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The misdiagnosis of epilepsy: Appraising risks and managing uncertainty

Open ArchivePublished:December 06, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.029

      Highlights

      • Misdiagnosis of epilepsy remains common and the consequences for the individual significant.
      • Poor history taking and overreliance on laboratory test are the main causes of misdiagnosis.
      • Risks of a false positive diagnosis must be appraised against risks of a false positive diagnosis.
      • Even with the right level of clinical expertise diagnostic uncertainty cannot be completely eliminated.
      • Incorporation diagnostic uncertainty as a legitimate outcome can reduce the chance of misdiagnosis.

      Abstract

      Purpose

      To present evidence from the literature on the rates, underlying causes and consequences of the misdiagnosis of epilepsy and place these meaningfully within a practical framework of risk appraisal and managed diagnostic uncertainty towards informing a clinical practice that might make misdiagnosis less likely.

      Method

      Narrative review.

      Results

      Misdiagnosis of epilepsy remains common and the consequences for the individual significant.
      Evidence and critical appraisal are presented as regards the absolute level of risk associated with the false positive diagnosis epilepsy, and reasons as to why those risks need to be appraised against the risks associated to false negative diagnosis.

      Conclusions

      Diagnostic error is not entirely avoidable and a degree of uncertainty, and perforce risk, is intrinsic to the diagnostic process of epilepsy.
      The risks of a false negative diagnosis of epilepsy must be appraised against the also significant risks of a false positive diagnosis.

      Keywords

      1. Introduction

      Over the last 20 years there have been significant advances in epilepsy research in terms of the identification of underlying causes and mechanisms and the development of more tolerable and efficacious treatments. However, none of these advances are practically meaningful without an accurate diagnosis. Epilepsy is still overwhelmingly a clinical diagnosis and rates of misdiagnosed epilepsy remain stubbornly high.
      Consensus statements and guidelines consistently recommend early availability of and referral to specialist epilepsy services as a way of addressing this issue [
      • NICE
      The epilepsies: diagnosis and management of the epilepsies in children and young people in primary and secondary care.
      ,
      • SIGN
      Diagnosis and management of epilepsies in children and young people.
      ]. However the diagnosis of epilepsy can be challenging even for experienced clinicians [
      • Chadwick D.
      • Smith D.
      The misdiagnosis of epilepsy: the rate of misdiagnosis and wide treatment choices are arguments for specialist care of epilepsy. (Editorials).
      ]. The difficulty arises not so much from a greater or lesser ability to recognise epilepsy, but in the particular problems in assessment of risk and management of uncertainty specific to situations where epilepsy may be a possibility but a final diagnosis has to await further confirmation. The perceived risk of not treating, even in a circumstance where the probability of epilepsy is low, mitigates against circumspection and encourages practice that results in misdiagnosis [
      • Van Donselaar C.A.
      • Stroink H.
      • Arts W.F.
      How confident are we of the diagnosis of epilepsy?.
      ]. As such, as well as presenting evidence from the literature on the rates, underlying causes and consequences of the misdiagnosis of epilepsy, the intention of this paper is to place these meaningfully within a practical framework of risk appraisal and managed diagnostic uncertainty towards informing a clinical practice that might make misdiagnosis less likely.

