Encephalopathic Episodes Research Articles

Glutaric aciduria type 1 presenting with epilepsy

Glutaric aciduria type 1 (GA-1, OMIM 608801) is an autosomal-recessive disorder resulting from a deficiency of glutaryl-CoA dehydrogenase (GCDH). Clinical expression usually involves an acute encephalopathic episode in infancy, followed by the development of severe dystonia-dyskinesia. Other presentations include mild developmental delay, macrocephaly, and subdural haematoma. Seizures may occur with the acute encephalopathy but are unusual in the long term, unless motor or cognitive difficulties are severe. We report a 6-year-old female who was referred with recurrent epileptic seizures that proved difficult to control with first-line anticonvulsants. There was no history of encephalopathy. She had no neurological or developmental abnormalities. The electroencephalogram was profoundly abnormal with slow background and mixed multifocal and generalized spike-and-wave discharges. Seizures deteriorated on valproic acid. Cranial magnetic resonance imaging showed widened Sylvian fissures. Metabolic investigations revealed GA-1. She has improved on a low-protein diet, carnitine, levetiracetam, and lamotrigine. This is the first report of epileptic seizures as the sole presenting feature of GA-1 and it potentially adds to the clinical spectrum of this disorder. Furthermore, the case emphasizes the role of metabolic investigation when first- or second-line treatment of epilepsy is unsuccessful.

Importancia del diagnóstico precoz y el tratamiento temprano en el pronóstico de la aciduria glutárica tipo I

Glutaric Acidaemia type I (GA-I) is an autosomal recessive progressive neurodegenerative inborn error of metabolism caused by deficient activity of the enzyme glutaryl-CoA dehydrogenase (GCDH). In most cases, the diagnosis is established biochemically by the detection of glutaric acid and 3-hydroxy glutaric acid in urine and glutarylcarnitine in plasma. Patients excreting small amounts of glutaric acid may be overlooked. To investigate the value of expanded newborn screening by adding the measurement of urine glutarylcarnitine to conventional chromatography-mass spectrometry (GC-MS) in the diagnosis of GA-1. We report clinical and biochemical data in 5 GA-I patients diagnosed in our Hospital. Details regarding biochemical diagnosis are emphasised and the absence or presence of symptoms was correlated with neuroimaging findings, age at diagnosis and treatment. Two patients showed high glutarylcarnitine levels in plasma and were identified by routine newborn GC-MS screening. Following early appropriate treatment they are asymptomatic 6 years later. Two patients with delayed diagnosis displayed neurological sequels in spite of treatment. The remaining patient, who presented with encephalopathic episode at age 8 months showed normal glutarylcarnitine levels in routine plasma GC-MS but high urine glutarylcarnitine levels in a retrospectively screened urine sample from the newborn period. Early treatment seems to positively influence the clinical evolution of GA-I patients. Thus, improving the identification of GA-I represents an important diagnostic challenge. The urinary excretion of glutarylcarnitine is a specific biochemical marker of GA-I and allows the identification of patients without glutaric aciduria and with normal plasma acylcarnitine profiles.

Successful occlusion of spontaneous portosystemic shunts leading to encephalopathy in a non-cirrhotic patient by using the amplatzer vascular plug

A 55-year-old woman presented with recurrent, recently aggravated encephalopathic episodes. However, the patient had no evidence of liver cirrhosis, and her serum ammonia level was high. An abdominal computed tomography (CT) scan revealed two portal-systemic venous shunts and, accordingly, she was diagnosed as having non-cirrhotic portal-systemic encephalopathy due to portal-systemic shunts. The shunts were successfully occluded using Amplatzer vascular plugs, and this led to a normalization of her blood ammonia levels immediately after occlusion. Over a 3-month follow-up, the patient experienced no complications or symptoms, and no shunt recanalization was detected by CT. The described case demonstrates that the Amplatzer vascular plug offers a useful option for occluding portal-systemic shunts responsible for encephalopathy.

