Refractory epilepsy or intractable epilepsy is a group of epilepsy patients with a prolonged clinical course and a poor response to treatment with antiepileptic drugs (AEDs), i.e., three first-line drugs at “optimal” doses alone or The group of patients with seizures that have responded poorly to antiepileptic drug (AEDs) therapy, i.e., patients with seizures on the “optimal” dose of three first-line drugs alone or in combination for more than 2 years. The domestic definition is: frequent seizures at least 4 times per month, regular treatment with appropriate first-line ADEs, steady-state blood concentrations within the effective therapeutic range, no serious drug side effects; seizures uncontrolled for at least 2 years of observation, affecting daily life; no progressive central nervous system disease or occupying lesions. Refractory epilepsy accounts for approximately 20-30% of the number of people treated for epilepsy.
I. Causes of refractory epilepsy
(i) Medically refractory
1. Diagnostic errors
Misdiagnosis of non-epileptic events as epilepsy is seen especially in children. 20-25% of neurologically normal patients and 60% of children with low intelligence are identified by seizure assessment as non-epileptic events and should be differentiated on the basis of age at first presentation, key episodes in the history, and reasonable ancillary tests (e.g., video long-range EEG, polysomnography). In specific populations, children with epilepsy who are also suspected to have pseudoseizures, and children with low intelligence, early video EEG monitoring can help to establish the diagnosis and avoid excessive antiepileptic drug therapy.
2. Inappropriate choice of medication Misjudgment of the seizure type and failure to choose a first-line AED, which should be carefully considered and applied to the seizure type.
3. Inappropriate drug dose Too small a dose cannot achieve effective therapeutic blood concentrations, while too large a dose will induce aggravation of seizures. Therefore, the maximum and shortest efficacy of the drug should be judged by fully understanding the recommended dose of AEDs and the main pharmacokinetic parameters.
4. Inappropriate drug combination
There are individual differences in drug metabolism, and the combination of hepatic enzyme-induced AEDs (such as CBZ, PHT, PRM, PB) accelerates drug metabolism and fails to achieve effective blood concentrations. Apparently, newer generation antiepileptic drugs are less likely to be involved in pharmacokinetic interactions. With the exception of FBM, newer generation antiepileptic drugs hardly affect the pharmacokinetics of other antiepileptic drugs, but AEDs with hepatic enzyme-inducing effects accelerate the clearance of newer generation antiepileptic drugs (except GBP and VGB), while VPA (hepatic enzyme inhibitors) slow down the clearance of FBM and LTG. Attention should also be paid to the interaction of non-antiepileptic drugs with antiepileptic drugs and the effect on epileptic seizures. It should also be considered that the combination of AEDs with different mechanisms of action may theoretically expand the anticonvulsant spectrum of drugs.
5. Withdrawal seizure (Withdrawal seizure)
Regarding the time of drug withdrawal, the general principle is: at least 2 years without clinical seizures and no epileptiform activity on EEG; gradually reduce the drug and withdraw it until it stops for more than 3 to 5 years. In 330 patients who were seizure-free for at least 2 years and had been on monotherapy for ≥1 year, the recurrence rate and risk factors for recurrence were compared and evaluated after their continuation of monotherapy or gradual withdrawal of monotherapy. The results showed that the risk of recurrence of seizures was 2.9 times higher in those who discontinued the medication than in those who continued treatment. Twenty-nine cases (28%) in the continued monotherapy group and 113 cases (50%) in the discontinuation group had recurrent seizures (46 occurred after complete discontinuation and 67 occurred during the taper). The remission rates of seizures at 6, 12, 24, 36, and 60 months were 95%, 91%, 82%, 80%, and 68% in the former group and 88%, 74%, 57%, 51%, and 48% in the latter group, respectively.Multivariate analysis of the COX risk model showed that withdrawal, active disease duration (≥3 years), years of seizure remission (≤5 years), abnormal mental status, and partial epilepsy syndrome were all risk factors for seizure recurrence [6]. Although, EEG epileptiform activity per se does not affect the prognosis after drug discontinuation, EEG showing irregular widespread spikes and slow waves before drug discontinuation apparently has a clinically high recurrence rate (67%) and 33% in children without epileptiform discharges or with other types of epileptiform discharges after drug discontinuation.
