Epigallocatechin-3-Gallate Protects against Homocysteine-Induced Brain Damage in Rats.

High levels of homocysteine are implicated in many neurovascular and neurodegeneration diseases. Epigallocatechin 3-gallate (EGCG), one of green tea polyphenols, has potential anti-oxidative and anti-inflammatory activities. However, it has not been explored whether EGCG has an effect on homocysteine-induced neuro-inflammation and neurodegeneration. In this study, we investigated the effects of EGCG on memory deficit, oxidative stress, neuro-inflammation, and neurodegeneration in hyper-homocysteinemic rats after a 2 wk homocysteine injection by vena caudalis. We found that supplementation of EGCG could rescue deficit of spatial memory induced by homocysteine. Treatment of EGCG significantly reduced the expression of malondialdehyde, glial fibrillary acidic protein, tumor necrosis factor-α, and interleukin-1ß and increased glutathione level in the homocysteine-treated group. In TdT-mediated dUTP nick end labeling (TUNEL) assay and Fluoro-Jade B staining, supplementation of EGCG could attenuate the apoptotic neurons and neurodegeneration. Interestingly, EGCG significantly ameliorated homocysteine-induced cerebrovascular injury. Our data suggest that EGCG could be a promising candidate for arresting homocysteine-induced neurodegeneration and neuro-inflammation in the brain.

Ethanol Iris tenuifolia extract reduces brain damage in a mouse model of cerebral ischaemia.

In the previous experiments, the neuroprotective role of Iris tenuifolia Pall. (IT) in the model of middle cerebral artery occlusion (MCAO) was investigated. In addition, the concentrations of the cytokines tumour necrosis factor-alpha and interleukin-6 in blood plasma were measured. It was found that IT administered 1 hr prior to MCAO or immediately after MCAO reduced infarct volume significantly. IT application 1 and 4 hr after MCAO, respectively, was without any effect on infarct volume. There were no significant changes as regards tumour necrosis factor-alpha, whereas interleukin-6 concentrations were increased in blood plasma. This is the first evidence that flavonoids from Iris tenuifolia exert protective effects in the in vivo MCAO model. Our results suggest that these flavonoids are likely to be beneficial to humans by virtue of their ability to reduce infarct volume.

Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke, traumatic brain injury, and bacterial meningitis - a systematic review and meta-analysis.

BACKGROUND: The effectiveness of pharmacological strategies exclusively targeting secondary brain damage (SBD) following ischemic stroke, aneurysmal subarachnoid hemorrhage, aSAH, intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and bacterial meningitis is unclear. This meta-analysis studied the effect of SBD targeted treatment on clinical outcome across the pathological entities. METHODS: Randomized, controlled, double-blinded trials on aforementioned entities with 'death' as endpoint were identified. Effect sizes were analyzed and expressed as pooled risk ratio (RR) estimates with 95% confidence intervals (CI). 123 studies fulfilled the criteria, with data on 66,561 patients. RESULTS: In the pooled analysis, there was a minor reduction of mortality for aSAH [RR 0.93 (95% CI:0.85-1.02)], ICH [RR 0.92 (95% CI:0.82-1.03)] and bacterial meningitis [RR 0.86 (95% CI:0.68-1.09)]. No reduction of mortality was found for ischemic stroke [RR 1.05 (95% CI:1.00-1.11)] and TBI [RR 1.03 (95% CI:0.93-1.15)]. Additional analysis of "poor outcome" as endpoint gave similar results. Subgroup analysis with respect to effector mechanisms showed a tendency towards a reduced mortality for the effector mechanism category "oxidative metabolism/stress" for aSAH with a risk ratio of 0.86 [95% CI: 0.73-1.00]. Regarding specific medications, a statistically significant reduction of mortality and poor outcome was confirmed only for nimodipine for aSAH and dexamethasone for bacterial meningitis. CONCLUSIONS: Our results show that only a few selected SBD directed medications are likely to reduce the rate of death and poor outcome following aSAH, and bacterial meningitis, while no convincing evidence could be found for the usefulness of SBD directed medications in ischemic stroke, ICH and TBI. However, a subtle effect on good or excellent outcome might remain undetected. These results should lead to a new perspective of secondary reactions following cerebral injury. These processes should not be seen as suicide mechanisms that need to be fought. They should be rather seen as well orchestrated clean-up mechanisms, which may today be somewhat too active in a few very specific constellations, such as meningitis under antibiotic treatment and aSAH after surgical or endovascular exclusion of the aneurysm.

