Application of transcranial direct current stimulation in refractory seizures in tuberculous meningitis: a case report

Abstract

Tuberculous meningitis (TBM) is a devastating form of tuberculosis with high mortality and long-term neurological sequelae. Seizures, including refractory status epilepticus, are common complications and portend a poor prognosis. While neuromodulation techniques such as vagus nerve and deep brain stimulation have been used in refractory epilepsy, there are no prior reports of transcranial direct current stimulation (tDCS) in refractory seizures related to TBM. We report a 19-year-old woman with pulmonary tuberculosis who developed TBM with multiple central nervous system tuberculomas and refractory status epilepticus unresponsive to multiple antiseizure medications, intravenous anesthetics, and steroids. A structured course of cathodal tDCS was initiated (10 sessions, once daily for 10 days, 2 mA amplitude, 20 minutes per session, ramp-up 10 seconds, impedance 4 kΩ; cathode over electroencephalogram-localized epileptic focus, anode over contralateral supraorbital region). Following the intervention, sedation was successfully tapered, and the patient was discharged seizure-free on oral therapy. At the 1-month follow-up, she remained seizure-free and demonstrated clinical improvement, with no new neurological deficits. This case demonstrates the feasibility and potential benefit of tDCS as an adjunctive therapy for refractory seizures in TBM. While causality could not be established, this is the first report of tDCS application in TBM-related seizures. Controlled studies with objective neurophysiological endpoints are warranted.

Introduction

Tuberculous meningitis (TBM) is one of the most devastating forms of extrapulmonary tuberculosis, carrying high mortality and long-term disability. Seizure is a common feature and a cause of concern for such patients. The reported incidence of seizure in TBM varies widely, ranging from 30% to 74%, and can manifest as focal, generalized, or status epilepticus (SE) [1]. The cause of seizure is often multifactorial including meningeal irritation, cerebral edema, tuberculoma, and hydrocephalus either in isolation or in combination. SE in TBM is less frequent than the other types, occurring in 3.1% to 7.6% patients [2]. A retrospective analysis of 10 patients with TBM manifesting as SE showed that 60% suffered refractory SE, while 20% had super-refractory SE. Eight of those 10 patients required more than two antiseizure medications (ASMs) [3]. SE in TBM remains a feared complication resulting in high mortality despite the use of multiple ASMs. Neuromodulation has been increasingly recognized as an alternative therapy to refractory seizures [4]. To our knowledge, however, no prior reports describe transcranial direct current stimulation (tDCS) use in TBM-related refractory seizures. We present a patient with disseminated tuberculosis and refractory SE who improved following adjunctive tDCS.

Case Report

A 19-year-old female patients (body mass index, 19 kg/m²) presented with complaints of cough and fever for 4 weeks. She was diagnosed with pulmonary tuberculosis (gene xpert positive, rifampicin-sensitive) and started on antitubercular therapy (ATT) with isoniazid, rifampicin, pyrazinamide, and ethambutol (5 mg/kg, 10 mg/kg, 25 mg/kg, and 15 mg/kg, respectively). After 2 weeks, the patient developed headache, altered sensorium, and seizures including both generalized and focal seizures (right and left upper limbs). Initial examination revealed a Glasgow Coma Scale of E3V3M5, bilateral dilated and sluggish reactive pupils, generalized hyporeflexia, and bilateral mute plantar response. Laboratory reports revealed anemia with hemoglobin of 9.2 g/dL, with raised lymphocytes of 12,400 (92% neutrophils) and raised erythrocyte sedimentation rate (92 mm/hr). Her liver and renal function tests were within normal range. The magnetic resonance imaging of the brain revealed multiple discrete and conglomerated ring-enhancing lesions present in both the supratentorial and infratentorial regions, along with associated perilesional edema and meningeal enhancement (Figure 1). A cerebrospinal fluid study revealed a total cell count of 290 cells/dL with 90% lymphocytes, 128 mg/dL protein, and 42 mg/dL glucose (corresponding blood glucose level of 124 mg/dL). That patient had been diagnosed with disseminated tuberculosis with extrapulmonary involvement in the form of TBM with multiple central nervous system tuberculomas. She was administered ASMs (levetiracetam 500 mg twice daily and oxcarbazepine 300 mg twice daily), following which she developed skin rashes (Figure 2). Consequently, oxcarbazepine was withdrawn, and lacosamide (100 mg followed by 50 mg twice daily) was introduced. The patient continued to experience focal seizures involving both right and left upper limbs. Electroencephalogram (EEG) monitoring demonstrated recurrent ictal epileptiform discharges originating from bilateral frontal and parietal lobes (Figure 3). A combination of ASMs was tried (levetiracetam 500 mg twice daily, lacosamide 200 mg twice daily, clobazam 10 mg twice daily, perampanel 4 mg once daily), but seizures persisted. A trial of pulse methylprednisolone (500 mg intravenous infusion once daily for 5 days) was administered with no additional benefit. During intensive care unit stay, the patient also developed ATT-induced hepatitis, following which ATT was modified (streptomycin 750 mg intramuscular once daily, levofloxacin 750 mg once daily, ethambutol 800 mg once daily). Midazolam and propofol infusion were initiated and titrated to doses of 0.8 mg/kg/hr and 2 mg/kg/hr with cessation of seizures. However, seizures recurred on attempted tapering.