6. Patients have poor compliance with medication or have poor lifestyle and habits.
(II) True refractory
1. Primary structural abnormalities See congenital dysplasia and certain hereditary diseases.
(1) Congenital dysplasia: (1) Restricted cortical malformations. According to the degree of maturation and differentiation of abnormal cells, they are classified as small oval neurons, small and dysplastic astrocytes, giant cell neurons, neuronal origin of balloon cells, and glial origin of balloon cells. There are also abnormal cells in the subcortical white matter, with few myelinated fibers so the gray-white matter border is not clear. The same patient has multiple overlapping pathological images. (2) Gray matter heterotopia and multiple cerebellar gyri. Gray matter heterotopias are nodular or laminar in shape and are occasionally seen in syndromes of different neuronal migration diseases. In the multi-cerebellar gyrus, cortical neurons are often unstratified or only four-stratified, occasionally more pronounced in limited cortical malformations. (iii) Microdevelopmental malformations. Submural neurons, increased neurons in cortical layers 2 and 3, ectopic soft meningeal neuroglia, persistent cortical columnar configuration, clustered distribution of neurons and/or glia within the cerebral cortex, irregular laminar structures with abnormal nerve fiber networks, hypermyelination in superficial areas of the brain, isolated ectopic neurons and perivascular glial satellites in the white matter, and diffuse presence of granule cells in the dentate gyrus may be observed. ④ One side of the megalencephalon. The most characteristic diagnostic basis is hypermyelination of the deep cerebral cortex and white matter with increased density.
(2) Genetic disorders :
Neurodevelopmental defects caused by mutations in chromosomal genes such as cerebral facial hemangiomas and tuberous sclerosis that constitute neurocutaneous syndromes. Nodular sclerosis brain lesions include subventricular giant cell astrocytoma combined with calcification, cortical nodules, etc. Note the neuroimaging distinction. Some nodules are pathologically cool like limited cortical malformations or gangliogliomas.
2. Secondary pathological factors Include a variety of acquired injuries or diseases. The main ones are.
Hippocampal sclerosis (or medial temporal lobe sclerosis, Ammon’s horn sclerosis, HS) with or without pathologic changes outside the hippocampus. Progressive hippocampal sclerosis has been reported in patients with recurrent partial secondary generalized seizures as well as in patients with status epilepticus; approximately 6500 seizures with a 50% reduction in hippocampal volume. In refractory epilepsy, 55%-64.3% have HS; in those with HS, 83% have refractory epilepsy; in those without HS, the incidence of refractory epilepsy is 49%. 58% of patients with temporal lobe epilepsy have a large number of amyloid bodies (CA) detected at the HS lesion; CA can be regarded as a marker of HS when sclerotic changes are mild and correlates with the degree of sclerosis.
Brain tumors, pathological types include: (i) mixed neuronal gliomas, such as ganglioglioma, dysplastic neuroepithelioma of embryonic origin (DNET), oligodendroglioma, pleomorphic yellow astrocytoma, atypical fibrous astrocytoma, and cortical nodules with nodular sclerosis. ②Glioma, astroglioma of various degrees of differentiation, glioblastoma, and oligodendroglioma. ③Hemangioma, osteolipoma, etc. ④Tumor and developmental malformation coexist, commonly in mixed neuronal glioma such as ganglion cell glioma or the coexistence of DNET and cortical malformation. The incidence of refractory epilepsy for each brain lobe tumor was 34.6% for temporal lobe, 17.9% for frontal lobe, 10.3% for parietal lobe, and 5.1% for occipital lobe.
Cerebrovascular diseases such as arteriovenous malformation (AVM), cavernous hemangioma, aneurysmal subarachnoid hemorrhage, cerebral hemorrhage or cerebral infarction (including in utero or perinatal stroke) and hemiplegia-hemiplegia-epilepsy (HHE) syndrome
Infectious diseases or chronic inflammatory conditions of the central nervous system.
