드디어 찾았다. ALS(루게릭병) 치료 케이스 논문!!

[문형철]

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy. 

배경: 근위축성 측삭 경화증(ALS)은 대부분의 경우 3~5년 이내에 사망에 이르는 치명적인 질환입니다. 이 질병을 치료하기 위한 새로운 접근법이 필요합니다. 여기에서는 성공적인 치료법을 보고합니다.

Case Report: In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86 × 250 mg in 3 years) in combination with α-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely. 

사례 보고서: 근력 약화와 경직으로 고통받던 49세 남성 환자는 다른 질환을 배제하고 광범위한 검사를 시행한 결과 루게릭병의 변형인 진행성 근위축증으로 진단되었습니다. 잔류 아말감으로 인한 수은 노출로 추정되어 환자의 치아는 수복되었습니다. 그 후 환자는 α-리포산과 함께 2,3-디메르캅토프로판설페이트 나트륨(DMPS, 3년 동안 총 86 × 250 mg)을 복용한 후 셀레늄을 투여했습니다. 또한 그는 비타민과 미량 영양소를 섭취하고 채식을 유지했습니다. 소변에서 금속 배설이 모니터링되었습니다.

치료의 성공 여부는 근육 약화와 매혹을 점수화 한 다음 마지막으로 영향을받은 근육의 근전도 (EMG)를 통해 결정되었습니다. 첫 번째 개선은 치아 수복 후 발생했습니다. DMPS로 치료를 시작한 지 두 달 후 소변의 수은 수치가 증가했습니다(크레아티닌 248.4 µg/g). 1.5 년 후 근전도 검사에서 루게릭병의 전형적인 징후가 없음을 확인했습니다. 3년 후 환자는 완전히 회복되었습니다.

결론: 여기에 설명된 치료법은 일부 종류의 운동 신경 질환을 치료할 수 있는 유망한 접근법이며 엄격한 임상시험을 통해 추가 평가가 필요합니다.

Conclusions: The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further eval‎uation in rigorous trials.

https://ccforum.biomedcentral.com/articles/10.1186/cc1887

Case report: Severe mercuric sulphate poisoning treated with 2,3-dimercaptopropane-1-sulphonate and haemodiafiltration - Critica

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. Patients develop a progressive muscle phenotype characterized by spasticity, hyperreflexia, fasciculations, muscle atrophy, and paralysis. Depending on the disease variant, upper or lower neurons are damaged, or both [1]. The paralysis progresses affecting more and more muscles and the patients finally die from asphyxia. The median survival time after onset of symptoms is 32 months [2,3].

Despite considerable progress in understanding the cellular and molecular events in ALS [4], there is no generally accepted therapy besides riluzole, which may prolong survival by only 3 months [5]. Numerous new therapies are currently investigated [6], also including complementary medicine [7], and some of them may be promising. In the clinic of J.M., a plan of treating chronic diseases has been developed that involves eliminating risk factors, especially heavy metals, curing the sources of inflammation, and substituting with micronutrients and diets. Numerous patients have experienced considerable improvements. A case report of a successful treatment for secondary adrenal insufficiency with fibromyalgia has already been published [8].

Here, we report a case where progressive motor neuron disease (PMA), the variant of ALS involving only the lower motor neurons [9,] was treated successfully.

하부 운동 뉴런만 침범하는 루게릭병의 변종인 진행성 운동 뉴런 질환(PMA)을 성공적으로 치료한 사례[9,]를 보고합니다.

Case Report

Presenting Concerns

In October 2012, a 49-year-old male patient (non-smoker, non-drinker, 178 cm, 77 kg) observed a weakness in his right arm following the restarting of martial arts after having paused for 2 years. In December 2012, he experienced additional weaknesses in the left and right shoulder and in the right thigh, and since then he noticed fasciculations in the upper extremities as well as more frequent urination.

2012년 10월, 49세 남성 환자(비흡연, 비음주, 178cm, 77kg)는 2년간 중단했던 무술을 다시 시작한 후 오른팔에 힘이 약해지는 것을 관찰했습니다. 2012년 12월에는 왼쪽 어깨와 오른쪽 어깨, 오른쪽 허벅지에 추가로 힘이 약해졌고, 그 이후 상지에 감각이 둔해지고 소변을 자주 보는 증상이 나타났습니다.

Clinical Findings

After initial presentation at a resident neurologist, he was admitted in January 2013 to a neurological inpatient unit, and finally he presented in the clinic of J.M. in February 2013 (for a timeline, see table 1). The following findings were reported by the neurological inpatient unit. There was a slight paresis of the left arm, and the left upper arm was somewhat thinner than the right upper arm. In both arms and in both lower legs fasciculations were observed. In the arms, the intensity decreased from proximal to distal and from left to right. In the pronator drift test, the left arm pronated. The muscle reflexes were weak but more pronounced on one side. Pyramidal signs were negative. The superficial sensibility was unaffected. Fasciculations were also seen in the examinations in the clinic of J.M. in February 2013, as well as weakness of muscles in the left and right shoulder, the right triceps, and the right thigh. Additional symptoms were diarrhea and sleeping disorders.

