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Moyamoya disease: A retrospective study of 198 cases
Med Clin (Barc). 2019;153(12):441–445
www.elsevier.es/medicinaclinica
Original article
Moyamoya disease: A retrospective study of 198 cases Yan Ma a,b , Qiaoyun Guo a,b , Yali Yan a,b , Ye Zhang a,b , Zhijie Lin a,b , Jianying Zhang a,b,c , Kaijuan Wang a,b , Chunhua Song a,b,∗ a
Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China Henan Key Laboratory of Tumor Epidemiology, Zhengzhou 450001, Henan, China c Henan Academy of Medical and Pharmaceutical Sciences and Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China b
a r t i c l e
i n f o
Article history: Received 14 January 2019 Accepted 14 February 2019 Available online 8 June 2019 Keywords: Clinical features Moyamoya disease Chinese population
a b s t r a c t Background: Moyamoya disease belongs to rare diseases which are arousing public awareness of its importance in China. In order to investigate the clinical features of inpatients diagnosed Moyamoya disease, the study was conducted to collect clinical information data of subjects on demographic information and clinical characteristics in Henan, China. Methods: The data of 198 cases of Moyamoya disease from 56 tertiary hospitals in Henan province from January 2003 to June 2015 were collected retrospectively. Analysis was performed based on demographic, clinical and radiological characteristics of the patients. Results: The mean onset age was 44.03 ± 14.45 years old. Unilateral limb weakness (36.4%) was the most common physical examination. Primary clinical manifestation was headache and dizziness (50.3%). Cranial CT showed cerebral infarction was mainly located in the frontal lobe (27.4%). MRA and DSA showed lesions mainly located in the middle cerebral artery (30.3% and 18.7%). Conclusions: Clinical manifestations of Moyamoya disease varied. Early diagnosis was necessary to reduce the misdiagnosis rate of this disease. Symptoms, radiological characteristics, and lesion localization characteristics should be fully considered, especially for indicators with a certain onset age, headache and dizziness, lesion located in the frontal lobe of middle cerebral artery. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Enfermedad de moyamoya: estudio retrospectivo de 198 casos r e s u m e n Palabras clave: Características clínicas Enfermedad de moyamoya Población china
Antecedentes: La enfermedad de moyamoya pertenece al grupo de afecciones raras cuya importancia está despertando la conciencia pública en China. Con el fin de investigar las características clínicas de los pacientes hospitalizados en Henan (China) diagnosticados con la enfermedad de moyamoya, se llevó a cabo este estudio para recopilar información clínica sobre los pacientes junto con información demográfica y características clínicas. Métodos: Se recogieron retrospectivamente datos de 198 casos de la enfermedad de moyamoya en 56 hospitales terciarios de la provincia de Henan entre enero de 2003 y junio de 2015. El análisis se realizó con base en las características demográficas, clínicas y radiológicas de los pacientes. ˜ Resultados: La edad media de inicio de la enfermedad era de 44,03 ± 14,45 anos. La debilidad unilateral de las extremidades (36,4%) fue el hallazgo más común en las exploraciones físicas y la manifestación clínica primaria fue la combinación de dolor de cabeza y mareos (50,3%). La tomografía craneal mostró que el infarto cerebral afectaba principalmente al lóbulo frontal (27,4%). La angiografía de resonancia magnética y la angiografía por sustracción digital mostraron lesiones ubicadas principalmente en la arteria cerebral media (30,3 y 18,7%, respectivamente).
∗ Corresponding author. E-mail address: [email protected] (C. Song). https://doi.org/10.1016/j.medcli.2019.02.024 ˜ S.L.U. All rights reserved. 2387-0206 0025-7753/© 2019 Elsevier Espana,
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Conclusiones: Las manifestaciones clínicas de la enfermedad de moyamoya fueron muy variadas. El diagnóstico precoz resultó necesario para reducir la tasa de diagnósticos erróneos de esta enfermedad. Se deben considerar los síntomas, las características radiológicas y las características de ubicación en su totalidad, especialmente en el caso de indicadores con una edad específica de inicio, dolor de cabeza y mareos, o una lesión situada en el lóbulo frontal, en la arteria cerebral media. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction Rare diseases, also known as orphan disease, include rare genetic diseases, infectious diseases, autoimmune diseases and rare cancers. Rare diseases are serious and chronic with a particularly low prevalence which can be life-threatening, and impose a physical, psychological, and socioeconomic burden on patients, their families, society and public health systems.1–4 It was estimated that there were approximately 6000–8000 kinds of rare diseases which affected 6–8% of the population in the world.5 Rare diseases were estimated to affect 350–400 million people globally, and there were at least 10 million rare diseases patients according to the definition of WHO in China.6,7 This was a heavy burden. The real burden of rare diseases was difficult to estimate for each patient and their families. Missed or delayed diagnosis, shortage of effective drugs, and the high cost of currently available drugs were three features in treatment of rare diseases.8 At present, public awareness of rare diseases was increasing in China. Moyamoya disease (MMD) is one kind of rare diseases, coded as I67.5 in International Classification of Diseases (ICD 10), belonging to the circulatory system disease. It is a chronic, occlusive cerebrovascular disease with an unknown etiology which characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery (ICA) and an abnormal vascular network at the base of the brain.9,10 MMD was reported around the world, usually in East Asia, high incidence and prevalence were shown mainly in Korea, Japan, Taiwan, and China,11–14 especially in Japan and South Korea.15 Now the cause of MMD was still not clear. A recent study showed that RNF213 R4810K was identified as the major susceptibility gene.16 In China, a large epidemiological survey of clinical features of MMD have been reported only in Taiwan and Nanjing till now, no such survey has been reported in the province of Henan in China in existing literature. In a word, the aim of this study was to describe the clinical features of inpatients being attacked by MMD and to provide clues for the clinical diagnosis of MMD.
