Yoon Hang Kim, MD, MPH

Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

Published: July 2026  |  www.directintegrativecare.com

Abstract

NPRL3 (nitrogen permease regulator-like 3) encodes a subunit of the GATOR1 complex, the principal negative regulator of mTORC1 signaling. Loss-of-function mutations in NPRL3 cause constitutive mTOR pathway hyperactivation and are increasingly recognized as a significant cause of familial and sporadic focal epilepsy, often drug-resistant and associated with elevated SUDEP risk. A subset of children with NPRL3-related epilepsy also exhibit significant neuroimmune and behavioral features, prompting the use of immunomodulatory therapies such as intravenous immunoglobulin (IVIG).

This clinical review examines the rationale, evidence, and practical dosing framework for two complementary therapeutic approaches in this population: low-dose naltrexone (LDN) as a neuroinflammatory adjunct, and mTOR inhibitors (sirolimus/everolimus) as precision anti-seizure therapy. LDN acts primarily via TLR4 antagonism on microglia and compensatory upregulation of the opioid growth factor (OGF)–OGFr axis, reducing neuroinflammation through a mechanism independent of and complementary to IVIG. Preclinical evidence suggests naltrexone has anticonvulsant rather than proconvulsant properties. mTOR inhibitors directly target the pathway disinhibited by the NPRL3 mutation; while robustly effective in tuberous sclerosis complex, their efficacy in NPRL3 specifically has been inconsistent until recent data. The Carapancea et al. series (Epilepsia, July 2025)—the largest NPRL2/NPRL3-specific cohort to date—reported clinically meaningful seizure reduction (≥52%) in all four clients, with two achieving seizure freedom.

We present a weight-based pediatric LDN titration protocol, discuss timing considerations for children with nocturnal seizure phenotypes, and outline a sequencing framework for when and how to discuss mTOR inhibitor therapy with the treating epileptology team. The two approaches are mechanistically complementary (TLR4/microglial modulation vs. direct mTORC1 inhibition) with no known pharmacologic antagonism, and can coexist in the same treatment plan.

Introduction: NPRL3 and the mTORopathy Paradigm

NPRL3 is a highly conserved gene located on chromosome 16p13.3, encoding a 569-amino-acid protein that forms one of three subunits of the GATOR1 complex (alongside NPRL2 and DEPDC5). GATOR1 functions as the principal upstream inhibitor of mTORC1, blocking Rag GTPase-mediated recruitment of mTORC1 to the lysosomal membrane and preventing its activation. When NPRL3 carries a loss-of-function mutation, GATOR1 cannot perform this inhibitory function, resulting in constitutive mTORC1 hyperactivation. This drives abnormal cell growth, impaired neuronal migration, altered dendritic spine morphology, and dysregulated synaptic plasticity—the cellular hallmarks of the “mTORopathies” (Ricos et al., 2016; Li et al., 2021; Dainelli et al., 2023).

Clinically, NPRL3-related epilepsy typically presents as autosomal dominant focal epilepsy with variable foci (FFEVF), though phenotypes span nocturnal frontal lobe epilepsy, sleep-related hypermotor epilepsy, and focal epilepsy with or without focal cortical dysplasia on MRI. Penetrance is variable and often incomplete. GATOR1 mutations (DEPDC5, NPRL2, and NPRL3 collectively) are now recognized as the most significant genetic cause of familial focal epilepsy and carry a disproportionate risk of drug-resistant epilepsy (DRE) and sudden unexpected death in epilepsy (SUDEP) (Moloney et al., 2021; Baldassari et al., 2019).

This review addresses a common clinical scenario: a child with genetically confirmed NPRL3-related focal epilepsy, concurrent neuroimmune and behavioral symptoms managed with IVIG, and the question of whether LDN and/or mTOR inhibitor therapy may be rationally indicated. We synthesize the mechanistic rationale, published evidence, and practical dosing considerations for both approaches.

