Pediatric Neurology 52 (2015) 526e528
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Protein-Losing Enteropathy as a Rare Complication of the Ketogenic Diet Kengo Moriyama MD a, *, Mio Watanabe MD a, Yoshiyuki Yamada MD, PhD b, Takashi Shiihara MD, PhD a a b
Department of Neurology, Gunma Children’s Medical Center, Gunma, Japan Department of Allergy and Immunology, Gunma Children’s Medical Center, Gunma, Japan
abstract INTRODUCTION: The ketogenic diet is a valuable therapy for patients with intractable epilepsy, but it can result in a variety of complications that sometimes limits its usefulness. Hypoproteinemia is one of the common adverse effects of this diet, although the underling mechanism is largely unknown except for the diet’s reduced protein intake. Only one case of protein-losing enteropathy during the ketogenic diet has been reported. PATIENT DESCRIPTION: A previously healthy 9-year-old girl experienced fever for 5 days then suddenly developed convulsive seizures that subsequently evolved to severe refractory status epilepticus. After multiple antiepileptic drugs failed to improve the patient’s condition, we introduced the ketogenic diet. Although her seizures diminished, her course was complicated by hypoproteinemia. An abdominal dynamic scintigraphy and colonoscopy findings indicated protein-losing enteropathy with nonspecific mucosal inflammation. Her nutritional status deteriorated; thus, we discontinued the ketogenic diet. Her nutritional status gradually improved, whereas her seizures increased. DISCUSSION: Hypoproteinemia during the ketogenic diet is common, but the underlying etiologies are not well understood. Abdominal dynamic scintigraphy could be valuable for clarifying the etiology of hypoproteinemia during the ketogenic diet. Keywords: ketogenic diet, protein-losing enteropathy, scintigraphy, 99mTc-diethylene triamine pentaacetic acid human serum albumin
Pediatr Neurol 2015; 52: 526-528 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Since the 1920s, the ketogenic diet, high in fat and low in carbohydrates and protein, has been a valuable therapeutic approach for patients with intractable epilepsy, including severe refractory status epilepticus.1-3 However, the ketogenic diet is associated with a variety of complications, and hypoproteinemia is one of the common side effects; its underlying mechanism is largely unknown aside from reduced protein intake.4,5 There has been only one report of proteinlosing enteropathy during the ketogenic diet because of a soy
Article History: Received November 4, 2014; Accepted in final form January 17, 2015 * Communications should be addressed to: Dr. Moriyama; Department of Neurology; Gunma Children’s Medical Center; 779 Shimohakoda; Hokkitsu-machi; Shibukawa, Gunma 377-8577, Japan. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.009
allergy.6 We describe a girl with severe refractory status epilepticus whose course was complicated by protein-losing enteropathy during the ketogenic diet. Patient Description A previously healthy 9-year-old girl with a fever for 5 days presented sudden convulsive seizure clusters and was admitted to a local hospital; the day when her neurological deterioration began was designated as day of illness (DOI) 0. On DOI 1, she was transferred to our hospital because of intractable seizures. She presented partial seizures, typically beginning with lateral face twitches and proceeding to upper limb convulsions. Despite intravenous antiepileptic drug administration (midazolam and phenobarbital), her partial seizure clusters persisted. Routine blood tests, cerebrospinal fluid examination, and cranial computed tomography findings were all normal, except for mild cerebrospinal fluid pleocytosis (white blood cell count, 11/mL) and elevated cerebrospinal fluid cytokine levels (interleukin-6: 1518.54 pg/mL; interleukin-8: 17612.34 pg/mL; and interferon g-inducible protein-10: 28,331.46 pg/mL).7 Electroencephalography showed repetitive
K. Moriyama et al. / Pediatric Neurology 52 (2015) 526e528
527
TABLE. Timing of the Ketogenic Diet and Laboratory Data
DOI
TP (g/L) Alb (g/L) IgG (g/L)
1
15
28
41
48
79
67 41 10.78
57 27
38 19 2.79
46 21
61 29 8.00
71 46 8.60
Abbreviations: Alb ¼ Albumin DOI ¼ Day of illness IgG ¼ Immunoglobulin G KD ¼ Ketogenic diet TP ¼ Total protein The horizontal bar indicates timing of the ketogenic diet.
