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Biomedical subjects

Carl E Stafstrom

Publications and source records attributed to Carl E Stafstrom.

At least 19 recordsLinked to original sources
PubMed2006

Epilepsy: a review of selected clinical syndromes and advances in basic science.

Epilepsy is a common neurologic disorder that manifests in diverse ways. There are numerous seizure types and numerous mechanisms by which the brain generates seizures. The two hallmarks of seizure generation are hyperexcitability of neurons and hypersynchrony of neural circuits. A large variety of mechanisms alters the balance between excitation and inhibition to predispose a local or widespread region of the brain to hyperexcitability and hypersynchrony. This review discusses five clinical syndromes that have seizures as a prominent manifestation. These five syndromes differ markedly in their etiologies and clinical features, and were selected for discussion because the seizures are generated at a different 'level' of neural dysfunction in each case: (1) mutation of a specific family of ion (potassium) channels in benign familial neonatal convulsions; (2) deficiency of the protein that transports glucose into the CNS in Glut-1 deficiency; (3) aberrantly formed local neural circuits in focal cortical dysplasia; (4) synaptic reorganization of limbic circuitry in temporal lobe epilepsy; and (5) abnormal thalamocortical circuit function in childhood absence epilepsy. Despite this diversity of clinical phenotype and mechanism, these syndromes are informative as to how pathophysiological processes converge to produce brain hyperexcitability and seizures.

Animals↗
PubMed2005

Models of epilepsy in the developing and adult brain: implications for neuroprotection.

Repeated seizures cause a sequence of molecular and cellular changes in both the developing and adult brain, which may lead to intractable epilepsy. This article reviews this sequence of neuronal alterations, with emphasis on the kindling model. At each step, the opportunity exists for strategic intervention to prevent or reduce the downstream consequences of epileptogenesis and seizure-induced adverse plasticity. The concept of seizure-induced brain damage must be expanded to include behavioral and cognitive deficits, as well as structural neuronal damage and increased predisposition to seizures.

Adult↗
PubMed2005

Nonpharmacological treatment options for epilepsy.

Approximately one third of children with epilepsy have persistent seizures despite trials of multiple antiepileptic medications. For some of these patients, epilepsy surgery may provide freedom from seizures. However, in many cases, epilepsy surgery is not a viable treatment option. Nonpharmacological approaches are a useful adjunct to help manage seizures in these children. This review examines the role of vagus nerve stimulation, the ketogenic diet, and various forms of EEG biofeedback therapy in children with intractable epilepsy. Although the mechanism of action is not known precisely for any of these adjunctive therapies, they add an important and evolving dimension to the management of difficult to control epilepsy in children. In addition, pyridoxine-dependent seizures are discussed as an example of an etiology of refractory seizures that responds well to replacement therapy.

Allylamine↗
PubMed2005

Serial headache drawings by children with migraine: correlation with clinical headache status.

Children's artistic self-depictions of headache provide valuable insights into their experience of pain and aid in the diagnostic differentiation of headache types. In a previous study, we compared the clinical diagnosis (gold standard) and artistic diagnosis of headaches in 226 children. In approximately 90% of cases, the drawing predicted the clinical diagnosis of migraine versus nonmigraine headache correctly. In the present study, we explored whether headache drawings correlate with clinical improvement after treatment in children with migraine headaches followed longitudinally. Children seen in the Pediatric Neurology Clinic with the chief complaint of headache were asked to draw a picture of what their headache feels like. On subsequent clinic visits, children with the clinical diagnosis of migraine were asked to draw another picture depicting their current headache. The two drawings were compared to assess whether there was improvement; this "artistic response" was then correlated with the child's clinical status (ie, whether the headaches were improved clinically). One hundred eleven children (66 girls, 45 boys) participated in the study, with a mean interval of 5.3 +/- 2.3 (standard error of the mean) months between the first and second visits. The mean age at the first visit was 11.6 +/- 3.1 years. The raters agreed that serial drawings were both improved or both not improved in 99 of the 111 cases (89%; interrater reliability kappa score of 0.767). Fifty-three children had improvements in their headaches and drawings, 3 children had an improved drawing but no clinical headache improvement, 32 children had no improvement in either their drawing or clinical headaches, and 11 children had improved headaches but no improvement in their drawing. The sensitivity of the drawings for clinical improvement was 0.83, and the specificity was 0.91. The predictive value of an improved headache drawing for an improved clinical response was 0.946. There was no correlation between specific treatment modality and artistic response. We concluded that children's headache drawings are a useful adjunct for the diagnosis of headache type and provide valuable insights into their experience of pain. The present data show that headache drawings can be used longitudinally to provide additional information about the clinical course. The technique is simple, inexpensive, and enjoyable for children and can be applied in a variety of clinical settings.

Adolescent↗
PubMed2004

Detrimental effects of the ketogenic diet on cognitive function in rats.

The ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that is widely used to treat epilepsy in children. Although the KD has been shown to be efficacious in the treatment of childhood epilepsy, the long-term effects of the KD on brain development are not clear. The objective of this study was to examine the long-term effects of the KD on visual-spatial memory, activity level, and emotionality in immature rats after status epilepticus (SE). Weanling rats were subjected to lithium/pilocarpine-induced SE or saline injections and were then randomized to either the KD or regular rat diet, both fed ad libitum. One month later, rats were evaluated for visual-spatial memory in the water maze, activity level in the open field test, and emotionality with the handling test. Spontaneous recurrent seizures were measured using videotaping, and seizure susceptibility was tested with flurothyl inhalation. Brains were weighed and examined for mossy fiber sprouting and cell loss. Although rats treated with the KD were active and seemed healthy, their weight gain was substantially lower than that in rats that received regular rat diet. The KD reduced the number of spontaneous seizures but had no discernible effect on flurothyl seizure susceptibility. KD-fed rats, with or without SE, had significantly impaired visual-spatial learning and memory compared with rats that were fed regular diet. The KD had minimal effects on activity level and emotionality. Rats that were treated with the KD had significantly impaired brain growth. No differences in pathology scores between the KD and regular diet groups were seen after SE. Despite reducing the number of spontaneous seizures after SE, the KD resulted in severe impairment in visual-spatial memory and decreased brain growth, with no effect on mossy fiber sprouting. This study raises concerns about the long-term effects of the KD on brain development.

Animals↗
PubMed2004

Effects of nimodipine on the behavioral sequalae of experimental status epilepticus in prepubescent rats.

OBJECTIVE: The goal of this study was to investigate the potential protective effects of nimodipine (ND), a calcium channel blocker, on the acute manifestations and long-term behavioral sequalae of experimental status epilepticus (SE). METHODS: Three groups of Postnatal Day (P) 35 rats undergoing kainic acid (KA)-induced SE were injected with phenobarbital (PB) and/or ND, and were subsequently compared with rats injected with KA alone and normal control rats. Behavioral parameters were assessed by the Morris water maze, open field, and handling tests at P125-P135. Acute seizures and spontaneous recurrent seizures (SRS) were assessed by videotape techniques. RESULTS: PB reduced the severity of SE acutely, and protected completely against subsequent long-term SRS, memory impairment, and hyperactivity, and partially against aggressivity. ND alone had no effect on acute seizure activity, but did protect against subsequent SRS and memory impairment, and partially against aggressivity. When administered together, PB and ND had effects similar to those seen with PB alone. However, in addition, and unlike the PB- and ND-alone groups, the PB-ND group was completely protected against KA-induced increased aggressivity. CONCLUSIONS: Activation of L-type calcium channels contributes to the long-term behavioral sequalae of KA-induced SE, but is not essential for the development and maintenance of SE. ND has protective effects in SE when given alone or in conjunction with a traditional antiepileptic drug. Calcium channel blockers should be further investigated as add-on protective agents in models of SE and possibly in clinical trials.

Aggression↗
PubMed2004

Seizures in the developing brain cause adverse long-term effects on spatial learning and anxiety.

PURPOSE: Seizures in the developing brain cause less macroscopic structural damage than do seizures in adulthood, but accumulating evidence shows that seizures early in life can be associated with persistent behavioral and cognitive impairments. We previously showed that long-term spatial memory in the eight-arm radial-arm maze was impaired in rats that experienced a single episode of kainic acid (KA)-induced status epilepticus during early development (postnatal days (P) 1-14). Here we extend those findings by using a set of behavioral paradigms that are sensitive to additional aspects of learning and behavior. METHODS: On P1, P7, P14, or P24, rats underwent status epilepticus induced by intraperitoneal injections of age-specific doses of KA. In adulthood (P90-P100), the behavioral performance of these rats was compared with that of control rats that did not receive KA. A modified version of the radial-arm maze was used to assess short-term spatial memory; the Morris water maze was used to evaluate long-term spatial memory and retrieval; and the elevated plus maze was used to determine anxiety. RESULTS: Compared with controls, rats with KA seizures at each tested age had impaired short-term spatial memory in the radial-arm maze (longer latency to criterion and more reference errors), deficient long-term spatial learning and retrieval in the water maze (longer escape latencies and memory for platform location), and a greater degree of anxiety in the elevated plus maze (greater time spent in open arms). CONCLUSIONS: These findings provide additional support for the concept that seizures early in life may be followed by life-long impairment of certain cognitive and behavioral functions. These results may have clinical implications, favoring early and aggressive control of seizures during development.

Animals↗
PubMed2003

NMDA-induced seizures in developing rats cause long-term learning impairment and increased seizure susceptibility.

