- Email: [email protected]
Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy
Brain & Development xxx (2016) xxx–xxx www.elsevier.com/locate/braindev
Original article
Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy Yuichi Abe a,⇑, Tetsuro Sakai a, Akihisa Okumura b, Shinjiro Akaboshi c, Mitsumasa Fukuda d, Kazuhiro Haginoya e, Shin-ichiro Hamano f, Kouichi Hirano g, Kenjiro Kikuchi h, Masaya Kubota i, Sooyoung Lee j, Yoshihiro Maegaki k, Masafumi Sanefuji l, Sachiko Shimozato m, Motomasa Suzuki n, Yasuhiro Suzuki o, Mitsugi Takahashi p, Kenji Watanabe q, Masashi Mizuguchi r, Hideo Yamanouchi a a
Department of Pediatrics, Saitama Medical University, Japan b Department of Pediatrics, Aichi Medical University, Japan c Department of Pediatrics, National Hospital Organization, Tottori Medical Center, Japan d Department of Pediatrics, Graduate School of Medicine, Ehime University, Japan e Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Japan f Division of Neurology, Saitama Children’s Medical Center, Japan g Department of Pediatric Neurology, Hamamatsu City Welfare and Medical Center for Development, Japan h Department of Pediatrics, Jikei University School of Medicine, Japan i Division of Neurology, National Center for Child Health and Development, Japan j Fukuoka Children’s Hospital, Department of Critical care Medicine, Japan k Division of Child Neurology, Faculty of Medicine, Tottori University, Japan l Department of Pediatrics, Graduate school of Medical Sciences, Kyusyu University, Japan m Department of Pediatrics, Eiju General Hospital, Japan n Department of Pediatric Neurology, Aichi Children’s Health and Medical Center, Japan o Department of Pediatric Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, Japan p Takahashi Children’s Clinic, Japan q Department of Pediatrics, Kagoshima City Hospital, Japan r Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Japan Received 7 December 2015; received in revised form 16 January 2016; accepted 21 January 2016
Abstract Background: This study aimed to clarify the characteristics of acute encephalopathic episodes in patients with congenital adrenal hyperplasia (CAH), which we termed ‘‘CAH-associated encephalopathy (CAHE).” Methods: This retrospective study was conducted using a questionnaire as a nationwide survey of patients with CAH with acute encephalopathy and related episodes. Results: Fifteen patients were recruited on the bases of clinical data that supported a diagnosis of CAHE. Fourteen patients displayed seizures at onset, and 12 patients exhibited refractory seizures. Deep coma lasting >24 h was noted in 12 patients. Neuroimaging studies revealed some heterogeneous features. Diffuse or focal edematous lesions in the cerebrum, which produce high signal intensity on diffusion-weighted magnetic resonance imaging or low density on computer tomography, were found in
⇑ Corresponding author at: Department of Pediatrics, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. Tel./fax: +81 49 276 1219. E-mail address: [email protected] (Y. Abe).
http://dx.doi.org/10.1016/j.braindev.2016.01.007 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
2
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
the acute period in all 15 patients. In the chronic period, 14 patients survived, 11 of whom had some degree of neurological sequelae. Moreover, various degrees of cerebral shrinkage were observed in 11 of 14 surviving patients. Surprisingly, there were no abnormal neuroimaging findings in the basal ganglia, brainstem, and cerebellum in any patient. Conclusion: Our results indicated that patients with CAH have a risk of developing CAHE, and thus, they should be followed closely because not only status epilepticus or deep coma but also minor symptoms, such as fever and nausea, may lead to CAHE. Because CAHE may feature some heterogeneous encephalopathic episodes, further validation is needed to clarify its etiology. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Congenital adrenal hyperplasia; Congenital adrenal hyperplasia-associated encephalopathy; Acute encephalopathy; Acute encephalopathy with biphasic seizures and late reduced diffusion; Acute encephalopathy with febrile convulsive status epilepticus; Hemiconvulsion-hemiplegiaepilepsy syndrome; Clinically mild encephalopathy/encephalitis with reversible splenial lesion type 2
1. Introduction Acute encephalopathy is one of the most severe diseases of both infancy and childhood, and patients have symptoms of prolonged seizures and deep coma. Subsequently, acute encephalopathy typically causes some residual damage to motor function, cognition, or both in varying degrees. Some types of acute encephalopathy have been defined in terms of specific findings of clinical features, neuroimaging, or the pathomechanism, and acute encephalopathy is heterogeneously caused by viral infection, drugs, and metabolic disorders [1–9]. Recently, apart from these classified encephalopathy syndromes, some patients with congenital adrenal hyperplasia (CAH) presenting with acute encephalopathy or encephalopathic episodes have been reported [10–12]. CAH is a collective group of disorders involving the lack of an adrenal corticosteroid-synthesizing enzyme, which leads to variable degrees of excesses or shortages of glucocorticoids, mineralocorticoids, or adrenal androgens, and more than 95% of all cases of CAH are caused by 21-hydroxylase deficiency [13]. However, the clinical course or characteristics of patients with CAH who present with encephalopathic episodes accompanied by brain lesions on magnetic resonance imaging (MRI) have not been clearly elucidated, and organized discussions have not been conducted [10–12]. In this study, to clarify the entire picture of acute encephalopathy or encephalopathic episodes in CAH, which we refer to as ‘‘CAH-associated encephalopathy” (CAHE), we conducted a nationwide survey under the endorsement of the Japanese Society of Child Neurology. 2. Materials and methods In this study, we conducted a retrospective study of patients with CAHE in Japan using a questionnaire form. The investigation period of the primary study
was from January 1, 2010 to December 31, 2010. In the primary survey, a questionnaire about patients with CAH and acute encephalopathic episodes was sent to 1,061 child neurologists board-certified by the Japanese Society of Child Neurology. The first questionnaire determined whether participants had any experience with patients with CAHE. A second detailed questionnaire about CAHE was sent to each positive responder in the first survey. The secondary research lasted until March 31, 2015. All patients were previously diagnosed with CAH by hormonal blood examination and/or genetic examination. The items of the second questionnaire related to CAHE were as follows: background information such as gender, age at onset, development, types of CAH, and treatment for CAH; pre-symptomatic presentation with CAH (prodromal symptoms and conditions such as fever, cough, vomiting, and diarrhea); encephalic symptoms in the acute period (type of initial seizures, duration, consciousness, and secondary seizures); blood examination (complete blood cell count, blood, glucose, and electrolytes); cerebrospinal fluid (CSF) examination (cell count, protein, and glucose); electroencephalogram (EEG); brain imaging [computed tomography (CT) or MRI]; and sequelae (wholly neurological, physical, or residual epilepsy of CAHE). Furthermore, each research collaborator provided both reports and brain images for patients when possible. We defined the day on which signs of encephalopathy, including seizure or coma, became apparent as day 1. In each case, the neurological condition was evaluated using the Pediatric Cerebral Performance Category Scale (PCPCS), which classifies the level of neurologic function in pediatric patients into six categories as follows: (1) (normal performance), (2) (mild disability), (3) (moderate disability), (4) (severe disability), (5) (a persistent vegetative state), and (6) (brain death or death) [14]. Epilepsy as a sequela after CAHE was classified into four degrees as follows: seizure-free, no epileptic episode occurred in the absence of antiepileptic drug treatment; mild, epileptic episodes were
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
mostly controlled with anti-epileptic drug therapy during the chronic period or seizures occurred more than once a year; moderate, seizures occurred more than once a month; and severe, seizures occurred daily. This investigation was conducted as a part of The Committee for the Etiology, Diagnosis and Treatment of Severe and Intractable Acute Encephalopathy in Japan. This retrospective investigation adhered to the ethical Guideline for Epidemiological Researches instituted by the Ministry of Health, Labour and Welfare, Japan. In addition, this study was approved by the ethical committee of Saitama Medical University Hospital (approval number: 13-080-1). 3. Results 3.1. Brief overview of the primary and secondary surveys In the primary survey, responses were received from 479 of 1061 doctors (45%), and 25 patients with suspected CAHE were revealed. In the secondary survey, we finally obtained clinical data for 15 of 25 patients with CAHE. We presented a summary of their clinical results in Table 1 and their neuroimaging findings in Table 2. In our study, Cases 3 and 6 represented two of three cases studied by Lee et al. and Case 8 represents the study of Saito et al. [10,12]. 3.2. Background and presymptomatic findings (Table 1) In the secondary survey, the patients with CAHE included 11 males (73%) and 4 females (27%). In total, 13 (87%) and 2 patients (13%) were diagnosed with 21hydroxylase deficiency and congenital lipoid adrenal hyperplasia, respectively. The median and mean ages at onset of CAHE were 2.7 and 3.3 years, respectively. Before the primary symptoms of encephalopathy appeared, all patients had received glucocorticoid and/ or mineralocorticoid supplementation. All patients exhibited appropriate neurological development for their ages before they developed encephalopathy. Fever was the most common prodromal symptom of CAHE (12/15 patients, 80%). In the three afebrile patients (Cases 1, 2, and 9), vomiting with or without diarrhea was the first prodromal symptom. It was confirmed that influenza type A antigen was detected in Case 3, and the titer of anti-influenza type A antibody was elevated in Case 13. Parainfluenza virus was detected in Case 7.
