Re: Re: 글루텐을 제거한 식단을 하고 셀리악-＞루게릭병 치료된 사례 - 네이처 리뷰 논문..

[문형철]

Abstract

Background A 44-year-old male presented to a general neurology clinic with a 6-month history of progressive right-sided spastic hemiparesis without sensory symptoms or signs. The thigh muscle in the affected leg showed signs of wasting. The patient had a remote family history of celiac disease.

Investigations Neurological examination, neurophysiological studies, brain MRI scan, routine blood tests, duodenal biopsy, cerebrospinal fluid analysis including polymerase chain reaction test for JC virus DNA, serological testing for HIV and for the presence of serum antibodies to endomysium, gliadin and tissue transglutaminase.

Diagnosis Celiac disease with neurological involvement, mimicking amyotrophic lateral sclerosis.

Management Strict gluten-free diet.

배경 

44세 남성이 감각 증상이나 징후 없이 6개월 동안 진행성 우측 경련성 편마비 증상을 보이며 종합 신경과에 내원했습니다. 영향을 받은 다리의 허벅지 근육이 소실되는 징후를 보였습니다. 환자는 셀리 질병의 먼 가족력이 있었습니다.

조사 

신경학적 검사, 신경생리학적 연구, 뇌 MRI 스캔, 일상적인 혈액 검사, 십이지장 생검, JC 바이러스 DNA에 대한 중합효소 연쇄반응 검사를 포함한 뇌척수액 분석, HIV에 대한 혈청학적 검사 및 엔도미시움, 글리아딘 및 조직 트랜스글루타미나제에 대한 혈청 항체 존재 여부.

진단

근위축성 측삭 경화증을 모방 한 신경 학적 침범이있는 셀리악 질병.

관리

엄격한 글루텐 프리 식단으로 2년 만에 호전

The case

A 44-year-old male was referred for a specialist neurological opinion with a 6-month history of progressive right leg weakness, and wasting and intermittent painful spasms of his right quadriceps. In the preceding month the patient had also noticed progressive weakness of his right arm and difficulty when writing. He had no sensory symptoms. The patient's only past medical history of note was migraine with aura. His family history revealed that a maternal aunt had celiac disease, a sister had Crohn's disease, and his maternal grandmother had multiple sclerosis. The referring neurologist had considered a provisional diagnosis of amyotrophic lateral sclerosis (ALS), but had not started the patient on riluzole.

44세 남성이 6개월 전부터 오른쪽 다리 힘이 약해지고 오른쪽 대퇴사두근의 소모성 및 간헐적 통증 경련을 호소하며 신경과 전문의의 진찰을 의뢰했습니다. 그 전 달에도 환자는 오른쪽 팔의 점진적인 쇠약과 글씨를 쓸 때 어려움을 느꼈습니다. 감각 증상은 없었습니다. 환자의 유일한 과거 병력은 아우라를 동반한 편두통이었습니다. 가족력 조사 결과 외숙모는 셀리악병, 여동생은 크론병, 외할머니는 다발성 경화증을 앓고 있는 것으로 밝혀졌습니다. 의뢰한 신경과 전문의는 근위축성 측삭 경화증(ALS)의 잠정 진단을 고려했지만 환자에게 릴루졸 치료를 시작하지는 않았습니다.

Examination revealed right-sided spastic hemiparesis with a pyramidal pattern of leg weakness (Medical Research Council Grade 4–/5 in hip flexion, 4+/5 in hip extension, 4/5 in knee flexion and 4–/5 in ankle dorsiflexion) associated with mild wasting of the right quadriceps. The patient had generalized bilateral hyperreflexia, sustained right ankle clonus and a right extensor plantar response. Results of cranial nerve, cerebellar and sensory examinations were normal.

