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.
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...]]>
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...]]>
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...]]>
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
Research on the subjective experience of dissociative (psychogenic non-epileptic) seizures (DS) is dominated by that on objective semiology.