Low-Dose Naltrexone: Mechanism of Action

TLR4 Antagonism on Microglia

Independent of its opioid receptor activity, naltrexone inhibits Toll-like receptor 4 (TLR4) signaling on microglia and astrocytes, the central nervous system’s primary immune surveillance cells. TLR4 is a pattern recognition receptor that, when activated by damage-associated molecular patterns (DAMPs) or bacterial lipopolysaccharide (LPS), drives a neuroinflammatory cascade: release of TNF-α, IL-1β, IL-6, nitric oxide, and reactive oxygen species from activated microglia. Naltrexone acts as a non-competitive TLR4 antagonist, reducing this cascade. Importantly, the TLR4 mechanism operates independently of the opioid receptor, meaning its anti-inflammatory effect persists throughout the dosing interval rather than only during the brief 4–6 hour period of receptor blockade (Younger & Parkitny, 2014; Kučić et al., 2021).

Microglial TLR4 modulation is particularly relevant in epilepsy, where neuroinflammation is increasingly recognized as both a consequence of and contributor to seizure propagation. Activated microglia release factors that lower seizure threshold, amplify excitotoxicity, and contribute to the behavioral and cognitive comorbidities seen in children with epilepsy.

Endorphin Rebound and the OGF–OGFr Axis

At low doses (1–4.5 mg), naltrexone transiently blocks opioid receptors for 4–6 hours, typically during sleep when dosed at bedtime. The body detects this brief blockade and responds with compensatory upregulation of endogenous opioid production: beta-endorphin, met-enkephalin (also known as opioid growth factor, OGF), and their receptors (including OGFr). The resulting 18–20 hour window of enhanced OGF–OGFr interaction produces immunomodulatory, anti-proliferative, and cell-cycle regulatory effects via p16 and p21 cyclin-dependent kinase inhibitors. This is the mechanism underlying LDN’s effects in autoimmune conditions, chronic pain, and, in oncology models, suppression of the PI3K/AKT/mTOR pathway (Zagon & McLaughlin; Liu et al., 2021).

The mTOR Connection: A Hypothesis, Not a Clinical Rationale

The OGF–OGFr axis has been shown to suppress PI3K/AKT/mTOR signaling in cervical cancer cell lines and xenograft models (Liu et al., Transl Oncol 2021). Since NPRL3 disease is defined by mTOR overactivation, it is tempting to construct a unified narrative in which LDN addresses the root cause. However, this reasoning should be applied cautiously. The OGF/mTOR suppression data derive from oncology tissue-culture and xenograft models, not neurons or epilepsy. The magnitude of mTOR inhibition achieved by LDN is far less than that of direct mTOR inhibitors (sirolimus, everolimus), and even those agents have produced inconsistent seizure outcomes in NPRL3 specifically (see mTOR Inhibitor section below). The honest and defensible framing for LDN in this population is as a neuroinflammatory adjunct, with the mTOR connection noted as hypothesis-generating rather than as a clinical rationale for seizure control.

LDN in Pediatric Neuroimmune and Epilepsy Populations

PANS/PANDAS Precedent

Pediatric acute-onset neuropsychiatric syndrome (PANS) and its streptococcal-triggered subset (PANDAS) represent the closest clinical analog to the neuroimmune phenotype described in this case: sudden-onset neuropsychiatric symptoms driven by autoimmune or inflammatory processes, managed with IVIG or corticosteroids, with LDN used adjunctively to modulate the immune system and reduce neuroinflammation. Published guidance suggests pediatric doses of 0.5–2 mg/day for this population, with the recommendation to start at 0.1 mg/kg and titrate gradually (New Drug Loft, 2026; Boules, 2025).

Autism and Neurodevelopmental Populations

Naltrexone has been studied in children with autism spectrum disorder since the 1990s, initially at moderate doses (0.5–2 mg/kg/day) targeting self-injurious behaviors, hyperactivity, and stereotyped behaviors. Multiple studies demonstrated improvements in socialization, eye contact, and pain sensitivity. Modern clinical practice favors truly low doses (1.5–4.5 mg) for these indications, targeting irritability and aggression as part of a broader integrative plan. The proposed mechanism—immune modulation and microglial TLR4 antagonism—aligns with the growing evidence of immune dysregulation and chronic neuroinflammation in neurodevelopmental conditions (Elchaar et al., 2006; LDN Research Trust).

Seizure Safety: A Reassuring Profile

The seizure-safety question is the most common concern raised when LDN is considered in a child with epilepsy. The evidence is reassuring on three fronts:

First, the seizure contraindication commonly associated with “naltrexone” in clinical practice derives from Contrave (naltrexone/bupropion), where the risk and the epilepsy contraindication attach to the bupropion component, not to naltrexone. Naltrexone monotherapy does not carry a seizure-disorder contraindication in its FDA labeling.