레지던트 신경과 전문의에게 첫 진료를 받은 후 2013년 1월 신경과 입원실에 입원하였고, 2013년 2월 최종적으로 J.M.의 클리닉에 내원하였습니다(타임라인은 표 1 참조). 신경과 입원실에서는 다음과 같은 소견을 보고했습니다. 왼쪽 팔에 약간의 마비가 있었고 왼쪽 상완이 오른쪽 상완보다 다소 얇았습니다. 양쪽 팔과 양쪽 아래 다리에서 매혹이 관찰되었습니다. 팔의 경우 근위에서 원위로, 왼쪽에서 오른쪽으로 강도가 감소했습니다. 내전근 드리프트 테스트에서 왼팔이 내전되었습니다. 근육 반사는 약했지만 한쪽에 더 두드러졌습니다. 피라미드 징후는 음성이었습니다. superficial sensibility은 정상이습니다. 2013 년 2 월 J.M. 클리닉의 검사에서도 왼쪽 및 오른쪽 어깨, 오른쪽 삼두근 및 오른쪽 허벅지 근육의 약화와 함께 fasciculation이 나타났습니다. 추가 증상은 설사와 수면 장애였습니다.

Table 1

Disease History

The patient had received numerous vaccinations (table 1); no adverse reactions were reported. In 2004, the patient had suffered from severe meningomyeloencephalitis from a herpes zoster infection: two days after a hit in the neck during combatant sports, the disease started with paralysis of the bladder. Subsequently, the patient developed nausea, loss of vision, fever, somnolence, as well as paresthesia and paralysis of the whole body starting at the thorax level. The patient could not walk any more, although some leg movements were possible. Later, he had feelings of heat in the back of his legs. Magnetic resonance imaging (MRI) showed several prolapsed cervical discs. Further examinations in a neurologic clinic showed nystagmus, indistinct articulation, highly increased immunoglobulin G (IgG) levels for herpes zoster in the serum, increased protein, IgG, lactate, and a number of lymphocytes in the cerebrospinal fluid. The patient received antiviral and antibacterial therapy. Within 6 weeks, the paralyses diminished gradually. The overall recovery took 3-4 years. With respect to the later diagnosis of ALS in 2012, it is remarkable that no findings were reported in the electromyography (EMG) and in the nerve conduction studies.

환자는 여러 차례 예방 접종을 받았으며(표 1), 부작용은 보고되지 않았습니다. 2004년 환자는 대상포진 감염으로 인한 중증 수막뇌뇌염을 앓고 있었는데, 격투기 경기 중 목을 가격당한 지 이틀 후 방광 마비 증상이 시작되었습니다. 그 후 환자는 메스꺼움, 시력 상실, 발열, 졸음, 흉부 수준에서 시작하여 전신의 감각 이상 및 마비가 발생했습니다. 환자는 일부 다리 움직임은 가능했지만 더 이상 걸을 수 없었습니다. 나중에 그는 다리 뒤쪽에 열감이있었습니다. 자기 공명 영상 (MRI)은 여러 개의 경추 디스크 탈출을 보여주었습니다. 신경과 클리닉에서 실시한 추가 검사에서 안진, 불명료한 발음, 혈청 내 대상포진 면역글로불린 G(IgG) 수치 증가, 뇌척수액 내 단백질, IgG, 젖산염 및 다수의 림프구 증가가 나타났습니다. 환자는 항 바이러스 및 항균 치료를 받았습니다. 6 주 이내에 마비가 점차 감소했습니다. 전반적인 회복에는 3-4 년이 걸렸습니다.

 2012년 이후 루게릭병 진단과 관련하여 근전도 검사(EMG)와 신경전도 검사에서 아무런 소견이 보고되지 않았다는 점이 주목할 만합니다.

Diagnostic Focus and Assessment

In the neurological impatient unit, the investigations focused on the possibility of a motor neuron disease, investigating the cervical spinal stenosis and addressing the meningomyeloencephalitis diagnosed in 2004. While the MRI scan of the brain showed no abnormalities, the spinal MRI scan showed degenerative changes, i.e. cervical spondylosis with multisegmental spinal stenosis without myelopathy. In the EMG, signs of acute and chronic denervation were found in several muscles:

- Musculus (M.) masseter: chronic denervation;

- M. vastus medialis, right side: acute and chronic denervation;

- M. tibialis anterior, right side: chronic denervation;

- M. gastrocnemius caput lateralis, left side: chronic denervation;

- M. biceps brachialis, left side: chronic denervation;

- M. adductor digiti minimi, right side: chronic denervation;

- M. deltoideus, right side: acute and chronic denervation.

Fasciculations were only detected in the arms and legs. The motor nerve conduction velocity of the ulnar nerve (Nervus (N.) ulnaris) was unchanged while the sensible conduction velocity was decreased on both sides, but to a higher degree at the left side. The motor-evoked potentials of the arms and legs were normal. No F-waves were found in investigations of the N. medianus and N. ulnaris. Electroneurographic examinations of the N. axillaris showed a reduction of the amplitude, which was more pronounced on the left side compared to the right side.

