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Clinical characteristics and long-term outcomes of moyamoya syndrome associated with neurofibromatosis type 1
Journal of Clinical Neuroscience 22 (2015) 286–290
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Clinical characteristics and long-term outcomes of moyamoya syndrome associated with neurofibromatosis type 1 Cong Han a, Wei-Zhong Yang a, Hong-Tao Zhang b, Ting Ye a, Lian Duan a,⇑ a b
Department of Neurosurgery, 307 Hospital, PLA, 8 Dong-Da Street, Fengtai District, Beijing 100071, China Department of Radiology, 307 Hospital, PLA, Beijing, China
a r t i c l e
i n f o
Article history: Received 11 February 2014 Accepted 25 May 2014
Keywords: Clinical characteristics Moyamoya Neurofibromatosis Prognosis Treatment
a b s t r a c t Moyamoya syndrome (MMS) associated with neurofibromatosis type 1 (NF1) has rarely been reported anywhere in the world, particularly in Asia. Because of the rarity of this disorder, its natural history, clinical symptoms, management, and follow-up findings remain unclear. The objective of this study was to evaluate the clinical presentation, neurological imaging, and long-term outcomes of patients with this disease by reviewing Chinese patients with MMS associated with NF1. A retrospective review was conducted from the moyamoya disease (MMD) and MMS patient database of our hospital. Six patients who were diagnosed with MMS associated with NF1 between January 2003 and October 2013 were identified. The clinical symptoms were transient ischemic attack (TIA, three patients), headache (one patient), intracerebral hemorrhage (one patient), and cerebral infarction (one patient). The mean age of diagnosis for NF1 and MMS was 2.7 ± 2.1 years (range, 1–6 years) and 11.4 ± 8.3 years (range, 3.5–23 years), respectively. Five of six patients (nine hemispheres) underwent revascularization surgery, and their clinical symptoms were stable during a 46.3 ± 36.1 month (range, 18–108 month) follow-up. One non-surgical patient had a new infarct that resulted in visual field deficits during follow-up. Three patients had radiographic follow-up, and the postoperative angiograms showed successful revascularizations in the operated hemispheres. To conclude, the clinical and radiographic features for MMS-NF1 are similar to those of typical MMD. Routine vascular screening for NF1 patients is necessary for the early identification of MMS and other cerebral arteriopathies. Revascularization surgery may prevent the progression of clinical symptoms and reduce the risk of subsequent strokes. Ó 2014 Published by Elsevier Ltd.
1. Introduction Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis or occlusion of the intracranial internal carotid artery (ICA) that gradually progresses to the proximal branches of the anterior, middle, and posterior cerebral arteries. Due to the gradual stenosis of these arteries, a collateral network of vessels forms at the base of the brain. The etiology of MMD is unknown; therefore, the association of MMD-type angiographic findings with another systemic disease, such as neurofibromatosis type 1 (NF1), is usually called moyamoya syndrome (MMS). NF1 is a common, inherited, autosomal-dominant multisystem genetic disorder with multiple clinical manifestations, including café au lait spots, neurofibromas, freckling, optic nerve gliomas, Lisch nodules, and distinct bone lesions. ⇑ Corresponding author. Tel.: +86 10 6694 7156; fax: +86 10 6217 7976. E-mail address: [email protected] (L. Duan). http://dx.doi.org/10.1016/j.jocn.2014.05.046 0967-5868/Ó 2014 Published by Elsevier Ltd.