      2. Misdiagnosis

      2.1 Prevalence of misdiagnosis

      Reported misdiagnosis rates vary substantially with estimates ranging between 2% and 71%. This wide variation reflects the heterogeneity across studies in terms of setting, inclusion of patients with refractory epilepsy, diagnostic criteria, diagnostic methods and the experience of the referring clinician [
      • Xu Y.
      • Nguyen D.
      • Mohamed A.
      • Carcel C.
      • Li Q.
      • Kutlubaev M.A.
      • et al.
      Frequency of a false positive diagnosis of epilepsy: a systematic review of observational studies.
      ,
      • Stroink H.
      • Van Donselaar C.A.
      • Geerts A.T.
      • Peters A.C.
      • Brouwer O.F.
      • Arts W.F.
      The accuracy of the diagnosis of paroxysmal events in children.
      ,
      • Josephson C.B.
      • Rahey S.
      • Sadler R.M.
      Neurocardiogenic syncope: frequency and consequences of its misdiagnosis as epilepsy.
      ,
      • Scheepers B.
      • Clough P.
      • Pickles C.
      The misdiagnosis of epilepsy: findings of a population study.
      ,
      • Leach J.P.
      • Lauder R.
      • Nicolson A.
      • Smith D.F.
      Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment?: the Wrexham area epilepsy project.
      ,
      • Smith D.
      • Defalla B.A.
      • Chadwick D.W.
      The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic.
      ,
      • Zaidi A.
      • Clough P.
      • Cooper P.
      • Scheepers B.
      • Fitzpatrick A.P.
      Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause.
      ,
      • Uldall P.
      • Alving J.
      • Hansen L.K.
      • Kibaek M.
      • Buchholt J.
      The misdiagnosis of epilepsy in children admitted to a tertiary epilepsy centre with paroxysmal events.
      ,
      • Alsaadi T.M.
      • Thieman C.
      • Shatzel A.
      • Farias S.
      Video-EEG telemetry can be a crucial tool for neurologists experienced in epilepsy when diagnosing seizure disorders.
      ,
      • Benbadis S.R.
      • O'Neill E.
      • Tatum W.O.
      • Heriaud L.
      Outcome of prolonged video-EEG monitoring at a typical referral epilepsy center.
      ,
      • Chowdhury F.A.
      • Nashef L.
      • Elwes R.D.
      Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty.
      ]. With the exception of the studies below, such studies are likely to be confounded, and their populations too highly selected, to derive a ‘base rate’ of misdiagnosis that would inform practitioners addressing the needs of patients presenting following an apparently first seizure, or the majority of those diagnosed with epilepsy who are never deemed ‘treatment refractory’.
      By contrast two purposely designed studies addressed the prevalence of misdiagnosis within the community. In the UK an early study assessing the prevalence of epilepsy within the community, reviewed the diagnosed of 214 patients from seven general practice surgeries. Following review by an epilepsy specialist, alternative causes for the attack disorder were found in 49 (23%) mostly a cardiovascular cause or psychogenic non-epileptic seizures (PNES) [
      • Scheepers B.
      • Clough P.
      • Pickles C.
      The misdiagnosis of epilepsy: findings of a population study.
      ]. Another UK based study identified 275 patients with epilepsy treated with antiepileptic drugs (AED) from 26 general practices. All patients were reviewed by two experienced epilepsy specialists who concluded that the diagnosis of epilepsy was in doubt in 16.3% of patients [
      • Leach J.P.
      • Lauder R.
      • Nicolson A.
      • Smith D.F.
      Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment?: the Wrexham area epilepsy project.
      ].
      Thus the misdiagnosis rate in unselected patients with a diagnosis of epilepsy may be in the region of 20%.
      Higher rates of misdiagnosis are found in adults or children with apparently treatment refractory epilepsy referred to secondary care in and outside the UK [
      • Xu Y.
      • Nguyen D.
      • Mohamed A.
      • Carcel C.
      • Li Q.
      • Kutlubaev M.A.
      • et al.
      Frequency of a false positive diagnosis of epilepsy: a systematic review of observational studies.
      ]. When Smith et al. retrospectively reviewed the diagnosis of relatively unselected patients referred to an epilepsy clinic, the overall misdiagnosis rate amongst the 184 patients with the diagnosis of epilepsy and treated with antiepileptic drugs was 26.1% (46/184). In this study the most common conditions to be mistaken for epilepsy were PNES and syncope and more than half of the patients were on medication [
      • Smith D.
      • Defalla B.A.
      • Chadwick D.W.
      The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic.
      ]. A further study, specifically excluding patients with suspected PNES, still found that of 74 patients referred to an epilepsy clinic, half of whom were deemed to have refractory epilepsy, 41.9% had an alternative, most commonly syncopal or cardiovascular, cause of their symptoms [
      • Zaidi A.
      • Clough P.
      • Cooper P.
      • Scheepers B.
      • Fitzpatrick A.P.
      Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause.
      ]. A retrospective survey of children admitted to a tertiary centre in Denmark found that 30% of the children referred with a definite diagnosis, did not have epilepsy [
      • Uldall P.
      • Alving J.
      • Hansen L.K.
      • Kibaek M.
      • Buchholt J.
      The misdiagnosis of epilepsy in children admitted to a tertiary epilepsy centre with paroxysmal events.
      ].
      Even more selected case series from secondary care that would be expected to include more unusual presentations generally confirm syncope followed by PNES as the most common conditions underlying misdiagnosis [
      • Xu Y.
      • Nguyen D.
      • Mohamed A.
      • Carcel C.
      • Li Q.
      • Kutlubaev M.A.
      • et al.
      Frequency of a false positive diagnosis of epilepsy: a systematic review of observational studies.
      ]. The ‘typical’ scenario of epilepsy misdiagnosis conforms to a relatively prosaic narrative of short lived and in all probability benign ‘collapses’ whose resolution may be mistaken for a response to AED. The possibility exists that a substantial minority of patients with apparently remitted epilepsy on treatment do not have epilepsy.
      Finally it is important to point out that although higher proportions of misdiagnosis have been found amongst non-experts, figures of over 20% have also been reported amongst patients under the care of specialists and referred on to tertiary centres [
      • Alsaadi T.M.
      • Thieman C.
      • Shatzel A.
      • Farias S.
      Video-EEG telemetry can be a crucial tool for neurologists experienced in epilepsy when diagnosing seizure disorders.
      ,
      • Benbadis S.R.
      • O'Neill E.
      • Tatum W.O.
      • Heriaud L.
      Outcome of prolonged video-EEG monitoring at a typical referral epilepsy center.
      ].

