Our paper summarizes experiences at the Clinic for Special Children caring for 36 neonates with classical maple syrup disease over an 11 year period. We describe an approach to care that includes diagnosis and management of the at-risk and ill neonate, general pediatric care during common intercurrent illnesses, chronic nutritional care, and in-hospital management of severe metabolic intoxication and brain edema. The effects of maple syrup disease upon the growth, development, and health of the patient are related to many interacting variables which are listed in Table 4 - Determinants of Outcome in Patients With Maple Syrup Disease. (See end of article) The medical approach to management of this biochemical disorder must consider such variables throughout the lifetime of the patient. Prevention of malnutrition and intoxication of the brain is obviously just as important for the teenager and adult as for the infant and child.
The management of the disorder during intercurrent illnesses is particularly problematic for parents and physicians. Few follow-up programs have recognized the need to routinely monitor amino acids levels and change management protocols during common illnesses. Our experience clearly shows that episodes of metabolic intoxication that require hospitalization resulted from the stress of intercurrent infections. Equally important, minor illnesses commonly cause increases in blood leucine concentrations and imbalances among the other essential neutral amino acids that compete with leucine for entry into the brain. Such imbalances persist for long periods of time if adjustments in therapy are not made to correct these abnormalities. Chronic deficiencies of valine and tyrosine are particularly common problems in patients with maple syrup disease.
Brain edema remains the most dangerous problem caused by maple syrup disease. It appears to us that there are three phases of brain edema in an ill patient with maple syrup disease. First, there is focal water accumulation in deep gray matter, which is readily seen by brain MRI, and dysfunction of these deep brain ganglia correlates with neurological findings and changes in behavior. Second, diffuse swelling of the brain develops and is seen clinically as somnolence, stupor or coma. This phase of general brain swelling is not well seen by MRI, as is true for early diffuse edema in patients with diabetic coma, hyperammonemia, and hypernatremic dehydration. Third, as the brain volume increases to more than 5-7% of its initial volume, the brain is pressed against the base of the skull, blood flow is interrupted in specific arteries causing focal ischemic strokes, then rapid swelling due to injury and diffuse ischemia, venous congestion, generalized loss of blood flow and brain death.
We have known for several years that brain edema worsens rapidly in association with rapid decreases in serum sodium concentration and osmolarity. Since the submission of this manuscript we have learned that these decreases in serum osmolarity and generalized brain swelling itself may be the result of high levels of a brain hormone called vasopressin.
Two effects of this brain hormone are familiar to all of us - thirst and a concentrated urine. Vasopressin is a hormone that normally protects against dehydration and shock. Vasopressin not only allows the kidneys to hold onto water, it also normally prevents excessive shrinkage of the brain by stimulating the uptake of sodium and water by a diffuse network of cells called astrocytes. Decreases in blood pressure, vomiting, dehydration, high serum sodium, glucose, or urea concentrations (all of which cause increases in serum osmolarity) provoke release of vasopressin by the brain. In the setting of increased blood and brain leucine, hyperosmolar dehydration and the associated prolonged increases in vasopressin become risk factors for the excessive and abnormal uptake of sodium and water by the brain and the development of critical brain edema. Patients at highest risk for brain edema are those who present with advanced signs of leucine intoxication including recurrent vomiting in the setting of dehydration, high serum osmolarity, and who have intense thirst caused by high vasopressin levels. Studies are underway at the Clinic and Lancaster General Hospital using neuro-imaging techniques and endocrinologic monitoring to better understand how to manage such patients to prevent progression to critical edema. We expect such studies will help explain and prevent acute brain swelling associated with maple syrup disease and several different biochemical disorders.
* Dr. Morton prefers to call MSUD maple syrup disease.