Unexplained syncope—is screening for carotid sinus hypersensitivity indicated in all patients aged >40?years?

Objective

To determine the frequency, age distribution and clinical presentation of carotid sinus hypersensitivity (CSH) among 373 patients (age range 15–92 years) referred to two autonomic referral centres during a 10‐year period.

Methods

Carotid sinus massage (CSM) was performed both supine and during 60° head‐up tilt. Beat‐to‐beat blood pressure, heart rate and a three‐lead electrocardiography were recorded continuously. CSH was classified as cardioinhibitory (asystole ⩾3 s), vasodepressor (systolic blood pressure fall ⩾50 mm Hg) or mixed. All patients additionally underwent autonomic screening tests for orthostatic hypotension and autonomic failure.

Results

CSH was observed in 13.7% of all patients. The diagnostic yield of CSM was nil in patients aged <50 years (n = 65), 2.4% in those aged 50–59 years (n = 82), 9.1% in those aged 60–69 years (n = 77), 20.7% in those aged 70–79 years (n = 92) and reached 40.4% in those >80 years (n = 57). Syncope was the leading clinical symptom in 62.8%. In 27.4% of patients falls without definite loss of consciousness was the main clinical symptom. Mild and mainly systolic orthostatic hypotension was recorded in 17.6%; evidence of sympathetic or parasympathetic dysfunction was found in none.

Conclusions

CSH was confirmed in patients >50 years, the incidence steeply increasing with age. The current European Society of Cardiology guidelines that recommend testing for CSH in all patients >40 years with syncope of unknown aetiology may need reconsideration. Orthostatic hypotension was noted in some patients with CSH, but evidence of sympathetic or parasympathetic failure was not found in any of them.Unexplained syncope is a common medical problem. In our series of 641 patients with recurrent syncope, a definite diagnosis could not be established in 28%, despite an extensive diagnostic investigation.¹ This is consistent with the literature, where figures range from 13% to 42% depending on populations studied and diagnostic algorithms used.²Carotid sinus hypersensitivity (CSH) refers to the occurrence of asystole ⩾3 s (cardioinhibitory CSH), a fall in systolic blood pressure of ⩾50 mm Hg (vasodepressor CSH) or both (mixed CSH), after carotid sinus massage (CSM). In patients with syncope of unknown origin and CSH on CSM, carotid sinus syndrome (CSS) is usually diagnosed, although the phenomenon of CSH has also been observed in up to 35% of asymptomatic older people in a recent study and there is no consistent definition of CSS in the literature.^3,4,5,6 To avoid confusion we will therefore refer to CSH instead of CSS throughout this paper, being well aware that the frequency of CSH may exceed that of CSS.CSH is a recognised cause of recurrent syncope and is increasingly recognised as accounting for unexplained falls in elderly people.^7,8 The diagnostic yield of CSM in patients >65 years presenting with syncope or unexplained falls was up to 45%, in studies by Kenny et al.^8,9,10 Subsequent studies that also included younger patients >50 or 60 years, however, have found lower prevalence rates of CSH, in the range of 17–21%.^11,12,13 Indeed, CSH was found to be rare in patients <50 years in a recent study by Puggioni et al,¹⁴ namely 4% in those aged <41 years and 11% in those aged 41–50 years.Despite these figures, the current European Society of Cardiology (ESC) guidelines still recommend testing for CSH in all patients >40 years who have unexplained syncope after basic evaluation consisting of history, physical examination including orthostatic blood pressure measurements and standard electrocardiography (ECG).^15,16 More data on the diagnostic yield of CSM in populations including patients <50 years of age are therefore needed to estimate the yield and thus cost effectiveness of these guidelines.In this study, we evaluated the results of CSM performed during a 10‐year period in two autonomic referral centres with an extensive regional and national patient‐referral base. We determined the frequency and clinical characteristics, especially the age distribution, of patients with CSH. Additionally, we analysed the detailed cardiovascular autonomic function tests of all patients with CSH, with an emphasis on the presence of orthostatic hypotension and evidence for autonomic failure, as it has been suggested that these coexist with CSH^7,8,17 and may cause or contribute to syncope.     

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.     

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).     

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.     

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.     

Clinical features of double infection with tick-borne encephalitis and Lyme borreliosis transmitted by tick bite

Background

In Latvia and other endemic regions, a single tick bite has the potential to transmit both tick‐borne encephalitis (TBE) and Lyme borreliosis.