      2.2 Consequences of misdiagnosis

      In essence, a misdiagnosis of epilepsy carries with it all the secondary handicaps and limitations of a diagnosis of epilepsy in terms of stigma and social marginalisation, lifestyle limitation, employment and driving restrictions, and the side effects and potential teratogenic effects of AEDs [
      • Chadwick D.
      • Smith D.
      The misdiagnosis of epilepsy: the rate of misdiagnosis and wide treatment choices are arguments for specialist care of epilepsy. (Editorials).
      ,
      • Xu Y.
      • Nguyen D.
      • Mohamed A.
      • Carcel C.
      • Li Q.
      • Kutlubaev M.A.
      • et al.
      Frequency of a false positive diagnosis of epilepsy: a systematic review of observational studies.
      ,
      • Chowdhury F.A.
      • Nashef L.
      • Elwes R.D.
      Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty.
      ]. It seems reasonable to speculate that clinician’s insufficient understanding of the profound implications of a diagnosis of epilepsy in and of itself contributes to an over-readiness to make the diagnosis.
      Once established, the diagnosis of epilepsy is not readily challenged or reviewed even amongst specialists. Patients eventually correctly diagnosed as having PNES will on average have acquired their misdiagnosis, and its consequences, 7–10 years previously [
      • Oto M.
      • Reuber M.
      Psychogenic non-epileptic seizures: aetiology, diagnosis and management.
      ].
      Some populations court particular risk from misdiagnosis; specifically patients with unrecognised cardiogenic syncope or patients suffering from PNES.
      A small minority of patients with apparent syncope will transpire to have an underlying liability to serious arrhythmia, often but not always associated with ECG changes and if untreated associated with a high mortality rate [
      • Kapoor W.N.
      • Karpf M.
      • Wieand S.
      • Peterson J.R.
      • Levey G.S.
      A prospective evaluation and follow-up of patients with syncope.
      ,
      • Linzer M.
      • Grubb B.P.
      • Ho S.
      • Ramakrishnan L.
      • Bromfield E.
      • Estes N.M.
      Cardiovascular causes of loss of consciousness in patients with presumed epilepsy: a cause of the increased sudden death rate in people with epilepsy?.
      ]. Speculative prescription of AED in this circumstance has potentially disastrous results.
      Psychiatric morbidity in PNES populations is substantial and worsens the prognosis. A misdiagnosis of epilepsy not only misattributes the primary psychological nature of the attacks but also prevents appropriate treatment of the substantial associated psychiatric morbidity [
      • Oto M.
      • Reuber M.
      Psychogenic non-epileptic seizures: aetiology, diagnosis and management.
      ].
      Particular risks of iatrogenic harm are incurred by PNES patients presenting with prolonged attacks misattributed to apparent status when this leads to inappropriate use of high doses of intravenous medication or even admission to the Intensive Care Unit and intubation, with all the morbidity that this entails [
      • Walker M.C.
      • Howard R.S.
      • Smith S.J.
      • Miller D.H.
      • Shorvon S.D.
      • Hirsch N.P.
      Diagnosis and treatment of status epilepticus on a neurological intensive care unit.
      ].
      The economic consequences of misdiagnosis are also significant; figures form NICE guidelines estimated the direct total national medical costs between 164 and 188 million pounds [
      • NICE
      The epilepsies: diagnosis and management of the epilepsies in children and young people in primary and secondary care.
      ]. As well as the costs of an erroneous diagnosis, “undiagnosing” epilepsy is also costly since reversing a diagnosis is at times more complicated and patients may require video EEG monitoring or inpatient admission for a diagnostic withdrawal of medication [
      • Smith D.
      • Defalla B.A.
      • Chadwick D.W.
      The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic.
      ].

