Perinatal Metabolic Encephalopathies

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Chapter 20 Perinatal Metabolic Encephalopathies

Rebecca N. Ichord

Introduction

Neurologic disease in the newborn poses great peril and great opportunity. Knowledge of the pathophysiologic basis for neurologic disease of metabolic origin in newborns has grown rapidly as a result of applying advanced molecular biological approaches to these conditions. Improved availability of specific metabolic testing provides the means to institute specific treatments that can be life-saving and protective of the developing brain. In the many diseases where specific curative treatments are not available, knowledge of underlying molecular and cellular defects provides a starting point for further evaluation of the links between molecular defect and clinical syndrome.

This chapter provides a general summary of metabolic encephalopathies in the newborn, divided into two broad categories:

1. correctable disturbances in glucose metabolism and ion balance that accompany other illnesses

2. genetically determined inborn errors of metabolism.

Genetically determined metabolic diseases are grouped according to predominant type and tempo of clinical symptomatology into one of four groups:

1. acute fulminant illnesses with metabolic crisis

2. epileptic encephalopathies

3. chronic encephalopathies with multi-organ involvement

4. chronic encephalopathies without multi-organ involvement (Box 20-1).

Box 20-1 Predominant Presenting Clinical Features in Neonatal Genetic Metabolic Disorders

Acute fulminant metabolic crisis

Urea cycle defects

Maple syrup urine disease (MSUD)

Organic acidopathies: isovaleric, propionic, methylmalonic

Oxidative phosphorylation disorders (OxPhos defects): pyruvate dehydrogenase (PDH) deficiency, pyruvate carboxylase (PC) deficiency, electron transport defects

Fructose-1,6-biphosphatase deficiency

Glutamine synthetase deficiency

Fatty acid oxidation defects: carnitine palmitoyltransferase deficiency type II (CPT II), mitochondrial trifunctional protein deficiency (MTP defects), malonyl CoA decarboxylase (MCD)

Chronic encephalopathy with multiple organ involvement

Mitochondrial disorders

Congenital defects of glycosylation (CDG)

Peroxisomal disorders

Cholesterol biosynthesis defects

Chronic encephalopathy without multiple organ involvement

l-amino acid decarboxylase (l-AAD) deficiency

Glutaric aciduria

GTP cyclohydrolase deficiency

Phenylketonuria (PKU)

Succinic semialdehyde dehydrogenase (SSADH) deficiency

A brief synopsis of each condition is provided, with emphasis on distinctive clinical features, diagnostic approach, and management. Comprehensive discussion of the molecular biology, pathophysiology, and genetics of these disorders may be found in several excellent reviews [Scriver et al., 2001; Hoffmann et al., 2010].

General Approach

Metabolic disease should be considered in the differential diagnosis of any newborn demonstrating symptoms or signs of encephalopathy, which are summarized in Table 20-1. While none of these abnormalities is specific to metabolic disease, the temporal pattern and specific constellation of symptoms taken together often suggest a metabolic disease. Encephalopathies caused by acute correctable metabolic perturbations, such as in hypoglycemic encephalopathy, typically follow a monophasic course that resolves in proportion to the timeliness of correction of the metabolic perturbation. The tempo of genetically determined metabolic diseases is more variable than acquired acute injury such as hypoxia or trauma. It often has a delayed or subacute presentation with unexplained disturbances in state of arousal or neonatal behaviors, such as feeding or visual attentiveness, or with the emergence of myoclonic seizures or movement disorder. Chronic encephalopathies that initially manifest in the newborn period are increasingly being linked to determine metabolic disease genetically. These disorders may have few or no features that distinguish them as metabolic, presenting with nonspecific signs such as hypotonia, depressed neonatal behaviors, or poor feeding. Nervous system manifestations of metabolic disease are generalized in nature, with depression of consciousness or irritability. Motor abnormalities and brainstem dysfunction parallel the severity of disturbed consciousness in a nonlocalizing manner. Suspicion of an inborn error of metabolism should be elevated by any of the following patterns:

1. involvement of multiple components of the nervous system (brain, special senses, peripheral nerves, skeletal muscle, autonomic nervous system)

2. involvement of multiple organ systems

3. systemic symptoms such as prominent unexplained vomiting, hyperpnea in the absence of lung disease, or unusual body or urine odors.

