The effect of depression and side effects of antiepileptic drugs on injuries in patients with epilepsy.

BACKGROUND AND PURPOSE: People with epilepsy are at increased risk of accidents and injuries but, despite several studies on this subject, data regarding preventable causes are still contradictory. The aim of this study was to investigate the relationship between injuries, side effects of antiepileptic drugs (AEDs) and depression. METHODS: Data from a consecutive sample of adult patients with epilepsy attending the outpatient clinics at St George's University Hospital in London were included. All patients were asked if they had had any injury since the last clinic appointment and completed the Liverpool Adverse Event Profile (LAEP) and Neurological Disorders Depression Inventory for Epilepsy. RESULTS: Among 407 patients (243 females, mean age 43.1 years), 71 (17.4%) reported injuries since the last appointment. A two-step cluster analysis revealed two clusters with the major cluster (53.5% of the injured group) showing a total score for LAEP ≥45, a positive Neurological Disorders Depression Inventory for Epilepsy screening and presence of AED polytherapy. A total score for LAEP ≥45 was the most important predictor. CONCLUSIONS: Antiepileptic drug treatment should be reviewed in patients reporting injuries in order to evaluate the potential contribution and burden of AED side effects.

Clinical correlates of memory complaints during AED treatment.

OBJECTIVES: To investigate clinical correlates of memory complaints (MC) during anti-epileptic drug (AEDs) treatment in adults with epilepsy with special attention to the role of depression, using user-friendly standardized clinical instruments which can be adopted in any outpatient setting. MATERIALS & METHODS: Data from a consecutive sample of adult outpatients with epilepsy assessed with the Neurological Disorder Depression Inventory for Epilepsy (NDDIE), the Adverse Event Profile (AEP) and the Emotional Thermometer (ET) were analysed. RESULTS: From a total sample of 443 patients, 28.4% reported MC as 'always' a problem. These patients were less likely to be seizure free (18.3% vs 34.3%; P < 0.001), had a high number of previous AED trials (4 vs 3; P < 0.001) and high AEP total scores (49 vs 34.2; P < 0.001). There was no correlation with specific AED type or combination. Depression was the major determinant with a 2-fold increased risk (95%CI 1.15-3.86; P = 0.016). When depression was already known and under treatment, patients with MC were less likely to be in remission from depression despite antidepressant treatment (11.9% vs 1.6% P < 0.001). Among patients without depression, those reporting MC presented with significantly high scores for depression (3.3 vs 2; t = 3.07; P = 0.003), anxiety (4.5 vs 2.7; t = 4.43; P < 0.001), anger (3 vs 2; t = 2.623; P = 0.009) and distress (3.8 vs 2.2; t = 4.027; P < 0.001) than those without MC. CONCLUSIONS: Depression has to be appropriately treated and full remission from depression should represent the ultimate goal as subthreshold or residual mood and anxiety symptoms can contribute to MC.

Pregabalin add-on for drug-resistant partial epilepsy.

BACKGROUND: Epilepsy is a common chronic neurological disease with an estimated prevalence of 1% in the United Kingdom. Approximately a third of these people continue to have seizures despite drug treatment. In order to try to improve outcomes a number of new antiepileptic drugs have been developed and pregabalin is one of these. OBJECTIVES: To summarize evidence from randomized, controlled trials regarding the efficacy and tolerability of pregabalin when used as an add-on antiepileptic drug in treatment-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register (July 2007), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2007), Medline (1966 to March 2007) and contacted Pfizer Inc (the manufacturers of pregabalin) to identify published, unpublished, and ongoing trials. SELECTION CRITERIA: We included randomized controlled double-blind trials comparing pregabalin with placebo for people with drug-refractory partial epilepsy. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal for any reason, treatment withdrawal for adverse events, and nature of adverse events. DATA COLLECTION AND ANALYSIS: Two review authors (DL and AGM) independently selected and assessed suitable trials and extracted data. Primary analyses were by intention-to-treat (ITT). Results are presented as relative risks (RR) with 95% confidence intervals (CI). MAIN RESULTS: Four suitable trials (1397 participants) were identified and included in the analysis. Trials tested doses of pregabalin ranging from 50 mg to 600 mg per day. For the primary outcome, 50% or higher seizure reduction was significantly more likely in patients randomized to pregabalin than to placebo (RR 3.56, 95% CI 2.60 to 4.87). A dose response analysis suggested increasing effect with increasing dose. Pregabalin was not significantly associated with seizure freedom (RR 2.73, 95% CI 0.72 to 10.33). Patients were significantly more likely to have pregabalin withdrawn for any reason (RR 1.43, 95% CI 1.11 to 1.85) or for adverse effects (RR 2.47, 95% CI 1.80 to 4.17). Ataxia, dizziness, somnolence and weight gain were significantly associated with pregabalin. AUTHORS' CONCLUSIONS: Pregabalin, when used as an add-on drug for treatment-resistant partial epilepsy, is significantly more effective than placebo at achieving a 50% or greater seizure reduction. Results demonstrate efficacy for doses from 150 mg to 600 mg per day, with no evidence for plateauing of effect at the doses tested. The trials included in this review were of short duration and longer term trials are needed to better inform clinical decision making.