Fasciculations 은 팔과 다리에서만 발견되었습니다. 척골 신경의 운동 신경 전도 속도(척골 신경(N.) 척골)는 변함이 없었고 감각 전도 속도는 양쪽 모두 감소했지만 왼쪽에서 더 높은 정도였습니다. 팔과 다리의 운동 유발 전위는 정상이었습니다. 정중근과 척골의 조사에서 F 파는 발견되지 않았습니다. 겨드랑이 신경의 전기 신경전도 검사에서 진폭이 감소한 것으로 나타났는데, 이는 오른쪽에 비해 왼쪽에서 더 두드러졌습니다.

Total protein was slightly increased in the spinal liquor (81.8 mg/dl), resulting from an increase in albumin (54.8 mg/dl). Cell counts, glucose and lactate levels were within the normal limits. Intrathecal antibodies were not detected. Standard laboratory tests were without relevant findings. There were no antibodies to gangliosides in the serum. The creatine phosphokinase levels were unchanged. In the end, these findings led to the diagnosis of progressive muscle atrophy (PMA) [2]. Table 2 shows the rationale for the exclusion of relevant differential diagnoses.

총 단백질은 척추액(81.8 mg/dl)에서 약간 증가했으며, 이는 알부민(54.8 mg/dl)의 증가로 인한 결과였습니다. 세포 수, 포도당 및 젖산염 수치는 정상 범위 내에 있었습니다. 척수강 내 항체는 검출되지 않았습니다. 표준 실험실 검사에서는 관련 소견이 없었습니다. 혈청에서 강글리오사이드에 대한 항체는 발견되지 않았습니다. 크레아틴 포스 포 키나제 수치는 변하지 않았습니다. 결국 이러한 결과는 진행성 근위축증(PMA) 진단으로 이어졌습니다[2]. 표 2는 관련 감별 진단을 배제한 근거를 보여줍니다.

Table 2

Differential diagnoses of ALS and corresponding findings in the patient

In February 2013, just after the diagnosis of PMA, the patient presented in the clinic of J.M., where additional parameters in blood and urine were investigated. 25-Hydroxyvitamin D3 (14 µg/l, reference 30-60 µg/l), omega-3 index (4.44, reference > 8), and creatinine in urine (0.28 g/l, reference 0.8-2.0) were decreased. Cystatin C (0.81 mg/l, reference 0.56-0.95 mg/l), however, was within the normal limits, indicating normal glomerular filtration. Borrelia-specific IgG and IgM were negative; a later lymphocyte transformation test for Lyme borreliosis was also negative.

2013 년 2 월 PMA 진단 직후 환자는 혈액 및 소변의 추가 매개 변수가 조사 된 J.M.의 클리닉에 발표되었습니다. 25- 하이드 록시 비타민 D3 (14 µg/l, 기준 30-60 µg/l), 오메가 -3 지수 (4.44, 기준> 8) 및 소변의 크레아티닌 (0.28 g / l, 기준 0.8-2.0)이 감소했습니다. 그러나 시스타틴 C(0.81 mg/l, 기준 0.56-0.95 mg/l)는 정상 범위 내에 있어 사구체 여과 기능이 정상임을 나타냅니다. 보렐리아 특이 IgG 및 IgM은 음성이었으며 나중에 라임 보렐리 증에 대한 림프구 형질 전환 검사도 음성이었습니다.

Analysis of the history with respect to mercury exposure showed unprotected removal of 16 amalgam fillings in 1999. Exposure to mercury from the preservative thimerosal may have occurred by vaccinations and from the use of contact lens fluids. The analysis of metals in pubic hair, however, provided a mercury concentration within the normal limits and minor changes for copper and iron.

수은 노출과 관련된 이력을 분석한 결과 1999년에 16개의 아말감 충전재를 보호없이 제거한 것으로 나타났습니다. 방부제 티메로살의 수은 노출은 백신 접종과 콘택트렌즈 액 사용으로 인해 발생했을 수 있습니다. 그러나 음모의 금속 분석 결과 수은 농도는 정상 범위 내에 있었고 구리와 철의 경우 약간의 변화가 있었습니다.

The status of the teeth in February 2013 was as follows: teeth 18, 16, 28, 38, 41, 46, 48 were missing, in the cavitation of the 2 missing teeth 16 and 46, osteonecrosis was observed. Teeth 14, 15, 17, 24-27, 37-35, 44, 45, and 47 had gold or ceramic denture. Three teeth with root canal fillings (25-27) showed apical osteitis.

2013년 2월 치아 상태는 다음과 같았습니다: 18, 16, 28, 38, 41, 46, 48번 치아가 결손되었고, 결손된 16번과 46번 치아 2곳의 공동화에서 골괴사가 관찰되었습니다. 14, 15, 17, 24-27, 37-35, 44, 45, 47 치아에는 금 또는 세라믹 틀니가 있었습니다. 근관 충전이 있는 3개 치아(25-27)에서 치근단 골염이 나타났습니다.