Immune disorders such as multiple sclerosis, myasthenia gravis, or other systemic connective tissue diseases.
Metabolic diseases, such as lysosomal disease, mitochondrial encephalomyopathy.
Chronic alcoholism.
Alzheimer’s disease.
Scarring or iron deposition, calcification. Iron deposits are often seen in scarred brain gyri caused by head trauma, inflammation, ischemia, and often around hemangiomas or AVMs. Iron-containing haematoxylin, glial scars and foamy vesicles constitute the pathological picture, the latter being thought to be an astrocyte-associated structure associated with iron deposition in the neurofibrillary network.
3. Presence of multidrug resistance gene (MDR1) in the brain
The P-glycoprotein encoded by MDR1 is an energy-dependent pump that transports hydrophobic molecules from the cell to the outside, and when P-glycoprotein is overexpressed in the brain, AEDs are transported out of the cell leading to attenuation of drug effects. The expression of MDR1 and multidrug resistance-associated protein (MRP1) in the excision site and surrounding normal tissues revealed that reactive astrocytes in the tumor nodules or sclerotic hippocampus as well as in the dysplastic neurons showed dense and abundant expression of MRP1 and MDR1 immunoreactivity to a greater extent than reactive glial fibrillary acidic protein-positive astrocytes in adjacent normal tissues, suggesting that the overexpression of drug-resistant protein The overexpression of drug resistance proteins reduces the drug concentration within the interstitial matrix of epileptogenic lesions, and the patient’s drug resistance is due to insufficient accumulation of AEDs in the brain.
4. Persistence of epileptogenic factors.
III. Forecasting factors of refractory epilepsy
(i) Drug control rate of epilepsy
1. seizure type and drug control rate (sillanpaa, 1993) Nearly 100% for anhedonic seizures; 59%-98% for tonic clonic seizures (GTCS); 54% for partial motor seizures; 42% for complex partial seizures (CPS); 40%-50% for West syndrome; 20%-40% for Lennox-Gastaut syndrome; Mixed seizures 33%. If the rate of drug control of epilepsy is set at 60% as a good response to treatment with AEDs, then all the latter 5 types mentioned above are likely to develop refractory epilepsy.
The site of origin of epilepsy and the rate of drug control (Semah, 1998) is 20% for temporal lobe epilepsy (31% for temporal lobe epilepsy without HS, 10% for temporal lobe epilepsy with HS, and only 3% for temporal lobe epilepsy combined with dual pathological changes in other sites such as HS, developmental malformations of the brain or multiple lobar lesions); 33% for parietal lobe epilepsy; 35% for occipital lobe epilepsy and 37% for frontal lobe epilepsy. This shows that temporal lobe epilepsy is the most common refractory epilepsy and HS is the main determinant causing refractoriness.
3. Neuroimaging suggested causes of structural brain abnormalities with drug control rate Post-stroke epilepsy 54%; vascular malformation 50%; tumor 46%; head trauma 30%; cortical dysplasia 24%; HS 11%; overlapping lesions 3%; MRI normal 42%. Another parallel study showed that the rate of pharmacological control of epilepsy in patients with partial seizures was 42% in HS, 54% in cortical dysplasia, 55% in cortical atrophy, 57% in cortical gliosis, 60% in primary tumors, 67% in cerebral infarction, and
MRI was normal in 58%.