Second, Sturgeon et al. (Epilepsia Open, 2021) demonstrated that naltrexone exhibited anticonvulsant properties in a genetic zebrafish model of Dravet syndrome (scn1Lab mutants), decreased seizure-like events in wild-type mouse neocortical slices, and reduced seizure duration and number in a pentylenetetrazole (PTZ) mouse model. The authors concluded that naltrexone is a candidate drug for seizure treatment.

Third, ultra-low-dose naltrexone has been shown to potentiate anticonvulsant effects of both low-dose morphine and cannabinoid agonists in PTZ seizure models (Honar et al., 2004; Bahremand et al., 2008), suggesting that at low doses, opioid receptor modulation favors seizure protection rather than provocation.

Clinical interpretation: LDN is not expected to worsen seizures at doses of 0.5–4.5 mg. A seizure diary should be maintained to document any changes, but the preclinical evidence consistently points toward neutral-to-favorable seizure effects.

mTOR Inhibitor Therapy: The Rapamycin/Sirolimus Question

Rationale

The mechanistic logic is direct: NPRL3 loss-of-function disables GATOR1 and causes constitutive mTORC1 hyperactivation; sirolimus (rapamycin) and everolimus are allosteric mTORC1 inhibitors; everolimus is FDA-approved for seizures in tuberous sclerosis complex (TSC) based on the EXIST-3 trial; therefore, mTOR inhibitors represent a precision-medicine approach to GATOR1-related epilepsies. In rodent models, rapamycin reduced seizure frequency and extended survival in Depdc5 conditional knockout mice (Yuskaitis et al., 2018, 2019). Both rapamycin and everolimus also have well-documented anti-neuroinflammatory properties: reducing microglial activation, promoting M1-to-M2 microglial polarization, decreasing pro-inflammatory cytokine production, and enhancing regulatory T cell function (Xie et al., 2014; Trivisano et al., 2017). This dual action—direct mTOR pathway normalization plus neuroinflammation control—makes the theoretical case particularly compelling in a child with both an mTORopathy and a neuroimmune phenotype.

NPRL3-Specific Evidence: The Published Case Experience

Despite the compelling rationale, translating mTOR inhibitor success from TSC to NPRL3 has been inconsistent. The complete published experience in NPRL3 specifically, as of July 2025, includes the following:

Positive Cases

The first case report (Cincinnati Children’s, Seizure 2019) described an infant with NPRL3-related drug-resistant epilepsy and cortical malformation who became seizure-free within three weeks of starting sirolimus. Complete seizure control was maintained for 3.5 months until treatment was discontinued due to recurrent infections, but the seizure freedom allowed time for the child to grow before epilepsy surgery. This was the first published evidence of mTOR inhibitor efficacy in NPRL3.

Negative Cases

A second infant with NPRL3-related hemimegalencephaly and super-refractory status epilepticus showed no improvement on sirolimus despite dose escalation and proceeded to hemispherotomy (Starnes et al., Seizure 2023). The Moloney et al. GATOR1 case series (Eur J Neurol, 2023) found robust seizure reduction (74–86%) in three DEPDC5 loss-of-function clients, but seizure worsening in the single NPRL3 client (splice-site variant). The authors specifically noted that the anti-seizure benefit of rapamycin was less impressive in Nprl3 knockout mice compared with Depdc5 knockouts.

The Carapancea 2025 Series: A Turning Point

Carapancea et al. (Epilepsia, published online July 12, 2025) reported the largest NPRL2/NPRL3-specific cohort to date: four clients with intractable focal seizures (baseline 15–301 seizures/month, having failed 6–14 anti-seizure medications) treated with add-on everolimus. Ages at treatment initiation ranged from 1 month to 26 years. Daily doses ranged from 3.75 to 11.5 mg with trough levels between 5 and 8.7 ng/mL. Two clients became seizure-free within two months of treatment. One of these experienced seizure recurrence when trough levels dropped below 4 ng/mL, with seizure freedom regained when levels were restored—providing a dose-response signal. The other two clients achieved clinically meaningful seizure reductions of 52% and 86%, respectively. Adverse effects included stomatitis (leading to discontinuation in one client), hyperlipidemia, and recurrent respiratory infections (resolving with dose reduction). The authors concluded that everolimus add-on may be effective in substantially reducing seizures in NPRL2- and NPRL3-related epilepsies, while emphasizing the need for strict surveillance, especially in young clients.

