Encephalopathy Episodes Research Articles

VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Treatment practices of the disorder have changed over the past 10-15years since this disorder was included in newborn screening programs and patients were diagnosed pre-symptomatically. A genotype-phenotype correlation has been suggested but the discovery of novel mutations make this knowledge limited. Herein, we describe our experience in treating patients (n=22) diagnosed through newborn screening and mutational confirmation and followed up over a median period of 104months. We report five novel mutations. In 2013 we formalised our treatment protocol, which essentially follows a European consensus paper from 2009 and our own experience. The prescribed low natural fat diet is relaxed for patients who are asymptomatic when reaching age 5years but medium-chain triglyceride oil is recommended before and after physical activity regardless of age. Metabolic stability, growth, development and cardiac function are satisfactory in all patients. There were no episodes of encephalopathy or hypoglycaemia but three patients had episodes of muscle pain with our without rhabdomyolysis. Body composition studies showed a negative association between dietary protein intake and percent body fat. Larger patient cohort and longer follow up time are required for further elucidation of genotype-phenotype correlations and for establishing the role of dietary protein in metabolic stability and long-term healthier body composition in patients with VLCAD deficiency.

Acquired hepatocerebral degeneration

Acquired hepatocerebral degeneration is a rare, mostly irreversible neurological syndrome that occurs in patients with chronic liver disease, particularly in those with surgically or spontaneously induced portosystemic shunts. Typical magnetic resonance findings are T1 hyperintensity in the pallidum, substantia nigra, periaquaductal gray matter. In this paper, we report a case of a 51-year-old woman presented with hepatic encephalopathy episodes and typical magnetic resonance findings, who does not develop any neurological signs or symptoms, nor cognitive decline in the follow up period, lasting for 3 years.

Implications and benefits of the use of rifaximin for preventing episodes of hepatic encephalopathy

108 British Journal of Healthcare Management 2016 Vol 22 No 3 © 2 01 6 M A H ea lth ca re L td Encephalopathy has a wide manifestation of signs and symptoms, from non-specific personality changes to unresponsiveness and coma. Recurrences are frequent after an overt episode of encephalopathy, with a 40% recurrence rate within 6 months. In the USA, encephalopathy is the main reason for 110,000 hospitalizations annually (Stepanova et al, 2009), while there are no such figures available in the UK. The most widely used treatment for encephalopathy is lactulose, which is a laxative in liquid form. The efficacy of lactulose, however, is not universal, and many patients develop recurrent episodes of encephalopathy requiring hospitalisation on this drug. Moreover, increasing doses to control encephalopathy symptoms are associated with diarrhoea. Therefore, the treatment of patients with recurrent hepatic encephalopathy despite the use of lactulose remains an unmet clinical need. A randomised, double-blind, placebo-controlled trial has shown that rifaximin significantly reduces the episodes of recurrent encephalopathy in adult patients with two or more previous episodes of overt encephalopathy in the last 6 months as compared with placebo (Bass et al, 2010). Rifaximin, although effective, is costly with the estimated cost of a 6-month treatment being £1689.65. Recently, the National Institute for Health and Care Excellence (NICE) (2015) technology appraisal guidance TA337 addressed the use of rifaximin for preventing episodes of overt hepatic encephalopathy in patients with cirrhosis. The guidance followed 4 evidence submissions by the manufacturing company, each of which provided alternative modeling for costEmmanuel A Tsochatzis, Senior Clinical Lecturer and Honorary Consultant, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK Implications and benefits of the use of rifaximin for preventing episodes of hepatic encephalopathy

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

What we know: the inflammatory basis of hepatic encephalopathy.

Central Nervous System (CNS) degeneration appearing in patients with cirrhosis is responsible for cognitive and persistent motor impairments that lead to an important impact on life quality. Brain injury affects certain areas of the CNS that might affect two types of cells: neurons and astrocytes. The process leading to brain injury could be induced by portosystemic shunting accompanied by hyperammonemia and by the activation of peripheral inflammation, manifested as episodic encephalopathy. Hyperammonemia combined with a decrease on the BCA/AAA ratio induces alterations of energetic metabolism and the formation of free radicals in the CNS. This process would be stimulated by the activation of peripheral inflammatory mediators that could act on receptors of the blood brain barrier such as TLR4, activating inflammatory responses in the CNS. As a result, a persistent activation of microglia and an irreversible neuronal and astrocytic injury would be induced. A new knowledge of the mechanisms leading to brain injury in cirrhosis would develop protective strategies to correct changes of nitrogen metabolism and inflammation.