atherosclerosis, arterial interlayer and tumor. The criteria included three principal factors as follows: (1) stenosis or occlusion at the terminal portion of the internal carotid artery (ICA) and/or at the proximal portion of the anterior and/or middle cerebral arteries; (2) abnormal vascular networks in the vicinity of the occlusive or stenotic lesions in the arterial phase; and (3) lesion bilaterality.18 Statistical analysis The whole data were input in Epidata database, including demographic characteristics, physical examination, clinical features and radiological characteristics. None personal privacy of patients was involved. In the study, data were described using frequency, proportion, mean and standard deviation. All analyses were performed by using SPSS software, version 21.0. Results Demographic characteristics There were 91 males and 107 females among the 198 patients diagnosed MMD and the ratio of male-to-female was 1:1.18. The mean age at diagnosis was 44.03 ± 14.45 years old (range, 4–78 years). There were two peaks in age distribution both in male and female, which was similar to the total (Fig. 1). There were 4 cases having family history, whose mothers clinically diagnosed. More details could be seen in Table 1 and Fig. 1. Physical examination and clinical manifestation The mean systolic blood pressure was 130 mmHg, in the meantime, mean diastolic blood pressure was 83 mmHg. The average heart rate was 78 beats per minute. The most common physical symptom was weakness on one side of the body (35.9%), followed by paroxysmal or persistent dizziness (27.3%). As for clinical symptoms, the primary was headache and dizziness (49.5%), followed by cerebral infarction (36.9%). More details could be seen in Table 2.
Methods
Self-reported symptoms
Subjects
Most patients had more than one complaint. Among 198 patients, dizziness could be seen as the most common complaint (29.8%), followed by headache (22.7%), limb weakness (19.2%), numbness of limbs (11.1%). More details could be seen in Table 3.
This study was a retrospective analysis of 198 subjects with the final diagnosis of MMD in 56 tertiary hospitals located in Henan Province from January 1st 2003 to June 30th 2015. The selected hospitals were the top three general hospitals, top three specialized hospitals and the affiliated teaching hospitals of the medical undergraduate college who had the ability to identify, diagnose or treat MMD. The data of hospitalized patients were searched by ICD in the case information system of these hospitals through a predetermined questionnaire. After that the information was extracted and recorded except for the patient’s privacy information. As for the recruited cases, all cases were diagnosed in line with the criteria proposed by the Research Committee on Spontaeous Occlusion of the Circle of Willis in 1997.17 The diagnosis of MMD must exclude other causes of intracranial vascular stenosis, such as
Imaging examination Results of CT examination of patients with MMD showed 84 cases appearing cerebral infarction which mostly located in the frontal lobe (27.4%). Cerebral hemorrhage sites were mainly located in the ventricle, and cerebral infarction and cerebral hemorrhage could coexist. More details could be seen in Table 3. Examination results of brain magnetic resonance imaging (MRA) of MMD showed lesions located in the middle cerebral artery (MCA) (30.3%), followed by internal carotid artery (ICA) (20.2%), anterior cerebral
Y. Ma et al. / Med Clin (Barc). 2019;153(12):441–445
443
21 Total 18
Male Female
Percentage
15 12 9 6 3 0 0-4
5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 ≥70 Age(years)
Fig. 1. Distribution of age of MMD in male, female and total subjects. Table 1 Demographic characteristics of cases (N, %).
Treatment
Variables
All patients
Gender Men Women Male:female ratio
91 (46.0) 107 (54.0) 1:1.18
Family history Yes No
4 (2.0) 194 (98.0)
Residential area Rural Urban
91 (46.0) 107 (54.0)
Surgery Yes No
67 (33.8) 131 (66.2)
Blood pressure (¯x ± s, mmHg) Systolic pressure Diastolicpressure Heart rate x¯ ± s, / min
130.0 ± 17.8 83.0 ± 10.9 78.4 ± 10.9
NRCMIS, New Rural Cooperative Medical Insurance Scheme.
artery (ACA) (16.2%), posterior cerebral artery (PCA) (9.1%); the results of digital subtraction angiography (DSA) examination were consistent with MRA (Table 4).
Considering the treatment of the patients, 14.6% used vasodilators, 21.2% used calcium antagonists, 27.8% used medicine for reducing intracranial pressure. 31.3% of the subjects choosing to use surgery. More details could be seen in Table 2.