      2.3 Reasons for the misdiagnosis of epilepsy

      As in medicine more generally there are no short cuts to an accurate clinical diagnosis. Epilepsy misdiagnosis however, of all medical missteps, seems to occur within a particular matrix of factors that discourage circumspection and encourage immediate diagnosis on a basis of an inadequate history, traditional but unreliable ‘red flags’, over-interpretation or misuse of medical investigations (mainly EEG), and the inaccurate perception that the immediate clinical course will be grave if intervention is delayed.
      The single most important factor in epilepsy misdiagnosis is the failure to appreciate the importance of a thorough and expert clinical history and its corroboration by a witness description [
      • Smith D.
      • Defalla B.A.
      • Chadwick D.W.
      The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic.
      ]. Rather than diagnostic insight, ‘expertise’ in this circumstance applies more to perseverance in seeking a history and witness description as well as reservation of judgement when these are unavailable.
      To complicate matters, epileptic seizures can manifest in many ways and although there are constellations of features that would alert the clinician to the possibility of the diagnosis one way or another, there is no single pathognomonic semiological feature that would in isolation absolutely endorse a diagnosis of epilepsy or non-epilepsy. Unfortunately many of the often rehearsed ‘red flags’ of clinical tradition (self-injury, attacks arising from apparent sleep, urinary incontinence) have been shown to have little or no discriminant value, and for the most part are actively misleading if taken in isolation [
      • Oto M.
      • Reuber M.
      Psychogenic non-epileptic seizures: aetiology, diagnosis and management.
      ].
      Laboratory investigations are of limited value in epilepsy diagnosis at the level of the individual patient and in the context of practical decision making. None has sufficient sensitivity or specificity to confirm or rule out a diagnosis.
      Interictal EEG is a valuable test in the further investigation of an established diagnosis of epilepsy, however it has little role in diagnosis per se. Overreliance on and misinterpretation of routine EEGs has been found to be a contributory factor in the misdiagnosis of epilepsy [
      • Smith D.
      • Defalla B.A.
      • Chadwick D.W.
      The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic.
      ].
      Interpreting EEG reports can be as challenging as interpreting the EEG itself. Non-specific EEG abnormalities are not uncommon in the general population and more frequently observed in populations at higher risk of manifesting non-epileptic attacks, especially those prescribed some types of psychotropic medication. To the inexperienced a subsequent report of ‘non-specific focal slowing’, might be sufficient to consolidate suspicion into diagnosis [
      • Benbadis S.R.
      • Tatum W.O.
      Over-interpretation of EEGs and misdiagnosis of epilepsy.
      ,
      • Fattouch J.
      • Di Bonaventura C.
      • Strano S.
      • Vanacore N.
      • Manfredi M.
      • Prencipe M.
      • et al.
      Over-interpretation of electroclinical and neuroimaging findings in syncopes misdiagnosed as epileptic seizures.
      ]. A study investigating EEG abnormalities in patients with PNES found that over 50% of patients had had one or more EEGs reported as abnormal [
      • Reuber M.
      • Fernández G.
      • Bauer J.
      • Singh D.D.
      • Elger C.E.
      Interictal EEG abnormalities in patients with psychogenic nonepileptic seizures.
      ].
      More complex and time consuming investigations, such as simultaneous video EEG recording, have an undeniable role as a diagnostic aid. However their reliability also depends on an accurate clinical history and its usefulness is limited to situations where there is a reasonable probability of capturing a typical attack.
      The role of neuroimaging in diagnosing epilepsy has clear limitations. An abnormal brain scan does not automatically confirm the diagnosis of epilepsy. MRI scans in particular can also be a source of error, as non-specific abnormalities or incidental findings may be misinterpreted as the cause for the attack disorder [
      • Fattouch J.
      • Di Bonaventura C.
      • Strano S.
      • Vanacore N.
      • Manfredi M.
      • Prencipe M.
      • et al.
      Over-interpretation of electroclinical and neuroimaging findings in syncopes misdiagnosed as epileptic seizures.
      ].

