Previously, controlled trials have demonstrated the efficacy and tolerability of fixed doses of incobotulinumtoxinA (Xeomin, NT 201, botulinum toxin type A free from complexing proteins) to treat cervical dystonia (CD). To explore the clinical relevance of these findings, this study evaluated long-term use of flexible dosing regimens of incobotulinumtoxinA in a setting close to real-life clinical practice.
Patients with CD received five injection sessions of incobotulinumtoxinA using flexible intervals (10–24 weeks) and dosing (≤300 Units) based on patients’ needs. Outcome measures included Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), the Dystonia Discomfort Scale (DDS), Investigator Global Assessment of Efficacy (IGAE) and Patient Evaluation of Global Response (PEGR).
Of 76 patients enrolled (men: 34%; naïve to botulinum toxin: 25%), 64 completed the study, receiving treatment over a duration of 49.3–114.1 weeks (total maximum duration: 121 weeks). Mean TWSTRS-Total and DDS scores significantly improved from study baseline to 4 weeks after each injection session (ranges of improvement: TWSTRS-Total: –11.7 to –14.3; DDS: –20.2 to –23.0). Up to 81.6% of investigators rated the efficacy as ‘good’ or ‘very good’ (IGAE) and up to 78.9% of patients rated the treatment response as ‘improved’ (PEGR). The most common adverse events were dysphagia, nasopharyngitis and headache.
In this long-term study, incobotulinumtoxinA was administered using more flexible dosing regimens than those permitted in previous controlled trials. Repeated injections of highly purified incobotulinumtoxinA are effective and well tolerated for the treatment of CD in a setting close to real-life clinical practice.
Despite its positive effects in the treatment for motor symptoms in PD, DRT leads to a number of motor and non-motor side effects. Non-motor side effects include dopamine dysregulation syndrome (DDS) occurring in 3% to 4% of PD patients taking DRT. DDS is characterised by compulsive DRT seeking and hoarding, self-medication and withdrawal symptoms.
Important insights into this condition are offered in the paper by Cilia and colleagues,
Previous observational studies reported beneficial effects of the Mediterranean diet (MedDiet) on cognitive function, but results were inconsistent. We assessed the effect on cognition of a nutritional intervention using MedDiets in comparison with a low-fat control diet.
We assessed 522 participants at high vascular risk (44.6% men, age 74.6 ± 5.7 years at cognitive evaluation) enrolled in a multicentre, randomised, primary prevention trial (PREDIMED), after a nutritional intervention comparing two MedDiets (supplemented with either extra-virgin olive oil (EVOO) or mixed nuts) versus a low-fat control diet. Global cognitive performance was examined by Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT) after 6.5 years of nutritional intervention. Researchers who assessed the outcome were blinded to group assignment. We used general linear models to control for potential confounding.
After adjustment for sex, age, education, Apolipoprotein E genotype, family history of cognitive impairment/dementia, smoking, physical activity, body mass index, hypertension, dyslipidaemia, diabetes, alcohol and total energy intake, participants allocated to the MedDiet+EVOO showed higher mean MMSE and CDT scores with significant differences versus control (adjusted differences: +0.62 95% CI +0.18 to +1.05, p=0.005 for MMSE, and +0.51 95% CI +0.20 to +0.82, p=0.001 for CDT). The adjusted means of MMSE and CDT scores were also higher for participants allocated to the MedDiet+Nuts versus control (adjusted differences: +0.57 (95% CI +0.11 to +1.03), p=0.015 for MMSE and +0.33 (95% CI +0.003 to +0.67), p=0.048 for CDT). These results did not differ after controlling for incident depression.
An intervention with MedDiets enhanced with either EVOO or nuts appears to improve cognition compared with a low-fat diet.
ISRCTN:35739639
Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD.
Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD.
Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6–67). Nine patients were wheelchair users (26–56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively.
This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a ‘skipped’ DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.
The risk of suicide behaviours post–deep brain stimulation (DBS) surgery in Parkinson’s disease (PD) remains controversial. We assessed if suicide ideation and behaviours are more common in PD patients (1) randomised to DBS surgery versus best medical therapy (BMT); and (2) randomised to subthalamic nucleus (STN) versus globus pallidus interna (GPi) DBS surgery.
In Phase 1 of the Veterans Affairs CSP 468 study, 255 PD patients were randomised to DBS surgery (n=121) or 6 months of BMT (n=134). For Phase 2, a total of 299 patients were randomised to STN (n=147) or GPi (n=152) DBS surgery. Patients were assessed serially with the Unified Parkinson's Disease Rating Scale Part I depression item, which queries for suicide ideation; additionally, both suicide behaviour adverse event data and proxy symptoms of increased suicide risk from the Parkinson's Disease Questionnaire (PDQ-39) and the Short Form Health Survey (SF-36) were collected.
In Phase 1, no suicide behaviours were reported, and new-onset suicide ideation was rare (1.9% for DBS vs 0.9% for BMT; Fisher's exact p=0.61). Proxy symptoms of relevance to suicide ideation were similar in the two groups. Rates of suicide ideation at 6 months were similar for patients randomised to STN versus GPi DBS (1.5% vs 0.7%; Fisher's exact p=0.61), but several proxy symptoms were worse in the STN group.
Results from the randomised, controlled phase of a DBS surgery study in PD patients do not support a direct association between DBS surgery and an increased risk for suicide ideation and behaviours.
A 15-year-old adolescent was admitted to the emergency department after a car accident because of severe traumatic brain injury. Upon arrival, he was sedated and intubated because of a Glasgow Coma Scale score below 8. He had isocoria with reactive pupils. An occipital puncture wound (diameter 2 cm) was profusely bleeding. His blood pressure was 85/45 mm Hg. Laboratory values identified a haemoglobin level of 4.6 mmol/l. A CT scan of the brain demonstrated a comminuted-depressed fracture of the parietal bone in the midline with a rupture of the superior sagittal sinus (SSS) and secondary thrombosis (
A 24-year-old female who had suffered a pedestrian traffic accident underwent conservative management for traumatic diffuse axonal injury at the Department of Neurosurgery in a University Hospital. The patient showed a stuporous mental state at admission and the patient's Glasgow Coma Scale score was 9 at that time. Brain MRI performed at 7 weeks from onset showed leukomalactic lesions in the body, isthmus and splenium of the corpus callosum (
Diffusion tensor imaging (DTI), a form of diffusion-weighted MRI that can be used for reconstruction of images of neural tracts, was acquired at 7 weeks after onset using a six-channel head coil on a 1.5T Philips Gyroscan Intera...]]>
POEMS syndrome (Crow-Fukase syndrome) is a multisystem disorder characterised by polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. Vascular endothelial growth factor (VEGF) is significantly elevated in serum and used as a good biomarker for diagnosis and disease activity.
In randomised trials testing treatments for acute ischaemic stroke, imaging markers of tissue reperfusion and arterial recanalisation may provide early response indicators.
To determine the predictive value of structural, perfusion and angiographic imaging for early and late clinical outcomes and assess practicalities in three comprehensive stroke centres.
We recruited patients with potentially disabling stroke in three stroke centres, performed magnetic resonance (MR) or CT, including perfusion and angiography imaging, within 6 h, at 72 h and 1 month after stroke. We assessed the National Institutes of Health Stroke Scale (NIHSS) score serially and functional outcome at 3 months, tested associations between clinical variables and structural imaging, several perfusion parameters and angiography.
Among 83 patients, median age 71 (maximum 89), median NIHSS 7 (range 1–30), 38 (46%) received alteplase, 41 (49%) had died or were dependent at 3 months. Most baseline imaging was CT (76%); follow-up was MR (79%) despite both being available acutely. At presentation, perfusion lesion size varied considerably between parameters (p<0.0001); 40 (48%) had arterial occlusion. Arterial occlusion and baseline perfusion lesion extent were both associated with baseline NIHSS (p<0.0001). Recanalisation by 72 h was associated with 1 month NIHSS (p=0.0007) and 3 month functional outcome (p=0.048), whereas tissue reperfusion, using even the best perfusion parameter, was not (p=0.11, p=0.08, respectively).
Early recanalisation on angiography appeared to predict clinical outcome more directly than did tissue reperfusion. Acute assessment with CT and follow-up with MR was practical and feasible, did not preclude image analysis, and would enhance trial recruitment and generalisability of results.
Quantifying progression and delineating the onset of progression in multiple sclerosis (MS) have been subjects of considerable debate over many years. Particularly, as the current standard measures of disability, such as the expanded disability status scale (EDSS)
They raise several important and sometimes controversial points, none more contentious than the role of relapses in the development of progression. They find that early relapses within the first 2 years do significantly influence the timing of onset of progression with participants with three or more relapses in the first 2 years of disease reaching secondary progression multiple sclerosis (SPMS) some 4.8 years earlier than those with...]]>
Sensorimotor integration is impaired in patients with Parkinson's disease (PD). Short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI) measured with transcranial magnetic stimulation (TMS) can be used to measure sensorimotor integration. Subthalamic nucleus (STN) deep brain stimulation (DBS) has been found to restore these abnormalities, but the time course of these changes is not known. We prospectively evaluated the short-term and long-term effects of STN DBS on SAI, LAI and proprioception. We hypothesised plasticity changes induced by chronic stimulation are necessary to normalise sensorimotor integration and proprioception.
Patients with PD were studied preoperatively, at 1 month and more than 6 months postoperatively. SAI was tested with median nerve stimulation to the wrist preceding TMS pulse to motor cortex by ~20 ms and LAI by 200 ms. Proprioception (distance and spatial errors) in the arm was quantitatively assessed. For postoperative assessments, patients were studied in the medication-off/stimulator-off, medication-off/stimulator-on, medication-on/stimulator-off and medication-on/stimulator-on conditions.
11 patients with PD and 10 controls were enrolled. Preoperatively, SAI and proprioception was abnormal during the medication-on conditions and LAI was reduced regardless of the medication status. STN DBS had no significant effect on SAI, LAI and proprioception at 1 month. However, at 6 months SAI, LAI and distance errors were normalised in the medication-on/stimulator-on condition. Spatial error was normalised with DBS on and off.
Chronic STN DBS in PD normalises sensorimotor integration and proprioception, likely through long-term plastic changes in the basal ganglia thalamocortical circuit.
Each disorder was initially considered mutually exclusive. Bickerstaff and colleagues believed that BBE is a purely CNS disease, whereas FS as a variant of Guillain-Barré syndrome is therefore an inflammatory ‘neuropathy’. However, in addition to the common major manifestations of...]]>
Patients treated with natalizumab for active relapsing–remitting multiple sclerosis (MS) benefit from its high efficacy and excellent tolerability; this was shown in the pivotal studies
Cognitive domain deficits can occur after aneurysmal subarachnoid haemorrhage (aSAH) though few studies systemically evaluate its impact on 1-year outcomes.
We aimed to evaluate the pattern and functional outcome impact of cognitive domain deficits in aSAH patients at 1 year.
We carried out a prospective observational study in Hong Kong, during which, 168 aSAH patients (aged 21–75 years and had been admitted within 96 h of ictus) were recruited over a 26-month period. The cognitive function was assessed by a domain-specific neuropsychological assessment battery at 1 year after ictus. The current study is registered at ClinicalTrials.gov of the US National Institutes of Health (NCT01038193).
Prevalence of individual domain deficits varied between 7% to 15%, and 13% had two or more domain deficits. After adjusting for abbreviated National Institute of Health Stroke Scale and Geriatric Depressive Scale scores, unfavourable outcome (Modified Rankin Scale 3–5) and dependent instrumental activity of daily living (Lawton Instrumental Activity of Daily Living<15) were significantly associated with two or more domain deficits and number of cognitive domain deficits at 1 year. Two or more domain deficits was independently associated with age (OR, 1.1; 95% CI 1.1 to 1.2; p<0.001) and delayed cerebral infarction (OR, 6.1; 95% CI 1.1 to 33.5; p=0.036), after adjustment for years of school education.