CAPOS syndrome and hemiplegic migraine in a novel pedigree with the specific ATP1A3 mutation

ObjectiveIdentification and characterization of a novel pedigree with ATP1A3 mutations presenting with CAPOS syndrome and hemiplegic migraine. MethodsWe have carried out clinical examinations of a three-generation pedigree with CAPOS syndrome and analyzed the ATP1A3 gene to identify causative mutations. The pedigree is of Slavic origin from Southeastern Europe. ResultsThe clinical phenotype comprised cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss. Pes cavus was present in two of the four patients studied. The symptoms were triggered by fever and varied in severity in family members, exhibiting a chronic progressive course with or without relapses/remissions. The ATP1A3 c.2452G>A mutation was identified in the affected members of the family, while one of the mutation carriers exhibited both CAPOS and hemiplegic migraine. ConclusionsThis study confirms that the specific c.2452G>A mutation in the ATP1A3 gene is associated with the CAPOS syndrome in pedigrees of different ethnic backgrounds. In patients with febrile episodes of ataxic encephalopathy or weakness, or both, genetic analysis of the ATP1A3 gene should be warranted. This is also the first report showing the co-occurrence of hemiplegic migraine and CAPOS syndrome in a patient with ATP1A3 mutations. Migraine has not been previously documented in ATP1A3 mutation carriers.

Hepatology highlights

Hepatology highlights

Endovascular treatment of acute and chronic portal vein thrombosis in patients with cirrhotic and non-cirrhotic liver.

Treatment of patients with portal vein thrombosis (PVT) differs due to different etiology and wide range of symptoms but certain patients seems to benefit from endovascular intervention. To assess the safety and efficiency of endovascular treatment of acute and chronic PVT in patients with cirrhotic and non-cirrhotic liver. Twenty-one patients with PVT treated with an endovascular procedure in 2002-2013 were studied retrospectively. Data on etiology, onset and extension of thrombus, presenting symptoms, methods of intervention, portal pressure gradients, complications, recurrence of symptoms, re-interventions, clinical status at latest follow-up, and survival were collected. Four non-cirrhotic patients with acute extensive PVT and bowel ischemia were treated with local thrombolysis, in three combined with placement of a transjugular intrahepatic portosystemic shunt (TIPS) placement. Three recovered and have survived more than 6 years. In six non-cirrhotic patients with chronic PVT and acute or threatening variceal bleeding recanalization and TIPS were successful in three and failed in three. Eleven cirrhotic patients with PVT and variceal bleeding or refractory ascites were successfully treated with recanalization and TIPS. Re-intervention was performed in five of these patients and five patients died, three within 12 months of intervention. Four cirrhotic patients had episodes of shunt-related encephalopathy and three had variceal re-bleeding. TIPS was found to be effective in reducing portal hypertension in patients with PVT. In patients with extensive PVT and bowel ischemia treatment with TIPS combined with thrombolysis should be considered.

P83 A case of HIV associated neurocognitive impairment (Hand) responding to haart switch

Background/introduction We describe a case of a 34 yr old Black African women fully suppressed on HAART for 9 yrs presenting with recurrent episodes of HIV encephalopathy with abnormal MRI brain scan and detectable HIV in CSF. Following ARV switch her cognitive function and scans had improved and remains undetectable in CSF. Aim(s)/objectives Started HAART in 2005 and remained asymptomatic and fully suppressed on (Kivexa/Atvr/rit) CD4 > 500 mm. Presented initially in 2014 to Neurology with acute confusion, headaches and convulsions. CSF revealed pleocytosis with V/L 811 copies and neg for infective screen. MRI scan revealed diffuse non-specific signals consistent with HIV encephalopathy. On recovery she was monitored in clinic and remained virologically controlled but with residual neurocognitive impairment characterised by short term memory loss and difficulty concentrating. She then represented 9 months later with focal motor signs and confusion resolving within 48 hrs MRI scan no focal lesion. Rpt CSF revealed V/L of 960 copies. Results In view of persistant CSF viraemia she was switched to higher CPE score (from 7 to 12) HAART regimen of Trizivir/Maraviroc. Subsequently she fully recovered cognitive function and rpt CSF at 3/12 confirmed full suppressed VL with resolving brain scan. Discussion/conclusion This case demonstrates that in well controlled pts on HAART who develop presumptive neuro-HIV and in absence of other potential causes, the value of CSF V/L in in constructing a HAART regimen with improved CSF penetration can result in significant improvement in both clinical and objective markers such as MRI scans.