      3. Uncertainty

      3.1 Clinician’s perception of risk and management of diagnostic uncertainty

      Epilepsy is associated with an increased risk of morbidity and mortality. However there are also significant risks attached to misdiagnosing epilepsy and these need equal consideration. Unfortunately, over and above concerns at the lack of access to trained opinion, reported rates of misdiagnosis still suggest that clinicians perceive missing a diagnosis of epilepsy and not treating seizures as being riskier than “erring on the side of caution” and treating despite insufficient clinical information and the risks of exposure to unnecessary AED.
      Although probably informed by a range of concerns, unwarranted treatment of a poorly sustained or uncertain diagnosis of epilepsy seems to have as its basis a perception of risks that can only be addressed by prompt AED treatment and whose course will be one of inevitable deterioration, increased morbidity and even mortality otherwise.
      As already mentioned, mortality rates amongst people with epilepsy are higher than in the general population. However, most of the increased mortality is attributable to the underlying comorbidities, and only a small percentage relates to the direct consequences of seizures [
      • Hitiris N.
      • Mohanraj R.
      • Norrie J.
      • Brodie M.J.
      Mortality in epilepsy.
      ]. Early treatment with AED reduces early recurrence of seizures but does not change the long term outcome and has no influence on mortality [
      • Marson A.
      • Jacoby A.
      • Johnson A.
      • Kim L.
      • Gamble C.
      • Chadwick D.
      • et al.
      Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial.
      ,
      • Lhatoo S.D.
      • Johnson A.L.
      • Goodridge D.M.
      • MacDonald B.K.
      • Sander J.W.
      • Shorvon S.D.
      Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long‐term, prospective, population-based cohort.
      ]. It has been argued that there is a need to review the risks and benefits of routine prescription of AED for newly diagnosed patients in the light of a finding that spontaneous remission of the epilepsies may occur in up to 30% of patients [
      • Kwan P.
      • Sander J.W.
      The natural history of epilepsy: an epidemiological view.
      ,
      • McIntosh A.M.
      • Berkovic S.F.
      Treatment of new-onset epilepsy: seizures beget discussion.
      ].
      Therapeutic trials of AED are undertaken on occasion to resolve uncertainty. In fact most paroxysmal attack disorders will follow a course far too variable to distinguish a response, and as the majority are benign and self-limiting an apparent but spurious response to AED is more likely than not. A lack of response to AED is often listed as a diagnostic pointer to PNES but a significant proportion of patients with PNES, given the near universal psychiatric comorbidity, would be expected to demonstrate the substantial placebo response common to all non-psychotic psychiatric disorders [
      • Oto M.
      • Reuber M.
      Psychogenic non-epileptic seizures: aetiology, diagnosis and management.
      ].
      Far from intending to minimise the significant risks associated with epilepsy, the points raised in this section attempt to contextualise these risks within the population of patients presenting for the first time with paroxysmal attacks of uncertain cause and at most risk of misdiagnosis and all that this entails.