Discussion The study showed the data about patients diagnosed with MMD collected from 56 tertiary hospitals of Henan Province in China during January 1st 2003 to June 30th 2015. In this study, clinical features of inpatients were mainly described. MMD is a chronic, occlusive cerebrovascular disease characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery (ICA) and an abnormal vascular network at the base of the brain.9 The etiology of MMD is still unknown. However, a recent study discovered the ring finger protein 213 gene (RNF213) could be used as a susceptibility gene for MMD.16 Recent revised diagnostic criteria for definitive MMD requires catheter angiography in unilateral cases, whereas bilateral cases can be promptly diagnosed by either catheter angiography or MRA.15 As for the differential diagnosis, diseases such as atherosclerosis, autoimmune disease, meningitis, brain tumors, Down’s syndrome, von Recklinghausen’s disease, head injury, cerebrovascular lesions
Table 2 Physical examination, clinical manifestation and treatment of cases (N, %). Yes
No
Not check/not applied
Physical examination Weakness on one side of the body Hemiplegia on one side of the body or both Involuntary movement of the body Disturbance of consciousness Paroxysmal or persistent dizziness Meningeal irritation
71 (35.9) 8 (4.0) 17 (8.6) 25 (12.6) 54 (27.3) 11 (5.6)
124 (62.6) 186 (93.9) 176 (88.9) 170 (85.9) 139 (70.2) 171 (86.4)
3 (1.5) 4 (2.0) 5 (2.5) 3 (1.5) 5 (2.5) 16 (8.1)
Clinical manifestation Paropsia Headache and dizziness Cerebral infarction Transient cerebral ischemia Cerebral hemorrhage
28 (14.1) 98 (49.5) 73 (36.9) 22 (11.1) 53 (26.8)
164 (82.8) 97 (49.0) 118 (59.6) 169 (85.4) 139 (70.2)
6 (3.0) 3 (1.5) 7 (3.5) 7 (3.5) 6 (3.0)
Medicine treatment Vasodilators Calcium antagonists Medicine for reducing intracranial pressure Surgical treatment
29 (14.6) 42 (21.2) 55 (27.8) 62 (31.3)
164 (82.8) 150 (75.8) 143 (72.2) 121 (61.1)
5 (2.5) 6 (3.0) 0 (0.0) 15 (7.6)
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Table 3 Chief complaint and CT examination results of cases (N, %). Chief complaint Symptom
CT examination results Number (%)
Headache Dizziness Limb activity disorder Limb weakness Numbness of limbs Vomit Vision disorder Alalia Disturbance of consciousness Cerebral hemorrhage Cerebral infraction Forgetfulness Physical examination
Total (n)
45 (22.7) 59 (29.8) 13 (6.6) 38 (19.2) 22 (11.1) 12 (6.1) 12 (6.1) 17 (8.6) 18 (9.1) 15 (7.6) 8 (4.0) 4 (2.0) 11 (5.6)
198
Cerebral infarction area
Number (%)
Cerebral hemorrhage area
Number (%)
Frontal lobe Parietal lobe Temporal lobe Occipital lobe Basal ganglia Anterior cerebral artery Middle cerebral artery Internal carotid Ventricle Centrum semiovale Corona radiata Corpus callosum Thalamus Cerebral hemisphere Brainstem Total (n)
23 (27.4) 15 (17.9) 15 (17.9) 9 (10.7) 21 (25.0) 4 (4.8) 15 (17.9) 7 (8.3) 14 (16.7) 4 (4.8) 3 (3.6) 1 (1.2) 1 (1.2) 2 (2.4) 1 (1.2) 84
Frontal lobe Parietal lobe Temporal lobe Occipital lobe Basal ganglia Ventricle Brain parenchyma Subarachnoid space Arteria supraorbitalis Epidural hematoma Thalamus Corona radiata Hard retinal inferior vena Internal carotid
7 (15.6) 4 (8.9) 8 (17.8) 1 (2.2) 8 (17.8) 10 (22.2) 4 (8.9) 8 (17.8) 1 (2.2) 1 (2.2) 2 (4.4) 1 (2.2) 1 (2.2) 1 (2.2)
Table 4 Lesion site of imaging examination (N, %).
ICA MCA ACA PCA Not check
Head MRA examination
Head DSA examination
40 (20.2) 60 (30.3) 32 (16.2) 18 (9.1) 48 (24.2)
20 (10.1) 37 (18.7) 15 (7.6) 9 (4.5) 117 (59.1)
after head irradiation and others must be excluded first.17 Quasimoyamoya disease affects bilateral or unilateral hemisphere with underlying disease.9 Comprehensive consideration of clinical, laboratory and imaging diagnosis could identify these diseases. In the study, the number of female patients was more than male patients, and the male-to-female ratio was 1:1.18. It was consistent with the previous studies that MMD was more common in women.12,19 Data from several studies have demonstrated that the distribution of presentation age revealed a bimodal distribution with two peaks both happening in childhood and adulthood.12,14,15,19–21 Besides, some existing studies indicated that there was no age peak in childhood.12,22 There was a bimodal distribution with two peaks in 10–14 and 40–44 years in this study, which confirmed that MMD could happen focused on the teenagers and the age 40–50. The disease showed an obvious familial tendency, in which there was a 6–12% risk of developing MMD if a person had a first-degree relative diagnosed with MMD.23 Moreover, the data of familial occurrence of MMD had been variably reported: 1.48% or 5.2% in China,14,20 and 10–15% in Japan.24,25 However, in this study, 4 cases were identified with familial tendency of MMD, consisting 2% of whole cases, lower than that in Japanese population. Maybe a genetic factor played a role in the incidence of MMD. The study showed headache and dizziness was the primary clinical manifestations. Several studies reported that there were two types of presentation, ischemia and hemorrhage.12,18,19,26,27 Lian Duan had reported that in their cohort, transient ischemic attack was found as the most common initial clinical manifestation.20 In this study, headache and dizziness was discovered as the most clinical manifestations presented in MMD patients. It was a nonspecific performance. G. Acker also explained that headache was regarded as an initial symptom only if it was the only symptom of the patient.19 Since the manifestation was only an auxiliary diagnosis which could not confirm the disease, further examination such as imaging examination was necessary to further confirming the disease.
