Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Mesial temporal lobe epilepsy is the most prevalent form of epilepsy and among the most resistant to medical treatment. Hippocampal sclerosis is a frequent pathological substrate, but other lesions in mesial temporal structures give rise to the same electroclinical syndrome. Although the etiology of hippocampal sclerosis and the natural history of mesial temporal lobe epilepsy are inadequately understood, referral to a comprehensive epilepsy center is important when seizures persist after a trial of first-line medications and interfere with daily living. Patients with mesial temporal lobe epilepsy often are excellent candidates for surgical treatment, with 70% to 90% becoming free of disabling seizures after treatment. Best results with respect to quality of life are obtained when surgical therapy is soon after failure of medications.
• Mesial temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is a common form of epilepsy.
• Mesial temporal lobe epilepsy with hippocampal sclerosis often is progressive with worsening seizures, cognitive function, and depression.
• When medications fail to fully control seizures, resective surgery can be highly effective.
Hippocampal sclerosis was first identified during postmortem examination of the brains of patients with chronic epilepsy in 1825 by Bouchet and Cazauvieilh, but it was thought to be an effect rather than a cause of epileptic seizures (10). By the late 19th century, John Hughlings Jackson associated clinical ictal manifestations that we now characterize as focal seizures with impaired awareness (complex partial seizures) as related to structural lesions in the mesial temporal lobe, and suggested a causal relationship (46; 47). After the introduction of the EEG, these ictal behaviors were demonstrated to be correlated with electrographic abnormality in the mesial temporal lobe (48; 48). Evidence for a causal role of hippocampal sclerosis and for the existence of a syndrome came initially from the work of Murray Falconer, who performed en bloc anterior temporal lobe resections for medication resistant temporal lobe seizures (27). As a result of careful pathological evaluation of the resected specimens, mesial temporal sclerosis was shown to be the most common substrate of this condition, and its removal resulted in a good surgical outcome (28). A workshop was convened by the International League Against Epilepsy to determine if mesial temporal lobe epilepsy with hippocampal sclerosis is a syndrome or a disease, and it was concluded that it was neither and probably represents a number of different syndromes (97).
A characteristic clinical picture of mesial temporal lobe epilepsy with hippocampal sclerosis has been described (19; 31; 96; 99; 100; 20).
The first habitual seizures usually occur in late childhood or early adolescence. The first recognized ictal event might be a bilateral tonic-clonic seizure or a focal seizure with impaired awareness or interaction. Temporal lobe seizures are usually preceded by an aura. Classically, the most common aura is some type of visceral experience such as nausea, butterflies, or rising epigastric sensation (31). This may be accompanied by fear, but fear may exist alone, and this is another common aura. Other less common auras include olfactory and gustatory hallucinations, alteration of visual perceptions (micropsia, macropsia), and distortions of memory (déjà vu, jamais vu). Some auras have no counterpart in common human experience and, therefore, cannot be described. Auras can occur in isolation (focal seizures without impaired awareness, previously known as simple partial seizures), as well as in association with seizures with impairment, and patients may recall occasional auras years before they experienced the first habitual focal seizure with impairment. The focal seizure with impairment commonly begins with a motionless stare and oroalimentary automatisms (eg, lip smacking, chewing, or swallowing), during which the patient is usually, but not always, unresponsive. Gestural automatisms as well as reactive automatisms also are common ictally, postictally, or both during and after the seizure. A number of lateralizing features can occur (59; 100; 20). When dystonic posturing occurs, it is contralateral to the side of seizure onset, whereas unilateral automatisms are ipsilateral (often in combination with contralateral tonic or dystonic posturing). Head deviation early in the seizure is usually ipsilateral to the side of seizure onset, but abnormally forced head turning late in the seizure (version) is contralateral and often a prelude to bilateral tonic-clonic activity. Seizures due to mesial temporal lobe epilepsy without hippocampal sclerosis caused by parahippocampal and inferior temporal lobe structural abnormality may manifest with earlier and bilateral motor signs, which are more typically found with extratemporal lobe epilepsy (75).
Postictal dysphasia reflects seizure origin in the language dominant hemisphere and is frequently associated with a prolonged postictal state. These lateralizing findings may be less reliable in patients with bilateral independent temporal spikes (87). Patients are amnesic for the seizure and often for part of the postictal period, even though they may make semi-appropriate responses to the environment during these times. The aura is usually remembered. Seizures rarely secondarily generalize when patients are treated with antiseizure medication, and some patients never experience bilateral tonic-clonic seizures.
