Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Myoclonic-atonic epilepsy is a genetic generalized epilepsy that begins between the ages of 7 months and 6 years (peak age 2 to 4 years) in previously normal children. It starts with frequent and usually lengthy febrile and afebrile generalized tonic-clonic seizures. Myoclonic, atonic, myoclonic-atonic, and absence seizures usually follow a few weeks later. Seizures are frequent and may cause traumatic falls. Nonconvulsive status epilepticus, sometimes lasting for many hours or days, is common. Interictal EEG shows brief, generalized 2 to 4 Hz spike/polyspike-wave discharges. Ictal EEG depends on the seizure type. Myoclonic-atonic seizures manifest with discharges of irregular spike-wave or polyspike-wave complexes at a frequency of 2.5 to 3 Hz, or faster. Atonia is usually concurrent with the slow wave of a single- or polyspike-wave complex. Prognosis is uncertain because of various diagnostic criteria and treatment strategies. In general, seizures remit 2 to 4 years after onset, but some cognitive impairment may occur. Treatment is usually with a combination of valproate and small doses of lamotrigine; other antiepileptic drugs such as ethosuximide and clonazepam may be used. Carbamazepine, phenytoin, and vigabatrin are amongst the contraindicated drugs. Ketogenic diet or modified Atkins diet may be therapeutic in drug-resistant cases. In this article, the author details the clinical manifestations, etiology, EEG, differential diagnosis, prognosis, and optimal management of patients with epilepsy with myoclonic-atonic seizures, also known as Doose syndrome.
• Epilepsy with myoclonic-atonic seizures (also known as Doose syndrome) is a genetically determined generalized (idiopathic/genetic) epilepsy with onset in infancy and early childhood.
• It manifests with frequent and multiple types of seizure (generalized tonic-clonic, myoclonic-atonic, atonic, and absence seizures). Myoclonic-atonic seizures with falls are the defining symptoms.
• EEG shows frequent generalized discharges of spike/polyspike-slow wave at varying frequencies of 2.5 to 3 Hz or higher.
• Differential diagnosis is often demanding and requires exclusion of structural epilepsies and epileptic encephalopathies that may imitate epilepsy with myoclonic-atonic seizures.
• The prognosis of seizures is usually good, but cognition may be affected.
• Early onset of treatment, mainly with a combination of valproate and small doses of lamotrigine, may prevent development of cognitive disturbances. Ketogenic diet or modified Atkins diet should be considered for drug resistant cases, and it may be therapeutic. Other antiepileptic medications have also been used to treat specific seizure types as part of myoclonic-atonic epilepsy, including topiramate, ethosuximide, rufinamide, and cannabidiol.
Doose and colleagues introduced the concept of a specific clinical entity with myoclonic-atonic seizures being the core of the disorder, which he called “centrencephalic myoclonic astatic petit mal” (16; 19). This disorder has been accepted as an epileptic syndrome by the ILAE, initially under the name “myoclonic-astatic epilepsy” (12) and “epilepsy with myoclonic-atonic seizures” (04; Commission on Classification and Terminology of the International League Against Epilepsy 2014). It is also referred to as “Doose syndrome” (33), particularly the pure form of genetic nonstructural epilepsy with myoclonic-atonic seizures (52).
The ILAE Task Force considered “epilepsy with myoclonic-astatic seizures” to be an idiopathic generalized epilepsy (22), a view similar to that of Doose. Epilepsy with myoclonic-astatic seizures belongs to the epilepsies with primarily generalized seizures, including absence epilepsies, juvenile myoclonic epilepsy, and infantile and juvenile idiopathic epilepsy with generalized tonic-clonic seizures. Like these types of epilepsy, epilepsy with myoclonic-astatic seizures is genetically determined, with little nongenetic variability. Doose proposed the following features: genetic predisposition (high incidence of seizures and/or genetic EEG patterns in relatives); mostly normal development and no neurologic deficits before onset; primarily generalized myoclonic, astatic, or myoclonic-astatic seizures, short absences, and mostly generalized tonic-clonic seizures; generalized EEG patterns (spikes and waves, photosensitivity, 4 to 7 Hz rhythms); and no multifocal EEG abnormalities (but often pseudofoci) (17).
