Ryu et al. BMC Neurology
(2020) 20:164
https://doi.org/10.1186/s12883-020-01742-z

CASE REPORT

Open Access

Lithium induced reversible Splenial lesion
in neuroleptic malignant syndrome like
symptoms: two case reports
Han Uk Ryu1†, Ji Yeon Chung2†, Byoung-Soo Shin3 and Hyun Goo Kang3*

Abstract
Background: Lithium is primarily used to treat bipolar disorder and is known to cause several acute neurological
complications. Reversible splenial lesions (RSLs) may be evident in antiepileptic drug toxicity or withdrawal,
infections, and other phenomena. We report two cases of RSL presenting as neuroleptic malignant syndrome-like
symptoms (NMSLS) with lithium associated neurotoxicity.
Case presentation: A 28-year-old woman was admitted after taking increased dosages of lithium for schizophrenia.
She experienced generalized tremor, rigidity, dysarthria, high fever, and tachycardia. Symptoms and brain lesion
recovered 2 weeks after discontinuation of lithium. The second case involved a 59-year-old woman who was
receiving treatment for bipolar disorder since 1988. When lithium was administered for impatience and aggressive
behavior, her mental state deteriorated and fever developed, along with generalized tremor in the extremities. Brain
magnetic resonance imaging (MRI) in both patients showed a reversible oval-shaped lesion localized to the
splenium of the corpus callosum. Both patients were defined as neuroleptic malignant syndrome-like symptoms
(NMSLS) based on the DSM-5 diagnostic criteria for neuroleptic malignant syndrome. The suspected etiology of our
cases was lithium associated neurotoxicity according to their clinical course and medical information. Our patients
fully recovered in 10–14 days after the discontinuation of lithium.
Conclusions: The patients experienced similar clinical courses and had similar radiological findings of RSL.
Manifestations in both cases were related to lithium associated neurotoxicity and this should be considered in
patients with RSL and NMSLS.
Keywords: Lithium, Neuroleptic malignant syndrome, Reversible splenial lesion

Background
Lithium is often used as a treatment of choice for patients with bipolar disorders [1]. Despite its utility in
psychiatric treatment, lithium has a narrow therapeutic
range, which may easily lead to unexpected neurological
* Correspondence: hgkang@jbnu.ac.kr
†
Han Uk Ryu and Ji Yeon Chung contributed equally to this work.
3
Department of Neurology, Research Institute of Clinical Medicine of
Jeonbuk National University – Biomedical Research Institute of Jeonbuk
National University Hospital, Deokjin-gu, Jeonju-si, Jeonbuk-do 54907, South
Korea
Full list of author information is available at the end of the article

complications such as encephalitis, convulsion, tremor,
gait ataxia, altered mental state, and neuroleptic malignant syndrome-like symptoms (NMSLS) [2]. Reversible
splenial lesion (RSL) of the corpus callosum has been reported to be a nonspecific finding associated with clinical symptoms of mild encephalitis or encephalopathy.
Several etiologies, including antiepileptic medication, alcohol abuse, hypoglycemia, infection, electrolyte imbalance, and trauma are related to the development of RSL
[3]. Although RSL has various causes, an association
with psychiatric drugs, such as lithium, has not been

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Ryu et al. BMC Neurology

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proven. We encountered two patients with RSL and
NMSLS who had taken lithium for bipolar disorder.

Case presentation
Case 1

A 28-year-old woman, who had schizophrenia since
2014, was referred to the emergency department in an
altered mental state. She had been taking lithium at
1200 mg/day for 4 years: quetiapine at 400 mg/day, clonazepam at 0.5 mg/day, and risperidone at 5 mg/day for
several months (Fig. 1). The lithium dosage was increased to 1800 mg/day, 12 days before admission, due
to her disoriented speech and aggressive behavior. The
patient was referred to our hospital after 2 days of generalized tremor, rigidity, dysarthria, high fever (38 °C), and
tachycardia (120 beats/min). Vital signs at admission included blood pressure at 130/100 mmHg, heart rate at
104 beats/min, and body temperature at 37.2 °C. Her
lithium level was 1.24 mmol/L, slightly higher than the