Protection of the Blood-Brain Barrier as a Therapeutic Strategy for Brain Damage.

Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood-brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. The characteristic pathophysiological conditions caused by BBB disruption are brain edema resulting from an excessive increase of brain water content, inflammatory damage caused by infiltrating immune cells, and hemorrhage caused by the breakdown of microvessel structures. Because these pathogenic features induced by BBB disruption cause fatal conditions, their improvement is a desirable strategy. Many studies using experimental animal models have focused on molecules involved in BBB disruption, including vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs) and endothelins (ETs). The inhibition of these factors in several experimental animals was protective against BBB disruption caused by several types of brain damage, and ameliorated brain edema, inflammatory damage, and hemorrhagic transformation. In patients with brain damage, the up-regulation of these factors was observed and was related to brain damage severity. Thus, BBB protection by targeting VEGFs, MMPs, and ETs might be a novel strategy for the treatment of brain damage.

Prognostic factors that increase the risk for reduced white matter volumes and deficits in attention and learning for survivors of childhood cancers.

OBJECTIVE: In children, CNS-directed cancer therapy is thought to result in decreased cerebral white matter volumes (WMV) and subsequent neurocognitive deficits. This study was designed as a prospective validation of the purported reduction in WMV, associated influential factors, and its relationship to neurocognitive deficits in a very large cohort of both acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT) survivors in comparison to an age similar cohort of healthy sibling controls. PROCEDURES: The effects of host characteristics and CNS treatment intensity on WMV were investigated in 383 childhood cancer survivors (199 ALL, 184 BT) at least 12 months post-completion of therapy and 67 healthy siblings that served as a control group. t-Tests and multiple variable linear models were used to assess cross-sectional WMV and its relation with neurocognitive function. RESULTS: BT survivors had lower WMV than ALL survivors, who had less than the control group. Increased CNS treatment intensity, younger age at treatment, and greater time since treatment were significantly associated with lower WMV. Additionally, cancer survivors did not perform as well as the control group on neurocognitive measures of intelligence, attention, and academic achievement. Reduced WMV had a larger impact on estimated IQ among females and children treated at a younger age. CONCLUSIONS: Survivors of childhood cancer that have undergone higher intensity therapy at a younger age have significantly less WMV than their peers and this difference increases with time since therapy. Decreased WMV is associated with significantly lower scores in intelligence, attention, and academic performance in survivors.

Long-term outcomes after new onset seizure in children living with HIV: A cohort study.

OBJECTIVE: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure. METHODS: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality. RESULTS: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence. SIGNIFICANCE: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures. PLAIN LANGUAGE SUMMARY: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures.

Intracerebral electrographic activity following a single dose of diazepam nasal spray: A pilot study.

OBJECTIVE: Rescue benzodiazepine medication can be used to treat seizure clusters, which are intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. The NeuroPace RNS® System is a device that detects abnormal electrographic activity through intracranial electrodes and administers electrical stimulation to control seizures. Reductions in electrographic activity over days to weeks have been associated with the longer-term efficacy of daily antiseizure medications (ASMs). In this pilot study, electrographic activity over hours to days was examined to assess the impact of a single dose of a proven rescue therapy (diazepam nasal spray) with a rapid onset of action. METHODS: Adult volunteers (>18 years old) with clinically indicated RNS (stable settings and ASM usage) received a weight-based dose of diazepam nasal spray in the absence of a clinical seizure. Descriptive statistics for a number of detections and a sum of durations of detections at 10-min, hourly, and 24-h intervals during the 7-day (predose) baseline period were calculated. Post-dose detections at each time interval were compared with the respective baseline-detection intervals using a 1 SD threshold. The number of long episodes that occurred after dosing also were compared with the baseline. RESULTS: Five participants were enrolled, and four completed the study; the excluded participant had recurrent seizures during the study. There were no consistent changes (difference >1 SD) in detections between post-dose and mean baseline values. Although variability was high (1 SD was often near or exceeded the mean), three participants showed possible trends for reductions in one or more electrographic variables following treatment. SIGNIFICANCE: RNS-assessed electrographic detections and durations were not shown to be sensitive measures of short-term effects associated with a single dose of rescue medication in this small group of participants. The variability of detections may have masked a measurable drug effect. PLAIN LANGUAGE SUMMARY: Rescue drugs are used to treat seizure clusters. Responsive neurostimulation (RNS) devices detect and record epilepsy brain waves and then send a pulse to help stop seizures. This pilot study looked at whether one dose of a rescue treatment changes brain activity detected by RNS. There was a very wide range of detections, which made it difficult to see if or how the drug changed brain activity. New studies should look at other types of brain activity, multiple doses, and larger patient groups.