In patients with aSAH, cognitive domain deficits worsened functional outcomes at 1 year. Delayed cerebral infarction was an independent risk factor for two or more domain deficits at 1 year.
Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort.
DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations.
All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin.
We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.
Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre.
Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3–6 monthly intervals.
The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50–70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis.
Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.
Single nucleotide polymorphisms (SNPs) on chromosome 9p21 have been recently associated with intracranial aneurysms and stroke. In this study, we tested the association between the rs1333040C>T polymorphism on the 9p21 locus and sporadic brain arteriovenous malformations (BAVMs).
We studied 78 patients with sporadic BAVMs and 103 unaffected controls. Genomic DNA was isolated from peripheral blood and the rs1333040C>T polymorphism was assessed by PCR–restriction fragment length polymorphism using the BsmI restriction endonuclease.
We found that the distribution of the three genotypes (TT/TC/CC) of the rs1333040 polymorphism was significantly different between cases and controls (p=0.02). Using dominant, recessive and additive genetic models, we found that the TT genotype and the T allele were significantly more common in the BAVM group than in controls. We also evaluated whether the rs1333040 polymorphism was associated with prototypical angio-architectural features of BAVMs (such as nidus size, venous drainage pattern and Spetzler–Martin grading) and with the occurrence of seizures and bleeding. We detected a significant association between the homozygous T allele in the recessive model and BAVMs with a nidus >4 cm in diameter. Deep venous drainage was significantly more frequent among subjects carrying at least one T allele in the dominant model. Patients with seizures showed a significant association with the TT genotype and the T allele in all genetic models examined whereas those who experienced intracranial bleeding showed a significant association with the T allele in the trend model.
This is the first study demonstrating an association between an SNP of the 9p21 region and sporadic BAVMs. Our results emphasise the relevance of this chromosomal locus as a common risk factor for various forms of cerebrovascular diseases.
Pharmacoresistant epilepsy can be treated by either resection of the epileptic focus or functional isolation of the epileptic focus through complete disconnection of the pathways of propagation of the epileptic activity.
To evaluate long-term seizure outcome and complications of temporal lobe disconnection (TLD) without resection for mesial temporal lobe epilepsy (MTLE).
Data of 45 patients operated on for intractable MTLE using a functional disconnection procedure have been studied. Indication of TLD surgery was retained after a standard preoperative evaluation of refractory epilepsy and using the same criteria as for standard temporal resection.
Mean follow-up duration was 3.7 years. At the last follow-up, 30 patients (67%) were completely seizure-free (Engel-Ia/International League Against Epilepsy class 1) and 39 patients (87%) remained significantly improved (Engel-I or -II) by surgery. Actuarial outcome displays a 77.7% probability of being seizure-free and an 85.4% probability of being significantly improved at 5 years. No patient died after surgery and no subdural haematoma or hygroma occurred. Permanent morbidity included hemiparesis, hemianopia and oculomotor paresis found in three, five and one patient, respectively, after TLD.
TLD is acceptable alternative surgical technique for patients with intractable MTLE. The results of TLD are in the range of morbidity and long-term seizure outcome rates after standard surgical resection. We observed a slightly higher rate of complications after TLD in comparison with usual rates of morbidity of resection procedures. TLD may be used as an alternative to resection and could reduce operating time and the risks of subdural collections.
The paper by Weinstock-Guttman et al
There is now an emerging body of circumstantial evidence for a potential role for cholesterol and lipids in MS. In an analysis of 8983 patients from the North American Research Committee on MS (NARCOMS) registry,...]]>
Voltage-gated potassium channels (VGKC) are essential for the cellular action potential. Antibodies against the VGKC-complex are associated with a wide spectrum of diseases involving both the peripheral and central nervous system, including neuromyotonia, Morvan disease, limbic encephalitis, faciobrachial dystonic seizures and cerebellar ataxia.
We identified...]]>
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by progressive paralysis, leading to death from respiratory failure within 3–7 years. Approximately 5% of the cases are familial in nature, mostly inherited in an autosomal dominant mode. A relatively high rate of concurrence of ALS and multiple sclerosis (MS), a progressive inflammatory disorder of the central nervous system, has recently been reported.
The coincidence of ALS...]]>
More than 60% of patients worldwide with Creutzfeldt-Jakob disease (CJD) associated with dura mater graft (dCJD) have been diagnosed in Japan. The remarkable frequency of dura mater grafts in Japan may possibly contribute to the elevated incidence of dCJD, but reasons for the disproportionate use of this procedure in Japan remain unclear. We investigated differences between dCJD patients in Japan and those elsewhere to help explain the more frequent use of cadaveric dura mater and the high incidence of dCJD in Japan.
We obtained data on dCJD patients in Japan from the Japanese national CJD surveillance programme and on dCJD patients in other countries from the extant literature. We compared the demographic, clinical and pathological features of dCJD patients in Japan with those from other countries.
Data were obtained for 142 dCJD patients in Japan and 53 dCJD patients elsewhere. The medical conditions preceding dura mater graft transplantation were significantly different between Japan and other countries (p<0.001); in Japan, there were more cases of cerebrovascular disease and hemifacial spasm or trigeminal neuralgia. Patients with dCJD in Japan received dura mater graft more often for non-life-threatening conditions, such as meningioma, hemifacial spasm and trigeminal neuralgia, than in other countries.
Differences in the medical conditions precipitating dura mater graft may contribute to the frequent use of cadaveric dura mater and the higher incidence of dCJD in Japan.
Research conducted in the past decade challenges the traditional view that essential tremor (ET) is characterised exclusively by movement disorder, and increasingly shows that these patients have deficits in cognitive and behavioural functioning. The available evidence suggests that this impairment might arise from dysfunction in either the fronto-subcortical or cortico-cerebellar circuits. Although abnormalities in the fronto-subcortical circuits could imply difficulty in lying, no study has investigated deception in patients with ET.
To examine the cognitive functions regulating deception in patients with ET, we used a computerised task, the Guilty Knowledge Task (GKT). We also tested a group of patients with Parkinson's disease (PD), a disease associated with a known difficulty in lie production, and a group of healthy subjects (HS).
In the GKT for deception, patients with ET responded less accurately than HS (p=0.014) but similarly to patients with PD (p=0.955). No differences between groups were found in truthful responses (p=0.488).
Besides confirming impaired deception in patients with PD, our results show a lie production deficit in patients with ET also. These findings suggest that difficulty in lying is an aspecific cognitive feature in movement disorders characterised by fronto-subcortical circuit dysfunction, such as PD and ET. Current knowledge along with our new findings in patients with ET—possibly arising from individually unrecognised extremely mild, cognitive difficulties—should help in designing specific rehabilitative programmes to improve cognitive and behavioural disturbances in patients.
To investigate the associations of serum lipid profile with disease progression in high-risk clinically isolated syndromes (CIS) after the first demyelinating event.
High density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were obtained in pretreatment serum from 135 high risk patients with CIS (≥2 brain MRI lesions and ≥2 oligoclonal bands) enrolled in the Observational Study of Early Interferon β-1a Treatment in High Risk Subjects after CIS study (SET study), which prospectively evaluated the effect of intramuscular interferon β-1a treatment following the first demyelinating event. Thyroid stimulating hormone, free thyroxine, 25-hydroxy vitamin D3, active smoking status and body mass index were also obtained. Clinical and MRI assessments were obtained within 4 months of the initial demyelinating event and at 6, 12 and 24 months.
The time to first relapse and number of relapses were not associated with any of the lipid profile variables. Higher LDL-C (p=0.006) and TC (p=0.001) levels were associated with increased cumulative number of new T2 lesions over 2 years. Higher free thyroxine levels were associated with lower cumulative number of contrast-enhancing lesions (p=0.008). Higher TC was associated as a trend with lower baseline whole brain volume (p=0.020). Higher high density lipoprotein was associated with higher deseasonalised 1,25-dihydroxy vitamin D3 (p=0.003) levels and a trend was found for deseasonalised 25-hydroxy vitamin D3 (p=0.014).
In early multiple sclerosis, lipid profile variables particularly LDL-C and TC levels are associated with inflammatory MRI activity measures.
The diagnosis of LBD is difficult for clinicians, even for specialists, particularly at the beginning of the disease. The diagnosis criteria, known as McKeith criteria, have a really high specificity—more than 95%—for LBD dementia.
Cerebral venous thrombosis (CVT) is an important cause for stroke in the young where the role for decompressive craniectomy is not well established.
To analyse the outcome of CVT patients treated with decompressive craniectomy.
Clinical and imaging features, preoperative findings and long-term outcome of patients with CVT who underwent decompressive craniectomy were analysed.
Over 10 years (2002–2011), 44/587 (7.4%) patients with CVT underwent decompressive craniectomy. Diagnosis of CVT was based on magnetic resonance venography (MRV)/inferior vena cava (IVC). Decision for surgery was taken at admission in 19/44 (43%), within 12 h in 5/44 (11%), within first 48 h in 15/44 (34%) and beyond 48 h in 10/44 (22%). Presence of midline shift of ≥10 mm (p<0.0009) and large infarct volume (mean 146.63 ml; SD 52.459, p<0.001) on the baseline scan influenced the decision for immediate surgery. Hemicraniectomy was done in 38/44 (86%) and bifrontal craniectomy in 6/44 (13.6%). Mortality was 9/44 (20%). On multivariate analysis (5% level of significance) age <40 years and surgery within 12 h significantly increased survival. Mean follow-up was 25.5 months (range 3–66 months), 26/35 (74%) had 1 year follow-up. Modified Rankin Scale (mRs) continued to improve even after 6 months with 27/35 (77%) of survivors achieving mRs of ≤2.
This is the largest series on decompressive craniectomy for CVT in literature to date. Decompressive craniotomy should be considered as a treatment option in large venous infarcts. Very good outcomes can be expected especially if done early and in those below 40 years.
Dopamine dysregulation syndrome (DDS) refers to a compulsive pattern of dopaminergic drug misuse complicating Parkinson's disease (PD). To date, few data are available on DDS risk factors, cognitive profile and long-term outcome.
In this retrospective case-control study, consecutive PD outpatients fulfilling criteria for DDS were assessed over a 6-year period (2005–2011). They were compared with 70 PD cases matched for age at onset, gender and disease duration, and with 1281 subjects with motor fluctuations and dyskinesias. DDS patients and matched controls underwent extensive neuropsychological assessment. Strategies for DDS patients management and the outcome at the last follow-up visit were recorded.
Thirty-five patients with DDS were identified, reporting history of depression, family history of PD and drug abuse, greater difference between ‘Off’ versus ‘On’ motor symptoms compared to age-matched controls. They had younger age at onset (but not any gender difference) compared to general PD population. Cognitive profile of DDS did not show major abnormalities, including executive functions. DDS patients have been followed up for 3.2±2.1 years and remission was recorded in 40% of cases. Negative DDS outcome was significantly associated with poor caregiver supervision. Sustained remission occurred more commonly on clozapine and on duodenal levodopa infusion and subthalamic nucleus deep brain stimulation (STN-DBS) than on apomorphine pump treatment.
Clinicians should be aware of risk factors predisposing to DDS. Duodenal levodopa infusion and, less consistently, STN-DBS were more commonly associated with DDS remission. Effective caregiving plays a key role in long-term behavioural outcome.
To ascertain the hypothesis that the phenotypic differences between Bickerstaff's brainstem encephalitis (BBE) and Miller Fisher syndrome (MFS) are derived from the differences in the effects of sera on blood–brain barrier (BBB) and blood–nerve barrier.
Antibodies against GQ1b are frequently detected in BBE and MFS, and these two disorders may share the same pathogenesis, but the clinical phenotypes of BBE and MFS are substantially different.
The effects of sera obtained from BBE patients, MFS patients and control subjects were evaluated with regard to the expression of tight junction proteins and transendothelial electrical resistance in human brain microvascular endothelial cells (BMECs) and human peripheral nerve microvascular endothelial cells.
