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Table of Contents    
BRIEF REPORT
Year : 2021  |  Volume : 69  |  Issue : 6  |  Page : 1781-1784

Effect of Low-Dose Naltrexone on Egyptian Children with Intractable Epilepsy: A Case Series Study


1 Department of Neurology, Cairo University, Giza, Egypt
2 Department of Clinical Neurophysiology, Cairo University, Giza, Egypt

Date of Submission20-Feb-2021
Date of Decision05-May-2021
Date of Acceptance25-Jul-2021
Date of Web Publication23-Dec-2021

Correspondence Address:
Dr. Nesma Mounir
Department of Neurology and Clinical Neurophysiology, Cairo University, Kasr Al-Aini Hospital, Al-Manyal Street, Garden City, Cairo 11562
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.333523

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 » Abstract 


Epilepsy is a chronic neurological disorder affecting 50 million patients worldwide, in need of continuous treatment, while 30% of them are refractory to treatment. Despite multiple antiepileptic drugs are available for the treatment of epilepsy, still refractory epilepsy especially in children represents a social burden in developing countries. Low-dose naltrexone (LDN) has been proposed as an immune modulator in multiple diseases and proved benefit especially in diseases with immune dysregulation. The purpose of this study is to demonstrate the effect of LDN in the treatment of children with intractable epilepsy and discuss its potential role in epileptogenesis process.


Keywords: Children, intractable epilepsy, low-dose naltrexone, treatment
Key Message: Low-dose naltrexone (LDN) was prescribed in children with interactable epilepsy and showed marked improvement based on its mechanism of action as immune modulator. This opens the scope of considering LDN as possible therapeutic in patients with interactable epilepsy.


How to cite this article:
Abokrysha NT, Kishk NA, Nawito AM, Mounir N. Effect of Low-Dose Naltrexone on Egyptian Children with Intractable Epilepsy: A Case Series Study. Neurol India 2021;69:1781-4

How to cite this URL:
Abokrysha NT, Kishk NA, Nawito AM, Mounir N. Effect of Low-Dose Naltrexone on Egyptian Children with Intractable Epilepsy: A Case Series Study. Neurol India [serial online] 2021 [cited 2022 Jan 18];69:1781-4. Available from: https://www.neurologyindia.com/text.asp?2021/69/6/1781/333523




Naltrexone is an opioid antagonist with high affinity to μ-opioid receptors. It acts on different pharmacological targets according to the Hormetic principle,[1] that a given pharmacological drug exerts different effects qualitatively in relation to its quantity. Based on this principle, low-dose naltrexone (LDN) ranging from 1 to 5 mg/day was observed to exert a different mechanism of action from high-dose naltrexone. It has been proved beneficial in many diseases, particularly in states of chronic inflammation and immune dysregulation, as in Crohn's disease,[2] multiple sclerosis,[3] chronic pain as in fibromyalgia, chronic low back pain, diabetic neuropathy, and malignant pain.[4] Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures. Evidence supports the role of neuroinflammation and immune modulation in the process of epileptogenesis.[5] The main objective of this study is to demonstrate the effect of LDN on children with intractable epilepsy. The study proposal was revised and approved by the ethical committee of the Neurology Department, Cairo University. The aim and nature of the study were explained to each patient before inclusion in the study. Informed oral consent was obtained from parents or guardian of the children before enrollment.

Cases

Clinical data discussed in detail in [Table 1].
Figure 1: Interictal EEG of case one before starting LDN showing bilateral epileptiform discharge with accentuation over the right parieto-central region

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Figure 2: Another trace of Case 1 showing the same findings

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Figure 3: MRI brain (FLAIR) shows right post central parietal neuroglial cyst

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Figure 4: Interictal EEG 3 months after LDN shows no epileptiform discharge, excessive fast activities are due to the effect of low dose benzodiazepine

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Table 1: Clinical data of cases

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 » Discussion Top


Up to our knowledge, this is the first study to suggest LDN as a treatment for epilepsy. Despite low certainty evidence derived from this case series, adding LDN to the treatment of intractable epileptic patients was noticed to show marked improvement even in symptomatic epilepsy. This improvement was not only on the clinical basis, but also noticed in follow-up electroencephalogram (EEG). Previous studies demonstrated the effect of ultra-low dose naltrexone (100 fg/kg–10 ng/kg), which could significantly potentiate the anticonvulsant effect of morphine at doses 0.5–3 mg/kg,[6] yet the scientific data about using LDN in the treatment of epilepsy are scanty. The standard dose of naltrexone is 50–150 mg/day has been used as an opioid antagonist. It follows the standard dose-effect curve, while LDN ranging from 1–5 mg/day has shown a different mechanism of action as it has multiple dose-dependent pharmacological targets with different effects. It specifically binds to toll-like receptors 4 (TLR4), which are a family of innate system receptors, acting as TLR-4 antagonist leading to down streaming of signaling of two important pathways, myeloid differentiation primary response (MYD88) and Toll/IL-1R (TIR) domain-containing adapter-inducing IFN-β (TRIF).[7] Both pathways lead to inflammatory end products as interleukin-1 (IL-1) and tumor necrosis factor-alpha, interferon beta 1, and nitric oxide.[8] The effect of LDN leads to attenuation of the proinflammatory profile of the activated microglial cells having expressed TLR4. The role of toll-like receptor in neuroinflammation was observed in the glial of central nervous system, yet LDN was considered as a glial modulator.[9] Previous studies support that neuroinflammation contributes to the pathogenesis of tuberous sclerosis through increased expression of specific chemokines and cytokines particularly IL-1 in astrocytes, which could explain the noticed improvement of tuberous sclerosis patients to LDN.[10] From the above evidence, we assume that the mechanism of action of LDN through suppressing neuroinflammation and immune modulation could contribute to decreased seizure frequency in patients with intractable epilepsy.


 » Conclusion Top


Our study noticed a marked improvement in children with intractable epilepsy after adding LDN on both the clinical and electrophysiological basis. This finding could open the window to a possible way of medical treatment in cases with intractable epilepsy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Calabrese EJ. Hormetic mechanisms. Crit Rev Toxicol 2013;43:580-606.  Back to cited text no. 1
    
2.
Li Z, You Y, Griffin N, Feng J, Shan F. Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy. Int Immunopharmacol 2018;61:178-84.  Back to cited text no. 2
    
3.
Agrawal YP. Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses 2005;64:721-4.  Back to cited text no. 3
    
4.
Younger J, Parkitny L, McLain D. The use of Low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol 2014;33:451-9.  Back to cited text no. 4
    
5.
Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol 2013;244:11-21.  Back to cited text no. 5
    
6.
Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 2011;34:269-81.  Back to cited text no. 6
    
7.
Wang X, Zhang Y, Peng Y, Hutchinson MR, Rice KC, Yin H, et al. Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. Br J Pharmacol 2016;173:856-69.  Back to cited text no. 7
    
8.
Selfridge BR, Wang X, Zhang Y, Yin H, Grace PM, Watkins LR, et al. Structure-activity relationships of (+)-naltrexone-inspired Toll-like receptor 4 (TLR4) antagonists. J Med Chem 2015;58:5038-52.  Back to cited text no. 8
    
9.
Walker L, Sills GJ. Inflammation and epilepsy: The foundations for a new therapeutic approach in epilepsy? Epilepsy Curr 2012;12:8-12.  Back to cited text no. 9
    
10.
Zhang B, Zou J, Rensing NR, Yang M, Wong M. Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol Dis 2015;80:70-9.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

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