검사 결과 우측 대퇴사두근의 경미한 소모와 관련된 피라미드 패턴의 다리 약화(고관절 굴곡 4/5, 고관절 신전 4+/5, 무릎 굴곡 4/5, 발목 배측 굴곡 4/5)를 동반한 우측 경련성 반신마비가 발견되었습니다. 환자는 전신성 양측 과반사, 지속적인 우측 발목 클로너스 및 우측 신전 족저 반응을 보였습니다. 뇌신경, 소뇌 및 감각 검사 결과는 정상이었습니다.

T2 and fluid-attenuated inversion recovery brain MRI sequences revealed a region of hyperintensity along the course of the left corticospinal tract, arising from the subcortical white matter of the precentral gyrus and following the posterior limb of the internal capsule into the brainstem (Figure 1A). Gadolinium-enhanced MRI did not reveal any contrast enhancement. Repeat neuroimaging 2 months later revealed more-extensive changes in the same pattern, with additional involvement of the opposite (right) subcortical region of the precentral gyrus (Figure 1B).

T2 및 유체 감쇠 역전 회복 뇌 MRI 시퀀스에서는 좌측 피질척수관을 따라 전중격의 피질하 백질에서 발생하여 내부 캡슐의 후부를 따라 뇌간으로 이어지는 고강도 영역이 확인되었습니다(그림 1A). 가돌리늄 강화 MRI에서는 조영증강이 나타나지 않았습니다. 2개월 후 신경 영상 촬영을 반복한 결과, 전대상회 반대쪽(오른쪽) 피질 하부 영역이 추가로 침범하는 등 동일한 패턴에서 더 광범위한 변화가 나타났습니다(그림 1B).

Figure 1: Coronal fluid-attenuated inversion recovery MRI of the patient's brain demonstrating regions of hyperintensity at initial presentation and 2 months later, with partial resolution following 9 months on a gluten-free diet.

(A) Initially the hyperintensity is confined to the subcortical white matter of the left motor region, descending via the internal capsule into the brainstem. (B) Two months later there is more-extensive hyperintensity visible in the left hemisphere, and limited involvement of the right motor cortex. (C) After 9 months on a gluten-free diet, the hyperintensity of the left corticospinal tract is more confined, and the right motor cortical changes have resolved. Neuroradiological improvement was accompanied by substantial clinical improvement of the patient's right-sided hemiparesis.

Full size image

Electromyography (EMG) of the masseter, biceps, first dorsal interosseous extensor digitorum communis and the vastus medialis muscles demonstrated widespread fasciculations, reduced recruitment of motor units, and frequent complex polyphasic waveforms. Fibrillation potentials were recorded in the right vastus lateralis. Results of nerve conduction studies were normal. Cerebrospinal fluid analysis revealed that all constituents were normal and a polymerase chain reaction test for JC virus was negative.

교근, 이두근, 제1등 등쪽 골간 신전근 및 광배근의 근전도 검사(EMG)에서 광범위한  fasciculations , 운동 단위의 모집 감소, 빈번한 복잡한 다상 파형이 나타났습니다. 우측 외측 광대근에서 세동 전위가 기록되었습니다. 신경전도 검사 결과는 정상이었습니다. 뇌척수액 분석 결과 모든 성분이 정상이었고 JC 바이러스에 대한 중합 효소 연쇄 반응 검사는 음성이었습니다.

Routine blood tests revealed a mild microcytic anemia (hemoglobin 129 g/l, normal range 120–140 g/l; mean corpuscular volume 78 fl, normal range 80–98 fl) with low levels of serum iron (3.5 µmol/l [20 g/dl], normal range 45–300 µmol/l [251–1,676 g/dl]), serum ferritin (17 pmol/l; normal range 45–675 pmol/l) and serum folate (8.6 nmol/l, normal range 7–40 nmol/l). Results of a subsequent antiendomysial antibody test were positive (IgA level 5.88 g/l). Duodenal biopsy analysis demonstrated villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes (Marsh 3A), consistent with gluten-sensitive enteropathy (celiac disease). Tests for HIV type 1 and 2 antibodies were negative.

