Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome–associated seizures disorder

Objective

Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K⁺/H⁺ exchange and in Ca²⁺ homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside.

Methods

Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1.

Results

Three unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1.

Significance

We consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM1.

Epilepsia 2014

Genotype/phenotype in tuberous sclerosis complex: Associations with clinical and radiologic manifestations

Objectives

Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5–20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC.

Methods

Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance).

Results

Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26–2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder.

Significance

The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD.

Epilepsia 2014

Neuropathological features of multiple system atrophy with cognitive impairment

Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA-related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's-related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA-specific α-synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted. 

Movement Disorders 2014

The clinical spectrum of laryngeal dystonia includes dystonic cough: Observations of a large series

Laryngeal dystonia is a movement disorder of the muscles within the larynx, which most commonly manifests as spasmodic dysphonia (SD). Rarer reported manifestations include dystonic respiratory stridor and dyscoordinate breathing. Laryngeal dystonia has been treated successfully with botulinum neurotoxin (BTX) injections since 1984. We reviewed prospectively collected data in a consecutive series of 193 patients with laryngeal dystonia who were seen at St. Vincent's Hospital between 1991 and 2011. Patient data were analyzed in Excel, R, and Prism. Laryngeal dystonia manifested as SD (92.7%), stridor (11.9%), dystonic cough (6.2%), dyscoordinate breathing (4.1%), paroxysmal hiccups (1.6%), and paroxysmal sneezing (1.6%). There were more women (68.4%) than men (31.6%), and the average age at onset was 47 years. A positive family history of dystonia was present in 16.1% of patients. A higher incidence of extra-laryngeal dystonia (ie, torticollis and blepharospasm) and concurrent manifestations of laryngeal dystonia were present in patients with dystonic cough, dyscoordinate breathing, paroxysmal sneezing, and hiccups than in other patients (P = 0.003 and P < 0.0001, respectively). The average starting dose of BTX decreased from 2.3 to 0.5 units between 1991 and 2011. The median treatment rating was excellent across all subgroups. Patients with adductor SD, stridor, extra-laryngeal dystonia and male patients had relatively better treatment outcomes. Technical failures were rare (1.1%). Dysphonia secondary to vocal cord paresis followed 38.7% of treatments. Laryngeal dystonia manifests predominantly as SD, but other manifestations include stridor, dyscoordinate breathing, paroxysmal cough, hiccups, and sneezing. BTX injections are very effective across all subgroups. Severe adverse events are rare. 

Movement Disorders 2014

ARHGEF28 gene exon 6/intron 6 junction mutations in Chinese amyotrophic lateral sclerosis cohort

It was reported that the intron 6, + 1 del G (GT>TT) mutation of the ARHGEF28 gene generates a shortened protein that might be related to amyotrophic lateral sclerosis (ALS). We sequenced this mutation in 25 familial ALS (FALS), 357 sporadic ALS (SALS) patients, and 442 healthy control subjects. We found just two SALS patients exhibited the mutation so that the incidence of this mutation was 0.52% (2/382) of all the ALS patients. The clinical features of the mutation-positive patients were quite different from the case reported in a previous study. These characteristics differed in terms of gender, site of onset, cognitive function, and family history.

Amyotroph Lateral Scler Frontotemporal Degener. 2014

Detection of a novel frameshift mutation and regions with homozygosis within ARHGEF28 gene in familial amyotrophic lateral sclerosis.

Rho guanine nucleotide exchange factor (RGNEF) is a novel NFL mRNA destabilizing factor that forms neuronal cytoplasmic inclusions in spinal motor neurons in both sporadic (SALS) and familial (FALS) ALS patients. Given the observation of genetic mutations in a number of mRNA binding proteins associated with ALS, including TDP-43, FUS/TLS and mtSOD1, we analysed the ARHGEF28 gene (approx. 316 kb) that encodes for RGNEF in FALS cases to determine if mutations were present. We performed genomic sequencing, copy number variation analysis using TaqMan real-time PCR and spinal motor neuron immunohistochemistry using a novel RGNEF antibody. In this limited sample of FALS cases (n=7) we identified a heterozygous mutation that is predicted to generate a premature truncated gene product. We also observed extensive regions of homozygosity in the ARHGEF28 gene in two FALS patients. In conclusion, our findings of genetic alterations in theARHGEF28 gene in cases of FALS suggest that a more comprehensive genetic analysis would be warranted.