Late-onset temporal lobe epilepsy with unilateral mesial temporal sclerosis and cognitive decline: a diagnostic dilemma.

We present a patient with new onset temporal lobe epilepsy and cognitive decline in his sixth decade with unilateral hippocampal atrophy on structural brain imaging, compatible with mesial temporal sclerosis. This unusual clinical scenario presented a challenging differential diagnosis since it may overlap with primary cognitive disorders, including early-onset Alzheimer's disease and some forms of frontotemporal dementia, and the recently elucidated syndrome of non-paraneoplastic limbic encephalitis associated with voltage-gated potassium channel antibodies.

Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer's disease.

BACKGROUND/AIMS: To investigate the frequency of epilepsy at the time of diagnosis of Alzheimer's disease (AD). METHODS: Observational study, Cognitive Function Clinic population, over a 6-year period (2000-2005 inclusive). RESULTS: In a cohort of 177 patients with newly diagnosed clinically probable AD, 12 (6.8%) had a history of seizure disorder and/or were using anti-epileptic medications at the time of diagnosis. In 6 of these cases (3.4%), seizure onset was approximately concurrent with the onset of cognitive decline, and no symptomatic or provoking factor for seizures other than AD was identified. CONCLUSION: Although epileptic seizures are more common later in the course of AD, nonetheless they may accompany the onset of, and be symptomatic of, the disease, perhaps reflecting a shared pathogenesis.

Prevention of osteoporosis in glucocorticoid-treated neurology patients.

OBJECTIVES: Iatrogenic, including corticosteroid-induced osteoporosis is preventable with administration of osteoprotective biphosphonates. The best medical practice is published in the National Guidelines: UK Osteoporosis Consensus Group (1998, update 2002). We conducted an audit in prednisolone-treated general neurology patients, to assess compliance to national guidelines, raise awareness of osteoporosis prevention, and improve clinical practice in a tertiary neurology referral centre. METHODS AND RESULTS: Preintervention: Of the 48 cases (21 male) identified twenty-nine (61%) received osteoporosis prophylaxis. Nineteen (40%) were given biphosphonates, while 10 (21%) hormone replacement therapy or calcium and Vitamin D. INTERVENTION: Results were presented to the consultant body. Postintervention: Data were collected prospectively on 48 patients (30 male) in year 2001. Thirty-eight (79%) received prophylaxis: 35 (73%) were started on biphosphonates, while 3 (6%) on calcium and Vitamin D. This process was repeated 2 years later to assess sustainability. Of the 48 patients, 44 (92%) received prophylaxis: 41 (86%) were taking biphosphonates, while 3 (6%) calcium and Vitamin D. CONCLUSION: We present an original and complete audit on osteoporosis prophylaxis in a typical population of neurology patients. Though initial results were similar to previous reports, our audit led to significant improvement in clinical practice. National guidelines could not be followed meticulously, as our centre has no regular access to bone densitometry. Our patient population had other risk factors for osteoporosis apart from steroid use. Therefore, we recommend that neurologists in this setting use osteoporosis prophylaxis for all their patients on long-term corticosteroids.

Neurological presentation of intravascular lymphoma: report of two cases and discussion of diagnostic challenges.

About a third of patients with intravascular lymphoma (IVL) present to the neurologist with symptoms mimicking thromboembolic events. Diagnosis is difficult, and often made postmortem. As remission may be induced in almost half of patients with combination chemotherapy, early diagnosis of this rare disease is essential. We report two cases of IVL. A 62-year-old male presented with hyperacute myelopathy followed by cortical ischaemic events. The diagnosis was reached with frontal cortical and meningeal biopsy. A 56-year-old female had symptoms of transient ischaemic events, subacute dementia, weight loss and fever. As the disease progressed, she developed nephrotic syndrome and thrombocytopenia. Diagnosis was made postmortem. Our cases illustrate that IVL should be considered in the differential diagnosis of cerebral and systemic vasculitis and subacute bacterial endocarditis. Literature suggests IVL can also mimic Creutzfeld-Jakob disease and paraneoplastic encephalomyelitis.

Paying attention to the thalamic reticular nucleus.

