Parents be sure your doctor is aware of the information in this article on cerebral (brain) edema. This report on the control of glucose, sodium and water in ill persons with MSUD can be a lifesaver and has already helped save several critically ill children. We want to stress the significance of this information. The terminology may be difficult for many of us, but I encourage everyone to read the article.
Brain edema is the most dangerous complication of MSUD and is usually the cause of death during metabolic crisis. The following recent experience with brain edema markedly changed my understanding and treatment of the problem.
Case summary: In late May 1995 I admitted a 3 year old Mennonite girl with maple syrup urine disease (MSUD) to Lancaster General Hospital. For several days before admission she had poor appetite and intermittent vomiting. There were large ketones in her urine, but her urine DNPH test cleared intermittently. Her serum leucine level was only 5 mg/dl (380 µM) the day before admission and was 6 mg/dl (650 µM) when she was admitted. Twelve hours after admission, when she was receiving MSUD hyperalimentation, and her serum leucine was 4 mg/dl (300 µM), and her serum 2-ketoisocaproic acid was less than 200 µM, she developed critical brain edema. Her pupils became dilated and her breathing stopped. MSUD hyperalimentation was continued, and her biochemistries remained stable while mannitol and hypertonic saline were used to rapidly increase her serum osmolarity. Over a 48 hour period, it became increasingly apparent to me that her clinical improvement and deterioration were better predicted by changes in serum sodium and osmolarity than by branched chain amino acid levels. Her sensitivity to low serum osmolarity resolved over 36 to 48 hours; she gradually became more stable, then began to recover. Now, four months after the brain edema, she is left with a mildly unsteady walk and run, and her voice is uneven, probably because of injury to the cerebellum. But I remain hopeful that in time she will recover completely.
Critical brain edema in patients with MSUD most often develops after 6 to 24 hours of intravenous therapy. Patients, who may have been alert when admitted, become drowsy, irritable, and disoriented. At a time when amino acid levels are decreasing and the patient would be expected to improve, the important signs of illness such as vomiting, headache, and mental status suddenly worsen. The risk of brain swelling is not predicted well by branched chain amino or keto acid levels. The most severe cases of edema I have managed developed life threatening brain edema when plasma leucine concentrations were only 4 and 9 mg/dl (300 and 650 µM). Risk factors for critical brain edema include: recurrent vomiting, prolonged ketonuria prior to admission, persistent ketonuria after IV therapy is started, serum sodium less than 135 mEq/l, serum osmolarity less than 275 mOsm/l, rapid increases of blood glucose to levels greater than 200 mg/dl, and the use of intravenous solutions that contain less than 140 mEq/l of sodium. Critical edema such as the above patient had, can be seen on MRI scan of the brain as an increase in T2 signal (whiteness) throughout cerebral and cerebellar hemispheres and is especially prominent in the basal ganglia and brainstem.
Based upon recent MRI studies done on mildly symptomatic children with MSUD, I now suspect that all patients with MSUD who are ill have some degree of brain edema. Critical edema that causes pressure on the base of the brain and brainstem is a late final stage of a process that begins before the patient is admitted to the hospital. MRI's of the brains of children with neurological signs such as ataxia, vomiting, hyperactivity, dystonic posturing, hallucinations, nightmares, and memory loss show focal areas of edema in the brainstem and cerebellum, the basal ganglia and thalamus, and the medial regions of the temporal lobes. Neurological signs of brain intoxication develop before generalized swelling of the brain and pressure on the base of the brain. Such signs of intoxication appear to correlate with edema or metabolic derangements within selective regions of the brain.
The cerebral edema that occurs in MSUD is not unlike that associated with diabetic ketoacidosis and hypernatremic dehydration. In all three conditions, water is pulled from the vascular and extracellular space into the intracellular spaces of the brain by intracellular metabolites with osmotic activity. In diabetes and MSUD, generation of these metabolites is associated with prolonged ketosis. The amount of water that enters the brain under the influence of such metabolites is controlled in large part by the sodium concentration in the extracellular space. The balance of extracellular sodium and pathologic intracellular osmolites determines whether critical edema develops. The use of intravenous fluids that cause rapid expansion of intravascular fluids and low serum sodium concentrations, either due to dilution with free water or losses through the kidney, favors the diffusion of water into the intracellular space of the brain and other organs.
Figure 1 shows the effect of a decrease in serum sodium from 137 to 126 mEq/l upon intracellular water assuming that the intracellular osmolites are fixed at 1425 mOsm. As the extracellular osmolarity decreases to 252 mOsm/l, because of the decrease in serum sodium concentration, water diffuses into intracellular space to dilute the intracellular osmolites to a concentration of 252 mOsm/l. When the new equilibrium is established, the extracellular osmolarity equals the intracellular osmolarity and intracellular water has increased by approximately 9%.