The occurrence of MMS associated with NF1 (MMS-NF1) is rare. Fewer than 100 patients with MMS-NF1 have been reported in the literature at the time of writing [1–2]. Although MMD occurs frequently in Asian countries, most MMS-NF1 patients have been reported in Europe and USA. In addition, there is a scarcity of reports on the treatment and long-term follow-up of these patients. The objective of this study was to report the clinical presentation, neurological imaging, management, and long-term follow-up of several Chinese MMS-NF1 patients. 2. Methods 2.1. Patient selection We reviewed the patient database of our hospital and selected the MMS patients who were also diagnosed with NF1 between July 2003 and October 2013. All of the patients included met the USA National Institutes of Health diagnostic criteria for NF1 [3]. The diagnosis of MMS was established in accordance with the criteria
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developed by the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis in 2012 [4]. 2.2. Clinical data and neuroimaging
of NF1 ranged from 1 to 6 years, with a median age of 2.7 ± 2.1 years. The mean age of diagnosis for MMS was 11.4 ± 8.3 years (range, 3.5–23 years). The interval from diagnosis of NF1 to MMS was 8.8 ± 7.0 years (range, 1–17 years). Indications for neurological imaging at the time of treatment included transient ischemic attack (three patients), headache (one patient), intracerebral hemorrhage (one patient), and cerebral infarction (one patient). Four patients were neurologically intact (mRS score 0), and two patients had minimal neurological deficit (mRS score 1). The NF1 clinical features in the other systems are also shown in Table 1.
The clinical information collected included sex, age at NF1 diagnosis, age at MMS diagnosis, clinical manifestations of vasculopathy, neurological imaging findings, treatment, and follow-up outcome. All of the patients underwent MRI of the brain with magnetic resonance angiography (MRA). Conventional digital subtraction angiography (DSA) was also conducted to confirm the diagnosis and to plan treatment. The severity of MMS was measured using Suzuki stages [5]. Brain perfusion single-photon emission computerised tomography (SPECT) was performed to evaluate the hemodynamic status. Based on the SPECT findings, the severity of the cerebral perfusion abnormality was classified as defective (with perfusion being the same as or less than that of white matter) or decreased (compared with contralateral grey matter). DSA, MRI with MRA, and SPECT were conducted during the follow-up. The preoperative and postoperative neurological imaging results were reviewed by an independent neuroradiologist.
Preoperative imaging and data were available for all patients. Most of the hemispheres (5/10) were in Suzuki stage 4, and the others were in stage 1 (two hemispheres), stage 2 (two hemispheres), or stage 6 (one hemisphere). Defective or decreased perfusion was revealed by SPECT in all six patients (Table 2). Three patients had radiographic follow-up after surgery, and all three presented radiographic progression (Fig. 1).
2.3. Treatment
3.3. Treatment and follow-up outcome
Most of the patients with cerebral vasculopathy were advised to undergo revascularization surgery on the side containing the lesion. Before the operation, a carefully designed preoperative evaluation was performed to identify indications and surgical goals. The postsurgical collateral vessels were graded according to the method described by Matsushima et al. [6], where ‘‘good’’ indicates that the postsurgical collateral vessels achieved revascularization of two-thirds of the middle cerebral artery (MCA) distribution, ‘‘fair’’ indicates that the postsurgical collateral vessels achieved revascularization of one-third to two-thirds of the MCA distribution, and ‘‘poor’’ indicates that the postsurgical collateral vessels achieved very little or no revascularization. The functional status of each patient was graded according to the modified Rankin Scale (mRS).
Five patients (nine hemispheres) underwent revascularization surgery, and eight hemispheres were subjected to encephaloduroarteriosynangiosis (EDAS), which is a standard indirect revascularization procedure. One hemisphere was subjected to a superficial temporal artery (STA)–MCA bypass, and one patient was treated with aspirin (Table 2). All six patients underwent clinical follow-up, and three underwent radiographic follow-up. The average duration of follow-up was 46.3 ± 36.1 months (range, 18–108 months). At the time of the most recent follow-up, the clinical symptoms of the five patients who underwent revascularization surgery were stable, and the degree, frequency, and durations of transient ischemic attacks and headaches were decreased. The patient who presented with hemorrhage did not suffer from rebleeding. The patient who had been treated with aspirin suffered a new infarct that resulted in new visual field deficits, and the mRS score deteriorated during follow-up (2 versus 1). During radiographic follow-up, the postoperative angiogram showed good collaterals in one hemisphere and fair collaterals in the other five hemispheres (Table 2).