P51 – 2927: Intermittent encephalopathy and evolving movement disorder in a child with SCN8A mutation

Objective Epileptic encephalopathy associated with SCN8A mutations have been increasingly recognised. Seizures in almost all cases are progressive with only a handful with an extended seizure-free period. They can be associated with various movement disorders. We report the first case of SCN8A with intermittent epileptic encephalopathy and describe his evolving movement disorder. Methods A 4.5 year old boy developed jitteriness on day 2 for which no cause was found. At 2 months old he developed epilepsy and at 5 months he had epileptic encephalopathy. Despite being seizure-free with a normal EEG after, he did not regain his skills fully and had feeding difficulties requiring gastrostomy. He had 3 further episodes of epileptic encephalopathy, of which he would progress developmentally in between although not to expected level for age. Seizures appeared to respond to Phenytoin initially but latterly response to various interventions were temporary if not ineffective. He developed intermittent ataxia and choreoathetoid movements and acquired microcephaly. Previously normal brain MRI now shows significant cerebellar atrophy. Results Following extensive investigations he was found to be heterozygous for the c.3967G>T; p(Ala1323Ser) mutation in the SCN8A gene on next-generation sequencing and confirmed with Sanger sequencing. Conclusion Our knowledge of SCN8A mutation phenotype is currently expanding with more cases being identified through next-generation sequencing. A patient may have more than one type of movement disorder and the progression of seizures may be waxing and waning. It is hoped that further understanding of the gene function and genotype-phenotype correlation we would be able to offer a clearer prognosis and treatment for these patients and families.

Spontaneous portosystemic shunts in noncirrhotic patients presenting with encephalopathy

Portosystemic shunts (PSS) are common in patients with chronic liver disease and portal hypertension, however, their occurrence in noncirrhotic individuals is likely under appreciated. Patients may present with symptoms of hepatic encephalopathy and/or gastrointestinal bleeding and undergo extensive work up for liver disease to no avail. Often, these patients suffer for years with accruing medical expenses and numerous hospitalizations related to repeated episodes of encephalopathy. The underlying cause may go undiagnosed or misdiagnosed as occult hepatic dysfunction or even a neuropsychological disorder. In many cases, abdominal CT imaging demonstrates the abnormal portosystemic connection well before it is recognized as the cause of symptoms. In this brief report, we discuss three cases presenting with symptoms of encephalopathy and report successful management with endovascular occlusion of the portosystemic shunts.

Heterologous Expression in Yeast of Human Ornithine Carriers ORNT1 and ORNT2 and of ORNT1 Alleles Implicated in HHH Syndrome in Humans.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive metabolic disorder usually presenting in the neonatal period with intermittent episodes of hyperammonemia, psychomotor delay, and progressive encephalopathy. Adult cases usually evolve into frank spastic paraparesis. The syndrome is caused by mutations in SLC25A15/ORNT1 encoding the mitochondrial ornithine transporter; a second ornithine transporter, ORNT2 of unknown function, is also present in most placental mammals. ORNT2 is believed to originate from an ancient retro-transposition event. In yeast Saccharomyces cerevisiae the major function of the transporter (encoded by Arg11) is to shuttle ornithine from the mitochondrial matrix to the cytosol. Its inactivation abolishes growth in the absence of arginine.In this work, we used functional complementation in S. cerevisiae to characterize the function of human ORNT2 and to test the pathogenicity of ORNT1 mutations found in HHH patients. Notably, we found that human ORNT1 but not ORNT2 complements the deletion of the yeast gene, despite their high level of homology. However, we identified some key residues in ORNT2, which may recover its functional competence when replaced with the corresponding residues of ORNT1, suggesting that roles of the two transporters are different. Moreover, we used this system to test a series of missense mutations of ORNT1 identified in patients with HHH syndrome. All mutations had a detrimental effect on the functionality of the human gene, without however clear genotype-phenotype correlations. Our data support yeast as a simple and effective model to validate missense mutations occurring in patients with HHH.