Therapeutic Focus and Assessment

The therapy aimed at removing all possible sources of inflammation or chronic intoxication. For this purpose, 3 teeth were extracted. Instead, a removable prosthesis was incorporated. The osteitis in the regions of the 2 missing teeth was treated, and the metal denture in the remaining teeth was replaced by zirconium oxide denture. All dental procedures were made with proper safety measures to minimize the patient's exposure to metals and other dental materials, dusts, and fine particles. A black tattoo was removed. Analysis for heavy metals in the removed tissue showed detectable levels of aluminum (850 µg/kg), arsenic (10 µg/kg), lead (60 µg/kg), nickel (850 µg/kg), zinc (400 µg/kg), and tin (100 µg/kg). The mercury levels were below the limit of detection (2.5 µg/kg). In addition, the titanium screws left over in the knee from former surgery were removed because a lymphocyte transformation test and a special test showed type-IV sensitivity to titanium.

이 치료법은 가능한 모든 염증 또는 만성 중독 원인을 제거하는 것을 목표로했습니다. 이를 위해 치아 3 개를 발치했습니다. 대신 탈착식 보철물이 통합되었습니다. 빠진 치아 2 개 부위의 골염을 치료하고 나머지 치아의 금속 틀니를 산화 지르코늄 틀니로 교체했습니다. 모든 치과 시술은 금속 및 기타 치과 재료, 먼지 및 미세 입자에 대한 환자의 노출을 최소화하기 위해 적절한 안전 조치를 취하여 이루어졌습니다. 검은 문신이 제거되었습니다. 제거된 조직에서 중금속을 분석한 결과 알루미늄(850 µg/kg), 비소(10 µg/kg), 납(60 µg/kg), 니켈(850 µg/kg), 아연(400 µg/kg), 주석(100 µg/kg)이 검출 가능한 수준으로 검출되었습니다. 수은 수치는 검출 한계치(2.5 µg/kg) 이하였습니다. 또한 림프구 형질 전환 테스트와 특수 검사에서 티타늄에 대한 4형 민감성이 나타나 이전 수술에서 무릎에 남은 티타늄 나사를 제거했습니다.

After an initial phase of 2 weeks where the patient took only vitamins and micronutrients (table 3), a chelation therapy was started. Once per week the patient received an intravenous (i.v.) infusion of α-lipoic acid (600-1,200 mg), followed by sodium 2,3-dimercaptopropanesulfate (DMPS; 250 mg), together with potassium (6 mmol), magnesium (12 mmol), calcium (200 mg), and glutathione (GSH; 1,800 mg). Finally, after the DMPS infusion, sodium selenite (10-20 ml, 50 µg Se/ml) was i.v. injected separately. In addition to the i.v. infusion, DMPS (250 mg) was applied subcutaneously (s.c.) once per week. The treatment frequency was gradually reduced during therapy, resulting in 45 s.c. and 30 i.v. applications from March 26, 2013 until June 3, 2015. Until February 2, 2016, DMPS was applied orally 11 times (1 vial with 250 mg DMPS, mixed with 3 organic egg yolks, producing highly absorbable liposomal DMPS). Thus, overall, the patient received 86 DMPS applications.

환자가 비타민과 미량 영양소만 섭취한 2주간의 초기 단계(표 3)가 끝난 후 킬레이트 요법을 시작했습니다. 환자는 일주일에 한 번 α-리포산(600~1,200mg)을 정맥(정맥주사)으로 주입한 후 2,3-디메르캅토프로판설페이트 나트륨(DMPS, 250mg)과 칼륨(6mmol), 마그네슘(12mmol), 칼슘(200mg) 및 글루타치온(GSH, 1,800mg)을 함께 투여받았습니다. 마지막으로 DMPS 주입 후 셀레나이트 나트륨(10-20ml, 50µg Se/ml)을 별도로 정맥 주사했습니다. 정맥주사 외에도 DMPS(250 mg)를 주 1회 피하(s.c.)로 도포했습니다. 치료 기간 동안 치료 빈도는 점차 감소하여 2013년 3월 26일부터 2015년 6월 3일까지 45회 피하 주사 및 30회 정맥 주사를 실시했습니다. 2016년 2월 2일까지 DMPS를 11회 경구 투여했습니다(유기농 달걀 노른자 3개와 혼합하여 흡수성이 높은 리포솜 DMPS를 생성하는 250mg DMPS 1바이알). 따라서 환자는 전체적으로 86회의 DMPS 투여를 받았습니다.

Table 3

Daily dosages of orally applied vitamins, micronutrients, and other supplements

In addition, the patient was advised to keep a vegetarian diet with a high proportion of raw, unprocessed food (60-70% of daily intake), also including wild herbs, and to reduce carbohydrate and especially gluten intake.

The patient's compliance with this therapy has been excellent. Motivated by the continuous improvement of his health, he has been following the instructions up to now.

또한 환자는 야생 허브를 포함하여 가공되지 않은 날 음식(일일 섭취량의 60-70%)의 비율이 높은 채식 식단을 유지하고 탄수화물, 특히 글루텐 섭취를 줄이도록 권고받았습니다.

이 요법에 대한 환자의 순응도는 매우 우수했습니다. 지속적인 건강 개선에 동기를 부여받은 그는 지금까지 지침을 따르고 있습니다.