multifocal spike or sharp wave discharges intermixed with a few seconds of suppression phases. Cranial magnetic resonance imaging at DOI 7 revealed high signal lesions on T2-weighted and diffusion-weighted images at involving both the amygdala and hippocampi. High-dose phenobarbital (the highest serum concentration was 69.5 mg/mL) and levetiracetam did not control her seizures. On DOI 10, she was intubated and needed mechanical ventilation. She was diagnosed with acute encephalopathy with refractory, repetitive partial seizures.8,9 Other antiepileptic drugs, including intravenous fosphenytoin and lidocaine, were not effective. A 3:1 (lipid:nonlipid) ketogenic milk formula was started on DOI 15 through a feeding tube. She became ketotic on DOI 17, the occurrence of seizures decreased to less than 50% on DOI 19, and she was extubated on DOI 22. Her body weight decreased gradually; her lowest body mass index was 12.1 kg/m2 (less than the third percentile). Hypoproteinemia, hypoalbuminemia, and hypogammaglobulinemia became evident, whereas proteinuria was absent (Table). On DOI 30, a 99mTcdiethylenetriamine-pentaacetic acid serum albumin scintigraphy showed tracer accumulation in the small intestine within 1 hour after the injection and in the descending colon after 6 hours (Figure).10,11 On DOI 41, a colonoscopy revealed slightly edematous ileocecal mucosa; as a result, we
discontinued the ketogenic diet. Ileal biopsies revealed interstitial hyperemia and edema in villi and lymphoproliferation in the lamina propria. Interstitial hyperemia and plasma cell predominant infiltration of the lamina propria and decreased goblet cells were observed in colonic biopsies. These findings were consistent with a diagnosis of protein-losing enteropathy. After resuming a regular diet, the seizure frequency increased; however, the patient’s nutritional status improved. She was discharged on DOI 223 and has developed a learning disability and experiences seizures daily, and thus attends a special school.
Discussion
Acute encephalopathy with refractory, repetitive partial seizures is one of the catastrophic pediatric neurological disorders in which previously normal children develop a fever followed by refractory status epilepticus.8 Similar conditions are diagnosed, for which several other terms are used worldwide, such as devastating epilepsy in school-age
FIGURE. Anterior images of the abdomen after 99mTc-diethylenetriamine pentaacetic acid human serum albumin injection on day of illness 30. Radionuclide accumulations are shown in the small intestine (arrows) after 1 hour (A) and in the descending colon (arrowhead) after 6 hours (B). The small intestine could be the source of the leakage.
528
K. Moriyama et al. / Pediatric Neurology 52 (2015) 526e528
children, new-onset refractory status epilepticus, and feverinduced refractory epileptic encephalopathy; however, until now, a diagnostic category for these medical conditions has not been standardized globally and the underlying pathophysiologies have not been fully clarified.9 Although we did not examine brain histology, preceding fever, cerebrospinal fluid mild pleocytosis, elevated cerebrospinal fluid cytokines, and bilateral limbic lesions on cranial magnetic resonance imaging all suggest inflammation of an encephalitic nature.7,8 According to Kang et al. and Suo et al., hypoproteinemia is common during the ketogenic diet, as found in 12 of 129 patients (9.3%) and 39 of 317 patients (12.3%), respectively.4,5 Neither study identified a clear etiology underlying hypoproteinemia other than insufficient protein intake. There has been only one report of protein-losing enteropathy during the ketogenic diet.6 Endoscopy and intestinal biopsy revealed villus blunting and eosinophilia, and the patient was diagnosed with allergic gastroenteritis from a soy allergy. However, the cause of protein-losing enteropathy in our patient was not evident, other than the ketogenic diet itself. Abdominal dynamic scintigraphy is a useful diagnostic approach for the detection of protein leakage.10-12 Chiu et al. investigated the diagnostic value of 99mTc-human serum albumin scintigraphy for protein-losing enteropathy and reported a 96% sensitivity (25 of 26 patients were positive) and a 100% specificity (all 12 controls were negative) without any adverse reactions.11 To clarify the underlying etiology for hypoproteinemia during the ketogenic diet, an abdominal dynamic scintigraphy could be valuable, and future studies are warranted. The authors are grateful to Dr. H. Sakuma (Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) for the cerebrospinal fluid cytokine examination and advice regarding the diagnosis and treatment of our patient.