Objective

To analyse both the clinical features and differential diagnosis of combined tick‐borne infection with TBE and Lyme borreliosis, in 51 patients with serological evidence, of whom 69% had tick bites.

Results

Biphasic fever suggestive of TBE occurred in 55% of the patients. Meningitis occurred in 92%, with painful radicular symptoms in 39%. Muscle weakness occurred in 41%; in 29% the flaccid paralysis was compatible with TBE. Only two patients presented with the bulbar palsy typical of TBE. Typical Lyme borreliosis facial palsy occurred in three patients. Typical TBE oculomotor disturbances occurred in two. Other features typical of Lyme borreliosis detected in our patients were distal peripheral neuropathy (n = 4), arthralgia (n = 9), local erythema 1–12 days after tick bite (n = 7) and erythema chronicum migrans (n = 1). Echocardiogram abnormalities occurred in 15.

Conclusions

Patients with double infection with TBE and Lyme borreliosis fell into three main clinical groups: febrile illness, 3 (6%); meningitis, 15 (30%); central or peripheral neurological deficit (meningoencephalitis, meningomyelitis, meningoradiculitis and polyradiculoneuritis), 33 (65%). Systemic features pointing to Lyme borreliosis were found in 25 patients (49%); immunoglobulin (Ig)M antibodies to borreliosis were present in 18 of them. The clinical occurrence of both Lyme borreliosis and TBE vary after exposure to tick bite, and the neurological manifestations of each disorder vary widely, with considerable overlap. This observational study provides no evidence that co‐infection produces unusual manifestations due to unpredicted interaction between the two diseases. Patients with tick exposure presenting with acute neurological symptoms in areas endemic for both Lyme borreliosis and TBE should be investigated for both conditions. The threshold for simultaneous treatment of both conditions should be low, given the possibility of co‐occurrence and the difficulty in ascribing individual neurological manifestations to one condition or the other.The Baltic region is an endemic focus for both tick‐borne encephalitis (TBE) and Lyme borreliosis transmitted by ticks.^1,2,3,4 In Latvia, 7061 cases of TBE and 3566 cases of Lyme borreliosis were registered between 1994 and 2003, out of a population of 2.4 million. Both tick species present in Latvia, Ixodes ricinus and persulcatus, can transmit the encephalitis virus, the borreliosis spirochete and more rarely erlichiosis. A single tick bite has the potential to transmit both infections.⁵ Despite their different clinical courses, TBE and Lyme borreliosis have neurological features in common: lymphocytic meningitis, flaccid or spastic limb weakness and cranial nerve involvement. Thus, differentiating between these disorders is important, given different approaches to treatment.Of the two infections, only TBE runs a biphasic course with the initial prodomal period of influenza‐like symptoms usually developing 1–2 weeks after the tick bite. Hence, after an asymptomatic period lasting 2–10 days, about a third of infected patients enter a second phase with aseptic meningitis.² Subsequently, 2–10% in Western TBE subtype or 10–25% in Eastern TBE subtype develop encephalitis, myelitis or meningoencephalomyelitis typically manifesting as combinations of flaccid paresis of the limbs, usually arms and neck, bulbar dysfunction, disorientation, aphasia and spastic paresis.^1,2 A poliomyelitis‐like syndrome is described in central European TBE.⁶ Manifestations of TBE in the Baltic may be heterogeneous, given that infection with the Western, Far Eastern and Siberian subtypes all cause human infection in Latvia.⁷ Although severe manifestations usually subside after 3–6 weeks, the convalescence period of TBE may be very long, with nearly 40% having a postencephalitic syndrome at 4 years.⁸ The uptake of TBE vaccination is increasing in the Baltic region.Classical Lyme borreliosis differs considerably from TBE and produces local and generalised forms, systemic involvement, and development over several stages. Its acute and chronic courses pose problems of diagnosis and management.^1,9 Diagnosis of neuroborreliosis requires a definite or possible tick bite, erythema migrans or seropositivity, and typical peripheral or central nervous system involvement.¹⁰ In early neuroborreliosis (2–10 weeks after tick bite) the most common neurological abnormalities are meningitis, meningoradiculoneuritis and cranial neuritis, particularly facial palsy.^1,9,10,11 Progressive chronic encephalomyelitis, polyneuritis and cerebrovascular disorders are later manifestations of Lyme borreliosis, usually occurring months after the initial infection. Neurological features are noted in 10–12% of all patients with Lyme borreliosis in Europe¹ and in 10–15% of patients in Northern America.¹¹ Neurological manifestations in 330 European patients with Lyme borreliosis included radicular pain (70%), headache (18%), peripheral paresis (45%), central paresis (4%), sensory disturbances (44%) and facial palsy (39%).¹ Borrelia infection takes a subclinical or minimally symptomatic course in up to 80% of the population after tick bites.¹² Importantly, borreliosis is treatable with antibiotics.TBE infection can be proven by specific and sensitive ELISA detection of antibody in cerebrospinal fluid (CSF), or by detection of genome through polymerase chain reaction.¹³ Serum IgM antibodies can remain positive for ⩾10 months.^2,14 By contrast, serological tests for Lyme borreliosis infection are less sensitive and specific to variable onset and occurrence of specific IgM and IgG antibodies, with recognised persistent seronegatives; direct detection of a pathogen is rarely possible, and reliance must be placed on interpreting the laboratory investigations in the light of the clinical picture.^13,15,16 Demonstration of intrathecal antibody production provides a specific test,¹⁷ but is not sensitive in detecting all forms of neuroborreliosis.¹⁵ Despite their different clinical courses, TBE and Lyme borreliosis have neurological features in common: lymphocytic meningitis, flaccid or spastic limb weakness, and cranial nerve involvement. Pain, particularly in a radicular distribution, and sensory disturbance are regarded as features more typical of Lyme borreliosis than TBE.Only limited information on double infection with TBE and Lyme borreliosis is available. Single cases, small series or serologically defined series with limited clinical information are described from Germany, Slovenia, Central Russia and Finland.^{18,19,20,21,22,23,24} This retrospective clinical observational study analyses the clinical features and problems of differential diagnosis in patients with evidence of both TBE and Lyme borreliosis infection in Latvia.     