3
The elapsed time from the onset of the prodromal signs to the appearance of the encephalopathic symptoms was <24 h in 13 of 15 patients (Cases 1–9, 11–13, and 15%, 87%), whereas the interval was unknown in two patients (Cases 10 and 14). At the appearance of encephalopathy, both additional corticosteroid and glucose were administered intravenously to 9 of 15 patients (Cases 1, 2, 5, 6, 8, 9, 11, 14, and 15), and an additional corticosteroid without glucose was administered to four patients (Cases 3, 7, 10, and 12). Case 4 was treated with an intravenous antiepileptic drug as an initial therapy for symptoms of encephalopathy instead of an additional corticosteroid and glucose. Regarding Case 13, the details of the initial medication for CAHE were unspecified. Four patients (Cases 3, 8, 10, and 13) concurrently received hypothermia therapy during their acute period. 3.4. Symptoms of encephalopathy (Table 1) Excluding Case 3, 14 patients had at least one seizure (first seizure), and status epilepticus (SE), including continuous and/or clustered seizures, lasting >30 min was found in 12 of 15 patients (80%). Two patients (Cases 13 and 15) experienced seizures lasting <5 min. Case 3 only had a prolonged and deep coma without any apparent seizures. Excluding the non-convulsive patient (Case 3), 9 of 14 patients with seizures (64%) had either tonic or tonic–clonic generalized seizures, and five patients (36%) had hemiconvulsions. Impaired consciousness was prolonged in all 15 patients, and 12 of 15 patients (80%) experienced a deep coma lasting >24 h. Recurrent seizures (biphasic secondary seizures) in the acute period, which were distinctly different from either first seizures or epilepsy as a sequela, appeared in six patients (40%, Cases 2, 6, 7, 9, 12, and 14). 3.5. Blood and CSF examinations (Table 1) Plasma glucose levels were low (<70 mg/dl) in 10 patients (67%, Cases 1, 2, 4, 6, 9, 11, 12, 13, 14, and 15), including four patients with undetectable glucose levels (Cases 2, 9, 13, and 14). Metabolic acidosis and mild hyponatremia (125–135 mEq/l) were detected in seven patients (47%). Both the protein level and cell count of CSF were slightly elevated in Case 11 (cell count: 16/ll; protein: 31 mg/dl) and were normal in the remaining patients. Cases 3 and 15 presented with disseminated intravascular coagulation (data not shown).
3.3. Treatments (data not shown) 3.6. EEG (Table 1) At the appearance of their prodromal symptoms, an additional oral glucocorticoid was administered to three patients (Cases 4, 6, and 7). In addition, theophylline was administrated to only one patient (Case 5).
EEG in the acute period was performed in 10 patients (67%), and some pathogenic patterns were found as follows: diffuse high-voltage slow waves in six patients
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
4
Case
1 2
3*** 4 5 6*** 7 8*** 9 10 11 12 13 14 15
Sex
M M F F M M M F M M M M M F M
The age of onset
Type of CAH
2y8 m 1y5 m 9y5 m 4y0 m 2y7 m 2y10 m 2y6 m 5y3 m 2y9 m 2y9 m 1y10 m 2y3 m 2y8 m 1y10 m 4y2 m
21OHD 21OHD 21OHD CLAH 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD CLAH 21OHD
Prodrome *
Type of
Duration
2nd-Seizure**
Fever
Vomit
Diarrhea
1st-Seizure
Seizure
Coma
+ + + + + + + + + + + +
+ + + + + + + +
+ + + + +
Hemi-SE Hemi-SE None GTCS-SE GTS-SE GTS-Clst GTS-Clst GTS-Clst hemi- SE GTS-Clst hemi-Clst GTS-SE GTS-twice hemi-Clst GTS
2h 1h None 1h 30 min 7h 1h 150 h 2h 4h 24 h 3h <5 min 3h 3 min
1 day 4 days 14 days <1 day 1 day <1 day 24 days 26 days 12 days <1 day 2 days 11 days Permanent 20 days Permanent
+ + + + + +
Blood level of glucose (mg/dl)
EEG in acute period
Sequelae
Clinical day
Findings
PCPCS score
Epilepsy
41 Undetectable 111 67 NA 54 NA 73 Undetectable 131 25 32 Undetectable Undetectable 23
Day1 Day1 Day2 Day1 Day1 ND ND Day1 Day1 Day4 Day1 Day1 ND ND ND
Diffuse HVS Hemi-HVS Diffuse HVS Diffuse HVS Diffuse HVS ND ND Diffuse HVS Hemi-HVS Diffuse LV Ictal pattern Diffuse HVS ND ND ND
1 1 1 2 2 2 (HP) 3 3 3 (HP) 4–5 4–5 4–5 5 4–5 6 (deceased)
Seizure-free Seizure-free Seizure-free Seizure-free Moderate Seizure-free Moderate Severe Severe Mild Seizure-free Moderate Moderate Severe NA
EEG, electroencephalogram; 21OHD, 21-hydroxylase deficiency; CLAH, congenital lipoid adrenal hyperplasia; GTS, Generalized tonic seizure; GTCS, Generalized tonic-clonic seizure; SE, Status epilepticus; Clst, cluster; HVS, Diffuse high voltage slow wave; HP, Hemiparesis; ND, not done; NA, not available; PCPCS, Pediatric Cerebral Performance Category Scale [16]. * >38 °C. ** Recurrent seizures in the acute period differing from the 1st seizures. *** Cases 3, 6, and 8 were described in previous case reports [10,12].
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Table 1 Summary of clinical and EEG manifestations.
Case
Acute period
Subacute or chronic period
Clinical day
MRI/CT
Distribution
Findings
1* 2 3** 4 5 6*,** 7 8*,** 9 10* 11 12 13 14 15
Day1 Early Day2 Day6 Day1 Day3 Day2 Day2 Day2 Day2 Day1 Day2 Day2 Day2 Day1
MRI MRI MRI MRI CT MRI CT MRI MRI CT CT MRI CT CT CT
bil-F-SCWM uni-F-SCWM bil-deep WM bil-F, P, T bil-diffuse uni-F-SCWM bil-diffuse bil-SCWM, Cortex uni-O-SCWM bil-diffuse bil-diffuse bil.-Cortex bil-diffuse uni-diffuse bil-diffuse
DWI " ADC DWI " ADC DWI " ADC DWI " low density DWI " ADC low density DWI " ADC DWI " ADC Low density Low density DWI " Low density Low density Low density
; ; ; ; ; ;
Notes
Clinical day
CT/MRI
Distribution
Findings
Day54 Day24 Chronic Day39 Chronic Day90 Day44 Day60 Day36 Chronic Chronic Day49 Chronic Chronic NA
MRI MRI MRI MRI CT MRI MRI MRI MRI CT CT MRI CT CT NA
– – – bil-F bil-diffuse uni-Cortex, WM bil-Cortex, WM bil-Cortex, WM uni-WM bil-diffuse bil-diffuse bil-WM bil-diffuse uni-diffuse NA
Normal Normal Normal Atrophy Atrophy T1W" FLAIR" T1W" FLAIR" T1W" FLAIR" Atrophy Atrophy Atrophy Atrophy Atrophy Atrophy NA
Bilateral, frontal lobe dominant, reversible Unilateral, frontal lobe dominant, reversible Deep white matter and splenium, reversible Bilateral, dominant lesion in frontal lobe Diffuse brain atrophy Unilateral, cortical necrosis and white matter-atrophy Bilateral, cortical necrosis and white matter-atrophy Bilateral, cortical necrosis and white matter-atrophy Unilateral, volume loss in white matter Diffuse brain atrophy Diffuse brain atrophy Bilateral, volume loss in white matter Diffuse brain atrophy Hemispheric brain atrophy
MRI, magnetic resonance imaging; CT, computed tomography; bil, bilateral; uni, unilateral; F, frontal lobe; P, parietal lobe; T, temporal lobe; O, occipital lobe; SC, subcortical; WM, white matter; DWI, diffusion weighted images; ADC, apparent diffusion coefficient; T1W, T1-weighted; FLAIR, fluid-attenuated inversion recovery images; NA, not available. * CT or MR imaging was shown in Figs. 1 and 2. ** Cases 3, 6, and 8 were described in previous case reports [10,12].
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx 5
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Table 2 Summary of neuroimaging.
