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线粒体癫痫的原因: 评估、诊断和治疗(2)  

2015-10-07 01:23:35|  分类: 疾病与治疗 |  标签: |举报 |字号 订阅

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When to Consider a Mitochondrial Disorder in a Patient With Epilepsy

It seems highly likely that epilepsy arising due to mitochondrial disease is underrecognized, given the estimated prevalence of mitochondrial disorders,[16] the oligosymptomatic basis of many patients with mitochondrial disease,[1,51] the often long diagnostic odyssey, and the impact of active investigation in other mitochondrial disorders.[51] Here, we flag clinical features that may indicate an underlying mitochondrial etiology in a patient with a seizure disorder. However, these are by no means diagnostic and alternative pathologies should also be contemplated in the diagnostic workup.

Clinical Features

Epilepsy in Association with Undiagnosed Multisystem Disease. Individuals with epilepsy and two or more of the clinical features below, without other unifying diagnosis, should be tested for the mt.3243A > G mutation in the first instance,[1]before moving on to consider other appropriate investigations, outlined later.

  • Cardiomyopathy

  • Deafness

  • Developmental delay or cognitive decline

  • Diabetes mellitus

  • Gastrointestinal disturbance (constipation and/or irritable bowel syndrome)

  • Migraine

  • Chronic progressive external ophthalmoplegia

  • Retinopathy

There should be a low threshold for POLG testing for people presenting with seizures and liver dysfunction.

Complex Childhood-onset Epilepsy. Individuals with childhood-onset epilepsy ultimately diagnosed with a respiratory chain defect often experience preceding symptoms of failure to thrive, psychomotor delay, ataxia;[8] encephalopathy, multiorgan symptomatology, or a fluctuating clinical course.[10]Furthermore, mitochondrial disorders are a recognized cause of epileptic encephalopathy:[44,52]conditions where the seizures themselves are thought to contribute to intellectual decline.

Family History. Our clinical experience mirrors reports of patients describing seemingly disparate clinical presentations in family members, which taken together, clinically suggest a unifying mitochondrial disorder.[4,5,7,10]

Features of the Epilepsy Itself

Status Epilepticus. Mitochondrial diseases are a key consideration in recurrent or refractory episodes of convulsive or nonconvulsive status epilepticus in adults or children.[4,7,8,23–25,28,33,39,42]

Epilepsia Partialis Continua. Epilepsia partialis continua is characterized by persistent focal seizures with retained consciousness. It is a feature of several mitochondrial disorders, including mt.3243A > G MELAS[4] (often in association with stroke like episodes) and AHS.[26] It can also occur with twinkle (C10orf12)[44] and POLG[39,42] mutations. Although it has been described on occasion in LS,[53] this does not appear to be a common feature of the disorder.[7,19,20]

Occipital Lobe Epilepsy. Occipital lobe epilepsy is an uncommon clinical presentation, affecting 2% to 13% of those with focal epilepsies.[54] Occipital lobe epilepsy can arise due to recognized electroclinical syndromes, as well as symptomatic causes;[55] however, seizures associated with mt.3243A > G MELAS and POLG have a clearly documented posterior predilection–particularly early in the disease course.[4,33,42]

Myoclonic Epilepsy. Myoclonic epilepsy is a cardinal feature of MERRF,[5,6] and widely recognized in other mitochondrial disorders.[10,56] Typically, mitochondrial myoclonic seizures are associated with clinical progression or other parameters of complex disease, setting them apart from the benign childhood and juvenile myoclonic epilepsies. Other causes of progressive myoclonic epilepsy should be considered.[57]

Recognized Electroclinical Syndrome. The following electroclinical syndromes have been reported in several cohorts to have a mitochondrial contribution:

Other electroclinical syndromes associated with mitochondrial diseases occur less frequently and are reviewed elsewhere.[9]

Investigative Features

Electroencephalogram. There is not a single "characteristic mitochondrial EEG." Indeed, the most frequently identified abnormalities are nonspecific and include generalized slowing (60%),[2,11]multifocal discharges, focal discharges or generalized discharges (all 40%).[2] Photosensitivity has been reported in patients with both MELAS and MERRF,[3,5] and although hyperventilation is safe in this patient cohort, it does not appear to increase the diagnostic yield.[36] Nonetheless, despite these nonspecific features, the EEG may show traits suggesting a mitochondrial disorder. These include:

  • EEG abnormalities with a posterior predilection[4,39,42]

  • Periodic lateralized epileptiform discharges (PLEDS) in children are suggestive of MELAS[4]

  • Focal high-voltage delta waves with polyspikes (FHDPS) may occur in acute stroke-like lesions in MELAS—although the other clinical features may prompt the diagnosis, rather than the EEG[61]

