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Amos Fox helped chore as usual on the family farm this summer. It could have been quite different for him and his family if it hadn't been for Dr. Holmes Morton. This article is an unedited account of Amos' successful brain surgery as written by Dr. Morton for this Newsletter. Hopefully what was learned from this experience will be of value in treating other children with MSUD. Thank you Dr. Morton for taking time to share this important information with us.

Last Spring I was asked by Joyce, Alma and Weaver Fox, and others interested in the case to write about the hospital management of a 13 year old boy with classical MSUD who underwent surgery to remove a brain tumor. I have found it difficult to write a summary of the case because details of his treatment were complex and my conclusions preliminary. Nevertheless, I think the case raises important questions about treatment of MSUD which parents, patients, and physicians who read the MSUD Newsletter should be aware.


DAILY MONITORING OF MSUD AND RECOGNITION OF UNDERLYING ILLNESSES:
The earliest sign of Amos' tumor was difficulty with control of his MSUD. Alma found that the urine DNPH test was positive regardless of changes in diet which previously brought his MSUD under control. If Alma had not used DNPH tests to monitor Amos, and had she not made repeated efforts to improve his metabolic control, then the diagnosis of the tumor would certainly have been delayed. As discussed below, the pressure of the tumor upon the brain stem caused vomiting and such severe metabolic derangements that without Alma's careful monitoring I think Amos might have died from metabolic intoxication before the underlying cause was discovered.

Although Amos' tumor was an unusual cause of loss of metabolic control, his case is an example of the importance of daily monitoring with DNPH and careful dietary records for the general health care of these patients. When a patient who has been under good control with a fixed leucine intake of 20 mg/kg-day becomes leucine intolerant as shown by repeatedly positive DNPH tests then their management must immediately be changed and a reason sought for the loss of metabolic control. More common causes of sudden changes in the leucine tolerance are painful injuries, viral infections such as influenza, childhood hepatitis, immunization reactions, hidden dental abscesses, chronic inner ear, sinus or urinary tract infections. Uncommon but by no means rare problems such as hyperthyroidism and insulin dependent diabetes would also cause loss of metabolic control in MSUD patients long before other signs of these disorders would lead to diagnosis. Monthly or twice yearly blood leucine measurements are not adequate for early detection of such problems. I have no doubt that careful control (and records) of daily leucine and caloric intake and routine monitoring of urine DNPH will decrease the frequency of life-threatening metabolic illness in children with MSUD and will help early recognition of important underlying conditions.


LIFE-THREATENING METABOLIC ILLNESSES PROVOKED BY SURGERY OR INJURY:

Surgery or injuries that involve prolonged, stressful, or painful recoveries are especially dangerous to children who have MSUD. Plans to monitor and manage MSUD must be made carefully. Throughout Amos' hospitalization urine DNPH tests and serum amino acid analysis were done 1-4 times daily as needed to monitor the frequent changes in therapy. Serum branched chain keto-acids were also measured to study the relationship between the urine DNPH reaction, blood amino acids, and keto-acids. MSUD hyperalimentation was started through a secure central venous line before surgery. His surgery was delayed until the serum leucine was 5 mg/dl. Even before his operation Amos' leucine level was difficult to control because of the tumor and because of the effects of a steroid called Dexamethasone which was given to reduce the brain swelling caused by the tumor. Although this steroid is known to stimulate the breakdown of protein, Amos' neurosurgeon, Dr. Edward Garitto, felt the medication was necessary, and I agreed that with careful management of MSUD the likely benefit of the medication outweighed its risk.

The brain surgery and the first 12 hours after surgery passed without difficulty. The earliest sign of worsening metabolic control was increased blood glucose and resistance to the insulin which was added to keep the blood glucose in the normal range. Over the period 12-24 hours after surgery the DNPH test changed from clear to cloudy and leucine increased from 6 mg/dl to 10 mg/dl regardless of MSUD hyperalimentation and high doses of insulin. Although it was possible to prevent further increases in leucine, I was aware that the nutritional support necessary to control his MSUD was far greater than expected. In other MSUD patients, in and out of hospital, I have found that caloric intakes of 1.5-2 times the calculated basal metabolic rate of the patient will stop protein breakdown and usually steadily lower serum leucine. Amos' basal metabolic rate when he is well is approximately 28 Cal/kg per day (1000 Cal/day). My initial goals were 60 Cal/kg-day as glucose and 1 gram/kg-day protein in the form of a MSUD amino acid mixture for intravenous use. By day #3 after surgery serum leucine level could just be kept below 12 mg/dl with hyperalimentation rates of 110 Cal/kg-day and 1.8 g/kg-day of MSUD amino acids combined with high insulin infusion rates (0.5 units/kg-hour). Dexamethasone was stopped 3 days after surgery because of my concern about the difficulty of lowering leucine. Insulin requirements decreased rapidly over the 24 hours after Dexamethasone was stopped, but the leucine remained very resistant to change. In 24 hours leucine could only be lowered from 10 to 8 mg/dl regardless of a MSUD hyperalimentation rate of 122 Cal/kg-24 hours and MSUD amino acid mixtures of 1.8 g/kg-24 hrs.