Amyotroph Lateral Scler Frontotemporal Degener. 2013

Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention

Sudden unexpected death in epilepsy (SUDEP) is cited as the cause of nearly 2,000 deaths per year in the USA alone, and accounts for as many as 15% of epilepsy-related deaths. Controversy prevails over the relative contributions of cardiac failure and respiratory arrest to SUDEP. Here, the authors discuss the mechanisms that cause cardiac, respiratory and arousal abnormalities during the ictal and postictal periods, and highlight possible preventive interventions that might reduce the risk of SUDEP.

Nature Reviews Neurology 2014

The hidden genetics of epilepsy—a clinically important new paradigm

The aetiology of most epilepsies used to be regarded as unknown, but in the past few years, massively parallel gene-sequencing techniques and clinical genetic studies have revealed that many forms of epilepsy—including those formerly labelled as idiopathic or acquired—are likely to have a genetic basis. Increased understanding of the genetic architecture of epilepsies has important implications for genetic testing, treatment selection and counselling. Furthermore, understanding the genetic background of epilepsies can guide neurobiological research for novel therapies.

Nature Reviews Neurology 2014

Representing Sex in the Brain, One Module at a Time

Sexually dimorphic behaviors, qualitative or quantitative differences in behaviors between the sexes, result from the activity of a sexually differentiated nervous system. Sensory cues and sex hormones control the entire repertoire of sexually dimorphic behaviors, including those commonly thought to be charged with emotion such as courtship and aggression. Such overarching control mechanisms regulate distinct genes and neurons that in turn specify the display of these behaviors in a modular manner. How such modular control is transformed into cohesive internal states that correspond to sexually dimorphic behavior is poorly understood. We summarize current understanding of the neural circuit control of sexually dimorphic behaviors from several perspectives, including how neural circuits in general, and sexually dimorphic neurons in particular, can generate sexually dimorphic behaviors, and how molecular mechanisms and evolutionary constraints shape these behaviors. We propose that emergent themes such as the modular genetic and neural control of dimorphic behavior are broadly applicable to the neural control of other behaviors.

Neuron 2014

Correlation of Parkinson Disease Severity and 18F-DTBZ Positron Emission Tomography

Importance  Currently, diagnosis of Parkinson disease is mainly based on clinical criteria characterized by motor symptoms including bradykinesia, rigidity, resting tremor, and postural instability. Reliable in vivo biomarkers to monitor disease severity and reflect the underlying dopaminergic degeneration are important for future disease-modifying therapy in Parkinson disease.

Objectives  To use [18F]9-fluoropropyl-(+)-dihydrotetrabenazine (18F-DTBZ; [18F]AV-133) positron emission tomography (PET) to explore the characteristics of vesicular monoamine transporter type 2 imaging in patients with Parkinson disease (PD) with different severity levels as well as to investigate its capability in monitoring clinical severity.

Design, Setting, and Participants  Regional uptakes for 18F-DTBZ PET of different disease stages were measured. Seventeen healthy control participants and 53 patients in 3 groups of mild, moderate, and advanced stages of PD were recruited for 18F-DTBZ PET scans from the Movement Disorders Clinic in the Chang Gung Memorial Hospital, Taiwan.

