Reye-like syndrome following treatment with the pantothenic acid antagonist, calcium hopantenate.

Three senile patients developed fatal acute encephalopathy while receiving calcium hopantenate. The clinical, biochemical, and pathological picture was similar to Reye's syndrome. Calcium hopantenate is a pantothenic acid antagonist. The serum levels of calcium hopantenate were high in coma, and that of pantothenic acid examined in one patient was lowered. Evidence obtained indicated that the Reye-like syndrome might be caused by calcium hopantenate possibly due to the induction of pantothenic acid deficiency.     

A case of the Rett syndrome with acute encephalopathy induced during calcium hopantenate treatment

We report a girl with the Rett syndrome who had acute encephalopathy probably induced by calcium hopantenate (HOPA). This 4-year-6-month-old girl had a history of moderate developmental delay and had received HOPA administration when first admitted at 2 years 6 months of age with hypoglycemia, hyperammonemia, lactic and pyruvic acidemia, and non-ketotic dicarboxylic aciduria. After this episode, she showed the rapid destructive stage of the Rett syndrome, i.e., severe psychomotor retardation with loss of speech, peculiar stereotypic hand movements, autistic behavior and seizures. Despite subsequent investigations, including analysis of urinary metabolites of organic and amino acids, measurement of serum carnitine and a muscle biopsy, we could not clarify the primary metabolic abnormalities in this girl.     

Metabolic acidosis and hypoglycemia during calcium hopantenate administration--report on 5 patients

Calcium hopantenate (HOPA) has been widely used as an activator of cerebral metabolism in Japan. However, several cases of acute encephalopathy during HOPA administration were recently reported, which were characterized by marked metabolic acidosis and hypoglycemia. The encephalopathy in these patients was named Reye-like syndrome because of the similarity to Reye's syndrome in children. The purposes of this presentation are to report on 5 patients with acute encephalopathy developing during HOPA administration, to summarize their symptoms and clinical courses, and to discuss the pathogenesis of metabolic acidosis and hypoglycemia. Initial characteristics of the clinical course in all patients were loss of appetite, nausea and vomiting, followed by unconsciousness. Laboratory examinations revealed marked metabolic acidosis, severe hypoglycemia, hyperlactacidemia, leukocytosis, ketonuria, and increased Ht and BUN. A few days after development of the initial symptoms, mild renal and liver dysfunction, and elevation of serum amylase were observed in all patients. Hyperlactacidemia was present in 4 in the initial period. Blood concentration of HOPA was 2.131 micrograms/ml in patient 1 (8-10 hours after final administration), and 10.7 micrograms/ml in patient 5 (24 hours after final administration). These values are extremely high, because usually HOPA concentration is almost negligible 7 hours after the drug is taken. As the pathogenesis of acute encephalopathy due to HOPA administration, the failure of fatty acid beta-oxidation has been proposed by some investigators. However, the serum concentrations of CoA, pantothenic acid and carnitine during the initial stage were not reduced in our patients. Furthermore, it is very difficult to explain the severe hypoglycemia in terms of the beta-oxidation theory.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reye syndrome and reye-like syndrome

Reye syndrome is an acute metabolic encephalopathy, largely affecting children and adolescents. In Reye-like syndrome, because of inborn errors of metabolism, hypoglycemia, hypoketonemia, elevated ammonia, and organic aciduria are often evident. It is well-known that fatty-acid oxidation defects can present as Reye-like syndrome. The most commonly diagnosed metabolic disorder in association with Reye syndrome has been medium-chain acyl coenzyme A dehydrogenase deficiency. The present consensus seems to be that Reye syndrome is very rare, and that any child suspected of manifesting this disorder should undergo investigations for inborn errors of metabolism. We recently treated a child with "Reye-like illness" who possibly manifested a long-chain acyl dehydrogenase deficiency, and who had also ingested aspirin. We discuss the possible pathogenesis of the disorder in this child. The end results of mitochondrial dysfunction in Reye syndrome and Reye-like illness may be similar.     