6
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
(Cases 1, 3, 4, 5, 8, and 12), hemispheric high-voltage slow waves in two patients (Cases 2 and 9), diffuse low-voltage activities in one patient (Case 10), and continuous ictal patterns in one patient (Case 11). 3.7. Prognosis and sequelae (Table 1) Fourteen patients (93%) were alive with or without sequelae of varying severity, whereas one patient (Case 15) died in the early period. In the secondary research, each neurological prognosis written in the completed questionnaire was re-evaluated using PCPCS scores [14]. Among the 14 survivors, 11 (79%) had some neurological impairment as follows: six (43%) had PCPCS scores of 2–3 (mild to moderate disability) and five (36%) had PCPCS scores of 4–5 (severe disability or coma or vegetative state). Only three patients (Cases 1, 2, and 3) had no residual neurological sequelae caused by CAHE episodes. Epileptic sequelae occurred in eight surviving patients (57%). Specifically, mild, moderate, or severe epilepsy was identified in one (7%), four (29%), and three patients (21%), respectively. Finally, the remaining six surviving patients (43%) had no epilepsy as a sequela.
3.8. Neuroimaging (Table 2 and Figs. 1 and 2) Neuroimaging of patients with CAHE showed heterogeneous findings. In the acute period, bilateral focal edematous brain lesions were found in Case 1 (Fig. 1A), and unilateral focal brain lesions were identified in Cases 2, 4, 6 (Fig. 1B), and 9. Bilateral diffuse or multifocal brain lesions were noted in nine patients [60%, Cases 3, 5, 7, 8 (Fig. 1C), 10 (Fig. 1D), 11, 12, 13, and 15], and a unilateral diffuse hemispheric lesion was found in Case 14. From the point of view of the depth of the brain lesions, subcortical white matter (SCWM) lesions sparing the cortex were found in four patients, namely Cases 1 (Fig. 1A), 2, 6 (Fig. 1B), and 9, and SCWM lesions including the bilateral frontal lobes were present in Case 8 (Fig. 1C). However, lesions in the bilateral cortex excluding the white matter were found in Case 12. There were also lesions of both the splenium and bilateral deep white matter in one patient (Case 3). The depth of the brain lesion was unclear in eight patients [Case 4 on MRI and Cases 5, 7, 10 (Fig. 1D), 11, 13, 14, and 15 on CT].
Fig. 1. Brain imaging of each patient in the early period. (A) Magnetic resonance imaging (MRI; diffusion-weighted imaging: DWI) of Case 1 on day 1 revealed high signal intensity in the bilateral frontal lobes of the subcortical white matter (SCWM) (arrow). (B) MRI (DWI) of Case 6 on day 3 revealed high signal intensity in the right-side frontal lobe of the SCWM (arrow). (C) MRI (DWI) of Case 8 on day 2 revealed diffuse high signal intensity in the cortex. (D) Computed tomography image of Case 10 on day 2 revealed diffuse low densities.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
In the subacute or chronic period, brain imaging for 11 of 14 surviving patients [79%, Cases 4, 5, 6 (Fig. 2B), 7, 8 (Fig. 2C), 9, 10 (Fig. 2D), 11, 12, 13, and 14] revealed atrophic findings of varying severity. Diffuse brain atrophy was found in seven patients [Cases 5, 7, 8 (Fig. 2C), 10 (Fig. 2D), 11, 12, and 13], and two other patients had hemispheric brain atrophy (Cases 9 and 14). Cases 4 and 6 (Fig. 2B) displayed restricted lesions in the bilateral frontal area. In three patients [Cases 1 (Fig. 2A), 2, and 3], there was no obvious abnormality on MRI despite somewhat abnormal imaging findings in the acute period. On the contrary, from the viewpoint of the depth of the brain lesions, high signal intensity in the cortex on T1-weighted and fluid attenuation inversion recovery (FLAIR) images and high signal intensity in the white matter on T2-weighted images were found in three patients [Cases 6 (Fig. 2B), 7, and 8 (Fig. 2C)]. Conversely, high signal intensity in the white matter excluding the cortex was noted on T2-weighted images for Cases 9 and 12. Surprisingly, no abnormal signal intensity on MRI or density on CT was detected for lesions in the basal ganglia, brainstem, and cerebellum in any patients.
7
4. Discussion Previous studies reported that some pediatric patients with CAH and acute encephalopathic episodes exhibited symptoms of impaired consciousness with or without convulsions following prodromal symptoms such as fever, vomiting, and/or diarrhea [10–12]. In this study, all 15 pediatric patients with CAH presented with prodromal and minor symptoms before each encephalopathic episode. Those prodromal symptoms also antedated the onset of adrenal crisis complicated with CAH. Adrenal crisis is the most dangerous complication of CAH, but even if patients develop adrenal crisis, they should recover following the administration of additional corticosteroids and other supportive treatments [15]. However, in this study, 13 of 15 patients with CAHE failed to recover from severe first seizures and prolonged coma following standard treatments for adrenal crisis. The initial seizures tended to be prolonged in 12 of 15 patients with CAHE, but we could not find a definite association between seizure duration and the neurological prognoses. In fact, Cases 13 and 15 had only brief seizures lasting <5 min but presented with
Fig. 2. Brain imaging of each patient in the subacute or chronic period. (A) Magnetic resonance imaging (MRI; fluid attenuation inversion recovery: FLAIR) of Case 1 on day 54 showed no abnormal signal intensities (abnormal high intensities in the bilateral frontal lobes of both the subcortical white matter and cortex vanished). (B) MRI (FLAIR) of Case 6 on day 90 revealed abnormal high intensities in the right-side frontal lobe of the white matter (arrow). (C) MRI (T1-weighted image) of Case 8 on day 60 revealed diffuse high signal intensities in the white matter and cortex with atrophy (arrow). (D) Computed tomography image of Case 10 on day 110 revealed diffuse atrophy in the cortex and white matter.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
8
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
prolonged deep comas, and these patients had poor prognoses. Two previous studies also reported that patients with CAH went into deep comas without convulsion, and they were diagnosed with acute encephalopathy featuring brain lesions on MRI [10,11]. If a patient with CAH develops a coma, it may be difficult to distinguish CAHE from adrenal crisis during the early phase in clinical practice. Therefore, when a patient with CAH exhibits (1) symptoms of adrenal crisis, (2) resistance to the standard treatment for adrenal crisis, and (3) a prolonged deep coma irrespective of the presence of intractable seizures, we should suspect that the patient has developed CAHE. Neuroimaging in each patient with CAHE revealed the heterogeneous nature of the disease. In the early period, focal or diffuse edematous lesions on CT or MRI were found in cerebral white matter with or without the involvement of the cerebral cortex in all 15 patients. In particular, five of eight patients who underwent MRI presented with specific findings in the bilateral or unilateral subcortical cerebral white matter (Cases 1, 6, and 8: Fig. 1a–c). These findings on MRI were characteristic and resembled a type of acute encephalopathy, namely acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) [5,16], otherwise known as acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) [4]. Both AESD and AEFCSE are recognized as almost the same spectrum of encephalopathy, which we termed ‘‘AESD-spectrum encephalopathy syndrome” in this study. In addition, AESD-spectrum encephalopathy syndrome may partially overlap acute infantile encephalopathy predominantly affecting the frontal lobes [17] and hemicon vulsion-hemiplegia-epilepsy syndrome (HHES) [18]. These types of acute encephalopathy present with SE and prolonged deep coma with fever and subsequently progress to include edematous lesions with high signal intensity in the cerebral SCWM on diffusion-weighted imaging (DWI) or low density on CT. The characteristic neuroimaging findings typically appear between the third and ninth day when secondary seizures often occur, and high signal intensity for cortical lesions on DWI or T2-weighted images is revealed in this late period [5]. In this study, within a few days after the first seizures, biphasic secondary seizures appeared in six patients with CAHE (40%, Cases 2, 6, 7, 9, 12, and 14), and three of the six patients [Cases 2, 6, (Fig. 1B) and 9] with recurrence of convulsions exhibited highintensity lesions in the unilateral SCWM on DWI. In fact, the findings on MRI of the three patients with recurrent seizures resemble those found in patients with AESD-spectrum encephalopathy syndromes, but the time at which the characteristic finding appeared on MRI was earlier than that of typical AESD-spectrum encephalopathy syndromes. Furthermore, one patient with biphasic seizures (Case 12) displayed a high-