According to a new report published in JAMA Neurology, a subset of patients with amyotrophic lateral sclerosis (ALS) are seropositive for transglutaminase 6 (TG6) antibodies, which are associated with sensitivity to the wheat protein gluten. The results raise the possibility that gluten sensitivity, which commonly manifests as the digestive disorder coeliac disease, can also present as an ALS-like syndrome that might be ameliorated by a gluten-free diet.

JAMA 신경학에 발표된 새로운 보고서에 따르면 근위축성 측삭 경화증(ALS) 환자의 일부가 밀 단백질 글루텐에 대한 민감성과 관련이 있는 트랜스글루타미나제 6(TG6) 항체에 혈청 양성 반응을 보인다고 합니다. 이 결과는 일반적으로 소화 장애인 체강 질병으로 나타나는 글루텐 과민증이 글루텐 프리 식단으로 개선될 수 있는 루게릭병과 유사한 증후군으로 나타날 수 있다는 가능성을 제기합니다.

https://jamanetwork.com/journals/jamaneurology/fullarticle/2241558

Credit: NPG

Study leader Vivian Drory explains that the research was prompted by a patient in her clinic with ALS, who had also recently been diagnosed as having coeliac disease. “We looked at whether this association had been described before, and found two case reports,” she says. “This led us to examine whether these cases are pure chance associations, so we examined our ALS clinic population cross-sectionally for gluten-sensitivity markers.”

Various neurological manifestations have been reported in patients with gluten sensitivity. One such manifestation, the movement disorder gluten ataxia, has been linked to the presence of serum TG6 antibodies. Drory and colleagues measured the levels of several different antibodies in 150 patients with ALS and 115 healthy controls. Most notably, 23 (15.3%) of the patients with ALS were seropositive for TG6 IgA, compared with only five (4.3%) of the controls.

If confirmed in future studies, the new findings could provide a case for considering gluten sensitivity in the differential diagnosis of ALS, with the possibility of dietary intervention in patients who meet the necessary criteria. A cautious approach is warranted, however, as patients with ALS have previously been shown to benefit from high calorie intake, which might be difficult to achieve with a gluten-free diet.

Drory's team is now conducting a prospective study involving patients in the early stages of ALS (<2 years' disease duration). Those participants who are found to be seropositive for gluten-related antibodies will be given the option of a gluten-free diet, which will be closely monitored by a specialist dietician. “This study will allow us to make better assumptions on the role of gluten-related antibodies in motor neuron degeneration, and also to explore the feasibility of a therapeutic approach in the subset of antibody-positive patients,” Drory concludes.

Follow-up and Outcomes

Several laboratory investigations were performed to follow the therapy. The most important results are provided here.

Metals in the urine were determined in spot urine samples at the start of the chelation therapy, and after 1 and 2 months. The patient was asked to urinate before i.v. infusion of DMPS. About 45 min after finishing the infusion, urine was collected. For mercury, the first 2 measurements (4.3 and 3.9 µg/g creatinine, respectively) were below the reference value of 50 µg/g creatinine for DMPS challenge. Finally, in the third measurement, 1 month later and after 7 DMPS infusions, there was a strong increase in mercury to 248.4 µg/g creatinine. The high zinc values in the urine (3,130.6 to 6,581.8 µg/g creatinine, reference 2,000-9,000 µg/g creatinine) indicate that zinc was substituted successfully before and after the chelation therapy.

After the treatment of his teeth, already before the chelation therapy, the patient felt immediate relief. The muscular strength was increased, which he recognized by improvements when climbing stairs. Figure 1 shows the course of the most prominent findings during the 3 years of treatment. With the exception of the left shoulder muscle, the weakness diminished within 4 months after treatment start. The general health improved; the patient took up jogging and went to a gym regularly. He gained muscle mass and body weight. His performance in sports became even better than before the diagnosis of PMA. After 1.5 years, a neurologist confirmed the absence of ALS by EMG of the affected muscles.

크레딧: NPG
연구 책임자인 비비안 드루리는 자신의 클리닉에서 최근 루게릭병 진단을 받은 루게릭병 환자에게서 이 연구가 촉발되었다고 설명합니다. "이 연관성이 이전에 설명된 적이 있는지 살펴본 결과 두 건의 사례 보고를 발견했습니다."라고 그녀는 말합니다. "이 사례들이 순수한 우연에 의한 연관성인지 조사하기 위해 루게릭병 클리닉 환자군을 대상으로 글루텐 민감성 마커를 단면적으로 조사했습니다."

글루텐 민감성 환자에서 다양한 신경학적 증상이 보고되었습니다. 이러한 증상 중 하나인 운동 장애 글루텐 운동 실조증은 혈청 TG6 항체의 존재와 관련이 있습니다. Drory와 동료들은 루게릭병 환자 150명과 건강한 대조군 115명을 대상으로 여러 가지 항체 수치를 측정했습니다. 가장 주목할 만한 점은 루게릭병 환자 중 23명(15.3%)이 TG6 IgA 혈청 양성 반응을 보인 반면, 대조군에서는 5명(4.3%)만이 양성 반응을 보였다는 점입니다.

