A Comprehensive Review of Neurologic Manifestations of COVID-19 and Management of Pre-existing Neurologic Disorders in Children.

Since the first reports of SARS-CoV-2 infection from China, multiple studies have been published regarding the epidemiologic aspects of COVID-19 including clinical manifestations and outcomes. The majority of these studies have focused on respiratory complications. However, recent findings have highlighted the systemic effects of the virus, including its potential impact on the nervous system. Similar to SARS-CoV-1, cellular entry of SARS-CoV-2 depends on the expression of ACE2, a receptor that is abundantly expressed in the nervous system. Neurologic manifestations in adults include cerebrovascular insults, encephalitis or encephalopathy, and neuromuscular disorders. However, the presence of these neurologic findings in the pediatric population is unclear. In this review, the potential neurotropism of SARS-CoV-2, known neurologic manifestations of COVID-19 in children, and management of preexisting pediatric neurologic conditions during the COVID-19 pandemic are discussed.

Variable manifestations of familial hemiplegic migraine associated with reversible cerebral edema in children.

Three children with familial hemiplegic migraine presented with right-sided weakness, speech difficulty, altered mental status, and gait abnormalities. These persistent aura signs were accompanied by left-sided slowing and cerebral dysfunction, documented by electroencephalograms. Cranial magnetic resonance imaging revealed cortical edema restricted to the left cerebral hemisphere. Follow-up electroencephalogram and imaging studies produced normal results 1-4 months afterward. However, cognitive changes persisted. Genetic testing demonstrated variable results: one child manifested a CACNA1A mutation compatible with familial hemiplegic migraine type 1, whereas another demonstrated an ATP1A2 sequence alteration. No known mutations were evident in the third child, with minor head trauma thought to precipitate the familial hemiplegic migraine. These findings demonstrate the variable clinical and genetic heterogeneity of childhood familial hemiplegic migraine.

Valproate attenuates dextroamphetamine-induced subjective changes more than lithium.

Dextroamphetamine administration in healthy controls produces a range of subjective and physiological effects, which have been likened to those occurring during mania. However, it is uncertain if these can be attenuated by lithium since conflicting results have been reported. To date there have been no previous studies examining the effects of valproate on dextroamphetamine-induced mood and physiological changes. The current study was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n=12), 900 mg lithium (n=9), or placebo (n=12) pre-treatment for 14 days. Subjective and physiological measures were then obtained prior to administration of a 25 mg dose of dextroamphetamine, and at two time points after administration. Differences in the response to dextroamphetamine were assessed between the three treatment groups. The results of this study show that pre-treatment with lithium only significantly attenuated dextroamphetamine-induced change in happiness, while valproate pre-treatment significantly attenuated the effects of dextroamphetamine on happiness, energy, alertness and on the diastolic blood pressure. These results suggest that lithium and valproate do not have the same mechanism of action on dextroamphetamine-induced changes, and this finding may relate to differences in their mechanism of action in mood disorders.

Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation.

BACKGROUND: Previous studies have suggested that both lithium and valproate may decrease phosphoinositol second messenger system (PI-cycle) activity. There is also evidence that dextroamphetamine may increase PI cycle activity. It was previously demonstrated that dextroamphetamine administration in volunteers causes a region and task dependent decrease in brain activation in healthy volunteers. The current study assessed the effect of 14 days pretreatment with lithium and valproate on these dextroamphetamine-induced changes in regional brain activity in healthy volunteers. METHODS: This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n = 12), 900 mg lithium (n = 9) or placebo (n = 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after administration of dextroamphetamine (25 mg). Changes in the number of activated pixels and changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after dextroamphetamine administration were then determined. RESULTS: In keeping with previous findings dextroamphetamine administration decreased regional brain activation in all three tasks. Pretreatment with lithium attenuated changes in the word generation paradigm and the spatial attention task, while pretreatment with valproate attenuated the changes in the working memory task. CONCLUSIONS: These results suggest that both lithium and valproate can significantly attenuate dextroamphetamine-induced changes in brain activity in a task dependent and region specific manner. This is the first human evidence to suggest that both lithium and valproate may have a similar effect on regional brain activation, conceivably via similar effects on PI-cycle activity.

Dextroamphetamine causes a change in regional brain activity in vivo during cognitive tasks: a functional magnetic resonance imaging study of blood oxygen level-dependent response.

BACKGROUND: Dextroamphetamine is known to have profound effects on both subjective and physiologic measurements, but it is unclear to what extent these behavioral changes are a direct result of altered regional brain activation. One method to measure this is to use functional magnetic resonance imaging (fMRI). METHODS: In the present study, fMRI was used to measure both the spatial extent of changes (the number of pixels activated) and the magnitude of the blood oxygen level-dependent (BOLD) response. We examined the effects of motor, verbal, memory, and spatial attention task during fMRI in 18 healthy volunteers. Functional MRI measurements were obtained at baseline and again 75 min after an oral dose of 25 mg dextroamphetamine. RESULTS: Dextroamphetamine caused a decrease in the number of activated pixels and the magnitude of the BOLD response during the three cognitive tasks tested but not during the motor task. These changes were region and task specific. CONCLUSIONS: This is the first study to examine the effect of dextroamphetamine on the number of activated pixels and the BOLD response during the performance of a range of cognitive and motor tasks. Our results suggest that dextroamphetamine causes measurable decreases in brain activity in a variety of regions during cognitive tasks. These changes might be linked to behavioral changes observed after dextroamphetamine administration and could possibly be mediated by alterations in dopaminergic activation.