The metabolic course of Reye's syndrome: distinction between survivors and nonsurvivors

We compared the levels of hormones and metabolites in the plasma of 37 survivors of Reye's syndrome with the levels in 8 fatal cases, at four time periods within 72 hours of admission. The most prominent differences were found for norepinephrine (NE), which was significantly elevated in fatal cases compared with survivors at all periods. Lactate and dopamine were elevated in the earlier periods. Epinephrine and alpha-amino acid nitrogen were also elevated in fatal cases, but the differences usually were not significant. NE elevation may reflect an increased sympathoadrenal medullary output associated with brain edema, compounded by impaired hepatic clearance of monoamines. Skeletal muscle ischemia from NE-induced vasoconstriction may explain the association between lactic acidemia and the severity of encephalopathy.     

Drug‐resistant epilepsy after treatment for childhood acute lymphocytic leukaemia: from focal epilepsy to Lennox‐Gastaut syndrome

Drug‐resistant epilepsy, not associated with acute brain complications or central nervous system leukaemic involvement, can develop in patients treated for acute lymphocytic leukaemia during childhood. It has been postulated that this rare complication may be due to CNS oncological treatment neurotoxicity, related to intrathecal drugs, such as methotrexate, and brain radiotherapy. We report four patients who developed drug‐resistant epilepsy sometime after receiving treatment for acute lymphocytic leukaemia. All patients were female and received intrathecal methotrexate. One received additional intrathecal cytarabine, and two concomitant brain radiotherapy. Two developed Lennox‐Gastaut type syndrome, one multifocal epilepsy, and one focal epilepsy related to a radiotherapy‐induced cavernous angioma. The development of drug‐resistant epilepsy after treatment for acute lymphocytic leukaemia is a rare complication that may vary, from focal epilepsy to an epileptic encephalopathy. This may appear even years after the treatment has finished and is most likely associated with treatment‐related neurotoxicity.     

Clinical and biochemical studies in a case of acute encephalopathy associated with calcium hopanthenate administration

A case with acute disturbance of consciousness associated with calcium hopanthenate (HOPA) administration was reported. He was a 3-year-old boy with autistic developmental delay, had orally taken 1.5 g of HOPA daily for 3 months. Clinical manifestations consisted of fever, vomiting and coma. Laboratory examination revealed severe hypoglycemia and metabolic acidosis, but there were no hepatic enzyme abnormalities. Analysis of urinary organic acid profile showed that very large amounts of medium and long chain dicarboxylic acids and omega-1 hydroxy-fatty acids were excreted. In particular, 2-hydroxysebacic acid, the accumulation of which has only been reported in the urine of patients with Zellweger syndrome and neonatal adrenoleukodystrophy (NALD), was observed. Analysis of urinary acylcarnitines showed that acetylcarnitine was predominant and C6-C10 dicarboxylic acylcarnitines were also excreted. He was treated with and rapidly responded to intravenous glucose and bicarbonate. After withdrawal of the drug he has had no problems and dicarboxylic aciduria disappeared. A CT scan showed symmetric, low density areas in periventricular white matter, especially around the posterior horns of the lateral ventricles. A T2-weighted MRI scan revealed high-intensity signal in the white matter corresponding to areas of low density on CT scan. We conclude that that a large amount of HOPA administration may cause encephalopathy by the inhibition of both mitochondrial and peroxisomal beta-oxidation.     