일상적인 혈액 검사 결과 경미한 적혈구 빈혈(헤모글로빈 129g/l, 정상 범위 120-140g/l, 평균 적혈구 용적 78㎗, 정상 범위 80-98㎗)과 낮은 수준의 혈청 철(3.5µmol/l [20g/dl], 정상 범위 45-300µmol/l [251-1,676g/dl]), 혈청 페리틴(17pmol/l, 정상 범위 45-675pmol/l) 및 혈청 엽산(8.6 nmol/l, 정상 범위 7-40 nmol/l)이 발견되었습니다. 이후 항내시경 항체 검사 결과는 양성이었습니다(IgA 수치 5.88g/l). 십이지장 생검 분석 결과 글루텐 민감성 장병증(셀리악병)과 일치하는 융모 위축, 토굴 증식 및 상피 내 림프구 증가(Marsh 3A)가 나타났습니다. HIV 1형 및 2형 항체 검사 결과는 음성이었습니다.

The patient was started on a gluten-free diet approximately 7 months after the onset of his initial neurological symptoms. No drugs, including riluzole or other agents with neuroprotective potential, were given. At a follow-up examination 9 months after initiation of treatment, the patient's right arm function, assessed by the neurologist who performed the initial examination, had returned to normal. Improvement in the patient's right leg function was more limited, wasting was still present and there was some residual spasticity. He was now able to walk unaided, however, and his handwriting and ability to fasten buttons had returned to normal. Repeat MRI demonstrated partial resolution of the corticospinal tract changes (Figure 1C). EMG examination was not repeated after treatment. The patient's antigliadin antibody response fell from pretreatment levels of IgA 34 U/ml and IgG 44 U/ml (normal <15 U/ml for both) to IgA 18 U/ml and no detectable IgG antibody. The patient was actively followed up for 2.5 years after his initial presentation, with no evidence of neurological relapse.

환자는 초기 신경 증상이 시작된 지 약 7개월 후에 글루텐 프리 식단을 시작했습니다. 릴루졸 또는 신경 보호 가능성이 있는 기타 약물을 포함한 어떠한 약물도 투여하지 않았습니다. 치료 시작 9개월 후 추적 검사에서 초기 검사를 수행한 신경과 전문의가 평가한 환자의 오른팔 기능은 정상으로 회복되었습니다. 환자의 오른쪽 다리 기능 개선은 더 제한적이었고, 근육 소모는 여전히 존재했으며 약간의 경직이 남아있었습니다. 그러나 이제 도움 없이 걸을 수 있게 되었고 필기력과 단추를 잠그는 능력도 정상으로 돌아왔습니다. 반복적인 MRI 검사에서 피질척수 변화의 부분적인 해결이 입증되었습니다(그림 1C). 치료 후 근전도 검사는 반복하지 않았습니다. 환자의 항글리아딘 항체 반응은 치료 전 수준인 IgA 34 U/ml 및 IgG 44 U/ml(두 수치 모두 정상 <15 U/ml)에서 IgA 18 U/ml로 떨어졌으며 IgG 항체는 검출되지 않았습니다. 

환자는 최초 증상 발현 후 2.5년 동안 적극적으로 추적 관찰되었으며 신경학적 재발의 증거는 없었습니다.

Discussion of diagnosis

In this Case Study, the patient's initial presentation consisted of a progressive motor syndrome in the absence of sensory signs, with clinical evidence of upper and lower motor neuron degeneration, electromyographic evidence of widespread acute denervation, and hyperintensity in the corticospinal tracts revealed by MRI. In view of these findings, while acknowledging the unusual hemiparetic presentation and strikingly territorial nature of the white matter changes seen on MRI, a diagnosis of amyotrophic lateral sclerosis (ALS) was initially considered by the referring neurologist. The apparent presentation of a rare ALS variant in association with celiac disease—a condition with various neurological manifestations—made it entirely appropriate, however, to review the initial diagnosis and institute treatment for celiac disease. Ultimately, improvement in the patient's symptoms following treatment for celiac disease rendered the diagnosis of ALS untenable.

