INTRODUCTION:

Lennox Gastaut syndrome (LGS) is a severe epileptic encephalopathy that appears in childhood. LGS is characterized by a slow spike wave pattern on electroencephalogram (EEG), cognitive impairment, and multiple seizure types. Seizure types typically include tonic, atonic, and atypical absence, but may include other types, such as tonic–clonic, myoclonic, or partial seizures. This mixture of seizure types, along with the need to use more than one type of medication, makes LGS one of the most complicated epilepsies to treat successfully.

There are currently 6 treatment options for LGS: valproate, felbamate, lamotrigine, topiramate, rufinamide, and clobazam, and several others that are used off label, each of which has benefits and limitations.

There are several factors that must be considered when determining which medication to use when treating patients with LGS, including efficacy, which is assessed by seizure frequency, tolerability, and the anticipated duration of treatment. It is reasonable to consider non-medical treatments like callosotomy, vagus nerve stimulation, and deep brain stimulation after failure of two to three AEDs. The different steps of this continuous therapeutic approach should depend on various factors, including patient characteristics, severity of seizures and mental handicap, and local availability of sophisticated techniques. Patients with LGS experience a range of different seizure types, the condition is notoriously difficult to treat and seizures in LGS are usually not fully controlled¹.

It is a rare epileptic encephalopathy with a peak age of onset of 3–5 years of age. Reported prevalence rates for LGS vary widely from 1–10% of all childhood epilepsies. Incidence is estimated at 1:1,000,000 inhabitants per year, and the estimated prevalence is 15/100,000. LGS represents 5-10% of epileptic patients, and 1-2% of all childhood epilepsies. The mortality rate is around 5% but is only rarely directly related to the epilepsy itself. Death is usually associated with accidents or episodes of status epilepticus².

LGS has a major impact on the Health-Related Quality of Life of the affected child as well as their caregivers. Along with physicians, nurses, and other health care providers, the primary caregiver in a family is generally the mother, with support from the father and siblings. The burden of care and the effects of the disease on the child necessitate adjustments in family life and affect family organization, communication, and relationships. Inevitably, LGS affects the physical, emotional, social, and financial health of the family. Despite the anxiety, stress, and hardship caused by this intractable condition, many parents also report that their families are stronger and closer as a result of the experience. Improvements in the treatment of LGS and support for the family with a child with LGS would likely help improve the health-related quality of life of the affected child as well as the rest of the family³.

Case Details:

A male patient of age 11 years was admitted in peadiatric department with chief complaints of low grade (100⁰F) fever 3 days back which lasted for 5 days with 2-3 episodes per day, not associated with chills and rigors and relieved with medications. Child has throat pain with difficulty in swallowing both solids and liquids which improved from last 2 days and cough associated with cold and watery nasal discharge, productive more at nights since 1 week. He also has noisy breathing which increases while breathing, facial puffiness, pedal edema and decreased frequency of urine since 3 days. Child has 4-5 episodes of seizures like activity with multiple semiology of tonic clonic movement of both upper limbs with up rolling of eyes and stiffening of body lasting for 1 minute and another episode of seizure during sleep for 20-30minutes. His developmental history includes that the child did not cry immediately after birth, cried with stimulation, Neonatal Intensive Care Unit admission on day 2 of life for 10days, he had 1^st episode of seizure at age 1 year.

His past history includes that the child had seizures with fever up to 6 years of age and later 5-6 episodes with multiple semiologies. Child was evaluated at multiple hospitals where he had gone under CT Brain thrice reported – Basal ganglia calcifications (2009), multiple sepsis of calcifications in capilloganglionic regions causing increased seizures (2013). Child was presented to NRI General Hospital thrice in status epilepticus for which he was started on levetiracetam, phenytoin but continued to have seizures. Child was done with MRI Brain in NRI General Hospital reported that – small hyper intensities focused at bilateral periventricular mainly at occipital region, hypoxic injury. Child was started on multiple AED’s. He was referred to National Institute of Mental Health And Neurosciences and diagnosed as Lennox Gastaut Syndrome and Refractory Epilepsy. Child was again readmitted in NRI General Hospital in April 2019 in status epilepticus with right hemiplagia condition for which he was mechanically ventilated but continued to have uncontrolled seizures thus started on Midazolam infusion for 2 days and IV Ceftrixone.