45
Cerebral angiography was recognized as the gold standard both for diagnosing MMD and assessing its progression.18 The clinical diagnosis of MMD depends on imaging diagnosis. In this study, referring to 198 cases with MMD, cranial CT showed cerebral infarction was mainly located in the frontal lobe, and MRA examination showed abnormal ventricles was located mainly in the middle cerebral artery lesions of cerebral hemorrhage (MCA), consistent with DSA examination results. Such results about detailed location of abnormal area were not found in previous articles. Maybe what described could be helpful for the clinical doctors. Until now, there was no clear guideline for the surgical treatment of MMD. There was a study mainly based on three criteria: nonemergency status, symptoms of ischemia or hemorrhage and the patient’s condition warranting surgery.21 It was reported surgery usually reserved for the symptomatic and/or progressive patients.23 Concerning to the treatment, most of the patients would choose surgical operation as a method to cure the disease.19,26,28 Surgical revascularization is the standard cure for the symptoms of MMD which can alleviate headaches by improving perfusion pressure and cerebral circulation.17,18,28 It was recommended if the patient manifested a progression of cerebrovascular occlusive lesions or ischemic symptoms.14 However, in this study, only 33.9% of the patients chose surgical treatment, and most of the patients chose conservative treatment mainly by taking medicine to relieve symptoms. Conservative treatment was mainly focused on improving ischemic symptoms, which cannot prevent the progression of disease. For example, vasodilators such as sodium nitroprusside, calcium antagonists such as verapamil and nifedipine, medicine for reducing intracranial pressure such as mannitol were used to ease symptoms. It was recommended antiplatelets drugs could treat ischemic MMD, but lacking of adequate clinical evidence.29 However, long-term use of aspirin and other antiplatelets drugs could result in bleeding, adverse to the prognosis of patients. The data were collected from 56 tertiary hospitals of Henan Province in China, which was precious. However, some limitations should be taken into consideration. The study was based on the data collected retrospectively from the records of 56 hospitals in a province of China. It was a pity that the information was directly recorded in a specific questionnaire instead of face to face interview. As the limitation of the questionnaire, it was such a pity that more information could not get such as Suzuki stage, mRS, magnetic resonance blood-flow scanning, specific surgical methods, additional Chinese medicine treatment, the prognosis, complications, and long-time outcomes. Regardless, there is an
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urgent need that some new studies no matter about cause or treatment about MMD should be done deeply in this field in China in the future, which would help more people. The sooner MMD is found, the less pain the patient may undertake. In the future, the government should pay more attention to the life of rare disease patients while the total number is at least 10 million.7 As for the clinical doctors, rich clinical experience and skills about MMD is necessary. Conclusions Clinical manifestations of Moyamoya disease varied. Early diagnosis was necessary to reduce the misdiagnosis rate of this disease. Symptoms, radiological characteristics, and lesion localization characteristics should be fully considered, especially for indicators with a certain onset age, headache and dizziness, lesion located in the frontal lobe of middle cerebral artery. Conflict of interests The authors declare that they have no conflict of interest. References 1. Gong S, Wang Y, Pan X, Zhang L, Huang R, Chen X, et al. The availability and affordability of orphan drugs for rare diseases in China. Orphanet J Rare Dis. 2016;11:20, http://dx.doi.org/10.1186/s13023-016-0392-4. 2. Liu Z, Fang H, Slikker W, Tong W. Potential reuse of oncology drugs in the treatment of rare diseases. Trends Pharmacol Sci. 2016;37:843–57, http://dx.doi.org/10.1016/j.tips.2016.06.010. 3. Orphanet: About rare diseases; 2016. http://www.orpha.net/consor/cgi-bin/ Education AboutRareDiseases.php?lng=EN/ [accessed 25.04.16]. 4. Simoens S, Cassiman D, Dooms M, Picavet E. Orphan drugs for rare diseases: is it time to revisit their special market access status? Drugs. 2012;72:1437–43, http://dx.doi.org/10.2165/11635320-000000000-00000. 5. Franco P. Orphan drugs: the regulatory environment. Drug Discov Today. 2013;18:163–72, http://dx.doi.org/10.1016/j.drudis.2012.08.009. 6. Gulbakan B, Ozgul RK, Yuzbasioglu A, Kohl M, Deigner HP, Ozguc M. Discovery of biomarkers in rare diseases: innovative approaches by predictive and personalized medicine. EPMA J. 2016;7:24, http://dx.doi.org/10.1186/s13167-016-0074-2. 7. Jin X, Chen L. Orphan drug development in China – turning challenges into opportunities. Intract Rare Dis Res. 2016;5:308–13, http://dx.doi.org/10.5582/irdr.2016.01025. 8. Gao J, Song P, Tang W. Rare disease patients in China anticipate the sunlight of legislation. Drug Discov Therap. 2013;7:126–8 https://www.ncbi.nlm.nih.gov/pubmed/23917862 9. Fujimura M, Tominaga T. Diagnosis of moyamoya disease: international standard and regional differences. Neurol Med Chir (Tokyo). 2015;55:189–93, http://dx.doi.org/10.2176/nmc.ra.2014-0307. 10. ICD-10 Version; 2016. http://apps.who.int/classifications/icd10/browse/2016/ en#/I60-I69/ [accessed 19.05.16]. 11. Ahn IM, Park D-H, Hann HJ, Kim KH, Kim HJ, Ahn HS. Incidence prevalence, and survival of moyamoya disease in Korea. Stroke. 2014;45:1090–5, http://dx.doi.org/10.1161/STROKEAHA.113.004273.