Is recurrent perseveration a product of deafferented functional systems with otherwise normal post-activation decay rates?

Recent work in neuropsychology, clinical aphasiology and neuropharmacology have presented evidence that the causative substrates of recurrent perseveration in adults with aphasia are more recondite and subject to distinct interpretations than originally thought. This article will discuss and evaluate how various proposals from theory, from the clinic and from drug therapy interact and compete in the search for a cause or causes of recurrent perseveration.

l-Theanine Ameliorates d-Galactose-Induced Brain Damage in Rats via Inhibiting AGE Formation and Regulating Sirtuin1 and BDNF Signaling Pathways.

The maintenance of homeostasis is essential for mitigating stress and delaying degenerative diseases such as Alzheimer's disease (AD). AD is generally defined as the abnormal production of ß-amyloid (Aß) and advanced glycation end products (AGEs). The effects of l-theanine on Aß and AGE generation were investigated in this study. Decreased AGEs and Aß 1-42 levels were reflected by increased acetylcholine (ACh) concentration and acetylcholinesterase (AChE) activity inhibition compared to model rats. l-Theanine also inhibited nuclear factor-κB (p65) protein expression by activating sirtuin1 (SIRT1), reducing inflammatory factor expression, and downregulating the mRNA and protein expression of AGE receptors (RAGE). Superoxide dismutase 2 and catalase protein expressions were markedly upregulated by l-theanine, whereas oxidative stress-related injury was alleviated. The expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) was also found to be increased. H&E staining showed that the apoptosis of hippocampal neurons was mitigated by decreased Bax and cleaved-caspase-3 protein expression and the increase of Bcl-2 protein expression. Moreover, l-theanine increased the gene and protein expression of brain-derived neurotrophic factor (BDNF). These findings suggest that the potential preventive effects of l-theanine against AD may be attributed to its regulation of SIRT1 and BDNF proteins and its mitigation of AGEs/RAGE signaling pathways in the brain tissue of AD model rats.

Neferine Protects against Hypoxic-Ischemic Brain Damage in Neonatal Rats by Suppressing NLRP3-Mediated Inflammasome Activation.

Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. Given the prevalence of HIE and the associated fatality, further studies on its pathogenesis are warranted. Oxidative stress and neuroinflammatory injury are two important factors leading to brain tissue injury and nerve cell loss in HIE. Neferine, an alkaloid extracted from lotus seed embryo, exerts considerable effects against several diseases such as cancers and myocardial injury. In this study, we demonstrated the neuroprotective effect of neferine on HIE and hypothesized that it involves the inhibition of neuronal pyroptosis, thereby ameliorating neurological inflammation and oxidative stress. We demonstrated that the mRNA levels of proteins associated with pyroptosis including caspase-1, the caspase adaptor ASC, gasdermin D, interleukin- (IL-) 18, IL-1ß, and some inflammatory factors were significantly increased in neonatal HIBD model rats compared to those in the control group. The increase in these factors was significantly suppressed by treatment with neferine. We stimulated PC12 cells with CoCl2 to induce neuronal HIBD in vitro and investigated the relationship between neferine and pyroptosis by altering the expression of the NLRP3 inflammasome. The overexpression of NLRP3 partially reversed the neuroprotective effect of neferine on HIBD, whereas NLRP3 knockdown further inhibited caspase-1 activation and IL-1ß and IL18 expression. In addition, simultaneous alteration of NLRP3 expression induced changes in intracellular oxidative stress levels after HIBD. These findings indicate that neferine ameliorates neuroinflammation and oxidative stress injury by inhibiting pyroptosis after HIBD. Our study provides valuable information for future studies on neferine with respect to neuroinflammation and pyroptosis.

[Undetected Hashimoto encephalopathy--a diagnostic challenge in child psychiatry and child neurology]. / Die unerkannte Hashimoto-Enzephalopathie.