Seizures that are initially controlled with antiseizure medication can reappear after several years and then become medication resistant (07; 06). At this point they can occur as often as many times a week, but usually only several times a month. Precipitating factors include stress, sleep deprivation, and, in women, hormonal changes associated with the menstrual cycle.
Neurologic examination is usually normal with the exception of memory deficits, which are material-specific for the side of seizure onset, and possibly also social cognitive dysfunction (82; 09). Memory disturbances can become worse with frequent seizures and may improve when seizures are controlled. Evidence that mesial temporal lobe epilepsy with hippocampal sclerosis is associated with a higher incidence of behavioral disturbances, including depression and psychosis, than other forms of epilepsy remains uncertain (21; 52).
This 29-year-old, right-handed woman had a prolonged, predominantly right-sided febrile seizure when 9 months old. Immediately following the convulsion she was noted to have weakness on the right that resolved over 12 hours. She remained well until 14 years old, when she experienced a peculiar smell, lost consciousness, and began to salivate profusely. She then had a bilateral tonic-clonic seizure, and an antiseizure medication was started. Bilateral tonic-clonic seizures were controlled, but focal seizures with impairment persisted at a frequency of 4 to 15 monthly with perimenstrual clustering. Seizures consistently began with a peculiar olfactory hallucination she could not describe. She would then lose consciousness and exhibit semipurposeful activity.
Seizures continued to be poorly controlled despite trials with a variety of antiseizure medication, alone and in combination. She was evaluated for epilepsy surgery. Her MRI had findings compatible with left hippocampal sclerosis.
Neuropsychological testing revealed normal intelligence and a profile consistent with left temporal dysfunction. During continuous scalp EEG monitoring, an active left anterior to mid temporal sharp wave focus was recorded. Four seizures were recorded. They began with her typical aura followed by loss of contact and staring. The right hand and arm developed dystonic posturing, whereas the left hand performed semi-automatic repetitive movements. Towards the end of the seizure and just prior to bilateral tonic-clonic activity, she had extreme right head deviation. The EEG during seizures revealed consistent but delayed left temporal seizure onset and evolution. Intracarotid amobarbital testing demonstrated left hemisphere speech, absent left hemisphere memory function, and intact right hemisphere memory function.
She underwent a left selective amygdalohippocampectomy. Pathology revealed typical mesial temporal sclerosis. In the 6 years since surgery, she has had no seizures. She is currently taking no antiseizure medications.
Comment. This case is an almost classic example of mesial temporal lobe epilepsy. The history and findings at evaluation contain many of the components noted in the generic description of the syndrome.
Hippocampal sclerosis is the most common pathological substrate of mesial temporal lobe epilepsy, but other structural abnormalities within the anterior-mesial temporal lobe anatomic region also may be present with mesial temporal lobe epilepsy. These abnormalities may be due to numerous types of lesions, including malformations of development such as cortical dysplasia, vascular abnormalities such as a cavernous malformation, hamartia, and encephalomalacia such as from a cerebral infection (34). A combination of hippocampal sclerosis and another abnormality has been termed "dual pathology” (67), and about a third of patients with hippocampal sclerosis have dual pathology with the second abnormality almost always ipsilateral to the hippocampal sclerosis (45). Overall, the location(s) of the structural abnormality or abnormalities impact the clinical manifestation, so they may be considered to produce subtypes of mesial temporal lobe epilepsy (51).
Hippocampal sclerosis consists of hippocampal neuronal loss in a characteristic pattern, predominantly involving the hilar region, CA1, and dentate gyrus, with relative sparing of CA2 (01). The cause of hippocampal sclerosis is unknown. There is a high incidence of complicated febrile convulsions among patients with hippocampal sclerosis (28; 31; 71), and patients without this history often have had other cerebral injuries early in life (72; 77), suggesting a causative role of these events. Uncontrolled inflammation related to seizures and due to infection, trauma, or other environmental insult has been postulated (91; 102; 92). However, specific infections, cytokines, and antibodies also are now being considered as possibilities for at least a small percentage of patients (54; 93; 66; 76). Although controversial, there is increasing evidence that the epileptogenic process, once begun, is progressive (05; 72; 89). A familial form of mesial temporal lobe epilepsy has been described, and some of these patients develop medically intractable seizures and hippocampal sclerosis (13).
