Cells sort into regions and groups in part by their selective surface expression of particular classic cadherins during development. In the nervous system, cadherin-based sorting can define axon tracts, restrict axonal and dendritic arbors to particular regions or layers, and may encode certain aspects of synapse specificity. The underlying model has been that afferents and their targets hold in common the expression of a particular cadherin, thereby providing a recognition code of homophilic cadherin binding. However, most neurons express multiple cadherins, and it is not clear whether multiple cadherins all act similarly in shaping neural circuitry. Here we asked how two such cadherins, cadherin-8 and N-cadherin, influence the guidance and differentiation of hippocampal mossy fibers. Using organotypic hippocampal cultures, we find that cadherin-8 regulates mossy fiber fasciculation and targeting, but has little effect on CA3 dendrites. In contrast, N-cadherin regulates mossy fiber fasciculation, but has little impact on axonal growth and targeting. However, N-cadherin is essential for CA3 dendrite arborization. Both cadherins are required for formation of proper numbers of presynaptic terminals. Mechanistically, such differential actions of these two cadherins could, in theory, reflect coupling to distinct intracellular binding partners. However, we find that both cadherins bind b-catenin in dentate gyrus (DG). This suggests that cadherins may engage different intracellular signaling cascades downstream of b-catenin, coopt different extracellular binding partners, or target distinct subcellular domains. Together our findings demonstrate that cadherin-8 and N-cadherin are critical for generating the mossy fiber pathway, but that each contributes differentially to afferent and target differentiation, thereby complementing one another in the assembly of a synaptic circuit.

SUMMARYPurpose: To compare pharmacokinetics, tolerability, and efficacy of lamotrigine (LTG) in older versus younger adults. Methods: We studied 686 adult outpatients seen at our center over 5 years. We compared apparent clearance (CL) of LTG in the youngest (16-36 years; n = 247) and oldest (55-92 years; n = 155) tertiles. We analyzed oneyear retention for younger and older adults newly started on LTG, frequency of adverse effects causing intolerability, and rates of specific adverse effects. We also investigated 6-month seizure freedom. Key Findings: Median LTG CL of older adults taking LTG in monotherapy was approximately 22% lower compared to younger adults (28.8 vs. 36.5 ml/h/kg; p < 0.001). LTG CL in older adults was lower compared to younger adults in patients on polytherapy and on polytherapy without enzyme inducers or valproate. One-year retention for LTG was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults. Intolerability to LTG was higher in older (34.8%) versus younger adults (24.2%; p = 0.005). Imbalance, drowsiness, and dizziness were common intolerable side effects in both groups. Older patients had higher rates of intolerability due to imbalance (16% vs. 4%), drowsiness (13% vs. 7%), and tremor (5% vs. 2%) compared with younger patients. Rates of 6-month seizure freedom were comparable, and small numbers of each group benefited from very high levels of LTG (>15 lg/ml). Significance: LTG CL in monotherapy in older adults is approximately 20% lower than in younger adults. For a given serum LTG level, older adults are twice as likely to have significant adverse effects compared to younger adults. Older patients are more likely to experience imbalance, drowsiness, and tremor than younger patients. Younger adults tolerate LTG better than older adults, but one-year retention is comparable. Some patients may benefit from high serum levels of LTG. KEY WORDS: Antiepileptic drug, Older adults, Drug interactions, Elderly, Pharmacokinetics.Lamotrigine (LTG) is a commonly used antiepileptic drug (AED) that received approval by the U.S. Food and Drug Administration (FDA) in 1994 as adjunctive therapy for partial seizures in adults and later in pediatric patients (at least 2 years of age). In addition, LTG has been approved for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), primidone (PRM), or valproate (VPA) as the single AED (August, 2005;Gilliam et al., 1998) and for adjunctive treatment of primary generalized tonic-clonic seizures and generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients aged 2 years or older.The clinical management of seizures in older adults is often complicated by an increased likelihood of adverse effects (AEs) and potential interactions with multiple comedications. The effect of age and comedication on LTG pharmacokinetics in older adults has not been well studied. In this study we investigated drug and nondrug predictors of LTG clearan...

This information is current as of http://www.neurology.org/content/77/15/1494.full.html located on the World Wide Web at:The online version of this article, along with updated information and services, is rights reserved. Print New-onset refractory status epilepticus (NORSE) describes a prolonged seizure state of unknown etiology that occurs in a person without prior seizures. 1 The prognosis in the literature is poor. 1-4 We present a patient with NORSE who recovered after 4 months of coma.Case report. A healthy 29-year-old man with no epilepsy risk factors experienced 2 weeks of upper respiratory symptoms followed by lethargy. On admission to a regional hospital he was stuporous, febrile, and vomiting. The following day, he experienced multiple generalized convulsions requiring intubation. Ten days later, he was transferred to Columbia on continuous IV propofol and midazolam, as well as levetiracetam, phenytoin, and phenobarbital.Continuous EEG (cEEG) showed electrographic status epilepticus (figure e-1 on the Neurology ® Web site at www.neurology.org). Upon admission, he was comatose, with absent cranial nerve reflexes except for sluggishly reactive pupils. All autoimmune, paraneoplastic, and infectious laboratory studies were negative except for antinuclear antibody. Brain biopsy showed nonspecific inflammation; however, the etiology was never identified. See table e-1 for diagnostic tests and figure e-2 for select MRIs.His seizures were highly refractory, requiring high doses of IV midazolam, pentobarbital, and ketamine; treatments administered are listed in table e-2. He remained intubated in an iatrogenic coma for over 2 months. Weaning trials consistently resulted in unequivocal electrographic seizures without detectable clinical correlate. Anesthetic infusions were eventually weaned by maintaining very high phenobarbital levels in addition to high doses of 3 other antiepileptic drugs (AEDs). Phenobarbital levels were eventually allowed to drift down and occasional seizures were tolerated. He remained comatose for an additional 2 months.Medical complications included pulmonary emboli, bilateral brachial vein thromboses, bowel edema, hyperammonemia (maximum 598 M/L), cholestatic hepatitis (highest total/direct bilirubin 7.4/5.2), massive hepatomegaly with markedly elevated alkaline phosphatase (maximum 1,729 U/L), contractures in the distal extremities despite aggressive physical therapy, and severe critical illness neuromyopathy.He first followed commands on hospital day 120 while on 4 AEDs and with a phenobarbital level of 65.9 g/mL. Over the next several weeks, he was disinhibited, disoriented, and nearly quadriplegic.

A man in his 30s with encephalocraniocutaneous lipomatosis (ECCL), hydrocephalus, ventriculoperitoneal shunt, and Lennox-Gastaut syndrome was seen for epilepsy. He had multiple facial subcutaneous nodules (lipomas), near-blindness bilaterally, and right spastic hemiparesis. He was fluent, dysarthric, and followed one-step commands. A partially thrombosed internal carotid aneurysm was found on imaging (not shown).ECCL is a neurocutaneous syndrome resulting from ectomesodermal dysgenesis, characterized by choristomas (ocular tumors), hairless scalp lesions (nevus psiloliparus), lipomas (facial, intracranial, particularly at the cerebellopontine angle, or intraspinal), and calcifications (figure).1 Half of patients have seizures, onethird have moderate mental retardation, and some have intracranial vascular malformations.