The sera obtained from BBE patients decreased the transendothelial electrical resistance values and claudin-5 protein expression in BMECs, although the sera obtained from MFS patients had no effect on BMECs or peripheral nerve microvascular endothelial cells. This effect was reversed after the application of matrix metalloproteinase (MMP) inhibitor, GM6001. The presence or absence of anti-GQ1b antibodies did not significantly influence the results. MMP-9 secreted by BMECs was significantly increased after exposure to the sera obtained from BBE patients, whereas it was not changed after exposure to the sera obtained from MFS patients.
Only the sera obtained from BBE patients destroyed BBB and it might explain the phenotypical differences between BBE and MFS. BBE sera disrupted BBB, possibly via the autocrine secretion of MMP-9 from BBB-composing endothelial cells.
The diagnosis of brain death (BD) is based on clinical criteria including deep coma, brain stem areflexia and apnoea. Depending on different local guidelines, confirmatory technical tests are sometimes mandatory.
When conveying a new diagnosis of frontotemporal dementia (FTD) the clinician almost invariably encounters the following questions ‘Why has this happened?’ ‘Is there any treatment?’ and ‘Will our children get it?’ With the discovery of the MAPT and Progranulin mutations, and most recently pathological C9ORF72 repeat expansions,
One potential avenue of exploration is the role of inflammation and the immune system.
To characterise the natural history of Ullrich congenital muscular dystrophy (UCMD).
Questionnaire-based nationwide survey to all 5442 certified paediatric and adult neurologists in Japan was conducted from October 2010 to February 2011. We enrolled the 33 patients (age at assessment, 11±6.6 years) who were reported to have collagen VI deficiency on immunohistochemistry in muscle biopsies. We analysed the development, clinical manifestations, Cobb angle and %vital capacity (%VC) in spirogram.
Cobb angle over 30° was noted at age 9.9±5.3 years (n=17). The maximum progression rate was 16.2±10°/year (n=13). %VC was decreased exponentially with age, resulting in severe respiratory dysfunction before pubescence. Scoliosis surgery was performed in 3 patients at ages 5 years, 9 years and 10 years. Postoperative %VC was relatively well maintained in the youngest patient. Non-invasive ventilation was initiated at age 11.2±3.6 years (n=13). Twenty-five (81%) of 31 patients walked independently by age 1.7±0.5 years but lost this ability by age 8.8±2.9 years (n=11). Six patients never walked independently.
The natural history of scoliosis, respiratory function and walking ability in UCMD patients were characterised. Although the age of onset varied, scoliosis, as well as restrictive respiratory dysfunction, progressed rapidly within years, once they appeared.
Brainstem and cerebellar lesions are commonly associated with disorders of extraocular movements and these have localising value. The dorsal midbrain syndrome is characterised by (1) impaired voluntary vertical eye movements, (2) light-near dissociation of the pupillary response (pseudo-Argyll Robertson pupils), (3) convergence nystagmus on attempted upward gaze, (4) lid retraction (Collier sign) and (5) skew deviation.
A 63-year-old man presented with a sudden onset...]]>
Clinical and immunological evaluation of ‘incomplete’ Bickerstaff brainstem encephalitis (BBE).
We studied two patients with postinfectious brainstem syndromes who presented at National University Hospital Singapore. Laboratory work-up included measurement of antiganglioside antibodies.
Both patients displayed hypersomnolence and cerebellar-like ataxia in the absence of external ophthalmoplegia and carried high serum titres of IgG anti-GQ1b antibodies, strongly indicative of BBE.
Ophthalmoplegia can be absent or incomplete in BBE, and the absence of this clinical feature should not exclude BBE from the clinicians’ differential. Such cases of incomplete BBE could be defined as ‘ataxic hypersomnolence without ophthalmoplegia’.
The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored.
To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls.
Case control.
Academic medical centres.
129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels.
2 Comparison of autoimmune prevalence and follow-up logistic regression.
There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC.
svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.
The prevalence of Huntington's disease (HD) in the UK is uncertain. Recently, it has been suggested that the prevalence may be substantially greater than previously reported. This study was undertaken to estimate the overall UK prevalence in adults diagnosed with HD, using data from primary care.
The electronic medical records of patients aged 21 years or more, with recorded diagnoses of HD, were retrieved from the UK's General Practice Research Database. Prevalence was estimated from the number of persons with recorded diagnoses of HD, on 1 July each year, between 1990 and 2010. This number was divided by the total number of persons registered with participating general practices on that same date. These data were also used to estimate both age specific prevalence and prevalence in various regions of the UK.
A total of 1136 patients diagnosed with HD, aged 21 years or more, were identified from the database. The estimated prevalence (expressed per 100 000 population) rose from 5.4 (95% CI 3.8 to 7.5) in 1990 to 12.3 (95% CI 11.2 to 13.5) in 2010. Although an increased prevalence was observed within every age group, the most dramatic was in older patients. Age specific prevalence was highest in the 51–60 year age range (15.8 95% CI 9.0 to 22.3). The prevalence of adult HD was lowest in the London region (5.4 (95% CI 3.0 to 8.9)) and highest in the North East of England (18.3 (95% CI 8.6 to 34.6)) and Scotland (16.1 (95% CI 10.8 to 22.9)).
The prevalence of diagnosed HD is clearly substantially higher in the UK than suggested from previous studies. By extrapolation to the UK as a whole, it is estimated that there are more than 5700 people, aged 21 years or more, with HD. There has also been a surprising doubling of the HD population between 1990 and 2010. Many factors may have caused this increase, including more accurate diagnoses, better and more available therapies and an improved life expectancy, even with HD. There also appears to be a greater willingness to register a diagnosis of HD in patients’ electronic medical records. Such a high prevalence of HD requires more ingenuity and responsiveness in its care. How to appropriately care for, and respond to, so many individuals and families coping with the exigencies of HD demands our greatest resolve and imagination.
Research on the subjective experience of dissociative (psychogenic non-epileptic) seizures (DS) is dominated by that on objective semiology.
To determine the variability of serum IgG in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).
All 25 CIDP patients had active but stable disease and were treated with individually optimised fixed dose IVIg regimens. IgG was measured by turbidimetry and variability was defined as coefficient of variation (CV).
The intra-patient variability of the pre-treatment IgG levels, post-treatment levels and increase in serum IgG shortly after IVIg (IgG) was low (mean CV=3%, 4%, 10%). The inter-patient variability between patients treated with the same dose and interval was low in pre-treatment, post-treatment and IgG level (mean CV=13%, 11%, 20%). The IgG levels were associated with IVIg dosage (rs=0.78, p<0.001).
Clinically stable CIDP patients show a steady-state in serum IgG after serial IVIg infusions. The low intra- and inter-patient variability in IgG may indicate that constant levels are required to reach this stability.
MRI scan of the brain revealed the presence of a subacute ischaemic lesion in the left dorsolateral pons with the ipsilateral cisternal segment of the trigeminal nerve adjacent to the root entry zone (
Although Pisa syndrome and scoliosis are sometimes used interchangeably to describe a laterally flexed postural deviation in Parkinson's disease (PD), the imaging findings of Pisa syndrome in PD have not been previously studied in detail.
Patients with PD and Pisa syndrome (lateral flexion >10° in the standing position) were examined clinically and underwent radiological assessment using standing radiograph and supine CT scan of the whole spine.
Fifteen patients were included in this observational study. All patients had scoliosis on standing radiographs, and 12 had scoliosis persisting in the supine position. Scoliotic curves improved by a mean of 44% when patients moved from standing to supine. Only a quarter of patients with structural scoliosis had evidence of bony fusion on the side of their lateral deviation rendering their deformity fixed.
Pisa syndrome describes a patient who lists to the side whereas scoliosis is defined by spinal curvature and rotation and may not be associated with lateral flexion. The finding of ‘structural scoliosis’ in Pisa syndrome should not preclude intervening to improve posture as most patients had little or no evidence of structural bony changes even when the deformity had been present for a number of years.
To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS).
From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1–2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing–remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0–3.5, n=111) or moderately impaired (EDSS=4–6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores.
In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R2=0.74 in the whole group and R2=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R2=0.68), lesion volumes in moderately impaired relapse onset patients (R2=0.21) and whole brain atrophy in primary progressive MS (R2=0.34).
This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.
To determine whether four key neuropsychiatric and sleep related features associated with Parkinson's disease (PD) are associated with the motor handicap and demographic data.
The growing number of recognised non-motor features of PD makes routine screening of all these symptoms impractical. Here, we investigated the hypothesis that standard demographic data and the routine assessment of motor signs is associated with the presence of dementia, psychosis, clinically probable rapid eye movement (REM) sleep behavior disorder (cpRBD) and restless legs syndrome (RLS).
775 patients with PD underwent standardised assessment of motor features and the presence of dementia, psychosis, cpRBD and RLS. A stepwise feature elimination procedure with fitted logistic regression models was applied to identify which/if any combination of demographic and motor factors is associated with each of the four studied non-motor features. A within-study out-of-sample estimate of the power of the predicted values of the models was calculated using standard evaluation procedures.
Age and Hoehn&Yahr (H&Y) stage were strongly associated with the presence of dementia (p value<0.001 for both factors in the final selected model) while a combination of age, disease duration, H&Y stage, dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors was associated with the presence of psychosis. Disease duration and H&Y stage were the significant indicators of cpRBD, and the lack of significant motor asymmetry was the only significant feature associated with RLS-type symptoms but the evidence of association was weak.
Demographic and motor features routinely collected in patients with PD can estimate the occurrence of neuropsychiatric and sleep-related features of PD.
To examine dimensionality, reliability and validity of the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) using traditional classical test theory methods and Rasch analysis in order to provide a rationale for possible improvement of its metric quality.
Methodological research on ALSFRS-R collected in a consecutive sample of 485 patients with amyotrophic lateral sclerosis (ALS) attending three tertiary ALS centres.
The ALSFRS-R items showed good internal consistency but dimensionality analysis argues against the use of ALSFRS-R as a single score because the scale lacks unidimensionality. Parallel analysis and exploratory factor analysis revealed three factors representing the following domains: (1) bulbar function; (2) fine and gross motor function; and (3) respiratory function. Rasch analysis showed that all items in each domain fitted the respective constructs to measure, except for item No 9 ‘climbing stairs’ and item No 12 ‘respiratory insufficiency’. Rating categories did not comply with the criteria for category functioning. Collapsing the scale's 5 level ratings into 3 levels improved its metric quality.
The ALSFRS-R fails to satisfy rigorous measurement standards and should be, at least in part, revised. At present, ALSFRS-R should be considered as a profile of mean scores from three different domains (bulbar, motor and respiratory functions) more than a global total score. Further studies on ALSFRS-R using modern psychometric methods are warranted to confirm our findings and refine the metric quality of this scale, through a step by step process.
Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement.
We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology.
We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450.
Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.
To assess factors affecting the rate of conversion to secondary progressive (SP) multiple sclerosis (MS) and its subsequent evolution.
Among 806 patients with relapsing remitting (RR) onset MS from the London Ontario database, we used Kaplan–Meier, Cox regression and multiple logistic regression analyses to investigate the effect of baseline clinical and demographic features on (1) the probability of, and the time to, SP disease, (2) the time to bedbound status (Disability Status Scale (DSS 8)) from onset of progression.
The risk of entering the SP phase increased proportionally with disease duration (OR=1.07 for each additional year; p<0.001). Shorter latency to SP was associated with shorter times to severe disability. The same association was found even when patients were grouped by number of total relapses before progression. However, the evolution of the SP phase was not influenced by the duration of the RR phase. Male sex (HR=1.41; p<0.001), older age at onset (age ≤20 and 21–30 vs >30 HR=0.52 (p<0.001), 0.65 (p<0.001), respectively) and high early relapse frequency (1–2 attacks vs ≥3 HR=0.63 (p<0.001), 0.75 (p=0.04), respectively) predicted significantly higher risk of SP MS and shorter latency to progression. Times to DSS 8 from onset of progression were significantly shorter among those with high early relapse frequency (≥3 attacks), and among those presenting with cerebellar and brainstem symptoms.