intensity cortical edematous lesion on DWI on day 2, and two other patients (Cases 7 and 14) presented with diffuse low density of the unilateral or bilateral hemispheres on CT on day 2. On the contrary, one patient (Case 1) presented with only a monophasic convulsion and displayed high-intensity lesions in the unilateral cerebral SCWM on DWI on the day encephalopathy appeared. The clinical course of Case 1 was not typical of that of AESD-spectrum encephalopathy syndromes, but it partly corresponded to that of HHES, which often presents with only a monophasic seizure, whereas highintensity lesions on DWI are found in both the cerebral SCWM and cortex within a few days after the first seizure [19,20]. Different from all previous patients, Case 3 on day 2 featured symmetrical high-intensity legions in the deep white matter and splenium on DWI, and surprisingly, the findings were reversible. The findings resemble those of clinically mild encephalopathy/encephalitis with reversible splenial lesion type 2 [5,10,21,22]. Meanwhile, high signal intensity was observed in the cerebral cortex on T1-weighted or FLAIR images in Cases 6, 7, and 8 during the subacute or chronic stage (Fig. 2b–c). These findings may indicate cortical laminar necrosis. It remains possible that these findings could be caused by hypoglycemia due to adrenal crisis or triggered by hypoxia due to SE. Hypoglycemia causes neuronal death if glucose levels fall to <18 mg/dl [23]. However, the plasma glucose levels in the two patients (Cases 6 and 8) with high signal intensity in the cerebral cortex on T1-weighted or FLAIR images were not extremely low (54 and 73 mg/dl, respectively), and thus, the sensitivity of CAH itself to stress may be considered a possible cause of cortical laminar necrosis. In addition, SE may cause cortex-dominant necrosis [1]. In fact, the three patients with findings of cortical necrosis on MRI in the subacute or chronic period were exposed to long periods of seizure cluster. Thus, the findings of cortical necrosis on subacute or chronic MRI in the three patients may have been caused by excitotoxicity due to refractory seizures [1]. Meanwhile, acute necrotizing encephalopathy, hemorrhagic shock and encephalopathy syndrome, and Reye-like syndrome are known as other types of acute encephalopathy presumably caused by cytokine storm, and these types of acute encephalopathy often affect basal ganglia, brainstem, and cerebellum [1]. However, in this study, there were no patients with the typical course, laboratory data, and neuroimaging findings of these types of acute encephalopathy. However, Case 15 presented only with disseminated intravascular coagulation and systemic multi-organ failure and finally died in the early period. When patients with CAH contract an infection, they often receive additional treatment of steroids. However, even though the dose of steroids was increased appropriately, they occasionally may
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
exhaust glucocorticoids which suppress the secretion of some inflammatory cytokines, such as interleukin-1 (IL-1), IL-2, and tumor necrosis factor alpha [24]. Thus, this patient may have had some type of acute encephalopathy presumably caused by cytokine storm. A previous study illustrated that diffuse or focal white matter abnormalities on T2-weighted or FLAIR images were found in 22 adolescent or older patients with CAH [25]. Another study reported that 14 of 39 pediatric and young adult patients with CAH, including one patient with a known stroke during salt-wasting crisis, displayed white matter abnormalities or temporal lobe atrophy on MRI [26]. These reports indicated that there may be fragility of CAH in both the cortex and white matter. In this study, no patients with CAH had a past history of encephalopathy, and no residual finding was found on MRI. Concerning the remaining causes of CAHE, theophylline, which is a risk factor for acute encephalopathy or SE during fever, was administered to only one patient (Case 5) [27]. In this patient, CAH itself and the administration of theophylline may have led to acute encephalopathy. Furthermore, influenza type A virus infection was documented in two patients (Cases 3 and 13), and this virus is known to cause acute encephalopathy syndromes [1]. These results indicate that CAHE may be caused by further triggers, in addition to the host condition affected by CAH. A previous study of CAH with encephalopathic symptoms reported that there was a higher incidence of encephalopathy in patients with CAH than in the general population [28]. This indicated that the physiological instability of steroids in patients with CAH may have some potential to trigger encephalopathy, even if the patients with CAH are treated with current replacement therapy of corticosteroids. Therefore, our results indicated that these MRI findings and clinical course were not always generated by the same pathological condition, but the fragility of underlying CAH to some stress and excitotoxicity may often be contributory to both the brain lesions and their clinical conditions in diverse mechanisms. Our research can be summarized as follows. CAHE is a heterogeneous pathological condition. The initial symptoms of CAHE resemble those of adrenal crisis, and it is associated with prolonged coma and/or refractory seizures intractable to treatment. In addition, patients often develop neurological sequelae of varying severity. Neuroimaging of patients with CAHE revealed heterogeneous findings, including abnormal high signal intensity on DWI appearing in both the cerebral cortex and subcortical or deep white matter in the early period as well as focal or diffuse brain atrophy and abnormal signals. In conclusion, we have described the concept of CAHE, which is a heterogeneous pathological condition. Further research on CAHE is needed.
9
Acknowledgments This study was supported mainly by a Grant-in-Aid for Research on Measures for Intractable Diseases, Nos. H22-Nanji-Ippan-49, H25-Nanji-Ippan-009, and H27-Nanji-Ippan-028 from the Ministry of Health, Labour and Welfare, Japan. References [1] Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand 2007;115:45–56. [2] Gosalakkal JA, Kamoji V. Reye syndrome and reye-like syndrome. Pediatr Neurol 2008;39:198–200. [3] Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;19:81–92. [4] Shiomi M, Ishikawa J, Togawa M, Okazaki S, Kuki I, Kimura S, et al. A concept of acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) and theophylline as one of its precipitating causes (in Japanese). No To Hattatsu 2008;40:122–7. [5] Takanashi J. Two newly proposed infectious encephalitis/encephalopathy syndromes. Brain Dev 2009;31:521–8. [6] Yamanouchi H, Mizuguchi M. Acute infantile encephalopathy predominantly affecting the frontal lobes (AIEF): a novel clinical category and its tentative diagnostic criteria. Epilepsy Res 2006;70 (Suppl. 1) S263-8. [7] Mori H, Mizutani T, Yoshimura M, Yamanouchi H, Shimada H. Unilateral brain damage after prolonged hemiconvulsions in the elderly associated with theophylline administration. J Neurol Neurosurg Psychiatry 1992;55:466–9. [8] Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500. [9] Hoshino A, Saitoh M, Oka A, Okumura A, Kubota M, Saito Y, et al. Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes. Brain Dev 2012;34:337–43. [10] Lee S, Sanefuji M, Watanabe K, Uematsu A, Torisu H, Baba H, et al. Clinical and MRI characteristics of acute encephalopathy in congenital adrenal hyperplasia. J Neurol Sci 2011;306:91–3. [11] Grunt S, Steinlin M, Weisstanner C, Schoning M, Mullis PE, Fluck CE. Acute encephalopathy with unilateral cortical-subcortical lesions in two unrelated kindreds treated with glucocorticoids prenatally for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: established facts and novel insight. Horm Res Paediatr 2013;80:57–63. [12] Saito Y, Ogawa T, Nagaishi J, Inoue T, Maegaki Y, Ohno K. Laminar cortical necrosis in adrenal crisis: sequential changes on MRI. Brain Dev 2008;30:77–81. [13] Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005;365:2125–36. [14] Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr 1992;121:68–74. [15] Shulman DI, Palmert MR, Kemp SF. Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics 2007;119: e484–94. [16] Takanashi J, Tsuji M, Amemiya K, Tada H, Barkovich AJ. Mild influenza encephalopathy with biphasic seizures and late reduced diffusion. J Neurol Sci 2007;256:86–9. [17] Yamanouchi H, Kawaguchi N, Mori M, Imataka G, Yamagata T, Hashimoto T, et al. Acute infantile encephalopathy predominantly affecting the frontal lobes. Pediatr Neurol 2006;34:93–100.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
10
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
[18] Gastaut H, Poirier F, Payan H, Salamon G, Toga M, Vigouroux M. H.H.E. syndrome; hemiconvulsions, hemiplegia, epilepsy. Epilepsia 1960;1:418–47. [19] Yoshikawa H, Kitamura T. Serial changes on diffusion-weighted magnetic resonance imaging in encephalitis or encephalopathy. Pediatr Neurol 2006;34:308–11. [20] Yamazaki S, Ikeno K, Abe T, Tohyama J, Adachi Y. Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1A S218L mutation. Pediatr Neurol 2011;45:193–6. [21] Takanashi J, Barkovich AJ, Yamaguchi K, Kohno Y. Influenzaassociated encephalitis/encephalopathy with a reversible lesion in the splenium of the corpus callosum: a case report and literature review. AJNR Am J Neuroradiol 2004;25:798–802. [22] Tada H, Takanashi J, Barkovich AJ, Oba H, Maeda M, Tsukahara H, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004;63:1854–8. [23] Auer RN. Hypoglycemic brain damage. Metab Brain Dis 2004;19:169–75.
