Annals of Neurology
We hypothesize that epileptiform abnormalities (EA) in the electroencephalopgram (EEG) during the acute period following traumatic brain injury (TBI) independently predict first-year post-traumatic epilepsy (PTE1). We analyzed PTE1 risk factors in two cohorts matched for TBI severity and age (n=50). EA independently predict risk for PTE1 (OR 3.16[0.99 11.68]); subdural hematoma is another independent risk factor (OR 4.13 [1.18 39.33]). Differences in EA rates are apparent within 5 days following TBI. Our results suggest increased EA prevalence identifies patients at increased risk for PTE1, and that EA acutely post-TBI can identify patients most likely to benefit from anti-epileptogenesis drug trials. This article is protected by copyright. All rights reserved.
Objective: Ramsay Hunt syndrome (RHS) and Bell's palsy (BP) are typically known as facial nerve motor syndromes and are primarily unilateral. The aim of this study was to challenge this assertion because both conditions are also known to be associated with viruses that typically affect several nerves.
Methods: Ten participants with RHS, 12 with BP, all clinically unilateral, and 12 healthy controls were prospectively enrolled. Electrogustometric thresholds were measured bilaterally in the areas of the chorda tympani, the glossopharyngeal, and the major petrosal nerve. Also bilaterally, the taste function was tested using chemogustometry with different tastant concentrations. Again bilaterally, the morphology of the mucosa and the vessels of the anterior fungiform papillae were examined by contact endoscopy. Statistically, RHS and BP participants were compared with the healthy controls, and the paretic sides of RHS and BP were compared pairwise with their mobile sides.
Results: Electrogustometrically, the perception was reduced bilaterally in RHS (10-19 dB, p < 0.001) and BP (3-5 dB, p = 0.011 to 0.030) in all three innervation areas. Chemogustometrically, it was also reduced bilaterally in RHS (20-70%) and BP (8-50%). Papillary atrophies were 100% increased in RHS (p = 0.001) and BP (p < 0.001). They were more increased on the paretic side in RHS (30%, p = 0.078) and BP (83%, p < 0.001).
Interpretation: In these two clinically unilateral conditions, the gustatory perception and morphology are bilaterally affected, namely more in RHS and more on the paretic side. BP, known as an isolated motor condition, appears to be a cranial polyneuritis. A bilateral examination and therapeutic gustatory monitoring might follow these observations in evidence-based practice. This article is protected by copyright. All rights reserved.
By altering the intrinsic metabolism of the cell, including the upregulation of regeneration-associated genes (RAGs) and the production of structural proteins for axonal outgrowth, the conditioning lesion sets up an environment highly conducive to regeneration. In this review, we assess forty years of research to provide a comprehensive overview of the conditioning lesion literature, directed at: a) discussing the mechanisms of, and barriers to nerve regeneration that can be mitigated by the conditioning lesion; b) describing the cellular and molecular pathways implicated in the conditioning lesion effect; and c) deliberating on how these insights might be applied clinically. The consequential impact on regeneration is profound, with a conditioned nerve demonstrating longer neurite extensions in vitro, enhanced expression of RAGs within the dorsal root ganglia, early assembly and transportation of cytoskeletal elements, accelerated axonal growth, and improved functional recovery in vivo. Although this promising technique is not yet feasible to be performed in humans, there are potential strategies, such as conditioning electrical stimulation that may be explored to allow nerve conditioning in a clinically safe and well-tolerated manner. This article is protected by copyright. All rights reserved.
Objectives: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here we report the neuro-reparative effects of myeloablative allogeneic bone marrow transplantation in a humanised murine model of the disease.
Methods: Mice received a transplant of fluorescently-tagged sex mis-matched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioural motor performance tests. At six months post-transplant, mice were sacrificed for protein and histological analysis. In an attempt to augment numbers of bone marrow-derived cells integrating within the nervous system and improve therapeutic efficacy, a sub-group of transplanted mice also received monthly subcutaneous infusions of cytokines granulocyte-colony stimulating factor and stem cell factor.
