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Biomedical subjects

D H Lowenstein

Publications and source records attributed to D H Lowenstein.

At least 55 records · Page 3Linked to original sources
PubMed1994

Treatment of refractory generalized status epilepticus with continuous infusion of midazolam.

The optimal therapeutic approach for the patient with refractory generalized status epilepticus remains to be defined. We describe four patients with refractory generalized status epilepticus who were successfully treated with intravenous midazolam. Each patient had prolonged convulsive status epilepticus unresponsive to standard doses of intravenous benzodiazepines, phenytoin, and phenobarbital. The patients subsequently received midazolam administered as an intravenous bolus (200 micrograms/kg) followed by a continuous infusion (0.75 to 11 micrograms/kg/min) lasting 8 hours to 10 days. Clinical examination and scalp electroencephalographic monitoring documented the cessation of seizure activity within minutes of the loading dose in all patients. No significant adverse effects occurred during midazolam treatment. The one patient with prolonged midazolam infusion required fluid boluses and pressors for moderate hypotension, and the remainder of the patients safely tolerated midazolam despite preexistent hemodynamic instability. All patients recovered and maintained good seizure control. Intravenous midazolam appears to be an effective treatment for refractory generalized status epilepticus, and may represent a substantial improvement over current therapeutic approaches such as pentobarbital anesthesia.

Adult↗
PubMed1993

Neurotrophins and their receptors--current concepts and implications for neurologic disease.

Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 are members of a family of proteins (the neurotrophins) that promote the differentiation, growth, and survival of peripheral and central nervous system neurons. Recently, the trk family of proto-oncogenes has been found to encode signal-transducing receptors for these growth factors. This discovery has important implications for our understanding of the normal function of these factors in the developing and adult nervous system. In this review, we highlight recent advances in neurotrophin research and discuss their relevance to neurologic disease.

Animals↗
PubMed1993

Prolonged increases in neurotrophic activity associated with kainate-induced hippocampal synaptic reorganization.

Synaptic reorganization occurs in the hippocampus following various forms of seizure activity and injury, and may contribute to epileptogenesis. To address the hypothesis that neurotrophic factors play an inductive role in synaptic reorganization following seizures, we directly measured neurotrophic activity in rat hippocampal extracts after kainate injection or prolonged stimulation of the perforant path. Serial dilutions of hippocampal extracts were added to cultures of chick dorsal root ganglia, which are known to require trophic support from nerve growth factor and other neurotrophins, or ciliary ganglia neurons, which require trophic support from ciliary neurotrophic factor. Neurotrophic activity was significantly increased in hippocampal extracts harvested from 12 h to 2 months after kainate treatment, with the peak effect seen at seven days. This neurotrophic activity was substantially blocked by an anti-nerve growth factor antibody. Extracts at seven days also showed a significant increase in ciliary neurotrophic factor-like activity. Sulfide/silver histochemistry, which stains dentate granule cell axon terminals, revealed that mossy fiber sprouting was evident two weeks following kainate treatment and increased progressively over the next two to six weeks. Perforant path stimulation that produced hyperexcitability in the dentate gyrus, but no sprouting, failed to induce changes in neurotrophic activity. These results suggest there are significant increases in neurotrophic factors following kainate-induced seizures, and the increases may be related to kainate-induced hippocampal injury rather than seizures per se. Furthermore, the timecourse of increased neurotrophic activity parallels that of mossy fiber reorganization, and is consistent with the hypothesis that neurotrophic factors play a role in the injury-induced synaptic reorganization seen in epilepsy.

Animals↗
PubMed1993

Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus.

Memory dysfunction following mild human traumatic brain injury (TBI) is a common clinical observation, but the pathologic substrate underlying this loss of function has not been well-characterized. In the present study, we examined the effects of a mild lateral fluid percussion (FP) brain injury on memory dysfunction, neuronal cell loss in specific regions of the hippocampus, and breakdown of the blood-brain barrier (BBB). A Morris Water Maze (MWM) memory paradigm was used to assess memory retention in rats 42 h after lateral FP brain injury (n = 11) or sham injury (n = 10). At the completion of cognitive testing, animals were sacrificed and neuronal cell loss in the hippocampi was examined with Nissl staining. Immunoreactivity to anti-rat IgG was used to evaluate the extent of BBB disruption. A significant correlation was observed between posttraumatic memory scores and neuronal loss in the hilus of the dentate gyrus (p < 0.005). To our knowledge, these observations are the first to suggest an association between cognitive deficits following a mild experimental brain injury and neuropathological changes in the hippocampus.

Animals↗
PubMed1993

Status epilepticus at an urban public hospital in the 1980s.