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.     

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.     

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.     

Focal cortical dysplasia: long term seizure outcome after surgical treatment

Background

Studies of long term outcome after epilepsy surgery for cortical malformations are rare. In this study, we report our experience with surgical treatment and year to year long term outcome for a subgroup of patients with focal cortical dysplasia (FCD).

Methods

We retrospectively analysed the records of 49 patients (females n = 26; males n = 23; mean age 25 (11) years) with a mean duration of epilepsy of 18 years (range 1–45). Preoperative MRI, histological results based on the Palmini classification and clinical year to year follow‐up according to the International League Against Epilepsy (ILAE) classification were available in all patients.

Results

98% of patients had a lesion on preoperative MRI. In addition to lobectomy (n = 9) or lesionectomy (n = 40), 14 patients had multiple subpial transections of the eloquent cortex. The resected tissue was classified as FCD type II b in 41 cases with an extratemporal (88%) and FCD type II a in 8 cases with a temporal localisation (100%). After a mean follow‐up of 8.1 (4.5) years, 37 patients (76%) were seizure free, a subgroup of 23 patients (47%) had been completely seizure free since surgery (ILAE class 1a) and 4 patients (8%) had only auras (ILAE class 2). Over a 10 year follow‐up, the proportion of satisfactory outcomes decreased, mainly within the first 3 years. During long term follow‐up, 48% stopped antiepileptic drug treatment, 34% received a driver''s license and 57% found a job or training.

Conclusion

Surgical treatment of epilepsy with FCD is not only successful in the short term but also has a satisfying long term outcome which remains constant after 3 years of follow‐up but is not associated with better employment status or improvement in daily living.With the development of high resolution MRI in the past decade, cortical malformations have been detected more often in patients with drug resistant epilepsy.^1,2 Visualisation by MRI has aided diagnosis and surgical treatment of the largest group of cortical malformations (ie, the focal cortical dysplasias (FCDs)). Successful short term follow‐up with seizure free rates of 40–86% were described in several studies^{3,4,5,6,7,8,9} but only a few focused on long term outcome.^10,11,12 Most of these studies did not analyse subgroups of patients with the same histopathology, as other malformations or low grade gliomas were also included. The Engel classification,¹³ and not the newer International League Against Epilepsy (ILAE) classification,¹⁴ was used to describe the seizure outcome in all studies, and a year to year follow‐up, important for the long term course of these patients, was not included.The first aim of this study was a reclassification of all FCD cases according to the new Palmini classification¹⁵ to define a homogenous histopathological group. The second aim was to analyse the year to year long term outcome with respect to seizures according to the ILAE classification, antiepileptic drug (AED) use and socioeconomic outcome (eg, driving license and employment status).     

