Upward eye deviation as a precursor to epileptic spasms: A case successfully treated with early corpus callosotomy without adrenocorticotropic hormone therapy

Highlights

• •Upward eye deviation may represent an early ictal sign preceding typical epileptic spasms.
• •The patient remained seizure-free for over one year following corpus callosotomy.
• •Corpus callosotomy may be a feasible option even without prior ACTH therapy.

Abstract

Infantile epileptic spasms syndrome is characterized by epileptic spasms (ES), neurodevelopmental regression, and variable electroclinical features. Early recognition and prompt treatment are crucial for improving outcomes; however, subtle ictal manifestations are often overlooked by caregivers. We describe a male infant who exhibited repeated upward eye deviation beginning at 5 months of age, preceding the onset of typical ES. Prolonged scalp video electroencephalography (EEG) monitoring captured both isolated upward eye deviation and typical ES preceded by upward eye deviation. Despite the introduction of two antiseizure medications, ES persisted. Given the absence of lateralizing findings on neuroimaging and the presence of bilaterally synchronous ictal discharges on EEG, corpus callosotomy (CC) was performed at 7 months of age without prior adrenocorticotropic hormone (ACTH) therapy, in accordance with parental preference. The patient has remained seizure free for 1 year and 3 months postoperatively, with age-appropriate neurodevelopmental scores on the Vineland Adaptive Behavior Scales, Second Edition. This case highlights the importance of identifying subtle signs, such as upward eye deviation, as potential early ictal precursors in ES. CC may represent a viable first-line treatment in selected cases.

1. Introduction

Infantile epileptic spasms syndrome (IESS) denotes a clinical condition characterized by epileptic spasms (ES) during infancy, along with a heterogeneous spectrum of interictal electroencephalographic abnormalities, including hypsarrhythmia, multifocal, or focal epileptiform discharges, and variable degrees of neurodevelopmental regression [[1], [2], [3]]. IESS is typically associated with poor outcomes due to both intractable seizures and the early-onset neurodevelopmental regression, which may precede the first clinical seizure. Although the underlying etiology is the primary determinant of prognosis, early recognition and prompt treatment initiation are also crucial for improving long-term outcomes [[4], [5], [6]]. Consequently, the timely identification of abnormal episodes by caregivers is essential to facilitate early therapeutic intervention. However, caregivers often fail to recognize ES as seizures because ictal manifestations, such as minor head nods or subtle upward eye movements, are often too subtle to be identified as pathological [3,7,8].

Adrenocorticotropic Hormone (ACTH) therapy is one of the most effective treatments for IESS. According to the evidence-based guideline by Go et al., the short-term efficacy of ACTH therapy, defined as complete cessation of spasms within two weeks, ranges from 43 % to 75 % [9]. Even when ES disappears after the first ACTH therapy, it was reported to recur in approximately 50 % of patients [9]. While a significant proportion of patients may experience relapse following initial cessation of ES with ACTH therapy, it remains a crucial and effective therapeutic option for IESS.

Meanwhile, surgical interventions such as focal resection, corpus callosotomy (CC), and multilobar disconnection have also been reported [10,11,12,13]. CC was considered in patients with generalized or bilaterally synchronous seizures on EEG, especially when no resectable lesion was identified [10]. A recent meta-analysis of 360 patients demonstrated that a prolonged duration of ES prior to surgery was associated with a 7 % increase in the likelihood of postoperative recurrence per year, suggesting that early surgical intervention may improve outcomes [12]. These meta-analyses have suggested that structural etiologies are generally associated with better outcomes following resective surgery, whereas cryptogenic or unknown etiologies may benefit from disconnective procedures such as CC [12]. These findings indicate that early surgical intervention may increase the likelihood of successfully terminating ES.

We report a case in which the patient was initially identified solely on episodes of upward eye deviation prior to the onset of typical ES, and in whom CC was performed without preceding ACTH therapy, resulting in the successful cessation of ES.