We retrospectively reviewed the clinical course of adult patients treated for generalized status epilepticus (SE) at the San Francisco General Hospital (SFGH) from 1980 to 1989. The review was designed to determine whether the etiologies of SE at our hospital have changed over the last two decades, and to investigate the relationships between etiology, response to anticonvulsant therapy, and short-term clinical outcome. Of 154 patients reviewed, the four leading etiologies for SE were anticonvulsant drug withdrawal (39), alcohol-related (39), drug toxicity (14), and CNS infection (12). This pattern was essentially unchanged from observations made at SFGH in the 1970s. Sixty percent of all patients responded to first-line drug treatment (usually phenytoin +/- diazepam), and the remainder required an additional agent (usually phenobarbital) for control of SE. The best response to anticonvulsants occurred in patients with SE related to tumor, anticonvulsant drug withdrawal, or refractory epilepsy, and the poor responders had anoxia, drug toxicity, CNS infection, or other metabolic abnormalities. Seventy-six percent of the patients had good outcomes. Of the 22 patients who died, SE was a likely cause of death in only two (ie, 1.3% of the entire study group). Metabolic abnormalities, stroke, and anoxia were associated with particularly poor outcomes compared with other etiologies. These observations show that the etiologies of SE have remained similar over two successive decades, and that the etiology of SE may help predict both the initial response to drug therapy and the short-term outcome.

Adolescent↗
PubMed1993

Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus.

Pentobarbital coma (PBC) is a treatment for patients with refractory status epilepticus, but there are currently few guidelines for choosing when to initiate or continue this therapy. To identify potential prognostic factors in this setting, we reviewed the course of 17 adult patients treated with a standardized protocol of PBC for refractory status epilepticus over the past 6 years. PBC was extremely effective in aborting seizures in 16 of 17 patients, but 11 of the patients developed severe hypotension that required therapy with vasopressors. Six of the patients had full recoveries or developed only minimal residual deficits following PBC, two developed severe neurologic deficits, and nine died. Survival was associated with a history of epilepsy, absence of multiorgan failure before or during PBC, age < 40 years, and absence of hypotension requiring vasopressors during PBC. Long-term follow-up in seven of eight survivors (mean, 2.9 years; range, 1 to 5 years) showed that patients' conditions remained stable after discharge from the hospital. Thus, although PBC is effective in controlling ongoing seizures, the therapy frequently leads to significant hypotension. This side effect may be especially troublesome in patients with the negative prognostic indicators identified in this study. These findings highlight the need for alternative approaches in the management of these patients.

Adult↗
PubMed1992

Differential expression of K+ channel mRNAs in the rat brain and down-regulation in the hippocampus following seizures.

K+ channels are major determinants of membrane excitability. Differences in neuronal excitability within the nervous system may arise from differential expression of K+ channel genes, regulated spatially in a cell type-specific manner, or temporally in response to neuronal activity. We have compared the distribution of mRNAs of three K+ channel genes, Kv1.1, Kv1.2, and Kv4.2 in rat brain, and examined activity-dependent changes following treatment with the convulsant drug pentylenetetrazole. Both regional and cell type-specific differences of K+ channel gene expression were found. In addition, seizure activity caused a reduction of Kv1.2 and Kv4.2 mRNAs in the dentate granule cells of the hippocampus, raising the possibility that K+ channel gene regulation may play a role in long-term neuronal plasticity.

Animals↗
PubMed1992

Clinical and EEG features of status epilepticus in comatose patients.

We retrospectively evaluated the clinical and EEG features of status epilepticus (SE) in 47 comatose adult patients in whom SE was suspected clinically or because the EEG revealed repetitive electrographic seizures or continuous spike-and-wave activity. Three groups of patients were identified. Group-1 patients (n = 33) had SE both clinically and on EEG. They usually had subtle, clonic movements restricted to the eyes, face, and upper extremities, and the EEG most commonly showed repetitive electrographic seizures or continuous spike-and-wave activity. Group-2 patients (n = 9) also had subtle motor manifestations of seizures, but the EEG was not that of SE, consisting of either irregular slowing with frequent spikes and sharp waves, an irregular mixed-frequency background with episodic accentuation, or diffuse slowing; one patient also had an intermittent burst-suppression pattern. The five patients in Group 3 lacked any clinical signs of seizures, but the EEG showed repetitive electrographic seizures or continuous spike-and-wave activity. There were no significant differences between groups in etiology of SE, response to therapy, or outcome, and there was no obvious relationship between the EEG findings and duration of SE. We conclude that recognition of SE in comatose patients may require both clinical and EEG evaluation since either approach by itself may fail to establish the diagnosis. Furthermore, the EEG findings in established SE do not necessarily progress through the series of defined stages suggested by some authors.