Results: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and anti-oxidant defences were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow-derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite-like cells and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow-derived cell numbers were detected post-cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow-derived dorsal root ganglion satellite-like cells. Further improvements in motor coordination and activity were evident.
Interpretation: Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. This article is protected by copyright. All rights reserved.
Neurosurgery is an under-utilised treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary pre-surgical evaluation is vital for selecting patients and ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guide surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures, and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. This article is protected by copyright. All rights reserved.
Objective: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WAVE regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway.
Methods: We performed trio-based whole exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments.
Results: We identified three de novo CYFIP2 variants at the Arg87 residue in four unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2.
Interpretation: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway, and are associated with severe neurological disorders. This article is protected by copyright. All rights reserved.
Objectives: To determine if the level of metabolites in MR Spectroscopy (MRS) is a representative marker of underlying pathological changes identified in PET images in Alzheimer's disease (AD).
Methods: We performed PET-guided MRS in cases of probable AD, Mild Cognitive Impairment (MCI) and healthy controls (HC). All participants were imaged by 11 C-Pittsburgh Compound B (11C-PiB) and 18 F-fluorodeoxy-glucose (18F-FDG)-PET followed by 3T MRS. PET images were assessed both visually and using standardized uptake value ratios (SUVR). MRS voxels were placed in regions with maximum abnormality on amyloid (Aβ+s) and FDG (hypometabolic) areas on PET scans. Corresponding normal areas were selected in controls. The ratios of total N-acetyl group (tNA), myoinositol(mI), choline(Chol), glutamate+glutamine (Glx) over Creatine (Cr) were compared between these regions.
Results: Aβ+ regions had significantly higher (p=0.02) mI/Cr and lower tNA/Cr (p=0.02), while in hypometabolic areas only tNA/Cr was reduced (p=0.003). Multiple regression analysis adjusting for sex, age and education showed mI/Cr was only associated with 11C-PiB SUVR (p<0.0001). tNA/Cr, however was associated with both PiB (p=0.0003) and 18F-FDG SUVR (p=0.006). The level of mI/Cr was not significantly different between MCI and AD (p=0.28) but tNA/Cr showed significant decline from HC to MCI to AD (p=0.001, p=0.04).
Interpretation: mI/Cr has significant temporal and spatial associations with Aβ and could be potentially considered as a disease state biomarker. tNA is an indicator of early neurodegenerative changes and might have a role as disease stage biomarker and also as a valuable surrogate marker for treatment response. This article is protected by copyright. All rights reserved.
Reduced contrast sensitivity among older women is associated with increased risk of cognitive impairment
Objective: Several cross-sectional studies have reported an association between visual contrast sensitivity (a functional measure of low contrast vision) and poor cognitive performance or dementia, but no studies have investigated this association prospectively in a population based cohort with final adjudication of mild cognitive impairment (MCI)/dementia.
Methods: In a prospective, community-based study of aging women (Study of Osteoporotic Fractures), we analyzed whether visual contrast sensitivity was associated with increased risk of MCI or dementia and/or worse performance on various cognitive tests assessed 10 years later. Contrast sensitivity was assessed at baseline in each eye using a VISTECH VCTS 6500 wall chart. MCI/dementia was adjudicated by an expert panel. Multivariable logistic and linear regression models were analyzed.
Results: Of 1,352 White (88.2%) and African-American (11.8%) women with a mean age of 77.7 years (SD 3.3), 536 (39.6%) went on to develop MCI/dementia over 10 years. MCI/Dementia risk was more than doubled (OR 2.16, 95% CI 1.58 to 2.96) in women with the lowest quartile of contrast sensitivity compared to highest (p<0.0001 for the linear trend). Reduced baseline contrast sensitivity was also associated with lower performance on several cognitive measures assessed 10 years later.
Interpretation: Among older women, reduced contrast sensitivity is associated with a greater risk of MCI/dementia. These findings suggest that visual system neurodegeneration or dysfunction may parallel or precede dementia-related cortical or subcortical degeneration, and that contrast sensitivity testing may be useful in identifying aging adults at high risk for dementia. This article is protected by copyright. All rights reserved.