Nimodipine in acute ischemic stroke: a double-blind controlled study

Nimodipine (BAY e 9736), a new dihydropyridine derivative, has been shown to reduce neurological deficits and mortality induced by acute cerebral ischemia in experimental studies. We investigated the effects of this calcium antagonist in patients with acute ischemic stroke through a randomized, double-blind, parallel-designed trial in which nimodipine was compared with placebo. Forty-one of 54 screened cases were found to fulfil the inclusion criteria (sudden occurrence of a focal neurological deficit secondary to an acute ischemic event in the carotid area diagnosed after a complete neurological work-up) and entered the study. Nineteen of them were treated with nimodipine (40 mg t.i.d. administered for 28 days) and the remaining 22 with placebo, given in identical tablets. In all patients the treatment started within 12 h after the onset of the symptoms. Course and intensity of the neurological deficit were evaluated by the Mathew Scale (slightly modified). Forty patients concluded the trial. Nimodipine was withdrawn in one case following the occurrence of a skin rash whose causative relation with the test drug could not be clarified. Altogether, however, nimodipine was well tolerated and no severe cardiovascular adverse reactions were observed. In terms of efficacy, the scores obtained by the Mathew Scale showed a higher rate of improvement on nimodipine than on placebo, thus indicating that patients receiving the latter drug did not fare as well as those receiving the test medication. Our data suggest that nimodipine may be beneficial in the treatment of acute stroke.     

Case of methylmalonic acidemia presenting clinically Leigh encephalopathy

A 1-year-old boy with methylmalonic acidemia had symmetrical lesions of the bilateral basal ganglia, which suggested Leigh encephalopathy. The findings on brain magnetic resonance imaging (MRI) and his physical condition greatly improved by the intravenous administration of vitamin B1. We hypothesized that in this case, clinical Leigh encephalopathy was caused by a impairment of the activity of pyruvate carboxylase induced by the accumulation of methylmalonyl CoA and an impairment of energy production due to a lack of vitamin B1, especially impairment of the activity of pyruvate dehydrogenase complex during an acute worsening of methylmalonic acidemia. Thus, in the treatment of methylmalonic acidemia, attention should be paid to vitamin B1 deficiency. During an acute worsening, vitamin B1 should be administered by intravenous drip injection.     

Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome

Patients receiving paclitaxel for cancer treatment often develop an acute pain syndrome (paclitaxel-associated acute pain syndrome, P-APS), which occurs immediately after paclitaxel treatment. Mechanisms underlying P-APS remain largely unknown. We recently reported that rodents receiving paclitaxel develop acute pain and activation of spinal microglial toll like receptor 4 (TLR4) by paclitaxel penetrating into the spinal cord is a critical event in the genesis of P-APS. Our current study dissected cellular and molecular mechanisms underlying the P-APS. We demonstrated that bath-perfusion of paclitaxel, at a concentration similar to that found in the cerebral spinal fluid in animals receiving i.v. paclitaxel (2 mg/kg), resulted in increased calcium activity in microglia instantly, and in astrocytes with 6 min delay. TLR4 activation in microglia by paclitaxel caused microglia to rapidly release interleukin-1β (IL-1β) but not tumor necrosis factor α, IL-6, or interferon-γ. IL-1β release from microglia depended on capthepsin B. IL-1β acted on astrocytes, leading to elevated calcium activity and suppressed glutamate uptake. IL-1β also acted on neurons to increase presynaptic glutamate release and postsynaptic AMPA receptor activity in the spinal dorsal horn. Knockout of IL-1 receptors prevented the development of acute pain induced by paclitaxel in mice. Our study indicates that IL-1β is a crucial molecule used by microglia to alter functions in astrocytes and neurons upon activation of TLR4 in the genesis of P-APS, and targeting the signaling pathways regulating the production and function of IL-1β from microglia is a potential avenue for the development of analgesics for the treatment of P-APS.     

Acute encephalopathy in children with Dravet syndrome

Purpose: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome. Methods: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms. Key Findings: There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8–184 months). All children had status epilepticus followed by coma as the initial manifestation. Two different distributions of brain lesions were observed on diffusion‐weighted images during the acute phase: cerebral cortex–dominant lesions with or without deep gray matter involvement and subcortical‐dominant lesions. Four children died; nine survived with severe sequelae, and two had moderate sequelae. Significance: We must be aware that acute encephalopathy is an important complication in children with Dravet syndrome, and associated with fulminant clinical manifestations and a poor outcome.     