Table 20-1 Neurologic Signs and Symptoms of Neonatal Metabolic Disease

Neurologic Examination Category	Finding in Affected Infant with Metabolic Disease
Alterations in consciousness Mild to moderate Severe	Excessively irritable, or somnolent but awakens with light stimulation Unarousable, but withdraws purposefully Comatose, responds to pain only by posturing, or not at all
Brainstem dysfunction	Pupillary abnormalities Oculomotor deficits Depressed or disordered suck and swallow function Disordered control of breathing (hyperpnea, apnea) High-pitched (“cerebral”) cry
Cortical special senses	Absent arousal to sound, poor or absent visual fixation
Tone and movement abnormalities	Generalized hypotonia or hypertonia Nonepileptic myoclonus Dystonia, rigidity, opisthotonus, oculogyric crises
Reflex abnormalities	Exaggerated deep tendon reflexes Disturbed neonatal reflex behaviors (e.g., Moro, grasp)
Seizures	Myoclonic, clonic, tonic, subtle, apnea
Neuromuscular abnormalities	Diffusely absent tendon reflexes, bilateral symmetric facial or limb weakness, respiratory insufficiency
Autonomic dysfunction	Temperature instability, gastrointestinal dysmotility

Once a metabolic encephalopathy is suspected, further evaluation should proceed urgently. The most common causes of acute encephalopathy not due to metabolic disease can usually be identified based on history, known risk factors, and the results of first-stage laboratory and imaging studies. These include hypoxic-ischemic injury, intracranial hemorrhage, trauma, stroke, venous thrombosis, effects of congenital heart disease on brain function (e.g., hypoxia, ischemia), central nervous system (CNS) infection, and intoxication. It should be emphasized that many neonates with encephalopathy are assumed incorrectly to have suffered “asphyxia” when, in fact, they have a static disease of prenatal origin, or a metabolic disease that decompensated in the face of the metabolic stress of birth. A diagnosis of perinatal hypoxic-ischemic encephalopathy should be made with certainty only when there is unequivocal evidence of severe compromise of circulation and gas exchange in the peripartum period, such as in the case of uterine rupture, placental separation, or fetal or neonatal circulatory arrest. In the absence of such certainty, the differential diagnosis should remain broad until a comprehensive evaluation is complete.

Diagnosis is further delineated by appropriate staged laboratory studies, as shown in Table 20-2. The aim of the initial evaluation is to narrow down the differential diagnosis and simultaneously treat potentially life-threatening or handicapping conditions as quickly as possible. The results of “first-stage” studies will reveal abnormalities requiring immediate correction, such as hypoglycemia, hyponatremia, hypocalcemia, or hypoxia. They will further define other organ involvement, such as renal, cardiac, or hepatocellular dysfunction. A constellation of abnormalities on the initial screening testing may suggest a particular inborn error of metabolism (Figure 20-1). If the results of first-stage assessment, combined with clinical history, examination, and neuroimaging, do not provide a specific diagnosis, they should provide the rationale for choosing appropriate “second-stage” studies. These are aimed at identifying the category of metabolic defect, and in some cases provide a probable specific diagnosis that can be verified in “third-stage” studies, in which DNA or tissue sampling provides material for enzyme quantification or genetic analysis. A careful family history should be obtained to ascertain consanguinity, known inherited metabolic disease, excess fetal loss, or infant demise in a sibling under similar circumstances.

Table 20-2 Laboratory Evaluation of the Infant with Suspected Metabolic Encephalopathy

First Stage Survey and Screening	Second Stage Identify Category of Metabolic Defect	Third Stage Verify Enzyme or Gene Defect
Blood Glucose Electrolytes Mg⁺⁺, Ca⁺⁺, PO₄ BUN, creatinine Liver enzymes CBC, platelets, PT, PTT Arterial blood gas Ammonia Lactate, pyruvate	Blood Quantitative plasma amino acids Very long chain fatty acids Acyl carnitine profile Isoelectric transferrin point Copper, ceruloplasmin levels Cholesterol Uric acid	Tissue biopsy (muscle, liver) for enzyme assay Skin fibroblast culture for enzyme assay DNA studies and specific gene mutation probes Family studies
Urine Ketone bodies, reducing substances Protein, blood Cells	Urine Quantitative amino acids Organic acids Galactose Sulfites Xanthine, hypoxanthine Uric acid Ribosides
CSF Glucose, protein Cell count Microbiology	CSF Quantitative amino acids Neurotransmitters – Biopterin metabolites Lactate, pyruvate

BUN, blood urea nitrogen; CBC, complete blood count; CSF, cerebrospinal fluid; PT, prothrombin time; PTT, partial thromboplastin time.