이 사례 연구에서 환자의 초기 증상은 감각 징후가 없는 진행성 운동 증후군으로 구성되었으며, 상하 운동 뉴런 변성의 임상적 증거, 광범위한 급성 탈신경화의 근전도학적 증거, MRI로 밝혀진 피질 척수의 과강도 등이 있었습니다. 이러한 소견을 고려할 때, 의뢰 신경과 전문의는 MRI에서 보이는 비정상적인 반신마비 증상과 백질 변화의 현저한 영역적 특성을 인정하면서 근위축성 측삭 경화증(ALS) 진단을 처음에 고려했습니다. 그러나 다양한 신경학적 증상을 보이는 셀리악병과 연관된 희귀한 루게릭병 변종이 명백하게 나타났기 때문에 초기 진단을 재검토하고 셀리악병 치료를 시작하는 것이 전적으로 적절했습니다. 결국, 셀리악병 치료 후 환자의 증상이 호전되면서 루게릭병 진단을 유지할 수 없게 되었습니다.

Screening for celiac disease was prompted by the discovery of microcytic anemia with low serum iron and folate levels. Antiendomysial antibodies—a highly sensitive and specific marker for gluten-sensitive enteropathy—were detected. The confirm‎atory duodenal biopsy analysis demonstrated the triad of villous atrophy, crypt hyperplasia and increase in the number of intraepithelial lymphocytes that characterizes celiac disease. IgG and IgA antigliadin antibodies and anti-tissue transglutaminase antibodies were also detected—these have greater sensitivity for extraintestinal manifestations of celiac disease than do antiendomysial antibodies.1

셀리악 질병에 대한 선별 검사는 혈청 철분과 엽산 수치가 낮은 미세 적혈구 빈혈이 발견되면서 촉발되었습니다. 글루텐 민감성 장병증에 대한 매우 민감하고 특이적인 마커인 Antiendomysial antibodies가 검출되었습니다. 십이지장 생검 확진 분석에서는 셀리악병을 특징짓는 융모 위축, 선와증식, 상피내 림프구 수 증가의 세 가지 증상이 나타났습니다. 또한 IgG and IgA antigliadin antibodies and anti-tissue transglutaminase antibodies 도 검출되었는데, 이 항체들은  antiendomysial antibodies 보다 셀리악병의 장외 증상에 대한 민감도가 더 높습니다.1

Celiac disease is an immune-mediated systemic disease. For every patient presenting with the classic symptoms of gastrointestinal involvement and malabsorption, there are an estimated eight patients with 'silent' disease or with extraintestinal manifestations. Celiac disease is preval‎ent in 1 in 100 individuals in most European countries and in the US.2 The pathological trigger is gluten, a protein commonly found in rye, barley and wheat. Celiac disease has a strong hereditary component: its preval‎ence in first-degree relatives ranges from 10–20%.3 The human leukocyte antigen DQ2 is present in 90% of cases.

셀리악 질병은 면역 매개성 전신 질환입니다. 위장 침범 및 흡수 장애의 전형적인 증상을 보이는 환자 한 명당 약 8명의 '침묵의' 질병 또는 장외 증상( extraintestinal manifestations )을 보이는 환자가 있는 것으로 추정됩니다. 셀리악병은 대부분의 유럽 국가와 미국에서 100명 중 1명꼴로 발병합니다.2 병리적 유발 요인은 호밀, 보리, 밀에서 흔히 발견되는 단백질인 글루텐입니다. 셀리악병은 유전적 요소가 강하며, 1촌 친척의 유병률은 10~20%에 달합니다.3 인간 백혈구 항원 DQ2는 90%의 사례에서 존재합니다.