  • Rhythmic high amplitude delta with superimposed spikes and polyspikes (RHADS) strongly suggest POLG mutations causing AHS.[26,27]

Few definitive studies have examined EEG changes throughout the disease course, but progression is a feature.[39,61]

Neuroimaging. Brain imaging may be normal, particularly in nonsyndromic mitochondrial disease[11] or early in the disease course.[42] In one series, over half of patients with MERRF had normal cerebral imaging.[6] However, several features have been identified frequently in those with respiratory chain defects and seizures, including prominent and progressive cerebral atrophy,[5,6,8,10,11,42] cortical signal change,[5,6] stroke-like episodes,[4,5,6,33] and symmetrical extracortical lesions (such as signal change within the brainstem, basal ganglia, or thalamus).[11,39,42]

How Should I Investigate?

The ultimate aim of investigation is to reach a molecular genetic diagnosis. This obviates the need for ongoing investigation, aids management and follow-up, and enables individuals and their families to access appropriate genetic counselling. Although genetic testing of symptomatic individuals can be undertaken by general pediatricians or neurologists, the detection and interpretation of mtDNA mutations is particularly challenging due to the effects of heteroplasmy. Heteroplasmy describes a cardinal feature of mitochondrial disorders, whereby mtDNA mutation loads are carried at different levels in different tissues. This contributes to the highly variable phenotypic features of mitochondrial disorders, even within families. Consequently, if the diagnostic tissue has a low mutant mtDNA heteroplasmy level, the mutation may not be identified. Furthermore, the identification of a mtDNA mutation has particularly complex implications for relatives, and genetic counseling for family members is usually best undertaken by those with specific expertise.[62]

Syndromic Presentations

The approach to the investigation of a person with a syndromic presentation is relatively straightforward: appropriate targeted genetic testing.

Nonsyndromic Presentations

Many patients have nonsyndromic presentations, however, and for them the diagnostic process is often longer (Fig. 2). Many will undergo muscle or skin biopsy looking for biochemical evidence of mitochondrial dysfunction, and to help target genetic testing. Although invasive, it is well tolerated, has a low complication rate, and can be done under local anesthesia as a day case procedure (in adult patients). Samples provide invaluable information regarding the structure (histochemistry) and function (respiratory chain enzyme analysis) of muscle. Furthermore, muscle tissue can be used for further genetic analysis, as determined by the clinical features.

线粒体癫痫的原因: 评估、诊断和治疗(2) - 保健品与健康 - 健康之路

 

Future Direction

The impact of next-generation sequencing techniques on diagnosis will be determined as this becomes increasingly available at academic centers.[15] In addition, diagnostic biomarkers, as well as markers of disease progression are an area of active research. This is particularly salient as disease-modifying treatments are developed, and established markers of respiratory chain dysfunction such as lactate and pyruvate are neither sensitive nor specific.[63] Although fibroblast growth factor-21 (FGF-21) has shown some promise as a diagnostic tool, its use is not embedded in clinical practice.[64,65]


Management of Mitochondrial Epilepsy

Supportive Care

As seizures in mitochondrial disorders may be triggered, or exacerbated, by metabolic disturbance, physicians should aim to regulate the biochemical milieu by ensuring appropriate hydration, normalizing blood glucose, managing acidosis, and treating concomitant infections where present.[66]

Mitochondrial "cocktail" therapy consisting of co-enzyme Q10, vitamin B complex, vitamins C and E, and L-carnitine has been used to treat a variety of respiratory chain defects. In one study, the carers of 48 children with seizures and a RCD were asked to report changes in seizure rate, behavior, and development.[12] Although 75% reported improvements, the study was not primarily designed to assess drug efficacy. Furthermore, the 2012 Cochrane review did not identify any evidence-based disease modifying treatments for mitochondrial disease.[67]

The remaining sections therefore focus on the symptomatic treatment of seizures arising in the context of respiratory chain disorders.

Antiepileptic Drugs

There are few high quality trials to inform best use of antiepileptic medications in mitochondrial disease specifically. However, in common with epilepsies arising from other causes, the choice of medication should largely depend upon whether the seizure disorder has a focal or generalized onset.

A wide range of antiepileptic drugs (AEDs) are used to control seizures in mitochondrial disease, including carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, topiramate, and sodium valproate. Many patients are on more than a single drug.[8,11]Furthermore, treatment efficacy is difficult to assess due to the lack of trials and the heterogeneous nature of seizures in mitochondrial disease, which are often progressive.