Although it was increasingly apparent that Amos was in an unusual high catabolic state, I questioned if the amino acid mixture in the hyperalimentation was for some reason ineffective÷in retrospect this was not true. To test this idea, on the 6th post-operative day I asked Amos (who was surprisingly cooperative) to drink 60 oz of MSUD formula (40 Cal/kg-day) and I provided another 35 Cal/kg-day as intravenous glucose. Despite this Caloric intake of 2700 Calories (2.5 times his normal basal metabolic rate) and the amino acid mixture in MSUD formula, his leucine increased from 8 mg/dl at 10 AM to 18 mg/dl at 4 AM the next morning and to 31 mg/dl 14 hours later. The DNPH test became strongly positive, and he became disoriented and showed other signs of intoxication. This was an extremely rapid and dangerous increase in leucine. Hyperalimentation was restarted with glucose infusion rate of 150 Cal/kg-24 hours, 4 gm/kg-24 hours of the MSUD amino acid mixture, insulin was used as needed to keep the blood sugar normal, and infusion of intravenous fat was started. The total daily caloric was more than 180 Cal/kg-day, nonetheless, his leucine level was again very difficult to control. Serum leucine decreased only from 31 mg/dl to 28 mg/dl between day 7 and 8 and Amos continued to show signs of intoxication.

It was apparent that Amos was in an extreme protein catabolic state which could not be controlled by the calories, glucose, amino acids in the hyperalimentation solution alone. The cause and the means to control the abnormal state had to be found. I knew that the effects of Dexamethsone upon glucose and insulin had been gone for several days, blood cultures were negative, there were no signs of infection in the surgical wound, and even his thyroid function tests had been checked and were normal. I reasoned that the abnormal hypermetabolic state must be related to the effects of surgery upon the brain-stem itself and most likely were caused by adrenalin-like chemicals released as a result of brain stem irritation or swelling. Hyperalimentation, intralipid, and insulin were continued and a medication called Propranolol was given at the same dose used to control the severe catabolic effects caused by extreme hyperthyroidism. Propranolol at this high dose blocks the effects of the catacholamines which are adrenalin-like compounds released by nerves that originate in the brain stem and by the adrenal gland.

Within six hours after intravenous propranolol was given the leucine level had fallen from 28 mg/dl to 21 mg/dl and continued to fall rapidly÷serum leucine decreased from 28 to 12 mg/dl in the first 24 hours and 12 to 3 mg/dl in the next 24 hours. The urine DNPH test became negative when serum leucine was 15-12 mg/dl and isoleucine was 3.5-2.5 mg/dl. Propranolol was initially given intravenously and then was continued as an oral medication. Intralipid was stopped and hyperalimentation was slowly weaned over three days while MSUD formula and food were started. His DNPH remained clear and leucine levels ranged from 1-3 mg/dl until discharge with a daily calorie intake of 60-80 Cal/kg-24 hours, total protein 0.6 g/kg-24 hours and leucine at 10-20 mg/kg-24 hours. Amos remained on a well controlled diet and propranolol by mouth throughout his subse- quent radiation therapy. His DNPH remained clear and his average serum leucine level over this 3 month period was less than 4 mg/dl. Now 10 months later he is well, active, and there are no signs of recurrence of the tumor.


FINAL COMMENTS:
Physicians who work in neurological intensive care units are aware that patients often have severe protein wastage after brain surgery or injury. I think Amos' severe metabolic illness after surgery was similar. I would also speculate that a similar high catabolic state develops in the final stages of fatal illnesses of MSUD. As brain intoxication worsens and brain swelling develops, that catacholamines are released from the brain which stimulate extremely high rates of protein breakdown and rapidly fatal intoxica- tion. I expect that beyond a certain stage of illness the metabolic effects of these signals cannot be easily reversed by MSUD hyperalimentation alone as was seen in Amos' case. Control of such hypercatabolic states will require a combination of careful nutritional management and use of medications that block catabolic signals and stimulate protein synthesis. Insulin and propranolol were used in Amos' management and are inexpensive, relatively safe, widely available. Other medications such as growth hormone or more selective catecholamine or cortisol antagonists may ultimately prove even more effective.

The rate at which Amos' leucine fell between days 9 and 11 was extremely fast÷on day 9 the rate was 16 mg/24 hours, over a 48 hour period the leucine fell from 28 to 3 mg/dl or 12.5 mg/dl per 24 hours. The paper by Dr. Berry about MSUD hyperalimentation reported a rate of decrease of leucine of only 4.5 and 6.5 mg/dl per day. In my opinion this combination of MSUD hyperalimentation and medication to block catabolic signals will also prove to be more effective and safer than peritoneal dialysis. The rate of fall of leucine in Dr. Scriver's 8 cases treated with combined intravenous and nutritional therapy and peritoneal dialysis averaged only 4.5 mg/dl - 24 hours with a range of 1 to 10 mg/dl. I do not think that Amos' case could have been managed with peritoneal dialysis. As MSUD hyperalimentation becomes more widely available, I believe peritoneal dialysis will be considered an obsolete method of treatment for MSUD.

I have recently treated another severely intoxicated 6 year old MSUD patient with methods similar to those used in Amos' case with similar metabolic results and full recovery. Although encouraged by the results, I must emphasize that my observations discussed here are preliminary and unpublished. Other clinical studies will have to be completed before the approach is accepted as standard therapy.

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The MSUD Family Support Group is currently funding several research projects and we are proactively looking for researchers interested in developing new treatments or finding a cure for MSUD. Significant funding is necessary if we are to accomplish this goal.
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