¹⁶ This study showed that stimulation of the STN induced a significant improvement in Parkinsonian motor symptoms and activities of daily living 3–4 years after surgery. Among the adverse events, the authors reported memory decline or psychiatric disturbances (including hallucinations, delirium, depression, apathy and anxiety), which occurred in about 30% of the patients.In two recent investigations, the long‐term outcome of bilateral DBS of STN was investigated in patients with a 5‐year follow‐up.^17,18 In one study conducted on 49 patients with Parkinson''s disease,¹⁷ cognitive performance was assessed by means of the Mattis Dementia Rating Scale (MDRS)¹⁹ and a frontal‐lobe score.⁴ Five years after surgery, there was a marked improvement of both motor function, while off drugs, and activities of daily living, a statistical trend towards a decline on the MDRS (reflecting the appearance of progressive dementia in three patients between the third and the fifth postoperative years) and a significant decline in the average frontal‐lobe score. Another study carried out on 37 patients with Parkinson''s disease¹⁸ also assessed cognitive performance by means of MDRS¹⁹ and a frontal score.²⁰ Five years after the implantation, there was an improvement in Parkinsonian motor symptoms and activities of daily living and a reduction of levodopa‐related motor complications and levodopa daily doses. However, a significant decline in cognitive performance was detected on the MDRS and the frontal score.To our knowledge, no extensive neuropsychological data have been reported so far in patients with a follow‐up >3 years. The aim of the present study was to assess the long‐term cognitive and behavioural outcome after bilateral DBS of the STN in a series of patients followed up for 5 years after surgery.     

Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study

Background

Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD).

Objective

We conducted a phase I–II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD.

Methods

Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1–3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT‐PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson''s Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson''s Disease Rating Scale III score in the off‐medication state. Seven patients had ¹⁸F‐dopa positron emission tomography scans before and 1 year after transplantation.

Results

Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6–12 months after transplantation (5–74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15–48%). None of the patients developed off‐period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non‐significant 5% increase in mean putaminal ¹⁸F‐dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal ¹⁸F‐dopa uptake (r = −0.829; p = 0.042).

Conclusions

CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.Parkinson disease (PD) is a progressive neurodegenerative disorder of unknown aetiology. Its main pathological hallmark is the degeneration of midbrain dopaminergic neurons projecting to the striatum, although other neuronal systems are also affected.¹ Current pharmacological and surgical therapies are symptomatically effective but their long term utility is limited because of disease progression.^2,3 Therefore, there is a need for neuroprotective and/or neurorestorative therapies capable of arresting or reversing the neurodegenerative process.Over the past two decades, cell replacement therapies have been tested in PD patients with the objective of restoring the striatal dopaminergic deficit.⁴ Transplantation of fetal mesencephalic neurons, the most frequently used technique, can increase the striatal dopamine storage, but does not always produce the expected clinical benefit and may induce disabling off‐medication dyskinesias.^5,6 Thus it appears that the ectopic placement of dopamine secreting cells in the striatum is not the ideal approach to compensate for progressive nigrostriatal neuronal loss.⁷ Given this scenario, the clinical applicability of other transplantation procedures based on a similar rationale (eg, intrastriatal grafting of porcine mesencephalic neurons, retinal pigment epithelial cells or stem cell derived dopaminergic neurons) is, for the moment, uncertain.More recently, other strategies aiming to protect or restore the nigrostriatal pathway have emerged. Glial cell line derived neurotrophic factor (GDNF) has been shown to exert neuroprotective and neurorestorative actions in animal models of PD.^8,9,10 The clinical efficacy of GDNF has been assayed in clinical trials, but the method of delivery is a critical issue. Whereas intraventricular administration failed to induce clinical benefit,¹¹ intraputaminal infusion showed promising results,^12,13 although a placebo controlled trial using this route has been halted because of lack of efficacy and safety concerns about recombinant human GDNF administration.¹⁴ Other alternative methods being tested experimentally in parkinsonian animals include in vivo gene therapy using GDNF encoding viral vectors^15,16,17 and the intrastriatal grafting of recombinant GDNF producing cell lines.^18,19,20,21 Carotid body (CB) glomus cells are neural crest derived dopaminergic cells that express high levels of GDNF. Glomus cell GDNF production is resistant to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration, and maintained in aged rodents or after intrastriatal grafting.^22,23 The survival rate of these cells after transplantation (>70%) is particularly high as hypoxia stimulates their growth and function. Moreover, CB grafts performed in young rats remain active for the entire animal lifespan.^22,23 Transplantation of CB cell aggregates has been shown to induce a neurotrophic mediated recovery in animal models of PD^{22,23,24,25,26,27} and stroke.^28,29We conducted a phase I–II video blinded clinical study to assess the long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with advanced PD. In a pilot report of our first six patients, we showed this procedure to be feasible.³⁰ Here we report the clinical outcomes and prognostic factors in the whole study (n = 13), as well as ¹⁸F‐dopa positron emission tomography (PET) outcomes in a subgroup of patients (n = 7).