Balancing Efficacy and Safety: Transcranial Direct Current Stimulation as an Adjunctive Intervention for Persistent Auditory Verbal Hallucinations in a Case of Schizophrenia and Seizure Disorder with Incomplete Hippocampal Inversion

Abstract

Incomplete hippocampal inversion (IHI) is associated with epilepsy and schizophrenia, often leading to persistent auditory verbal hallucinations (AVH). This case study discusses a 23-year-old with diagnosed with schizophrenia, intellectual disability, and a seizure disorder, having AVH non-responsive to multiple antipsychotics. Magnetic resonance imaging indicated left hippocampal IHI. In view of the increased risk of seizure with clozapine, transcranial direct current stimulation (tDCS) was administered, targeting the left temporoparietal junction using cathodal stimulation and left dorsolateral prefrontal cortex using anodal stimulation. Following 20 sessions over 10 days, AVH significantly improved, with Scale for the Assessment of Positive Symptoms and Auditory Hallucination Rating Scale scores reducing by over 70%, maintaining at a 3-month follow-up. This case highlights tDCS as an effective adjunctive treatment for AVH in schizophrenia with structural brain abnormalities, emphasizing the need for further research into tDCS effects on hippocampal-temporoparietal connectivity.

INTRODUCTION

Incomplete hippocampal inversion (IHI), also known as “hippocampal malrotation,” is identified by a hippocampus that is more rounded, oriented vertically, and positioned more medially than in typical presentation [1]. IHI has been consistently linked with epilepsy, with a prevalence of up to 50% [1]. Moreover, the prevalence and severity of IHI are notably higher in individuals with schizophrenia [2]. It has been hypothesized that anomalies in hippocampal activity and its interplay with the temporoparietal junction (TPJ) may serve as a potential mechanism in the development of psychotic symptoms [3]. In individuals diagnosed with schizophrenia and persistent auditory verbal hallucinations (AVH), a decrease in connectivity between the left TPJ and the left hippocampus was observed [4]. This reduction in connectivity is inversely correlated with the severity of AVH, suggesting a role of default mode network in Schizophrenia [5]. Transcranial direct current stimulation (tDCS) has been investigated as a treatment modality for AVH in schizophrenia owing to its potential role in altering the disrupted functional connectivity in the brain [6]. We are reporting a case study of an individual with schizophrenia and a seizure disorder exhibiting IHI, whose AVH showed improvement following the application of tDCS.

CASE

Ms. R, a 23-year-old lady, presented with a history of delayed developmental milestones, mild intellectual disability disorder, and seizure disorder from the age of 9 years, with the last episode occurring at the age of 20 years, characterized by semiology indicative of complex partial seizures and currently on oxcarbazepine 600 mg/day. In the background of the above history, from the last four years, the patient experienced symptoms initially characterized by mutism, staring, perseveration, food refusal, and sleep disturbance followed by second and third-person AVH (derogatory in nature) and delusion of persecution leading to significant distress and bio-socio-occupational dysfunction. She was diagnosed with schizophrenia. A magnetic resonance imaging of the brain revealed asymmetrical dilatation of the left temporal horn with malrotation of the left hippocampus (Fig. 1) [7]. The serum autoimmune panel was negative, and cerebrospinal fluid analysis was normal. An electroencephalogram (EEG) study also did not reveal any current abnormality. The patient had no clinical response to risperidone 4 mg/day, followed by failed adequate trials of olanzapine 20 mg/day and a combination of aripiprazole 20 mg/day and quetiapine 400 mg/day. She had persisting 2nd and 3rd person AVH, with a baseline Scale for the Assessment of Positive Symptoms (SAPS) score of 22 and Auditory Hallucination Rating Scale (AHRS) score of 24. Given the failure of multiple antipsychotics and the risk of seizure with clozapine, conventional tDCS was chosen as an add-on treatment for persistent AVH. During this time, she was continued on oxcarbazepine 600 mg/day, aripiprazole 20 mg/day, and fluoxetine 60 mg/day as per her previous treatment regimen, with no further changes during the course of tDCS. She had been on these medications for the last four months. Direct current of 2 mA was administered using two 35 cm² electrodes through an indigenous device (WISER tES, NIMHANS, India) with cathode positioned over the left TPJ (the midpoint of T3-P3, 10-20 EEG system) and anode over the left dorsolateral prefrontal cortex (DLPFC) (F3). The patient underwent 20 sessions of tDCS over 10 days, receiving two sessions daily. Each session lasted 20 minutes, with an intersession interval of 20 minutes. The protocol was informed by previous literature [8] and a recent meta-analysis [6], which suggests that a higher frequency of sessions (i.e., two sessions per day) yields better outcomes. There was a significant improvement in AVH following tDCS, and SAPS and AHRS scores were six each, showing about 72% and 75% reduction. The observed improvement was found to persist during the 3-month follow-up period during which the patient was maintained on the same medications. She reported no significant adverse effects and tolerated the sessions well.

Fig. 1.

Hippocampal malrotation on the left side. Qualitative and quantitative evaluations of magnetic resonance imaging brain both suggested the presence of hippocampal malrotation. Features indicative of malrotation of the left hippocampus included a rounded appearance, a deeper or more vertically oriented collateral sulcus, displacement of the fornix, and enlargement of the temporal horn [7]. Specifically, the hippocampal diameter ratio was higher on the left side (0.87) than on the right side (0.67), indicating a more rounded shape. Moreover, the DITS height ratio and DITS angle were increased on the left side (0.39, 68°) compared to the right side (0.13, 42°), suggesting a verticalization of the collateral sulcus.

DITS, dominant inferior temporal sulcus.

DISCUSSION

In this case, we describe the effective use of conventional tDCS as a safe augmenting strategy for persistent AVH in a patient with schizophrenia and seizure disorder having structural abnormality (IHI). Moreover, the sustained short-term improvement indicates that tDCS effectively maintains positive outcomes, even in more complex clinical settings. Anatomical abnormalities such as IHI are often associated with difficult-to-treat schizophrenia. This case underscores the importance of considering individualized treatment approaches, such as tDCS, for comprehensive care in such challenging clinical scenarios. The observed improvement may be due to the tDCS effect on the connectivity between the left hippocampus and left TPJ. However, to date, no study has systematically assessed the change in functional connectivity between the hippocampus and TPJ post-tDCS. There is a need for further examination to address and understand this aspect comprehensively.