Reversible posterior leucoencephalopathy syndrome associated with bone marrow transplantation

Reversible posterior leucoencephalopathy syndrome (RPLS) has previously been described in patients who have renal insufficiency, eclampsia, hypertensive encephalopathy and patients receiving immunosuppressive therapy. The mechanism by which immunosuppressive agents can cause this syndrome is not clear, but it is probably related with cytotoxic effects of these agents on the vascular endothelium. We report eight patients who received cyclosporine A (CSA) after allogeneic bone marrow transplantation or as treatment for severe aplastic anemia (SSA) who developed posterior leucoencephalopathy. The most common signs and symptoms were seizures and headache. Neurological dysfunction occurred preceded by or concomitant with high blood pressure and some degree of acute renal failure in six patients. Computerized tomography studies showed low-density white matter lesions involving the posterior areas of cerebral hemispheres. Symptoms and neuroimaging abnormalities were reversible and improvement occurred in all patients when given lower doses of CSA or when the drug was withdrawn. RPLS may be considered an expression of CSA neurotoxicity.     

Clinical features of encephalopathy in children with cancer requiring cranial magnetic resonance imaging

We analyzed acute neurotoxic problems attributable to chemotherapy or immunosuppression in the context of childhood neoplastic diseases, based on clinical and neuroradiologic findings. This retrospective single-center study reviewed the acute neurologic complications of 62 children receiving conventional chemotherapy or hematopoietic stem cell transplantation from July 2005-July 2008. We excluded patients with central nervous system metastasis and various neurotoxic manifestations not usually requiring cranial magnetic resonance imaging. Of 62 patients, 12 (19.3%) developed acute neurologic complications. The most common complications included posterior reversible encephalopathy syndrome in six of 12 (50%) patients, and Wernicke's encephalopathy in three of 12 (25%) patients. Other complications included chemical arachnoiditis, grey matter injury induced by postchemotherapeutic angiopathy, and leukoencephalopathy. Posterior reversible encephalopathy syndrome was accompanied by hypertensive episodes in most patients (5/6), and Wernicke's encephalopathy was evident with altered mental status in malnourished children. These data indicate that posterior reversible encephalopathy syndrome and Wernicke's encephalopathy are the predominant complications in children undergoing chemotherapy or hematopoietic stem cell transplantation. Early radiologic and clinical evaluation and prompt treatment for these complications are necessary to prevent their progression to irreversible brain damage.     

Serotonin and amino acids: partners in delirium pathophysiology?

Delirium may be the result of dysfunction of multiple interacting neurotransmitter systems. Changes in the levels of various amino acids being precursors of cerebral neurotransmitters may affect their function and, thus, contribute to the development of delirium. Serotonin is one of the neurotransmitters that may play an important role in medical and surgical delirium. Normal serotonin synthesis and release in the human brain is, among others, dependent on the availability of its precursor tryptophan (Trp) from blood. The essential amino acid Trp competes with the other large neutral amino acids (LNAA) tyrosine, phenylalanine, valine, leucine, and isoleucine for transport across the blood-brain barrier. This competition determines its uptake into the brain, represented by the ratio of the plasma level of Trp to the sum of the other LNAA. The plasma ratio of Trp/LNAA, plasma level of Trp, and serotonin in plasma and platelets have been used as indirect peripheral measures for central serotonergic functioning. Both increased and decreased serotonergic activity have been associated with delirium. Serotonin agonists can induce psychosis, both elevated Trp availability and increased cerebral serotonin have been associated with hepatic encephalopathy, and excess serotonergic brain activity has been related to the development of the serotonin syndrome of which delirium is a main symptom. On the other hand, alcohol withdrawal delirium, delirium in levodopa-treated Parkinson patients, and postoperative delirium have been related to reduce cerebral Trp availability from plasma suggesting diminished serotonergic function. Rick factors for delirium such as severe illness, surgery, and trauma can induce immune activation and a physical stress response comprising increased activity of the limbic-hypothalamic-pituitary-adrenocortical axis, the occurrence of a low T3 syndrome, and, possibly, changes in the permeability of the blood-brain barrier. There are indications that these changes have their effect on plasma amino acid concentrations, e.g., Trp, and multiple cerebral neurotransmitters, including serotonin. This stress response may be different depending on the stage of illness being acute or chronic. It will require further study to determine the complex influence of the stress response and immune activation on plasma amino acids, neurotransmitter function and the development of delirium, especially in the more vulnerable older patients.     