Main Outcomes and Measures  The severity of disease in patients with PD was quantified by modified Hoehn-Yahr Scale, Unified Parkinson Disease Rating Scale total scores and subscores of posture instability and gait disturbance, tremor, akinesia, and rigidity while not taking medication. Both voxelwise- and volume of interest–based image analyses were performed. The specific uptake ratio (SUR) of each volume of interest and voxel was calculated as (target uptake − reference uptake) / reference uptake using the occipital reference region from magnetic resonance imaging–based spatially normalized 18F-DTBZ images for each participant. Average SUR images were displayed as 2-dimensional and 3-dimensional to illustrate the image patterns in each group. The nonparametric Kruskal-Wallis test on regional SUR was used for group comparison between healthy control participants and patients with PD at different stages. Quantitative parameters were correlated with severity of disease and disease duration by Spearman correlation. Voxelwise analysis for evaluating dopaminergic neuron decline of different PD stages was performed by SPM5.

Results  The 2-dimensional and 3-dimensional 18F-DTBZ PET images demonstrated that the reduction of vesicular monoamine transporter type 2 availability was obviously correlated with the severity of disease in patients with PD. The mean reductions of vesicular monoamine transporter type 2 density for the caudate, putamen, and substantia nigra were 27.29%, 63.26%, and 31.03% for mild PD; 61.76%, 81.54%, and 48.41% for moderate PD; and 81.78%, 89.47%, and 66.62% for advanced PD, respectively. The SURs of bilateral striatal regions exhibited significantly exponential correlations to stage; disease duration; Unified Parkinson Disease Rating Scale motor score; posture instability and gait disturbance; and akinesia, rigidity, and tremor scores.

Conclusions and Relevance  In PD, 18F-DTBZ PET is a potential imaging biomarker for measuring dopaminergic degeneration in vivo and monitoring the severity of disease.

JAMA Neurology 2014

The Idiopathic Intracranial Hypertension Treatment Trial Clinical Profile at Baseline

Importance  To our knowledge, there are no large prospective cohorts of untreated patients with idiopathic intracranial hypertension (IIH) to characterize the disease.

Objective  To report the baseline clinical and laboratory features of patients enrolled in the Idiopathic Intracranial Hypertension Treatment Trial.

Design, Setting, and Participants  We collected data at baseline from questionnaires, examinations, automated perimetry, and fundus photography grading. Patients (n = 165) were enrolled from March 17, 2010, to November 27, 2012, at 38 academic and private practice sites in North America. All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation between −2 dB and −7 dB. All but 4 participants were women.

Main Outcomes and Measures  Baseline and laboratory characteristics.

Results  The mean (SD) age of our patients was 29.0 (7.4) years and 4 (2.4%) were men. The average (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 39.9 (8.3). Headache was the most common symptom (84%). Transient visual obscurations occurred in 68% of patients, back pain in 53%, and pulse synchronous tinnitus in 52%. Only 32% reported visual loss. The average (SD) perimetric mean deviation in the worst eye was −3.5 (1.1) dB, (range, −2.0 to −6.4 dB) and in the best eye was −2.3 (1.1) dB (range, −5.2 to 0.8 dB). A partial arcuate visual field defect with an enlarged blind spot was the most common perimetric finding. Visual acuity was 85 letters or better (20/20) in 71% of the worst eyes and 77% of the best eyes. Quality of life measures, including the National Eye Institute Visual Function Questionnaire–25 and the Short Form–36 physical and mental health summary scales, were lower compared with population norms.

Conclusions and Relevance  The Idiopathic Intracranial Hypertension Treatment Trial represents the largest prospectively analyzed cohort of untreated patients with IIH. Our data show that IIH is almost exclusively a disease of obese young women. Patients with IIH with mild visual loss have typical symptoms, may have mild acuity loss, and have visual field defects, with predominantly arcuate loss and enlarged blind spots that require formal perimetry for detection.

Neurology 2014

Longitudinal follow-up of SWEDD subjects in the PRECEPT Study

Objective: To compare the clinical and imaging characteristics of those PRECEPT (Parkinson Research Examination of CEP-1347 Trial) subjects with a scan without evidence of dopaminergic deficit (SWEDD) to those with dopamine transporter (DAT) deficit scans at study baseline and during a 22-month follow-up.