Hippocampal sclerosis consists of selective neuronal cell loss in specific subfields, with particular susceptibility of somatostatin and neuropeptide Y-containing hilar neurons (16; 73). Surviving neurons can show abnormalities consisting of loss of dendritic spines, beading of dendritic processes, and reduction in the dendritic domain. Sprouting of dentate granule cell axons (mossy fibers) has been demonstrated, with terminals extending back to the proximal fields of granule cell dendrites (90), presumably producing monosynaptic recurrent excitatory circuits. Although a number of other disturbances have been described in human sclerotic hippocampus (04; 12; 17), there is no overall reduction in GABA-containing inhibitory interneurons or their terminals, and it is likely that sprouting and abnormal synaptic reorganization involve other hippocampal neuronal populations, both excitatory and inhibitory (02). Enhanced sensitivity to glutamate may also be an important part of the pathophysiology of medial temporal lobe epilepsy (11). Studies in experimental animal models have demonstrated the appearance of abnormal NMDA receptor-mediated excitation, whereas both animal and human studies suggest enhanced inhibition, at least in the interictal state. These changes could predispose surviving hippocampal neurons to abnormal hypersynchronous discharges that develop in small clusters and coalesce to produce propagation to other limbic and nonlimbic structures, producing the manifestations of focal seizures (18; 95).
Although one hippocampus is predominantly involved in most patients, there is usually evidence of contralateral hippocampal epileptiform disturbances as well as both functional and structural extrahippocampal abnormalities (57). The epileptogenic region must extend beyond one mesial temporal area because occasionally patients continue to have their habitual auras following otherwise successful anterior temporal lobe resection. The full extent of the epileptogenic region is not known; however, it is likely to include the thalamus, the posterior cingulate, and precuneus (56; 68). Resting-state (interictal) functional MRI on a group-level has identified functional connectivity abnormalities between hippocampi in unilateral mesial temporal lobe epilepsy and within regions of the frontal and parietal lobes (80; 36; 81; 37). Complementing this, group-level, extratemporal white matter network abnormalities have been identified in bilateral frontal and parietal lobes (84; 69). Overall, advanced structural and functional imaging investigations have further supported the understanding of mesial temporal lobe epilepsy as a condition that extends across a network of brain regions with multiple hubs between the abnormal connections (14; Jin et al 2015).
Focal seizures are the most common seizure type, and 40% of epileptic patients report focal seizures with impairment (33). Not all focal seizures with impairment, however, are of mesial temporal lobe origin. Approximately 40% of these seizures originate elsewhere (20). In 1 study, half of patients seen in an epilepsy outpatient clinic had a diagnosis of temporal lobe epilepsy, and half of these had evidence of hippocampal sclerosis on MRI (86). Of patients whose epileptogenic region is sufficiently well localized to 1 temporal lobe to warrant temporal resection, 60% to 70% have hippocampal sclerosis (01). The others have small alien tissue lesions such as hamartomas or glial tumors, vascular and congenital malformations, and nonspecific findings.
Mesial temporal lobe epilepsy is associated with a high incidence of complicated febrile convulsions and specific cerebral injuries, such as infection and trauma, usually before 5 years of age (72; Mathern et al 1998). Birth trauma does not appear to be an important risk factor.
Focal seizures with impairment of consciousness can originate from many brain areas. Furthermore, not all mesial temporal onset seizures are due to hippocampal sclerosis. No definitive characteristics distinguish focal seizures reflecting mesial temporal lobe epilepsy from focal seizures generated from neocortex or due to mesial temporal lesions other than hippocampal sclerosis (79). However, mesial temporal lobe epilepsy is not likely to be the diagnosis when seizures are brief and frequent; involve early focal motor, somatosensory, visual or auditory signs and symptoms, drop attacks, or often become bilateral tonic-clonic; there are associated neurologic or cognitive impairments other than memory loss; or there are interictal epileptiform EEG findings that are extratemporal or bilaterally synchronous (19; 96; 20; 20). There are, however, exceptions. Temporal lobe seizures that become medically refractory before the age of 12 years are relatively unlikely to be due to hippocampal sclerosis (101), although mesial temporal lobe epilepsy is probably underdiagnosed in children (38). Definitive diagnosis requires pathological evidence of hippocampal sclerosis or other mesial temporal lesions, with improvement of the epileptic condition following surgical removal. In patients with the typical clinical picture, however, diagnosis can be made with a high degree of confidence by demonstration of hippocampal atrophy and increased T2-weighted or FLAIR signal on MRI (63; 61), anterior temporal ictal EEG onset, and temporal hypometabolism with interictal PET (18), all on the same side. Sensitivity for diagnosing mesial temporal lobe epilepsy may be enhanced with other PET tracers (41). Ictal SPECT also exhibits a characteristic pattern for mesial temporal lobe epilepsy (55).