Long term follow-up of the first 70 operated adults in the Goteborg Epilepsy Surgery Series with respect to seizures, psychosocial outcome and use of antiepileptic drugs

Objective

To compare long term (10 years) seizure outcome, psychosocial outcome and use of antiepileptic drugs (AED) with the 2 year follow‐up in adults after resective epilepsy surgery.

Methods

All adults (n = 70) who underwent resective epilepsy surgery from 1987 to 1995 in the Göteborg Epilepsy Surgery Series were included. Fifty‐four had undergone temporal lobe resections and 16 extratemporal resections (12 frontal). A cross‐sectional follow‐up in the form of a semistructured interview was performed in late 2003.

Results

Mean follow‐up was 12.4 years (range 8.6–16.2). Of the 70 patients (51% males), five (7%) were dead (three as a result of non‐epilepsy related causes). Of the 65 patients interviewed, 38 (58%) were seizure‐free at the long term follow‐up: 65% of the patients with temporal lobe resections and 36% of the patients with extratemporal resections. Of the 35 patients who were seizure‐free at the 2 year follow‐up, 3 (9%) had seizures at the long term follow‐up. Of the 30 patients who had seizures at the 2 year follow‐up, 6 (20%) were seizure‐free at the long term follow‐up. Of all 65 patients, 45 (69%) had the same seizure status as the 2 year follow‐up. Sixteen (25%) had an improved seizure status and 4 (6%) had a worsened status. Of the seizure‐free patients, 11 (29%) had ceased taking AED, 28 (74%) were working and 25 (66%) had a driving license.

Conclusions

Adult patients who are seizure‐free 2 years after resective epilepsy surgery are most likely to still be seizure‐free 10 years later. Most are working and have obtained a driving license.Epilepsy surgery is a well established treatment for medically intractable epilepsy.^1,2 The ultimate aims of epilepsy surgery are to reduce the frequency and intensity of seizures and thereby to improve quality of life. Most studies of the effectiveness of epilepsy surgery have focused on seizure outcome of anterior temporal lobe resections 1–2 years after surgery. One randomised controlled study² and multiple clinical series have shown that approximately two thirds of patients become free of seizures with impairment of awareness. It has also been shown that quality of life scores improve after temporal lobe resection, especially in seizure‐free patients who also have a trend towards better social function (see Engel et al,³ Jones et al⁴ and Malmgren et al⁵).Concern has been raised about the long term seizure outcome of epilepsy surgery. Several studies have described late seizure recurrences after initial success, sometimes but not always related to discontinuation of antiepileptic drugs (AED).^6,7,8 On the other hand, it has been suggested that seizure outcome at 2 years after surgery in patients subjected to temporal lobectomy predicts the long term outcome.^6,9,10,11,12However, there are only a few studies concerning long term outcome beyond 5 years (ie, presenting data with 10 years of follow‐up).¹³ Most have only included patients subjected to temporal lobectomy and very little is known about the long term seizure outcome for patients who have undergone other resection types.Patients'' aims for epilepsy surgery are, however, not limited to seizure relief. The five commonest aims for patients during presurgical evaluation cited in the study by Taylor et al¹⁴ were: desire for work, driving of motor vehicles, independence, socialising and freedom from drugs (see also Gilliam et al¹⁵). Psychosocial outcomes (eg, employment status, educational status and driving a vehicle) are seldom reported in long term studies. Of the few studies reporting psychosocial aspects, the average follow‐up time is no more than 5 years and most of them have only included patients subjected to temporal lobectomy^4,16,17,18 (see Guldvog et al¹⁹).The Göteborg Epilepsy Surgery Series is a multidisciplinary prospective follow‐up of all patients subjected to epilepsy surgery in Göteborg since its start in 1987. We have previously described the 2 year outcome regarding alterations in seizure frequency,²⁰ general cognitive function, and memory²¹ and psychiatric morbidity²² in the first 70 consecutive operated adults. The aim of this study was to compare the long term (>10 years) outcome concerning seizure status, psychosocial issues and use of AED with the 2 year follow‐up in these well characterised 70 adults.     

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.     

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.     

Case control study of diffusion tensor imaging in Parkinson's disease

Background

Preliminary work has shown that diffusion tensor MRI (DTI) may contribute to the diagnosis of Parkinson''s disease (PD).

Objectives

We conducted a large, prospective, case control study to determine: (1) if fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values on DTI in the basal ganglia and substantia nigra are different between patients with PD and healthy controls; and (2) the predictive value of these parameters and their clinical utility.