References 1. Hartman AL, Gasior M, Vining EP, Rogawski MA. The neuropharmacology of the ketogenic diet. Pediatr Neurol. 2007;36: 281-292. 2. Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010;51:2033-2037. http://dx.doi.org/10.1111/j.15281167.2010.02703.x. 3. O’Connor SE, Richardson C, Trescher WH, et al. The ketogenic diet for the treatment of pediatric status epilepticus. Pediatr Neurol. 2014;50: 101-103. http://dx.doi.org/10.1016/j.pediatrneurol.2013.07.020. 4. Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia. 2004;45:1116-1123. 5. Suo C, Liao J, Lu X, et al. Efficacy and safety of the ketogenic diet in Chinese children. Seizure. 2013;22:174-178. http://dx.doi.org/10. 1016/j.seizure.2012.11.014. 6. DiMario Jr FJ, Holland J. The ketogenic diet: a review of the experience at Connecticut Children’s Medical Center. Pediatr Neurol. 2002;26:288-292. 7. Sakuma H, Tanuma N, Kuki I, Takahashi Y, Shiomi M, Hayashi M. Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus. J Neurol Neurosurg Psychiatry; 2014;. http://dx.doi.org/10.1136/ jnnp-2014e309388. 8. Sakuma H, Awaya Y, Shiomi M, et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand. 2010;121:251-256. http://dx.doi.org/10.1111/j.1600-0404.2009.01198.x. 9. Ismail FY, Kossoff EH. AERRPS, DESC, NORSE, FIRES: multi-labeling or distinct epileptic entities? Epilepsia. 2011;52:e185-e189. http:// dx.doi.org/10.1111/j.1528-1167.2011.03293.x. 10. Suzuki C, Higaki S, Nishiaki M, et al. 99mTc-HSA-D scintigraphy in the diagnosis of protein-losing gastroenteropathy due to secondary amyloidosis. J Gastroenterol. 1997;32:78-82. 11. Chiu N, Lee BF, Hwang SJ, Chang JM, Liu GC, Yu HS. Protein-losing enteropathy: diagnosis with 99mTc-labeled human serum albumin scintigraphy. Radiology. 2001;219:86-90. 12. Braamskamp MJ, Dolman KM, Tabbers MM. Clinical practice. Protein-losing enteropathy in children. Eur J Pediatr. 2010;169: 1179-1185. http://dx.doi.org/10.1007/s00431-010-1235-2.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Protein-Losing Enteropathy as a Rare Complication of the Ketogenic Diet Kengo Moriyama MD a, *, Mio Watanabe MD a, Yoshiyuki Yamada MD, PhD b, Takashi Shiihara MD, PhD a a b
Department of Neurology, Gunma Children’s Medical Center, Gunma, Japan Department of Allergy and Immunology, Gunma Children’s Medical Center, Gunma, Japan
abstract INTRODUCTION: The ketogenic diet is a valuable therapy for patients with intractable epilepsy, but it can result in a variety of complications that sometimes limits its usefulness. Hypoproteinemia is one of the common adverse effects of this diet, although the underling mechanism is largely unknown except for the diet’s reduced protein intake. Only one case of protein-losing enteropathy during the ketogenic diet has been reported. PATIENT DESCRIPTION: A previously healthy 9-year-old girl experienced fever for 5 days then suddenly developed convulsive seizures that subsequently evolved to severe refractory status epilepticus. After multiple antiepileptic drugs failed to improve the patient’s condition, we introduced the ketogenic diet. Although her seizures diminished, her course was complicated by hypoproteinemia. An abdominal dynamic scintigraphy and colonoscopy findings indicated protein-losing enteropathy with nonspecific mucosal inflammation. Her nutritional status deteriorated; thus, we discontinued the ketogenic diet. Her nutritional status gradually improved, whereas her seizures increased. DISCUSSION: Hypoproteinemia during the ketogenic diet is common, but the underlying etiologies are not well understood. Abdominal dynamic scintigraphy could be valuable for clarifying the etiology of hypoproteinemia during the ketogenic diet. Keywords: ketogenic diet, protein-losing enteropathy, scintigraphy, 99mTc-diethylene triamine pentaacetic acid human serum albumin
Pediatr Neurol 2015; 52: 526-528 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Since the 1920s, the ketogenic diet, high in fat and low in carbohydrates and protein, has been a valuable therapeutic approach for patients with intractable epilepsy, including severe refractory status epilepticus.1-3 However, the ketogenic diet is associated with a variety of complications, and hypoproteinemia is one of the common side effects; its underlying mechanism is largely unknown aside from reduced protein intake.4,5 There has been only one report of proteinlosing enteropathy during the ketogenic diet because of a soy