2.4. Statistical analyses Descriptive statistics only were used in this study.
3.2. Neurological imaging findings
3. Results 4. Discussion 3.1. Clinical features A total of six patients, two boys and four girls, were enrolled in the study. During this period, 2008 MMD and MMS patients were managed in our hospital. As a result, the proportion of MMS-NF1 patients was 0.3% (6/2008) in this period. The clinical features of all of the patients are summarised in Table 1. The age at diagnosis
According to some recent studies, the incidence of cerebrovascular diseases in NF1 is 2.5–6% [7–9]. MMD-type changes were a significant proportion of the neurological imaging findings, at 47% (7/15 patients), in the study by Ghosh et al. [9] and 76% (13/ 17 patients) in the study by Rea et al. [8]. There are also several case reports indicating an association of MMS and NF1 [10–11].
Table 1 Clinical features of patients with moyamoya syndrome associated with neurofibromatosis type 1 Patient
Sex
Age at diagnosis of NF1, y
Age at diagnosis of MMS, y
Clinical features of NF1
Neurological symptoms
mRS
1 2 3 4 5
F F F F M
4 1 6 1 1
17 3.5 23 16 5
TIA TIA Infarction Hemorrhage Headache
0 0 1 0 1
6
M
3
4
Café au lait spots, skin-fold freckling, neurofibromas Café au lait spots, skin-fold freckling Café au lait spots, skin-fold freckling Café au lait spots, skin-fold freckling Café au lait spots, plexiform neurofibroma, skin-fold freckling, bone lesion café au lait spots, neurofibromas
TIA
0
F = female, M = male, MMS = moyamoya syndrome, mRS = modified Rankin Scale, NF1 = neurofibromatosis type 1, TIA = transient ischemic attack, y = years.
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Table 2 Neurological imaging findings and treatment outcomes of patients with moyamoya syndrome associated with neurofibromatosis type 1 Patient
1 2
3 4 5 6
Vascular findings
Right ICA occlusion, moyamoya (unilateral) Left MCA (M2) and ACA stenosis, right MCA stenosis, moyamoya (bilateral)
Right ICA occlusion Left MCA stenosis, right ICA occlusion, moyamoya (bilateral) Left ICA occlusion, right MCA stenosis, moyamoya (bilateral) Left and right ICA occlusion, moyamoya (bilateral)
Suzuki stage
SPECT
Left
Right
0
4
Defective
2
1
0 2
mRS*
Treatment
Followup, m
Matsushima scale
Progression
Left
Right
Symptom
Suzuki stage
mRS#
29
–
Unclear
Stable
Unclear
0
EDAS
19
Fair
Fair
Stable
0
– EDAS
Aspirin EDAS
32 18
– Unclear
Unclear Unclear
Infarction Stable
Left (2 ? 4) Right (1 ? 4) Unclear Unclear
STAMCA EDAS
EDAS
72
Fair
Fair
Stable
EDAS
108
Good
Fair
Stable
Left
Right
0
–
EDAS
Decreased
0
EDAS
6 4
Decreased Decreased
1 0
4
1
Decreased
1
3
4
Decreased
0
Right (1 ? 2) Left (3 ? 5) Right (4 ? 5)
1?2 0 1 0
ACA = anterior cerebral artery, EDAS = encephaloduroarteriosynangiosis, ICA = internal carotid artery, m = months, MCA = middle cerebral artery, mRS = modified Rankin Scale, SPECT = single-photon emission computerised tomography, STA-MCA = superficial temporal artery–middle cerebral artery bypass. * mRS at presentation. # mRS at last follow-up.