The onset of SP MS is the dominant determinant of long-term prognosis, and its prevention is the most important target measure for treatment. Baseline clinical features of early relapse frequency and age at onset can be used to select groups at higher risk of developing severe disability based on the probability of their disease becoming progressive within a defined time period.
DEMENTIA OF FRONTAL LOBE TYPE1 Published: 1988;51:353–61 FRONTAL LOBE DEMENTIA AND MOTOR NEURON DISEASE2 Published: 1990;53:23–32 CLINICAL AND NEUROPATHOLOGICAL CRITERIA FOR FRONTO-TEMPORAL DEMENTIA3 Published: 1994;57:416–18
David Neary and Julie Snowden reflect on developments in the understanding of frontotemporal dementia and motor neuron disease since their publications two decades ago
At the beginning of the 1980s the establishment view in the English speaking world was that there were two primary causes of dementia: Alzheimer's disease and vascular disease. Pick's disease was an acknowledged pathological entity but considered sufficiently rare to have little clinical relevance for dementia patients presenting to neurology or psychiatry clinics. In any case it could not be distinguished from Alzheimer's disease in life. It was against this prevailing background that I set up our early onset dementia clinic with Julie Snowden as principal neuropsychologist. My early interest in cognitive neurology and dementia had been consolidated during a sabbatical in Boston in 1976, where...]]>
Professor Ralf Gold and his team
1. The earlier PML is diagnosed, the better the prognosis. In the Bochum series, the mean interval from the first clinical and/or MRI evidence to the definite diagnosis by John Cunningham virus (JCV)-DNA detection in the cerebrospinal fluid (CSF) was 30 days. In two patients, suspicious lesions were detected on routine MRI without accompanying clinical symptoms. 2. Treatment should begin as...]]>
To describe the clinical and genetic findings in a family affected by neurodevelopmental delay and cerebellar ataxia.
The affected mother and her two children underwent clinical assessments followed by radiological, neurophysiological and cytogenetic investigations.
All three affected members exhibited varying degrees of delay in attaining motor and cognitive milestones, along with learning difficulties and cerebellar ataxia. All three harboured a new 670 kb deletion of chromosome 12q21. Two genes, KCNC2 and ATXN7L3B, lie within the deleted region.
This family's complex phenotype is associated with a new chromosomal deletion, which suggests potential roles for the two genes, KCNC2 and ATXN7L3B, in human neurological disease.
Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI).
Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort.
ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP.
These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasise the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.
The patient was born with third-degree horizontal nystagmus, strabismus convergens and congenital morning glory optic disc anomalies (MGDAs) (
Physical examination showed bitemporal hemianopsia and her known third-degree horizontal nystagmus, strabismus divergens and medial cleft scar (
In order to...]]>
Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder associated with considerable relapse-related disability. Immunosuppression is the mainstay of treatment but many patients do not tolerate first-line immunosuppressive agents, or experience ongoing relapses.
To evaluate the effectiveness and tolerability of methotrexate in aquaporin-4 antibody seropositive NMO spectrum disorders.
Retrospective observational case series of 14 aquaporin-4 antibody positive NMO and NMO spectrum disorder patients treated with methotrexate at two specialist centres within the UK. Annualised relapse rates, Expanded Disability Status Scale scores and tolerability were evaluated.
Median duration of treatment with methotrexate was 21.5 months (range 6–28 months) and only three patients were prescribed it first line. Median annualised relapse rate significantly decreased following treatment (0.18 during methotrexate therapy vs 1.39 premethotrexate; p<0.005). On treatment, 43% patients were relapse free, although this increased to 64% when relapses occurring within the first 3 months of treatment or on subtherapeutic doses were excluded. Disability stabilised or improved in 79%. No patients stopped methotrexate due to adverse effects.
Methotrexate is a commonly prescribed drug in general practice and when used in NMO it reduces relapse frequency, stabilises disability and is well tolerated, even in patients who have failed one or more other treatments. We would therefore recommend methotrexate as a treatment option in NMO patients who do not tolerate first-line therapy, experience ongoing relapses or in situations where financial constraints limit the available treatment options.
In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed ‘split hand’. Previous axonal excitability studies have suggested increased nodal persistent sodium current and reduced potassium current in motor axons in ALS, but the extent of excitability changes in APB and ADM axons in ALS has never been compared.
To elucidate the peripheral axonal pathophysiology of split hand.
In both APB and ADM motor axons of 21 patients with ALS and 17 age-matched normal controls, threshold tracking was used to measure excitability indices such as strength-duration time constant (SDTC; a measure of persistent sodium current) and threshold electrotonus.
In normal controls, SDTC was significantly longer for APB than ADM axons, suggesting that axonal excitability is physiologically higher in APB axons. Compared with normal controls, patients with ALS had longer SDTC and greater threshold changes in depolarising threshold electrotonus in both APB and ADM axons. Furthermore, the difference in extent of SDTC prolongation between normal subjects and patients with ALS was greater in APB than ADM axons.
APB axons have physiologically higher excitability than ADM axons, and, in ALS, the hyperexcitability is more prominent in APB axons. Although cortical mechanisms would also be involved, more prominent hyperexcitability of APB axons may contribute to development of split hand, and the altered axonal properties are possibly associated with motor neuronal death in ALS.
The review of Ammirat et al
As to pituitary adenoma resection, Ammirat et al
To investigate the pattern of cortical thinning in Parkinson's disease (PD) across different disease stages and to elucidate to what extent cortical thinning is related to cognitive impairment.
Ninety-six subjects including 39 controls and 57 PD patients participated in this study. PD subjects were divided into three groups (early, n=24; moderate, n=18; with dementia, n=15). High field structural brain MRI images were acquired in a 3T scanner and analyses of cortical thickness and surface were carried out. Vertex-wise group comparisons were performed and cortical thickness was correlated with motor and cognitive measures.
We found a positive correlation between Mini-Mental State Examination scores and cortical thickness in the anterior temporal, dorsolateral prefrontal, posterior cingulate, temporal fusiform and occipitotemporal cortex. Unified Parkinson's Disease Rating Scale-III (motor subsection) scores showed a robust negative correlation with caudate volumes. We found that disease stage in PD was associated with thinning of the medial frontal (premotor and supplementary motor cortex), posterior cingulate, precuneus, lateral occipital, temporal and dorsolateral prefrontal cortex. Discriminant analysis and a receiver operating characteristics approach showed that mean cortical thickness and hippocampus volume have 80% accuracy in identifying PD patients with dementia. PD stage and PD dementia can be characterised by a specific pattern of cortical thinning.
We conclude that measuring cortical thickness can be useful in assessing disease stage and cognitive impairment in patients with PD. In addition, cortical thickness may be useful in identifying dementia in PD.
A lot of the focus has rightly been on the role of vitamin D due to its pleuripotent effects on the immune system; however, recent work has suggested that sunlight itself may be an independent modulator of MS clinical course and MS onset acting on inflammation...]]>
Expansions of a hexanucleotide repeat in C9ORF72 are a common cause of familial amyotrophic lateral sclerosis (ALS) and a small proportion of sporadic ALS cases. We sought to examine clinical and neurophysiological features of familial and sporadic ALS with C9ORF72 expansions.
C9ORF72 was screened for expansions in familial and sporadic ALS. Clinical features of expansion positive cases are described. Cortical excitability studies used novel threshold tracking transcranal magnetic stimulation techniques with motor evoked responses recorded over the abductor pollicis brevis.
Analysis of large clinical cohorts identified C9ORF72 expansions in 38.5% (72/187) of ALS families and 3.5% (21/606) of sporadic ALS cases. Two expansion positive families were known to carry reported ANG mutations, possibly implicating an oligogenic model of ALS. 6% of familial ALS cases with C9ORF72 expansions were also diagnosed with dementia. The penetrance of ALS was 50% at age 58 years in male subjects and 63 years in female subjects. 100% penetrance of ALS was observed in male subjects by 86 years, while 6% of female subjects remained asymptomatic at age 82 years. Gender specific differences in age of onset were evident, with male subjects significantly more likely to develop ALS at a younger age. Importantly, features of cortical hyperexcitability were apparent in C9ORF72-linked familial ALS as demonstrated by significant reduction in short interval intracortical inhibition and cortical silent period duration along with an increase in intracortical facilitation and motor evoked potential amplitude, indicating that cortical hyperexcitability is an intrinsic process in C9ORF72-linked ALS.
The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML).
To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML.
An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls.
Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML.
Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted.
Vascular endothelial growth factor (VEGF) plays an essential role in the pathophysiology of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome. Anti-VEGF antibody (bevacizumab) appears to be an attractive therapeutic option. The aim of this study is to investigate the effects of bevacizumab for patients with POEMS syndrome.
We reported six POEMS patients treated with bevacizumab and reviewed the literature.
The serum VEGF levels decreased immediately after bevacizumab administration in all six patients. However, four patients had entirely no clinical response, and two of them died. The remaining two showed improvement that could be explained by combined treatments. We also reviewed the literature and found 11 patients treated with bevacizumab; of these, only one was treated with bevacizumab alone. 10 had combined treatments, and four died without any response.
Both our experience and the literature suggest ambiguous effects of bevacizumab; inhibition of VEGF alone may be insufficient because multiple cytokines are upregulated, or aberrant neo-vascularization may have already fully developed in the advanced stage of POEMS syndrome.
Late-onset limb-girdle muscle weakness with tubular aggregates, effective cholinesterase inhibitors and spared extraocular muscles are hallmarks of glycosylation defect-associated congenital myasthenia.
Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by germline mutations in genes encoding molecules expressed at the neuromuscular junction. In all, 14 genes (CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, RAPSN, SCN4A, MUSK, DOK7, PLEC1, LAMB2, COLQ, CHAT, AGRN) had been identified in association with CMS by 2006. All the identified molecules function exclusively at the neuromuscular junction except for choline acetyltransferase, which is also essential for cholinergic synapses in the central nervous system.
Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis.
We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in meta-analyses, and assessed small study bias.
58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE 4 with CAA (4 present vs absent, pooled OR 2.7, 95% CI 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE 2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor β1 gene (two studies, 449 participants), translocase of outer mitochondrial membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (~200 participants) of APOE and hereditary CAA or familial Alzheimer's disease.
There is convincing evidence for a dose dependent association between APOE 4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA.
Fasciculation potentials (FPs) are a spontaneous discharge of a motor units, frequently, but not invariably, visible as a muscle contraction.
Cognitive impairment and dementia are common after stroke. It is unclear if risk differs between ischaemic stroke subtypes. Lacunar strokes might be less likely to affect cognition than more severe, larger cortical strokes, except that lacunar strokes are associated with cerebral small vessel disease (SVD), which is the commonest vascular cause of dementia.
We searched MEDLINE and PsychINFO for studies of mild cognitive impairment (MCI) or dementia after lacunar or cortical ischaemic stroke. We calculated the OR for cognitive impairment/dementia in lacunar versus non-lacunar stroke, and their incidence and prevalence in lacunar stroke as a pooled proportion.
We identified 24 relevant studies of 7575 patients, including 2860 with lacunar stroke; 24% had MCI or dementia post stroke. Similar proportions of patients with lacunar and non-lacunar stroke (16 studies, n=6478) had MCI or dementia up to 4 years after stroke (OR 0.72 (95% CI 0.43 to 1.20)). The prevalence of dementia after lacunar stroke (six studies, n=1421) was 20% (95% CI 9 to 33) and the incidence of MCI or dementia (four studies, n=275) was 37% (95% CI 23 to 53). Data were limited by short follow-up, subtype classification methods and confounding.
Cognitive impairment appears to be common after lacunar strokes despite their small size, suggesting that associated SVD may increase their impact. New prospective studies are required with accurate stroke subtyping to assess long term outcomes while accounting for confounders.
