NIHR Queen Square Dementia Biomedical Research Unit

Abstract Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug-resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well-preserved hippocampal specimens: HS International League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly in CA1 and CA4 regions, compared to CA1 predominant neuronal cell loss and gliosis (HS ILAE type 2), or CA4 predominant neuronal cell loss and gliosis (HS ILAE type 3). Surgical hippocampus specimens obtained from patients with TLE may also show normal content of neurons with reactive gliosis only (no-HS). HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control. CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.

Serial proton magnetic resonance spectroscopy (MRS), was carried out at 1-2 monthly intervals on eight patients with multiple sclerosis who presented with evidence of a large acute cerebral white matter lesion. An MRS was obtained from acute lesions (volumes of interest 4-12 ml), which at presentation showed gadolinium-diethylenetriamine penta-acetic acid enhancement, and from similar volumes of normal appearing white matter lateral to the lesion and nearer the scalp. Follow-up ranged from 4 to 9 months (mean 6 months). Short echo spectra from acute enhancing lesions invariably showed the presence of large resonances at 0.9 and 1.3 p.p.m. compared with normal appearing white matter and healthy age matched controls, indicating that these peaks were not the result of voxel contamination from scalp fat. These resonances, which probably represent lipid products of myelin breakdown, were detected in lesions which had been enhancing for < 1 month and remained elevated for a mean of 5 months (range 4-8 months). The results provide evidence that short echo proton MRS can detect myelin breakdown products and that myelin breakdown occurs during the initial inflammatory stage of lesion development. The ratio of N-acetylaspartate (NAA) (a neuronal marker) relative to creatine was reduced in acute lesions and in normal appearing white matter. In six of the lesions studied there was, however, a subsequent rise in the NAA/creatine ratio indicating that axonal loss is not the only mechanism of reduction in the NAA/creatine ratio.

<b><i>Background:</i></b> Cluster headache, when compared with migraine or tension-type headache, is an uncommon form of primary neurovascular headache. However, with a prevalence of approximately 0.1% and a lengthy history of disabling and distressing episodic pain, cluster headache is an important neurologic problem. <b><i>Methods:</i></b> Patients (n = 230) were recruited from our specialist clinic (24%) or from support groups (76%). All patients had a detailed history taken by at least two physicians and were assigned diagnoses according to the International Headache Society Diagnostic Guidelines. <b><i>Results:</i></b> The pain characteristics were of a strictly unilateral, predominantly retro-orbital (92%) and temporal pain (70%). Of the cranial autonomic features, lacrimation (91%) was the most common. Nausea (50%), photophobia (56%), and phonophobia (43%) often were noted, as was a sense of agitation or restlessness in 93% of patients. Typical migrainous aura was noted in 14% of this cohort. Most patients (79%) had episodic cluster headache, which was largely the same clinically as chronic cluster headache except for the persistence of attacks over time. The overall male-to-female ratio in this sample was 2.5:1, and this has decreased with time. Neither oral contraceptive use, menses, menopause, nor hormone replacement therapy had any consistent effect on cluster headache in women. Less than half of the patients had tried injectable sumatriptan, and many had not tried high-flow oxygen. Several unproven preventative agents that usually are used in migraine and an array of alternative therapies had been used; none of the latter was consistently effective. <b><i>Conclusion:</i></b> Patients with cluster headache offer a population of primary headache patients with devastating acute attacks of pain. The syndrome is stereotyped with effective evidence-based treatments that are prescribed in only half of patients having cluster headache.

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in C9orf72 carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in C9orf72 carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI-the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials-CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in GRN carriers) and CSF poly(GP) dipeptide repeat protein levels (in C9orf72 carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.

Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346-4515 pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11-200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immunotherapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross-sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n = 13) (P < 0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenotype. Immunotherapy is associated with excellent control of the frequently anti-epileptic drug refractory seizures, hastens time to recovery, and may prevent the subsequent development of cognitive impairment observed in this study.

