Minami et al. Journal of Medical Case Reports
https://doi.org/10.1186/s13256-023-03887-0(2023) 17:140

Journal of
Medical Case Reports

Open Access

CASE REPORT

Pediatric fulminant malignant hyperthermia
with severe electroencephalographic
abnormality and brain damage: a case report
Sakura Minami1* , Azusa Ikeda2, Kaori Yamada1, Aya Kajihama1, Hiroyuki Shimizu1 and Hiroyuki Nagafuchi1

Abstract
Background Malignant hyperthermia is an extremely dangerous condition that can occur with exposure to volatile
inhalant anesthetics and depolarizing muscle relaxants, and that requires immediate intervention. Neurological complications have rarely been reported, with no reports of electroencephalographic abnormalities or encephalopathy.
Here, we report a case of severe electroencephalographic abnormality in the acute phase of malignant hyperthermiathat eventually led to diffuse cerebral cortical damage.
Case presentation A 15-month-old Japanese boy underwent a Rastelli procedure to correct a double-outlet rightventricle and pulmonary atresia. Sevoflurane was used for induction and maintenance of anesthesia during surgery.
After withdrawal from the heart–lung machine, his body temperature rose at a rate of 0.1 ℃/minute, and when he left
the operating room, his core body temperature had reached 42 ℃. After admission to the intensive care unit, tachycardia, high P­ aCO2, and progressive metabolic acidosis were observed. A clinical grading scale score of 63 indicatedmalignant hyperthermia, and dantrolene was administered. The pupils were dilated, and the electroencephalogram
showed persistent generalized continuous multifocal spikes. Midazolam, levetiracetam, and fosphenytoin wereadministered without improvement, and thiamylal and ketamine were infused continuously. After the electroencephalogram shifted to burst suppression, the epileptic firing gradually decreased, and the background electroencephalogram became lower in amplitude. Magnetic resonance imaging of the head performed after the patient was
hemodynamically stable suggested diffuse cerebral cortical damage. Severe mental retardation, hypertonia, andquadriplegia were observed as neurological complications.
Conclusions In this case, despite the use of high-dose anticonvulsants, the patient showed severe electroencephalogram abnormality, resulting in diffuse cortical damage. Hyperthermia is known to damage the central nervous system
by causing increased brain pressure and cerebral edema, which may have triggered the severe neuronal excitationthat we observed in this case. The presence of systemic inflammatory response syndrome and the patient’s background, including young age and ethnicity, might also have been factors. Malignant hyperthermia can be complicated by encephalopathy, and continuous electroencephalogram monitoring should be considered.
Keywords Brain disease, Cardiac surgical procedures, Case report, Malignant hyperthermia, Pediatrics,
Electroencephalography*Correspondence:
Sakura Minami
sakurappi27@gmail.com
Full list of author information is available at the end of the article© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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Minami et al. Journal of Medical Case Reports(2023) 17:140

Background
Malignant hyperthermia (MH), which requires immediate intervention, is an extremely dangerous condition
that can occur with exposure to volatile inhalant anesthetics and depolarizing muscle relaxants. In MH, therate of calcium (Ca) release from the sarcoplasmic reticulum is enhanced by exposure to inducing agents. The
intracellular Ca concentration becomes uncontrollably
high, resulting in abnormal, sustained muscle contraction[1]. As a result, large amounts of adenosine triphosphate
are consumed and metabolism is abnormally increased,
which can cause hyperthermia and multiple organ damage [2]. The incidence is as low as 1 in 40,000 cases inadults and 1 in 15,000 cases in children [3], but there havebeen many reports and investigations of its occurrence asa serious complication of anesthesia. Mortality rates havedecreased to approximately 5% since dantrolene cameinto use as a treatment [4], but complications that affectprognosis, such as cardiac and renal dysfunction, may
remain [4–6].
Neurological sequelae, such as impaired consciousness,have been reported as a complication of MH [6], but thedetailed pathogenesis has not been reported, and there
have been no reports of cases with electroencephalogram(EEG) abnormalities or encephalopathy. As neurologicalsequelae can significantly worsen a patient’s functional
prognosis, careful consideration of the pathogenesis of
the condition and appropriate intervention is essential.
We report a case of pediatric fulminant MH with diffuse cerebral cortical damage and severe EEG abnormality detected by continuous EEG monitoring in the acutephase.
Case presentation
The patient was a 15-month-old Japanese boy (height
73 cm, weight 9 kg) with a history of vertebral defects,
anal atresia, and cardiac defects (VATER association)
but no significant family medical history. Preoperative
development was good, with age-appropriate mental
function [Pediatric Cerebral Performance Category Scale(PCPC) = 1]. The patient underwent Rastelli surgery tocorrect a double-outlet right ventricle (DORV) and pulmonary atresia. Sevoflurane, midazolam, fentanyl, androcuronium were used as anesthetics during surgery.
Sevoflurane was used for approximately 3 hours frominduction of anesthesia to the start of cardiopulmonary
bypass (CPB). Preoperative blood gases were normal, but
metabolic acidosis developed (pH 7.26; base excess, −7.1;­PaCO2, 43.5 mmHg; H­ CO3−, 19.2 mmol/L; anion gap,
10.8; and lactate concentration, 0.7 mmol/L) after thestart of surgery. In addition, end-tidal ­CO2 was elevated,
requiring adjustment of the ventilation of the anesthesia
machine. The core body temperature before the start ofPage 2 of 6