Adolescent↗
PubMed1992

Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus.

Despite intensive study, the neurobiological basis of epilepsy and persistent memory impairment following traumatic head injury remains unknown. Since abnormalities of the hippocampus are known to be associated with temporal lobe seizures and memory dysfunction, we investigated the effects of experimental traumatic brain injury on hippocampal structure and function in the rat. Using a model of fluid-percussion injury, we have discovered that neurons of the dentate hilus are vulnerable to a brief, unilateral impact to the extradural surface of the brain. One week after trauma, there was a dramatic reduction in hilar neurons ipsilateral to the impact, and a milder but significant decrease in neurons on the contralateral side as well. This neuronal loss was highly selective since adjacent dentate granule and pyramidal neurons appeared relatively unaffected. Immunocytochemistry showed that the hilar cell loss included a loss of somatostatin-immunoreactive neurons, and degeneration stains provided evidence that irreversible hilar injury occurred within 4 hr of impact. To assess the functional effects of the hilar damage, dentate granule cell field potentials were measured in response to perforant path stimulation. This revealed abnormal dentate granule cell hyperexcitability at 2.0 Hz stimulation in many of the injured animals. The presence of abnormal hyperexcitability correlated with the loss of hilar neurons. Thus, a momentary impact to the surface of the brain can cause selective, bilateral hippocampal injury with associated abnormalities in dentate gyrus physiology. Furthermore, the pattern of cell loss is similar to that observed in some patients with temporal lobe epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Heat shock protein expression in vulnerable cells of the rat hippocampus as an indicator of excitation-induced neuronal stress.

The inducible 72 kDa heat shock protein (HSP72) has been shown to be protective in non-neuronal cells and neurons in culture, but its function and the control of its expression in the CNS are poorly understood. Although HSP72 is induced in neurons in vivo by neurotoxic compounds that produce seizures and neuronal damage, it is unknown if its expression is a specific response to excitation per se or to "stressful" or potentially injurious excitation, or if it is a marker or mediator of irreversible injury. We have attempted to identify the nature of the stimulus for HSP72 expression by utilizing focal electrical stimulation that can either excite or destroy postsynaptic cells, depending on the duration of afferent stimulation. Previous studies have demonstrated that intermittent stimulation of the main hippocampal afferent pathway for 24 hr evokes synchronous discharges in dentate granule cells but does not injure them. However, the same stimulation irreversibly destroys three of the four cell populations innervated by the granule cells. The three vulnerable populations are the dentate hilar mossy cells, the somatostatin/neuropeptide Y (NPY)-immunoreactive hilar neurons, and the CA3c pyramidal cells. The fourth and relatively resistant population is the GABA-immunoreactive dentate basket cells. In this study, we have localized HSP72 expression immunocytochemically in the hippocampal dentate gyrus in response to nontoxic durations of potentially neurotoxic afferent stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Experimental pneumococcal meningitis causes central nervous system pathology without inducing the 72-kd heat shock protein.

We examined whether experimental pneumococcal meningitis induced the 72-kd heat shock protein (HSP72), a sensitive marker of neuronal stress in other models of central nervous system (CNS) injury. Brain injury was characterized by vasculitis, cerebritis, and abscess formation in the cortex of infected animals. The extent of these changes correlated with the size of the inoculum (P less than 0.003) and with pathophysiologic parameters of disease severity, i.e., cerebrospinal fluid (CSF) lactate (r = 0.61, P less than 0.0001) and CSF glucose concentrations (r = -0.55, P less than 0.0001). Despite the presence of numerous cortical regions having morphologic evidence of injury, HSP72 was not detected in most animals. When present, only rare neurons were HSP72 positive. Western blot analysis of brain samples confirmed the paucity of HSP72 induction. The lack of neuronal HSP72 expression in this model suggests that at least some of the events leading to neuronal injury in meningitis are unique, when compared with CNS diseases associated with HSP72 induction.

Animals↗
PubMed1991

Change in pattern of muscle activity following botulinum toxin injections for torticollis.

Twenty patients with torticollis had electromyographic studies of their neck muscles performed before and after a series of local injections of botulinum toxin. The pattern of muscle activity changed after the injections, and this effect persisted even after head position had returned to baseline. Patients who did not experience any clinical benefit from the injections also demonstrated a change in the pattern of muscle activity. These results suggest that the underlying abnormality in torticollis usually involves a general motor program for head position, rather than the activity of individual neck muscles.

Adult↗
PubMed1991

Up regulation of calbindin-D28K mRNA in the rat hippocampus following focal stimulation of the perforant path.