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Original article
Moyamoya disease: A retrospective study of 198 cases Yan Ma a,b , Qiaoyun Guo a,b , Yali Yan a,b , Ye Zhang a,b , Zhijie Lin a,b , Jianying Zhang a,b,c , Kaijuan Wang a,b , Chunhua Song a,b,∗ a
Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China Henan Key Laboratory of Tumor Epidemiology, Zhengzhou 450001, Henan, China c Henan Academy of Medical and Pharmaceutical Sciences and Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China b
a r t i c l e
i n f o
Article history: Received 14 January 2019 Accepted 14 February 2019 Available online 8 June 2019 Keywords: Clinical features Moyamoya disease Chinese population
a b s t r a c t Background: Moyamoya disease belongs to rare diseases which are arousing public awareness of its importance in China. In order to investigate the clinical features of inpatients diagnosed Moyamoya disease, the study was conducted to collect clinical information data of subjects on demographic information and clinical characteristics in Henan, China. Methods: The data of 198 cases of Moyamoya disease from 56 tertiary hospitals in Henan province from January 2003 to June 2015 were collected retrospectively. Analysis was performed based on demographic, clinical and radiological characteristics of the patients. Results: The mean onset age was 44.03 ± 14.45 years old. Unilateral limb weakness (36.4%) was the most common physical examination. Primary clinical manifestation was headache and dizziness (50.3%). Cranial CT showed cerebral infarction was mainly located in the frontal lobe (27.4%). MRA and DSA showed lesions mainly located in the middle cerebral artery (30.3% and 18.7%). Conclusions: Clinical manifestations of Moyamoya disease varied. Early diagnosis was necessary to reduce the misdiagnosis rate of this disease. Symptoms, radiological characteristics, and lesion localization characteristics should be fully considered, especially for indicators with a certain onset age, headache and dizziness, lesion located in the frontal lobe of middle cerebral artery. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Enfermedad de moyamoya: estudio retrospectivo de 198 casos r e s u m e n Palabras clave: Características clínicas Enfermedad de moyamoya Población china
Antecedentes: La enfermedad de moyamoya pertenece al grupo de afecciones raras cuya importancia está despertando la conciencia pública en China. Con el fin de investigar las características clínicas de los pacientes hospitalizados en Henan (China) diagnosticados con la enfermedad de moyamoya, se llevó a cabo este estudio para recopilar información clínica sobre los pacientes junto con información demográfica y características clínicas. Métodos: Se recogieron retrospectivamente datos de 198 casos de la enfermedad de moyamoya en 56 hospitales terciarios de la provincia de Henan entre enero de 2003 y junio de 2015. El análisis se realizó con base en las características demográficas, clínicas y radiológicas de los pacientes. ˜ Resultados: La edad media de inicio de la enfermedad era de 44,03 ± 14,45 anos. La debilidad unilateral de las extremidades (36,4%) fue el hallazgo más común en las exploraciones físicas y la manifestación clínica primaria fue la combinación de dolor de cabeza y mareos (50,3%). La tomografía craneal mostró que el infarto cerebral afectaba principalmente al lóbulo frontal (27,4%). La angiografía de resonancia magnética y la angiografía por sustracción digital mostraron lesiones ubicadas principalmente en la arteria cerebral media (30,3 y 18,7%, respectivamente).
∗ Corresponding author. E-mail address: [email protected] (C. Song). https://doi.org/10.1016/j.medcli.2019.02.024 ˜ S.L.U. All rights reserved. 2387-0206 0025-7753/© 2019 Elsevier Espana,
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Conclusiones: Las manifestaciones clínicas de la enfermedad de moyamoya fueron muy variadas. El diagnóstico precoz resultó necesario para reducir la tasa de diagnósticos erróneos de esta enfermedad. Se deben considerar los síntomas, las características radiológicas y las características de ubicación en su totalidad, especialmente en el caso de indicadores con una edad específica de inicio, dolor de cabeza y mareos, o una lesión situada en el lóbulo frontal, en la arteria cerebral media. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction Rare diseases, also known as orphan disease, include rare genetic diseases, infectious diseases, autoimmune diseases and rare cancers. Rare diseases are serious and chronic with a particularly low prevalence which can be life-threatening, and impose a physical, psychological, and socioeconomic burden on patients, their families, society and public health systems.1–4 It was estimated that there were approximately 6000–8000 kinds of rare diseases which affected 6–8% of the population in the world.5 Rare diseases were estimated to affect 350–400 million people globally, and there were at least 10 million rare diseases patients according to the definition of WHO in China.6,7 This was a heavy burden. The real burden of rare diseases was difficult to estimate for each patient and their families. Missed or delayed diagnosis, shortage of effective drugs, and the high cost of currently available drugs were three features in treatment of rare diseases.8 At present, public awareness of rare diseases was increasing in China. Moyamoya disease (MMD) is one kind of rare diseases, coded as I67.5 in International Classification of Diseases (ICD 10), belonging to the circulatory system disease. It is a chronic, occlusive cerebrovascular disease with an unknown etiology which characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery (ICA) and an abnormal vascular network at the base of the brain.9,10 MMD was reported around the world, usually in East Asia, high incidence and prevalence were shown mainly in Korea, Japan, Taiwan, and China,11–14 especially in Japan and South Korea.15 Now the cause of MMD was still not clear. A recent study showed that RNF213 R4810K was identified as the major susceptibility gene.16 In China, a large epidemiological survey of clinical features of MMD have been reported only in Taiwan and Nanjing till now, no such survey has been reported in the province of Henan in China in existing literature. In a word, the aim of this study was to describe the clinical features of inpatients being attacked by MMD and to provide clues for the clinical diagnosis of MMD.