He who is faithfully analysing many different cases of epilepsy is doing far more than studying epilepsy. Hughlings Jackson
Déjà vu is an infrequent and nebulous mental experience—a mismatch between subjective perceptions of memory and retrieval itself.
There has been a constant problem with the TLE literature and our understanding of déjà vu more generally. Despite the fact that in other domains we have learned a great deal about cognition through the study of epilepsy—I would say cognitive neuropsychology is indebted to it—there has always been the idea that déjà vu in TLE is abnormal. The relationship between...]]>
Ion channel disorders are one of the most challenging areas in neurology and basic neuroscience with more than 27 500 results in a PubMed search and an increasing annual publication rate. They have become of particular relevance in muscle disorders (eg, myotonias), epilepsy (eg, benign familial neonatal epilepsy), paraneoplastic syndromes (eg, antibodies against ion channels as in Isaac's syndrome) cerebellar ataxias (eg, episodic ataxias
To investigate whether gravitational valves reduce the risk of overdrainage complications compared with programmable valves in ventriculoperitoneal (VP) shunt surgery for idiopathic normal pressure hydrocephalus (iNPH).
Patients with iNPH may benefit from VP shunting but are prone to overdrainage complications during posture changes. Gravitational valves with tantalum balls are considered to reduce the risk of overdrainage but their clinical effectiveness is unclear.
We conducted a pragmatic, randomised, multicentre trial comparing gravitational with non-gravitational programmable valves in patients with iNPH eligible for VP shunting. The primary endpoint was any clinical or radiological sign (headache, nausea, vomiting, subdural effusion or slit ventricle) of overdrainage 6 months after randomisation. We also assessed disease specific instruments (Black and Kiefer Scale) and Physical and Mental Component Scores of the Short Form 12 (SF-12) generic health questionnaire.
We enrolled 145 patients (mean (SD) age 71.9 (6.9) years), 137 of whom were available for endpoint analysis. After 6 months, 29 patients in the standard and five patients in the gravitational shunt group developed overdrainage (risk difference –36%, 95% CI –49% to –23%; p<0.001). This difference exceeded predetermined stopping rules and resulted in premature discontinuation of patient recruitment. Disease specific outcome scales did not differ between the groups although there was a significant advantage of the gravitational device in the SF-12 Mental Component Scores at the 6 and 12 month visits.
Implanting a gravitational rather than another type of valve will avoid one additional overdrainage complication in about every third patient undergoing VP shunting for iNPH.
Osler noted, ‘It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has’. In amyotrophic lateral sclerosis (ALS), a previously functional motor system undergoes a catastrophic, typically rapid degeneration, with a median survival from symptom onset of 3 years.
ALS abruptly ended the career of American baseball hero Lou Gehrig in 1941. ‘The Iron Horse’ never missed a game, and his record of 2130 consecutive appearances stood until 1995. A legendary athlete, he is seen to jump over a chair in Rawhide,
On admission, our patient fulfilled the criteria for major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000), presenting with depressed mood, insomnia, psychomotor retardation and inappropriate guilt. Moreover, she experienced intense hopelessness due to her history of facial pain resistant to medical therapy, which led her to refuse other therapeutic approaches. Furthermore, years back she had been told that other neurological...]]>
A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement.
We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations.
Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present.
These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype.
Behavioural disorders associated with compulsive use of dopaminergic drugs for Parkinson's disease (PD) such as dopamine dysregulation syndrome (DDS) and impulse control disorders (ICDs) may have devastating consequences and are challenging to manage. Whether or not such patients should undergo subthalamic nucleus (STN) deep brain stimulation (DBS) is controversial. A few case reports and small series have reported contrasting effects of STN DBS on dopamine misuse and ICDs, while a recent prospective study found clear beneficial effects of STN DBS on these disorders.
We conducted an observational study on 110 consecutive parkinsonian patients scheduled for STN DBS surgery. Patients were assessed preoperatively through extensive behavioural and psychiatric evaluations and divided into two groups: with or without compulsive dopaminergic medication use. Evaluations were repeated 1 year after surgery in both groups.
Before surgery 18 patients (16.3%) were compulsive dopamine users of whom 12 (10.9%) fulfilled all criteria for DDS. 90% of these patients also had at least one ICD compared to 20% in the group without compulsive dopamine use. One year after surgery, one patient had persistent compulsive dopamine use, while no new occurrences were reported in the group without the condition before surgery. STN DBS did not provoke any major psychiatric complications and ICDs were reduced in all patients.
Our results suggest that STN DBS may reduce compulsive use of dopaminergic medication and its behavioural consequences. Whether this improvement is the result of STN DBS or the consequence of better treatment management remains to be established.
While the dust has yet to settle on the diagnostic facts of the matter, interviews with patients, their families and many experts made abundantly clear how unpalatable a diagnosis of conversion disorder can...]]>
Oligoclonal bands (OCBs) unique to the cerebrospinal fluid are used in the diagnosis of multiple sclerosis (MS). The precise prevalence of OCBs in MS and clinically isolated syndrome (CIS) is unknown. The influence of OCBs on clinical outcomes has not been quantified. OCB prevalence has been associated with latitude in a single study, if confirmed this would provide avenues for further study.
Using a systematic review and meta-analysis approach, the proportion of OCB-positive MS and CIS and the influence of OCBs on clinical outcomes were calculated. The relationship between latitude and OCB prevalence was calculated using linear regression.
Seventy-one articles were included. Overall, 87.7% of 12 253 MS and 68.6% of 2685 CIS patients were OCB positive. OCB-positive MS patients had an OR of 1.96 of reaching disability outcomes, although a number of negative studies did not provide data. OCB-positive CIS patients had an OR of 9.88 of conversion to MS. Latitude predicted OCB status in MS patients (p=0.009) but not in CIS patients.
This is the largest study of OCB prevalence in MS and CIS. OCB positivity strongly predicts conversion from CIS to MS. The relationship between latitude and OCBs is confirmed, and this finding warrants further investigation.
Subarachnoid haemorrhage (SAH) patients have an excess mortality proportion in long-term outcome studies because of the high rate of cerebrovascular and cardiovascular deaths. The aim of the present study was to assess the excess long-term mortality among patients with unruptured aneurysms with no previous SAH and to compare excess mortality after coiling, clipping and without treatment.
Between 1989 and 1999, a total of 1294 patients with intracranial aneurysms were admitted to our hospital. Of these, 1154 had previous SAH and were excluded leaving 140 patients with 178 intracranial unruptured aneurysms as the study population. The patients were followed up until death or by the end of April 2011. Causes of death were determined. Relative survival ratios (RSR
Mean follow-up time was 13 years (range 1–19). During the follow-up period, 36% of patients died. Death was caused by cerebrovascular event in half of the cases. There were 12% excess mortality at 15 years in men and 35% excess mortality in women compared with general population. Excess mortality among women over 50 years was significantly higher than that among men (p=0.018).
Patients with untreated unruptured aneurysms have 50% excess long-term mortality compared with general population. Men with treated unruptured aneurysms have a survival proportion comparable with matched general population. Women, instead, have 28% excess mortality after surgical treatment and 23% excess mortality after endovascular treatment of unruptured aneurysms.
Psychogenic movement disorders are disorders of movements that cannot be explained by a known neurological disorder and are assumed to be associated with psychiatric symptoms such as depression and anxiety.
To examine the neuropsychological profile of patients with psychogenic movement disorders.
We examined cognitive functioning using neuropsychological tests in 26 patients with clinically established psychogenic jerky movement disorders (PMD). We included 16 patients with Gilles de la Tourette syndrome (GTS) who served as a patient control group, in addition to 22 healthy control subjects. Non-credible test performance was detected using a Symptom Validity Test (SVT). Psychopathology was also assessed.
Apart from a worse performance on a verbal memory task, no evidence of neuropsychological impairments was found in our PMD sample. Interestingly however, patients with PMD reported more cognitive complaints in daily life and performed worse on the SVT than the two other groups. Patients with GTS did not report, or show, cognitive impairments. In patients with PMD, we found associations between verbal learning, SVT performance and severity of depression and anxiety complaints.
We conclude that some patients with PMD show non-credible cognitive symptoms. In contrast, no evident cognitive impairments were present in patients with PMD or GTS. Our study underlines the importance of assessment of non-credible response in patients with PMD. Additionally, non-credible response might aid in the differentiation of PMD from other movement disorders.
In addition, a definition of dementia that focuses on cognitive symptoms might conceal early non-cognitive symptoms. In fact, we have learned from diverse recent studies that dementia is often preceded by depressive symptoms years before the onset of cognitive decline. It remains...]]>
To investigate whether poststroke dementia (PSD) diagnosed after ischaemic stroke predicts recurrent ischaemic stroke in long-term follow-up.
We included 486 consecutive patients with ischaemic stroke (388 with first-ever stroke) admitted to Helsinki University Central Hospital who were followed-up for 12 years. Dementia was diagnosed in 115 patients using the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III) criteria. The effects of risk factors and PSD on survival free of recurrent stroke were estimated using Kaplan–Meier log-rank analyses, and the HRs for stroke recurrence were calculated using Cox proportional hazards models.
In the entire cohort, patients with PSD had a shorter mean time to recurrent stroke (7.13 years, 95% CI 6.20 to 8.06) than patients without dementia (9.41 years, 8.89 to 9.92; log rank p<0.001). This finding was replicated in patients with first-ever stroke (6.89 years, 5.85 to 7.93 vs 9.68 years, 9.12 to 10.24; p<0.001). In Cox univariate analysis, PSD was associated with increased risk for recurrent stroke both in the entire cohort (HR 2.02; 95% CI 1.47 to 2.77) and in those with first-ever stroke (2.40; 1.68 to 3.42). After adjustment for the significant covariates of age, atrial fibrillation, peripheral arterial disease and hypertension, PSD was associated with increased risk for recurrent stroke both in the entire cohort (1.84; 1.34 to 2.54) and in those with first-ever stroke (2.16; 1.51 to 3.10).
Poststroke dementia predicts recurrence of ischaemic stroke in long-term follow-up and should be considered when estimating prognosis.
White matter hyperintensities (WMHs) are associated with vascular cognitive impairment (VCI) but fail to correlate with neuropsychological measures. As proton MR spectroscopy (1H-MRS) can identify ischaemic tissue, we hypothesised that MRS detectable brain metabolites would be superior to WMHs in predicting performance on neuropsychological tests.
60 patients with suspected VCI underwent clinical, neuropsychological, MRI and CSF studies. They were diagnosed as having subcortical ischaemic vascular disease (SIVD), multiple infarcts, mixed dementia and leukoaraiosis. We measured brain metabolites in a white matter region above the lateral ventricles with 1H-MRS and WMH volume in this region and throughout the brain.
We found a significant correlation between both total creatine (Cr) and N-acetylaspartyl compounds (NAA) and standardised neuropsychological test scores. Cr levels in white matter correlated significantly with executive function (p=0.001), attention (p=0.03) and overall T score (p=0.007). When lesion volume was added as a covariate, NAA also showed a significant correlation with executive function (p=0.003) and overall T score (p=0.015). Furthermore, while metabolite levels also correlated with total white matter lesion volume, adjusting the Cr levels for lesion volume did not diminish the strength of the association between Cr levels and neuropsychological scores. The lowest metabolite levels and neuropsychological scores were found in the SIVD group. Finally, lesion volume alone did not correlate significantly with any neuropsychological test score.
These results suggest that estimates of neurometabolite levels provide additional and useful information concerning cognitive function in VCI not obtainable by measurements of lesion load.
It has been hypothesised that physical activity is a risk factor for developing amyotrophic lateral sclerosis (ALS), fuelled by observations that professional soccer players and Gulf War veterans are at increased risk. In a population based study, we determined the relation between physical activity and risk of sporadic ALS, using an objective approach for assessing physical activity.