The thalamic reticular nucleus can be divided into a number of sectors, each concerned with a different function (sight, touch, hearing, movement or 'limbic' functions). Each sector is connected to more than one thalamic nucleus and to more than one cortical area, and each sector has topographically mapped connections with the thalamus and the cortex. We consider the known details of these connections and show: (1) that they are not the same for each sector; (2) that the reticular nucleus serves as a nexus, where several functionally related cortical areas and thalamic nuclei can interact, modifying thalamocortical transmission through the inhibitory connections that go from the reticular cells to thalamic relay cells; and (3) that we need much more detailed information about these highly organized connections before we can understand exactly how the thalamic reticular nucleus might be influencing thalamocortical pathways in attentional mechanisms or in other, as yet undefined, roles.

Complexities in the thalamocortical and corticothalamic pathways.

It is now a century since Kölliker (Handbuch der Gewebelehre des Menschen. Nervensystemen des Menschen und der Thiere, Vol. 2, 6th edn. Engelmann, Leipzig, 1896) described the thalamic reticular nucleus as the 'Gitterkern' or lattice nucleus on the basis of the fibrous latticework that is the characteristic feature of this part of the ventral thalamus and adjacent parts of the internal capsule. We suggest that the fibre reorganization produced in this lattice is a fundamental requirement for linking orderly maps in the thalamus to corresponding cortical maps by two-way thalamocortical and corticothalamic connections; these connections involve divergence, convergence and mirror reversals, which all have to occur between the thalamus and the cortex. Apart from the thalamic reticular nucleus, two transient groups of cells, the perireticular nucleus (located in the internal capsule lateral to the reticular nucleus) and the cells of the cortical subplate, are prominent along the course of axons linking the cortex and thalamus early in development. The functions of these two cell groups are not known. However, since early in development complex patterns of reorganization, defasciculation and crossings occur in the regions of these cells, it is likely that they play a role in creating the latticework of the adult. The latticework that characterizes the thalamic reticular nucleus of mammals can also be identified in the ventral thalamus of non-mammalian brains, formed along the course of the fibres that join the dorsal thalamus to the telencephalon. We suggest that the ubiquitous presence of such a zone of fibre reorganization is integral to the functioning of the thalamocortical pathways, and that the complexity of thalamic connections produced in the lattice has been central to the evolutionary success of the thalamotelencephalic system.

The course and termination of corticothalamic fibres arising in the visual cortex of the rat.

Corticothalamic axons have been studied in adult Lister hooded rats with single or dual injections of tracers into the visual cortex. Labelled axons leave medial and lateral injection sites in separate or partially overlapping bundles along parallel trajectories in the subcortical white matter. In the internal capsule they converge and both bundles enter roughly the same sector of the thalamic reticular nucleus (TRN). Their reticular terminal fields, however, differ. Axons from a medial injection site innervate more lateral parts of the TRN than do the axons from lateral injection sites. The most medial third of the TRN is not innervated from area 17 but receives a topographically arranged input from peristriate cortex (Crabtree and Killackey, 1989, Eur. J. Neurosci., 1, 94-109; Coleman and Mitrofanis, 1996, Eur. J. Neurosci., 8, 388-404). The two groups of axons then separate in the dorsal thalamus, axons from medial parts of visual cortex turning caudally into lateral regions of the lateral geniculate nucleus, whereas fibres from more lateral cortex continue into medial parts of the nucleus. Connolly and van Essen (1984, J. Comp. Neurol., 226, 544-564) and Nelson and LeVay (1985, J. Comp. Neurol., 240, 322-330) have shown that in the geniculocortical pathway the two groups of fibres cross over in the subcortical white matter, probably in the region of the subplate. We show that the corticothalamic pathway also has a crossing, but it occurs in, or close to, the diencephalon itself, in the region of the perireticular nucleus. This result suggests that each of these pathways, the geniculocortical and the corticogeniculate, may undergo reorganization within distinct cerebral zones, one diencephalic for the corticothalamic axons and the other telencephalic for the thalamocortical axons.

Evidence for a projection from the perireticular thalamic nucleus to the dorsal thalamus in the adult rat and ferret.