Child was gradually weared off and was kept on oral anti epileptics like levetiracetam, valproate sodium and clobazam. Present history of child is that he has history drooling of saliva and severe intellectual diasability His laboratory findings like Hemoglobin, Platelet count, ESR, Electrolytes, Sr. Proteins, Sr. Albumin, Sr. Globulin and T/D/I Bilirubin were slightly abnormal. Based on chief complaints of the child he was confirmed as of LRTI, Broncho Pneumonia. On day 1 child was started with IV fluids @85ml/hr, Inj.Ceftriaxone @75ml/kg/dose IV BID, Neb. Asthalin 2^nd hourly, Syp. Valproate sodium 15ml PO BID, T. Clobazam ½ tab PO BID, Nasoclear drops 2*-2* 2^nd hourly, Syp. Multidec 5ml PO BID, T. Azithromycin 500mg 1 tab PO OD for 5 days, Inj. Azithromycin @50ml IV OD and O/E child has fever 102⁰F, bouts of cough and increased shortness of breath. On day 2, Syp.Ambroxol 5ml PO BID, Syp. Potassium chloride, T. Predisolone 1 tab PO BID are added while IV fluids and Inj. Azithromycin were stopped, O/E child continued to have similar complaints. On day 3, Naso clear drops, Syp.

Potassium chloride was stopped and child has similar complaints along with positive wheeze and crepts. On day 5, child has drooling of saliva, abnormal speech frequency, shortness of breath and fever of 98.4⁰F and T. Azithromycin was stopped. On day 6, T. Glycopyrolate 0.4mg/kg/dose PO TID, T. Cefpodoxime 1 tab PO BID were added and Inj. Ceftriaxone, T. Predisolone were stopped and O/E child has decrease in cough, noisy breathing, but continued to have drooling of saliva. On day 8, T. Cefpodoxime, Ned.Asthalin were stopped and child has occasional cough with drooling of saliva, no fresh complaints. On day 9, child has been discharged with Syp. Levetiracetam 12ml PO BID, Syp. Valproate sodium 15ml PO BID, T. Clobazam 2 tabs PO BID, T. Glycopyrolate 1 tab PO BID as his usual medications.

DISCUSSION:

Lennox-Gastaut syndrome (LGS) is a catastrophic epileptic encephalopathywhich affects males slightly more often than females. For about one third of the children affected might previously have infantile spasms or underlying brain disorder but etiology can be idiopathic. These cases are referred to as cryptogenic Lennox-Gastaut syndrome. These patients tend to have worse prognosis than those of cryptogenic etiology. It was noted, however, that these potential causative factors are different in different populations, and that in developing countries LGS was mainly secondary to trauma and infections.

In a study of childhood recurrent seizures in Red Cross memorial hospital in Cape Town, South Africa, 11% suffered from meningitis or encephalitis as a precipitating factor and 55% were intellectually handicapped. Most patients who had both grand mal and myoclonic seizures suffered from LGS. In another study in Cape Town, it was found that 43% of childhood epilepsy was symptomatic. This figure is even higher than other figures found in studies conducted predominantly in tropical African countries. LGS does not usually run in families but genetic factors may play a role in the etiology. In 20–50% of cases the child has previously had infantile spasms with underlying brain disorder (also known as symptomatic West syndrome)⁴.

In a study conducted by J. J. Chevrie et al, eighty cases of childhood epileptic encephalopathy with slow spike wave (CEEWSSW) were studied. Fifty three patients had definite brain damage and infantile spasms (secondary group), the remaining 27 showed no significance (primary group). The spasms persisted in 70 % of cases in secondary group. The proportion of severely and moderately retarded children was higher in secondary group than in the remaining patients. This was explained by the earlier age at the first seizure. This study correlates with our patient’s history of peri-natal insult with severe intellectual disability and onset of 1^st seizure at the age 1 year⁵.