1. The nature, distribution and function of rectifying channels in rat spinal root myelinated axons has been assessed with selective blocking agents and a variety of intracellular and extracellular recording techniques. 2. The electrotonic responses of roots poisoned with tetrodotoxin (TTX) to constant current pulses had fast (rise time much less than 1 ms) and slow components, which were interpreted in terms of Barrett & Barrett's (1982) revised cable model for myelinated nerve. Depolarization evoked a rapid outward rectification (time constant, tau approximately 0.5 ms), selectively blocked by 4-aminopyridine (4AP, 1 mM), and a slow outward rectification (tau approximately 15 ms), selectively blocked by tetraethylammonium (TEA, 1 mM) or Ba2+ (0.5 mM). Hyperpolarization evoked an even slower inward rectification, selectively blocked by Cs+ (3 mM) but not by Ba2+. 3. From the different effects of the blocking agents on the fast and slow components of electrotonus, it was deduced (a) that the inward rectification is a property of the internodal axon, (b) that the slow outward rectifier is present at the nodes, and probably the internodes as well, and (c) that the 4AP-sensitive channels have a minor nodal and a major internodal representation. 4. TEA and Ba2+ reduced the accommodation of roots and fibres not poisoned with TTX to long current pulses, whereas 4AP facilitated short bursts of impulses in response to a single brief stimulus. 5. TEA and Ba2+ also abolished a late hyperpolarizing after-potential (peaking at 20-80 ms), while 4AP enhanced the depolarizing after-potential in normal fibres, and abolished an early hyperpolarizing after-potential (peaking at 1-3 ms) in depolarized fibres. Corresponding to the later after-potentials were post-spike changes in excitability and conduction velocity, which were affected similarly by the blocking agents. Cs+ increased the post-tetanic depression attributable to electrogenic hyperpolarization. 6. The physiological roles of the three different rectifying conductances are discussed. It is also argued that the prominent ohmic 'leak conductance', usually ascribed to the nodal axon, must arise in an extracellular pathway in series with the rectifying internodal axon.

The technique of hydrogen clearance by an inhalation method is discussed. The electronic instrumentation necessary to secure stability and reproducibility from the recordings is described. Clearance rates in gray matter of about 80 ml/100 gm per minute in the cortex and putamen have been obtained, and of about 20 ml/100 gm per minute in white matter.Clearance curves have invariably been monoexponential in character in white matter, and in over half the cases in the putamen. In the remainder of the putamen curves and in 60% of the cortical clearance curves, the curves could be resolved into only two exponentials. Using bicompartmental analysis, the fast-clearing components of biexponential curves in both cortex and deep nuclei gave the same figures as clearance curves of an entirely monoexponential character from these two tissues. The importance of recirculation time, concentration of hydrogen inhalation, and verification of the tissue placement by subsequent dissection are discussed. The capacity of the method to detect sudden changes in flow during clearance is described.

We performed semiautomated quantitative measurement of brain magnetic resonance imaging (MRI) abnormalities seen at presentation and at 5-year follow-up in 84 patients presenting with an acute clinically isolated syndrome of the optic nerves, brainstem, or spinal cord suggestive of multiple sclerosis (MS). At follow-up, 34 (40%) had developed clinically definite and four (5%) clinically probable MS. Patients who developed MS during follow-up had a higher lesion load at presentation than those who did not. There was a strong correlation of the MRI lesion load at presentation with both the increase in lesion load over the next 5 years and disability at follow-up. Increasing initial lesion load correlated with a decreasing time to development of MS clinically (r = -0.328, p < 0.05). At follow-up, disability and brain lesion load were strongly correlated in patients who had developed MS. These results establish that MRI at presentation with clinically isolated syndromes suggestive of MS is useful in predicting the subsequent clinical course and the development of new MRI lesions. This suggests that quantitative brain MRI will be helpful in selecting patients with early clinical MS for treatment trials and for subsequent monitoring of their response to treatment.

Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists alpha-CGRP-(8-37) and BIBN4096BS. Cats were anaesthetised with alpha-chloralose, and using halothane during surgical preparation. A craniotomy and C1/C2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25-30 Hz by microiontophoresis of L-glutamate (n = 43 cells). Microiontophoresis of alpha-CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by l-glutamate, demonstrating a non-presynaptic site of action for CGRP. alpha-CGRP-(8-37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED50 31 microg kg(-1)). The maximal effect observed within 30 min of administration. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache.

The clinical characteristics of 84 patients with pituitary tumour who had troublesome headache were investigated. The patients presented with chronic (46%) and episodic (30%) migraine, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT; 5%), cluster headache (4%), hemicrania continua (1%) and primary stabbing headache (27%). It was not possible to classify the headache according to International Headache Society diagnostic criteria in six cases (7%). Cavernous sinus invasion was present in the minority of presentations (21%), but was present in two of three patients with cluster headache. SUNCT-like headache was only seen in patients with acromegaly and prolactinoma. Hypophysectomy improved headache in 49% and exacerbated headache in 15% of cases. Somatostatin analogues improved acromegaly-associated headache in 64% of cases, although rebound headache was described in three patients. Dopamine agonists improved headache in 25% and exacerbated headache in 21% of cases. In certain cases, severe exacerbations in headache were observed with dopamine agonists. Headache appears to be a significant problem in pituitary disease and is associated with a range of headache phenotypes. The presenting phenotype is likely to be governed by a combination of factors, including tumour activity, relationship to the cavernous sinus and patient predisposition to headache. A proposed modification of the current classification of pituitary-associated headache is given.