atherosclerosis, arterial interlayer and tumor. The criteria included three principal factors as follows: (1) stenosis or occlusion at the terminal portion of the internal carotid artery (ICA) and/or at the proximal portion of the anterior and/or middle cerebral arteries; (2) abnormal vascular networks in the vicinity of the occlusive or stenotic lesions in the arterial phase; and (3) lesion bilaterality.18 Statistical analysis The whole data were input in Epidata database, including demographic characteristics, physical examination, clinical features and radiological characteristics. None personal privacy of patients was involved. In the study, data were described using frequency, proportion, mean and standard deviation. All analyses were performed by using SPSS software, version 21.0. Results Demographic characteristics There were 91 males and 107 females among the 198 patients diagnosed MMD and the ratio of male-to-female was 1:1.18. The mean age at diagnosis was 44.03 ± 14.45 years old (range, 4–78 years). There were two peaks in age distribution both in male and female, which was similar to the total (Fig. 1). There were 4 cases having family history, whose mothers clinically diagnosed. More details could be seen in Table 1 and Fig. 1. Physical examination and clinical manifestation The mean systolic blood pressure was 130 mmHg, in the meantime, mean diastolic blood pressure was 83 mmHg. The average heart rate was 78 beats per minute. The most common physical symptom was weakness on one side of the body (35.9%), followed by paroxysmal or persistent dizziness (27.3%). As for clinical symptoms, the primary was headache and dizziness (49.5%), followed by cerebral infarction (36.9%). More details could be seen in Table 2.
Methods
Self-reported symptoms
Subjects
Most patients had more than one complaint. Among 198 patients, dizziness could be seen as the most common complaint (29.8%), followed by headache (22.7%), limb weakness (19.2%), numbness of limbs (11.1%). More details could be seen in Table 3.
This study was a retrospective analysis of 198 subjects with the final diagnosis of MMD in 56 tertiary hospitals located in Henan Province from January 1st 2003 to June 30th 2015. The selected hospitals were the top three general hospitals, top three specialized hospitals and the affiliated teaching hospitals of the medical undergraduate college who had the ability to identify, diagnose or treat MMD. The data of hospitalized patients were searched by ICD in the case information system of these hospitals through a predetermined questionnaire. After that the information was extracted and recorded except for the patient’s privacy information. As for the recruited cases, all cases were diagnosed in line with the criteria proposed by the Research Committee on Spontaeous Occlusion of the Circle of Willis in 1997.17 The diagnosis of MMD must exclude other causes of intracranial vascular stenosis, such as
Imaging examination Results of CT examination of patients with MMD showed 84 cases appearing cerebral infarction which mostly located in the frontal lobe (27.4%). Cerebral hemorrhage sites were mainly located in the ventricle, and cerebral infarction and cerebral hemorrhage could coexist. More details could be seen in Table 3. Examination results of brain magnetic resonance imaging (MRA) of MMD showed lesions located in the middle cerebral artery (MCA) (30.3%), followed by internal carotid artery (ICA) (20.2%), anterior cerebral
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443
21 Total 18
Male Female
Percentage
15 12 9 6 3 0 0-4
5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 ≥70 Age(years)
Fig. 1. Distribution of age of MMD in male, female and total subjects. Table 1 Demographic characteristics of cases (N, %).
Treatment
Variables
All patients
Gender Men Women Male:female ratio
91 (46.0) 107 (54.0) 1:1.18
Family history Yes No
4 (2.0) 194 (98.0)
Residential area Rural Urban
91 (46.0) 107 (54.0)
Surgery Yes No
67 (33.8) 131 (66.2)
Blood pressure (¯x ± s, mmHg) Systolic pressure Diastolicpressure Heart rate x¯ ± s, / min
130.0 ± 17.8 83.0 ± 10.9 78.4 ± 10.9
NRCMIS, New Rural Cooperative Medical Insurance Scheme.
artery (ACA) (16.2%), posterior cerebral artery (PCA) (9.1%); the results of digital subtraction angiography (DSA) examination were consistent with MRA (Table 4).
Considering the treatment of the patients, 14.6% used vasodilators, 21.2% used calcium antagonists, 27.8% used medicine for reducing intracranial pressure. 31.3% of the subjects choosing to use surgery. More details could be seen in Table 2.