      3.2 Managing uncertainty

      An accurate diagnosis of epilepsy is often possible following a detailed history and a good eyewitness account. However there are situations where absent or vague eye witness descriptions or unusual clinical presentations of attacks make reaching a definite diagnosis challenging or impossible at least in the short term. As already mentioned in this circumstance diagnostic tests may not be helpful and potentially misleading.
      As doctors we are trained to accurately diagnose disease, adopt clear diagnostic labels and offer appropriate treatment to patients. In general clinicians feel uncomfortable with diagnostic uncertainty. Committing to a definite diagnosis eliminates this uncertainty but from that moment determines the future management of the attack disorder and forecloses the consideration of an alternative diagnosis.
      Delaying the diagnosis of epilepsy until one is absolutely certain is clearly not possible. Even when a diagnosis is made by a panel of experts the false positive rate is around 5% [
      • Stroink H.
      • Van Donselaar C.A.
      • Geerts A.T.
      • Peters A.C.
      • Brouwer O.F.
      • Arts W.F.
      The accuracy of the diagnosis of paroxysmal events in children.
      ]. Ultimately, misdiagnosis is not merely difficult to avoid; it is inherent. For this reason clinicians should always be mindful that diagnoses may be wrong and adopt a practice where diagnoses are routinely questioned and reviewed.
      As a reflection of a greater ability to recognise limitations in the clinical information and incorporate an awareness of the risk of misdiagnosis, experts are more likely to admit diagnostic uncertainty than non specialists. It has been suggested that adopting the label of “possible epilepsy” or “unclassified paroxysmal event” as a positive diagnostic category could reduce the rate of misdiagnosis by quasi-operationally incorporating diagnostic uncertainty as a legitimate option and avoiding precipitate diagnosis based on incomplete information [
      • Chowdhury F.A.
      • Nashef L.
      • Elwes R.D.
      Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty.
      ,
      • Beach R.
      • Reading R.
      The importance of acknowledging clinical uncertainty in the diagnosis of epilepsy and non-epileptic events.
      ].

      4. Conclusion

      Misdiagnosis of epilepsy remains common and the consequences for the individual significant [
      • Xu Y.
      • Nguyen D.
      • Mohamed A.
      • Carcel C.
      • Li Q.
      • Kutlubaev M.A.
      • et al.
      Frequency of a false positive diagnosis of epilepsy: a systematic review of observational studies.
      ]. Improved services, training, and in particular early access to specialist assessment, as recommended by expert authorities, are unexceptionably likely to lead to a reduction in misdiagnosis as part of a general improvement in epilepsy care. However other factors have to be considered. Epilepsy by its nature presents suddenly and dramatically, is initially assessed outwith specialist services, and even within specialist settings is associated with a singularly complex matrix of perceived risk and diagnostic uncertainty [
      • Chowdhury F.A.
      • Nashef L.
      • Elwes R.D.
      Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty.
      ]. These factors inevitably militate against a considered and accurate diagnosis in a substantial number of cases.
      In this article I have attempted to present what is known on epilepsy misdiagnosis within the context of risk assessment, acknowledged uncertainties and practical decision making that impacts directly on patient care. Often, rather than the ability to clinically recognise epilepsy, the decision making errors that lead to misdiagnosis are more about poor management of the possibility of epilepsy, even when the pre-test probability is acknowledged to be low, because of a misperception of the dangers of diagnostic delay and an exaggerated perception of the benefits of proceeding on an uncertain diagnosis.
      Acknowledging that uncertainty and diagnostic error cannot be completely eliminated, encouraging a clinical stance where deferring a diagnosis is a legitimate option, and routine review and reconsideration of apparently secure diagnoses, would make the process safer and reduce the chance of erroneous and harmful misdiagnosis.

      Conflict of interest statement

      None.

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