636 sporadic ALS patients and 2166 controls, both population based, completed a semistructured questionnaire on lifetime history of occupations, sports and hobbies. To objectively compare the energy cost of a lifetime history of occupational and leisure time physical activities and to reduce recall bias, metabolic equivalent scores were assigned to each activity based on the Compendium of Physical Activities.
ALS patients had significantly higher levels of leisure time physical activity compared with controls (OR 1.08, 95% CI 1.02 to 1.14, p=0.008). No significant difference was found between patients and controls in the level of vigorous physical activities, including marathons and triathlons, or in occupational activity. Cumulative measures of physical activity in quartiles did not show a dose–response relationship.
An increased risk of ALS with higher levels of leisure time physical activity was found in the present study. The lack of association with occupational physical activity and the absence of a dose–response relationship strengthen the hypothesis that not increased physical activity per se but rather a genetic profile or lifestyle promoting physical fitness increases ALS susceptibility.
There is little information on the earliest changes in motor unit (MU) physiology in amyotrophic lateral sclerosis (ALS) and the development of the classical neurophysiological features of ALS over time.
We studied the earliest abnormalities in MU physiology in ALS and changes over time.
Observational, cross-sectional and longitudinal study.
We studied the tibialis anterior (TA) muscle in three groups of subjects; 73 patients with ALS, 10 with benign fasciculation and 37 healthy control subjects. In the ALS group, 61 had normal strength in the TA muscle and 12 had TA muscle strength of 4 on the medical research council scale. In all subjects we evaluated the presence of fasciculation potentials (FPs) and fibrillation/sharp-waves (fibs-sw), and quantified MU potentials (MUPs) and jitter. Twenty-six ALS patients with TA muscle of normal strength were investigated in serial studies.
FPs were recorded in TA muscles (medical research council 5) of 21 ALS patients with normal MUPs. Longitudinal studies confirmed that the patients presenting with FPs as the only abnormality progressed to MUP instability before large MUPs associated with fibs-sw were detected. FPs from ALS patients with no other neurophysiological change were simpler than in patients in whom there were also fibs-sw and neurogenic MUPs. The complexity of FPs in patients with weak TA muscle was greater than in the latter group. FPs in patients with benign fasciculations were simpler than FPs in ALS patients with normal TA muscle strength.
FPs are a very early marker of ALS and anticipate MUP instability or reinnervation, consistent with a very early phase of increased axonal excitability. Later, widespread neuronal dysfunction causes widespread fibs-sw and loss of MUPs with compensatory reinnervation. Our results confirm the importance of FP morphology analysis in the differential diagnosis of ALS and other disorders, and indicate that benign FPs represent a different phenomenon.
Hereditary liability to pressure palsies (HNPP) is an autosomal dominant disorder of myelination resulting in susceptibility to pressure palsies from compression or stretching of peripheral nerves.
This study examined axonal excitability at two sites (one distal and one proximal) in five patients with biopsy and genetically proven HNPP to understand the pathophysiology of the disease. Comparisons were made with age-matched control subjects as well as five Charcot-Marie-Tooth type 1A patients to contrast the findings and explain the different phenotypes of diseases affecting the same gene.
Changes in axonal excitability were found in HNPP subjects, but these were not uniform along the nerve: at the wrist there were prominent alterations in threshold electrotonus, whereas at the elbow there were only subtle alterations in the recovery cycle and the response to strong long-lasting hyperpolarisation. Threshold was raised at both sites, but the nerves were probably not hyperpolarised. Not unexpectedly, changes in CMT1A subjects were more marked than those in HNPP subjects and were uniform along the nerve.
Structural abnormalities at the node of Ranvier are sufficient to explain the changes in axonal excitability in HNPP, and these abnormalities would predispose the nerves to conduction block when subjected to pressure or stretch.
The paper by Ammirati and Colleagues
This conclusion is reached on the basis of what is purported to be a meta-analysis of the pertinent published English literature. They present a detailed and time consuming, but, in the opinion of this reviewer, deeply flawed methodology.
In fact, the actual numbers of vascular complications leading to this conclusion were 14 of 3023 microscopic cases reported from 1997 through 2009 and 26 of 1887 endoscopic cases reported from 2002 through 2011. It should be noted that nearly half of the vascular complications from microscopic surgery were reported by one group. Somehow this is made to be...]]>
The current criteria for conversion disorder in the Diagnostic and Statistical Manual of Mental Disorders rely on the assumption that neurological disorders can be distinguished from conversion disorders through clinical assessment. This study aims to assess inter-rater agreement among clinicians with experience in the diagnosis of various hyperkinetic jerky movements, including psychogenic jerks.
60 patients with psychogenic jerks, myoclonus or tics were rated by international experts using a standardised survey resembling daily clinical practice. The survey included the following diagnostic steps: a short video offering a visual impression of the patients and their jerky movements, medical history, neurological examination (on video), additional investigations and the findings of a standardised psychiatric interview. The diagnosis and diagnostic certainty were scored after each step.
After all clinical information was given, moderate inter-rater agreement was reached (=0.56±0.1) with absolute agreement (100%) of experts on the diagnosis in 12 (20%) patients and reasonable agreement (>75%) in 43 (72%) patients. Psychiatric evaluation did not contribute to inter-rater agreement or diagnostic certainty.
Our findings illustrate the fact that experienced movement disorder specialists moderately agree on the clinical diagnosis of jerky movements. Clinical assessment, especially by a team of clinicians in challenging individual cases, might improve diagnostic agreement.
Survival after malignant middle cerebral artery infarcts is dismal. In 2007, a pooled analysis of randomised trials in Europe demonstrated a substantial survival benefit from decompressive hemicraniectomy, with a number needed to treat of 2 for survival. Our objective was to review factors driving the nationwide utilisation of this potentially lifesaving procedure in the USA.
Data from the Nationwide Inpatient Sample for 2001–2009 were reviewed. Hospitalisations with a discharge diagnosis of an acute ischaemic stroke were included. Hemicraniectomy utilisation was determined within this subset. Nationwide estimates of utilisation were calculated for each year. Trends across the years were estimated for various subgroups.
From 2001 to 2009, there were an estimated 4 909 519 acute ischaemic stroke discharges. The estimated frequency of hemicraniectomy increased from 118 (0.02% of stroke discharges in 2001) to 804 (0.15% of stroke discharges in 2009) (trend p<0.001). The increased utilisation was greatest for younger subjects (age<45 years; trend p<0.001) and men (trend p<0.001). Urban teaching hospitals were responsible for the greatest increase in hemicraniectomy utilisation: from 0.05% of stroke discharges in 2001 to 0.28% in 2009. The increase was steady and sustained over the decade. In comparison, rural and urban non-teaching hospitals showed a much smaller improvement in utilisation.
Utilisation of hemicraniectomy in the USA has increased significantly, in line with compelling results from European clinical trials. Early transfer of patients with malignant infarctions to urban teaching centres could potentially extend the survival benefit to a larger population.
In treating idiopathic normal pressure hydrocephalus (INPH) with a shunt there is always a risk of underdrainage or overdrainage. The hypothesis is tested whether patients treated using an adjustable valve preset at the highest opening pressure leads to comparable good clinical results with less subdural effusions than in a control group with an opening pressure preset at a low pressure level.
A multicentre prospective randomised trial was performed on a total of 58 patients suspected of INPH. Thirty patients were assigned to (control) group 1 and received a Strata shunt (Medtronic, Goleta, USA) with the valve preset at a performance level (PL) of 1.0, while 28 patients were assigned to group 2 and received a Strata shunt with the valve preset at PL 2.5. In this group the PL was allowed to be lowered until improvement or radiological signs of overdrainage were met.
Significantly more subdural effusions were observed in the improved patients of group 1. There was no statistically significant difference in improvement between both groups overall.
On the basis of this multicentre prospective randomised trial it is to be recommended to treat patients with INPH with a shunt with an adjustable valve, preset at the highest opening pressure and lowered until clinical improvement or radiological signs of overdrainage occur although slower improvement and more shunt adjustments might be the consequence.
Under proper supervision first-line treatments for chronic fatigue syndrome are effective and safe but research into second-line treatment is required.
In the paper by Smith and Wessely,
A wide range of diagnostic criteria are used in research and clinical practice
It is suggested that disturbed CSF dynamics are involved in the pathophysiology of idiopathic normal pressure hydrocephalus (INPH). The pulsatility curve describes the relationship between intracranial pressure (ICP) and the amplitude of cardiac related ICP pulsations. The position of baseline ICP on the curve provides information about the physiological state of the CSF dynamic system. The objective of the study was to investigate if shunt surgery modifies the pulsatility curve and the baseline position on the curve, and how this relates to gait improvement in INPH.
51 INPH patients were investigated with lumbar CSF dynamic investigations preoperatively and 5 months after shunt surgery. During the investigation, ICP was measured at baseline, and then a CSF sample was removed, resulting in pressure reduction. After this, ICP was regulated with an automated infusion protocol, with a maximum increase of 24 mm Hg above baseline. The pulsatility curve was thus determined in a wide range of ICP values. Gait improvement was defined as a gait speed increase ≥0.1 m/s.
The pulsatility curve was unaltered by shunting. Baseline ICP and amplitude were reduced (–3.0±2.9 mm Hg; –1.1±1.5 mm Hg; p<0.05, n=51). Amplitude reduction was larger for gait improvers (–1.2±1.6 mm Hg, n=42) than non-improvers (–0.2±0.5 mm Hg, n=9) (p<0.05) although mean ICP reduction did not differ.
The pulsatility curve was not modified by shunt surgery, while the baseline position was shifted along the curve. Observed differences between gait improvers and non-improvers support cardiac related ICP pulsations as a component of INPH pathophysiology.
To evaluate the very long-term clinical outcome of surgery for mesial temporal lobe epilepsy and unilateral hippocampal sclerosis (MTLE/HS) without atypical features. The impact of surgical technique and postoperative reduction of medication on this outcome was investigated.
Prospective longitudinal cohort follow-up study for up to18 years.
Epilepsy surgery centre in a university hospital.
108 patients who underwent unilateral MTLE/HS.
Surgery for MTLE/HS.
Engel classification (I). Clinical evaluations were based on systematic interviews in person or by phone. Kaplan-Maier survival curves estimated the probability of remaining seizure free. The impact of medication management in the postoperative outcome was analysed using Cox regression.
The probability of remaining completely seizure-free at 12 and 18 years after MTLE/HS surgery was 65% and 62%, respectively. The risk of having any recurrence was 22% during the first 24 months and increased 1.4% per year afterwards. Type of surgical technique (selective amygdalohippocampectomy vs anterior temporal lobectomy) did not impact on outcome. Remaining on antiepileptic drugs and history of generalised clonic seizure diminished the probability of remaining seizure free.
MTLE/HS surgery is able to keep patients seizure free for almost up to two decades. Removal of the neocortex besides the mesial portion of the temporal lobe does not lead to better chances of seizure control. These findings are applicable to the typical unilateral MTLE/HS syndrome and cannot be generalised for all types of TLE. Future longitudinal randomised controlled studies are needed to replicate these findings.
To assess the relationships of sun exposure history, supplementation and environmental factors to vitamin D levels in multiple sclerosis (MS) patients and to evaluate the associations between sun exposure and MRI measures.
This study included 264 MS patients (mean age 46.9±10 years, disease duration 14.6±10 years; 67.8% relapsing–remitting, 28% secondary progressive and 4.2% primary progressive MS) and 69 healthy controls. Subjects underwent neurological and 3 T MRI examinations, provided blood samples and answered questions to a structured questionnaire. Information on race, skin and eye colour, supplement use, body mass index (BMI) and sun exposure was obtained by questionnaire. The vitamin D metabolites (25-hydroxy vitamin D3, 1, 25-dihydroxy vitamin D3 and 24, 25-dihydroxy vitamin D3) were measured using mass spectrometry.