[24] Padgett D, Loria R, Sheridan J. Steroid hormone regulation of antiviral immunity. Ann N Y Acad Sci 2000;917:935–43. [25] Bergamaschi R, Livieri C, Uggetti C, Candeloro E, Egitto MG, Pichiecchio A, et al. Brain white matter impairment in congenital adrenal hyperplasia. Arch Neurol 2006;63:413–6. [26] Nass R, Heier L, Moshang T, Oberfield S, George A, New MI, et al. Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy. J Child Neurol 1997;12:181–6. [27] Yoshikawa H. First-line therapy for theophylline-associated seizures. Acta Neurol Scand 2007;115:57–61. [28] Kawashima Y, Hanaki K, Kinoshita T, Nagaishi J, Kanzaki S. A nation wide survey for the incidence of the central nervous system complications in treated patients with congenital adrenal hyperplasia (in Japanese). Horumonn To Rinsho 2002;50:1165–9.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Original article
Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy Yuichi Abe a,⇑, Tetsuro Sakai a, Akihisa Okumura b, Shinjiro Akaboshi c, Mitsumasa Fukuda d, Kazuhiro Haginoya e, Shin-ichiro Hamano f, Kouichi Hirano g, Kenjiro Kikuchi h, Masaya Kubota i, Sooyoung Lee j, Yoshihiro Maegaki k, Masafumi Sanefuji l, Sachiko Shimozato m, Motomasa Suzuki n, Yasuhiro Suzuki o, Mitsugi Takahashi p, Kenji Watanabe q, Masashi Mizuguchi r, Hideo Yamanouchi a a
Department of Pediatrics, Saitama Medical University, Japan b Department of Pediatrics, Aichi Medical University, Japan c Department of Pediatrics, National Hospital Organization, Tottori Medical Center, Japan d Department of Pediatrics, Graduate School of Medicine, Ehime University, Japan e Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Japan f Division of Neurology, Saitama Children’s Medical Center, Japan g Department of Pediatric Neurology, Hamamatsu City Welfare and Medical Center for Development, Japan h Department of Pediatrics, Jikei University School of Medicine, Japan i Division of Neurology, National Center for Child Health and Development, Japan j Fukuoka Children’s Hospital, Department of Critical care Medicine, Japan k Division of Child Neurology, Faculty of Medicine, Tottori University, Japan l Department of Pediatrics, Graduate school of Medical Sciences, Kyusyu University, Japan m Department of Pediatrics, Eiju General Hospital, Japan n Department of Pediatric Neurology, Aichi Children’s Health and Medical Center, Japan o Department of Pediatric Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, Japan p Takahashi Children’s Clinic, Japan q Department of Pediatrics, Kagoshima City Hospital, Japan r Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Japan Received 7 December 2015; received in revised form 16 January 2016; accepted 21 January 2016
Abstract Background: This study aimed to clarify the characteristics of acute encephalopathic episodes in patients with congenital adrenal hyperplasia (CAH), which we termed ‘‘CAH-associated encephalopathy (CAHE).” Methods: This retrospective study was conducted using a questionnaire as a nationwide survey of patients with CAH with acute encephalopathy and related episodes. Results: Fifteen patients were recruited on the bases of clinical data that supported a diagnosis of CAHE. Fourteen patients displayed seizures at onset, and 12 patients exhibited refractory seizures. Deep coma lasting >24 h was noted in 12 patients. Neuroimaging studies revealed some heterogeneous features. Diffuse or focal edematous lesions in the cerebrum, which produce high signal intensity on diffusion-weighted magnetic resonance imaging or low density on computer tomography, were found in
⇑ Corresponding author at: Department of Pediatrics, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. Tel./fax: +81 49 276 1219. E-mail address: [email protected] (Y. Abe).
http://dx.doi.org/10.1016/j.braindev.2016.01.007 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
2
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
the acute period in all 15 patients. In the chronic period, 14 patients survived, 11 of whom had some degree of neurological sequelae. Moreover, various degrees of cerebral shrinkage were observed in 11 of 14 surviving patients. Surprisingly, there were no abnormal neuroimaging findings in the basal ganglia, brainstem, and cerebellum in any patient. Conclusion: Our results indicated that patients with CAH have a risk of developing CAHE, and thus, they should be followed closely because not only status epilepticus or deep coma but also minor symptoms, such as fever and nausea, may lead to CAHE. Because CAHE may feature some heterogeneous encephalopathic episodes, further validation is needed to clarify its etiology. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Congenital adrenal hyperplasia; Congenital adrenal hyperplasia-associated encephalopathy; Acute encephalopathy; Acute encephalopathy with biphasic seizures and late reduced diffusion; Acute encephalopathy with febrile convulsive status epilepticus; Hemiconvulsion-hemiplegiaepilepsy syndrome; Clinically mild encephalopathy/encephalitis with reversible splenial lesion type 2
1. Introduction Acute encephalopathy is one of the most severe diseases of both infancy and childhood, and patients have symptoms of prolonged seizures and deep coma. Subsequently, acute encephalopathy typically causes some residual damage to motor function, cognition, or both in varying degrees. Some types of acute encephalopathy have been defined in terms of specific findings of clinical features, neuroimaging, or the pathomechanism, and acute encephalopathy is heterogeneously caused by viral infection, drugs, and metabolic disorders [1–9]. Recently, apart from these classified encephalopathy syndromes, some patients with congenital adrenal hyperplasia (CAH) presenting with acute encephalopathy or encephalopathic episodes have been reported [10–12]. CAH is a collective group of disorders involving the lack of an adrenal corticosteroid-synthesizing enzyme, which leads to variable degrees of excesses or shortages of glucocorticoids, mineralocorticoids, or adrenal androgens, and more than 95% of all cases of CAH are caused by 21-hydroxylase deficiency [13]. However, the clinical course or characteristics of patients with CAH who present with encephalopathic episodes accompanied by brain lesions on magnetic resonance imaging (MRI) have not been clearly elucidated, and organized discussions have not been conducted [10–12]. In this study, to clarify the entire picture of acute encephalopathy or encephalopathic episodes in CAH, which we refer to as ‘‘CAH-associated encephalopathy” (CAHE), we conducted a nationwide survey under the endorsement of the Japanese Society of Child Neurology. 2. Materials and methods In this study, we conducted a retrospective study of patients with CAHE in Japan using a questionnaire form. The investigation period of the primary study
was from January 1, 2010 to December 31, 2010. In the primary survey, a questionnaire about patients with CAH and acute encephalopathic episodes was sent to 1,061 child neurologists board-certified by the Japanese Society of Child Neurology. The first questionnaire determined whether participants had any experience with patients with CAHE. A second detailed questionnaire about CAHE was sent to each positive responder in the first survey. The secondary research lasted until March 31, 2015. All patients were previously diagnosed with CAH by hormonal blood examination and/or genetic examination. The items of the second questionnaire related to CAHE were as follows: background information such as gender, age at onset, development, types of CAH, and treatment for CAH; pre-symptomatic presentation with CAH (prodromal symptoms and conditions such as fever, cough, vomiting, and diarrhea); encephalic symptoms in the acute period (type of initial seizures, duration, consciousness, and secondary seizures); blood examination (complete blood cell count, blood, glucose, and electrolytes); cerebrospinal fluid (CSF) examination (cell count, protein, and glucose); electroencephalogram (EEG); brain imaging [computed tomography (CT) or MRI]; and sequelae (wholly neurological, physical, or residual epilepsy of CAHE). Furthermore, each research collaborator provided both reports and brain images for patients when possible. We defined the day on which signs of encephalopathy, including seizure or coma, became apparent as day 1. In each case, the neurological condition was evaluated using the Pediatric Cerebral Performance Category Scale (PCPCS), which classifies the level of neurologic function in pediatric patients into six categories as follows: (1) (normal performance), (2) (mild disability), (3) (moderate disability), (4) (severe disability), (5) (a persistent vegetative state), and (6) (brain death or death) [14]. Epilepsy as a sequela after CAHE was classified into four degrees as follows: seizure-free, no epileptic episode occurred in the absence of antiepileptic drug treatment; mild, epileptic episodes were
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
mostly controlled with anti-epileptic drug therapy during the chronic period or seizures occurred more than once a year; moderate, seizures occurred more than once a month; and severe, seizures occurred daily. This investigation was conducted as a part of The Committee for the Etiology, Diagnosis and Treatment of Severe and Intractable Acute Encephalopathy in Japan. This retrospective investigation adhered to the ethical Guideline for Epidemiological Researches instituted by the Ministry of Health, Labour and Welfare, Japan. In addition, this study was approved by the ethical committee of Saitama Medical University Hospital (approval number: 13-080-1). 3. Results 3.1. Brief overview of the primary and secondary surveys In the primary survey, responses were received from 479 of 1061 doctors (45%), and 25 patients with suspected CAHE were revealed. In the secondary survey, we finally obtained clinical data for 15 of 25 patients with CAHE. We presented a summary of their clinical results in Table 1 and their neuroimaging findings in Table 2. In our study, Cases 3 and 6 represented two of three cases studied by Lee et al. and Case 8 represents the study of Saito et al. [10,12]. 3.2. Background and presymptomatic findings (Table 1) In the secondary survey, the patients with CAHE included 11 males (73%) and 4 females (27%). In total, 13 (87%) and 2 patients (13%) were diagnosed with 21hydroxylase deficiency and congenital lipoid adrenal hyperplasia, respectively. The median and mean ages at onset of CAHE were 2.7 and 3.3 years, respectively. Before the primary symptoms of encephalopathy appeared, all patients had received glucocorticoid and/ or mineralocorticoid supplementation. All patients exhibited appropriate neurological development for their ages before they developed encephalopathy. Fever was the most common prodromal symptom of CAHE (12/15 patients, 80%). In the three afebrile patients (Cases 1, 2, and 9), vomiting with or without diarrhea was the first prodromal symptom. It was confirmed that influenza type A antigen was detected in Case 3, and the titer of anti-influenza type A antibody was elevated in Case 13. Parainfluenza virus was detected in Case 7.
