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\title{Characteristics and treatments of patients with significantly elevated
creatine kinase levels induced by seizures: case report and literature
review}



\author[1]{kai wang}%
\author[1]{jinwei Yang}%
\author[2]{wenhao Xu}%
\author[1]{Lei Wang}%
\author[1]{Yu Wang}%
\affil[1]{First Affiliated Hospital of Anhui Medical University}%
\affil[2]{The First Affiliated Hospital of Anhui Medical University Department of Otorhinolaryngology and Head and Neck Surgery}%


\vspace{-1em}



  
  \date{June 01, 2024}


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\textbf{Characteristics and treatments of patients with significantly
elevated creatine kinase levels induced by seizures: case report and
literature review}

Kai Wang, Jinwei Yang, Wenhao Xu, Lei Wang, Yu Wang*

The First Affiliated Hospital of Anhui Medical University

Correspondence: Yu Wang

Department of Neurology, The First Affiliated Hospital of Anhui Medical
University

Jixi Road 218, Shushan District, Hefei, Anhui Province 230032,

People's Republic of China. Email yw4d@hotmail.com

\textbf{ABSTRACT}

\textbf{Background:} Motor signs accompanying seizures have been
considered to result in over-exertion of muscles and have the ability to
cause elevated levels of serum creatine kinase (CK). There were no
previous studies on the treatment of seizure-induced elevated CK. We
summarized the characteristics and treatments of six patients with
significant elevation of CK after seizure onset.

\textbf{Case report:} There were four males and two females, the age
range was 16 to 68 years. The CK levels were greater than 5,000 U/L in
five of the six patients and the highest CK level was 39,300 U/L. All
patients exhibited an estimated glomerular filtration rate (eGFR)
\textless{} 90 ml/min/1.73m\textsuperscript{2}. No patient developed
renal failure or required continuous renal replacement therapy. We
determined that serial assessment of CK, myoglobin, eGFR, and
electrolytes should be performed in patients following seizures.
Furthermore, fluid resuscitation, urine alkalization, and diuretic
agents should be administrated when CK are significantly elevated after
seizure onset.

\textbf{Conclusions:} Serial assessment of CK levels after seizures
should be performed, especially when the patient experiences electrolyte
disorders. Fluid resuscitation, urine alkalization, and diuretic agents
also should be administrated to patients when they exhibit a
significantly elevated CK or myoglobin after seizures.

\textbf{Keywords:} Creatine kinase, Seizures, HyperCKemia, Acute kidney
injury, Treatment

\textbf{Background}

Elevated serum creatine kinase (CK) could indicate muscle cell damage
due to muscle trauma, strenuous exercise, or the use of certain drugs
{[}1-3{]}. Numerous cytoplasmic components within muscle cells exit
through the damaged sarcolemma, including myoglobin and electrolytes,
which are involved in acute kidney injury (AKI) and possible cardiac
dysrhythmia {[}1, 4, 5{]}.

Motor signs associated with seizures, including tonic, clonic, and
myoclonic movements, can be considered muscle overuse {[}1, 6{]}.
Seizures can induce elevated CK levels, which might serve as a marker to
distinguish epileptic seizures from non-epileptic seizures {[}7-10{]}.
Seizures have been identified as the cause of 4.0\% of the cases of
rhabdomyolysis (RM) and 6.1\% of the exertional RM cases {[}11, 12{]}.
One study demonstrated that renal replacement therapy or in-hospital
mortality due to seizures accounted for 6.0\% of patients with CK
\textgreater{} 5,000 U/L {[}13{]}. Elevated CK levels induced by
seizures have been observed in clinical practice, but the occurrence has
not received much attention, and there are few published reports on this
topic. Given that CK levels can be elevated when seizures occur, this
could lead to severe complications. Therefore, appropriate treatment
should be provided that might improve the prognosis of patients with
seizure onset.

However, rare cases of significantly elevated CK caused by seizures were
reported in clinical practice, and there were no previous studies on the
treatment of seizures induced elevated CK. In this study, we summarized
the characteristics and treatments of six patients with significantly
elevated CK levels induced by seizures. We anticipated that the results
reported here would encourage more attention to this infrequent
complication associated with seizures.