In most organ systems an increase of intracellular water of 5 to 10% is well tolerated but swelling of the brain is limited by the skull. Figure 2 shows the tolerance for brain swelling in relation to body weight and age. The neonate and the adult have a slightly increased tolerance of brain edema as compared to the child. The neonate may tolerate an increase in brain water of 10 to 15% because of the open sutures of the skull. A 4 to 9 year old child will only tolerate an increase of brain weight (water) of 5 to 8% before developing critical pressure. The larger ventricles of an adult allow an increase in brain water of approximately 10% before critical pressure develops.
The effects of treatment of acute cerebral edema with hypertonic solutions of saline and mannitol are also represented in Figure 1. When mannitol 2 grams/kg of body weight is given, the osmolarity in the extracellular space transiently increases by approximately 38 mOsm/l and causes a 7% decrease in intracellular water. Similarly if hypertonic saline is given to restore the sodium concentration in the extracellular fluid, then intracellular volume is restored to the initial state. In the patient, losses of mannitol and sodium into the urine require ongoing administration of these osmolites to the extracellular space to prevent reaccumulation of intracellular water. Mannitol (2 g/kg) and hypertonic saline should be given slowly intravenously over 20 to 30 minutes to prevent a transient increase in intracranial pressure associated with a rapid increase in central venous and arterial pressures. When lasix is used for diuresis, care must be taken not to cause hyponatremia. Hypertonic saline infusions should be used to keep serum sodium concentrations to the range of 140 to 145 mEq/l. An infusion of 5 mEq/kg of NaCl as 3 or 5% saline will cause an increase in serum sodium of 5 to 6 mEq/l. Sodium, in contrast to glucose, does not cross from the vascular space into the nervous system and opposes the entry of water into the brain. In experimental animals, infusion of 10 mEq/kg of 3% sodium chloride or sodium bicarbonate over 60 minutes causes a sustained decrease in intracranial pressure of more than 50 mm H20. (Kravath et al. Clinically significant changes from rapidly administered solutions: Acute Osmol Poisoning, Pediatrics 46: 267, 1970.)
It is necessary to use high glucose infusion rates to control catabolism associated with MSUD, however, insulin should be used to prevent hyperglycemia, and solutions of glucose in water, without NaCl, should never be used. Glucose rapidly enters the brain and, if unopposed by sodium, pulls water from the vascular space into the central nervous system. In experimental animals, infusion of 20 ml/kg of 5% dextrose in water over 10 minutes causes an abrupt increase in intracranial pressure of more than 50 mm H2O. (Pediatrics 46: 267, 1970.)
I recently summarized the management of an ill patient with MSUD as follows: successful treatment of MSUD depends upon inhibition of protein catabolism and sustained support of protein synthesis. Serum and intracellular concentrations of leucine are decreased by sustained rates of endogenous protein synthesis. To induce and sustain the anabolic state, the patient must have a total caloric intake of at least 2 to 3 times his or her basal metabolic rate, and a total protein intake of the MSUD amino acid mixture from MSUD formula or hyperalimentation equal to 2 to 3 grams/kg of body weight per day. Optimal rates of protein synthesis are obtained when 35 to 45% of the total caloric intake is from fat. In the initial few hours of therapy, insulin and propranolol may be needed to overcome counter-regulatory hormones in the severely ill patient. Isoleucine and valine deficiency must also be prevented. These essential amino acids become deficient within 6 to 12 hours after the start of effective therapy and must be provided at a rate sufficient to maintain serum levels of 4 to 5 mg/dl (300 to 400 µM). Isoleucine and valine supplements of 70 to 150 mg/kg-24 hours are typically needed for a neonate and 10 to 30 mg/kg-24 hours for the older child. The central nervous system is especially vulnerable to isoleucine and valine deficiency. Other adjuncts to therapy include glutamine, alanine, thiamine, and pyridoxine which are nutritional supplements added to formula and hyperalimentation solutions to limit the effects of increased leucine and 2-ketoisocaproic acid upon transamination. Recovery from acute metabolic intoxication finally does depend upon control of multiple interdependent variables that serve to sustain protein synthesis, reestablish transamination cycles and amino acid synthesis at other thiamine dependent enzyme complexes.
I would now add to this overview that the prevention and treatment of cerebral edema in a patient with maple syrup urine disease depends heavily upon basic principles of fluid and electrolyte therapy. The biochemical derangements that cause the branched chain amino acids to increase, and that cause prolonged ketosis, appear to produce osmolites within cells of the brain that make MSUD patients vulnerable to brain edema. This is true for patients with MSUD just as it is true for patients with diabetes mellitus and hypernatremic dehydration. In our efforts to gain control of metabolism, what we do with glucose, sodium, and water determines whether the balance tips toward or away from critical brain edema. These are preliminary observations, but I think they will prove to be useful in the care of children with MSUD and other metabolic disorders.
This article was first printed in the summer '95 issue of the Clinic for Special Children Newsletter. I asked Dr. Morton's permission to reprint that article; he kindly agreed. The article as printed here is his 11/17/95 revision. We are always interested in articles on recent treatments for MSUD. Send them to me, the editor, please. Also let me know where to get permission to reprint them, if possible.
Cerebral Edema & Maple Syrup Urine Disease
- Written by Holmes Morton M.D.