향후 연구에서 이 새로운 결과가 확인되면 루게릭병의 감별 진단에 글루텐 민감성을 고려할 수 있는 근거가 될 수 있으며, 필요한 기준을 충족하는 환자에게 식이 요법을 시행할 수 있을 것으로 보입니다. 그러나 루게릭병 환자는 글루텐 프리 식단으로는 달성하기 어려울 수 있는 고칼로리 섭취가 도움이 되는 것으로 이전에 밝혀졌기 때문에 신중한 접근이 필요합니다.

현재 Drory 박사팀은 루게릭병 초기 단계(유병 기간 2년 미만)의 환자를 대상으로 전향적 연구를 진행하고 있습니다. 글루텐 관련 항체 혈청 양성이 확인된 참가자에게는 글루텐 프리 식단을 선택할 수 있는 옵션이 주어지며, 전문 영양사가 면밀히 모니터링할 것입니다. "이 연구를 통해 운동 신경세포 퇴행에서 글루텐 관련 항체의 역할에 대해 더 나은 가정을 세우고, 항체 양성 환자의 하위 집합에서 치료 접근법의 타당성을 탐색할 수 있을 것입니다."라고 Drory는 결론을 내립니다.

Fig. 1

Time course of improvement of symptoms during treatment. Scores were rated at 0-10, with 10 being the maximum; fasciculation and body weight were established independently or through measurement; all other variables were scored by the patient at every visit on a 10-point numerical rating scale.

Discussion

Comprehensive investigations led to the diagnosis of PMA based on:

- clinical findings (weakness and fasciculations) in 2 body regions (shoulder and lower legs);

- EMG findings of denervation in 2 body regions (arms and legs) as well as

- bulbar signs in EMG (denervation of m. masseter).

PMA is distinguished from ALS by a lack of effects on the upper motor neuron. The close relationship of the 2 diseases is, however, reflected by the fact that upper motor neuron findings often appear at later stages of PMA, and degeneration of upper motor neurons is also found in the majority of PMA patients if autopsy is performed. In addition, patients with a PMA phenotype carry pathogenic mutations known from ALS. Therefore, PMA is considered to be a variant of ALS [9].

When eval‎uating the success of the therapy, it is also important to rule out misdiagnosis, because similar diseases might be better treatable than ALS. As described above, the diagnostic process was thorough and several alternative diagnoses to motor neuron diseases can be excluded, as summarized in table 2. A finding that is not typical of ALS is a slightly increased quotient of albumin in the spinal fluid/serum of 11.2 × 10-3. A range of 6.5 × 10-3 - 8 × 10-3 is considered as normal at the age of the patient. For ALS patients, maximum values of 10 × 10-3 have been reported [10]. As this is the only parameter changed in the spinal fluid, a few diagnoses besides ALS may account for this finding. One of them is cervical spinal stenosis. As the patient had cervical spinal stenosis, this may have caused the observed albumin increases in the spinal fluid [11]. In addition, a reduced sensory nerve conduction velocity is not typical of ALS. According to Kollewe and Petri [12], however, it does not contradict this diagnosis.

PMA는 상부 운동 뉴런에 영향을 미치지 않는다는 점에서 ALS와 구별됩니다. 그러나 두 질환의 밀접한 관계는 상부 운동 뉴런 소견이 종종 PMA 말기에 나타나고 부검을 실시하면 대부분의 PMA 환자에서 상부 운동 뉴런의 퇴행이 발견된다는 사실에 반영되어 있습니다. 또한 PMA 표현형을 가진 환자는 루게릭병에서 알려진 병원성 돌연변이를 가지고 있습니다. 따라서 PMA는 루게릭병의 변종으로 간주됩니다 [9].

치료의 성공 여부를 평가할 때 유사한 질병이 루게릭병보다 더 잘 치료될 수 있기 때문에 오진을 배제하는 것도 중요합니다. 위에서 설명한 바와 같이 진단 과정은 철저했으며 표 2에 요약된 바와 같이 운동 신경 질환에 대한 몇 가지 대체 진단을 배제할 수 있습니다. 루게릭병에서 전형적이지 않은 소견은 척수액/혈청 내 알부민 수치가 11.2 × 10-3으로 약간 증가한다는 것입니다. 환자의 나이에 따라 6.5 × 10-3 - 8 × 10-3의 범위가 정상으로 간주됩니다. 루게릭병 환자의 경우 10 × 10-3의 최대값이 보고되었습니다 [10]. 이것이 척수액에서 변화된 유일한 파라미터이므로 루게릭병 외에 몇 가지 진단이 이 결과를 설명할 수 있습니다. 그중 하나가 경추 척추관 협착증입니다. 환자에게 경추 척추관 협착증이 있었기 때문에 척추액에서 알부민 증가가 관찰되었을 수 있습니다 [11]. 또한 감각 신경 전도 속도 감소는 루게릭병의 전형적인 증상이 아닙니다. 그러나 콜레베와 페트리[12]에 따르면 이 진단과 모순되지 않는다고 합니다.

To allow a consistent eval‎uation, it would have been desirable if the hospital that had first diagnosed the motor neuron disease had examined the patient after the therapy. This option was proposed several times to the patient. However, for personal reasons (as the physician told him that he will die in 1-2 years, the patient fell into a deep depression and considered suicide), the patient refrained from returning to this hospital but chose to see the resident neurologist who had first sent him to the hospital. The resident neurologist registered the absence of motor neuron disease in his EMG examinations, which can be taken as confirmation of the successful therapy.