In one series of adults and children, those with seizures were identified from a population with diagnosed respiratory chain disorders. Of these, 72% were "easily controlled" with AEDs and 28% were refractory.[2] In contrast, other series report that 5 to 15% achieve seizure freedom with antiepileptic medication,[8,11] highlighting the highly variable prognosis. Although this probably reflects different patient selection methods between series, it serves to emphasize that seizure freedom is a realistic and achievable goal for select patients with RCDs.

In addition to considering efficacy, clinicians should be aware of potential interactions between antiepileptic medications and mitochondrial function. Although many are described, most have no implications for widespread clinical practice.[68] The exception to this is use of sodium valproate use in those with a polymerase gamma (POLG) mutation, which may precipitate irreversible liver failure. Consequently, there is a move to screen for POLG mutations before starting it in children with refractory epilepsy.[28] It seems appropriate to test adults in appropriate clinical circumstances.

Intensive Care Support

Status epilepticus or epilepsia partialis continua may require intensive care support for induction of anesthetic coma. There is no evidence base to guide specific treatment, and it is likely that a combination of antiepileptic medications will be used. Magnesium infusion is recommended as a treatment for super-refractory status epilepticus[69] and its use in status epilepticus due to recessivePOLG mutations has been described in two cases, both of whom showed improvement in seizure control.[70]

The prognosis following intensive care unit (ICU) admission for seizures has not been well reported in the context of mitochondrial disease specifically. In a series of 11 patients with mitochondrial disorders admitted to an ICU with seizures, 4 died, suggesting the prognosis is poor.[71] This is largely in keeping with figures reported elsewhere for the outcome of individuals following status epilepticus.[72] Therefore, end-of-life care is a salient issue to consider for such patients, even while active management is ongoing.

Ketogenic Diet

The ketogenic diet has an increasing evidence base for use in mitochondrial disease and may have applications in the treatment of seizure disorders arising due to either nuclear or mitochondrial DNA defects.[8,12,73,74] Predicting who will respond to ketogenic diet is not currently possible. However, in one study, 75% of individuals had a reduction in seizures of more than 50%, and half of people became seizure free.[12] Furthermore, ketogenic diet may be a useful adjunct to traditional pharmaceutical agents in the acute setting,[73,75] although this effect is not universal and reporting bias is likely to be evident.[42] Whether the ketogenic diet modifies the prognosis or disease course of mitochondrial disease is currently unknown. Specialist dietician input is required, and further support can be found from Matthew's Friends (in the UK)–a support group for those embarking on the ketogenic diet.[76]

Surgical Management

The current evidence base for the surgical management of mitochondrial seizures is limited to case reports and small case series. In the case of vagus nerve stimulation, five children with an electron transport chain deficiency did not experience seizure reduction following vagus nerve stimulator implantation.[77] However, the patient population was small and heterogeneous, both in terms of the underlying genetic etiology and the seizure type. As such, it has limited ability to guide clinical application.

Traditional epilepsy surgery programs are usually inappropriate for those with mitochondrial disorders. However, palliative hemispherectomy in AHS has been described,[29] which enabled a patient to leave intensive care and die at home. The report was well received[78,79] and as refractory seizures are a common end-stage feature of mitochondrial disease, select cases may benefit from such an approach.

Palliative Care

As mentioned, many mitochondrial disorders cause premature death,[7,8,24] and for those with seizures, many deaths occur due to neurologic decompensation.[8] Accordingly, palliative care requirements should be anticipated by the clinical team.[80,81]

Summary

Epilepsy is a common feature of mitochondrial disorders, occurring in approximately one in three of all people with a confirmed respiratory chain defect.[2] Although seizures are highly heterogeneous in both manifestation and severity, there are often additional clinical indicators to suggest underlying mitochondrial dysfunction. Furthermore, although catastrophic (often) early-onset seizure disorders arise due to mitochondrial disease, for many individuals, seizures can be successfully managed with routine antiepileptic drugs.[2]

The investigation of suspected mitochondrial disease may be complex, particularly in nonsyndromic presentations. However, the increasing integration of next-generation sequencing technologies into clinical practice is likely to revolutionize the current diagnostic pathway. Far from removing clinicians from this diagnostic process, accurate interpretation of genetic variants requires skilled clinical phenotyping, and as such, physicians' clinical skills will continue to be needed at the "coal face."

Although approaches to prevent the transmission of mitochondrial disorders are being actively developed, these will not be appropriate in all circumstances.[82] As such, the need for disease-modifying treatments in mitochondrial disorders will remain a priority for both those working in the field, and those affected by the disorders. Identifying the clinical features and genetic basis of mitochondrial disorders is just the first step in this process. Multicenter international collaboration will be required to conduct natural history studies of genetically defined cohorts, and thereby ensure the scientific robustness of future clinical trials.[83]


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