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upper normal limit (0.5–1.0 mmol/L). The patient was
diagnosed with NMSLS, and all medications, including
lithium, were discontinued. Brain magnetic resonance
imaging (MRI) revealed an oval-shaped, high signal intensity lesion on diffusion-weighted imaging (DWI) with
decreased apparent diffusion coefficient (ADC) values
localized to the splenium of the corpus callosum (Fig. 2a).
The patient fully recovered in 2 weeks and experienced
no relapses after further treatment with quetiapine, clonazepam, and risperidone.
Case 2

A 59-year-old woman in an altered mental state, who
was diagnosed as having bipolar disorder since 1988,
was referred to the hospital due to impatience and aggressive behavior. As treatment with lorazepam 0.5 mg/
day, haloperidol 5 mg/day, trazodone 25 mg/day, and
zotepine 50 mg/day for 2 days was insufficient in controlling her symptoms of hyperactivity with grandiosity

Fig. 1 Timeline and clinical course of the patient. The neuroleptic malignant syndrome symptoms disappeared after discontinuing lithium
treatment, by 14 and 10 days, respectively

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Fig. 2 Brain magnetic resonance imaging of the two patients (a, Case 1; b, Case 2). Diffusion weighted imaging in both demonstrated a high
signal intensity lesion in the mid portion of the splenial corpus callosum and showed low signal intensity on the apparent diffusion coefficient
map, suggestive of cytotoxic edema

and decreased need for sleep. Lithium (1200 mg/day)
was added (Fig. 1). Two days later, her mental capacity
declined. After 7 days, she developed fever (38 °C) and
generalized tremor in both the arms and legs. Her blood
pressure, heart rate, and respiration rate were 150/100
mmHg, 80 beats/min, and 20 breaths/min, respectively.
Laboratory investigations revealed mild leukocytosis but
no other specific abnormal values. Her lithium level was
0.31 mmol/L and a cerebrospinal fluid study revealed no
abnormalities. Brain MRI revealed swollen splenium of
the corpus callosum and restriction in diffusion was observed on DWI with decreased ADC values (Fig. 2b).
The patient fully recovered in 10 days after the discontinuation of lithium only.

The causal mechanisms of RSL are unclear. Although
the splenium has a relatively weak blood supply from
the posterior pericallosal artery compared with other
parts of the corpus callosum, it is unlikely that lesions
are caused by ischemic injury. A previous study showed
Table 1 DSM-V Diagnostic Criteria for NMS [4]
A. Development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication
B. Two (or more) of the following
1) Diaphoresis
2) Dysphagia
3) Tremor
4) Incontinence

Discussion and conclusions
As our present cases had a symptoms of NMS but does
not match the diagnostic criteria of NMS exactly established by DSM-5, we described our patients as NMSLS
(Table 1) [4]. The clinical presentation of RSL is nonspecific and depends on the event that may have caused the
condition, such as encephalopathy or encephalitis. In a
previous study, patients who showed RSL by brain MRI
presented with a range of symptoms including confusion, gait ataxia, and seizure [3].

6) Mutism
7) Tachycardia
8) Elevated or labile blood pressure
9) Leukocytosis
10) Laboratory evidence of muscle injury (eg, elevated creatine
phosphokinase)
C. The symptoms in criteria A and B are not due to another substance
or a neurological or other general medical condition
D. The symptoms in criteria A and B are not better accounted for by a
mental disorder.