CPB was 36 °C. Cooling was started with cannulation,and the lowest body temperature reached was 28 °C. At
the end of the intracardiac surgery, heating was started,and body temperature was allowed to reach 37 °C, over a
20 minute period. After withdrawal from CPB, his bodytemperature rose at a rate of 0.1 ℃/minute, and when he
was taken out of the operating room, his core body temperature was 42 ℃. The total operative time was 316 minutes, and CPB time was 162 minutes. The patient wasadmitted to the intensive care unit (ICU) with intubation.
Vital signs on ICU admission were as follows: heartrate, 200 beats per minute (bpm), sinus tachycardia;
blood pressure, 105/68 mmHg (adrenaline at 0.05 μg/kg/
minute and olprinone at 0.2 μg/kg/minute were administered); Glasgow Coma Scale (GCS), 3 (E1VTM1); pupil
diameter, 5/5 mm; S­ pO2, 100% [already intubated, ventilator set to synchronized intermittent mandatory ventilation (SIMV); ­FIO2, 0.6; positive end-expiratory pressure(PEEP), 4; peak inspiratory pressure (PIP), 24; ventilation
frequency, 30]; and rectal temperature, 40.1 ℃. Arterial
blood gas analysis showed metabolic acidosis with pH
7.25; base excess, -9.9 mEq/L; P­ aCO2, 37.9 mmHg; P­ aO2,
250 mmHg; ­HCO3−, 16.3 mmol/L; anion gap, 20.7; ­Na+,
148 mmol/L; ­K+, 4.9 mmol/L; C­ l−, 111 mmol/L; and lactate concentration, 10.5 mmol/L. In about 1 hour, endtidal ­CO2 gradually rose to 56 mmHg and ­PaCO2 rose
to 129 mmHg. Respiratory settings were raised to adriving pressure of 27, but a further increase in ­PaCO2
to 138 mmHg occurred, resulting in hypercapnia. The
core body temperature also rose to 41 °C and did notdecrease despite multiple ice packs, cooling with a circulating water mattress, gastric lavage with cold saline
solution, and rapid administration of cold isotonic crystalloid. Blood tests showed elevated creatinine kinase(2202 U/L), myoglobin (45,840 ng/mL), and interleukin-6 (IL-6) (79.5 pg/mL). The patient had refractorytachycardia, hyperthermia, elevated ­PaCO2, progressive
metabolic acidosis, and a MH clinical grading scale score[7] of 63 (MH rank 6), which indicated fulminant MH.
Therefore, the first dose of dantrolene was administeredapproximately 4 hours after the patient became hyperthermic, according to the dosage recommended by theJapanese Society of Anesthesiologists. Dantrolene wasadministered at an initial dose of 2 mg/kg, followed byadditional doses of 1 mg/kg each. A total of 5 mg/kg wereadministered, and a decrease in ­PaCO2 was observed. In
addition, continuous hemodiafiltration was started due
to uncontrolled hyperthermia and metabolic acidosis.
Sedation with midazolam, fentanyl, dexmedetomidine,and vecuronium was administered to prevent a further
increase in body temperature due to body movement
and to avoid circulatory failure due to arousal. Body temperature dropped to 38 °C within 30 minutes of starting

