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线粒体癫痫的原因: 评估、诊断和治疗(1)  

2015-10-07 01:14:22|  分类: 疾病与治疗 |  标签: |举报 |字号 订阅

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Hannah E. Steele, MBBS, MRCP; Patrick F. Chinnery, PhD, FRCP, FRCPath

Abstract

Mitochondrial disorders are frequently associated with seizures. In this review, the authors discuss the seizure patterns and distinguishing features of mitochondrial epilepsy, alongside the indications for investigating, and how to investigate epilepsy from a mitochondrial perspective. Finally, they discuss management strategies for this complex group of patients.

Introduction

Seizures are a common and highly heterogeneous feature of mitochondrial disease. They can arise at any age, may be the presenting feature of the underlying biochemical defect, and can occur in the absence of a clear family history despite the genetic etiology. Furthermore, they are frequently a secondary feature in a complex phenotype; thus, detailed semiology is often lacking,[1] although increasingly this is being addressed.[2–7] The heterogeneous patient populations used in many of the series describing seizures add a further challenge to seizure interpretation.[2,3,8–12]

Ictal activity in mitochondrial disease may result from metabolic disturbance, encephalopathy, or an acquired structural lesion such as a stroke-like episode. However, seizures may occur without these factors. Furthermore, the mechanisms are not mutually exclusive. Accordingly, epilepsy in mitochondrial disease straddles the genetic and structural/metabolic categories in the 2010 International League Against Epilepsy (ILAE) classification of the epilepsies outlined in Table 1.[13]

A large driver for the restructuring of this classification is the ongoing advance in genetic medicine and diagnostic technologies,[13] exemplified by increasing descriptions of epilepsy causing gene variations[14] and mirrored in the field of mitochondrial disease.[15] As a combined consequence of the phenotypic diversity, the increasing genetic complexity and a historical paucity of detailed seizure semiology, the clinician is faced with a considerable challenge in identifying, classifying, and treating epilepsy arising due to mitochondrial disease.

The aim of this review is therefore to provide the nonspecialist reader with:

  • An introduction to the etiology and clinical features of mitochondrial disorders

  • An overview of epilepsy in the context of both syndromic and nonsyndromic mitochondrial disease

  • A practical approach of when to consider a mitochondrial disorder in a patient with epilepsy

  • A schema to investigate epilepsy with a suspected mitochondrial basis

  • An overview of mitochondrial seizure management

Mitochondrial Disease Overview

Mitochondrial disorders are genetically determined metabolic diseases arising due to biochemical deficiency of the respiratory chain. They affect around 1 in 5,000 of the population in the United Kingdom (UK).[16]

The mitochondrial respiratory chain sits in the inner mitochondrial membrane and is responsible for the efficient generation of ATP through the process of oxidative phosphorylation (OXPHOS). The chain comprises five complexes, each with multiple subunits, which are coded for by both mitochondrial and nuclear genomes. A relevant mutation in either genome may therefore compromise respiratory chain function with resultant cellular ATP deficiency. Consequently, the clinical features of mitochondrial disorders are most evident in tissues with high-energy demands, with the central and peripheral nervous systems being particularly susceptible.

Recognition of mitochondrial phenotypes may be complex. However, there are certain features (Fig. 1) that suggest a bioenergetic deficit. Specific symptom combinations may enable a clinician to diagnose one of the canonical mitochondrial disorders such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), or MERRF (myoclonic epilepsy and ragged-red fibers). However, many individuals are oligo-symptomatic and consequently do not fulfil requirements for a syndromic diagnosis.

线粒体癫痫的原因: 评估、诊断和治疗 - 保健品与健康 - 健康之路


 

Epilepsy in Syndromic Mitochondrial Disease

Epilepsy is a major phenotypic feature of several syndromic mitochondrial disorders, including Leigh syndrome, Alpers–Huttenlocher syndrome, MELAS, and MERRF.

Leigh Syndrome

Leigh syndrome (LS) is a progressive, neurodegenerative syndrome characterized by impaired mitochondrial function (OMIM 256000). The genetic basis of LS is complex, but approximately 50% of cases arise due to mutations in SURF1, a complex IV assembly gene.[9]

A striking feature of LS is the characteristic bilateral, focal neuropathological change evident on magnetic resonance (MR) brain imaging. It is the most common manifestation of mitochondrial disease in children, and symptom onset usually occurs between 3 and 12 months. However, the diagnosis should be considered in older individuals, including adults, with suggestive clinical features.[17,18] Prognosis is poor, with death often occurring in early infancy.