Methods: Baseline (n = 799) and 22-month follow-up (n = 701) [¹²³I] β-CIT SPECT scans were acquired. The percent change in [¹²³I] β-CIT striatal binding ratio, the percentage of subjects requiring dopaminergic therapy, the change in Unified Parkinson's Disease Rating Scale (UPDRS) score, and the PRECEPT Study investigators’ diagnosis at study termination were compared between SWEDD and DAT deficit subjects.

Results: SWEDD subjects (n = 91) compared with DAT deficit subjects (n = 708) showed reduced UPDRS score at baseline (18.7 [SD 8.5] vs 25.5 [SD 10.5], p < 0.05) and minimal change in both [¹²³I] β-CIT striatal binding ratio (−0.2% [SD 12.2] vs −8.5% [SD 11.9], p < 0.0001) and UPDRS score (0.5 [SD 6.9] vs 10.5 [SD 8.9], p < 0.0001) at follow-up assessments. At PRECEPT termination, the diagnosis by study investigators was changed from Parkinson disease (PD) to other disorders not associated with DAT deficit in 44% (95% confidence interval 34.2, 54.7) of SWEDD subjects compared with 3.6% (95% confidence interval 2.3, 5.1) of DAT deficit subjects.

Conclusion: These results indicate that subjects identified as having a SWEDD, with DAT imaging within the normal range, have minimal evidence of clinical or imaging PD progression. These data strongly suggest that SWEDD subjects are unlikely to have idiopathic PD

Neurology 2014

Risk of cerebral arteriovenous malformation rupture during pregnancy and puerperium

Objective: To determine whether the risk of arteriovenous malformation (AVM) rupture is increased during pregnancy and puerperium.

Methods: Participants included 979 female patients with intracranial AVM admitted to Beijing Tiantan Hospital between 1960 and 2010. Two neurosurgery residents reviewed medical records for each case. Of them, 393 patients with ruptured AVM between 18 and 40 years of age were used for case-crossover analysis. Number of children born and clinical information during pregnancy and puerperium were retrieved to identify whether AVM rupture occurred during this period.

Results: Of the 979 women, 797 hemorrhages occurred during 25,578 patient-years of follow-up, yielding an annual hemorrhage rate of 3.11%. The annual AVM hemorrhage rate in patients aged 18 to 40 years (n = 579) was 2.78%, lower than the rate in other age groups (odds ratio = 0.75, 95% confidence interval 0.65–0.86, p < 0.05). Of the 393 patients with rupture of AVM aged 18 to 40 years, 12 hemorrhages occurred in 12 patients over 452 pregnancies, yielding a hemorrhage rate of 2.65% per pregnancy or 3.32% per year. Among the remaining 381 patients, 441 hemorrhages occurred during 10,627 patient-years of follow-up, yielding an annual hemorrhage rate of 4.14%. The odds ratio for rupture of AVM during pregnancy and puerperium, compared with the control period, was 0.71 (95% confidence interval 0.61–0.82).

Conclusions: No increased risk of hemorrhage was found in patients with cerebral AVM during pregnancy and the puerperium. We therefore would not advise against pregnancy in women with intracranial AVM.

Neurology 2014

Happy Easter

Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives

Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and ¹⁸F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as µmol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P < 0.001), anterior vermis (40%, P < 0.001) and fusiform gyrus (20%, P < 0.001) compared with controls or siblings, and lower metabolism in hippocampus (12%, P = 0.05) compared with controls, and showed significant intersubject variability (decreases in vermis ranged from 18% to 60%). Participants with ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic rates including hyperactivity in globus pallidus indicative of basal ganglia involvement. Changes in basal ganglia metabolism offer potential insight into targeting strategies for therapeutic deep brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives suggests that heterozygocity influences the function of these brain regions.

JAMA Neurology 2014

Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome

Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1a) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast withScn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K⁺ channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.

Brain 2014

Swiss Cheese Striatum Clinical Implications

Objective  To determine the clinical features associated with SCS detected on MRI scans.