Atypical clinical course in juvenile metachromatic leukodystrophy involving novel arylsulfatase A gene mutations

A male and female with juvenile metachromatic leukodystrophy (MLD) with unusual manifestations are presented, each involving a novel arylsulfatase A gene mutation. One patient demonstrated acute intermittent encephalopathic episodes for 1 year after having received the diagnosis of MLD at the age of 6 years. The other patient presented at the age of 5 years with acute hemiparesis, which was diagnosed as acute disseminated encephalomyelitis and resolved in 3 weeks. After 2 years of remission he started to show progressive neurological deterioration. The episodic manifestations in both patients were associated with acute, resolving cerebral lesions on magnetic resonance imaging accompanying or preceding the classical demyelinating lesions of MLD. The diagnosis of MLD was based on arylsulfatase A enzyme activity levels and genetic analysis, and after the exclusion of neurological conditions such as encephalitis, vasculopathy, or mitochondrial disorders. The pathogenesis of this previously undescribed finding in MLD is unknown but might be related to a susceptibility of myelin to acute damage.

Atypical phenotype in a boy with a maple syrup urine disease

Maple syrup urine disease (MSUD) is a metabolic disorder due to a block in the decarboxylation step in the catabolic pathways of the branched-chain amino acids (BCAAs). We describe an atypical presentation in an infant male. The patient presented with psychomotor retardation, profound hypotonia and elevated plasma levels of BCAAs, but no elevation of alloisoleucine. Cranial magnetic resonance imaging showed prominent diffuse CSF spaces, delayed myelin maturation and symmetrical signal abnormality within the globi pallidi, midbrain, dorsal pons and medulla. The cerebellar white matter was specifically spared. A mitochondrial disorder was suggested. After correction of feeding problems with G-tube feeds, his high BCAAs persisted and, on fourth analysis, alloisoleucine was seen. Subsequent fibroblast enzyme and mutation analysis confirmed MSUD due to E(1)-alpha subunit deficiency. After starting dietary treatment, there was no significant improvement in his hypotonia or his psychomotor development. However, the high signal within the globi pallidi had resolved. MSUD may have diverse clinical presentations, and should be considered in children who present with chronic psychomotor delay but no acute encephalopathic episodes. BCAA levels may not be very high, alloisoleucine may not always be detected in MSUD even with severe enzyme deficiency, and imaging may be misleading if seen in the chronic phase only.

Glutaric aciduria types I and II

Glutaric aciduria type I is an autosomal recessive disorder resulting from a deficiency of glutaryl-CoA dehydrogenase. This leads to an accumulation of glutaric and 3-hydroxyglutaric acids and secondary carnitine deficiency. The symptomatology is discussed, especially those resulting from lesions in the basal ganglia, and the encephalopathic episodes which are often precipitated by infections. The variability of the clinical presentation is stressed. The most serious complications are collections of fluid and blood in the middle fossae, the bleeding resulting from rupture of bridging veins. The prognosis does not seem to be related to the extent of the enzyme deficiency. The diagnosis is confirmed by identifying the abnormal acids in the urine and the deficiency of the enzyme in cultured fibroblasts. The differential diagnosis is reviewed: from other biochemical disorders and from other cerebral lesions. Treatment is by special diet and carnitine supplementation. The dystonia can prove difficult to treat, and surgery may be needed to remove the collections of fluid and blood. Glutaric aciduria type II is caused by a deficiency of either electron transport flavoprotein or of electron transport flavoprotein oxoreductase. The symptoms can be mild or severe. The former may only occur in times of stress, and the latter include congenital anomalies, especially of the kidneys and heart. The pathology of these are discussed. The demonstration of organic acids in the urine and the results of muscle and liver biopsies confirm the diagnosis, and treatment with a special diet and supplementation with carnitine and riboflavine is effective.

Glutaric aciduria type I and kynurenine pathway metabolites: A modified hypothesis

Glutaric aciduria type I is an inborn error of organic acid metabolism that demonstrates a particular temporal vulnerability (acute encephalopathic episodes in infancy) and a spatial vulnerability (acute striatal necrosis, focused on the putamen). Excitotoxic mechanisms involving 3-hydroxyglutaric acid as the major neurotoxin have been suggested. This paper proposes a role for metabolites of the kynurenine pathway in the pathogenic process and modifies the hypothesis of Heyes. Deficiency of glutaryl-CoA dehydrogenase blocking the glutarate pathway and activation of indoleamine 2,3-dioxygenase in macrophages/monocytes by intercurrent inflammation may increase flux down the kynurenine pathway towards the production of quinolinic acid. Quinolinic acid is neurotoxic and is an endogenous agonist at N-methyl-D-aspartate receptors. Synergistic excitation of these receptors by quinolinic acid and 3-hydroxyglutaric acid, which alone does not have sufficient potency, may be involved in the pathogenesis of striatal necrosis.

