GLUT1 deficiency is caused by a lack of energy in the brain due to the inability of the central nervous system to take up glucose, a substrate of brain energy metabolism, resulting in symptoms such as intellectual disability, intractable epilepsy that does not respond to conventional antiepileptic drug therapy, spastic paralysis, cerebellar ataxia, and involuntary movements such as dystonia, myoclonus, or exertion-induced dyskinesia (Ito et al. 2015; Larsen et al. 2015; Leen et al. 2010; Tang et al. 2017). For this disease, a ketogenic diet is used to provide ketone bodies to supplement the energy needs of the brain with sources other than glucose (Gumus et al. 2015; Klepper 2008). A ketogenic diet should be started as soon as the diagnosis is made because it significantly improves the patient’s quality of life if started before the brain damage progresses (Klepper et al. 2020; Veggiotti and De Giorgis 2014). In the present case, the patient was started on a ketogenic diet immediately after diagnosis; the symptoms of our patient significantly improved, although he still had epilepsy, spastic paralysis, and cerebellar ataxia. In addition, epilepsy, ataxia, and involuntary movements are known to be aggravated during fasting and fatigue (Hao et al. 2017; Schwantje et al. 2020), and epilepsy due to surgical invasion during surgical correction treatment was of concern. A single mild epileptic seizure was noted during the first orthognathic surgery, maxillary osteotomy, but this was not different from the normal frequency. During the second orthognathic surgery, SSRO, postoperative infection developed, and the frequency of epilepsy (tonic, atonic, and convulsive seizures) increased transiently. This was thought to be due to excessive stress and poor ketogenic diet intake.
In order to monitor ketogenic diet, serum ketone and urine ketone are utilized (Kossoff et al. 2018). Although serum ketone is more accurate, it is more expensive and requires finger pricks (Kossoff et al. 2018). In the present case, serum beta-hydroxybutyrate (BOH) was not always available for measurement in our hospital. Therefore, serum BOH was monitored only preoperatively and intraoperatively as a special case. After the surgery, we monitored urine ketones.
Patients with GLUT1 deficiency, such as the present patient, often have blunted pain senses. This makes it difficult to recognize the signs of infection and the degree of improvement. In the first surgery reported by Motoki et al., post-extraction infection developed, but improvement was observed after administration of antimicrobial agents and cleaning of the extraction socket (Motoki et al. 2020). However, due to pain insensitivity, the patient did not complain of pain at an early stage, and infection was only found when the inflammation was considerably advanced. After maxillary osteotomy, there was no notable swelling at the time of discharge, but the CRP was 1.9, which was abnormal; therefore, the patient was discharged under continuous clarithromycin administration. However, no abnormalities were observed in the healing process of the wound after discharge. During the last SSRO, infection was observed on the 10th day of surgery. However, 2 weeks after discharge, infection was again observed, and anti-inflammatory treatment was required. The patient did not complain of symptoms until pain and swelling became marked. This case is a reminder of how important the signs of pain are for clinicians.
Many adverse effects have been reported to develop during ketogenic diet therapy. Side effects of ketogenic therapy include gastrointestinal disorders, hyperlipidemia, coronary artery disease, renal calculi, slowed growth, cardiac abnormalities, pancreatitis, and hepatic dysfunction (Kossoff et al. 2018). As for gastrointestinal symptoms, constipation is very common, but not diarrhea (Kossoff et al. 2018). MCT is known to cause gastrointestinal side effects such as diarrhea (Liu 2008). In the present case, no diarrhea was observed during the fasting test or tooth extraction. However, diarrhea occurred frequently after the more invasive maxillary osteotomy. This diarrhea may be caused by several factors, including the change in the food form, increase of MCT intake, and an antibiotic-induced bacterial shift phenomenon. Although the patient’s ketogenic diet was usually solid food, it was changed to a completely liquid formula containing a large amount of MCT. For intractable diarrhea, we increased the amount of protein and dietary fiber in the diet, which contained few carbohydrates, for digestibility and nutritional support, but the symptom did not improve immediately. It was considered that diarrhea improved slowly because the diet consisted mainly of fat.
Furthermore, Kossoff et al. (2018) reported that vomiting and abdominal pain are the common side effects. In the present case, similar to that reported by Motoki et al., the patient vomited during the fasting test, and the antiemetic drug metoclopramide was administered before resuming eating (Motoki et al. 2020). In the case of tooth extraction and maxillary osteotomy, administration of antiemetic metoclopramide before the start of meals prevented vomiting. In the postoperative period of mandibular osteotomy, IMF is required, and vomiting during IMF may lead to choking. In the present case, postoperative management by spontaneous oral intake, such as ensuring sufficient food intake and IMF time, was considered difficult. Therefore, we decided to manage the patient by tube feeding, which makes it easy to control the calorie intake and meal time, and we released IMF for an hour after the formula infusion to reduce the risk of aspiration of gastric contents. In addition, the amount of food was gradually increased in order for the patient to gradually become accustomed to the ketogenic diet (Fig. 4). The patient’s family was also instructed to give gummies from early on to prevent vomiting during IMF. Although no vomiting was observed during or immediately after meals, it was observed when the patient went to the toilet at night on the 12th day of the surgery, but aspiration and choking were avoided because IMF was quickly released. As IMF is necessary for surgical orthodontic treatment, it was considered important to take measures.
In summary, we reported the surgical orthodontic treatment of a patient with GLUT1 deficiency, a rare disease. Surgical orthodontic treatment in GLUT1 deficiency can be performed relatively safely by maintaining the diet, taking measures against epilepsy and vomiting, and using antimicrobial agents in close collaboration with pediatricians, anesthesiologists, pharmacists, and nutritionists.