Nowadays, the problem of defining epilepsy with myoclonic-atonic seizures may reflect a lack of specific diagnostic criteria and undefined boundaries of certain epileptic syndromes. Several epilepsy syndromes manifest with myoclonic-atonic seizures, such as Dravet syndrome, Lennox-Gastaut syndrome, and atypical benign partial epilepsy of childhood. Cases of benign and severe myoclonic epilepsy in infants may have been included in epilepsy with myoclonic-atonic seizures (17; 58). However, it is generally accepted that children with myoclonic-atonic epilepsy are otherwise normal, with no discernible causes other than a strong genetic epileptic background, and these cases probably represent the genuine, genetic (idiopathic) syndrome of epilepsy with myoclonic-atonic seizures or “Doose syndrome.” This distinguishes “Doose syndrome” from structural epilepsies and epileptic encephalopathies with myoclonic and atonic seizures.
The ILAE “epilepsy diagnosis” manual considers epilepsy with myoclonic-atonic seizures as a childhood epilepsy syndrome of an epileptic encephalopathy and is described as follows:
Epilepsy with myoclonic-atonic seizures (previously known as epilepsy with myoclonic astatic seizures, or Doose syndrome) is a syndrome characterized by the presence of myoclonic-atonic seizures in an otherwise normal child who may have a history of febrile and/or afebrile seizures. There is often a family history of seizures.
Clinical context: This syndrome is characterized by seizures that have onset between 6 months and 6 years of age (peak 2 to 4 years). In two thirds of children febrile seizures and generalized convulsive seizures precede the onset of myoclonic-atonic and atonic seizures. Both sexes are affected, with a male predominance (ratio 2:1). Antecedent and birth history is unremarkable. Neurological examination and head size are normal. Development and cognition are typically normal; however, impairments may develop at or after seizure onset.
Caution: Glucose transporter disorders should be excluded.
Note: Epilepsy with myoclonic-atonic seizures is considered an 'epileptic encephalopathy'. This term denotes the concept that the epileptic activity itself might directly contribute additional cognitive and behavioral impairments over those expected from the underlying etiology alone, and that suppression of epileptic activity might minimize this additional impairment.
Myoclonic-atonic seizures are mandatory seizure types to this syndrome. Atonic and myoclonic seizures are frequent. Myoclonic-atonic status epilepticus is common.
• Febrile seizures
• Absence seizures—seen in half the patients, typically with myoclonic jerks, facial myoclonia, and atonia (not just loss of awareness).
• Atypical absence seizures
• Tonic seizures are rare; the presence of tonic seizures is linked to a higher frequency of cognitive impairment.
• Generalized convulsive seizures
• Nonconvulsive status epilepticus is common, lasting for hours to days and manifests as cognitive impairment with repetitive myoclonic (affecting face, eyelids, and limbs) and atonic seizures.
• Epileptic spasms
• Focal seizures
Pattern of inheritance.
Complex (polygenic) inheritance with variable penetrance.
A minority of cases may be explained by variants in SCN1A and SLC2A1.
Family history of seizures/epilepsy.
There is frequently a family history of febrile seizures (in 50% of cases); other seizures/epilepsy syndromes may also occur in families. Epilepsy with myoclonic-atonic seizures is seen in families with other individuals with genetic epilepsy with febrile seizures plus, suggesting common genetic etiological factors.
The background may be normal or show generalized slowing. Background biparietal theta is usually seen.
Caution: Focal slowing consistently over 1 area is not seen→consider structural brain abnormality.
Generalized spike-and-wave and polyspike-and-wave occur.
Caution: Focal discharges are not seen→consider structural brain abnormality.
Intermittent photic stimulation may trigger generalized spike-and-wave and polyspike-and-wave, and myoclonic-atonic seizures.
EEG abnormality is enhanced by sleep deprivation and by sleep. Generalized spike-and-wave often becomes fragmented with sleep deprivation or in sleep. Fragmented generalized spike-and-wave can appear focal or multifocal but usually is not consistently seen in 1 area. The morphology of the focal spike-and-wave typically appears similar to the generalized spike-and-wave.
The myoclonic component is associated with a generalized spike or polyspike. The atonic component is associated with the aftergoing high voltage slow wave.
Neuroimaging is normal.
• Atypical childhood epilepsy with centrotemporal spikes
• Lennox-Gastaut syndrome
• Dravet syndrome
• Myoclonic epilepsy in infancy
• Progressive myoclonus epilepsies
A survey from a large group of experts identified preferred diagnostic tests, electroclinical features, and investigations for myoclonic-atonic epilepsy (44). Clinically, there should be a history suggestive of myoclonic-atonic seizures, EEG with generalized discharges, normal neuroimaging, and normal development before seizure onset. Recommended work up includes EEG, MRI, amino acids, organic acids, fatty acid/acylcarnitine profile, microarray, genetic panel, lactate/pyruvate, and CSF studies.
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