Synthesis: How to Think About mTOR Inhibitors for This Population

The Carapancea 2025 data shift the evidence from “hypothesis only” to “emerging positive signal with caveats.” Prior to this paper, the NPRL3 experience was essentially 2 positive and 2 negative—a coin flip. The new series, while small and uncontrolled, adds 4 clients with all 4 achieving clinically meaningful (≥52%) seizure reduction and 2 achieving seizure freedom. The dose-response relationship observed (seizure recurrence at sub-therapeutic trough levels, resolution with restoration) strengthens the causal inference.

The practical question is sequencing and risk stratification, which depends on the individual child’s seizure burden and drug-resistance status:

Sirolimus vs. Everolimus: Practical Considerations

Everolimus has been more widely studied in epilepsy (EXIST-3 trial), has demonstrated superior anti-neuroinflammatory activity compared with rapamycin in kainic acid-induced seizure models (Trivisano et al., 2017), and has a shorter half-life with more predictable pharmacokinetics. Most epilepsy centers with mTOR inhibitor experience use everolimus. However, sirolimus was the agent used in the first successful NPRL3 case report and is sometimes preferred for its lower cost. Everolimus is FDA-approved for seizures in TSC only; sirolimus is FDA-approved for transplant immunosuppression (≥13 years) and lymphangioleiomyomatosis. Any use in NPRL3-related epilepsy is off-label.

Critical safety note: mTOR inhibitor therapy is immunosuppressive. In a child already receiving IVIG for neuroimmune symptoms, the addition of an mTOR inhibitor requires careful risk–benefit discussion regarding cumulative immunosuppressive burden, particularly regarding infection risk. Monitoring includes drug trough levels (target 5–15 ng/mL for everolimus), CBC, lipid panel, hepatic and renal function, and infection surveillance. This is a decision for the treating pediatric neurology and immunology team.

Pediatric LDN Dosing Protocol

Starting Dose and Assessment

For a neurologically fragile child with active epilepsy and neuroimmune disease, a starting dose of 0.5 mg daily is appropriate and conservative. This aligns with published guidelines for PANS/PANDAS-type presentations (0.5–2 mg/day) and with weight-based protocols that initiate therapy at 0.1 mg/kg/day for children under 40 kg. The child in question has tolerated 0.5 mg, establishing a safe starting baseline.

Titration Framework

Step 1: Hold at 0.5 mg daily for a minimum of 2–4 weeks (longer than in a routine case) to establish a clean baseline for seizure frequency and behavioral symptoms. A daily seizure/behavior diary is the primary monitoring tool.

Step 2: If tolerated with no seizure increase, titrate to 1.0 mg daily. Hold for 2–4 weeks.

Step 3: Continue titrating in 0.5 mg increments every 2–4 weeks toward a modest target of 1.5–3 mg, guided by weight and clinical response. Stop at the lowest effective dose.

Practical ceiling: In a child with active epilepsy and neuroimmune disease, 1.5–3 mg represents a reasonable practical ceiling. Advance beyond 3 mg only if there is clear dose-response benefit and no adverse signal.

Timing Considerations

The standard recommendation is bedtime dosing to maximize the overnight OGF rebound. However, two factors may warrant individualized timing in NPRL3-related epilepsy: (1) vivid dreams and sleep disruption are the most common pediatric LDN side effects, and (2) NPRL3-related epilepsy frequently includes nocturnal/sleep-related seizure phenotypes (nocturnal frontal lobe epilepsy, sleep-related hypermotor epilepsy). Introducing a sleep-architecture variable in a child with nocturnal seizures may confound interpretation of nighttime events. If bedtime dosing coincides with any uptick in nocturnal seizures or sleep disruption, a switch to morning dosing is a clean, low-cost adjustment that preserves the TLR4 mechanism while shifting the OGF rebound to daytime.

Formulation and Drug Interactions

LDN must be compounded as a liquid suspension or micro-dose capsule by a reputable compounding pharmacy—not by splitting commercially available 50 mg tablets. LDN is metabolized primarily by aldo-keto reductase enzymes in the liver with minimal CYP involvement, so anti-seizure medication interactions are expected to be minimal. The one absolute contraindication is concurrent opioid agonist use. The child’s complete medication list should be reviewed against this rule at each visit.