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that restricted diffusion imaging was reversible, with no
residual lesion on follow-up with fluid attenuated inversion recovery MRI. In addition, the morphology and position of the lesion did not match those of an ischemic
lesion. Several possible mechanisms have been suggested
as the cause of RSL, one of which is arginine vasopressininduced disruption of body fluid homeostasis [5]. Others
have proposed reversible demyelination due to infectious
diseases or anti-epileptic drug toxicities. Regardless of the
etiology, splenial lesion has a tendency toward a benign
clinical course and reversible radiological findings on
MRI. Some researchers have proposed a new clinicoradiological syndrome for RSL [6].
The suspected etiology of RSL in our cases was lithium
associated neurotoxicity, which was associated with the
clinical symptoms of NMSLS. In the first case, lithium
had been taken for 4 years and the dose adjustment increased the level beyond the therapeutic range. We
speculate that lithium intoxication played an important
role in causing RSL. Despite the normal lithium level in
the second case, lithium associated neurotoxicity was
considered the cause of NMSLS because the clinical
symptoms were concurrent with lithium treatment. Lithium associated neurotoxicity does not always correlate
with serum lithium levels [7]. Interaction with other
neuroleptic drugs may have increased lithium associated
neurotoxicity and clinical symptoms. We suspect that
lithium intoxication played a crucial role in the development of RSL as abnormal symptoms and brain MRI
findings in our cases recovered after tapering lithium.
Lithium has a narrow therapeutic range, which may
easily permit neurological toxicity [7]. The target dose of
lithium is 0.6–1.2 mEq/L for maintenance and 1.0–1.5
mEq/L for manic episode control; nevertheless, neurological toxicity may be evident despite being in the
therapeutic range [7]. Several cases have been reported
that lithium with antipsychotics might be associated with
NMS [8, 9]. Those cases suggested that lithium toxicity
can occur neurotoxic effect with NMS, but none of them
showed combined lesion of RLS. To our best knowledge,
there has been only one RSL case reportedly related to
lithium intoxication; the serum lithium level was in the
upper limit of the normal range (0.94 mEq/L) and
NMSLS was not present [10]. In both of our cases, the
initial splenial lesion on MRI had disappeared upon
follow-up examination, suggesting cytotoxic edema. Reversible splenial lesion is reported to have a consistent
pattern of neuroimaging abnormalities characterized by
round lesions with hyperintense signals in fluidattenuated inversion recovery MRI and hypointense signals in T1-weighted images [11].
We experienced two cases of RSL with lithium associated neurotoxicity. Therefore, careful monitoring and
evaluation of patients taking antipsychotic drugs and

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lithium, who show toxic neuropsychiatric symptoms, is
recommended. Lithium intoxication should be considered a possible etiology of RSL with NMSLS, and this
approach may help to differential diagnosis of additional
workup It would be important that the NMS patients
systematically get an MRI to detect RSLs, especially the
patients with changes in consciousness.
Abbreviations
ADC: apparent diffusion coefficient; DWI: diffusion-weighted imaging;
MRI: magnetic resonance imaging; NMSLS: neuroleptic malignant syndromelike symptoms; RSL: reversible splenial lesion
Acknowledgements
Not applicable.
Authors’ contributions
HUR and HGK participated the design of this research. HUR, JYC and BSS
collected and analyzed the raw clinical data. HUR, BSS, and HGK carried out
computational studies and wrote the manuscript. All authors have read and
approved the final manuscript.
Funding
This research was supported by “Research Base Construction Fund Support
Program” funded by Jeonbuk National University, 2019. The funders had no
role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Availability of data and materials
All data and material supporting our findings are contained within the
manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consents were obtained from our patients for publication
of this case report and any accompanying images. Our patients were able to
converse with others at the moment we obtained the informed consents. A
copy of the written consents are available for review by the editor of this
journal.
Competing interests
HGK is a member of the editorial board (Associate Editor) of this journal. The
other authors declared no conflicts of interest with respect to the research,
authorship, funding, and/or publication of this article.
Author details
1
Department of Neurology, Jeonbuk National University Medical School,
Jeonju, South Korea. 2Department of Neurology, Chosun University School of
Medicine, Gwangju, South Korea. 3Department of Neurology, Research
Institute of Clinical Medicine of Jeonbuk National University – Biomedical
Research Institute of Jeonbuk National University Hospital, Deokjin-gu,
Jeonju-si, Jeonbuk-do 54907, South Korea.
Received: 13 January 2020 Accepted: 21 April 2020

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