\textbf{Case Report}

From January 2022 to January 2023, we observed six patients who
experienced significant CK elevations after seizure onset. Five patients
exhibited CK \textgreater{} 5,000 U/L within three days after admission.
As shown in Table 1 (Part I), there were four males and two females, and
the age range was 16 to 68 years. Only patient 6 was currently consuming
alcohol. Concerning the patients' disease history, three patients had
hypertension, and one patient had autoimmune encephalitis. The other
patients did not have any history of prior major disease. All patients
had no history of statin usage. The patients also did not exhibit any
significant fever, hyperventilation, tachycardia, or hyperpiesia at
admission.

The patients' seizure histories are shown in Table 2. Patient 2 had been
diagnosed with epilepsy for six months, and he had been taking sodium
valproate. Four patients had probable provoked indications before
seizures {[}14{]}, including bowel preparations, vaccination, vomiting,
or diarrhea. Based on the diagnostic criteria for seizures proposed by
the International League Against Epilepsy {[}6{]}, motor signs were
described as tonic or tonic-clonic in two patients. The seizures were
described as ``convulsions'' in the other patients, as medical history
providers could not describe ``tonic,'' ``clonic,'' or ``myoclonic''
precisely. All patients displayed impaired awareness during their
seizures, and four had recurring seizures. However, only patient 4 had a
recurrence with impaired interictal awareness. The seizure duration for
all patients was a maximum of five minutes. No epileptiform discharges
were observed on video electroencephalogram (VEEG) after admission for
any of the patients. Magnetic resonance imaging indicated that only
patient 2 exhibited a brain lesion in the left frontal lobe that was a
probable epileptic focus {[}14{]}.

We summarized the results from the laboratory tests for CK, myoglobin,
electrolytes, and the estimated glomerular filtration rate (eGFR)
because we focused on the seizure-induced elevation of CK and its
complications. The interval between the first onset to admission (IT)
ranged from one to three days. As shown in Table 1 (Part II) and Figure
1, the CK levels increased gradually starting on the first day, peaked
at three to five days, and decreased significantly at six to seven days.
The CK levels may return to normal ten days after seizures. The level of
CK was greater than 5,000 U/L in five of the six patients and the
highest CK level was 39,300 U/L in patient 2. Significantly elevated
myoglobin (4,194 \selectlanguage{greek}μ\selectlanguage{english}g/L) was observed in patient 5. However, there was no
positive correlation between the elevated CK and myoglobin. The eGFR was
calculated using an equation validated in the Chinese population
{[}15{]}. Three patients exhibited an eGFR \textless{} 90
ml/min/1.73m\textsuperscript{2} and one patient had an eGFR \textless{}
60 ml/min/1.73m\textsuperscript{2} on admission. There were several
significant electrolyte disorders in patients 4 and 6, who had
hyponatremia, hypokalemia, or hypomagnesemia.

The treatment protocols are presented in Table 3. We used conservative
measures to prevent AKI, which might be induced by muscle damage,
including fluid resuscitation, urine alkalization, and diuretic agents.
The CK levels in all patients decreased significantly during treatment
after admission, and they exhibited a higher eGFR at discharge compared
to their eGFR at admission.

\textbf{Discussion}

Seizures have the ability to increase CK levels and even increase the
rate of in-hospital mortality {[}2, 12, 13{]}. Bosch et al. proposed
that less severe RM with few symptoms and no renal failure could be
designated hyperCKemia {[}2{]}. No patient developed renal failure or
needed renal replacement therapy in the present study. Therefore, in
this study, it was appropriate to define elevated CK as hyperCKemia.

In the current study, patients did not experience any trauma, metabolic
disorders, alcohol abuse, exposure to drugs or toxins, infection or
sepsis, myocardial infarction, or other diseases associated with
hyperCKemia {[}2, 7{]}. However, significant electrolyte disorders
caused by bowel preparation, vomiting, and diarrhea were observed in
patient 4 (hyponatremia and hypomagnesemia) and patient 6 (hypokalemia
and hypomagnesemia). Among the different electrolyte disorders,
hypokalemia and hypophosphatemia are known to cause damage to myocytes
{[}1{]}, but hypophosphatemia was not observed in our cases.