A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy

We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy.     

Extensive Reversible Brain Magnetic Resonance Lesions in a Patient with HELLP Syndrome

A severe form of toxemia of pregnancy with microangiopathic hemolytic anemia, elevated /iver enzymes, and /ow platelets has been called the HELLP syndrome. A patient with the HELLP syndrome developed a severe, reversible encephalopathy. Brain computed tomography and magnetic resonance imaging showed abnormalities consistent with edema limited to the posterior circulation territory. The location of the lesions and their occurrence in the HELLP syndrome support suggestions that the vulnerability of posterior structures in eclamptic encephalopathy is due to a vascular susceptibility of the posterior circulation and that endothelial cell dysfunction plays an important role in the pathogenesis of eclamptic encephalopathy.     

Clinical characteristics of acute encephalopathies associated with influenza H1N1-2009 in children

We report 12 cases of acute encephalopathy associated with influenza H1N1-2009 treated according to Japanese guideline (2009). In all 12 cases, electroencephalogram presented diffuse or localized high-amplitude slow waves. Brain CT and MRI showed abnormalities in 4 and 6 cases, respectively. We used hypothermia therapy for 5 patients. One patient showed impairment in short term memory, while the rest of the patients showed no sequelae. These 12 cases presented here suggest the early recognition and therapy according to the newly proposed guideline may reduce severe sequelae and mortality by acute encephalopathy associated with influenza H1N1-2009.     

Effect of ammonia on calcium homeostasis in primary astrocyte cultures

Calcium influx, accumulation and efflux were studied in primary cultures of rat astrocytes treated with ammonium chloride. Treatment of the cells for 3 days with 10 mMN4Cl resulted in a 35% reduction in 45Ca influx. The decrease in calcium influx was dose-dependent between 2 and 10 mM NH4Cl. Short-term (30 min) exposure to ammonia had no effect on calcium influx. Calcium accumulation, as measured by 20-min exposure to 45Ca, decreased after treating cultures with 10 mM NH4Cl for one or 3 days; a greater effect was observed after the 3-day treatment. Studies with lanthanum, an inhibitor of calcium transport, indicated that the effect of ammonia was not due to non-specific leakage of calcium. Calcium efflux was not affected by exposure of the cultures to ammonium chloride. Purinergic-evoked calcium influx and mobilization was not altered by ammonia. While the mechanism(s) of calcium homeostasis affected by long-term hyperammonemia remain to be defined, these results suggest that reduced astrocytic calcium may be related to the pathogenesis of ammonia-related disorders such as hepatic encephalopathy.     

Different clinical manifestations of hyperammonemic encephalopathy

Valproate is an effective anticonvulsant. Although it is usually well tolerated, it has been associated with many neurological, hematopoietic, hepatic, and digestive system side effects. Among these side effects, hyperammonemia without clinical or laboratory evidence of hepatotoxicity is rare and is an important clinical consideration. The aim of this article was to evaluate the reasons for the unexpected symptoms observed in seven patients with epilepsy patients during valproate treatment. We evaluated seven adult patients with localization-related epilepsy who presented with different acute or subacute neurological symptoms related to valproate-induced hyperammonemic encephalopathy. Four of the seven patients had acute onset of confusion, decline in cognitive abilities, and ataxia. Two had subacute clinical symptoms, and the other patient had symptoms similar to those of acute toxicity. These unusual clinical symptoms and similar cases had not been reported in the literature before. Serum ammonia levels were elevated in all seven patients. After discontinuation of valproate, complete clinical improvement was observed within 5-10 days. On the basis of our work, we suggest that the ammonia levels of a patient who has new neurological symptoms and has been taking valproate must be checked. Clinicians should be aware that these clinical symptoms may be related to valproate-induced hyperammonemic encephalopathy. The symptoms have been observed to resolve dramatically after withdrawal of the drug.