Article History: Received November 4, 2014; Accepted in final form January 17, 2015 * Communications should be addressed to: Dr. Moriyama; Department of Neurology; Gunma Children’s Medical Center; 779 Shimohakoda; Hokkitsu-machi; Shibukawa, Gunma 377-8577, Japan. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.009
allergy.6 We describe a girl with severe refractory status epilepticus whose course was complicated by protein-losing enteropathy during the ketogenic diet. Patient Description A previously healthy 9-year-old girl with a fever for 5 days presented sudden convulsive seizure clusters and was admitted to a local hospital; the day when her neurological deterioration began was designated as day of illness (DOI) 0. On DOI 1, she was transferred to our hospital because of intractable seizures. She presented partial seizures, typically beginning with lateral face twitches and proceeding to upper limb convulsions. Despite intravenous antiepileptic drug administration (midazolam and phenobarbital), her partial seizure clusters persisted. Routine blood tests, cerebrospinal fluid examination, and cranial computed tomography findings were all normal, except for mild cerebrospinal fluid pleocytosis (white blood cell count, 11/mL) and elevated cerebrospinal fluid cytokine levels (interleukin-6: 1518.54 pg/mL; interleukin-8: 17612.34 pg/mL; and interferon g-inducible protein-10: 28,331.46 pg/mL).7 Electroencephalography showed repetitive
K. Moriyama et al. / Pediatric Neurology 52 (2015) 526e528
527
TABLE. Timing of the Ketogenic Diet and Laboratory Data
DOI
TP (g/L) Alb (g/L) IgG (g/L)
1
15
28
41
48
79
67 41 10.78
57 27
38 19 2.79
46 21
61 29 8.00
71 46 8.60
Abbreviations: Alb ¼ Albumin DOI ¼ Day of illness IgG ¼ Immunoglobulin G KD ¼ Ketogenic diet TP ¼ Total protein The horizontal bar indicates timing of the ketogenic diet.
multifocal spike or sharp wave discharges intermixed with a few seconds of suppression phases. Cranial magnetic resonance imaging at DOI 7 revealed high signal lesions on T2-weighted and diffusion-weighted images at involving both the amygdala and hippocampi. High-dose phenobarbital (the highest serum concentration was 69.5 mg/mL) and levetiracetam did not control her seizures. On DOI 10, she was intubated and needed mechanical ventilation. She was diagnosed with acute encephalopathy with refractory, repetitive partial seizures.8,9 Other antiepileptic drugs, including intravenous fosphenytoin and lidocaine, were not effective. A 3:1 (lipid:nonlipid) ketogenic milk formula was started on DOI 15 through a feeding tube. She became ketotic on DOI 17, the occurrence of seizures decreased to less than 50% on DOI 19, and she was extubated on DOI 22. Her body weight decreased gradually; her lowest body mass index was 12.1 kg/m2 (less than the third percentile). Hypoproteinemia, hypoalbuminemia, and hypogammaglobulinemia became evident, whereas proteinuria was absent (Table). On DOI 30, a 99mTcdiethylenetriamine-pentaacetic acid serum albumin scintigraphy showed tracer accumulation in the small intestine within 1 hour after the injection and in the descending colon after 6 hours (Figure).10,11 On DOI 41, a colonoscopy revealed slightly edematous ileocecal mucosa; as a result, we
discontinued the ketogenic diet. Ileal biopsies revealed interstitial hyperemia and edema in villi and lymphoproliferation in the lamina propria. Interstitial hyperemia and plasma cell predominant infiltration of the lamina propria and decreased goblet cells were observed in colonic biopsies. These findings were consistent with a diagnosis of protein-losing enteropathy. After resuming a regular diet, the seizure frequency increased; however, the patient’s nutritional status improved. She was discharged on DOI 223 and has developed a learning disability and experiences seizures daily, and thus attends a special school.
Discussion
Acute encephalopathy with refractory, repetitive partial seizures is one of the catastrophic pediatric neurological disorders in which previously normal children develop a fever followed by refractory status epilepticus.8 Similar conditions are diagnosed, for which several other terms are used worldwide, such as devastating epilepsy in school-age
FIGURE. Anterior images of the abdomen after 99mTc-diethylenetriamine pentaacetic acid human serum albumin injection on day of illness 30. Radionuclide accumulations are shown in the small intestine (arrows) after 1 hour (A) and in the descending colon (arrowhead) after 6 hours (B). The small intestine could be the source of the leakage.