(B) High risk factors for refractory epilepsy
The high-risk factors for partial seizures that indicate “refractory” are: (1) acquired brain injury; (2) neurological deficits; (3) mental retardation; (4) early age of onset; (5) seizure type, or combination of multiple seizure types: West syndrome, Lennox-Gastaut syndrome, complex partial seizures, or combined tonic-clonic Semah also performed a multivariate regression analysis of prognostic factors in partial epilepsy, while Kwan suggested that some patients with epilepsy are refractory from the beginning, rather than evolving over the course of the disease, because these patients show some “refractory” clinical features early in the course of the disease. These patients show some “refractory” clinical features early in the course of the disease, such as underlying structural brain abnormalities, more than 20 seizures before treatment, and failure to respond to the first AED. Highly drug-resistant epilepsy often suggests HS or a developmental malformation of the brain, and 14% of these patients were effective after switching to the 2nd AED, and only 3% were effective with the combination of both drugs. Perhaps due to differences in the expression of blood-brain barrier drug transporters, AEDs have limited access to epileptogenic foci, making it difficult to exert the desired effect until neurotoxic concentrations are reached.
The prognosis of infantile spasms (i.e., West syndrome) and Lennox-Gastaut syndrome (LGS) has also been studied by Rantala (1999). The data showed that in infantile spasms, 23%-54% evolved into LGS; while in LGS, 20%-36% had a history of infantile spasms. The prognosis is poor in patients with both infantile spasms and LGS who have underlying brain disease, while the prognosis is better in cryptogenic infantile spasms with no cases evolving into LGS. 87% of symptomatic infantile spasms and all symptomatic LGS have congenital or genetic defects resulting in brain malformations, progressive encephalopathy, chromosomal abnormalities and different syndromes.
IV. Diagnostic and treatment strategies for refractory epilepsy
(i) Diagnostic strategies
1. seizure? Pseudoseizures? Coexistence?
2. What are the types of seizures and syndrome classification?
3. Can a clear etiology or trigger be found?
4. Drug selection, dose, blood level and side effects? What is the patient’s compliance?
(B) Treatment strategy
Exclude medically refractory factors and use available drugs more rationally.
1. 11 evaluation criteria of AEDs
Multiple mechanisms of action; ideal pharmacokinetic characteristics; small drug interactions; wide spectrum of antiepileptic effects; simple and easy blood concentration testing; good safety, no specific somatic reactions; no sedative effects; low neuropsychological effects; no potential teratogenicity; no long-term side effects; easy to use by physicians.
2. Drug application strategy
When the first AED has reached the maximum tolerated amount and the blood concentration is within the therapeutic range and the seizure can only be partially controlled, consider polypharmacy, and the addition of one drug may be more effective than the choice of the second monotherapy (selection or addition of an AED with a different mechanism of action than the first drug, small metabolic interactions, and small side effects). If the 2nd drug completely controls the seizure, slow withdrawal of the 1st drug after 6 months of complete absence of seizures may be considered and the presence or absence of seizures carefully recorded. If neither drug completely controls seizures, the diagnosis should be reassessed, consideration given to whether surgery is indicated, and whether more than 2 medications are needed.
There is evidence that CBZ may exacerbate certain generalized seizures in children, that VGB may exacerbate myoclonic seizures, that PHT, CBZ, and GBP exacerbate myoclonic epilepsy in adolescents, and, of particular note, that PHT and CBZ exacerbate certain seizure types in Lennox-Gastaut syndrome. Although the combination of VPA and TPM is considered a better combination, there are case reports of VPA predisposing to hyperammonemia and hyperammonic encephalopathy in the presence of TPM, manifested by sudden onset of impaired consciousness, focal neurological symptoms and signs, and increased seizure frequency. The possible mechanisms for the non-dose dependent effects of encephalopathy are (i) decreased glutamine synthesis and increased renal ammonia production; (ii) inhibition of aminomethylphosphate synthase; and (iii) decreased utilization of carnitine, so hepatic ammonia metabolism is slowed. This complication is usually reversed within days or weeks after discontinuation of the drug.
In conclusion, monotherapy should be preferred for new-onset epilepsy, and skilled application of drugs with different mechanisms may provide better results in refractory epilepsy when complete control is often not obtained with monotherapy.
Note: gabapentin (GBP), valproic acid (VPA), lamotrigine (LTG), tiagabine (TGB), carbamazepine (CBZ), phenytoin (PHT), felbamate (FBM), topiramate (TPM), aminoglutethimide (VGB), phenobarbital (PB)