Methods

DTI imaging was carried out in patients with PD and controls. FA and ADC values were obtained from various brain structures on the DTI scan using the diffusion tensor taskcard. The structures studied were: caudate, putamen, globus pallidus, thalamus and substantia nigra.

Results

151 subjects (73 PD patients, 41 men, 32 women; mean age 63.6 years) and 78 age and sex matched control subjects were studied. The FA value of the substantia nigra in patients with PD was lower compared with controls (0.403 vs 0.415; p = 0.001). However, no significant differences were demonstrated for FA or ADC values of other structures. Multiple regression analysis revealed that the clinical severity of PD correlated inversely with the FA value in the substantia nigra in patients with PD (regression coefficient −0.019). No single FA value had both a high positive and negative predictive power for PD.

Conclusions

We demonstrated in a large, prospective, case control study that the FA value in the substantia nigra on DTI was lower in PD compared with healthy controls, and correlated inversely with the clinical severity of PD. Further longitudinal studies would be helpful to assess the clinical utility of serial FA measurements of the substantia nigra in objective quantification of disease progression and monitoring of the therapeutic response.The diagnosis of Parkinson''s disease (PD) is usually made clinically, based on the presence of rest tremor, bradykinesia and rigidity.^1,2 However, in select cases, the diagnosis may not be clear, especially in patients without tremor. Large community based studies have also shown that there is considerable difficulty in diagnosing parkinsonism or PD among elderly subjects in clinical practice.^3,4 Subtle signs of parkinsonism can be detected on clinical examination in approximately 30% of apparently healthy community based elderly cohorts.^4,5,6Diffusion tensor imaging (DTI) is an MRI technique that can indirectly evaluate the integrity of white matter tracts by measuring water diffusion and its directionality in three dimensions.⁷ The magnitude (diffusivity) and directionality (anisotropy) of water molecular displacement by diffusion in the brain can be quantified by the apparent diffusion coefficient (ADC) and fractional anisotropy (FA), respectively.^{8,9,10,11,12,13,14,15} Studies have revealed age related declines in white matter FA of normal healthy adults in whom volume loss may not even be evident.^12,15,16 DTI changes have also been reported in structures with relatively low inherent anisotropy, such as the thalamus and putamen.^11,12,17A small pilot study reported lower FA values in the nigrostriatal projection of patients with PD.¹⁸ Another group showed that ADC values in the basal ganglia and substantia nigra were no different between patients with PD and controls.^19,20 To our knowledge, correlation of FA and ADC values on DTI with clinical severity, and determination of positive and negative predictive values of DTI parameters have not been demonstrated for PD. Hence, we conducted a large, prospective, case control study to determine the clinical utility of FA and ADC values on DTI in distinguishing patients with PD from healthy controls.     

Levodopa raises objective pain threshold in Parkinson's disease: a RIII reflex study

Background

Patients suffering from Parkinson''s disease (PD) describe painful sensations that could be related to neuropathic pain. Experimental data have indicated the involvement of basal ganglia and dopaminergic pathways in central nociceptive processing.

Aim

The objective of this study was to assess and compare the effect of levodopa on the objective pain threshold in patients with PD and healthy subjects.

Methods

The objective pain threshold was assessed by the nociceptive flexion reflex (RIII) in 13 PD patients and 10 healthy subjects. Patients and healthy subjects were evaluated under two randomised conditions: with levodopa (ON) and without (OFF).

Results

Levodopa significantly increased the RIII threshold of PD patients (6.9 (1.2) mA in the OFF condition vs 8 (1.1) mA in the ON position; p = 0.02). RIII threshold was significantly lower in PD patients than in healthy subjects in the OFF condition (6.9 (1.2) mA vs 9.7 (3.4) mA; p = 0.02). RIII threshold did not change after levodopa administration in healthy subjects.