Multivitamin supplementation (partial correlation rp=0.29, p<0.001), BMI (rp=–0.24, p=0.001), summer sun exposure (rp=0.22, p=0.002) and darker eye colour (rp=–0.18, p=0.015) had the strongest associations with vitamin D metabolite levels in the MS group. Increased summer sun exposure was associated with increased grey matter volume (GMV, rp=0.16, p=0.019) and whole brain volume (WBV, rp=0.20, p=0.004) after correcting for Extended Disability Status Scale in the MS group. Inclusion of 25-hydroxy vitamin D3 levels did not substantially affect the positive associations of sun exposure with WBV (rp=0.18, p=0.003) and GMV (rp=0.14, p=0.026) in the MS group.
Sun exposure may have direct effects on MRI measures of neurodegeneration in MS, independently of vitamin D.
Major depression is common in stroke patients and associated with increased rates of disability and mortality. Identifying depression may improve mental and physical health. The aim of this review was to determine the most accurate tool for detecting poststroke depression.
Seven databases were searched up to November 2012. Two authors selected studies using International Classification of Disease or Diagnostic and Statistical Manual diagnosis of depression as the reference standard. Two authors extracted data and assessed methodological quality. Included studies were synthesised using meta-analyses.
A total of 24 included studies provided data on 2907 participants. The Center of Epidemiological Studies-Depression Scale (CESD) (sensitivity: 0.75; 95% CI 0.60 to 0.85; specificity: 0.88; 95% CI 0.71 to 0.95), the Hamilton Depression Rating Scale (HDRS) (sensitivity: 0.84; 95% CI 0.75 to 0.90; specificity:0.83; 95% CI 0.72 to 0.90) and the Patient Health Questionnaire (PHQ)-9 (sensitivity: 0.86; 95% CI 0.70 to 0.94; specificity: 0.79; 95% CI 0.60 to 0.90) appeared to be the optimal measures for screening measures. However, the clinical utility of all tools was modest for case-finding.
There are a number of possible instruments that may help in screening for poststroke depression but none are satisfactory for case-finding. Preliminary data suggests the CESD, HDRS or the PHQ-9 as the most promising options. Although it should be noted such scales should not be used in isolation but followed up with a more detailed clinical assessment. While there is promising data for the PHQ-2 in other populations, it performed less well than other measures.
Management of psychogenic movement disorders (PMDs) is challenging for neurologists and, to date, there is no consensus about their treatment. Recent studies suggested a possible therapeutic effect of repeated transcranial magnetic stimulation (TMS) in psychogenic paralysis and tremor.
To document the clinical impact of TMS in PMDs.
We blindly video scored symptoms of consecutive patients with PMD who were recorded before and after TMS. TMS was delivered at low frequency (0.25 Hz) over the motor cortex contralateral to symptoms.
Twenty-four patients were included. They presented with dystonia, myoclonus, tremor, Parkinsonism or stereotypies. The median duration of symptoms before TMS was 2.8 years (6 months to 30 years). The overall score of 75% of patients improved by >50% and, furthermore, the clinical benefits were sustained upon protracted follow-up (median 19.8 months). There was no correlation between improvement and duration of symptoms before TMS.
TMS is a therapeutic option for PMDs, including chronic PMDs.
Population-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with several clinical syndromes including mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), maternally inherited deafness and diabetes (MIDD) and progressive external ophthalmoplegia (PEO). Many patients affected by this mutation exhibit a clinical phenotype that does not fall within accepted criteria for the currently recognised classical mitochondrial syndromes.
We have defined the phenotypic spectrum associated with the m.3243A>G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK.
10% of patients exhibited a classical MELAS phenotype, 30% had MIDD, 6% MELAS/MIDD, 2% MELAS/chronic PEO (CPEO) and 5% MIDD/CPEO overlap syndromes. 6% had PEO and other features of mitochondrial disease not consistent with another recognised syndrome. Isolated sensorineural hearing loss occurred in 3%. 28% of patients demonstrated a panoply of clinical features, which were not consistent with any of the classical syndromes associated with the m.3243A>G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic.
Following this study we propose guidelines for screening and for the management of confirmed cases.
Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations.
15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry.
Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of Kv1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia.
The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of Kv1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between Kv1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.
Ammirati and colleagues report the results of their meta-analysis comparing the results of the short-term outcome of pituitary surgery performed using a purely endoscopic approach versus a microscopic approach.
Antiepileptic drug therapy for epilepsy and mood disorders and pain management has been greatly enhanced and expanded by a growing array of therapeutic options. With choice comes the need for knowledge about the potential adverse effects of medications that may be taken lifelong. The adverse event profile of the established antiepileptic drug therapies is well established, but that of the newer agents continues to grow. Much of the known side effect profile comes from clinical trial data, which do not reflect the pattern or nature of use once an agent is marketed and available to the wider community.
Weight gain with some antiepileptic drugs has been well described, and this potential side effect should be included in the informed decision making of all patients. While valproate, and to a lesser extent carbamazepine and gabapentin are recognised to increase the weight of some patients, topiramate may produce weight loss. An...]]>
Déjà vu can occur as an aura of temporal lobe epilepsy and in some psychiatric conditions but is also common in the general population. It is unclear whether any clinical features distinguish pathological and physiological forms of déjà vu.
50 epileptic patients with ictal déjà vu, 50 non-epileptic patients attending general neurology clinics and 50 medical students at Edinburgh University were recruited. Data were collected on demographic factors, the experience of déjà vu using a questionnaire based on Sno's Inventory for Déjà Vu Experiences Assessment, symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale as well as seizure characteristics, anti-epileptic medications, handedness, EEG and neuroimaging findings for epileptic patients.
73.5% of neurology patients, 88% of students and (by definition) all epilepsy patients had experienced déjà vu. The experience of déjà vu itself was similar in the three groups. Epileptic déjà vu occurred more frequently and lasted somewhat longer than physiological déjà vu. Epilepsy patients were more likely to report prior fatigue and concentrated activity, associated derealisation, olfactory and gustatory hallucinations, physical symptoms such as headaches, abdominal sensations and fear. After controlling for study group, anxiety and depression scores were not associated with déjà vu frequency.
Déjà vu is common and qualitatively similar whether it occurs as an epileptic aura or normal phenomenon. However ictal déjà vu occurs more frequently and is accompanied by several distinctive features. It is distinguished primarily by ‘the company it keeps’.
To determine which neuropsychological test measures and which symptoms at presentation might best differentiate dementia with Lewy bodies (DLB) from Alzheimer's disease (AD).
Cases were from the Columbia University Alzheimer's Disease Research Center, and included cases with pathological diagnosis of pure DLB (n=12), mixed DLB and AD (DLB+AD n=23) and pure AD (n=89) who had Clinical Dementia Rating 0, 0.5 or 1 at their first visit. Clinical symptoms and neuropsychological test measures were compared for pure DLB, DLB+AD and pure AD using univariate analysis of covariance and separate logistic regression analyses.
Visual hallucinations, illusions and extrapyramidal tract signs were more frequent as clinical features of the early stage of pure DLB compared with AD. The pure DLB patients showed more impaired visuospatial function than pure AD or DLB+AD patients whereas memory function was more severely impaired in pure AD or DLB+AD than in pure DLB. Analysis of memory subscores suggested that failure of retrieval was the major contributor to the memory deficit of DLB. Multiple logistic regression analysis showed that visuospatial function and delayed memory recognition were independent predictors of pure DLB from pure AD and from DLB+AD. But test measures did not discriminate between DLB+AD and pure AD.
Visuospatial function was more affected in pure DLB than in AD while memory retrieval deficit was more affected in AD than in pure DLB, in the early stages of dementia. However, DLB+AD did not show significant neuropsychological difference from pure AD.
In amyotrophic lateral sclerosis, the deadliest form of motor neuron diseases, physicians observe the spread of non-painful paralysis with intact sensory function often presenting as asymmetric muscle atrophy and brisk or maintained reflexes. Using Awaji criteria to estimate upper and lower motor neuron signs in bulbar, cervical, thoracic and lumbar regions, and the highly sensitive electromyography (EMG), they diagnose amyotrophic lateral sclerosis (ALS) in a majority of the cases. The spread of symptoms is attributed to spinal motor neuron pathology, but experienced ALS neurologists will agree that a slowing of movement, loss of fine motor control and occurrence of mass or mirror movements indicate central motor pathway dysfunction, even in the absence of definite pyramidal signs. ALS naïve physicians may misinterpret these ‘soft signs’ of upper motor neuron dysfunction as stroke sequelae and not ALS related, and contribute to unnecessary delays in diagnosis. Unfortunately, we have no tool available...]]>
Early recognition of paediatric autoimmune encephalopathies is critical because they are treatable. Serological findings and response to immunotherapy are confirmatory.
The expedited diagnosis of an autoimmune neurological disorder is critical because early treatment facilitates improvement. The data reported by Hacohen et al from a multi-institutional experience of childhood autoimmune encephalopathies should promote early recognition of these disorders.
Autoimmunity ranks high in the differential diagnosis for encephalopathy. Suspicion is heightened when neuropsychiatric symptom onset is subacute, autoimmunity is recorded in the personal or family history, or serological findings are supportive. Autoantibody detection in serum or cerebrospinal fluid (CSF), with specificities either non-neural (eg, thyroid peroxidase or antinuclear) or neural (eg, N-methyl d-aspartate (NMDA) receptor or voltage-gated potassium channel (VGKC)-complex), provides a valuable clue. Objective improvement documentation following an immunotherapy trial (corticosteroids, intravenous immune globulin or plasmapheresis) aids the diagnosis, and provides a baseline for future reference.
Hacohen et al...]]>
Histological evidence is considered the only proof of primary central nervous system vasculitis (PCNSV). However, brain biopsy is often omitted or delayed because of the invasiveness and possible complications of the procedure. Circulating endothelial cells (CEC) were shown to be elevated in patients with active antineutrophil cytoplasmic antibody-associated vasculitis. We hypothesise that CEC are also elevated in patients with active PCNSV and may contribute to the diagnosis.
CEC were assessed in 18 patients, 3 of whom had biopsy-proven PCNSV and 15 clinical, cerebrospinal fluid and imaging data, highly suggestive of PCNSV. In 3 of these 15 patients CEC assessment was performed after initiation of successful immunosuppressive therapy. CEC numbers of all patients were compared to those of 16 healthy volunteers and 123 subjects with cerebrovascular risk factors and/or ischaemic stroke, who had been studied in our group before. CEC were assessed by immunomagnetic isolation from peripheral blood.
In patients with proven and suspected active PCNSV, CEC were extremely elevated (>400 cells/ml in most of the patients) and significantly higher than in healthy and disease controls (p≤0.01 for each group). CEC significantly decreased with immunosuppressive treatment.
For the first time it is shown that CEC are significantly elevated in patients with active PCNSV in contrast to other pathologies associated with brain infarction and correlate with disease activity. Sensitivity and specificity of the method for diagnosing PCNSV and the use of the method for treatment monitoring should be addressed in future prospective studies with a larger patient group.
To investigate antiepileptic drug (AED)-related weight changes in patients with epilepsy through a retrospective observational study.
We analysed the anonymised electronic primary care records of 1.1 million adult patients in Wales. We included patients aged 18 years and over with a diagnosis of epilepsy, whose body weight had been measured up to 12 months before starting, and between 3 and 12 months after starting, one of five AEDs. We calculated the weight difference after starting the AED for each patient.
1423 patients were identified in total. The mean difference between body weight after and before starting each AED (together with 95% CI and p values for no difference) were: carbamazepine (CBZ) 0.43 (–0.19 to 1.05) p=0.17; lamotrigine (LTG) 0.31 (–0.38 to 1.00) p=0.38; levetiracetam (LEV) 1.00 (0.16 to 1.84) p=0.02; sodium valproate (VPA) 0.74 (0.10 to 1.38) p=0.02; topiramate (TPM) –2.30 (–4.27 to –0.33) p=0.02.
LEV and VPA were associated with significant weight gain, TPM was associated with significant weight loss, and LTG and CBZ were not associated with significant weight change.
