Cytotoxic Lesions of the Corpus Callosum Associated with Influenza B and Levosulpiride-Induced Dystonia
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Starkey et al. [1] proposed the term “cytotoxic lesions of the corpus callosum” (CLOCCs) to more accurately describe the pathophysiological phenomenon characterized by transient lesions in the corpus callosum. CLOCCs are secondary findings on magnetic resonance imaging (MRI) that can be observed in a variety of diseases and conditions, including infections, drug reactions, vascular diseases, malignancies, metabolic disorders, trauma, and other entities [1]. In children, viral infections are the most common cause of CLOCCs, with influenza being the predominant virus [2]. However, the clinical presentations of influenza-associated CLOCCs typically include symptoms of encephalopathy or encephalitis, such as seizures, altered mental status, focal neurological deficits, among others [3,4].
Levosulpiride is widely used as a prokinetic drug for treating gastric motility disorders. It acts as a selective antagonist of dopamine D2 receptors and is known to induce extrapyramidal symptoms (EPS) [5]. Despite this, brain MRI examinations usually appear normal in patients exhibiting movement symptoms caused by levosulpiride [5,6]. To date, there have been no reported cases of CLOCCs associated with the use of levosulpiride.
Here, we report a rare case of CLOCC manifesting as cervical and oromandibular dystonia, which was triggered by levosulpiride and coincided with an influenza B infection.
A 15-year-old boy presented at the emergency room (ER) with dystonia that had developed suddenly 30 minutes earlier. Despite being able to speak, he experienced drooling, involuntary teeth clenching, and his head was turned to the left. This condition seemed to be segmental dystonia, affecting the cervical and oromandibular regions, while his alertness remained intact.
His vital signs were stable, with a blood pressure of 122/92 mm Hg, a heart rate of 88 beats per minute, a respiratory rate of 20 breaths per minute, and a body temperature of 36.8ºC. His developmental and medical history revealed no specific findings.
He had experienced a fever reaching 39.0ºC 2 days prior to his ER visit and had been previously diagnosed with influenza B infection, for which oseltamivir was prescribed. His symptoms of cough and rhinorrhea had persisted for 4 days. During this period, he had been taking acetylcysteine, levodropizine, pelargonium sidoides, and levosulpiride. A neurological examination showed no abnormalities in the cranial nerves; however, dystonia and myoclonic jerks were observed in his neck and jaw areas.
Laboratory findings indicated a hemoglobin level of 16.1 g/dL, white blood cell count of 3,050/μL, platelet count of 123,000/μL, and high-sensitivity C-reactive protein at 1.12 mg/dL. Lumbar puncture results revealed 1 white blood cell per mm³, protein at 30 mg/dL, and glucose at 59 mg/dL. MRI showed round hyperintense lesions in the splenium on fluid-attenuated inversion recovery imaging. These lesions were more clearly defined and hyperintense on diffusion-weighted imaging, with a maximum diameter of 6 mm and a significantly low apparent diffusion coefficient (Fig. 1A-C).
Brain magnetic resonance imaging of the patient. The initial images show a round hyperintense splenial lesion (arrows) on fluid-attenuated inversion recovery (A), more well-defined hyperintense with a maximum diameter of 6 mm on diffusion-weighted imaging (B), with a significantly low apparent diffusion coefficient (C). (D) One-week follow-up fluid-attenuated inversion recovery image shows complete disappearance of the lesion.
We administered lorazepam at a dosage of 0.1 mg/kg, which immediately alleviated the dystonia. Levosulpiride was discontinued due to suspected EPS. Treatment with oseltamivir for influenza B infection was continued. Immunotherapy, comprising steroids, immunoglobulin, and monoclonal antibodies, was not utilized.
No abnormalities were detected on the electroencephalography (EEG) conducted the following day after the symptoms had resolved. A follow-up MRI examination performed 1 week later revealed complete resolution of the lesion (Fig. 1D). The patient remained alert, his symptoms improved, and he was subsequently discharged.