Discussion The study showed the data about patients diagnosed with MMD collected from 56 tertiary hospitals of Henan Province in China during January 1st 2003 to June 30th 2015. In this study, clinical features of inpatients were mainly described. MMD is a chronic, occlusive cerebrovascular disease characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery (ICA) and an abnormal vascular network at the base of the brain.9 The etiology of MMD is still unknown. However, a recent study discovered the ring finger protein 213 gene (RNF213) could be used as a susceptibility gene for MMD.16 Recent revised diagnostic criteria for definitive MMD requires catheter angiography in unilateral cases, whereas bilateral cases can be promptly diagnosed by either catheter angiography or MRA.15 As for the differential diagnosis, diseases such as atherosclerosis, autoimmune disease, meningitis, brain tumors, Down’s syndrome, von Recklinghausen’s disease, head injury, cerebrovascular lesions
Table 2 Physical examination, clinical manifestation and treatment of cases (N, %). Yes
No
Not check/not applied
Physical examination Weakness on one side of the body Hemiplegia on one side of the body or both Involuntary movement of the body Disturbance of consciousness Paroxysmal or persistent dizziness Meningeal irritation
71 (35.9) 8 (4.0) 17 (8.6) 25 (12.6) 54 (27.3) 11 (5.6)
124 (62.6) 186 (93.9) 176 (88.9) 170 (85.9) 139 (70.2) 171 (86.4)
3 (1.5) 4 (2.0) 5 (2.5) 3 (1.5) 5 (2.5) 16 (8.1)
Clinical manifestation Paropsia Headache and dizziness Cerebral infarction Transient cerebral ischemia Cerebral hemorrhage
28 (14.1) 98 (49.5) 73 (36.9) 22 (11.1) 53 (26.8)
164 (82.8) 97 (49.0) 118 (59.6) 169 (85.4) 139 (70.2)
6 (3.0) 3 (1.5) 7 (3.5) 7 (3.5) 6 (3.0)
Medicine treatment Vasodilators Calcium antagonists Medicine for reducing intracranial pressure Surgical treatment
29 (14.6) 42 (21.2) 55 (27.8) 62 (31.3)
164 (82.8) 150 (75.8) 143 (72.2) 121 (61.1)
5 (2.5) 6 (3.0) 0 (0.0) 15 (7.6)
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Table 3 Chief complaint and CT examination results of cases (N, %). Chief complaint Symptom
CT examination results Number (%)
Headache Dizziness Limb activity disorder Limb weakness Numbness of limbs Vomit Vision disorder Alalia Disturbance of consciousness Cerebral hemorrhage Cerebral infraction Forgetfulness Physical examination
Total (n)
45 (22.7) 59 (29.8) 13 (6.6) 38 (19.2) 22 (11.1) 12 (6.1) 12 (6.1) 17 (8.6) 18 (9.1) 15 (7.6) 8 (4.0) 4 (2.0) 11 (5.6)
198
Cerebral infarction area
Number (%)
Cerebral hemorrhage area
Number (%)
Frontal lobe Parietal lobe Temporal lobe Occipital lobe Basal ganglia Anterior cerebral artery Middle cerebral artery Internal carotid Ventricle Centrum semiovale Corona radiata Corpus callosum Thalamus Cerebral hemisphere Brainstem Total (n)
23 (27.4) 15 (17.9) 15 (17.9) 9 (10.7) 21 (25.0) 4 (4.8) 15 (17.9) 7 (8.3) 14 (16.7) 4 (4.8) 3 (3.6) 1 (1.2) 1 (1.2) 2 (2.4) 1 (1.2) 84
Frontal lobe Parietal lobe Temporal lobe Occipital lobe Basal ganglia Ventricle Brain parenchyma Subarachnoid space Arteria supraorbitalis Epidural hematoma Thalamus Corona radiata Hard retinal inferior vena Internal carotid
7 (15.6) 4 (8.9) 8 (17.8) 1 (2.2) 8 (17.8) 10 (22.2) 4 (8.9) 8 (17.8) 1 (2.2) 1 (2.2) 2 (4.4) 1 (2.2) 1 (2.2) 1 (2.2)
Table 4 Lesion site of imaging examination (N, %).
ICA MCA ACA PCA Not check
Head MRA examination
Head DSA examination
40 (20.2) 60 (30.3) 32 (16.2) 18 (9.1) 48 (24.2)
20 (10.1) 37 (18.7) 15 (7.6) 9 (4.5) 117 (59.1)
after head irradiation and others must be excluded first.17 Quasimoyamoya disease affects bilateral or unilateral hemisphere with underlying disease.9 Comprehensive consideration of clinical, laboratory and imaging diagnosis could identify these diseases. In the study, the number of female patients was more than male patients, and the male-to-female ratio was 1:1.18. It was consistent with the previous studies that MMD was more common in women.12,19 Data from several studies have demonstrated that the distribution of presentation age revealed a bimodal distribution with two peaks both happening in childhood and adulthood.12,14,15,19–21 Besides, some existing studies indicated that there was no age peak in childhood.12,22 There was a bimodal distribution with two peaks in 10–14 and 40–44 years in this study, which confirmed that MMD could happen focused on the teenagers and the age 40–50. The disease showed an obvious familial tendency, in which there was a 6–12% risk of developing MMD if a person had a first-degree relative diagnosed with MMD.23 Moreover, the data of familial occurrence of MMD had been variably reported: 1.48% or 5.2% in China,14,20 and 10–15% in Japan.24,25 However, in this study, 4 cases were identified with familial tendency of MMD, consisting 2% of whole cases, lower than that in Japanese population. Maybe a genetic factor played a role in the incidence of MMD. The study showed headache and dizziness was the primary clinical manifestations. Several studies reported that there were two types of presentation, ischemia and hemorrhage.12,18,19,26,27 Lian Duan had reported that in their cohort, transient ischemic attack was found as the most common initial clinical manifestation.20 In this study, headache and dizziness was discovered as the most clinical manifestations presented in MMD patients. It was a nonspecific performance. G. Acker also explained that headache was regarded as an initial symptom only if it was the only symptom of the patient.19 Since the manifestation was only an auxiliary diagnosis which could not confirm the disease, further examination such as imaging examination was necessary to further confirming the disease.