Monitoring

A daily seizure diary (type, frequency, duration, time of day) is the primary outcome measure. Standardized behavioral rating at baseline and each dose step should track irritability, aggression, social engagement, sleep quality, and overall function. LDN titration schedule and seizure diary data should be shared with the treating epileptologist to ensure ASM adjustments are not confounded. If IVIG cycles are ongoing, document whether behavioral or seizure changes correlate with infusion timing to distinguish IVIG-response from LDN-response.

Conclusion

NPRL3-related focal epilepsy sits at the intersection of genetic mTOR pathway dysregulation and, in some children, a significant neuroimmune phenotype. This intersection creates an opportunity for mechanistically rational, complementary therapeutic strategies that address different facets of the disease biology.

Low-dose naltrexone is a well-tolerated, low-risk neuroinflammatory adjunct that acts primarily via TLR4 antagonism on microglia and compensatory OGF–OGFr axis upregulation. Its safety profile in the setting of epilepsy is reassuring: preclinical evidence consistently demonstrates anticonvulsant rather than proconvulsant properties, and the seizure-related contraindiction historically attributed to naltrexone actually belongs to bupropion in the Contrave combination. LDN is complementary to IVIG, acts on different immune arms, and can be titrated conservatively using the weight-based pediatric protocol outlined above. For the child described in this review, the current dose of 0.5 mg daily is an appropriate and conservative start; gradual titration toward 1.5–3 mg over several months, guided by seizure diary and behavioral monitoring, is the recommended approach.

mTOR inhibitor therapy (sirolimus or everolimus) represents a more aggressive but mechanistically targeted intervention that directly addresses the mTORC1 hyperactivation caused by NPRL3 loss-of-function. The evidence base for this approach in NPRL3 specifically has been strengthened substantially by the Carapancea et al. series (Epilepsia, July 2025), which demonstrated clinically meaningful seizure reduction in all four NPRL2/NPRL3 clients, with two achieving seizure freedom. This moves the evidence from anecdotal case reports with mixed results to an emerging positive signal, though still based on small, uncontrolled cohorts. mTOR inhibitor therapy should be considered in the setting of drug-resistant seizures (failed ≥2 appropriate ASMs) and should be led by the pediatric epileptology team, ideally at a center with mTOR inhibitor experience.

The two approaches—LDN and mTOR inhibitors—are not mutually exclusive. LDN targets neuroinflammation via TLR4/microglial modulation; sirolimus/everolimus targets mTORC1 directly and also reduces neuroinflammation through a separate mechanism (microglial polarization, Treg enhancement). There is no known pharmacologic antagonism between them. A sequenced approach—LDN first as a lower-risk neuroinflammatory adjunct, with mTOR inhibitor therapy discussed with epileptology if seizures remain drug-resistant—respects both the evidence hierarchy and the risk profile of each intervention.

All off-label therapies discussed in this review require informed consent, shared decision-making with the family, and co-management between the integrative medicine clinician, pediatric neurologist/epileptologist, and immunologist. The seizure diary and standardized behavioral monitoring are the essential tools for evaluating response and guiding titration decisions.

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About Dr. Kim

Yoon Hang Kim, MD, MPH is a board-certified physician in Preventive Medicine with extensive training in Integrative and Functional Medicine. He completed a residential Osher Fellowship in Integrative Medicine at the University of Arizona under Dr. Andrew Weil and holds certifications from the Institute for Functional Medicine (IFM Scholar), UCLA Medical Acupuncture, and the American Board of Integrative & Holistic Medicine. With over 20 years of clinical experience spanning academic medical centers (Miami Cancer Institute, University of Kansas Medical Center), integrative oncology programs, enterprise medical director roles, and direct-care practice, Dr. Kim brings a uniquely comprehensive perspective to complex cases at the intersection of conventional and integrative medicine.

Dr. Kim leads Direct Integrative Care (www.directintegrativecare.com), a membership-based telemedicine practice serving clients in Iowa, Illinois, Missouri, Texas, Georgia, and Florida, with an in-person clinical presence at Hill Country Integrative Medicine in Fredericksburg, TX. He is the author of multiple books on low-dose naltrexone and integrative medicine, and leads the LDN Support Group (9,000+ members), one of the largest communities dedicated to LDN education and support.