Figure 1. Magnetic resonance imaging of the brain showing multiple scattered circular hyperintense signal changes with central hypointensity suggestive of tuberculomas.

There is white matter perilesional edema in the fluid-attenuated inversion recovery sequence in the right frontal, right temporal, and left temporal lobes (A) and right frontal (B) and bilateral frontal lobes (C). The lesion showed pachymeningeal and leptomeningeal enhancement and multiple ring-enhancing lesions in axial T1-gadolinum contrast scans in the bilateral parieto-occipital lobes (D), conglomerated REL in the right fronto-parietal and left frontal lobes (E), and multiple conglomerated left frontal tuberculomas (F).

Figure 2. Erythematous macular skin rash due to oxcarbazepine.

Figure 3. Electroencephalogram showing multifocal spike and wave discharges in longitudinal bipolar double banana montage.

In view of RE, neuromodulation in the form of tDCS was planned. Frontal-parietal cortices were targeted with cathode stimulation starting from the right motor cortex in accordance with EEG findings. We used a constant current stimulator device, utilizing 2mA current with 10 seconds of ramp time in 20-minute daily sessions. Ten such sessions were planned over the same number of days (Table 1). During tDCS therapy, sedation was gradually tapered. By day 8 of sessions, midazolam and propofol were discontinued without recurrence of seizures; the time-aligned timeline is mentioned in Figure 4. The patient was discharged on oral ASMs and ATT. At 1 month of follow-up, she remained seizure-free and neurologically stable.

Table 1.

Transcranial direct current stimulation protocol

Stimulation parameter	Setting
Site	Cathode: electroencephalogramlocalized epileptic focus
	Anode: contralateral supraorbital region
Current amplitude	20 mA
Ramp time	10 seconds
Impedance	4 kΩ
Duration of session	20 minutes
Electrode	5 × 5 cm, rubber electrode
Frequency	Daily, 10 sessions over 10 days

Figure 4. Patient timeline with reference to seizure and treatment outcome.

(A) Intravenous anesthetic-sedation timeline and (B) multilayered time-aligned clinical timeline of the patient.

tDCS, transcranial direct current stimulation; ATT, antitubercular therapy; ASM, antiseizure medication; TB, tuberculosis.

Discussion

We present a patient of disseminated tuberculosis with TBM and tuberculoma, suffering refractory seizures, who improved substantially with several sessions of tDCS. Patients with TBM with seizures often have poor outcomes compared to those without seizures [5]. They have a two-fold increased risk of subsequent mechanical ventilation and high mortality [6]. A study comprising 478 TBM patients concluded that seizures in TBM are associated with a fourfold increased risk of death and long-term disability [7]. Thus, the importance of seizure control in such patients cannot be overemphasized. Neuromodulation therapy has emerged as an alternative therapy for resistant seizures. Three methods have been approved in refractory focal epilepsies including vagus nerve stimulation, deep brain stimulation of the anterior nucleus of thalamus, and closed-loop responsive neurostimulation [8]. tDCS is a noninvasive neuromodulation technique based on polarity in a neuronal network. Cathodal stimulation has an overall inhibitory effect on neuronal networks and is suitable for use in refractory seizures [9,10]. Cathodal tDCS is a safe and probably effective technique for seizure control in patients with drug-resistant focal epilepsy in a systematic review [8]. Despite this evidence, there are no published reports of tDCS for TBM-associated refractory seizures, and this case is the first-in-literature description. However, there are some limitations in our observation as only temporal association is demonstrated, and causality cannot be inferred. In addition, confounders included steroid therapy, ATT modification, and natural disease course, which might have contributed to seizure control. Since this is a single case, its generalizability is limited.

In conclusion, adjunctive tDCS represents a promising, low-cost, noninvasive therapy that has potential benefit for refractory seizures in TBM where invasive neuromodulation is impractical. While causality cannot be established, this report highlights its feasibility and indicates the need for systematic evaluation.