45
Cerebral angiography was recognized as the gold standard both for diagnosing MMD and assessing its progression.18 The clinical diagnosis of MMD depends on imaging diagnosis. In this study, referring to 198 cases with MMD, cranial CT showed cerebral infarction was mainly located in the frontal lobe, and MRA examination showed abnormal ventricles was located mainly in the middle cerebral artery lesions of cerebral hemorrhage (MCA), consistent with DSA examination results. Such results about detailed location of abnormal area were not found in previous articles. Maybe what described could be helpful for the clinical doctors. Until now, there was no clear guideline for the surgical treatment of MMD. There was a study mainly based on three criteria: nonemergency status, symptoms of ischemia or hemorrhage and the patient’s condition warranting surgery.21 It was reported surgery usually reserved for the symptomatic and/or progressive patients.23 Concerning to the treatment, most of the patients would choose surgical operation as a method to cure the disease.19,26,28 Surgical revascularization is the standard cure for the symptoms of MMD which can alleviate headaches by improving perfusion pressure and cerebral circulation.17,18,28 It was recommended if the patient manifested a progression of cerebrovascular occlusive lesions or ischemic symptoms.14 However, in this study, only 33.9% of the patients chose surgical treatment, and most of the patients chose conservative treatment mainly by taking medicine to relieve symptoms. Conservative treatment was mainly focused on improving ischemic symptoms, which cannot prevent the progression of disease. For example, vasodilators such as sodium nitroprusside, calcium antagonists such as verapamil and nifedipine, medicine for reducing intracranial pressure such as mannitol were used to ease symptoms. It was recommended antiplatelets drugs could treat ischemic MMD, but lacking of adequate clinical evidence.29 However, long-term use of aspirin and other antiplatelets drugs could result in bleeding, adverse to the prognosis of patients. The data were collected from 56 tertiary hospitals of Henan Province in China, which was precious. However, some limitations should be taken into consideration. The study was based on the data collected retrospectively from the records of 56 hospitals in a province of China. It was a pity that the information was directly recorded in a specific questionnaire instead of face to face interview. As the limitation of the questionnaire, it was such a pity that more information could not get such as Suzuki stage, mRS, magnetic resonance blood-flow scanning, specific surgical methods, additional Chinese medicine treatment, the prognosis, complications, and long-time outcomes. Regardless, there is an
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urgent need that some new studies no matter about cause or treatment about MMD should be done deeply in this field in China in the future, which would help more people. The sooner MMD is found, the less pain the patient may undertake. In the future, the government should pay more attention to the life of rare disease patients while the total number is at least 10 million.7 As for the clinical doctors, rich clinical experience and skills about MMD is necessary. Conclusions Clinical manifestations of Moyamoya disease varied. Early diagnosis was necessary to reduce the misdiagnosis rate of this disease. Symptoms, radiological characteristics, and lesion localization characteristics should be fully considered, especially for indicators with a certain onset age, headache and dizziness, lesion located in the frontal lobe of middle cerebral artery. Conflict of interests The authors declare that they have no conflict of interest. References 1. Gong S, Wang Y, Pan X, Zhang L, Huang R, Chen X, et al. The availability and affordability of orphan drugs for rare diseases in China. Orphanet J Rare Dis. 2016;11:20, http://dx.doi.org/10.1186/s13023-016-0392-4. 2. Liu Z, Fang H, Slikker W, Tong W. Potential reuse of oncology drugs in the treatment of rare diseases. Trends Pharmacol Sci. 2016;37:843–57, http://dx.doi.org/10.1016/j.tips.2016.06.010. 3. Orphanet: About rare diseases; 2016. http://www.orpha.net/consor/cgi-bin/ Education AboutRareDiseases.php?lng=EN/ [accessed 25.04.16]. 4. Simoens S, Cassiman D, Dooms M, Picavet E. Orphan drugs for rare diseases: is it time to revisit their special market access status? Drugs. 2012;72:1437–43, http://dx.doi.org/10.2165/11635320-000000000-00000. 5. Franco P. Orphan drugs: the regulatory environment. Drug Discov Today. 2013;18:163–72, http://dx.doi.org/10.1016/j.drudis.2012.08.009. 6. Gulbakan B, Ozgul RK, Yuzbasioglu A, Kohl M, Deigner HP, Ozguc M. Discovery of biomarkers in rare diseases: innovative approaches by predictive and personalized medicine. EPMA J. 2016;7:24, http://dx.doi.org/10.1186/s13167-016-0074-2. 7. Jin X, Chen L. Orphan drug development in China – turning challenges into opportunities. Intract Rare Dis Res. 2016;5:308–13, http://dx.doi.org/10.5582/irdr.2016.01025. 8. Gao J, Song P, Tang W. Rare disease patients in China anticipate the sunlight of legislation. Drug Discov Therap. 2013;7:126–8 https://www.ncbi.nlm.nih.gov/pubmed/23917862 9. Fujimura M, Tominaga T. Diagnosis of moyamoya disease: international standard and regional differences. Neurol Med Chir (Tokyo). 2015;55:189–93, http://dx.doi.org/10.2176/nmc.ra.2014-0307. 10. ICD-10 Version; 2016. http://apps.who.int/classifications/icd10/browse/2016/ en#/I60-I69/ [accessed 19.05.16]. 11. Ahn IM, Park D-H, Hann HJ, Kim KH, Kim HJ, Ahn HS. Incidence prevalence, and survival of moyamoya disease in Korea. Stroke. 2014;45:1090–5, http://dx.doi.org/10.1161/STROKEAHA.113.004273.
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