일관된 평가를 위해 운동 신경 질환을 처음 진단한 병원에서 치료 후 환자를 검사했더라면 더 좋았을 것입니다. 이 옵션은 환자에게 여러 번 제안되었습니다. 그러나 환자는 개인적인 이유(의사가 1~2년 안에 사망할 것이라고 말하자 환자는 깊은 우울증에 빠져 자살을 고려함)로 이 병원으로 돌아가지 않고 처음 자신을 이 병원으로 보냈던 신경과 레지던트에게 진료를 받기로 결정했습니다. 레지던트 신경과 전문의는 근전도 검사에서 운동 신경 질환이 없다고 기록했으며, 이는 성공적인 치료의 확인으로 간주 될 수 있습니다.

There is also the possibility of spontaneous healing of motor neuron disease. In fact, there are a few reports that ALS may be reversible, even without therapy [13,14,15]. The temporal association of the improvements with the therapy in the case of our patient, however, argues against spontaneous healing. In addition, several other ALS patients have improved considerably after therapy initiated by J.M. based on a similar protocol.

운동 신경 질환의 자연 치유 가능성도 있습니다. 실제로 루게릭병은 치료 없이도 가역적일 수 있다는 보고가 몇 건 있습니다[13,14,15]. 그러나 우리 환자의 경우 치료와 개선의 시간적 연관성은 자연 치유에 반대합니다. 또한 다른 여러 루게릭병 환자들도 유사한 프로토콜에 따라 J.M.이 치료를 시작한 후 상당히 호전되었습니다.

In conclusion, we are confident that the patient had indeed suffered from motor neuron disease and that his healing was a consequence of the therapy.

결론적으로, 우리는 환자가 실제로 운동 신경 질환을 앓고 있었으며 그의 치유가 치료의 결과라고 확신합니다.

The patient received a chelation therapy, to remove amalgam or other heavy metals originating from an assumed pervious exposure, although no residual amalgam was detected during the investigation of the teeth, and although the levels of mercury and other metals in the hair and after the first 2 DMPS challenges were within the normal reference values. According to the experience of J.M., a chelation therapy is already justified when exposure, e.g., from unprotected removal of dental amalgam, has been established in a patient's history, even without measuring abnormal values through normal routes of human biomonitoring. This is backed by data showing that verified exposure to mercury can lead to neurological symptoms despite normal biomonitoring results [16,17]. Furthermore, this approach is justified in hindsight by the fact that, finally, high mercury concentrations appeared in the urine of the patient during the chelation therapy, albeit with a delay of 2 months. The delay was probably due to an accumulation of mercury in deep compartments like the brain or the spine, where it is not readily accessible [18].

Mercury accumulates in interneurons and to a lesser degree in α-motoneurons, in amounts increasing with age. This may lead to motor neuron death and thus provides support to the view that exposure to mercury may be a contributing factor to ALS in susceptible individuals [19].

수은은 뉴런에 축적되고 α- 운동 뉴런에는 덜 축적되며 나이가 들면서 그 양이 증가합니다. 이는 운동 신경세포의 사멸로 이어질 수 있으며, 따라서 수은 노출이 루게릭병에 취약한 개인에게 루게릭병의 원인이 될 수 있다는 견해를 뒷받침합니다[19].

There are reports in the literature showing that chelation therapy is capable of reducing ALS or ALS-like symptoms after exposure to mercury [20], but there are also cases without success [21]. The chelation therapy applied here is different from earlier approaches. First, it is applied over a long period. Generally, with prolonged DMPS application, several peaks of mercury are observed in the urine in humans previously exposed to mercury [22], which is possibly due to the redistribution of mercury from deep compartments into tissues that are accessible to DMPS [23,24,25,26]. As it is known that mercury accumulates as inorganic mercury in the brain, it is important to cover these deep compartments by an appropriate therapy. The numerous applications were well tolerated by the patient, which is consistent with the low toxicity of DMPS [27].

In addition, the chelation therapy involves α-lipoic acid. α-Lipoic acid enters the brain and reverses the oxidant effects of mercury [28], but it is not capable of removing mercury from the brain [26]. As it also has chelating properties, it may contribute to the elimination of mercury from other compartments of the body. Finally, selenium plays an important role in the therapy. Selenium effectively binds to mercury and reduces its toxicity [29,30]. Thus, any remaining mercury that may not be bound to DMPS can be efficiently inactivated.

킬레이션 요법이 수은 노출 후 루게릭병 또는 루게릭병 유사 증상을 감소시킬 수 있다는 문헌 보고가 있지만[20], 성공하지 못한 사례도 있습니다[21]. 여기에 적용된 킬레이션 요법은 이전의 접근 방식과 다릅니다. 첫째, 장기간에 걸쳐 적용된다는 점입니다. 일반적으로 DMPS를 장기간 적용하면 이전에 수은에 노출된 사람의 소변에서 수은의 여러 피크가 관찰되는데[22], 이는 수은이 깊은 구획에서 DMPS에 접근 할 수있는 조직으로 재분배되기 때문일 수 있습니다 [23,24,25,26]. 수은은 뇌에 무기 수은으로 축적되는 것으로 알려져 있기 때문에 적절한 치료로 이러한 깊은 구획을 덮는 것이 중요합니다. 수많은 적용은 환자가 잘 견뎌냈으며, 이는 DMPS의 낮은 독성과 일치합니다 [27].