The literature is reviewed. Hashimoto encephalopathy is a steroid-responsive encephalopathy associated with Hashimoto thyroiditis (SREHT). The incidence of SREHT in childhood is underestimated. Two subtypes have been described. The diffuse progressive type is associated with insidious onset and progressive impairment of mental status, such as confusion, somnolence, and psychosis. The vasculitic type is characterized by acute stroke-like episodes associated with focal neurologic features and seizures. Hashimoto encephalopathy (SREHT) is a clinical condition with elevated thyroid antibody titers encompassing persistent or relapsing seizures, myoclonus, focal neurologic deficits and neuropsychiatric disorders such as psychosis, delusions and hallucinations, and affective disorders. By far, the vast majority of reports on paediatric and adult patients describe a dramatic clinical response to either methylprednisolone pulse therapy or daily oral prednisone or prednisolone.

From traumatic brain injury to posttraumatic epilepsy: what animal models tell us about the process and treatment options.

A large number of animal models of traumatic brain injury (TBI) are already available for studies on mechanisms and experimental treatments of TBI. Immediate and early seizures have been described in many of these models with focal or mixed type (both gray and white matter damage) injury. Recent long-term video-electroencephalography (EEG) monitoring studies have demonstrated that TBI produced by lateral fluid-percussion injury in rats results in the development of late seizures, that is, epilepsy. These animals develop hippocampal alterations that are well described in status epilepticus-induced spontaneous seizure models and human posttraumatic epilepsy (PTE). In addition, these rats have damage ipsilaterally in the cortical injury site and thalamus. Although studies in the trauma field provide a large amount of information about the molecular and cellular alterations corresponding to the immediate and early phases of PTE, chronic studies relevant to the epileptogenesis phase are sparse. Moreover, despite the multiple preclinical pharmacologic and cell therapy trials, there is no information available describing whether these therapeutic approaches aimed at improving posttraumatic recovery would also affect the development of lowered seizure threshold and epilepsy. To make progress, there is an obvious need for information exchange between the trauma and epilepsy fields. In addition, the inclusion of epilepsy as an outcome measure in preclinical trials aiming at improving somatomotor and cognitive recovery after TBI would provide valuable information about possible new avenues for antiepileptogenic interventions and disease modification after TBI.

Valproic acid-induced encephalopathy in very long course treated patients.

PRIMARY OBJECTIVE: In patients receiving valproate (VPA) treatment, valproate induced-encephalopathy (VIE) is among the most serious adverse side-effects and hyperammonaemia is a frequent and well-recognized event. This report evaluates adult patients receiving VPA for several years. RESEARCH DESIGN: This study was conducted in adult patients receiving VPA for several years. Many studies have evaluated blood ammonia levels and VPA-related encephalopathy in patients whose treatment was initiated for a few months. Most studies were conducted in children. METHODS AND PROCEDURES: This study looked at retrospectively occurrences of VIE in 63 patients who were receiving VPA for a minimum duration of at least 2 years. At the beginning of the study basal ammonaemia was measured for all patients. MAIN OUTCOMES AND RESULTS: This study reports a rather frequent onset of VIE. Long duration of VPA treatment was not correlated with encephalopathy onset. In seven cases temporary administration of lactulose alone was effective and VPA was continued. CONCLUSIONS: This study confirms that, under VPA treatment, hyperammonaemia is a current event; 25.4% patients presented isolated elevated ammonaemia when receiving VPA for very long durations. VPA therapy should be monitored closely and clinicians must be warned of VPA encephalopathy signs.

Caffeic acid phenethyl ester decreases the level of S-100B protein after middle cerebral artery [correction for after] occlusion in rabbits.

Effects of caffeic acid phenethyl ester (CAPE) on the serum S-100B levels were studied as an index for brain damage after permanent middle cerebral artery (MCA) occlusion in rabbits. Twenty rabbits were divided into four groups (n=5): control, sham, non-treatment and CAPE. The right MCA was occluded using a microsurgical procedure with bipolar coagulation and was then transected in non-treatment and CAPE groups. The rabbits in the sham group underwent a surgical procedure but the MCA was not occluded. No surgery was performed in the control group. CAPE was administered after MCA occlusion at the dose of 10 microg/kg, once a day intraperitoneally for 7 days in the CAPE group. Serum S-100B levels were determined on days 1, 2, 4 and 7. Serum S-100B level was significantly increased following permanent MCA occlusion. Posttreatment of CAPE significantly reduced the serum S-100B level. This study demonstrated that CAPE is capable of attenuating increased serum S-100B level induced by MCA occlusion in rabbits. CAPE may be useful as a neuroprotective agent.