528
K. Moriyama et al. / Pediatric Neurology 52 (2015) 526e528
children, new-onset refractory status epilepticus, and feverinduced refractory epileptic encephalopathy; however, until now, a diagnostic category for these medical conditions has not been standardized globally and the underlying pathophysiologies have not been fully clarified.9 Although we did not examine brain histology, preceding fever, cerebrospinal fluid mild pleocytosis, elevated cerebrospinal fluid cytokines, and bilateral limbic lesions on cranial magnetic resonance imaging all suggest inflammation of an encephalitic nature.7,8 According to Kang et al. and Suo et al., hypoproteinemia is common during the ketogenic diet, as found in 12 of 129 patients (9.3%) and 39 of 317 patients (12.3%), respectively.4,5 Neither study identified a clear etiology underlying hypoproteinemia other than insufficient protein intake. There has been only one report of protein-losing enteropathy during the ketogenic diet.6 Endoscopy and intestinal biopsy revealed villus blunting and eosinophilia, and the patient was diagnosed with allergic gastroenteritis from a soy allergy. However, the cause of protein-losing enteropathy in our patient was not evident, other than the ketogenic diet itself. Abdominal dynamic scintigraphy is a useful diagnostic approach for the detection of protein leakage.10-12 Chiu et al. investigated the diagnostic value of 99mTc-human serum albumin scintigraphy for protein-losing enteropathy and reported a 96% sensitivity (25 of 26 patients were positive) and a 100% specificity (all 12 controls were negative) without any adverse reactions.11 To clarify the underlying etiology for hypoproteinemia during the ketogenic diet, an abdominal dynamic scintigraphy could be valuable, and future studies are warranted. The authors are grateful to Dr. H. Sakuma (Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) for the cerebrospinal fluid cytokine examination and advice regarding the diagnosis and treatment of our patient.
References 1. Hartman AL, Gasior M, Vining EP, Rogawski MA. The neuropharmacology of the ketogenic diet. Pediatr Neurol. 2007;36: 281-292. 2. Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010;51:2033-2037. http://dx.doi.org/10.1111/j.15281167.2010.02703.x. 3. O’Connor SE, Richardson C, Trescher WH, et al. The ketogenic diet for the treatment of pediatric status epilepticus. Pediatr Neurol. 2014;50: 101-103. http://dx.doi.org/10.1016/j.pediatrneurol.2013.07.020. 4. Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia. 2004;45:1116-1123. 5. Suo C, Liao J, Lu X, et al. Efficacy and safety of the ketogenic diet in Chinese children. Seizure. 2013;22:174-178. http://dx.doi.org/10. 1016/j.seizure.2012.11.014. 6. DiMario Jr FJ, Holland J. The ketogenic diet: a review of the experience at Connecticut Children’s Medical Center. Pediatr Neurol. 2002;26:288-292. 7. Sakuma H, Tanuma N, Kuki I, Takahashi Y, Shiomi M, Hayashi M. Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus. J Neurol Neurosurg Psychiatry; 2014;. http://dx.doi.org/10.1136/ jnnp-2014e309388. 8. Sakuma H, Awaya Y, Shiomi M, et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand. 2010;121:251-256. http://dx.doi.org/10.1111/j.1600-0404.2009.01198.x. 9. Ismail FY, Kossoff EH. AERRPS, DESC, NORSE, FIRES: multi-labeling or distinct epileptic entities? Epilepsia. 2011;52:e185-e189. http:// dx.doi.org/10.1111/j.1528-1167.2011.03293.x. 10. Suzuki C, Higaki S, Nishiaki M, et al. 99mTc-HSA-D scintigraphy in the diagnosis of protein-losing gastroenteropathy due to secondary amyloidosis. J Gastroenterol. 1997;32:78-82. 11. Chiu N, Lee BF, Hwang SJ, Chang JM, Liu GC, Yu HS. Protein-losing enteropathy: diagnosis with 99mTc-labeled human serum albumin scintigraphy. Radiology. 2001;219:86-90. 12. Braamskamp MJ, Dolman KM, Tabbers MM. Clinical practice. Protein-losing enteropathy in children. Eur J Pediatr. 2010;169: 1179-1185. http://dx.doi.org/10.1007/s00431-010-1235-2.