The main motive of this report is to present a case of LGS with lower respiratory tract infection, Broncho-pneumonia. The treatment was given to the patient simultaneously for broncho pneumonia and LGS which was discussed earlier. Child has gained weight of 9 kgs from past 7 months probably due to his anti epileptic medication and also developed drooling of saliva. The anti epileptic drugs used in this patient include valproate, levetiracetam and clobazam. His complaints of broncho pneumonia were gradually relieved after treatment. The patient was discharged with his usual anti epileptic medications.

Non pharmacological management of LGS:

1. Immune treatment:

Prednisone was added to regular antiepileptic medications for the treatment of children with intractable epilepsy with LGS. Intravenous (IV) methyl prednisolone is also considered an option when other treatments fail or while preparing patients for non-pharmacological treatments. Since the success of steroids in epileptic encephalopathy and West syndrome, these drugs have been systematically tried in refractory epilepsies, including LGS. The efficacy and tolerability of steroids have not been fully established with a poorly understood mechanism of action. However, consider the use of corticotrophin or corticosteroids as a fourth-line treatment in acute or subacute deterioration of LGS⁶.

Intravenous immunoglobulins (IVIG): The immune system has been sometimes called the “circulating brain” because of the numerous, reciprocal and continuous interactions between the immune and neurological systems. Consequently, the concept that the immune system may play an active role in epileptogenesis has been developed in experimental animal models of epilepsy. It is observed that epileptic children treated with intramuscular immunoglobulins for recurrent infections had fewer seizures. However, it is suggested that IVIG might be effective in some patients with refractory epilepsy, including LGS despite the mechanism of action of IVIG remaining hypothetical such as antiviral effect, substitutive therapy in case of concomitant immune deficiency and idiotype-anti-idiotype interaction⁷.

2. Ketogenic diet and modified atkins diet:

The concept of ‘diet’ evolved and it was clear that a high-fat diet can mimic ketosis secondary to fasting. The ketogenic diet was first developed in the 1920s, when only a few AEDs were available. With the development of different AEDs this therapeutic option was used less frequently. This treatment may have serious long-term adverse effects and is difficult to manage for prolonged periods. Modified atkins diet is a high-protein, high-fat diet in which carbohydrates are severely restricted and the side effects were found to be mild. The ketogenic and modified atkins diet are found to be more effective and well tolerated in children with lennoxgastaut syndrome^8,9.

3. Callosotomy:

Callosotomy shows a lower efficacy for tonic-clonic seizures and is still considered as a palliative treatment. It is previously recommended for epileptic drop attacks (tonic, atonic seizures). Progress in new microsurgical techniques dramatically improved the safety of callosotomy. Complete callosotomy is recommended for children with severe mental handicap while a two-third or three-fourth anterior disconnection is preferred in later onset LGS or in cryptogenic cases with moderate mental handicap. However, acute disconnection syndrome (reduction in verbal output, urinary incontinence, apathy, hemineglect) or callosal split syndrome (intermanual conflict) may occur, temporarily for a few weeks or for more prolonged periods. Worsening of focal seizures may occur postoperatively. The degree of significant improvement reported after callosotomy is highly variable, depending on the time of publication, the extent of disconnection, the selection of patients, the seizure type analyzed and so on, but this improvement can be lost over time.

4. Vagus nerve stimulation (VNS):

VNS should only be considered for patients who have been rejected for surgery or after surgery failure. There is however one exception to this general rule: VNS is now recommended before callosotomy. This recommendation is essentially based on subjective data but above all because VNS is fully reversible with fewer surgical risks compared to callosotomy. Both techniques are considered as palliative treatments and seem to have equal efficacy even if results are difficult to analyze because of the multitude of different parameters. Only a few adverse events related to surgery or to the device and stimulation, including infection, transient pain, voice alteration, and increased coughing as for other implanted patients are observed. However, special care should be taken with patients who have swallowing difficulties, as stimulation may cause dysphagia and/or excessive salivation. In LGS, VNS shows a 24%–42% global seizure reduction with rare patients becoming seizure free¹⁰.