Calbindin-D28K is a constitutive Ca2(+)-binding protein expressed in hippocampal neurons that are resistant to various forms of excitotoxic injury. However, the local factors controlling calbindin-D28K expression within the central nervous system are unknown. We report that neuronal excitation via the perforant path leads to an increased expression of calbindin-D28K mRNA within dentate granule cells. This response is related specifically to stimulation that induces prolonged periods of bursting afterdischarges and precedes cellular injury. The up regulation of calbindin-D28K mRNA occurs during the type of neuronal activation associated with elevated cytosolic Ca2+ and suggests that the maintenance of Ca2+ homeostasis includes a system of feedback control at the level of gene expression.

Animals↗
PubMed1991

The stress protein response in cultured neurons: characterization and evidence for a protective role in excitotoxicity.

We used purified cultures of cerebellar granule cells to investigate the possible protective role of stress proteins in an in vitro model of excitotoxicity. Initial experiments used one- and two-dimensional polyacrylamide gel electrophoresis to confirm the induction of typical stress protein size classes by heat shock, sodium arsenite, and the calcium ionophore A23187. Immunoblot analysis and immunocytochemistry verified the expression of the highly inducible 72 kd heat shock protein (HSP72). Granule cell cultures exposed to glutamate showed evidence of cellular injury that was prevented by the noncompetitive NMDA antagonist MK-801, yet glutamate did not induce a detectable stress protein response. Nonetheless, preinduction of heat shock proteins was associated with protection from toxic concentrations of glutamate. These results imply that the HSP72 expression observed in in vivo models of excitotoxicity may not be directly related to the effects of excitatory amino acids. However, the ability of stress protein induction to protect against injury from glutamate may offer a novel approach toward ameliorating damage from excitotoxins.

Animals↗
PubMed1991

The temporal profile of 72-kDa heat-shock protein expression following global ischemia.

The potential role of the nonconstitutive 72-kDa heat-shock protein (HSP72) in selective neuronal vulnerability to ischemia was studied in rats subjected to graded global ischemia. Immunocytochemistry using a monoclonal antibody against HSP72 was performed on tissue collected after 24 hr of reperfusion. The appearance of HSP72 immunoreactivity correlated in a graded fashion with those regions known to be selectively vulnerable in ischemia. That is, HSP72 was induced in only hilar interneurons and CA1 pyramidal cells following brief ischemia. After intermediate durations of ischemia, HSP72 was expressed in the CA3 neurons and cortical layers 3 and 5, and after the longest intervals, HSP72 appeared in dentate granule cells. Heat-shock protein expression preceded cell death (assessed with acid fuchsin staining) in all regions. This temporal profile suggests that the capability of neurons to express HSP72 is unlikely to account for selective vulnerability of different brain regions following ischemia; its role in neuroprotection during ischemic injury in vivo remains unknown.

Animals↗
PubMed1990

Emergence of recreational drug abuse as a major risk factor for stroke in young adults.

OBJECTIVE: To investigate the clinical and epidemiologic relations between recreational drug abuse and stroke in young persons. DESIGN: A case-control study based on medical records. SETTING: San Francisco General Hospital, a 400-bed municipal hospital. PATIENTS: Consecutive sample of 214 patients aged 15 to 44 years, admitted between 1979 and 1988 with a diagnosis of ischemic or hemorrhagic stroke. An equal number of control patients admitted with diagnoses of status asthmaticus, acute appendicitis, or acute cholecystitis were matched to stroke patients by age, sex, and year of hospitalization. MEASUREMENTS AND MAIN RESULTS: Seventy-three patients with stroke (34%) were drug abusers compared with 18 (8%) of the controls. In 47 patients with stroke, temporal proximity of drug administration (n = 34) or infectious endocarditis (n = 13) suggested a direct association between drug abuse and stroke. After controlling for other identifiable stroke risk factors, the estimated relative risk for stroke among drug abusers compared with that among non-drug abusers was 6.5 (95% CI, 3.1 to 13.6), and this increased to 49.4 (CI, 6.4 to 379.0) for those patients whose symptoms began within 6 hours of drug administration. Among patients less than 35 years of age, drug abuse was the most commonly identified potential predisposing condition (47%), and it was the only condition with a significantly elevated relative risk for stroke (11.7; CI, 3.2 to 42.5). Further, a substantial rise in the proportion of drug-related strokes was observed in the last 3 years of the study (31% in 1986 to 1988, compared with 15% in 1979 to 1985, P = 0.008). Cocaine, especially recently, was the drug used most frequently in drug-related strokes. CONCLUSION: In an urban population such as ours, recreational drug abuse appears to be a prominent and growing risk factor for strokes in young adults.

Adolescent↗