3
The elapsed time from the onset of the prodromal signs to the appearance of the encephalopathic symptoms was <24 h in 13 of 15 patients (Cases 1–9, 11–13, and 15%, 87%), whereas the interval was unknown in two patients (Cases 10 and 14). At the appearance of encephalopathy, both additional corticosteroid and glucose were administered intravenously to 9 of 15 patients (Cases 1, 2, 5, 6, 8, 9, 11, 14, and 15), and an additional corticosteroid without glucose was administered to four patients (Cases 3, 7, 10, and 12). Case 4 was treated with an intravenous antiepileptic drug as an initial therapy for symptoms of encephalopathy instead of an additional corticosteroid and glucose. Regarding Case 13, the details of the initial medication for CAHE were unspecified. Four patients (Cases 3, 8, 10, and 13) concurrently received hypothermia therapy during their acute period. 3.4. Symptoms of encephalopathy (Table 1) Excluding Case 3, 14 patients had at least one seizure (first seizure), and status epilepticus (SE), including continuous and/or clustered seizures, lasting >30 min was found in 12 of 15 patients (80%). Two patients (Cases 13 and 15) experienced seizures lasting <5 min. Case 3 only had a prolonged and deep coma without any apparent seizures. Excluding the non-convulsive patient (Case 3), 9 of 14 patients with seizures (64%) had either tonic or tonic–clonic generalized seizures, and five patients (36%) had hemiconvulsions. Impaired consciousness was prolonged in all 15 patients, and 12 of 15 patients (80%) experienced a deep coma lasting >24 h. Recurrent seizures (biphasic secondary seizures) in the acute period, which were distinctly different from either first seizures or epilepsy as a sequela, appeared in six patients (40%, Cases 2, 6, 7, 9, 12, and 14). 3.5. Blood and CSF examinations (Table 1) Plasma glucose levels were low (<70 mg/dl) in 10 patients (67%, Cases 1, 2, 4, 6, 9, 11, 12, 13, 14, and 15), including four patients with undetectable glucose levels (Cases 2, 9, 13, and 14). Metabolic acidosis and mild hyponatremia (125–135 mEq/l) were detected in seven patients (47%). Both the protein level and cell count of CSF were slightly elevated in Case 11 (cell count: 16/ll; protein: 31 mg/dl) and were normal in the remaining patients. Cases 3 and 15 presented with disseminated intravascular coagulation (data not shown).
3.3. Treatments (data not shown) 3.6. EEG (Table 1) At the appearance of their prodromal symptoms, an additional oral glucocorticoid was administered to three patients (Cases 4, 6, and 7). In addition, theophylline was administrated to only one patient (Case 5).
EEG in the acute period was performed in 10 patients (67%), and some pathogenic patterns were found as follows: diffuse high-voltage slow waves in six patients
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
4
Case
1 2
3*** 4 5 6*** 7 8*** 9 10 11 12 13 14 15
Sex
M M F F M M M F M M M M M F M
The age of onset
Type of CAH
2y8 m 1y5 m 9y5 m 4y0 m 2y7 m 2y10 m 2y6 m 5y3 m 2y9 m 2y9 m 1y10 m 2y3 m 2y8 m 1y10 m 4y2 m
21OHD 21OHD 21OHD CLAH 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD 21OHD CLAH 21OHD
Prodrome *
Type of
Duration
2nd-Seizure**
Fever
Vomit
Diarrhea
1st-Seizure
Seizure
Coma
+ + + + + + + + + + + +
+ + + + + + + +
+ + + + +
Hemi-SE Hemi-SE None GTCS-SE GTS-SE GTS-Clst GTS-Clst GTS-Clst hemi- SE GTS-Clst hemi-Clst GTS-SE GTS-twice hemi-Clst GTS
2h 1h None 1h 30 min 7h 1h 150 h 2h 4h 24 h 3h <5 min 3h 3 min
1 day 4 days 14 days <1 day 1 day <1 day 24 days 26 days 12 days <1 day 2 days 11 days Permanent 20 days Permanent
+ + + + + +
Blood level of glucose (mg/dl)
EEG in acute period
Sequelae
Clinical day
Findings
PCPCS score
Epilepsy
41 Undetectable 111 67 NA 54 NA 73 Undetectable 131 25 32 Undetectable Undetectable 23
Day1 Day1 Day2 Day1 Day1 ND ND Day1 Day1 Day4 Day1 Day1 ND ND ND
Diffuse HVS Hemi-HVS Diffuse HVS Diffuse HVS Diffuse HVS ND ND Diffuse HVS Hemi-HVS Diffuse LV Ictal pattern Diffuse HVS ND ND ND
1 1 1 2 2 2 (HP) 3 3 3 (HP) 4–5 4–5 4–5 5 4–5 6 (deceased)
Seizure-free Seizure-free Seizure-free Seizure-free Moderate Seizure-free Moderate Severe Severe Mild Seizure-free Moderate Moderate Severe NA
EEG, electroencephalogram; 21OHD, 21-hydroxylase deficiency; CLAH, congenital lipoid adrenal hyperplasia; GTS, Generalized tonic seizure; GTCS, Generalized tonic-clonic seizure; SE, Status epilepticus; Clst, cluster; HVS, Diffuse high voltage slow wave; HP, Hemiparesis; ND, not done; NA, not available; PCPCS, Pediatric Cerebral Performance Category Scale [16]. * >38 °C. ** Recurrent seizures in the acute period differing from the 1st seizures. *** Cases 3, 6, and 8 were described in previous case reports [10,12].
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Table 1 Summary of clinical and EEG manifestations.
Case
Acute period
Subacute or chronic period
Clinical day
MRI/CT
Distribution
Findings
1* 2 3** 4 5 6*,** 7 8*,** 9 10* 11 12 13 14 15
Day1 Early Day2 Day6 Day1 Day3 Day2 Day2 Day2 Day2 Day1 Day2 Day2 Day2 Day1
MRI MRI MRI MRI CT MRI CT MRI MRI CT CT MRI CT CT CT
bil-F-SCWM uni-F-SCWM bil-deep WM bil-F, P, T bil-diffuse uni-F-SCWM bil-diffuse bil-SCWM, Cortex uni-O-SCWM bil-diffuse bil-diffuse bil.-Cortex bil-diffuse uni-diffuse bil-diffuse
DWI " ADC DWI " ADC DWI " ADC DWI " low density DWI " ADC low density DWI " ADC DWI " ADC Low density Low density DWI " Low density Low density Low density
; ; ; ; ; ;
Notes
Clinical day
CT/MRI
Distribution
Findings
Day54 Day24 Chronic Day39 Chronic Day90 Day44 Day60 Day36 Chronic Chronic Day49 Chronic Chronic NA
MRI MRI MRI MRI CT MRI MRI MRI MRI CT CT MRI CT CT NA
– – – bil-F bil-diffuse uni-Cortex, WM bil-Cortex, WM bil-Cortex, WM uni-WM bil-diffuse bil-diffuse bil-WM bil-diffuse uni-diffuse NA
Normal Normal Normal Atrophy Atrophy T1W" FLAIR" T1W" FLAIR" T1W" FLAIR" Atrophy Atrophy Atrophy Atrophy Atrophy Atrophy NA
Bilateral, frontal lobe dominant, reversible Unilateral, frontal lobe dominant, reversible Deep white matter and splenium, reversible Bilateral, dominant lesion in frontal lobe Diffuse brain atrophy Unilateral, cortical necrosis and white matter-atrophy Bilateral, cortical necrosis and white matter-atrophy Bilateral, cortical necrosis and white matter-atrophy Unilateral, volume loss in white matter Diffuse brain atrophy Diffuse brain atrophy Bilateral, volume loss in white matter Diffuse brain atrophy Hemispheric brain atrophy
MRI, magnetic resonance imaging; CT, computed tomography; bil, bilateral; uni, unilateral; F, frontal lobe; P, parietal lobe; T, temporal lobe; O, occipital lobe; SC, subcortical; WM, white matter; DWI, diffusion weighted images; ADC, apparent diffusion coefficient; T1W, T1-weighted; FLAIR, fluid-attenuated inversion recovery images; NA, not available. * CT or MR imaging was shown in Figs. 1 and 2. ** Cases 3, 6, and 8 were described in previous case reports [10,12].
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx 5
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Table 2 Summary of neuroimaging.