Amiloride Alleviates Neurological Deficits Following Transient Global Ischemia and Engagement of Central IL-6 and TNF-α Signal.

BACKGROUND: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine if blocking acid sensing ion channels (ASICs) using amiloride in the Central Nervous System can alleviate neurological deficits after the induction of CA and further examine the participation of PIC signal in the hippocampus for the effects of amiloride. METHODS: CA was induced by asphyxia and then cardiopulmonary resuscitation was performed in rats. Western blot analysis and ELISA were used to determine the protein expression of ASIC subunit ASIC1 in the hippocampus, and the levels of PICs. As noted, it is unlikely that this procedure is clinically used although amiloride and other pharmacological agents were given into the brain in this study. RESULTS: CA increased ASIC1 in the hippocampus of rats in comparison with control animals. This was associated with the increase in IL-1ß, IL-6 and TNF-α together with Caspase-3 and Caspase-9. The administration of amiloride into the lateral ventricle attenuated the upregulation of Caspase-3/Caspase-9 and this further alleviated neurological severity score and brain edema. Inhibition of central IL-6 and TNF-α also decreased ASIC1 in the hippocampus of CA rats. CONCLUSION: Transient global ischemia induced by CA amplifies ASIC1a in the hippocampus likely via PIC signal. Amiloride administered into the Central Nervous System plays a neuroprotective role in the process of global ischemia. Thus, targeting ASICs (i.e., ASIC1a) is suggested for the treatment and improvement of CA-evoked global cerebral ischemia.

alpha-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced brain injury and improves neurological reflexes and early sensorimotor behavioral performance in juvenile rats.

Our previous study showed that treatment with alpha-phenyl-n-tert-butyl-nitrone (PBN) after exposure to lipopolysaccharide (LPS) reduced LPS-induced white matter injury in the neonatal rat brain. The object of the current study was to further examine whether PBN has long-lasting protective effects and ameliorates LPS-induced neurological dysfunction. Intracerebral (i.c.) injection of LPS (1 mg/kg) was performed in postnatal day (P) 5 Sprague Dawley rat pups and PBN (100 mg/kg) or saline was administered intraperitoneally 5 min after LPS injection. The control rats were injected (i.c.) with sterile saline. Neurobehavioral tests were carried out from P3 to P21, and brain injury was examined after these tests. LPS exposure resulted in severe brain damage, including enlargement of ventricles bilaterally, loss of mature oligodendrocytes, impaired myelination as indicated by the decrease in myelin basic protein immunostaining, and alterations in dendritic processes in the cortical gray matter of the parietal cortex. Electron microscopic examination showed that LPS exposure caused impaired myelination as indicated by the disintegrated myelin sheaths in the juvenile rat brain. LPS administration also significantly affected neurobehavioral functions such as performance in righting reflex, wire hanging maneuver, cliff avoidance, negative geotaxis, vibrissa-elicited forelimb-placing test, beam walking, and gait test. Treatment with PBN, a free radical scavenger and antioxidant, provided protection against LPS-induced brain injury and associated neurological dysfunction in juvenile rats, suggesting that antioxidation might be an effective approach for therapeutic treatment of neonatal brain injury induced by infection/inflammation.

Selenium compounds counteract the stimulation of ecto-nucleotidase activities in rat cultured cerebellar granule cells: putative correlation with neuroprotective effects.

Glutamate is the main excitatory neurotransmitter in brain involved in pathophysiology of several brain injuries. In this context, glutamate showed to stimulate ecto-nucleotidase activities in cerebellar granule cells increasing extracellular adenosine levels, an important neuromodulator in the CNS able to prevent cell damage. The organoselenium compounds, such as ebselen and diphenyl diselenide [(PhSe)(2)], display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties. Ebselen was described to prevent glutamate-induced lipid peroxidation and cell death in cerebellar granule cells and (PhSe)(2) modify glutamatergic synapse parameters in vitro and in vivo. In the present study, we investigated the effects of ebselen or (PhSe)(2) on glutamate-induced stimulation of ecto-nucleotidase activities in rat cultured cerebellar granule cells. Glutamate increased nucleotide hydrolysis at lower concentrations (10 and 100 microM) than described in the literature and this effect was counteracted by both organoselenium compounds tested. Based on these results, we investigated the association of organoselenium effects with their antioxidant properties searching for redox site modulation by using the alkylant agent N-ethylmaleimide (NEM). Our results suggest that selenium compounds, as well as the well-known antioxidant trolox, can avoid the increase on glutamate-induced stimulation of ecto-nucleotidase activities probably due to their antioxidant properties.