Conclusion

These results provide evidence of a dopaminergic modulation of objective pain threshold in PD patients. In addition, the decrease in RIII threshold in PD patients, in the OFF condition, compared with controls, confirms the existence of an objective pain perception disturbance in PD.Pain is recognised as a feature of Parkinson''s disease (PD) and is reported by 40–75% of patients with PD.¹ Painful sensations are various (musculoskeletal, neuropathic pain) and may be present at any stage of the disease.^2,3Several anatomical, electrophysiological and pharmacological arguments are in favour of the involvement of the basal ganglia and dopaminergic pathways in central nociceptive processing.⁴There are only a few controversial studies on pain perception in PD. The pain threshold of patients with PD has been found to be lower than, higher than or equal to that of healthy subjects.^5,6,7 Recently, Djaldetti et al have shown that patients with PD have a lower subjective heat pain threshold than healthy subjects.⁸ To our knowledge, the effect of levodopa has only been assessed on the subjective pain threshold. Using two different experimental thermal stimulations (cold pressor test and thermotest with Peltier effect), we have previously shown that acute administration of levodopa significantly raised the subjective pain threshold of patients with PD.^9,10The nociceptive flexion reflex (RIII), a polysynaptic reflex, has been described as a useful tool for objectively investigating the pain threshold and its pharmacological modulation by analgesic drugs in normal subjects.^11,12The primary aim of the present study was to compare the effects of levodopa on objective pain threshold (RIII reflex) in pain free patients with PD and in healthy subjects. A secondary objective was to compare such parameters between these two groups.     

Gender differences in Parkinson's disease

Objective

To investigate gender differences in basic disease characteristics, motor deterioration and nigrostriatal degeneration in Parkinson''s disease (PD).

Methods

We studied 253 consecutive PD patients who were not receiving levodopa or dopamine agonists (disease duration ⩽10 years). We investigated the influence of gender and oestrogen status on: (1) age at onset, (2) presenting symptom, (3) severity and progression of motor symptoms (Unified Parkinson''s Disease Rating Scale III (UPDRS‐III) scores) and (4) amount and progression of nigrostriatal degeneration ([¹²³I]FP‐CIT single photon emission computed tomography measurements).

Results

Age at onset was 2.1 years later in women (53.4 years) than in men (51.3 years). In women, age at onset correlated positively with parity, age at menopause and fertile life span. Women more often presented with tremor (67%) than men (48%). Overall, patients presenting with tremor had a 3.6 year higher age at onset and a 38% slower UPDRS‐III deterioration. Mean UPDRS‐III scores at disease onset were equal for both genders, as was the rate of deterioration. Women had a 16% higher striatal [¹²³I]FP‐CIT binding than men at symptom onset and throughout the course of PD.

Conclusions

Our results suggest that, in women, the development of symptomatic PD may be delayed by higher physiological striatal dopamine levels, possibly due to the activity of oestrogens. This could explain the epidemiological observations of a lower incidence and higher age at onset in women. Women also presented more often with tremor which, in turn, is associated with milder motor deterioration and striatal degeneration. Taken together, these findings suggest a more benign phenotype in women with PD.There are several indications of gender differences in Parkinson''s disease (PD). Epidemiological studies have shown that both incidence and prevalence of PD are 1.5–2 times higher in men than in women.^1,2,3,4,5,6 Furthermore, in 6 out of 8 incidence studies mentioning gender specified age at onset, onset in women was slightly later than in men (by a mean of 2.2 years (range 1–4)).⁷ After progression into the clinical phase of the disease, women had better Unified Parkinson''s Disease Rating Scale (UPDRS) motor scores⁸ but a greater prevalence of dyskinesias^8,9 compared with men (at a disease duration of more than 5 years). Furthermore, men reported several parkinsonian symptoms more frequently than women when asked at a disease duration of 9 years.¹⁰ Gender differences in the earlier stage of PD, before initiation of dopamine agonists or levodopa, have not been investigated.The reported gender differences reflecting distinct time periods—before and after symptom onset—could be related to the different levels of circulating oestrogens in men and women. Several findings indicate that oestrogens may play a role in PD. In animal models of PD, oestrogens had a neuroprotective effect when administered prior to or coinciding with a toxic insult.^11,12,13 Secondly, the dopaminergic neurons in the substantia nigra and the striatal dopamine content were more vulnerable to chemical lesioning at dioestrus (low oestrogen) than at pro‐oestrus (high oestrogen).¹⁴ However, the possibly beneficial effects of oestrogens suggested by these reports could not be confirmed in humans. Postmenopausal oestrogen use in women was associated with both higher, lower and equal risks of PD.^15,16,17 Furthermore, trials of postmenopausal oestrogen supplementation, which started after symptom onset, did not affect parkinsonian symptoms.^18,19 However, women who had undergone ovariectomy or hysterectomy had an increased risk of PD.^20,21 Thus the precise nature and extent of gender differences and the role of oestrogens in PD remain unclear.Here we investigated whether and how gender affects both the preclinical and clinical disease stages, reflected by (1) the age of PD onset, (2) the presenting symptom, (3) the severity and progression of motor symptoms assessed with UPDRS derived variables and (4) the amount and progression of nigrostriatal degeneration assessed using [¹²³I]FP‐CIT single photon emission computed tomography (SPECT).     