Interictal EEG findings in patients with mesial temporal lobe epilepsy typically include unilateral or bilaterally-independent anterior temporal epileptiform discharges, best seen with basal (cheek, sphenoidal, earlobe, or true temporal) derivations. Regional temporal interictal slowing is seen in about half of the patients and is of lateralizing value (60). High-resolution MRI often demonstrates hippocampal atrophy with abnormal signal intensity and blurring of the hippocampal anatomy on one side (64). The same temporal lobe is hypometabolic on interictal FDG-PET (18; 35). Although interictal SPECT will often reveal an area of temporal hypoperfusion, the yield is low and not as reliable as PET hypometabolism; however, SPECT is valuable when used to demonstrate a characteristic ictal and postictal pattern (44). Proton magnetic resonance spectroscopy can demonstrate decreased N-acetylaspartate in the sclerotic mesial temporal lobe (43; 62). Neuropsychological evaluation commonly demonstrates memory dysfunction, which is material-specific to the involved hemisphere and has been related to the degree of hippocampal cell loss (78; 42). Ictal video-EEG recordings usually reveal a stereotyped ictal behavior and a characteristic ictal EEG onset consisting of rhythmic 5- to 7-Hz activity over 1 temporal lobe, either as the first electrographic change (initial focal onset) or within 30 seconds (delayed focal onset) (83). The presence of more than one stereotyped ictal behavior raises the likelihood that bilateral temporal lobe epilepsy may be present (70). Although diagnosis of mesial temporal lobe epilepsy and identification of the side of ictal onset for surgical therapy is now usually achievable in the majority of patients using noninvasive tests, when side of mesial temporal ictal onset is unclear, or there remains a possibility of neocortical ictal onset, additional long-term monitoring with intracranial electrodes is appropriate. Depth electrodes are useful for this purpose, but subdural strips or grids and foramen ovale electrodes can also be used, alone or in combination with depth electrodes (88).
All of the antiseizure medications that have demonstrated efficacy for focal-onset (partial) seizures may be considered as potentially efficacious for mesial temporal lobe epilepsy (30). Higher serum levels than those used for generalized onset seizures may be necessary, and medication should be increased until seizure freedom is achieved or unacceptable side effects occur. Prolonged trials of multiple drugs are not recommended in surgically remediable patients (20). Combinations of medications usually are ineffective when monotherapies have already failed. Because of the psychosocial consequences of disabling epilepsy in adolescence and early adulthood, patients who may have mesial temporal lobe epilepsy should be referred to epilepsy centers as soon as it is apparent that control cannot be achieved with first-line medications. These patients are excellent candidates for surgical treatment, and the evaluation can usually be performed noninvasively. When candidacy is present, an anterior temporal lobe resection can abolish disabling seizures in 70% to 90% of patients with low complication rates (20; 65; 23; 74), and seizure freedom at 18 years after surgery has been reported to be 62% (40). Gamma knife surgery, stereotactic laser or radiofrequency thermoablation, and direct brain stimulation of one of several described targets are possible alternative treatments to resective surgery, but the results of these other techniques are not established to have equivalently high success rates (03; 08; 26; 39; 53; 29; 15; 94). Vagus nerve stimulation is an alternative treatment when resective surgical therapy is not possible, but it rarely produces seizure freedom (85). Psychosocial intervention is also important in the management of many patients with mesial temporal lobe epilepsy, and it is particularly important for rehabilitation following successful surgery. The quality of life following surgical treatment depends on psychosocial factors such as family support and preexisting vocational and interpersonal skills, as well as age at surgical intervention.
The natural history of mesial temporal lobe epilepsy is not known because only patients with medically intractable seizures undergo surgical resection where the definitive pathological diagnosis can be made (06).
When seizures become refractory to medical treatment they are unlikely to remit spontaneously. If the condition continues, increasing memory problems and other comorbidities have been reported, including autonomic dysfunction (20; 58). This sequence of events suggests that mesial temporal lobe epilepsy could be a progressive epileptic disorder. There is also an elevated morbidity and mortality rate in patients with uncontrolled seizures (89). With early surgical intervention, patients with mesial temporal lobe epilepsy with hippocampal sclerosis have an excellent chance of cure and a subsequent normal life, and the surgical success likelihood is independent to the histopathologic subtype of hippocampal sclerosis (32).
Although no information is available that is specific to this syndrome and pregnancy, information is available on epilepsy and pregnancy.
John M Stern MD
Dr. Stern, Director of the Epilepsy Clinical Program at the University of California in Los Angeles, received honorariums from Eisai, Greenwich, SK Life Sciences, and UCB Pharma as an advisor and from Eisai, Greenwich, LivaNova, Neurelis, and UCB Pharma as a lecturer.See Profile
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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