Fig. 20-1 Algorithm for evaluation of suspected metabolic encephalopathy in neonates.

MCD, malonyl CoA decarboxylase deficiency; PLP, pyridoxine and pyridoxal 5′-phosphate dependency.

Neuroimaging should be obtained early in the course of diagnostic evaluation. While head cranial ultrasound or computed tomography (CT) can provide diagnostic clues and are sensitive to hemorrhage and major malformations, magnetic resonance imaging (MRI) is the preferred modality. Diffusion-weighted sequences add sensitivity, and when combined with standard anatomical imaging sequences and vascular studies such as MR angiography or venography, may provide a definitive diagnosis in many cases with nonspecific clinical findings. MR spectroscopy should be considered as part of the comprehensive imaging evaluation for children with encephalopathy of uncertain cause, as it can provide supportive evidence of primary metabolic disease.

Correctable Disturbances of Glucose and Salt Balance

Hypoglycemia

Hypoglycemia is common among critically ill newborns and is a frequent manifestation of inborn errors of metabolism. The definition of hypoglycemia is controversial. Blood glucose values reflect a dynamic balance between substrate availability and utilization, and in healthy newborns vary across a broad range, typically >2.2 μM (36 mg/dL), but reported as low as 1.3 μM (23 mg/dL) in healthy breastfed infants in the first few days of life. The risk of neurologic injury from hypoglycemia depends on multiple factors, including gestational age, availability of alternate substrates, metabolic rate, maturity and efficiency of glucose transport systems, status of oxidative metabolism, and differences in regional brain metabolic activity. As such, clinical factors such as coexistent hypoxic-ischemic injury, seizures, and the presence of hyperinsulinism strongly influence the occurrence and nature of hypoglycemia-related neuronal injury. These observations have led a number of investigators to propose an “operational” definition, whereby threshold blood glucose value, for example, 2.5 mmol/L (46 mg/dL), prompts treatment and further evaluation. This threshold may be modified up or down in individual cases, depending on clinical symptoms and factors likely to affect brain substrate demand, such as seizures or hypoxia, and alternative substrate availability, such as lactate or ketones or the effects of hyperinsulinism. Presently, there is insufficient evidence to define specific threshold values as predictive of neurologic injury in all clinical settings, and further research is needed on this point [Hay et al., 2009].

Disorders leading to neonatal hypoglycemia may be grouped into four broad categories: maladaptation to extrauterine life, hyperinsulinism, increased glucose consumption due to prior or intercurrent illness, and inborn errors of metabolism (Table 20-3). Maladaptation to extrauterine life affects premature infants and small-for-gestational-age infants due to low stores of fat, protein, and glycogen; inefficient ketogenesis and gluconeogenesis; or diminished tolerance of feedings. Hyperinsulinism is associated with maternal diabetes and gene defects affecting regulation of insulin production [Kapoor et al., 2009], and should be suspected when severe hypoglycemia (<2.6 mmol/L) without ketonuria in a well-nourished infant persists beyond the first 2 postnatal hours despite initiation of enteral feeds. Hypoglycemia from increased substrate utilization occurs during hypoxia or ischemia due to a shift from aerobic to anaerobic metabolism, sometimes compounded by decreased hepatic gluconeogenesis and ketogenesis. Brain glucose consumption is dramatically increased by seizures from any cause, and may exceed the capacity of cerebral energy metabolism in brain regions compromised by a recent ischemic insult. Inborn errors of metabolism may cause hypoglycemia due to enzyme deficiencies in glycogenolysis or gluconeogenesis, or as a result of hepatocellular dysfunction. The neurologic manifestations in these cases represent combined effects of the hypoglycemia and the metabolic disorder. Table 20-4 lists inborn errors of metabolism commonly associated with neonatal hypoglycemia. Neonatal hypoglycemia may be associated with congenital endocrinopathies affecting the hypothalamic-pituitary-adrenal axis as a result of major brain malformations of the hypothalamic-pituitary region, congenital adrenal hypoplasia, or hypothyroidism.