Profile of cognitive impairment in dementia associated with Parkinson's disease compared with Alzheimer's disease

Objective

To compare the profile of cognitive impairment in Alzheimer''s disease (AD) with dementia associated with Parkinson''s disease (PDD).

Methods

Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini‐Mental State Examination (MMSE) and the Alzheimer''s Disease Assessment Scale‐cognitive subscale (ADAS‐cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen''s d).

Results

Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS‐cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients.

Conclusion

The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.Alzheimer''s disease (AD) and Parkinson''s disease (PD) are the most common neurodegenerative diseases in the elderly. AD is primarily a dementing disease whereas PD is mainly characterised by a movement disorder. However, dementia is common among patients with PD (PDD), with an average point prevalence of 31%¹ and a cumulative prevalence close to 80%.² In PD, dementia is associated with rapid motor³ and functional decline,⁴ and increased mortality.⁵Cortical Lewy body pathology correlates best with dementia in PD^6,7,8,9; subcortical pathology¹⁰ and AD‐type pathology¹¹ have also been found to be associated with PDD. In addition to differences in morphological changes, AD and PDD also differ in the regional pattern of the pathology. In AD the first and most pronounced changes are found in the entorhinal cortex and parahippocampal region,¹² subsequently involving neocortical areas, including the posterior association cortices.¹³ In contrast, in patients with PD without dementia, brainstem nuclei and other subcortical structures are initially affected.¹⁴ In PDD, limbic areas, neocortical association cortices, and the motor cortex and primary sensory cortical areas are thought to be successively involved with disease progression.¹⁵Given the difference in the distribution and progression of pathology in AD and PDD, it is expected that their cognitive profiles would also differ.^16,17 AD is characterised by memory loss emerging in the early stages of the disease,¹⁸ primarily involving learning and encoding deficits¹⁹ which are associated with medial temporal lobe pathology.^20,21,22,23 As the disease progresses, deficits in language, praxis, visuospatial and executive functions gradually develop. In contrast, the cognitive deficits in the early stages of PDD are characterised by executive dysfunction, including impairment in attention²⁴ and working memory,^25,26,27 reflecting involvement of brainstem nuclei and frontal–subcortical circuits; deficits in visuoperceptual^28,29,30 and visuoconstructional tasks are also frequent.³¹ Memory impairment is often present^26,32,33,34 but whether it is primarily a consequence of frontally mediated executive deficits resulting in poor learning efficacy and retrieval, or whether involvement of limbic areas directly related to memory encoding (such as hippocampal atrophy) also contribute to memory impairment, is debated. Patients with PDD have difficulties in retrieving newly learned material, but perform better in recognition,³⁵ indicating that executive, rather than encoding, deficits, is the underlying mechanism. Conflicting results, however, have been reported recently^36,37 which could indicate that the type and mechanisms of memory deficits may vary within the PD group.³²Most studies investigating the cognitive profile of PDD patients included small samples which were not community based and thus not necessarily representative of the PD population at large. As there is evidence of interindividual heterogeneity,³³ such studies may not adequately reflect the cognitive profile of patients with PDD. In order to assess the profile of cognitive deficits in PDD compared with AD in larger patient populations, we analysed the baseline cognitive data from large clinical trials conducted with the cholinesterase inhibitor rivastigmine.^38,39     

A population based study of intracranial arachnoid cysts: clinical and neuroimaging outcomes following surgical cyst decompression in adults

Background

We have gradually adopted a liberal attitude towards surgical decompression of arachnoid cysts. This study describes the results from our institution.

Methods

Long term clinical and neuroimaging results of 156 adult patients (aged ⩾16 years) operated on for arachnoid cysts in our department during the period January 1987 to September 2004 were assessed based on their medical and neuroimaging records, and on a questionnaire.

Results

The clinical and/or neuroimaging results indicated that the cyst was successfully decompressed in all patients. 82% of patients were asymptomatic or had insignificant complaints at follow‐up. 12% reported no symptom relief whereas 6% experienced worsening of symptoms. The cyst disappeared after surgery, or was reduced to <50% of the preoperative volume, in 66% of cases. In another 24%, the postoperative volume was also reduced, but was larger than 50% of the original cyst volume. No reduction in fluid volume was observed in 10% of cases. There was no association between volume reduction and clinical improvement. A complication occurred in 26 patients (17%), all with temporal cysts, leading to reoperation in 11 patients (7.1%). In only two patients did the complication cause a permanent slight disability.