6
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
(Cases 1, 3, 4, 5, 8, and 12), hemispheric high-voltage slow waves in two patients (Cases 2 and 9), diffuse low-voltage activities in one patient (Case 10), and continuous ictal patterns in one patient (Case 11). 3.7. Prognosis and sequelae (Table 1) Fourteen patients (93%) were alive with or without sequelae of varying severity, whereas one patient (Case 15) died in the early period. In the secondary research, each neurological prognosis written in the completed questionnaire was re-evaluated using PCPCS scores [14]. Among the 14 survivors, 11 (79%) had some neurological impairment as follows: six (43%) had PCPCS scores of 2–3 (mild to moderate disability) and five (36%) had PCPCS scores of 4–5 (severe disability or coma or vegetative state). Only three patients (Cases 1, 2, and 3) had no residual neurological sequelae caused by CAHE episodes. Epileptic sequelae occurred in eight surviving patients (57%). Specifically, mild, moderate, or severe epilepsy was identified in one (7%), four (29%), and three patients (21%), respectively. Finally, the remaining six surviving patients (43%) had no epilepsy as a sequela.
3.8. Neuroimaging (Table 2 and Figs. 1 and 2) Neuroimaging of patients with CAHE showed heterogeneous findings. In the acute period, bilateral focal edematous brain lesions were found in Case 1 (Fig. 1A), and unilateral focal brain lesions were identified in Cases 2, 4, 6 (Fig. 1B), and 9. Bilateral diffuse or multifocal brain lesions were noted in nine patients [60%, Cases 3, 5, 7, 8 (Fig. 1C), 10 (Fig. 1D), 11, 12, 13, and 15], and a unilateral diffuse hemispheric lesion was found in Case 14. From the point of view of the depth of the brain lesions, subcortical white matter (SCWM) lesions sparing the cortex were found in four patients, namely Cases 1 (Fig. 1A), 2, 6 (Fig. 1B), and 9, and SCWM lesions including the bilateral frontal lobes were present in Case 8 (Fig. 1C). However, lesions in the bilateral cortex excluding the white matter were found in Case 12. There were also lesions of both the splenium and bilateral deep white matter in one patient (Case 3). The depth of the brain lesion was unclear in eight patients [Case 4 on MRI and Cases 5, 7, 10 (Fig. 1D), 11, 13, 14, and 15 on CT].
Fig. 1. Brain imaging of each patient in the early period. (A) Magnetic resonance imaging (MRI; diffusion-weighted imaging: DWI) of Case 1 on day 1 revealed high signal intensity in the bilateral frontal lobes of the subcortical white matter (SCWM) (arrow). (B) MRI (DWI) of Case 6 on day 3 revealed high signal intensity in the right-side frontal lobe of the SCWM (arrow). (C) MRI (DWI) of Case 8 on day 2 revealed diffuse high signal intensity in the cortex. (D) Computed tomography image of Case 10 on day 2 revealed diffuse low densities.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
In the subacute or chronic period, brain imaging for 11 of 14 surviving patients [79%, Cases 4, 5, 6 (Fig. 2B), 7, 8 (Fig. 2C), 9, 10 (Fig. 2D), 11, 12, 13, and 14] revealed atrophic findings of varying severity. Diffuse brain atrophy was found in seven patients [Cases 5, 7, 8 (Fig. 2C), 10 (Fig. 2D), 11, 12, and 13], and two other patients had hemispheric brain atrophy (Cases 9 and 14). Cases 4 and 6 (Fig. 2B) displayed restricted lesions in the bilateral frontal area. In three patients [Cases 1 (Fig. 2A), 2, and 3], there was no obvious abnormality on MRI despite somewhat abnormal imaging findings in the acute period. On the contrary, from the viewpoint of the depth of the brain lesions, high signal intensity in the cortex on T1-weighted and fluid attenuation inversion recovery (FLAIR) images and high signal intensity in the white matter on T2-weighted images were found in three patients [Cases 6 (Fig. 2B), 7, and 8 (Fig. 2C)]. Conversely, high signal intensity in the white matter excluding the cortex was noted on T2-weighted images for Cases 9 and 12. Surprisingly, no abnormal signal intensity on MRI or density on CT was detected for lesions in the basal ganglia, brainstem, and cerebellum in any patients.
7
4. Discussion Previous studies reported that some pediatric patients with CAH and acute encephalopathic episodes exhibited symptoms of impaired consciousness with or without convulsions following prodromal symptoms such as fever, vomiting, and/or diarrhea [10–12]. In this study, all 15 pediatric patients with CAH presented with prodromal and minor symptoms before each encephalopathic episode. Those prodromal symptoms also antedated the onset of adrenal crisis complicated with CAH. Adrenal crisis is the most dangerous complication of CAH, but even if patients develop adrenal crisis, they should recover following the administration of additional corticosteroids and other supportive treatments [15]. However, in this study, 13 of 15 patients with CAHE failed to recover from severe first seizures and prolonged coma following standard treatments for adrenal crisis. The initial seizures tended to be prolonged in 12 of 15 patients with CAHE, but we could not find a definite association between seizure duration and the neurological prognoses. In fact, Cases 13 and 15 had only brief seizures lasting <5 min but presented with
Fig. 2. Brain imaging of each patient in the subacute or chronic period. (A) Magnetic resonance imaging (MRI; fluid attenuation inversion recovery: FLAIR) of Case 1 on day 54 showed no abnormal signal intensities (abnormal high intensities in the bilateral frontal lobes of both the subcortical white matter and cortex vanished). (B) MRI (FLAIR) of Case 6 on day 90 revealed abnormal high intensities in the right-side frontal lobe of the white matter (arrow). (C) MRI (T1-weighted image) of Case 8 on day 60 revealed diffuse high signal intensities in the white matter and cortex with atrophy (arrow). (D) Computed tomography image of Case 10 on day 110 revealed diffuse atrophy in the cortex and white matter.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
8
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
prolonged deep comas, and these patients had poor prognoses. Two previous studies also reported that patients with CAH went into deep comas without convulsion, and they were diagnosed with acute encephalopathy featuring brain lesions on MRI [10,11]. If a patient with CAH develops a coma, it may be difficult to distinguish CAHE from adrenal crisis during the early phase in clinical practice. Therefore, when a patient with CAH exhibits (1) symptoms of adrenal crisis, (2) resistance to the standard treatment for adrenal crisis, and (3) a prolonged deep coma irrespective of the presence of intractable seizures, we should suspect that the patient has developed CAHE. Neuroimaging in each patient with CAHE revealed the heterogeneous nature of the disease. In the early period, focal or diffuse edematous lesions on CT or MRI were found in cerebral white matter with or without the involvement of the cerebral cortex in all 15 patients. In particular, five of eight patients who underwent MRI presented with specific findings in the bilateral or unilateral subcortical cerebral white matter (Cases 1, 6, and 8: Fig. 1a–c). These findings on MRI were characteristic and resembled a type of acute encephalopathy, namely acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) [5,16], otherwise known as acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) [4]. Both AESD and AEFCSE are recognized as almost the same spectrum of encephalopathy, which we termed ‘‘AESD-spectrum encephalopathy syndrome” in this study. In addition, AESD-spectrum encephalopathy syndrome may partially overlap acute infantile encephalopathy predominantly affecting the frontal lobes [17] and hemicon vulsion-hemiplegia-epilepsy syndrome (HHES) [18]. These types of acute encephalopathy present with SE and prolonged deep coma with fever and subsequently progress to include edematous lesions with high signal intensity in the cerebral SCWM on diffusion-weighted imaging (DWI) or low density on CT. The characteristic neuroimaging findings typically appear between the third and ninth day when secondary seizures often occur, and high signal intensity for cortical lesions on DWI or T2-weighted images is revealed in this late period [5]. In this study, within a few days after the first seizures, biphasic secondary seizures appeared in six patients with CAHE (40%, Cases 2, 6, 7, 9, 12, and 14), and three of the six patients [Cases 2, 6, (Fig. 1B) and 9] with recurrence of convulsions exhibited highintensity lesions in the unilateral SCWM on DWI. In fact, the findings on MRI of the three patients with recurrent seizures resemble those found in patients with AESD-spectrum encephalopathy syndromes, but the time at which the characteristic finding appeared on MRI was earlier than that of typical AESD-spectrum encephalopathy syndromes. Furthermore, one patient with biphasic seizures (Case 12) displayed a high-