2. Case presentation

A 1-year-and-8-month-old boy was born at 39 weeks of gestation via spontaneous vaginal delivery, weighing 3380 g at birth. He had no history of perinatal complications or neurodevelopmental delays. He was brought to medical attention due to repeated episodes of bilateral upward eye deviation that began at 5 months and 23 days of age. The patient exhibited bilateral upward eye deviation lasting 1–2 s, repeated 4–5 times per episode as a series. These series occurred 3–4 times per day, prompting concern from his parents. At 5 months and 30 days, the patient underwent an initial medical evaluation, during which an interictal EEG revealed spike & wave complexes in the bilateral posterior temporal and occipital regions. Given the stereotyped semiology and recurrence pattern, these episodes were suspected to represent early manifestations of ES, and phenobarbital at 30 mg/day (4 mg/kg/day) was initiated, but these episodes persisted. At 6 months and 10 days, the patient developed new symptoms, including bilateral upper limb elevation and head nodding, occurring twice daily in clustered episodes. Further evaluation was conducted when he was admitted to our hospital at 6 months and 12 days of age. Magnetic resonance imaging (MRI) did not reveal significant abnormalities (Fig. 1A). Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed no significant lateralized metabolic differences (Fig. 1B). Prolonged scalp video-EEG monitoring revealed a normal interictal background EEG, without evidence of hypsarrhythmia, and interictal epileptic discharges characterized by spike & wave complexes synchronously originated from both hemispheres, with a predominance in the bilateral occipital and posterior temporal regions. Two distinct patterns of habitual seizures were captured. In the first pattern, isolated episodes of upward eye deviation were observed. Ictal EEG findings demonstrated triphasic slow waves with low amplitude fast activity predominantly originating from the right posterior quadrant regions (Fig. 2A). An electrodecremental response was also observed (Fig. 2A). However, electromyogram (EMG) did not exhibit features consistent with typical ES (Fig. 2A). In the second pattern, 1–2-second symmetric contractions of the axial and proximal limb muscles with head nodding, consistently preceded by upward eye deviation. Ictal EEG findings demonstrated high amplitude triphasic slow waves with low amplitude fast activity synchronously originating from both hemispheres (Fig. 2B). An electrodecremental response was also observed (Fig. 2B). EMG exhibited a rhombus-shaped pattern, which is characteristic of typical ES (Fig. 2B).

Fig. 1.

Pre and Postoperative imaging findings. Preoperative magnetic resonance imaging (MRI) at 6 months and 14 days of age (A) and Fluorodeoxyglucose-positron emission tomography (FDG-PET) at 6 months and 15 days of age (B) did not reveal any abnormal findings. Postoperative MRI at 17 months and 5 days of age (C) and FDG-PET at 17 months and 6 days of age (D) did not any abnormal findings.

Fig. 2.

Prolonged scalp electroencephalography (EEG) and Electromyogram (EMG) findings. (A) Upward eye deviation was captured at 6 months and 12 days of age. Ictal EEG findings demonstrated triphasic slow waves with low amplitude fast activity originating predominantly from the right posterior quadrant regions. Electromyogram (EMG) did not exhibit features consistent with typical epileptic spasms (ES). (B) ES was captured at 6 months and 13 days of age, consisting of 1–2 s, symmetric contractions of axial and proximal limb muscles with head nodding, consistently preceded by upward eye deviation. Ictal EEG findings demonstrated that high amplitude triphasic slow waves with low amplitude fast activity synchronously originated from both hemispheres. EMG showed as a rhombus shape, typical EMG pattern characteristic of ES.

The Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) at 6 months and 15 days revealed standard scores within the normal range: Communication 103 (58 percentile), Daily Living Skills 99 (47 percentile), Socialization 115 (84 percentile), and Motor Skills 89 (23 percentile), indicating age-appropriate development across all domains. At 6 months and 25 days, despite initiating valproic acid at 150 mg/day (20 mg/kg/day) by the pediatric neurologist, upward eye deviation and ES persisted. Following a multidisciplinary epilepsy conference at our center, pediatric neurologists and neurosurgeons presented both medical management, including ACTH therapy, and surgical intervention as treatment options. After careful deliberation, CC was chosen primarily in accordance with the parents’ preference. CC was performed at 7 months and 2 days of age without any complications. At a follow-up of 1 year and 3 months postoperatively, the patient remained seizure-free. Postoperative MRI showed no abnormal findings (Fig. 1C). Postoperative FDG-PET showed no hypometabolic regions (Fig. 1D). Postoperative scalp EEG revealed no interictal epileptiform discharges. At 1 year and 3 months postoperatively, Vineland-II assessment demonstrated age-appropriate scores: Communication 98 (45 percentile), Daily Living Skills 95 (37 percentile), Socialization 97 (42 percentile), and Motor Skills 98 (45 percentile). Genetic testing was not performed in this case.

2.1. Institutional review board approval

This study was approved by the Ethics Committee of Juntendo University (16–163). The patient’s parents provided verbal and written consent for the publication of this case report and all accompanying images.

3. Discussion

This case highlights several important clinical considerations in the management of IESS. First, it emphasizes the significance of recognizing subtle pre-ES manifestations, particularly isolated upward eye deviation, as early ictal precursors. Although these initial episodes lacked the classic features of ES, their repeated and stereotyped behavior led to early suspicion and prompt evaluation. Such subtle signs are often overlooked by caregivers, which can delay treatment and worsen outcomes. Menderes et al. reported that only 50 % of families were able to recognize subtle ES as seizures, and despite prompt physician referrals, the average delay before seeking medical attention was 9.2 days [7]. In our case, early recognition by caregivers enabled intervention before the emergence of typical ES, suggesting that attention to subtle precursor signs, such as upward eye deviation, may aid in early diagnosis. It is important to distinguish paroxysmal upward eye deviation from paroxysmal tonic upgaze (PTU), a benign condition that usually presents with preserved consciousness and normal EEG findings. PTU is characterized by sustained upward eye deviation with neck flexion, down-beating saccades on attempted downgaze, and preserved horizontal eye movements, typically without alteration in consciousness or EEG changes [14]. In contrast, the upward eye deviation observed in this case lasted only a few seconds and was accompanied by impaired awareness and increased muscle tone, followed by clusters of typical epileptic spasms. Notably, the episodes were associated with ictal EEG changes on video-EEG. These findings were more consistent with early manifestations of ES rather than PTU.