Brain choline concentrations may not be altered in euthymic bipolar disorder patients chronically treated with either lithium or sodium valproate.

BACKGROUND: It has been suggested that lithium increases choline concentrations, although previous human studies examining this possibility using 1H magnetic resonance spectroscopy (1H MRS) have had mixed results: some found increases while most found no differences. METHODS: The present study utilized 1H MRS, in a 3 T scanner to examine the effects of both lithium and sodium valproate upon choline concentrations in treated euthymic bipolar patients utilizing two different methodologies. In the first part of the study healthy controls (n = 18) were compared with euthymic Bipolar Disorder patients (Type I and Type II) who were taking either lithium (n = 14) or sodium valproate (n = 11), and temporal lobe choline/creatine (Cho/Cr) ratios were determined. In the second part we examined a separate group of euthymic Bipolar Disorder Type I patients taking sodium valproate (n = 9) and compared these to controls (n = 11). Here we measured the absolute concentrations of choline in both temporal and frontal lobes. RESULTS: The results from the first part of the study showed that bipolar patients chronically treated with both lithium and sodium valproate had significantly reduced temporal lobe Cho/Cr ratios. In contrast, in the second part of the study, there were no effects of sodium valproate on either absolute choline concentrations or on Cho/Cr ratios in either temporal or frontal lobes. CONCLUSIONS: These findings suggest that measuring Cho/Cr ratios may not accurately reflect brain choline concentrations. In addition, the results do not support previous suggestions that either lithium or valproate increases choline concentrations in bipolar patients.

Lithium and valproate protect against dextro-amphetamine induced brain choline concentration changes in bipolar disorder patients.

BACKGROUND: Lithium may affect brain choline concentrations, and this effect has been proposed to potentially explain its clinical efficacy. Since dextro-amphetamine is a useful human model of mania, we were interested in determining firstly whether dextro-amphetamine would alter brain choline concentrations, and secondly to determine if lithium would protect against any such changes in bipolar patients. In addition, we wanted to determine if valproate would also have any effects upon choline levels. METHODS: Healthy controls (n=18) were compared with euthymic Bipolar Disorder patients (Type I and Type II) who were taking lithium (n=14) or valproate (n=11). We utilized (1)H-magnetic resonance spectroscopy ((1)H-MRS) in a 3.0T scanner to examine brain choline/phosphocholine+creatine (Cho/Cr) ratios. Changes in this ratio were measured to determine any changes in choline concentrations in the temporal lobe. RESULTS: The results showed that administration of dextro-amphetamine decreased the Cho/Cr ratios. In contrast, in both the lithium-treated and valproate-treated patients this decrease was not seen; this attenuation in the change in Cho/Cr ratio changes was statistically significant. It should be noted that Cho/Cr ratios were significantly higher at baseline in the controls compared to both groups of patients, which may have influenced the results. CONCLUSIONS: These findings are the first to examine the effects of dextro-amphetamine on brain choline concentrations. They show that while in controls dextro-amphetamine decreases choline concentrations, lithium and valproate both appear to protect against this effect in bipolar patients. However, as brain ratios were measured rather than the absolute concentration of choline, and these ratios were lowered in patients at baseline, these results must be regarded as preliminary and require replication in future studies.

Relationship of plasma amphetamine levels to physiological, subjective, cognitive and biochemical measures in healthy volunteers.

Acute administration of the stimulant dextro-amphetamine produces multiple physiological, subjective cognitive and biochemical changes. These effects are similar to those seen in mania, and may be a useful model for mania. The aim of the present study was more fully to determine the multiple effects of dextro-amphetamine and to relate these to changes in plasma levels of the drug. In a double-blind, placebo-controlled crossover study in 25 healthy volunteers (ages 18-45), the effects of 25 mg of oral dextro-amphetamine were examined. Physiological, subjective, cognitive changes, concentrations of amino acids and metabolites of biogenic amines period were related to changes in plasma amphetamine concentrations over 500 min. Peak concentrations of dextro-amphetamine occurred at 2.5-3.5 h post-administration and levels decreased to 75% of peak value after 500 min. The results from the present study indicate that the subjective psychological, cognitive and blood pressure changes frequently did not mirror the time course of plasma levels of the drug. Thus, there was no clear-cut relationship between plasma levels and effects. In addition, dextro-amphetamine caused no significant changes in amino acids or amino metabolite concentrations. In conclusion, while dextro-amphetamine administration definitely causes several changes which are seen in mania, there remain some physiological and metabolic differences between these two conditions.

Effects of dextroamphetamine, lithium chloride, sodium valproate and carbamazepine on intraplatelet Ca2+ levels.