人工肛門造設を行ったミトコンドリア脳筋症に伴う慢性偽性腸閉塞の1例

人工肛門造設を行ったミトコンドリア脳筋症に伴う慢性偽性腸閉塞の1例

Severe hyperammonemia in late-onset ornithine transcarbamylase deficiency triggered by steroid administration.

Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked disorder of urea synthesis leading to hyperammonemia. Several late-onset cases have been reported. Undiagnosed and untreated patients are at the risk of death or suffering from irreversible sequelae. We describe a 56-year-old patient who presented with acute encephalopathy after steroid treatment. Hyperammonemia due to OTCD was diagnosed and a mutation was found. This allowed us to diagnose two other family members with unexplained encephalopathy who are now asymptomatic on a low-protein diet. OTCD should be considered in any patient with hyperammonemic encephalopathy and immediate treatment should be given to avoid a fatal outcome. We emphasize the need to examine other family members if the diagnosis is confirmed, in order to prevent further life-threatening episodes of encephalopathy or neonatal coma of newborn.

Course of encephalopathy in a cirrhotic dialysis patient treated sequentially with peritoneal and hemodialysis.

End-stage kidney disease and advanced cirrhosis are sometimes seen concomitantly. There is no consensus on dialysis modality in terms of determining the optimal way of treating these patients. It has been suggested that peritoneal dialysis is a better choice for these patients, but efficacy of hemodialysis in stable cirrhotic patients has not been evaluated sufficiently. We report a case with advanced cirrhosis and end-stage kidney disease who was faced with hepatic encephalopathy episodes up on starting renal replacement therapy. The case is also interesting in that it reveals effects of hemodialysis and peritoneal dialysis on hepatic encephalopathy episodes and quality of life of the patient.

Treatment of Hyponatremic Encephalopathy With a 3% Sodium Chloride Protocol: A Case Series

3% sodium chloride solution is the accepted treatment for hyponatremic encephalopathy, but evidence-based guidelines for its use are lacking. A case series. Adult patients presenting to the emergency department of a university hospital with hyponatremic encephalopathy, defined as serum sodium level< 130 mEq/L with neurologic symptoms of increased intracranial pressure without other apparent cause, and treated with a continuous infusion of 500mL of 3% sodium chloride solution over 6 hours through a peripheral vein. Hyponatremic encephalopathy defined as serum sodium level< 130 mEq/L with neurologic symptoms of increased intracranial pressure without other apparent cause. Change in serum sodium level within 48 hours, improvement in neurologic symptoms, and clinical evidence of cerebral demyelination, permanent neurologic injury, or death within 6 months' posttreatment follow-up. There were 71 episodes of hyponatremic encephalopathy in 64 individuals. Comorbid conditions were present in 86% of individuals. Baseline mean serum sodium level was 114.1±0.8 (SEM) mEq/L and increased to 117.9±1.3, 121.2±1.2, 123.9±1.0, and 128.3±0.8 mEq/L at 3, 12, 24, and 48 hours following the initiation of 3% sodium chloride solution treatment, respectively. There was a marked improvement in central nervous system symptoms within hours of therapy in 69 of 71 (97%) episodes. There were 12 deaths, all of which occurred following the resolution of hyponatremic encephalopathy and were related to comorbid conditions, with 75% of deaths related to sepsis. No patient developed neurologic symptoms consistent with cerebral demyelination at any point during the 6-month follow-up period. Lack of a comparison group and follow-up neuroimaging studies. Number of cases is too small to provide definitive assessment of the safety of this protocol. 3% sodium chloride solution was effective in reversing the symptoms of hyponatremic encephalopathy in the emergency department without producing neurologic injury related to cerebral demyelination on long-term follow-up in this case series.

Rifaximin: a review of its use in reducing recurrence of overt hepatic encephalopathy episodes.