Glutaric aciduria type 1: Proton magnetic resonance spectroscopy findings

Glutaric aciduria type 1 is an inborn error of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-coenzyme A dehydrogenase. The disease often appears in infancy with an encephalopathic episode that results in acute basal ganglia and white matter degeneration. The neuroimaging findings in glutaric aciduria type 1 have been well defined. However, the changes in magnetic resonance spectroscopy, a noninvasive tool for identifying the biochemical state of the brain, are scarce in glutaric aciduria type 1. This report presents the magnetic resonance spectroscopy findings in a 19-month-old male with glutaric aciduria type 1. Magnetic resonance spectroscopy of right frontal white matter and right lentiform nuclei revealed decreased N-acetylaspartate/creatine ratio, slightly increased choline/creatine ratio, and increased myoinositol/creatine ratio, compared with the age-matched control patients. We thought that these changes were in accordance with neuroaxonal damage, demyelination, and astrocytosis in these areas. In conclusion, proton magnetic resonance spectroscopy provides a tool for assessing metabolic disturbances and the extent of brain damage noninvasively in glutaric aciduria type 1.

Subdural Hematomas and Glutaric Aciduria Type I

To the Editor. I have read with great interest the recent paper of Morris and co-workers on the evaluation of infants with subdural hematoma and suspected child abuse.1 Under these circumstances one important differential diagnosis may be missed without the appropriate diagnostic tests. Glutaric aciduria type I (GA-I) secondary to deficiency of glutaryl CoA dehydrogenase is an inborn error of lysine, hydroxylysine, and tryptophan metabolism that may occur as frequently as 1:30,000 newborns.2 Infants and children with GA-I may present with subdural effusions and/or subdural hematoma, which may be accompanied by retinal hemorrhages.2–5 Macrocephaly is either present at birth or may develop during the first months of life. Early development in most children with GA-I is completely unremarkable before their initial encephalopathic episode occurs on average at 12 months of life.2The presence of GA-I warrants diagnostic consideration in cases with subdural hematoma with no additional physical findings suggestive of child abuse.6 The diagnostic workup should include urine analysis of organic acids, plasma carnitine/acylcarnitine analysis, measurement of enzyme activity in fibroblasts or leukocytes, and/or mutation analysis.In Reply. Dr Bodamer raises an important point in the evaluation of infants for possible child abuse. There have been instances in which infants with GA-I have had subdural collections mistaken for abusive injuries.In our series, GA-I was part of the differential especially in the oldest infant, who presented with a dystonic movement disorder. Urine organic acid analysis was normal in this patient. His subsequent lack of neurologic problems after social intervention made fibroblast or leukocyte culture or other testing unnecessary.None of the other patients in the series had clinical presentations suggesting GA-I nor did they have computed tomography or magnetic resonance imaging changes associated with that diagnosis apart from the subdural hematomas. All have been followed for a lengthy period since the initial diagnosis without subsequent neurologic episodes.Trauma is the primary cause of most infant subdural hematomas. Defining the nature of the trauma can be difficult for a single physician, but a specialized team investigation can help define the nature of the trauma, preventing recurrence and its attendant brain injury and even death. We thank Dr Bodamer for his reminder about a more rare cause of this condition.

Glutaric aciduria type 1 (glutaryl-CoA-dehydrogenase deficiency): advances and unanswered questions. Report from an international meeting.

Infants with macrocephaly, young children with acute disease resembling encephalitis, and children with truncal hypotonia, ataxia, or dystonia may be affected by glutaric aciduria type I (GA 1, glutaryl-CoA-dehydrogenase deficiency), a not-so-rare autosomal recessive neurometabolic disease. Well-known features of GA1 are fronto-temporal brain atrophy with macrocephaly and acute encephalopathic episodes with striatal necrosis followed by dystonia, but some patients develop motor disease without overt crises and other biochemically affected individuals remain asymptomatic. Biochemical and molecular characterization is available and allows post- and prenatal diagnosis. The pathogenesis of fronto-temporal atrophy, macrocephaly, and basal ganglia necrosis is still not understood, and there is no close correlation between biochemical parameters and clinical outcome. There is, however, evidence suggesting that carnitine supplementation and anticatabolic treatment of intercurrent illness may arrest or prevent neurological deterioration, while the role of limitation of dietary lysine and tryptophane is not yet clear. Although pathogenetic aspects are poorly understood, the natural course of glutaric aciduria type 1 can be changed by early diagnosis and treatment. Coordinated research is needed to understand the pathogenesis of brain toxicity, to define the role of dietary therapy, and to explore the possibility of neonatal screening.