또한 킬레이션 요법에는 α- 리포산이 포함됩니다. α- 리포산은 뇌로 들어가 수은의 산화 효과를 역전 시키지만 [28] 뇌에서 수은을 제거 할 수는 없습니다 [26]. 또한 킬레이트 특성을 가지고 있기 때문에 신체의 다른 구획에서 수은을 제거하는 데 기여할 수 있습니다. 

마지막으로 셀레늄은 치료에서 중요한 역할을 합니다. 셀레늄은 수은에 효과적으로 결합하여 수은의 독성을 감소시킵니다 [29,30]. 따라서 DMPS에 결합되지 않은 나머지 수은은 효율적으로 비활성화될 수 있습니다.

Another factor that may have contributed to the therapy is the intensive dental treatment aiming at removing residential amalgam, other metals, and inflammation. No amalgam was detected, but metal linings were restored and the osteitis under 2 teeth of the patient was cured. Osteitis - also called fatty degenerative osteonecrosis, chronic ischemic bone disease, neuralgia-inducing cavitational osteonecrosis, or just jawbone cavitation - is characterized by hollow cavitations with soft tissue that have undergone fatty dystrophic changes, and by delamination of the bony sheath of the inferior alveolar nerve [31]. It may produce facial pain but can also be present for years as an asymptomatic process. Dramatically increased levels of RANTES and fibroblast growth factor 2 (FGF-2) can be detected in the fatty tissue removed by surgery, but no elevations in cytokines associated with acute inflammation [32,33]. RANTES is increased in the serum of patients with several chronic diseases, including ALS [34]. Surgical debridement of the tissue in the cavitations has led in several cases to an improvement of the neuralgic pain in the face [35], and also of immunological complaints, such as rheumatic, allergic, and other inflammatory diseases [33]. The fact that the patient felt immediate relief after treatment of his teeth even before the start of the chelation therapy points to a possible contribution of this treatment to healing. Furthermore, according to the experience of J.M., major improvements in the disease status of his patients are observed if teeth are cured at the start of the therapy, which involves - sometimes - radical eliminations of teeth.

치료에 기여했을 수있는 또 다른 요인은 주거용 아말감, 기타 금속 및 염증을 제거하는 것을 목표로하는 집중 치과 치료입니다. 아말감은 검출되지 않았지만 금속 라이닝이 복원되었고 환자의 치아 2 개 아래의 골염이 치료되었습니다. 지방성 퇴행성 골괴사, 만성 허혈성 골 질환, 신경통 유발 공동성 골괴사 또는 턱뼈 공동화라고도 하는 골염은 지방 영양 장애 변화를 겪은 연조직과 하치조 신경의 뼈 피막이 박리된 중공 공동이 특징입니다[31]. 안면 통증을 유발할 수 있지만 무증상 과정으로 수년간 지속될 수도 있습니다. 수술로 제거한 지방 조직에서 극적으로 증가한 RANTES 및 섬유아세포 성장인자 2(FGF-2) 수치가 검출될 수 있지만, 급성 염증과 관련된 사이토카인의 증가는 발견되지 않습니다[32,33]. 루게릭병을 포함한 여러 만성 질환 환자의 혈청에서 RANTES가 증가합니다[34]. 충치의 조직을 외과 적으로 제거하면 여러 경우에 얼굴의 신경통이 개선되고 [35] 류마티스, 알레르기 및 기타 염증성 질환과 같은 면역 학적 불만도 개선되었습니다 [33]. 환자가 킬레이트 요법을 시작하기 전에도 치아 치료 후 즉각적인 완화를 느꼈다는 사실은이 치료가 치유에 기여할 수 있음을 시사합니다. 또한 J.M.의 경험에 따르면 치료 시작시 치아가 치료되면 환자의 질병 상태가 크게 개선되는 것으로 관찰되며 때로는 치아의 급진적 제거가 포함됩니다.

Psychotherapy was initiated by the patient after the start of the therapy as a support for the emotional problems associated with his disease and its interpersonal consequences. In his own view, however, this was not the major causative factor for his improvement.

In conclusion, the therapy described here is a promising approach to treating some kinds of motor neuron disease. It should be eval‎uated more widely and rigorously.

Patient's Perspective

The patient noted down his experiences during the diagnosis and treatment of his disease; the text is publicly available [36].

Informed Consent

The patient consented to anonymous publication of his data, which is gratefully acknowledged by the authors.

Author Contributions

I.M. conducted the review of the case and wrote the manuscript. J.M. developed and conducted the therapy and organized a large part of the data collection. He also contributed to writing the paper and critical discussions. H.W. generated the idea for the study, developed the protocol, and partook in writing the paper and in critical discussions.

Disclosure Statement

None of the authors has any conflict of interest.

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