Second, this case suggests the potential efficacy of selecting CC as an initial treatment without preceding ACTH therapy. Although ACTH is considered a standard treatment for IESS, its effectiveness varies significantly depending on etiology. Daida et al. reported that the response rates to ACTH therapy were 64.0 % in the unknown-normal group, 65.0 % in the structural-acquired group, and only 30.6 % in the combined-congenital group, highlighting the importance of etiology-based treatment selection [15]. Furthermore, Thaher et al. reported that over 75 % of patients who received ACTH therapy required second-line treatments, and long-term follow-up revealed that 84 % had developmental delay and 45 % developed drug-resistant epilepsy [16]. In the present case, although no apparent abnormalities were observed on neuroimaging, CC was performed based on the presence of bilaterally synchronous ictal EEG discharges, intractable ES, and the family’s informed preference. The patient has remained seizure-free and has demonstrated age-appropriate developmental progress for more than 1 year postoperatively. This favorable course suggests the possibility of a subgroup of IESS in which early CC could be a viable treatment option. This highlights the importance of individualized treatment planning based on each patient’s clinical and electrographic features.

Although the follow-up period in this case is limited to 15 months, the sustained seizure freedom and preserved development are noteworthy. Baba et al. reported that patients without bilateral asynchronous epileptiform discharges 1 year after CC had favorable long-term seizure outcomes [10], and Umeda et al. found that most ES relapses occurred within 9 months after initial remission [17]. The clinical course in this case appears to be consistent with these findings. Continued long-term follow-up is warranted to monitor for potential ES recurrence and developmental changes.

4. Conclusion

This case suggests that upward eye deviation may serve as a precursor of ES, highlighting the importance of caregiver and clinician awareness of subtle ictal signs. There may also be a subgroup of IESS in which early CC is a viable treatment option. Further studies are warranted to clarify the long-term efficacy of ACTH and CC and to establish the optimal treatment sequence and timing for improved outcomes.

Ethical Statement

This study was approved by the Ethics Committee of Juntendo University (16–163). The patient’s parents provided verbal and written consent for the publication of this case report and all accompanying images.

CRediT authorship contribution statement

Yasushi Iimura: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Investigation, Data curation, Conceptualization. Hiroharu Suzuki: Writing – review & editing. Takumi Mitsuhashi: Writing – review & editing. Tetsuya Ueda: Writing – review & editing. Kazuki Nishioka: Writing – review & editing. Kazuki Nomura: Writing – review & editing. Shimpei Abe: Writing – review & editing. Takato Akiba: Writing – review & editing, Writing – original draft, Conceptualization. Shimpei Matsuda: Writing – review & editing, Writing – original draft, Conceptualization. Hidenori Sugano: Writing – review & editing. Akihide Kondo: Writing – review & editing.

Funding

This work was partly supported by the Ministry of Health, Labor, and Welfare Research Program on Rare and Intractable Diseases, Grant Number JPMH23FC1013 and Japan Agency for Medical Research and Development (AMED) under Grant Number JP24wm0625207.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Glossary

Adrenocorticotropic Hormone (ACTH)

A hormone used as a standard treatment for infantile epileptic spasms syndrome, which helps reduce seizures.

Corpus Callosotomy (CC)

A surgical procedure that involves disconnecting the corpus callosum, the structure connecting the two brain hemispheres, to reduce seizure spread.

Electroencephalogram (EEG)

A test that records electrical activity of the brain to detect abnormalities such as epileptic discharges.

Epileptic Spasms (ES)

Seizure type typically occurring in infancy, characterized by sudden head nodding and muscle contraction.

Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)

An imaging technique that measures brain metabolism to detect abnormalities.

Hypsarrhythmia

A chaotic and abnormal EEG pattern often associated with infantile spasms.

Infantile Epileptic Spasms Syndrome (IESS)

A severe epilepsy syndrome in infants marked by epileptic spasms and developmental regression.

Paroxysmal Tonic Upgaze (PTU)

A benign eye movement disorder characterized by upward gaze, which must be differentiated from epileptic spasms.

Vineland Adaptive Behavior Scales (Vineland-II)

A standardized assessment tool measuring social, communication, and motor skills in children.