OBJECTIVE: To explore the possible involvement of second-messenger pathways in the pathophysiology of bipolar disorder and the mechanism of action of mood stabilizers, we investigated the effects of dextroamphetamine (a model for mania) and the most widely used mood stabilizers, lithium chloride, sodium valproate and carbamazepine, on intraplatelet levels of calcium ion ([Ca2+). DESIGN: In the first part of the study, dextroamphetamine was administered in vivo in a double-blind, placebo-controlled, crossover design. In the second part of the study, platelets from untreated subjects were incubated in vitro with dextroamphetamine, lithium chloride, sodium valproate or carbamazepine. PARTICIPANTS: Fifteen healthy men between 18 and 45 years of age. OUTCOME MEASURES: Basal, thrombin-induced and serotonin- (5-HT) induced intraplatelet [Ca2+] determined by means of fura-2 fluorescent intensity. RESULTS: In vivo administration of dextroamphetamine had no effect on basal or agonist-induced intraplatelet [Ca2+]. However, in vitro basal platelet [Ca2+] was significantly higher in samples incubated with dextroamphetamine (86.8 nmol/L [standard error of the mean, SEM, 3.9], p < 0.001), lithium chloride (76.4 nmol/L [SEM 3.1], p < 0.002), sodium valproate (82.7 nmol/L [SEM 3.7], p < 0.001) and carbamazepine (84.8 nmol/L [SEM 3.3], p < 0.001) than in the controls (58.2 nmol/L [SEM 2.3]). Thrombin-induced and 5-HT-induced peak cytosolic [Ca2+] were significantly greater than control levels in samples incubated with carbamazepine (277.1 nmol/L [SEM 19.9] v. 195.8 nmol/L [SEM 12.2], p < 0.002; and 153.0 nmol/L [SEM 8.2] v. 115.4 nmol/L [SEM 5.7], p < 0.003, respectively). CONCLUSIONS: This study does not support the involvement of intraplatelet [Ca2+] in the dextroamphetamine model of mania; however, the modulation of intraplatelet [Ca2+] by the mood stabilizers lithium chloride, sodium valproate and carbamazepine implicates intracellular [Ca2+] in the therapeutic mechanisms of these drugs and the pathophysiological basis of mania.

Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients.

Previous studies have found that treatment with lithium over a 4-week period may increase the concentration of N-acetyl-aspartate (NAA) in both bipolar patients and controls. In view of other findings indicating that NAA concentrations may be a good marker for neuronal viability and/or functioning, it has been further suggested that some of the long term benefits of lithium may therefore be due to actions to improve these neuronal properties. The aim of the present study was to utilize H magnetic resonance spectroscopy ( H MRS) to further examine the effects of both lithium and sodium valproate upon NAA concentrations in treated euthymic bipolar patients. In the first part of the study, healthy controls (n =18) were compared with euthymic bipolar patients (type I and type II) who were taking either lithium (n =14) or sodium valproate (n =11), and NAA : creatine ratios were determined. In the second part, we examined a separate group of euthymic bipolar disorder patients taking sodium valproate (n =9) and compared these to age- and sex-matched healthy controls (n =11), and we quantified the exact concentrations of NAA using an external solution. The results from the first part of the study showed that bipolar patients chronically treated with lithium had a significant increase in NAA concentrations but, in contrast, there were no significant increases in the sodium valproate-treated patients compared to controls. The second part of the study also found no effects of sodium valproate on NAA concentrations. These findings are the first to compare NAA concentrations in euthymic bipolar patients being treated with lithium or sodium valproate. The results support suggestions that longer-term administration of lithium to bipolar patients may increase NAA concentrations. However, the study suggests that chronic administration of sodium valproate to patients does not lead to similar changes in NAA concentrations. These findings suggest that sodium valproate and lithium may not share a common mechanism of action in bipolar disorder involving neurotrophic or neuroprotective effects.

Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients.

BACKGROUND: It has been proposed that lithium may be clinically effective due to its actions on the phosphoinositol second messenger system (PI-cycle). Studies have also suggested that untreated manic patients may have raised myo-inositol and phosphomonoester (PME) concentrations and also that unmedicated euthymic bipolar patients may have lowered PME concentrations. The objective of the present study was to test the hypothesis that chronic treatment with either lithium or sodium valproate in patients with bipolar mood disorder leads to a normalization in the activity of the PI-cycle. METHODS: This study had two parts each with different MRS methodology. The first part compared healthy controls (n = 19) with euthymic bipolar patients who were taking either lithium (n = 16) or sodium valproate (n = 11) using both (1)H-MRS and (31)P-MRS. In the second part we examined a separate group of euthymic bipolar disorder patients taking sodium valproate (n = 9) and compared these with age and sex-matched healthy controls (n = 11) using (1)H-MRS. RESULTS: Both studies showed that there were no differences in either myo-inositol or phosphomonoester (PME) concentrations between controls and patients taking either medication. CONCLUSIONS: These findings examine two key components of the PI-cycle in treated euthymic bipolar (myo-inositol and PME concentrations). The results from this study are consistent with the suggestion that chronic treatment with either lithium or sodium valproate in bipolar patients may normalize PI-cycle functioning.