The observation that celiac disease is associated with a broad range of neurological symptoms was first made over 40 years ago.4 The most common of these neurological complications are ataxia and neuropathy,5 including pure motor variants, which have been reported to have EMG changes consistent with motor neuron disease.6 There was no evidence of ataxia or peripheral neuropathy, however, in the present case. Celiac disease can also be associated with seizures, dementia and myopathy. White matter changes associated with gluten sensitivity have been variously described as a form of multifocal leukoencephalopathy or as a more patchy process associated with prominent headache.7 To our knowledge, a syndrome of progressive hemiparesis with such striking changes to the corticospinal tract MRI as were seen in the present patient has not previously been reported in association with celiac disease.

셀리악 질병이 광범위한 신경학적 증상과 관련이 있다는 관찰은 40여 년 전에 처음 이루어졌습니다.4 이러한 신경학적 합병증 중 가장 흔한 것은 운동 실조증과 신경 병증이며,5 순수 운동 변형을 포함하여 운동 뉴런 질환과 일치하는 EMG 변화가있는 것으로보고되었습니다 .6 그러나 본 사례에서는 운동 실조증이나 말초 신경 병증의 증거가 없었습니다. 셀리악병은 발작, 치매 및 근병증과도 관련이 있을 수 있습니다. 글루텐 민감성과 관련된 백질 변화는 다초점 백질 뇌병증의 한 형태 또는 두드러진 두통과 관련된 더 고르지 못한 과정으로 다양하게 설명되어 왔습니다.7 우리가 아는 한, 본 환자에서와 같이 피질 척수 MRI에 눈에 띄는 변화를 보이는 진행성 편마비 증후군은 이전에 셀리악병과 관련하여 보고된 적이 없습니다.

The mechanism of neuronal damage in celiac-associated neurological disease is still unclear. One hypothesis is that perivascular inflammation might lead to the breakdown of the blood–brain barrier, allowing an influx into the brain of antibodies that cross-react with neural tissue. The arterial wall contains high levels of transglutaminase, and IgA deposits against transglutaminase 2 within the arterial wall of vessels from the cerebellum have previously been detected in a case of gluten ataxia. Anti-transglutaminase-2 IgA deposits in the gut have also been reported and they are considered to be the earliest markers of gluten sensitivity.8

셀리악 관련 신경 질환에서 신경 세포 손상의 메커니즘은 아직 명확하지 않습니다. 한 가지 가설은 혈관 주위 염증이 혈액-뇌 장벽을 파괴하여 신경 조직과 교차 반응하는 항체가 뇌로 유입될 수 있다는 것입니다. 동맥벽에는 높은 수준의 트랜스글루타미나제가 포함되어 있으며, 글루텐 운동 실조증의 경우 소뇌에서 나온 혈관의 동맥벽 내에 트랜스글루타미나제 2에 대한 IgA 침착물이 이전에 검출된 바 있습니다. 장내 항-트랜스글루타미나제-2 IgA 침착물도 보고되었으며, 이는 글루텐 감수성의 가장 초기 마커로 간주됩니다.8 신경학적 재발의 발생.

Differential diagnosis

This patient presented with symptoms consistent with ALS, although there were atypical features that suggested that other diagnoses needed to be excluded. ALS is a neurodegenerative condition of motor neurons with a consistent worldwide incidence of approximately 1–2 cases per 100,000 individuals per year, and a 3:2 male predominance. The majority (90–95%) of cases are apparently sporadic, and less than 2% of the total number of cases are associated with an underlying mutation of the superoxide dismutase 1 (SOD1) gene. The etiology of ALS is unknown, although there are multiple molecular hypotheses to explain the specificity of motor neuron degeneration.9

Despite anecdotal reports of exceptional cases, ALS is a condition with relentless progression, and riluzole, the single disease-modifying drug licensed for the condition, provides only an approximately 10% improvement in mean survival in a trial setting. Although around 5% of all patients with motor neuron disease, particularly but not exclusively those with primary lateral sclerosis, survive well into a second decade from symptom onset, periods of arrested disease progression or obvious improvement of symptoms are not observed during long-term follow-up in specialist clinics.10

As there is currently no cure for ALS and the mean survival time from symptom onset is 3–4 years, it is important to consider all potentially treatable diseases that might produce a similar syndrome. Clinicians should recognize, however, that in practice such 'mimics', although understandably appealing to anxious patients and their carers, are extremely rare.