Oral rifaximin 550 mg (Refero(®); Targaxan(®); Tixteller(®); Xifaxan(®)) twice daily, either alone or more commonly with medicines containing lactulose, is approved in several countries, including the UK, EU and USA, for use in adults with liver disease to reduce the recurrence of episodes of overt hepatic encephalopathy (HE). Rifaximin is a broad-spectrum antibacterial that acts locally in the gut to reduce intestinal flora, including ammonia-producing species, with hyperammonaemia considered to play a central role in the pathogenesis of HE. In a 6-month, multinational trial in patients with liver disease, rifaximin 550 mg twice daily (± lactulose) was an effective and well tolerated treatment for reducing the recurrence of HE episodes. At study end, rifaximin therapy significantly prolonged the time to the first breakthrough HE episode compared with placebo (± lactulose), irrespective of geographical region or baseline patient and disease characteristics. Rifaximin treatment also significantly reduced HE-related hospitalizations and improved health-related quality of life compared with placebo. Furthermore, the efficacy of rifaximin with or without lactulose in reducing the recurrence of overt HE episodes was maintained after up to 2.5 years of treatment, with no new safety signals arising during this period. This article reviews the pharmacology and therapeutic efficacy of rifaximin 550 mg twice daily in reducing the recurrence of overt HE episodes in adults with liver disease.

Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear.We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting.Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity.Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.

Devastating metabolic brain disorders of newborns and young infants.

Metabolic disorders of the brain that manifest in the neonatal or early infantile period are usually associated with acute and severe illness and are thus referred to as devastating metabolic disorders. Most of these disorders may be classified as organic acid disorders, amino acid metabolism disorders, primary lactic acidosis, or fatty acid oxidation disorders. Each disorder has distinctive clinical, biochemical, and radiologic features. Early diagnosis is important both for prompt treatment to prevent death or serious sequelae and for genetic counseling. However, diagnosis is often challenging because many findings overlap and may mimic those of more common neonatal conditions, such as hypoxic-ischemic encephalopathy and infection. Ultrasonography (US) may be an initial screening method for the neonatal brain, and magnetic resonance (MR) imaging is the modality of choice for evaluating metabolic brain disorders. Although nonspecific imaging findings are common in early-onset metabolic disorders, characteristic patterns of brain involvement have been described for several disorders. In addition, diffusion-weighted images may be used to characterize edema during an acute episode of encephalopathy, and MR spectroscopy depicts changes in metabolites that may help diagnose metabolic disorders and assess response to treatment. Imaging findings, including those of advanced MR imaging techniques, must be closely reviewed. If one of these rare disorders is suspected, the appropriate biochemical test or analysis of the specific gene should be performed to confirm the diagnosis.

Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene

BackgroundAcute necrotizing encephalopathy (ANE) is a rare and severe parainfectious central nervous system disease in which previously healthy children develop rapidly progressive coma following viral illness. While most ANE are sporadic, familial autosomal dominant ANE due to mutations in the RANBP2 gene has been recently reported (ANE1 or infection-induced acute encephalopathy-3 (IIAE3)). To date, only few IIAE3 families with ADANE episodes have been described. ObjectiveTo report a new family with ADANE, describe clinical and radiological features and discuss differential diagnosis including Leigh syndrome or multiple sclerosis. ObservationThe family included 3 symptomatic individuals and one 59year-old asymptomatic obligate carrier. Patients presented acute episodes of encephalopathy few days after common viral infection. Ages of onset ranged from 6months to 5years. Episodes not only occurred in childhood but also recurred in adulthood. Initial neurological signs included coma, focal neurological deficits and seizures. MRI showed typical necrotizing lesions primarily in the thalamus and brainstem, and in the temporal lobes and insula. CSF cell count and cultures were normal during episodes. RANBP2 gene screening identified pathogenic heterozygous c.1754C>T mutation (p.Thr585Met). Episodes led to cognitive or physical handicap in 2 patients and were fatal in one child. ConclusionIIAE3 or ADANE due to RANBP2 mutations has a large clinical heterogeneity. Our family illustrates the associated phenotypes from asymptomatic carrier to severe episodes of encephalopathy. Based on MRI features, the genetic IIAE3 diagnosis is important since prophylaxis and symptomatic management of infections may be beneficial, possibly in association with steroid or gammaglobulins.