During early development, the perireticular thalamic nucleus is very large (i.e. has many cells) and has a strong projection to the dorsal thalamus and to the cerebral neocortex. By adulthood, the nucleus has much reduced in size and only a few cells remain. It is not clear whether these perireticular cells that remain into adulthood maintain their connections with the dorsal thalamus and with the neocortex. This study examines this issue by injecting neuronal tracers into various nuclei of the dorsal thalamus (dorsal lateral geniculate nucleus, medial geniculate complex, ventroposteromedial nucleus, lateral posterior nucleus, posterior thalamic nucleus) and into different areas of the neocortex (somatosensory, visual, auditory). After injections of tracer into the individual nuclei of the rat and ferret dorsal thalamus, retrogradely-labelled perireticular cells are seen. In general, after each injection, the retrogradely-labelled perireticular cells lie immediately adjacent to a group of retrogradely-labelled reticular cells. For instance, after injections into the medial geniculate complex, perireticular cells adjacent to the auditory reticular sector are retrogradely-labelled, whilst after an injection into the dorsal lateral geniculate nucleus, retrogradely-labelled perireticular cells adjacent to the visual reticular sector are seen. By contrast, injections of tracer into various areas of the rat and ferret neocortex result in no retrogradely-labelled cells in the perireticular nucleus. Thus, unlike during perinatal development when perireticular cells project to both neocortex and dorsal thalamus, perireticular cells in the adult seem to project to the dorsal thalamus only: the perireticular projection to the neocortex appears to be entirely transient.

Organization of connections between the thalamic reticular and the anterior thalamic nuclei in the rat.

The thalamic reticular nucleus (TRN) receives topographically organized input from specific sensory nuclei such as the lateral geniculate nucleus. The present study shows this in the rat. However, the pattern of thalamic connections to the limbic reticular sector is unknown. Injecting biocytin into the ventral parts of anteroventral and anteromedial nuclei labeled neurons and axons in the rostral TRN. Filled axon collaterals and their terminals occupied a rectangular sheet in a plane close to the horizontal, and were confined to the inner zone (the medial portion) of the limbic TRN. Retrogradely filled cells were in the middle of the rostral pole in the same horizontal plane, receiving synapses from surrounding labeled boutons. In electron micrographs, thalamic terminals were found to contain round, densely packed synaptic vesicles and formed asymmetrical synapses onto reticular somata and dendritic profiles. Displacing the injection site along the dorso-ventral and rostro-caudal axis in the anterior nuclei produced corresponding shifts of antero- and retrograde labeling within the inner reticular zone. Projections from the dorsal portions of the anterior nuclei did not follow this pattern. Axons from the anterodorsal nucleus occupied the rostralmost tip of both inner and outer zones of the dorsal limbic sector. In accordance with earlier reports, the limbic sector was found to represent several dorsal thalamic nuclei parallel to each other medio-laterally. A topography is described for the limbic reticulo-thalamic connections, suggesting that the rostral TRN is able to influence circumscribed areas of the limbic thalamus.

Organization of cortical afferents to the rostral, limbic sector of the rat thalamic reticular nucleus.

The organization of limbic cortical afferents to the thalamic reticular nucleus (TRN) is described. Wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), biocytin, neurobiotin, or fluorescent dextrans was delivered into the rat cingulate, retrosplenial, and, for comparison, somatosensory cortices. In other species a slab-like arrangement of cortical terminals has been described for sensory TRN sectors. Here this is seen in the rat somatosensory sector. Terminals from limbic cortices did not cluster into slabs but were found to fill the entire thickness of distinct rostral TRN regions. The cingulate and retrosplenial recipient TRN regions overlap, as do the projections from these cortical areas to anterior thalamic nuclei. Retrosplenial fibres contacted the dorsal and rostral TRN, which is known to be connected to the retrosplenial-recipient anteroventral, anterodorsal, and laterodorsal thalamic nuclei. Cingulate terminals occupied more ventral regions of the rostral TRN. This area is connected to thalamic nuclei also innervated by the cingulate cortex: the mediodorsal and anteromedial nuclei. A loose, but clear, topography could be defined for the cingulate-reticular pathway: rostrocaudal and mediolateral directions in the cortex are represented by ventrodorsal and rostrocaudal directions in the TRN, respectively. This organization of limbic corticoreticular pathway corresponds to the arrangement of limbic corticothalamic connections. The ultrastructure of the limbic cortical axon terminals was similar to that of the cortical boutons (D-type) described previously. The labelled terminals formed asymmetrical synapses onto dendritic profiles of reticular neurons. These findings, together with data in the literature, show significant morphological and connectional differences within the TRN that imply functional heterogeneities.

Synapses upon the axon origin of dorsal horn neurons in the rat spinal cord.

Axon terminals synapsing with axon hillocks or origins of Golgi-impregnated and gold-toned neurons in the dorsal horn of the rat were shown in serial electron micrographs. Synapses occurred irrespective of the site (perikaryon or dendrite) and mode (with or without an axon hillock) of the axon origin. The synapsing axon terminals contained 3 populations of vesicles: pleomorphic and flattened synaptic vesicles and a combination of pleomorphic and dense-core vesicles. The membrane thickening in the axon-axon hillock synapses was of the symmetrical type.