Design, Setting, and Participants  A blinded, retrospective case-control study using medical records from 2000 to 2007 obtained from an MRI database at the Mayo Clinic in Rochester, Minnesota, of residents 40 years of age or older of Olmsted County, Minnesota, who had extensive Mayo Clinic medical records and MRI reports suggestive of SCS. Cases with a severe form of SCS (n = 27) were randomly selected for comparison with age-, sex-, and examination year–matched controls (n = 52) with a minimal form of SCS or no SCS.

Exposure  Magnetic resonance imaging.

Main Outcomes and Measures  Associations of clinical and imaging features with the presence of a severe form of SCS. Medical records were reviewed for clinical features such as parkinsonism, dementia, and vascular risk factors. The MRI scans were visually scored for degree of leukoaraiosis, central atrophy, and cortical atrophy.

Results  No significant differences were found between those with a severe form of SCS and controls in rates of parkinsonism (19% vs 17%; odds ratio, 1.09 [95% CI, 0.28-4.16]) or dementia of any type (30% vs 21%; odds ratio, 1.57 [95% CI, 0.48-5.13]). Vascular risk factors were not significantly different between groups. Swiss cheese striatum correlated with degree of leukoaraiosis (P < .001). Potential associations with visualized cortical atrophy (P = .01), nonobstructive urinary incontinence (18.5% vs 3.9%; P = .04), and syncope (37% vs 9.6%; P = .01) did not hold up after correction for the false discovery rate.

Conclusions and Relevance  Our study suggests that marked cribriform change in the striatum was not associated with the development of extrapyramidal clinical disorders, including parkinsonism. The association of SCS with leukoaraiosis suggests that it is part of a more generalized cerebrovascular process. Skepticism is called for when attributing clinical symptoms to this MRI finding.

JAMA Neurology 2014

Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions in C9orf72

Importance  Here we report a family with coexistence of multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) with hexanucleotide repeat expansions in C9orf72.

Observations  A 65-year-old woman had a 2-year history of ataxia with autonomic dysfunction but without motor neuron signs. She was diagnosed as having MSA based on her clinical history and the hot cross bun sign on brain magnetic resonance imaging. Her 62-year-old brother had progressive weakness, fasciculations, hyperreflexia, and active denervation on electromyography without cerebellar ataxia. He was diagnosed as having ALS. Both patients had a greater than 1000/2 hexanucleotide expansion in C9orf72.

Conclusions and Relevance  Patients with hexanucleotide repeat expansions in C9orf72 can present with MSA as well as ALS or frontotemporal dementia. We report this family with coexisting MSA and ALS, highlighting the phenotypic variability in neurologic presentations with hexanucleotide repeat expansions in C9orf72

JAMA Neurology 2014

Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study

Methods

For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale—Revised (CRS—R), cerebral 18F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS—R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale—Extended.

Findings

We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). 18F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85—98) and high congruence (85%, 77—90) with behavioural CRS—R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30—61) and had lower overall congruence with behavioural scores (63%, 51—73) than PET imaging. 18F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64—81), and fMRI in 36 of 65 patients (56%, 43—67). 13 of 42 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS—R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness.

Interpretation

Cerebral 18F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate.

Funding

The Belgian National Funds for Scientific Research (FNRS), Fonds Léon Fredericq, the European Commission, the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action, the University of Copenhagen, and the University of Liège.

Lancet 2014

Structural MRI correlates of apathy symptoms in older persons without dementia AGES-Reykjavik Study

Objective: We aimed to investigate the relation between apathy symptoms and structural brain changes on MRI, including white matter lesions (WMLs) and atrophy, in a large cohort of older persons.

Methods: Cross-sectional analyses are based on 4,354 persons without dementia (aged 76 ± 5 years) participating in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study. Apathy symptoms were assessed with 3 items from the 15-item Geriatric Depression Scale. Brain volumes and total WML volume were estimated on 1.5-tesla MRI using an automated segmentation program; regional WML load was calculated using a semiquantitative scale. Regression analyses were adjusted for age, sex, education, intracranial volume, vascular risk factors, physical activity, brain infarcts, depressive symptoms, antidepressants, and cognitive status.