Familiäre dystone Bewegungsstörung bei Leigh-Syndrom

Isolated periodic dystonia in the arms and legs was the first manifestation in three siblings with Leigh's syndrome. The symptomatology is identical and progressive in both brothers, whereas the progressive, dysto nie movements of the 14-year old sister have disappeared completely for the last three years. CSF lactate was increased in both brothers. All siblings showed MRI abnormalities of the globus pallidus with different pronounciation. Since the therapeutic use of α-liponic-acid the recurrent encephalopathic episodes disappeared in both boys without affecting the dystonic movements. The girl is asymptomatic without any therapy. Leigh's syndrome is a differential diagnosis in children with a first manifestation of periodic dystonic movements.

Survival and quality of life after portal blood flow preserving procedures in patients with portal hypertension and liver cirrhosis

Between 1979 and 1991, 156 patients with histologically proven liver cirrhosis, good liver function, and bleeding portal hypertension underwent operation with portal blood flow preserving procedures (selective shunts: 101; Sugiura-Futagawa: 55). Long-term results of the procedures and the quality of life of the 145 patients who survived the operation were studied. During the observation period (range 3 to 156 months), 28 patients died. The main causes of death were liver failure and hepatoma. Twenty-three patients were lost for follow-up. Twenty-six patients (18%) developed 1 or more encephalopathic episodes. Four patients (3%) experienced rebleeding. One hundred eight patients (74%) had a good quality of life, and 26 (18%) had a poor quality of life. Eleven (15%) of 73 patients with a history of alcoholism continued drinking. Five-year survival for the selective shunt group was 81% and for the devascularization group was 83%. In 81% of the patients, portal blood flow was maintained. It is concluded that both procedures are effective in the long-term. Most patients are able to rehabilitate from the use of alcohol, and most of them have a good quality of life. For patients with good liver function (whose main problem is bleeding), surgery is the best choice of treatment.

D-Lactate associated encephalopathy in short bowel syndrome: management with long-term non-absorbable oral antimicrobials

We describe a child with short bowel syndrome consequent upon jejunal atresia who developed recurrent episodes of D-Lactate associated encephalopathy. Three species of lactobacillus were isolated from the stool, each sensitive to neomycin. Oral neomycin administration resulted in rapid relief of all symptoms. Cessation of the neomycin on two occasions led to recurrent encephalopathic episodes which quickly resolved with recommencement of treatment. We discuss the possible aetiologies of this encephalopathy syndrome and the therapeutic options.

D-Lactate-Associated Encephalopathy After Massive Small-Bowel Resection

D-Lactate-associated encephalopathy is a rare clinical syndrome characterized by dizziness, ataxia, confusion, headaches, memory loss, lethargy, and aggressiveness which may progress to frank but reversible coma. It occurs in patients with profound dysfunction of the short-bowel syndrome and is believed to result from massive carbohydrate malabsorption with resultant over-production of D-lactate and other organic anions by the colonic flora. Extremely elevated serum levels of D-lactate (but not L-lactate) confirm the diagnosis, but currently D-lactate is not clearly established as the putative neurotoxin. We describe a patient who repeatedly developed D-lactate encephalopathy after surgical removal of nearly the entire jejunum and ileum. Markedly elevated D-lactate serum levels were documented during an encephalopathic episode. Potential pathophysiologic mechanisms and the treatment rationale are discussed.

Risk of serious illness in heterozygotes for ornithine transcarbamylase deficency

Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder associated with hyperammonemia. Heterozygous females have variable clinical expression, ranging from asymptomatic illness to recurrent episodes of hyperammonemic coma. We studied 17 OTC-deficient kindreds containing 114 women at risk for heterozygosity. Sixty-one of these women were designated heterozygotes by pedigree analysis, history of protein intolerance, protein tolerance tests, or DNA probe studies. Eleven (18%) of the 61 heterozygotes had experienced encephalopathic episodes; nine (82%) girls died during these episodes. Our findings indicate that there is a significant risk of symptomatic hyperammonemia in females heterozygous for OTC deficiency. We suggest that, within OTC-deficient kindreds, females at risk should be identified early, by means of protein tolerance tests and DNA probe studies. Those who develop significant hyperammonemia after a protein load should be considered for long-term alternate pathway therapy and should receive aggressive therapy during hyperammonemic episodes.