intensity cortical edematous lesion on DWI on day 2, and two other patients (Cases 7 and 14) presented with diffuse low density of the unilateral or bilateral hemispheres on CT on day 2. On the contrary, one patient (Case 1) presented with only a monophasic convulsion and displayed high-intensity lesions in the unilateral cerebral SCWM on DWI on the day encephalopathy appeared. The clinical course of Case 1 was not typical of that of AESD-spectrum encephalopathy syndromes, but it partly corresponded to that of HHES, which often presents with only a monophasic seizure, whereas highintensity lesions on DWI are found in both the cerebral SCWM and cortex within a few days after the first seizure [19,20]. Different from all previous patients, Case 3 on day 2 featured symmetrical high-intensity legions in the deep white matter and splenium on DWI, and surprisingly, the findings were reversible. The findings resemble those of clinically mild encephalopathy/encephalitis with reversible splenial lesion type 2 [5,10,21,22]. Meanwhile, high signal intensity was observed in the cerebral cortex on T1-weighted or FLAIR images in Cases 6, 7, and 8 during the subacute or chronic stage (Fig. 2b–c). These findings may indicate cortical laminar necrosis. It remains possible that these findings could be caused by hypoglycemia due to adrenal crisis or triggered by hypoxia due to SE. Hypoglycemia causes neuronal death if glucose levels fall to <18 mg/dl [23]. However, the plasma glucose levels in the two patients (Cases 6 and 8) with high signal intensity in the cerebral cortex on T1-weighted or FLAIR images were not extremely low (54 and 73 mg/dl, respectively), and thus, the sensitivity of CAH itself to stress may be considered a possible cause of cortical laminar necrosis. In addition, SE may cause cortex-dominant necrosis [1]. In fact, the three patients with findings of cortical necrosis on MRI in the subacute or chronic period were exposed to long periods of seizure cluster. Thus, the findings of cortical necrosis on subacute or chronic MRI in the three patients may have been caused by excitotoxicity due to refractory seizures [1]. Meanwhile, acute necrotizing encephalopathy, hemorrhagic shock and encephalopathy syndrome, and Reye-like syndrome are known as other types of acute encephalopathy presumably caused by cytokine storm, and these types of acute encephalopathy often affect basal ganglia, brainstem, and cerebellum [1]. However, in this study, there were no patients with the typical course, laboratory data, and neuroimaging findings of these types of acute encephalopathy. However, Case 15 presented only with disseminated intravascular coagulation and systemic multi-organ failure and finally died in the early period. When patients with CAH contract an infection, they often receive additional treatment of steroids. However, even though the dose of steroids was increased appropriately, they occasionally may
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
exhaust glucocorticoids which suppress the secretion of some inflammatory cytokines, such as interleukin-1 (IL-1), IL-2, and tumor necrosis factor alpha [24]. Thus, this patient may have had some type of acute encephalopathy presumably caused by cytokine storm. A previous study illustrated that diffuse or focal white matter abnormalities on T2-weighted or FLAIR images were found in 22 adolescent or older patients with CAH [25]. Another study reported that 14 of 39 pediatric and young adult patients with CAH, including one patient with a known stroke during salt-wasting crisis, displayed white matter abnormalities or temporal lobe atrophy on MRI [26]. These reports indicated that there may be fragility of CAH in both the cortex and white matter. In this study, no patients with CAH had a past history of encephalopathy, and no residual finding was found on MRI. Concerning the remaining causes of CAHE, theophylline, which is a risk factor for acute encephalopathy or SE during fever, was administered to only one patient (Case 5) [27]. In this patient, CAH itself and the administration of theophylline may have led to acute encephalopathy. Furthermore, influenza type A virus infection was documented in two patients (Cases 3 and 13), and this virus is known to cause acute encephalopathy syndromes [1]. These results indicate that CAHE may be caused by further triggers, in addition to the host condition affected by CAH. A previous study of CAH with encephalopathic symptoms reported that there was a higher incidence of encephalopathy in patients with CAH than in the general population [28]. This indicated that the physiological instability of steroids in patients with CAH may have some potential to trigger encephalopathy, even if the patients with CAH are treated with current replacement therapy of corticosteroids. Therefore, our results indicated that these MRI findings and clinical course were not always generated by the same pathological condition, but the fragility of underlying CAH to some stress and excitotoxicity may often be contributory to both the brain lesions and their clinical conditions in diverse mechanisms. Our research can be summarized as follows. CAHE is a heterogeneous pathological condition. The initial symptoms of CAHE resemble those of adrenal crisis, and it is associated with prolonged coma and/or refractory seizures intractable to treatment. In addition, patients often develop neurological sequelae of varying severity. Neuroimaging of patients with CAHE revealed heterogeneous findings, including abnormal high signal intensity on DWI appearing in both the cerebral cortex and subcortical or deep white matter in the early period as well as focal or diffuse brain atrophy and abnormal signals. In conclusion, we have described the concept of CAHE, which is a heterogeneous pathological condition. Further research on CAHE is needed.
9
Acknowledgments This study was supported mainly by a Grant-in-Aid for Research on Measures for Intractable Diseases, Nos. H22-Nanji-Ippan-49, H25-Nanji-Ippan-009, and H27-Nanji-Ippan-028 from the Ministry of Health, Labour and Welfare, Japan. References [1] Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand 2007;115:45–56. [2] Gosalakkal JA, Kamoji V. Reye syndrome and reye-like syndrome. Pediatr Neurol 2008;39:198–200. [3] Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;19:81–92. [4] Shiomi M, Ishikawa J, Togawa M, Okazaki S, Kuki I, Kimura S, et al. A concept of acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) and theophylline as one of its precipitating causes (in Japanese). No To Hattatsu 2008;40:122–7. [5] Takanashi J. Two newly proposed infectious encephalitis/encephalopathy syndromes. Brain Dev 2009;31:521–8. [6] Yamanouchi H, Mizuguchi M. Acute infantile encephalopathy predominantly affecting the frontal lobes (AIEF): a novel clinical category and its tentative diagnostic criteria. Epilepsy Res 2006;70 (Suppl. 1) S263-8. [7] Mori H, Mizutani T, Yoshimura M, Yamanouchi H, Shimada H. Unilateral brain damage after prolonged hemiconvulsions in the elderly associated with theophylline administration. J Neurol Neurosurg Psychiatry 1992;55:466–9. [8] Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500. [9] Hoshino A, Saitoh M, Oka A, Okumura A, Kubota M, Saito Y, et al. Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes. Brain Dev 2012;34:337–43. [10] Lee S, Sanefuji M, Watanabe K, Uematsu A, Torisu H, Baba H, et al. Clinical and MRI characteristics of acute encephalopathy in congenital adrenal hyperplasia. J Neurol Sci 2011;306:91–3. [11] Grunt S, Steinlin M, Weisstanner C, Schoning M, Mullis PE, Fluck CE. Acute encephalopathy with unilateral cortical-subcortical lesions in two unrelated kindreds treated with glucocorticoids prenatally for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: established facts and novel insight. Horm Res Paediatr 2013;80:57–63. [12] Saito Y, Ogawa T, Nagaishi J, Inoue T, Maegaki Y, Ohno K. Laminar cortical necrosis in adrenal crisis: sequential changes on MRI. Brain Dev 2008;30:77–81. [13] Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005;365:2125–36. [14] Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr 1992;121:68–74. [15] Shulman DI, Palmert MR, Kemp SF. Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics 2007;119: e484–94. [16] Takanashi J, Tsuji M, Amemiya K, Tada H, Barkovich AJ. Mild influenza encephalopathy with biphasic seizures and late reduced diffusion. J Neurol Sci 2007;256:86–9. [17] Yamanouchi H, Kawaguchi N, Mori M, Imataka G, Yamagata T, Hashimoto T, et al. Acute infantile encephalopathy predominantly affecting the frontal lobes. Pediatr Neurol 2006;34:93–100.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007
10
Y. Abe et al. / Brain & Development xxx (2016) xxx–xxx
[18] Gastaut H, Poirier F, Payan H, Salamon G, Toga M, Vigouroux M. H.H.E. syndrome; hemiconvulsions, hemiplegia, epilepsy. Epilepsia 1960;1:418–47. [19] Yoshikawa H, Kitamura T. Serial changes on diffusion-weighted magnetic resonance imaging in encephalitis or encephalopathy. Pediatr Neurol 2006;34:308–11. [20] Yamazaki S, Ikeno K, Abe T, Tohyama J, Adachi Y. Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1A S218L mutation. Pediatr Neurol 2011;45:193–6. [21] Takanashi J, Barkovich AJ, Yamaguchi K, Kohno Y. Influenzaassociated encephalitis/encephalopathy with a reversible lesion in the splenium of the corpus callosum: a case report and literature review. AJNR Am J Neuroradiol 2004;25:798–802. [22] Tada H, Takanashi J, Barkovich AJ, Oba H, Maeda M, Tsukahara H, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology 2004;63:1854–8. [23] Auer RN. Hypoglycemic brain damage. Metab Brain Dis 2004;19:169–75.
[24] Padgett D, Loria R, Sheridan J. Steroid hormone regulation of antiviral immunity. Ann N Y Acad Sci 2000;917:935–43. [25] Bergamaschi R, Livieri C, Uggetti C, Candeloro E, Egitto MG, Pichiecchio A, et al. Brain white matter impairment in congenital adrenal hyperplasia. Arch Neurol 2006;63:413–6. [26] Nass R, Heier L, Moshang T, Oberfield S, George A, New MI, et al. Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy. J Child Neurol 1997;12:181–6. [27] Yoshikawa H. First-line therapy for theophylline-associated seizures. Acta Neurol Scand 2007;115:57–61. [28] Kawashima Y, Hanaki K, Kinoshita T, Nagaishi J, Kanzaki S. A nation wide survey for the incidence of the central nervous system complications in treated patients with congenital adrenal hyperplasia (in Japanese). Horumonn To Rinsho 2002;50:1165–9.
Please cite this article in press as: Abe Y et al. Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.01.007