The clinical presentations of CLOCCs can vary depending on the underlying cause, with symptoms ranging from mild, such as headache and confusion, to severe, including seizures and altered consciousness. A recent systematic review indicates that viral infections are the most common cause of CLOCCs in children, accounting for 75% of cases. Among these, the influenza virus is the predominant pathogen, responsible for 46% of cases [2]. In contrast, drugs, toxins, and vaccinations contribute to only 2% of CLOCC cases in children, with mumps vaccination accounting for half of these instances [2]. In adults, drugs or toxins represent a more significant cause of CLOCCs, comprising 27% of cases, with antiseizure medications being the most common [2]. There have been no published cases of CLOCCs associated with levosulpiride in either children or adults.
CLOCCs associated with influenza typically present with seizures, common indicators of encephalopathy or encephalitis [4]. In our patient, however, symptoms manifested as cervical and oromandibular dystonia without accompanying seizures or altered consciousness. Although we initially suspected that the EPS was induced by levosulpiride, we could not dismiss the possibility of other neurological complications from influenza B, especially considering the patient's fever 2 days before the dystonia onset. Consequently, we performed an EEG, cerebrospinal fluid (CSF) analysis, and brain MRI. All results were normal except for the CLOCC, which was evident on the MRI.
CLOCCs can be categorized into two patterns based on size and location: (1) a small, round or oval lesion isolated in the center of the splenium, and (2) a lesion in the splenium that extends into the adjacent cerebral white matter or into the anterior portion of the corpus callosum, known as the "boomerang sign" [1]. In our patient, a typical well-defined ovoid hyperintense lesion was observed, confined to the splenium without any extension beyond it.
The MRI features of callosal lesions include hypointensity on T1-weighted images and hyperintensity on T2-weighted images, along with restricted diffusion and an absence of gadolinium enhancement. These characteristics indicate the presence of cytotoxic edema rather than vasogenic edema. The suggested pathomechanism involves cytokinopathy, which leads to excitotoxicity and subsequent intracellular edema.
In many cases of CLOCC, symptoms fully resolve within a month, and the prognosis is generally favorable when isolated reversible lesions are present. However, it is important to note that not all cases are completely reversible or have a favorable outcome [3].
In our patient, the dystonia resolved immediately following the administration of lorazepam, with no subsequent recurrence. The normal CSF analysis, normal EEG, and a small, isolated CLOCC lesion indicated a favorable prognosis. In situations where a poor prognosis is expected, immunotherapy might be considered beneficial, especially given the involvement of cytokinopathy-induced cytotoxic edema in CLOCC. However, our patient did not require immunotherapy, such as steroids or immunoglobulin. The dystonia resolved quickly, no further neurological symptoms were noted, and the CLOCC lesion was no longer visible on follow-up brain MRI conducted 1 week later.
Movement disorders such as dystonia, when associated with infection-related CLOCCs, are exceedingly rare. While a few case reports have documented movement symptoms such as ataxia or tremor, these typically occur alongside encephalopathy or other neurological manifestations. For instance, one case involved a patient with CLOCC linked to cerebral venous thrombosis, who exhibited gait ataxia and weakness in the lower extremities, among other neurological symptoms [7]. Additionally, alien hand syndrome, which involves involuntary motor activity and the perception that one's limb is foreign or acting of its own accord, has been reported in cases of CLOCCs [8].
In this case, only cervical and oromandibular dystonia were observed, without any signs of encephalopathy. These symptoms were not linked to abnormalities in the corpus callosum but were instead attributed to EPS caused by levosulpiride, compounded by an influenza B infection. EPS due to levosulpiride is more commonly reported in older adults than in children, and there have been no reported cases with confirmed CLOCCs. We believe that the combination of the influenza B infection and the EPS induced by levosulpiride contributed to the development of CLOCC in this patient.
Since there are no previously reported cases of CLOCCs associated with both influenza B infection and levosulpiride-induced EPS, this case may expand our understanding of the diverse presentations of CLOCCs.
This study was approved by the Institutional Review Board of the Gachon University Gil Medical Center (GBIRB2024-039). The requirement for informed consent for this retrospective study was waived by the board.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contribution
Conceptualization: KUC and HJK. Data curation: MYL, KUC, and HJK. Methodology: MYL and KUC. Project administration: HJK. Visualization: MYL. Writing-original draft: MYL. Writing-review & editing: HJK.