Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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The term “developmental and epileptic encephalopathy” was recognized by the International League against Epilepsy (ILAE) in 2017 as an epilepsy syndrome diagnosis in individuals whose developmental impairment occurs directly from their presumed genetic mutation (developmental encephalopathy) as well as developmental consequences related to frequent epileptic activity (epileptic encephalopathy). A pathologic genetic variant may be identified in a significant proportion of patients with developmental and epileptic encephalopathy. When the genetic mutation is known, this term can be replaced by the gene name associated with developmental and epileptic encephalopathy (DEE) such as KCN2A-DEE. Prognosis may be etiology-dependent, though generally with drug-resistant epilepsy and significant developmental delay.
• Developmental and epileptic encephalopathy encompasses a wide range of severe epilepsy syndromes often beginning in infancy and childhood.
• Clinical presentation typically includes early onset epilepsy with developmental impairment and abnormal EEG.
• The term developmental and epileptic encephalopathy can be used in whole or in part when appropriate.
• “Developmental and epileptic encephalopathy” is used when both developmental and epileptic encephalopathy play a role in the patient’s clinical presentation.
• Genetic testing, including whole-exome sequencing, may yield diagnosis in a significant proportion of patients.
• Aggressive treatment of seizures may improve a component of epileptic encephalopathy but does not improve developmental encephalopathy.
This section defines the terminology of developmental encephalopathy, epileptic encephalopathy, and developmental and epileptic encephalopathy.
Developmental encephalopathy describes a developmental impairment or intellectual disability that is static though the degree of disability may become more evident with age (15). Genetic causes of developmental encephalopathy are many, and patients may have a higher risk of epilepsy than the general population; however, there is no epileptic activity associated with developmental regression or further slowing of development (14).
An epileptic encephalopathy was first described by Dr. WJ West in 1841 in his letter to the editor of Lancet in which he wrote of his child with epileptic spasms, hypsarrhythmia, and developmental plateauing or regression, a triad that is now known as West syndrome. The term “epileptic encephalopathy” was coined by Dr. Charlotte Dravet in her 1965 thesis to describe the notion of abundant epileptic activity contributing to neurodevelopmental impairment, in the syndrome now known as Lennox-Gastaut (08).
The 2001 ILAE classification of epilepsy syndromes included epileptic encephalopathies of infancy and childhood as electroclinical syndromes with onset in early childhood and poor prognosis in terms of seizure control and neurodevelopmental outcome (08). In the 2010 ILAE Commission on Classification and Terminology, Berg and colleagues redefined the term epileptic encephalopathy as an electroclinical syndrome in which “the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (eg, cortical malformation)” (01). The epileptiform activity can cause regression in an individual with normal development or preexisting developmental delay who then shows developmental plateauing or regression, which can worsen over time. Notably, amelioration of epileptiform activity may improve the developmental consequences of the disorder (14).
In contrast, many severe genetic disorders have developmental consequences arising directly from the effect of the genetic mutation in addition to the effect of the frequent epileptic activity on development. It may be difficult to separate whether the epileptic or developmental component is the more important contributor in a patient’s presentation (14). This combination is now defined as “developmental and epileptic encephalopathy” by the 2017 ILAE Commission for Classification and Terminology (14).
The previously used term “symptomatic generalized epilepsy” includes a heterogenous group of patients with developmental encephalopathies and epilepsy, epileptic encephalopathies, developmental and epileptic encephalopathies, generalized epilepsy, or combined generalized and focal epilepsy. The 2017 ILAE Commission for Classification and Terminology allows for a more precise classification of a patient’s epilepsy syndrome.
A genetic mutation may cause a range of phenotypes from a self-limited epilepsy without developmental impairment to a developmental and epileptic encephalopathy. When a genetic etiology is identified, developmental and epileptic encephalopathies may be referred to by their gene name together with the word encephalopathy, such as KCNQ2 encephalopathy (14).
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