A mitochondrial encephalomyopathy: A combined 31P magnetic resonance and biochemical investigation

A 15-year-old girl presented with recurrent encephalopathic episodes, epilepsy, myopathy and chronic lactic acidosis. A muscle biopsy revealed the presence of ragged red fibres and mitochondria with paracrystalline inclusions. Biochemical studies on freshly isolated skeletal muscle mitochondria demonstrated a deficiency of NADH-CoQ reductase activity. Investigation of her gastrocnemius muscle at rest by phosphorus nuclear magnetic resonance displayed a reduced phosphocreatine concentration with elevated levels of inorganic phosphate and ADP. Abnormalities were also apparent in her brain spectrum. It is therefore possible that the mitochondrial defect present in skeletal muscle is also being expressed in the brain.

Prospective study of portasystemic encephalopathy after emergency portacaval shunt for bleeding varices

A prospective study of the development of encephalopathy was undertaken in 180 patients undergoing emergency portacaval shunt for bleeding esophageal varices between 1963 and 1978. The incidence of preoperative encephalopathy was 32 percent. Postoperatively, encephalopathy developed in 31.5 percent of 95 survivors and was severe in 7 percent of those survivors. Encephalopathy developed in most patients in the first and second follow-up years; in 10 year survivors, encephalopathy was virtually absent. Encephalopathy was more likely to occur in patients with encephalopathy at the time of shunt and in those who returned to alcoholism after shunt. Most encephalopathic episodes were precipitated by dietary indiscretion, often associated with alcoholism. Careful follow-up with attention to dietary compliance and abstinence from alcohol should make the risk of encephalopathy acceptable in relation to the unquestionable benefits of portacaval shunt in reducing the risk of variceal hemorrhage.

BURN ENCEPHALOPATHY IN CHILDREN

Numerous reports suggest that burn encephalopathy has an obscure etiology. It has been our experience, however, that the cause is usually readily discovered. Neurological disturbances ranging from hallucination, personality changes, and delirium to seizures and coma were encountered in 20 children among 140 admitted with acute thermal injury to our unit during a two-year period. Encephalopathy was not restricted to children with the most extensive burns. Hypoxia was the principal determinant in nine of the 20 cases, hypovolemia in one, sepsis in four, hvponatremia in four, while cortical vein thrombosis was the cause of focal seizures in one child. In but a single patient was the cause obscure. Encephalopathy associated with hypertension or hypercalcemia was not encountered. Ten children succumbed to their burns. Only one died as a primary result of his central nervous system insult, the rest having been lost because of uncontrolled infections. All survivors of encephalopathic episodes showed virtually complete neurological recovery despite severe and prolonged symptoms in several of the children.

Portasystemic shunts in the management of massive hemorrhage from esophageal varices due to cirrhosis of the liver

Twenty-four years ago the first successful application of portacaval shunts for variceal hemorrhage was described by Blakemore and Lord [1] and Whipple [Z]. Since then a torrent of reports has been published, mostly favorable, describing indications, technics and results of a variety of shunts. In spite of this, critical studies by Cohn and Blaisdell [3] and Nachlas [4] have raised serious doubts about the efficacy of these procedures in the prolongation of life or improvement of the well-being of survivors. Surgical mortality rates have been of sufficient magnitude in many series to give pause to the internist and may influence his decision in the direction of a conservative, nonoperative approach. The careful studies by Chalmers and his associates [5] currently raise serious doubts regarding the use of portacaval shunts for the prophylaxis of hemorrhage from esophageal varices in cirrhotic patients, Randomized studies by them [5] and by Lindenmuth [6] appear most convincing and show no benefit in terms of longevity. The decreased likelihood of postshunt hemorrhage is nullified by the increased incidence of disabling encephalopathic episodes. Chalmers et al [5] have also critically analyzed the role of portacaval shunts in the treatment of massive hemorrhage from esophageal varices due to cirrhosis of the liver and have appealed strongly for a randomized study to assess the possible value of surgical measures over a nonoperative regimen. To date no such study has been reported. Other than longevity there are important factors which may disenchant the objective observer on advising a portacaval shunt for his patient. Postshunt encephalopathic episodes have been estimated as occurring in 25 per cent of patients, with serious disability in perhaps half of these [ 71. Low