Triad of Leigh syndrome:

  1. Progressive neurodegeneration

  2. Mitochondrial impairment

  3. Characteristic bilateral central nervous system (CNS) lesions

Seizures occur in at least 40% of those with LS,[7,19] though some smaller case series report a prevalence of up to twice that.[20,21] In a large natural history study of 130 patients with LS, epilepsy was the fourth most common clinical feature, after movement disorders, ocular involvement, and feeding difficulties, both at presentation and throughout the disease course.[7] Over half of individuals with epilepsy due to LS have a generalized seizure disorder, with both myoclonic and absence seizures reported.[7] This supports the findings of smaller series where myoclonic seizures are a frequent occurrence.[21,22] Focal seizures and infantile spasms are also recognized, but occur less often and may co-exist with generalized seizures.[7]

Treatment of seizures associated with LS is difficult: They are frequently refractory (31–75%) and a cause of death.[7,23] Genetic heterogeneity may contribute to seizure risk, and there is emerging evidence that the presence of seizures in LS indicates a poor prognosis.[7,23]

Key Points: Leigh syndrome

  • Triad of neurodegeneration, mitochondrial dysfunction, and characteristic symmetrical CNS imaging change

  • Generalized seizures > focal seizures

  • Mainly presents in children, but consider in adults with appropriate clinical features

Alpers–Huttenlocher Syndrome

Alpers–Huttenlocher syndrome (AHS) is a life-limiting condition arising due to recessive mutations in the nuclear gene encoding the mitochondrial polymerase gamma (OMIM 203700). It causes a classical triad of intractable seizures with intellectual decline and liver dysfunction. It has a bimodal distribution of onset, with a first peak occurring in the preschool years, and a second in the late teens/early twenties.[24]

Seizures, including status epilepticus, are the primary feature of AHS in about half of patients, but for others, nonspecific features such as failure to thrive, may predominate initially.[24] Seizure emergence heralds inexorable cognitive decline regardless of when in the disease course it occurs. The onset is often explosive, and in common with LS, multiple seizure types often co-exist. However, in contrast to LS, focal seizures and myoclonus are most frequent in AHS.[25–27] Progression to epilepsia partialis continua (EPC) and secondary generalized status epilepticus is characteristic and refractory seizures are a recognized cause of death.[24,25,28,29] There are no disease-modifying treatments available. Consequently, clinicians should anticipate the need for palliative care provision. The use of sodium valproate is contraindicated due to the occurrence of fatal hepatotoxicity.

Key points: Alpers–Huttenlocher syndrome

  • Triad of intractable seizures, intellectual decline, and liver dysfunction

  • Focal seizures and myoclonus > generalized seizures

  • Avoid sodium valproate use

MELAS Due to mt.3243A > G Mutation

The mt.3243A > G mutation in the mitochondrial DNA (mtDNA) MTTL1 gene is the most frequently identified mutation causing MELAS. Other phenotypes may also arise due to this point mutation, such as CPEO (chronic progressive external ophthalmoplegia) and MIDD (maternally inherited diabetes and deafness). Conversely, MELAS may also be caused by other mtDNA mutations,[30] and has been described in association with nuclear DNA mutations such as POLG.[31,32]

In a cohort of individuals carrying the mt.3243A > G mutation, 24% of all symptomatic individuals manifested seizures.[1] There was a clear relationship between phenotype and seizure prevalence, with 50 to 62% of those with MELAS and MELAS overlap syndromes (MELAS with either MIDD or CPEO) experiencing seizures. In comparison, seizure prevalence was 25% in those with mixed neurologic features, 17% with MIDD/CPEO overlap, and just 8% with MIDD alone.[1]

For those with mt.3243A > G MELAS, focal seizures and prolonged focal status epilepticus encompassing occipital lobe status, EPC, hemiclonic status, nonconvulsive status, and spike-wave stupor dominate the clinical picture.[4,33] However, truly generalized seizures are reported in a minority.[4] Therefore, mt.3243A > G MELAS should be considered a disorder in which focal and primary generalized seizures can manifest, although there are few reports to date of this occurring in the same individual.[2–4]