To detect anatomical differences in areas related to motor processing between patients with motor conversion disorder (CD) and controls.
T1-weighted 3T brain MRI data of 15 patients suffering from motor CD (nine with hemiparesis and six with paraparesis) and 25 age- and gender-matched healthy volunteers were compared using voxel-based morphometry (VBM) and voxel-based cortical thickness (VBCT) analysis.
We report significant cortical thickness (VBCT) increases in the bilateral premotor cortex of hemiparetic patients relative to controls and a trend towards increased grey matter volume (VBM) in the same region. Regression analyses showed a non-significant positive correlation between cortical thickness changes and symptom severity as well as illness duration in CD patients.
Cortical thickness increases in premotor cortical areas of patients with hemiparetic CD provide evidence for altered brain structure in a condition with presumed normal brain anatomy. These may either represent premorbid vulnerability or a plasticity phenomenon related to the disease with the trends towards correlations with clinical variables supporting the latter.
Known risk factors for Alzheimer's disease and other dementias include medical conditions, genetic vulnerability, depression, demographic factors and mild cognitive impairment. The role of feelings of loneliness and social isolation in dementia is less well understood, and prospective studies including these risk factors are scarce.
We tested the association between social isolation (living alone, unmarried, without social support), feelings of loneliness and incident dementia in a cohort study among 2173 non-demented community-living older persons. Participants were followed for 3 years when a diagnosis of dementia was assessed (Geriatric Mental State (GMS) Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT)). Logistic regression analysis was used to examine the association between social isolation and feelings of loneliness and the risk of dementia, controlling for sociodemographic factors, medical conditions, depression, cognitive functioning and functional status.
After adjustment for other risk factors, older persons with feelings of loneliness were more likely to develop dementia (OR 1.64, 95% CI 1.05 to 2.56) than people without such feelings. Social isolation was not associated with a higher dementia risk in multivariate analysis.
Feeling lonely rather than being alone is associated with an increased risk of clinical dementia in later life and can be considered a major risk factor that, independently of vascular disease, depression and other confounding factors, deserves clinical attention. Feelings of loneliness may signal a prodromal stage of dementia. A better understanding of the background of feeling lonely may help us to identify vulnerable persons and develop interventions to improve outcome in older persons at risk of dementia.
In his thoughtful ‘reality check’ on the future of healthcare Roy Moynihan lists 10 reasons to be optimistic.
Dissociation is a mental process with psychological and somatoform manifestations, which is closely related to hypnotic suggestibility and essentially shows the ability to obtain distance from reality. An increased tendency to dissociate is a frequently reported characteristic of patients with functional neurological symptoms and syndromes (FNSS), which account for a substantial part of all neurological admissions. This review aims to investigate what heart rate variability (HRV), EEG and neuroimaging data (MRI) reveal about the nature of dissociation and related conditions.
Studies reporting HRV, EEG and neuroimaging data related to hypnosis, dissociation and FNSS were identified by searching the electronic databases Pubmed and ScienceDirect.
The majority of the identified studies concerned the physiological characteristics of hypnosis; relatively few investigations on dissociation related FNSS were identified. General findings were increased parasympathetic functioning during hypnosis (as measured by HRV), and lower HRV in patients with FNSS. The large variety of EEG and functional MRI investigations with diverse results challenges definite conclusions, but evidence suggests that subcortical as well as (pre)frontal regions serve emotion regulation in dissociative conditions. Functional connectivity analyses suggest the presence of altered brain networks in patients with FNSS, in which limbic areas have an increased influence on motor preparatory regions.
HRV, EEG and (functional) MRI are sensitive methods to detect physiological changes related to dissociation and dissociative disorders such as FNSS, and can possibly provide more information about their aetiology. The use of such measures could eventually provide biomarkers for earlier identification of patients at risk and appropriate treatment of dissociative conditions.
To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens.
Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007–2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase.
Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect.
Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.
Some years ago, just after starting as a consultant, a patient with an established diagnosis of multiple sclerosis (MS) asked me to prescribe Diet Coca-Cola for her. I was taken aback by the unusual nature of the request, and had to ask why. It turned out that she had watched a Channel 4 documentary programme on television the previous evening, in which a lady called Cari Loder had presented a proposal for a regime of treatment that appeared to benefit her MS. The combination was vitamin B12, a somewhat out-of-fashion antidepressant called Lofepramine, and L-phenylalanine in generous quantity. The latter, the TV commentary had advised, could readily be obtained by drinking a litre or two of Diet Coke every day.
To a new consultant, attempting to fashion my clinical practice around a sound scientific evidence base, this sounded like nonsense. I obtained a recording of the relevant TV programme and...]]>
Recent data suggest that theory of mind (ToM) deficits represent an early symptom of the behavioural variant of frontotemporal dementia (bvFTD). However, longitudinal data on the natural history of subjects presenting with isolated ToM deficits are lacking. The aim of the study was to verify if isolated ToM deficits represent an at-risk state for prefrontal dysfunction and bvFTD.
A population of healthy subjects (n=4150, age range: 50–60 years) completed a clinical and neuropsychological evaluation including the Reading the Mind in the Eyes Test (RMET), a widely used ToM task. From this group, we recruited a low-RMET group (n=83) including subjects with RMET scores lower than 2 SDs but an otherwise normal neuropsychological evaluation and a control group. All subjects underwent evaluation at baseline and after 2 years.
Subjects in the low-RMET group showed decline in prefrontal functions at follow-up. Moreover, at follow-up 12 subjects in the low-RMET group presented with findings suggestive of bvFTD. Neuropsychological performance was stable in the control group.
Our data suggest that isolated ToM deficits could represent an at-risk situation for the development of future prefrontal dysfunction and bvFTD. ToM evaluation should be included in neuropsychological protocols aimed to evaluate the early phases of dementia.
Levetiracetam is a well established second generation antiepileptic drug. It can be used as adjunctive or monotherapy treatment of partial-onset seizures with or without secondary generalisation, or of generalised tonic-clonic seizures.
The study is designed as a pragmatic superiority trial comparing levetiracetam monotherapy with either controlled-release carbamazepine or extended-release sodium valproate in newly diagnosed epilepsy. While it is quite easy to show superiority compared to placebo, head to head trials...]]>
The subthalamic nucleus (STN) is an efficient target for treating patients with Parkinson's disease as well as patients with obsessive–compulsive disorder (OCD) using high frequency stimulation (HFS). In both Parkinson's disease and OCD patients, STN-HFS can trigger abnormal behaviours, such as hypomania and impulsivity.
To investigate if this structure processes emotional information, and whether it depends on motor demands, we recorded subthalamic local field potentials in 16 patients with Parkinson's disease using deep brain stimulation electrodes. Recordings were made with and without dopaminergic treatment while patients performed an emotional categorisation paradigm in which the response varied according to stimulus valence (pleasant, unpleasant and neutral) and to the instruction given (motor, non-motor and passive).
Pleasant, unpleasant and neutral stimuli evoked an event related potential (ERP). Without dopamine medication, ERP amplitudes were significantly larger for unpleasant compared with neutral pictures, whatever the response triggered by the stimuli; and the magnitude of this effect was maximal in the ventral part of the STN. No significant difference in ERP amplitude was observed for pleasant pictures. With dopamine medication, ERP amplitudes were significantly increased for pleasant compared with neutral pictures whatever the response triggered by the stimuli, while ERP amplitudes to unpleasant pictures were not modified.
These results demonstrate that the ventral part of the STN processes the emotional valence of stimuli independently of the motor context and that dopamine enhances processing of pleasant information. These findings confirm the specific involvement of the STN in emotional processes in human, which may underlie the behavioural changes observed in patients with deep brain stimulation.
Body region of onset and functional disability are key components of disease heterogeneity in amyotrophic lateral sclerosis (ALS).
To evaluate patterns of grey matter pathology in the motor cortex and correlate focal structural changes with functional disability.
We conducted a single-centre neuroimaging study of a cohort of 33 cognitively normal patients with amyotrophic lateral sclerosis (ALS) and 44 healthy controls. A voxel-wise generalised linear model was used to investigate the distribution of disease burden within the motor cortex in relation to clinical disability.
Patients with bulbar onset have bilateral focal atrophy in the bulbar segment of the motor homunculus compared with patients with limb onset who have focal cortical changes in the limb segment of their motor strip. Furthermore, the extent to which different body regions are affected in ALS corresponds to the extent of focal grey matter loss in the primary motor cortex. Cortical ALS pathology also extends beyond the motor cortex affecting frontal, occipital and temporal regions.
Focal grey matter atrophy within the motor homunculus corresponds with functional disability in ALS. The findings support the existing concepts of cortical focality and motor phenotype heterogeneity in ALS.
Tremor is known to occur in patients with neuropathies although its reported prevalence varies widely. Tremor has been shown to cause disability in children with Charcot–Marie–Tooth disease but no data exit about the disability caused by tremor in inflammatory neuropathies. Little is known about the response of neuropathic tremor to treatment and why it selectively occurs in some people and not others.
This case control study investigates the presence and severity of tremor in 43 consecutively recruited patients with inflammatory neuropathies at the National Hospital for Neurology and Neurosurgery, London. Clinical assessment, including Fahn–Tolosa–Marin Scale for tremor, sensory scores, power scores and Overall Neuropathy Limitations Scale, were recorded. Results of nerve conduction studies were retrieved and assessed. Nine patients' tremors were recorded with accelerometry.
Tremor was most common in IgM paraproteinaemic neuropathies, as previously reported, but also occurred in 58% of those with chronic inflammatory demyelinating polyradiculoneuropathy and 56% of those with multifocal motor neuropathy with conduction block. We describe, for the first time, tremor in the majority of patients with multifocal motor neuropathy with conduction block. Tremor in all of these patients seems generally refractory to treatment except in a small number of cases where tremor improves with treatment of the underlying neuropathy. We provide evidence that tremor may add to disability in patients with inflammatory neuropathy. Mean tremor frequency was 6 Hz and did not vary with weight loading. We demonstrate for the first time that although tremor severity correlates with F wave latency, it is not sufficient to distinguish those with, from those without, tremor.
Tremor in inflammatory neuropathies is common, adds to disability and yet does not often respond to treatment of the underlying neuropathy. When present, tremor severity is associated with F wave latency.
To compare the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients with newly diagnosed epilepsy.
This unblinded, randomised, 52-week superiority trial (NCT00175903) recruited patients (≥16 years of age) with ≥2 unprovoked seizures in the previous 2 years and ≥1 in the previous 6 months. The physician chose VPA or CBZ as preferred standard treatment; each patient was randomised to standard treatment or LEV. The primary outcome was time to treatment withdrawal (LEV vs standard antiepileptic drugs (AEDs)). Analyses also compared LEV with VPA-ER, and LEV with CBZ-CR.
1688 patients (mean age 41 years; 44% female) were randomised to LEV (n=841) or standard AEDs (n=847). Time to treatment withdrawal was not significantly different between LEV and standard AEDs: HR (95% CI) 0.90 (0.74 to 1.08). Time to treatment withdrawal (HR (95% CI)) was 1.02 (0.74 to 1.41) for LEV/VPA-ER and 0.84 (0.66 to 1.07) for LEV/CBZ-CR. Time to first seizure (HR, 95% CI) was significantly longer for standard AEDs, 1.20 (1.03 to 1.39), being 1.19 (0.93 to 1.54) for LEV/VPA-ER and 1.20 (0.99 to 1.46) for LEV/CBZ-CR. Estimated 12-month seizure freedom rates from randomisation: 58.7% LEV versus 64.5% VPA-ER; 50.5% LEV versus 56.7% CBZ-CR. Similar proportions of patients within each stratum reported at least one adverse event: 66.1% LEV versus 62.0% VPA-ER; 73.4% LEV versus 72.5% CBZ-CR.
LEV monotherapy was not superior to standard AEDs for the global outcome, namely time to treatment withdrawal, in patients with newly diagnosed focal or generalised seizures.