5. Corticectomy/Lobar disconnection:

Corticectomy is a surgical procedure done to remove a specific portion of the cerebral cortex. It may be done in conjunction with another surgical procedure for seizure control in epilepsy. Some LGS cases with corticectomy may be seizure free or free from disabling seizures after resective surgery, sometimes completed by subpial transections in the eloquent cortex. However, each case needs a personalized presurgical evaluation, sometimes including invasive video-EEG to find the “driver” hemisphere and/or lobe. It is observed that parietal or frontal lobes are mainly involved in LGS¹¹.

6. Gamma-knife:

Gamma Knife stereotactic radiosurgery technology uses many small gamma rays to deliver a precise dose of radiation to a target. That is, the destruction of precisely selected areas of tissue using ionizing radiation rather than excision with a blade. Short-term follow-up reports the same amount of seizure reduction as classical callosotomy with a seizure reduction of 60%, especially of drop attacks. Gamma-knife callosotomy seems safer for the early short term, but longer follow-up periods are needed to exclude the risk of secondary brain tumor or radionecrosis¹².

7. Multiple subpial transaction (MST):

Multiple subpialtransection is a new approach for epilepsy surgery, it can be an alternative to resection/disconnection when the epileptogenic zone transcends critical areas in the brain, and removal of the cortex may result in serious deficits. MST is performed alone in functional areas or in combination with resection, cortectomy, lobe disconnection, etc. This technique is used in Landau-Kleffner and related syndromes and in focal epilepsies. In LGS, it is suggested that patients can improve dramatically after such surgery¹³.

8. Deep brain stimulation (DBS):

DBS is considered for targeting different subcortical structures such as the anterior thalamic nucleus, subthalamic nucleus, or amygdalo hippocampus in patients with refractory epilepsy and rejected for epilepsy surgery. LGS cases with most prominent diagnosis are considered well for deep brain stimulation¹⁴.

9. Neuroprotection:

Neuroprotection is successful only against some aspects of a complex cascade of multiple events during the repetition of seizures and the development of epilepsy, it might be a promising option in the treatment of refractory cases. Based on animal studies, some of the newer anti-epileptic drugs show possible neuroprotective activity in epilepsy. However, to prevent epileptogenesis, interventions need to be directed against the processes implicated in the brain changes that underlie hyperexcit-ability and not only in the prevention of neuronal death. Neuroprotection may not involve standard anti-epileptic drugs, but free radical scavengers to protect against oxidative injury, for example, or NMDA receptor antagonists. At the present time, there is no ongoing study of neuroprotection in LGS¹⁵.

10. Gene therapy:

Gene therapy represents an innovative and promising alternative for the treatment of refractory epileptic patients, especially if inaccessible to surgery. Several gene targets could be used to correct the balance between inhibitory and excitatory aspects of epilepsy with recombinant viral vectors or transduction of neuropeptide genes. Further investigations are required to demonstrate a therapeutic role of gene therapy in epilepsy and to evaluate safety concerns and possible side-effects¹⁶.

CONCLUSION:

Lennox gastaut syndrome is a rare, recurrent, childhood onsetepileptic condition characterized with multiple seizure types which include atonic, tonic and atypical absence seizures. The most common one being tonic seizures causing stiffening of body. These seizures also occur during sleep and wakefulness. In 1 out of 4 children, cause can be not found. About 2 – 5% of children with epilepsy have lennoxgastaut syndrome. Intellectual development is almost always impaired. Considerations of non pharmacological treatment can often reduce number of seizures in people with LGS. The number of seizures or doses of medications can lowered if diet therapy works well.

ACKNOWLEDGEMENT:

The author would like to thank the logistic and technical support given by Pharmacovigilance Programme of India, Indian Pharmacopoeia Commission, Ghaziabad, India and Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India for supporting the study.

CONFLICTS OF INTEREST:

The authors would declare that there are no conflicts of interest.

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Received on 02.07.2022 Modified on 04.11.2022

Research J. Pharm. and Tech 2023; 16(10):4493-4497.

DOI: 10.52711/0974-360X.2023.00732