Electroencephalogram (EEG) changes such as focal slowing or epileptiform changes are rather nonspecific, but tend to show a posterior predilection.[4] In contrast, it is reported that periodic lateralized epileptiform discharges (PLEDS) in children have a limited differential diagnosis, with MELAS being a possibility.[4]

It has been proposed that seizures in mt.3243A > G MELAS may occur in two distinct and predictable patterns.[4] In some individuals, seizures appear solely in the context of stroke-like episodes, and in others seizures also occur at other times. The implication of this observation for seizure management remains unclear—in particular whether select individuals require antiepileptic drugs only at times of metabolic crises. However, as the numbers reported to date are small, this observation requires substantiation in larger cohorts.

Key Points: mt.3243A > G MELAS

  • 50% individuals with mt.3243A > G MELAS have epilepsy

  • Focal seizures predominate and may be prolonged

  • Primary generalized seizures may also manifest

MERRF Due to mt.8344A > G Mutation

Myoclonic epilepsy with ragged-red fibers is characterized by myoclonic epilepsy, generalized seizures, particularly clonic, and ataxia.[3] It most frequently arises due to the mtDNA mt.8344A > G point mutation in MTTK, although there are also other pathogenic mutations.[34,35] Myoclonic epilepsy with ragged-red fibers is one of the progressive myoclonic epilepsies that are associated with progressive intellectual decline and refractory seizures.

In contrast to the seizure phenomenology in mt.3243A > G MELAS, generalized seizures predominate in MERRF. Indeed, in a large genotype–phenotype analysis of the mt.8344A > G mutation, focal seizures were not reported.[6] However, 25 to 35% of patients with mt.8344 MERRF experienced generalized seizures (not otherwise specified), and 35 to 45% experienced myoclonus. Furthermore, they are frequently the reason an individual comes to medical attention, again in contrast with mt.3243 MELAS, where other clinical features such as stroke-like episodes are more commonly the reason for medical attention. Around one in three people with MERRF present before the age of 16 years.[6] Additional systemic features co-exist in many patients with weakness (59%), hearing loss (35%), ataxia (23%), raised serum creatine kinase (44%), and lipomatosis (32%) being notably common.[6]

The interictal EEG may be normal, but often shows slow background activity in conjunction with generalized epileptiform discharges, such as spikes, polyspike, and irregular and slow wave complexes.[5] Hyperventilation is safe,[36] and photic stimulation may enhance generalized discharges.[3,5]

Key Points: mt.8344A > G MERRF

  • Generalized seizure disorder

  • Valproate can be a first-line treatment

Mixed Syndromic and Nonsyndromic Disorders

Recessive Polymerase Gamma- (POLG-) Related Disorders

Polymerase gamma is a DNA polymerase responsible for mtDNA repair and replication. Although POLG is encoded by nuclear DNA, it is the only DNA polymerase found in mitochondria; hence, POLG disorders are characterized by multiple mtDNA deletions that accumulate over time. Consequently, highly variable clinical features may arise due to either dominant or recessive mutations.[37]

Although CPEO characterizes the dominant disorders, the recessive disorders are more complex. There are several syndromes including mitochondrial recessive ataxia syndrome (MIRAS); myoclonic epilepsy myopathy sensory ataxia (MEMSA); spinocerebellar ataxia with epilepsy (SCAE); sensory ataxia with neuropathy, dysarthria, and ophthalmoplegia (SANDO); as well as AHS, described earlier. However, as many patients do not fulfill requirements for a syndromic diagnosis, particularly early in the disease course,[38,39] much of the literature pertaining to recessive POLG seizure manifestations considers these syndromes together. Consequently, our discussion reflects this.