N-methyl-D-aspartate (NMDA) receptors play a prominent role in the pathogenesis of epilepsy, yet few studies have used NMDA as a convulsant in whole animals. In developing rats, systemic NMDA induces seizures with a unique seizure phenotype ("emprosthotonic" or hyperflexion seizures) and electrographic pattern (electrodecrement). These features are not seen in kainic acid-induced seizures, suggesting that seizures activated by NMDA might cause different long-term consequences. Therefore, we investigated the effects of NMDA seizures during development on cognitive function and susceptibility to seizures in adulthood. Rat pups (P12-20) were injected with saline (n=36) or NMDA (n=64) at convulsant doses (15-30mg/kg, i.p.). After NMDA injection, a characteristic sequence of seizure activity was seen: initial behavioral arrest, followed by hyperactivity, agitation, and then emprosthotonus and generalized tonic-clonic seizures. Seizures were terminated 30min later by ketamine (50mg/kg, i.p.). On P85, rats underwent behavioral testing in the water maze. Rats that had experienced NMDA seizures as pups took significantly longer to learn the platform location over 5 days of testing, compared to controls. On P90, rats were injected with pentylenetetrazol (PTZ, 50mg/kg, i.p.) to assess their susceptibility to generalized seizures. NMDA-treated rats had decreased latency and increased duration of class V PTZ seizures. Cresyl violet-stained sections of cortex and hippocampus had no obvious cell loss or gliosis. In summary, NMDA causes a unique seizure phenotype in the developing brain, with subsequent deficits in spatial learning and an increased susceptibility to PTZ seizures in adulthood. This study provides additional evidence for long-term alterations of neuronal excitability and cognitive capacity associated with seizures during development.

Animals↗
PubMed2003

Seizure drawings: insight into the self-image of children with epilepsy.

Epilepsy is a chronic disorder that is associated with numerous psychological challenges, especially in children. Drawings have been underutilized as a method to obtain insight into psychological issues in children with epilepsy. We asked 105 children with epilepsy, ages 5 to 18 years, to draw a picture of what it is like to have a seizure. Across ages and epilepsy syndromes, the drawings showed evidence of impaired self-concept, low self-esteem, and a sense of helplessness and vulnerability. Overall, the drawings of human figures were less developed than expected for chronological age. In some drawings, indicators of underlying depression were found. When considered by epilepsy syndrome or seizure type, some specific artistic features were noted. Children with simple partial (motor) seizures drew distorted body parts, especially limbs. Those with complex partial seizures depicted sensory symptoms and mental status changes such as confusion. Children with generalized tonic-clonic seizures showed shaking extremities. Drawings by children with absence seizures illustrated mainly staring. In conclusion, drawings are a powerful method to examine the self-concept of children with epilepsy and gain insight into their feelings about themselves and their world.

Adolescent↗
PubMed2003

The ketogenic diet for the treatment of epilepsy: a challenge for nutritional neuroscientists.

The ketogenic diet (KD) is a high-fat, low-carbohydrate, adequate-protein diet that has been used for more than eight decades for the treatment of refractory epilepsy in children. Despite this long history, the mechanisms by which the KD exerts its anti-seizure action are not fully understood. Questions remain regarding several aspects of KD action, including its effects on brain biochemistry and energetics, neuronal membrane function and cellular network behavior. With the explosion of the KD use in the last 10 years, it is now imperative that we understand these factors in greater detail, in order to optimize the formulation, administration and fine-tuning of the diet. This review discusses what is known and what remains to be learned about the KD, with emphasis on clinical questions that can be approached in the laboratory. We encourage scientists with a primary interest in nutritional neuroscience to join with those of us in the epilepsy research community to address these urgent questions, for the benefit of children ravaged by intractable seizures.

Age Factors↗
PubMed2002

Downregulation of kainate receptors in the hippocampus following repeated seizures in immature rats.

There are significant differences in seizure-induced sequelae between the immature and mature brain. We have previously demonstrated that repeated doses of the chemoconvulsant kainic acid is associated with a progressive increase in severity of seizures in adult animals while in immature rats the opposite occurs; seizure intensity decreases with subsequent doses of kainic acid. Likewise, repeated kainic acid seizures causes severe hippocampal damage in mature rats while in the immature brain serial administration of kainic acid causes no demonstrable cell loss. Here we show that recurrent kainic acid seizures in immature rats are associated with a downregulation of kainate receptor binding. No histological damage was noted in any of the rats exposed to recurrent seizures. Furthermore, when tested for visual-spatial memory immature rats with recurrent kainate seizures did not differ from controls. The downregulation of KA receptors following repeated exposure to KA suggests that the decrease in glutamate receptor density might account in part for the observed lack of neuronal loss and decrease in seizure intensity in these animals.

Animals↗
PubMed2002

Infantile spasms: criteria for an animal model.

Infantile spasms is an epilepsy syndrome with several distinctive features, including age specificity during infancy, characteristic semiology (epileptic spasms), specific electroencephalographic patterns (interictal hypsarrhythmia and ictal voltage suppression), and responsiveness to the adrenocorticotropic hormone (ACTH). There is no adequate animal model of infantile spasms, perhaps due to these clinically unique features, that is specific for the developing human brain. An informative animal model would provide insights into the pathophysiology of this syndrome and form the basis for the development of innovative therapies. This chapter considers criteria for an "ideal" animal model of infantile spasms, as well as "minimal" criteria that we consider essential to yield useful information. Two animal models of infantile spasms have been described in rodents: seizures induced by corticotropin-releasing factor and N-methyl-D-aspartic acid. Neither of these models conforms exactly to the human analog, but each possesses intriguing similarities that provide testable hypotheses for future investigations.

Adrenocorticotropic Hormone↗