Mortality in people with epilepsy has been studied in many different populations. In population-based incidence cohorts of epilepsy with 7-29 years follow-up, there was up to a threefold increase in mortality, compared to the general population (standardized mortality ratios [SMR] ranged from 1.6 to 3.0). When studies include selected epilepsy populations where patients with frequent and severe seizures are more common, the mortality is even greater. Relative survivorship (RS) following the diagnosis of epilepsy was 91%, 85%, and 83% after 5, 10, and 15 years, respectively. In a population with childhood-onset epilepsy, RS was 94% and 88% after 10 and 20 years. The level of increased mortality is affected by several factors. In idiopathic epilepsy where the causes of seizures are unknown, the results are conflicting. There was no significant increase in mortality in studies from Iceland, France, and Sweden, a barely increased risk in a study from the United Kingdom, and a significantly increased risk in a study from the United States. In contrast, all studies report a significant increased mortality in remote symptomatic epilepsy (standardized mortality ratios [SMRs] ranging from 2.2 to 6.5). The highest mortality is found in patients with epilepsy and neurodeficits present since birth, including mental retardation or cerebral palsy (SMRs ranging from 7 to 50). Mortality is also affected by age, with the highest SMRs in children, the combined effect of low mortality in the reference population, and high mortality in children with neurodeficits and epilepsy. The highest excess mortality is found in the elderly, > or =75 years. A pronounced increase in mortality is found during the first year following the onset of seizures due to underlying severe diseases. The increased mortality remains in different studies 2-14 years following diagnosis. Most of the factors responsible for the increased mortality are related to the underlying disorder causing epilepsy with pneumonia, cerebrovascular disease, and neoplastic disorders (risk remains elevated when primary brain tumors are excluded), as the most frequently recorded causes. The most common direct seizure-related cause of death in adolescents and young adults is sudden unexpected death, which is 24 times more common than in the general population.

Eighteen patients with acute optic neuritis underwent optic nerve magnetic resonance imaging (MRI) before and after injection of gadolinium-diethylene triamine pentacetic acid (Gd-DTPA). Ten were re-examined 4 weeks later. Leakage of Gd-DTPA across the blood-optic nerve barrier was a consistent finding in the acute lesion, and its presence was associated with abnormal visual acuity and colour vision, retro-ocular pain on eye movement, and afferent pupillary defect, and a reduced amplitude of the P100 component of the visual evoked potential. Gd-DTPA leakage had ceased in 9/11 nerves when restudied 4 wks later, and this evolution was associated with improved visual acuity and an increased P100 amplitude. Leakage is likely to reflect inflammation, and we conclude that the latter plays an important part in the production of conduction block and clinical deficit, and that its resolution is an important step in clinical remission from acute episodes of demyelination.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Parkinson's disease (PD) is a progressive neurodegenerative illness with both motor and nonmotor symptoms. Deep brain stimulation (DBS) is an established safe neurosurgical symptomatic therapy for eligible patients with advanced disease in whom medical treatment fails to provide adequate symptom control and good quality of life, or in whom dopaminergic medications induce severe side effects such as dyskinesias. DBS can be tailored to the patient's symptoms and targeted to various nodes along the basal ganglia-thalamus circuitry, which mediates the various symptoms of the illness; DBS in the thalamus is most efficient for tremors, and DBS in the pallidum most efficient for rigidity and dyskinesias, whereas DBS in the subthalamic nucleus (STN) can treat both tremors, akinesia, rigidity and dyskinesias, and allows for decrease in doses of medications even in patients with advanced stages of the disease, which makes it the preferred target for DBS. However, DBS in the STN assumes that the patient is not too old, with no cognitive decline or relevant depression, and does not exhibit severe and medically resistant axial symptoms such as balance and gait disturbances, and falls. Dysarthria is the most common side effect of DBS, regardless of the brain target. DBS has a long-lasting effect on appendicular symptoms, but with progression of disease, nondopaminergic axial features become less responsive to DBS. DBS for PD is highly specialised; to enable adequate selection and follow-up of patients, DBS requires dedicated multidisciplinary teams of movement disorder neurologists, functional neurosurgeons, specialised DBS nurses and neuropsychologists.