Seizures are a common manifestation of the recessive POLGmutations, occurring in approximately 40% of those presenting in adulthood, and up to 85% of those presenting under the age of 5 years.[38] Although pathogenic mutations throughout the gene are reported,[38,40] two particular mutations are common in the European population: 1399G > A (p. A467T) and 2243G > C (p.W748S).[41] Individuals with compound heterozygous or homozygous changes in these variants have a mean age of symptom onset of 18 years. In over half of these people (63%), seizures are the presenting feature of the disorder.[42]

The hallmark of POLG-related seizures is progressive focal motor seizures, particularly affecting the upper limb, neck, or proximal trunk. Myoclonus is common, as are episodes of convulsive and nonconvulsive status epilepticus, including epilepsia partialis continua. Epilepsia partialis continua may remain focal for many years, but invariably progresses to refractory epileptic encephalopathy. Status epilepticus is almost ubiquitous.[39,42] Seizure onset is frequently explosive and progression fulminant.[39]

One clinical feature suggestive of POLG-related seizures is the occipital predilection in the early stages, characterized by visual disturbances including colored lights, scotoma, or visual blurring.[39,42] Many patients develop additional neurologic features as their condition progresses.[39] These include migraine, neuropathy, ataxia, and chronic progressive external ophthalmoplegia, clear indicators of a complicated epilepsy and ultimately of the underlying molecular diagnosis.

In addition to the clinical features, there are specific features in the EEG that suggest POLG mutations. These include rhythmic high amplitude delta with superimposed spikes and polyspikes (RHADS)[27] and asymmetric occipital lobe or central polyspikes/polysharp complexes with associated slowing.[26]Electroencephalogram changes correlate with magnetic resonance imaging (MRI) changes as well as the clinical epileptiform features.[39,42] The posterior predominance of seizure semiology, as seen in the EEG and MRI, reflects high metabolic activity in the occipital lobes rendering them vulnerable to the effects of bioenergetic dysfunction.[43]

Disease mortality in recessive POLG disorders is correlated with seizure severity and progression, and as with the other disorders mentioned above, status epilepticus is a common end-of-life event.[39] There is evidence that the genotype has an impact on survival, as those with compound heterozygous changes have a poorer prognosis than those with homozygous changes at either of the common European mutation sites described above.[39,40]

Key Points: Recessive POLG mutations

  • Seizures affect 40% of people presenting in adulthood and up to 85% of those presenting in childhood

  • Occipital predilection early in disease course

  • Prolonged focal motor seizures characteristic

  • Avoid sodium valproate due to risk of liver failure

Twinkle (C10orf2) Mutations

Twinkle (C10orf2) is a nuclear-encoded mitochondrial replicase. Mutations in twinkle result in the accumulation of mitochondrial DNA depletion, and consequently, the clinical features associated with these mutations mimic those seen with POLG. Chronic progressive external ophthalmoplegia arises due to dominant mutations in twinkle, whereas infantile-onset spinocerebellar ataxia (IOSCA) occurs with recessive mutations.

Seizures are seen in most of those with IOSCA (18/21 patients).[44] Typically, focal seizures and myoclonic jerks occur initially and then progress to epilepsia partialis continua and generalized status. Seizures are often triggered by infection or surgery, and are a common cause of death. Again, in common with POLG seizure disorders, PLEDs were identified on the EEG and progression of EEG findings was noted with disease progression.[44]

Epilepsy in Nonsyndromic Mitochondrial Disease

Nonsyndromic mitochondrial disease occurs frequently—particularly early in the disease course. Reflecting this, 50% to 70% of children manifesting seizures in the context of a respiratory chain defect (RCD) have a nonsyndromic diagnosis.[2,3,11,12] In contrast, similar adult patients have nonsyndromic features in approximately 40% of cases.[3]

Chevellier studied 165 adults and children with confirmed mitochondrial disease, of whom roughly a third (n = 60) had had a previously identified seizure.[2] Most patients included in the study had neither a (mitochondrial) syndromic (68%) nor molecular genetic diagnosis (72%). Perhaps surprisingly, 70% of this population was well controlled with treatment—although the proportion of these with and without a mitochondrial syndromic diagnosis is unknown. This is in keeping with the proportion of individuals with epilepsy of all causes who can achieve seizure freedom with appropriate medication.[45]

Mitochondrial Syndromes Associated With Infrequent Seizures

In contrast to the conditions described above, seizures are an uncommon phenotypic feature of many other classical mitochondrial disorders, including

  • Neuropathy, ataxia, retinitis pigmentosa (NARP)[46]

  • Kearns–Sayre syndrome (KSS)[47,48]

  • Leber's hereditary optic neuropathy (LHON)[49,50]

  • Maternally inherited diabetes and deafness (MIDD)[1]


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