Minami et al. Journal of Medical Case Reports(2023) 17:140

continuous hemodiafiltration (approximately 5 hours
after the patient became hyperthermic) and was controllable at 36 °C thereafter. Tachycardia improved witha decrease in body temperature, but cardiac arrhythmia(accelerated junctional rhythm) appeared 2 hours later,
and circulatory failure occurred. Therefore, temporary
epicardial pacing leads were inserted on the second day.
Sevoflurane was not used during this surgery, which was
performed without complications. Genetic testing for
MH could not be performed due to lack of consent fromthe parents.
After admission to the ICU concurrent with treatment
for MH, we noticed that the patient’s pupils were dilated.
Sedative agents and muscle relaxants were administered,and no abnormal muscle contractions were observed. A
bedside EEG showed persistent generalized continuous
multifocal spikes (Fig. 1A). Midazolam (0.1 mg/kg/hour),levetiracetam (30 mg/kg), and fosphenytoin (22.5 mg/kg) were administered, but without improvement. Thiamylal (5 mg/kg/hour) and ketamine (2 mg/kg/hour) were
infused continuously. The EEG then changed to burst
suppression with repeated high-amplitude multifocal
spikes and flat waves (Fig. 1B). From the second day, thefrequency of bursts gradually decreased, and the durationof the bursts gradually shortened (Fig. 1C). Continuous
thiamylal administration was terminated on day 7. Ketamine was also terminated on day 10, and the patient was
switched to oral phenobarbital. On day 12, a focal seizurein the left occipital region (Fig. 1D) was observed, which
resolved with increased phenobarbital dosage. On day 14,
the EEG was generally of low amplitude (Fig. 1E).
Rhabdomyolysis and acute kidney injury were also
observed as complications of MH. Creatinine kinase wasfound to be elevated on the first day, reached a maximum(203,000 IU/L) on day 4, then gradually decreased. Oliguria of 0.3 mL/kg/hour continued, showing impaired renal
function, but urine output gradually increased from day
7, and the patient was weaned off continuous hemodiafiltration on day 13. The patient’s accelerated junctional
rhythm improved with improvement in his general condition, and the temporary epicardial pacing leads were
removed on day 18. (Fig. 2).
Head magnetic resonance imaging (MRI) was performed on day 19, after the patient’s hemodynamic status had stabilized. Diffusion-weighted and T2-weighted
images showed diffuse hyperintensity predominantlyin the cerebral cortex, and T1-weighted images also
showed pale hyperintensity in the occipitoparietal cortex(Fig. 3a–c), suggesting diffuse cortical damage.
Spontaneous respiration and cough reflex were confirmed, and the patient was extubated on day 34. The
patient was discharged from the ICU on day 40 with
impaired consciousness (PCPC 4), generalized muscle

Page 3 of 6

stiffness, and residual muscle contractures. Six months
after onset, the patient continued rehabilitation, and hislevel of consciousness had improved (PCPC 3) but withresidual severe mental retardation, hypertonia of theextremities, and quadriplegia.

Discussion and conclusions
In this case, although genetic testing could not be performed, the clinical findings suggested MH. Severe EEG
abnormalities that were difficult to control were observedin the acute phase, and background EEG activity showed
low amplitude over time, suggesting functional decline.
Subacute brain MRI showed diffuse cortical damage andsevere neurological sequelae. Although the patient did
not fit any specific classification, the course of the disease
was considered similar to an acute encephalopathy.
The main causes of acute encephalopathy are metabolic abnormalities, systemic inflammatory reactions,and excitotoxicity. These three interrelated factors havebeen hypothesized to induce brain cell damage and functional impairment [8]. Systemic inflammatory reactions
and excitotoxicity are caused by hyperthermia and highconcentrations of circulating cytokines. Therefore, MH
is expected to be one of the possible triggers, although
this mechanism has not been previously reported in theliterature.
Hyperthermia causes severe brain cell edema and brain
cell damage by disrupting the blood–brain barrier (BBB)
and damaging vascular endothelial cells [9]. When excitatory amino acids increase and inhibitory amino acids
decrease due to hyperthermia, their balance is disrupted
and the BBB is thereby disrupted [9, 10]. When rats were
exposed to heat stress at 38 ℃ for 4 hours, the excitatory
amino acid glutamate increased markedly in the brain,
disrupting the BBB, decreasing regional blood flow, andcausing edema and cellular damage [11]. Thus, an abnormally high temperature or long duration of hyperthermia
may cause brain dysfunction.
A high cytokine state associated with MH may havebeen related to the brain damage observed in our case.
It has been reported that the activation of ryanodine
receptor 1 (RYR1), a Ca-release channel that is mutatedin individuals predisposed to MH, releases inflammatory
cytokines such as IL-6 from skeletal muscle cells [12, 13].
However, not all cases of MH cause severe brain damage as in the present case. We consider age and race as
background factors that could potentially explain theseverity of the brain damage observed in this case. The
symptoms of MH vary according to the age of onset.
Otsuki reported a comparison of Japanese pediatricpatients with MH stratified by age [14]. In the younger
age group (0–24 months), hyperthermia was the mostcommon first symptom and was a characteristic findingMinami et al. Journal of Medical Case Reports(2023) 17:140