Results: Compared to those with <2 apathy symptoms, participants with ≥2 apathy symptoms (49% of the cohort) had significantly smaller gray matter volumes (mean adjusted difference −3.6 mL, 95% confidence interval [CI] −6.2 to −1.0), particularly in the frontal and temporal lobes; smaller white matter volumes (mean adjusted difference −1.9 mL, 95% CI −3.6 to −0.3), mainly in the parietal lobe; and smaller thalamus volumes. They were also more likely to have WMLs in the frontal lobe (adjusted odds ratio = 1.08, 95% CI 0.9–1.3). Excluding participants with a depression diagnosis did not change the associations

Neurology 2014

Electrical source imaging in cortical malformation–related epilepsy: A prospective EEG-SEEG concordance study

Objective

Delineation of the epileptogenic zone (EZ) in refractory epilepsy related to malformations of cortical development (MCDs) often requires intracranial electroencephalography (EEG) recordings, especially in cases of negative magnetic resonance imaging (MRI) or discordant MRI and video-EEG findings. It is therefore crucial to promote the development of noninvasive methods such as electrical source imaging (ESI). We aimed to (1) analyze the localization concordance of ESI derived from interictal discharges and EZ estimated by stereo-EEG (SEEG); (2) compare the concordance of ESI, MRI, and electroclinical correlations (ECCs) with SEEG-EZ; and (3) assess ESI added value in the EZ localization.

Methods

We prospectively analyzed 28 consecutive patients undergoing presurgical investigation for MCD-related refractory epilepsy in 2009–2012. ESI derived from 64-channel scalp EEG was interpreted with blinding to, and subsequently compared with, SEEG-estimated EZ. Anatomic concordance of ESI with SEEG-EZ was compared with that of video-EEG and MRI. We further assessed ESI added value to ECC and MRI.

Results

Twelve patients (43%) had temporal and 16 (57%) had extratemporal epilepsy. MRI was negative in 11 (39%) and revealed a cortical malformation in 17 (61%). ESI was fully concordant with the EZ in 10 (36%) and partly concordant in 15 (53%). ECC presented a full and partial concordance with EZ in 11% and 82% of cases, respectively, and MRI in 11% and 46%, respectively. Of 11 patients with negative MRI, ESI was fully concordant with the EZ in 7 (64%) and partly concordant in 4 (36%). ESI correctly confirmed restricted or added localizations to ECC and MRI in 12 (43%) of 28 patients and in 8 (73%) of 11 patients with negative MRI.

Significance

ESI contributes to estimating the EZ in MCD-related epilepsy. The added value of ESI to ECC is particularly high in patients with MCD and negative MRI, who represent the most challenging cases for epilepsy surgery.

Epilepsia 2014

Italian recommendations for Lambert–Eaton myasthenic syndrome (LEMS) management

Lambert–Eaton myasthenic syndrome (LEMS) is a pre-synaptic disorder of the neuromuscular and autonomic transmission mediated by antibodies to voltage-gated calcium channels at the motor nerve terminal. LEMS is a quite rare and probably under-diagnosed disease: the onset may be slow and clinical signs are typically fluctuating, thus adding to the delay in diagnosis. LEMS weakness typically involves lower and upper limbs and the proximal muscles are predominantly affected. A significant proportion of patients also have dysfunction of the autonomic nervous system that may include dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension. LEMS recognition is based on clinical, electrophysiological and immunological criteria. Nearly 50–60 % of patients with LEMS have an underlying tumour that, in almost all cases, is a small-cell lung cancer; the onset of neurological symptoms generally precedes tumour detection. A careful screening for the early detection of the possible associated cancer is a crucial step for optimal disease management. The Italian Working Group on Myasthenic Syndromes developed diagnostic and therapeutic algorithms that could serve in routine clinical practice as tools for a patient-tailored approach.

Neurological Sciences 2014