Table 20-3 Causes of Neonatal Hypoglycemia

Category	Specific Disorders
Disorders of adaptation to extrauterine life	Prematurity Intrauterine growth retardation
Hyperinsulinism	Infants of diabetic mothers Maternal isoimmune disease Genetic defects of insulin secretion ABCC8, ATP binding cassette C KCNJ11, potassium channel J11 GLUD1, glutamate dehydrogenase GCK, glucokinase HADH, OH–acyl-CoA dehydrogenase SLC16A1, solute carrier 16-1 HNF4A, hepatocyte nuclear factor 4 alpha Beckwith–Wiedemann syndrome Maternal isoimmune disease Congenital disorders of glycosylation
Elevated glucose consumption	Hypoxia Global ischemia Seizures
Acquired or transient hepatic dysfunction	Post hypoxic-ischemic hepatocellular injury Infectious hepatitis Any cause of liver failure
Primary endocrine disorders	Hypopituitarism due to brain malformation Congenital adrenal insufficiency Adrenal hemorrhage Hypothyroidism
Inborn errors of metabolism	See Table 20-4

Table 20-4 Inborn Errors of Metabolism in which Neonatal Hypoglycemia is a Common Symptom

Category	Specific Disorders
Disorders of carbohydrate metabolism	Hereditary fructose intolerance Fructose 1,6-biphosphatase deficiency Glycogen storage diseases, esp. I and III
Fatty acid oxidation defects	Medium-chain and long-chain acyl-CoA dehydrogenase deficiencies Carnitine palmitoyl transferase II deficiency Mitochondrial trifunctional protein deficiency Malonyl-CoA decarboxylase deficiency (MCD)
Defects in ketone body synthesis	HMG CoA lyase deficiency
Gluconeogenesis defects	Holocarboxylase synthetase deficiency (multiple carboxylase deficiency) Pyruvate carboxylase deficiency
Disorders of branched chain amino acid catabolism and related organic acidurias	Maple syrup urine disease Propionic acidemia Methylmalonic acidemia Isovaleric acidemia Ethylmalonic aciduria 3-methyl-glutaconic aciduria 2-methyl-3-OHbutyryl-CoA dehydrogenase deficiency (MHBD)

The clinical signs and symptoms of hypoglycemia in the neonate are variable and nonspecific, exemplified by infants with hyperinsulinism. Signs and symptoms in the early stages may be dominated by signs of elevated circulating catecholamines: tachycardia, pallor, diaphoresis, irritability, jitteriness or tremor, and exaggerated tendon reflexes and neonatal reflexes (e.g., Moro reflex). Progressive depression of consciousness occurs as cerebral glucose stores are exhausted, associated with hypotonia, depressed reflexes, hypothermia, and often seizures. At its worst, uncorrected hypoglycemia at levels <1.0 μM in the absence of circulating ketone bodies will progress to coma, characterized by isoelectric electroencephalogram (EEG), cerebral edema, flaccid unresponsiveness, apnea, loss of brainstem reflexes, and circulatory collapse. Mild and moderate degrees of symptoms are rapidly reversed with glucose administration, whereas severe encephalopathy reflecting irreversible neuronal injury is not. Hypoglycemic coma is associated with irreversible neuronal necrosis and lasting neurologic deficits, with a predilection for parietal-occipital cortex and periventricular white matter [Burns et al., 2008]. Long-term sequelae may include microcephaly, cortical visual impairment, combined motor and cognitive handicap, and, in some cases, epilepsy [Tam et al., 2008].

The management of neonatal hypoglycemia remains a controversial subject [Hay et al., 2009]. High-risk infants should be screened for hypoglycemia, and provided exogenous feeds, intravenous or enteral, at rates and concentrations sufficient to maintain adequate blood glucose concentrations. Bedside screening for low blood glucose should be performed in any infant who develops signs and symptoms of acute encephalopathy. Symptomatic infants should be treated while the first-stage evaluation proceeds, as outlined in Table 20-2. If ketones are absent and the exogenous glucose requirement is high (>10 mg/kg/min), then hyperinsulinism should be suspected and further evaluated by measuring insulin levels. A paradigm for assessment of hypoglycemia in neonates is shown in Figure 20-2. According to the “operational” approach to the definition of hypoglycemia, treatment of acute symptomatic hypoglycemia should proceed immediately for any infant with a blood glucose <2.5 mmol/L (46 mg/dL), with a minibolus of 200 mg/kg using 10 percent dextrose infused over 2 minutes, followed by continuous infusion of 10 percent dextrose starting at 8 mg/kg/min and increasing as necessary to maintain stable blood glucose levels >2.6 mmol/L. Monitoring the effect of glucose administration on clinical symptoms, particularly the level of consciousness, can help clarify the neurologic significance of the hypoglycemia, and the need for evaluation for other causes of encephalopathy.