In the planning of MRI protocols to monitor disease activity in multiple sclerosis (MS), the clinical subtype needs to be considered. In this serial gadolinium-enhanced MRI study, we demonstrated differences between patients with early relapsing/remitting MS and benign MS in both the production of new lesions and the occurrence of enhancement.

Defining reference models for population variation, and the ability to study individual deviations is essential for understanding inter-individual variability and its relation to the onset and progression of medical conditions. In this work, we assembled a reference cohort of neuroimaging data from 82 sites (N=58,836; ages 2-100) and used normative modeling to characterize lifespan trajectories of cortical thickness and subcortical volume. Models are validated against a manually quality checked subset (N=24,354) and we provide an interface for transferring to new data sources. We showcase the clinical value by applying the models to a transdiagnostic psychiatric sample (N=1985), showing they can be used to quantify variability underlying multiple disorders whilst also refining case-control inferences. These models will be augmented with additional samples and imaging modalities as they become available. This provides a common reference platform to bind results from different studies and ultimately paves the way for personalized clinical decision-making.

Summary: Parietal and occipital seizures have been investigated relatively little. Recent interest in seizures of frontal lobe origin has led to a definition of several well‐identifiable clinical patterns of frontal lobe seizures. A similar delineation of the clinical and EEG pattern of parietal and occipital epilepsy, using modern investigations, appears appropriate, not least because the few reported series of surgical treatment in parietal and occipital epilepsy have indicated that operation may be relevant in selected cases, not only for removal of space‐occupying lesions. Such a study is currently being undertaken at the National Hospital for Neurology and Neurosurgery and The Chalfont Centre for Epilepsy with the aim of developing and evaluating diagnostic criteria for these seizures. From the existing literature we can conclude that precise incidence and prevalence are largely unknown. A recent community‐based study of 252 subjects with partial epileptic seizures in an epileptic population of 594, showed that parietal seizures and seizures of posterior origin each comprised 6.3% and central or sensory‐motor seizures comprised 32.5% of focal seizures in the 160 cases in which seizures could be subclassified (Manford et al., 1992). This incidence seems low for occipital seizures as compared with the 1953 study by Gibbs and Gibbs, who observed occipital epileptiform activity in 8% of subjects with focal epilepsy. The most prominent clinical manifestations of parietal epilepsy are elementary sensory phenomena at the beginning of seizures and elementary visual hallucinations in occipital epilepsy. These symptoms are not associated solely with posterior hemisphere epilepsy, however, and more studies are obviously needed to define how close this relation is. Scalp EEG is frequently negative or maybe misleading; further‐more, spread of epileptic discharges from the parietal and occipital lobes to frontal and temporal regions may obscure seizure origin. Because of these controversial symptoms, diagnostic criteria may be difficult to define. The wide difference in clinical and EEG manifestations between reported series of parietal and occipital epilepsy also reflects a considerable problem with patient sampling. Classification of epilepsy according to the anatomic division of the brain may be arbitrary, and it may be appropriate to define epileptic syndromes such as sensorimotor seizures or occipitotemporal seizures that cross such artificial divides.

Although serial MRI studies of the brain in relapsing-remitting MS have demonstrated frequent asymptomatic disease activity, less is known about the spinal cord. We carried out monthly gadolinium-enhanced brain and spinal cord MRI scans over 1 year in 10 patients with relapsing-remitting MS. Six of the patients had a total of 11 clinical relapses, eight of which involved the spinal cord. A total of 167 active (enhancing or new nonenhancing) lesions in the brain and 19 in the spinal cord were present. Only one active brain lesion was symptomatic compares with six spinal cord lesions. Overall, one-third of new spinal cord lesions were symptomatic, and three-quarters of clinical spinal cord relapses were associated with a new MRI lesion in a location appropriate to the symptoms. Activity in both the spinal cord and brain was more common around the time of relapse. There was a strong association between the spinal cord and brain MRI activity. We did not detect progressive spinal cord atrophy from measurements of a spinal cord cross-sectional area. We conclude that, in relapsing-remitting MS, imaging of the brain alone will detect 90% of active lesions; spinal cord MRI using current technology will therefore provide only modest gains in treatment trials in which lesion activity is the primary outcome measure. The lack of ++progressive spinal cord atrophy in these patients, suggesting that significant axonal loss has not occurred, is in keeping with their good recovery after relapse. That brain and spinal cord lesions occur concurrently implies a systemic trigger for disease activity.