Conclusion

Decompression of arachnoid cysts yields a substantial clinical benefit with a low risk of severe complications.Arachnoid cysts are benign congenital malformations of the arachnoid. They can be located along the craniospinal axis, with a predilection for the temporal fossa.¹ They may present with specific symptoms, such as sensorimotor symptoms corresponding to the location of the cyst, but more often they yield unspecific symptoms (eg, headache or dizziness, or symptoms related to suboptimal cerebral function, such as epilepsy or impaired cognition).^{2,3,4,5,6,7,8,9,10}The treatment of such cysts, particularly in the majority of the patients with moderate and unspecific symptoms, has been controversial.^{11,12,13,14,15} Many authors have expressed a reluctance to operate on these patients unless the symptoms are dramatic. This was also the initial attitude of the senior author. However, based on several observations of our own and those of others, we have gradually changed our view. When we encountered patients that were severely impaired, with symptoms such as headache or dizziness, and who also had radiologically expansive cysts, we found it logical to attempt to alleviate the complaints by surgical cyst decompression. It has been our accumulated experience that surgical decompression yields clinical improvement in most patients with arachnoid cysts. Also, a growing literature indicates that cyst decompression improves the function of neighbouring cerebral tissue, thus supporting the view that patients with unspecific symptoms and “clinically silent” cysts may also profit from surgical cyst decompression.^{4,6,7,8,9,10,16}Treating a benign condition that is not life threatening with surgery, with the aim of improving quality of life, can only be justified when a clear clinical benefit, and no severe complications, can be demonstrated. We therefore wished to describe our experience with a relatively liberal indication for surgical decompression of intracranial arachnoid cysts. We have recently published a similar study on our paediatric cyst patients.¹⁷     

Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations

Objective

To investigate a possible association of mutations in the PTEN‐induced putative kinase 1 (PINK1) gene with psychiatric disorders in a large family with monogenic parkinsonism.

Method

20 members of a family (4 homozygous, 11 heterozygous and 5 non‐mutation carriers) were investigated for the presence of psychiatric disorders using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM‐IV); information on three additional heterozygous mutation carriers was obtained according to the family history research diagnostic criteria.

Results

We found predominantly affective and schizophrenia spectrum disorders in 11 (61%) of the 18 mutation carriers and in 1 (20%) of the 5 mutation‐negative cases.

Conclusions

First, affective and psychotic symptoms may be part of the phenotypic spectrum or even the sole manifestation of PINK1 mutations. Second, patients with familial movement disorders associated with psychiatric conditions may serve as a valuable study population to explore (genetic) causes of neuropsychiatric disease.In patients with Parkinson''s disease (PD), a wide range of psychiatric disorders has been described including depression (20–50%),¹ psychosis (15–40%),^2,3 anxiety disorder (20–40%) and cognitive impairment (20%).² Psychiatric disorders may be the first or even the only manifestation in carriers of Parkin gene mutations, the most‐frequent known cause of early‐onset parkinsonism (EOP).⁴ Likewise, psychiatric problems have been reported in patients and their motor‐asymptomatic relatives with mutations in the recently detected PTEN‐induced kinase 1 (PINK1) gene, the second‐commonest cause of EOP.^5,6,7,8,9Two homozygous mutations in the PINK1 gene were initially described in three consanguineous families with EOP.⁶ The frequency of PINK1 mutations ranges from 1% to 8% in patients with PD of different ethnicities who are often selected for young age of onset and for family history (for review see Klein and Schlossmacher¹⁰). Most of the currently described mutations are localised near or within the functional serine/threonine kinase domain of PINK1 and are expected to result in a loss‐of‐function effect in vivo. Wild‐type PINK1 functions as a protein kinase that is mainly located within the mitochondria.Although PINK1‐associated parkinsonism is generally considered an autosomal recessive condition, a growing body of evidence has been accumulating that supports the notion of a single heterozygous mutation conferring disease susceptibility in at least a subset of patients.^6,8,9,10,11Currently, no studies have systematically assessed psychiatric symptoms in monogenic EOP. To investigate this possible association, we evaluated a large family with EOP with PINK1 mutations for the presence of psychiatric disorders.