Some studies indicated that a potassium level less than 2.0 mmol/L
observed in the initial evaluation could potentially cause RM {[}1,
16-18{]}. In the present study, it appeared that hypokalemia was not the
primary cause of hyperCKemia in patient 6, who exhibited a potassium
level of 2.66 mmol/L. No causal association has been established between
desmopressin acetate-induced hyponatremia and muscle injury in animal
studies {[}19{]}. In a clinical study, asymptomatic hyperCKemia was
associated with hyponatremia caused by diuretics and polydipsia, which
may have been complicated by AKI {[}20{]}. Compared to ultra-athletes
with normonatremia, exercise-associated hyponatremia is prone to develop
into exercise-associated RM {[}21{]}. Severe hyponatremia was observed
in patient 6, and we considered that hyponatremia might promote the
development of hyperCKemia. Hypomagnesemia was observed in two patients,
which may have been due to gastrointestinal losses as they had a history
of bowel preparation, vomiting, and diarrhea {[}22{]}. There was less
possibility of other causes of hypomagnesemia because these patients did
not have any history of hypomagnesemia, and their serum magnesium
gradually recovered after supplementation. Therefore, for these two
patients, hyperCKemia might have been caused synergistically by
electrolyte disorders and seizures.

Consequently, it was likely that the seizures experienced by the
patients in the present study caused the hyperCKemia. Other factors
might have been involved in the pathophysiological process associated
with muscle damage, especially the electrolyte disorders. Thus, we
recommend performing serial testing for levels of CK and electrolytes
after seizure onset.

Early and aggressive repletion of several liters of fluid to restore
renal perfusion and increase the urine flow rate is the primary
management for AKI {[}1, 2, 23{]}. We administered normal saline at
1,500 ml/day to the majority of patients with kidney function impairment
in the cases in this study. Fluid was administered at a rate of 2,500
ml/day to patient 6 due to his history of vomiting and diarrhea. Only
patient 6 had a lower eGFR (55.65 ml/min/1.73m\textsuperscript{2}).
However, patient 6 did not report any history of kidney function
impairment, such as renal disease, toxin exposure, or sepsis {[}24{]}.
Unfortunately, we could not investigate the reason for this outcome, as
patient 6 did not have a follow-up examination.

Urinary alkalization and diuretic agents were administrated to the
patients in this study. Alkaline urine might prevent lipid peroxidation,
redox-cycling, and myoglobin cast formation {[}2, 23{]}. Diuresis might
prevent the accumulation of debris in the renal tubules, increase renal
perfusion, and improve myoglobin excretion {[}1, 24{]}. Mannitol should
be avoided in anuric patients, and electrolytes should be monitored if
loop diuretics are used {[}1, 25{]}. Fortunately, no patient in this
study developed renal failure or required continuous renal replacement
therapy, probably due to the rate for renal failure was lower in
exertional RM or generalized tonic-clonic seizures {[}10, 12{]}. The
eGFR for all patients increased after treatment even though the recovery
level was less than 90 mL/min/1.73m\textsuperscript{2} at the time of
discharge. It might be necessary to conduct a follow-up examination.

\textbf{Conclusions}

Seizures have the ability to induce hyperCKemia and even cause RM.
Therefore, serial assessment of CK levels after seizures should be
performed, especially when the patient experiences electrolyte
disorders. Monitoring eGFR, electrolytes, and electrocardiography should
be performed in patients who exhibit hyperCKemia after seizures. Fluid
resuscitation, urine alkalization, and diuretic agents also should be
administrated to patients when they exhibit a significantly elevated CK
or myoglobin after seizures.

\textbf{Acknowledgments}

We wish to thank the patients for participating in this study.

\textbf{Ethics approval and consent to participate}

This study was approved by the Medical Ethics Committee of the First
Affiliated Hospital of Anhui Medical University (Hefei, China).Written
informed consent was obtained from the patient for publication of the
details of their medical case and any accompanying images.

\textbf{Data availability statement}

All data generated or analysed during this study are included in this
article. Further enquiries can be directed to the corresponding author.

\textbf{Declaration of Figures' Authenticity}

All figures submitted have been created by the authors who confirm that
the images are original with no duplication and have not been previously
published in whole or in part.

\textbf{Author Contributions}

WK and YJW conceptualized the work, collected the data, analyzed the
data and drafted the initial manuscript. WL and XWH collected the data,
analyzed the data, reviewed and revised the manuscript. WY
conceptualized and organized the work, reviewed and revised the
manuscript.

\textbf{Competing interests}

The authors declare that this article content has no competing
interests.

\textbf{Financial support}

This work was supported by Natural Science grants to Yu Wang (Grant No.
82071460) from the National Natural Science Foundation of China.

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