Prospective study examining remote effects of botulinum toxin a in children with cerebral palsy.

We examined the remote effects on muscle strength and functional decline of lower-extremity botulinum toxin A injections in children with cerebral palsy. This prospective study enrolled 34 children (19 boys, 15 girls; mean age, 7.7 years) diagnosed with spastic cerebral palsy. Patients were examined at baseline and 1 month to determine if they experienced a change in upper-extremity strength (handheld dynamometry) or function (Pediatric Outcomes Data Collection Instrument). Subjects were analyzed in aggregate and by dosing group (low dose, 0-10 U/kg body weight; high dose, 11-25 U/kg) to determine if injection dose was associated with a change in remote muscle strength or function. We measured baseline and 1-month postinjection strength in shoulder flexor, shoulder abductor, elbow flexor, elbow extensor, and finger flexor muscles. None of these remote muscle groups was significantly weaker at 1 month after injection. No correlation was evident between change in muscle strength and toxin dose. These findings indicate that doses of botulinum toxin A in the lower extremities, at up to 21 U/kg, do not affect upper-extremity strength. This information can help guide dosages of botulinum toxin A in the management of spasticity in children with cerebral palsy.

First-line therapy for theophylline-associated seizures.

Theophylline-associated seizures (TAS) are considered a neurologic emergency, as they can sometimes be intractable and difficult to stop with standard treatments such as intravenous administration of diazepam. As a consequence, a proportion of patients who experience status epilepticus while receiving theophylline will require endotracheal intubation. The optimal first-line therapy for TAS has not yet been fully investigated. We compared 54 cases of TAS with 779 cases of non-TAS, that had presented at a single institution between 1991 and 2002. Among the 54 cases of TAS, 36 experienced generalized tonic-clonic seizures, with the remainder experiencing partial seizures. TAS occurred mainly in children under 3 years of age, and serum theophylline levels were within the therapeutic range in 78% of the cases. The duration of TAS tended to be longer than for non-TAS, and intravenous administration of diazepam was less effective in controlling TAS (45%), compared with non-TAS (68%). Many cases required repeated injections of diazepam, and 15 cases (27%) eventually required endotracheal intubation. Reports concerning the therapy for TAS were also reviewed. Theophylline is known to antagonize the effects of benzodiazepines, and this may explain why drugs such as diazepam are relatively ineffective in treating TAS. In TAS, the prompt use of barbiturates is recommended when diazepam is not effective, to avoid potential brain injury secondary to status epilepticus.

Potassium channel antibody associated encephalopathy presenting with a frontotemporal dementia like syndrome.

OBJECTIVE: To describe a patient who presented with features suggestive of frontotemporal dementia (FTD) but with some atypical findings and antibodies to neuronal voltage-gated potassium channels (VGKC-Abs). DESIGN: Case report. SETTING: Mater Misericordiae University Hospital, Dublin, Ireland. RESULTS: An 82-year-old man presented with progressive changes in personality, social conduct, and executive function with preservation of memory, deteriorating from baseline to requiring acute hospitalization within 6 months. Transient deterioration (episodic speech arrest) with spontaneous recovery, atypical for frontotemporal dementia, was observed. The patient had an elevated VGKC-Ab titer (2624 pM [normal range, < 100 pM]), elevated protein levels in cerebrospinal fluid, and a negative evaluation for malignancy. Magnetic resonance imaging of brain was normal but [(18)F]-fluorodeoxyglucose positron emission tomographic imaging revealed bifrontal hypometabolism. A marked and sustained improvement with steroid therapy was observed. CONCLUSION: Workup for a potentially reversible autoimmune-mediated encephalopathy, including a VGKC-Ab titer, should be considered in patients presenting with rapidly progressive behavioral and cognitive decline.