Objective: Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J. Methods: Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological and biochemical approaches. Results: We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with non-uniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies (NCS), which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4-/-). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+. Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination. Interpretation: Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+. Injection of a Ca2+ chelator in Fig4-/- mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. This article is protected by copyright. All rights reserved.
Objective: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course?
Methods: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients.
Results: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis.
Interpretation: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.
VPS13 protein family members, VPS13A through VPS13C, have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including a frameshift, missense and a partial duplication with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia or tremor) and progressive spastic ataxia or paraparesis. Characteristic brain MRI shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and chorea-acanthocytosis. Muscle biopsy in one case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological disease and a possible role in mitochondrial function. This article is protected by copyright. All rights reserved.
Schwannomatosis and neurofibromatosis type 2 are hereditary tumor syndromes and peripheral neuropathy has been reported in both. We prospectively applied in-vivo morphometric measurement of dorsal root ganglia volume in 16 schwannomatosis, 14 neurofibromatosis type 2 patients, and 26 healthy controls by MR-Neurography. Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in neurofibromatosis type 2 (L3: +267%, L4: +235%, L5: +241%, S1: +300% and S2: +242%, Bonferroni-adjusted p<0.001) but not in schwannomatosis. Dorsal root ganglia may be a vulnerable site in origination of areflexia and sensory loss and a useful diagnostic marker in neurofibromatosis type 2. This article is protected by copyright. All rights reserved.
Objective: Loss of function of the astrocyte-specific protein MLC1 leads to the childhood onset leukodystrophy “megalencephalic leukoencephalopathy with subcortical cysts” (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.
Methods: We analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole cell patch-clamp recordings and K+-sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.
Results: An early onset of seizures is common in MLC. Similarly, in MLC mice we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.
Interpretation: Disturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. This article is protected by copyright. All rights reserved.
Objective: Voltage-gated sodium (Na+) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1, are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of four patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in two cases, p.Pro1333Leu, and p.Val1769Ala).
Methods: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and, in two cases (both with the variant p.Ile875Thr), diffuse polymicrogyria.
Results: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and, for two of three mutants (p.Ile875Thr and p.Pro1333Leu), a left-shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The anti-seizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels.
Interpretation: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain while providing additional insight into mechanisms of slow inactivation of Nav1.3. This article is protected by copyright. All rights reserved.
Objective: To determine relationships of memory complaints to cognitive function and decline, incident dementia, and neurodegenerative and other neuropathologies, as well as the population-attributable risk for dementia in older black and white persons.
Methods: 4015 community-based persons (28% black; 74% women; mean baseline age 78 years), were enrolled in one of four longitudinal cohort studies, and another 2937 in a population-based cohort. Memory scores, assessed using two questions (5-point Likert scales) were categorized as complaints present or absent. Global cognition and five cognitive domains were derived from annual neuropsychological tests. Dementia was assessed from these tests and additional data. Neuropathologic data were available for 1350 deceased with brain autopsies. Regression and mixed effects models were used to examine relationships of memory complaints to cognition and neuropathology.
Results: Baseline memory complaints (n=1310; 33% of 4015) were associated with lower cognition and faster decline in all domains (global score estimate = -0.032 [SE=0.004], p<0.0001), during a mean follow-up of 6 (SD=2) years. Persons with memory complaints had higher dementia risk (HR=1.64; 95%CI: 1.42-1.89) and odds of pathologic Alzheimer's disease (OR=1.96; 95%CI: 1.51-2.54), neocortical Lewy bodies (OR=2.47, 95%CI: 1.54-3.96), and other neurodegenerative pathologies. Results for dementia risk were similar among blacks and whites. Among 2937 older persons in a population-based cohort with similar data, the population-attributable risk for incident dementia due to memory complaints was 14.0% (95%CI: 2.6-23.0), and did not vary between the black and white groups.
Interpretation: Memory complaints are common in older black and white persons, and relate to cognitive decline, dementia risk, and neurodegenerative pathologies. This article is protected by copyright. All rights reserved.