Page 4 of 6

Fig. 1 Electroencephalographic findings. A Onset: generalized continuous multifocal spikes are observed. B Day 2: High-amplitude multifocal
spikes and low voltage are repeatedly observed, considered burst suppression. C Day 5: A decrease in multifocal spikes is observed. D Day 12: A
focal seizure occurs in the left occipital region. E Day 14: A decrease in the amplitude of the background electroencephalographic activity can beobserved

compared with other age groups. In our opinion, ourpatient may have been prone to symptoms of hyperthermia owing to his young age. Furthermore, we notedmarked regional differences in the reporting of acuteencephalopathy with acute necrotizing encephalopathies and acute encephalopathy with biphasic seizures.
Late reduced diffusion is more commonly reported inJapan and East Asia, suggesting racial genetic differences in its background incidence [15, 16]. The fact thatour patient was Japanese may have been a trigger for theencephalopathy.
This is a rare case of MH complicated by acute encephalopathy. Hyperthermia and the high cytokine state
due to MH may have triggered neuronal damage andMinami et al. Journal of Medical Case Reports(2023) 17:140

Page 5 of 6

Fig. 2 Clinical course of the patient. Dantrolene was administered, and body temperature was controlled by CRRT. The patient was treated withmidazolam, levetiracetam, and fosphenytoin, but without improvement, and after continuous administration of thiamylal and ketamine, the patient
was placed on oral phenobarbital. CRRT​ continuous renal replacement therapy, BT body temperature, CK creatinine kinase

Fig. 3 Magnetic resonance imaging findings: day 19. a Diffusion-weighted images show diffuse hyperintensity in the cerebral cortex. b
T2-weighted images show slight hyperintensity throughout the subcortical area. c T1-weighted imaging shows pale hyperintensity in the cortex,
mainly in the occipitoparietal lobe, which is considered to be due to a state of cortical laminar necrosis

persistent electrical excitation. The patient’s background,including younger age and race, may also have been factors in the development of the central nervous systemdisorders. Although this case left the patient with serious
sequelae, EEG examination from early onset allowed us

to recognize the strong disturbance and intervene early.
In the acute phase of MH, continuous EEG monitoring may be useful for evaluating central nervous systemcomplications.

Minami et al. Journal of Medical Case Reports(2023) 17:140

Abbreviations
MH	Malignant hyperthermia
Ca	Calcium
EEG	Electroencephalogram
CPB	Cardiopulmonary bypass
ICU	Intensive care unit
GCS	Glasgow Coma Scale
SIMV	Synchronized intermittent mandatory ventilation
PIP	Peak inspiratory pressure
PEEP	Positive end-expiratory pressureIL-6	Interleukin-6
MRI	Magnetic resonance imaging
PCPC	Pediatric Cerebral Performance Category Scale
BBB	Blood–brain barrier
RYR1	Ryanodine receptor 1
Acknowledgements
We thank the patient’s family for agreeing to the publication of this report.
Author contributions
All authors (SM, AI, KY, AK, HS, and HN) participated in the care of the patientand in revising this manuscript. All authors read and approved the final
manuscript.

Page 6 of 6

5.
6.

7.
8.
9.
10.

11.

Funding
Not applicable.
Availability of data and materials
The datasets used during the current study are available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
Ethical approval is not required at our institution to publish an anonymouscase report.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian for
publication of this case report and any accompanying images. A copy of thewritten consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Critical Care Medicine, Kanagawa Children’s Medical Center,
2‑138‑4 Mutsukawa, Minami‑ku, Yokohama, Kanagawa 232‑8555, Japan.
2
Department of Neurology, Kanagawa Children’s Medical Center, 2‑138‑4
Mutsukawa, Minami‑ku, Yokohama, Kanagawa 232‑8555, Japan.

12.

13.

14.
15.
16.

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Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Received: 8 February 2023 Accepted: 13 March 2023

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