The role of neuroimaging in the investigation of suspected ALS is most frequently to exclude cervical spine pathology, which can present clinically with upper and lower motor neuron signs in the limbs. In this case MRI conclusively excluded compressive pathology. Cerebral MRI can also be useful in patients with bulbar dysfunction to exclude an alternative cause such as stroke, demyelination or a brain stem tumor. Although hyperintensity of the corticospinal tracts on MRI—particularly with fluid-attenuated inversion recovery sequences—is a well established phenomenon in ALS cases,11 this sign has low diagnostic sensitivity and specificity. The hyperintensity seen in the present case, which was particularly extensive in the region of the precentral gyrus, showed an unusual degree of confluence.

The lesions in the present case were revealed by MRI to have some features in common with those seen in progressive multifocal leukoencephalopathy. The effects of progressive multifocal leukoencephalopathy are usually widespread, but a case has been described in which the lesions were confined to the pyramidal tract.12 For this reason, the present patient was tested for HIV and JC virus, with both tests being negative.

EMG can provide supportive evidence in the investigation of a case of suspected ALS, but it is only diagnostic in the context of a compatible clinical history and examination. The value of EMG in the investigation of ALS lies in the detection of subclinical lower motor neuron involvement in seemingly asymptomatic muscles, which could suggest a widespread degenerative process rather than focal denervation. Although changes suggestive of widespread denervation were observed in this patient, they were not of sufficient magnitude to enable a diagnosis of ALS to be made on purely electrophysiological grounds.

Treatment and management

In published reports of neurological complications of celiac disease, improvement with dietary modification has not been consistently reported, and the association of these complications with celiac disease consequently attracts controversy. Lack of improvement might be the result of unintentional poor dietary compliance, caused by variable food labeling practices and the fact that even minute traces of gluten, enough to perpetuate the immune response, can persist on cooking implements. The benefits of a gluten-free diet for patients with ataxia and neuropathy caused by gluten sensitivity have been demonstrated in systematic studies that closely monitored dietary adherence via regular assessment of antigliadin antibodies.13

Levels of antiendomysial, anti-tissue transglutaminase and antigliadin antibodies should diminish following avoidance of gluten, so incomplete recovery in the presence of persistently positive tests for these antibodies should prompt a thorough review of the patient's diet. Gluten-free products contain wheat that has been processed to remove most, but not all, of the gluten. For most patients, such small amounts of gluten are innocuous. For some very sensitive patients, however, even traces of gluten can be enough to perpetuate an immunological response, as indicated by the persistence of symptoms and positive tests for the relevant serological markers. In such cases a 'wheat-free' diet—a diet that avoids wheat completely and uses alternative sources of protein such as rice or corn flour—can be beneficial. As a result of the detection of residual antigliadin IgA levels, the patient discussed here is currently following a wheat-free diet.

Conclusions

The patient discussed in this Case Study presented with a syndrome of progressive hemiparesis associated with gluten-sensitive enteropathy. The clear clinical and neuroradiological improvements that followed treatment with a gluten-free diet are evidence that the syndrome of progressive hemiparesis represents another addition to the growing list of neurological manifestations of celiac disease.

The symptoms displayed by the patient in this case were initially suspected to result from ALS. This condition remains predominantly a clinical diagnosis, and the aim of diagnostic investigations is the exclusion of alternative 'mimic' syndromes that might be responsive to treatment. ALS is a condition with relentless progression; for this reason, the simple observation of an improvement in symptoms is most pertinent in rendering the diagnosis of ALS untenable.

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