To the best of our knowledge, our study represents the first report of a series of Chinese MMS-NF1 patients. The presence of MMS in MMS-NF1 patients is considered to be closely correlated with NF1. The NF1 pathogenic gene is found on chromosome 17, and candidate pathogenic genes for MMD have also been identified on this chromosome [2,12]. However, the reason why the vasculopathy affects only the intracranial ICA remains unclear. Some researchers have offered a ‘‘second hit’’ hypothesis [13], which states that a ‘‘second hit’’ mutation occurs on the NF1 gene or another locus that leads to vascular changes. In addition to the ‘‘second hit’’ hypothesis, racial differences may also be relevant to the pathogenesis of MMS-NF1 because most MMSNF1 patients have been reported in Europe and America, whereas cases in Asia and Africa are extremely rare. However, none of these hypotheses have been able to resolve whether MMD and NF1 are merely co-existing or if this disease is in fact pathogenically related MMS-NF1. In this study, we report six Chinese MMS-NF1 patients. The intervals from NF1 to the onset of the clinical neurological symptoms are variable, indicating that MMS and the other complications of NF1 may not present simultaneously. NF1 patients require close follow-up for the early detection of MMS to allow targeted interventions. Clinically, all six patients exhibited obvious symptoms, including transient ischemic attacks, headaches, infarctions, and hemorrhages. In contrast to our results, a certain number of asymptomatic patients were detected in the other studies [1,7–9]. The reasons for this difference may be attributed to the selection of the samples. Our hospital provides health supervision for MMD and MMS patients; thus, the patients always came to the hospital after the onset of the clinical neurological symptoms. Not all of the MMS-NF1 patients have clinical symptoms; however, MMS appears to have a significant risk for progression compared with the other cerebrovascular abnormalities associated with NF1. In our study, a patient who did not undergo surgery manifested a new visual field defect. Rosser et al. [7] noted that eight of 316 NF1 patients had arteriopathy, and moyamoya was a risk factor for stroke. Koss et al. [1] reported 39 MMS-NF1 patients in the USA. Although only 66% were symptomatic at the time of initial diagnosis, an increase in the percentage of newly symptomatic children (from 66% to 78%) was observed during follow-up.
Based on the radiographic characteristics, our study found that the MMS-NF1 patients were in every Suzuki stage. The study by Koss et al. also showed identical findings between the NF1-related moyamoya group and the non-NF1 moyamoya group [1]. To date, revascularization has been the most successful therapy for preventing strokes in MMD patients [14–15]. There is no consensus regarding the management of cerebral arteriopathy associated with NF1. Close monitoring with MRI/MRA is necessary for asymptomatic patients. Some studies recommended medical management with an antiplatelet agent such as aspirin, as it may reduce the risk of clot formation in narrowed arteries where platelet-rich clots can easily form [8–9]. However, most researchers recommend that MMS-NF1 patients undergo a revascularization procedure to reduce the risk of stroke [1,9]. In this study, eight hemispheres of five patients were subjected to EDAS, and one hemisphere was treated with a STA–MCA bypass. The clinical symptoms of the five patients, including those who underwent direct and indirect revascularizations, remained stable during follow-up. In the three patients who underwent radiographic follow-up, a progression in the Suzuki stage was observed in five hemispheres, and successful revascularization (one good, five fair in the Matsushima scale) was observed found in all of the operated hemispheres. The stable clinical manifestations may be attributed to surgical intervention. In addition, the disease progression observed in the non-surgical patient demonstrates the need for revascularization from another perspective. Postoperative cerebral angiograms demonstrated that both the direct and indirect revascularization surgeries were effective. However, the mechanisms that initiate the vascular changes remain unclear. Furthermore, it is unknown whether the NF1associated vasculopathy can affect the extracranial carotid artery. Therefore, the long-term outcomes of MMS-NF1 patients should be closely followed. The limitations of this study include its retrospective nature and the small number of patients. Another limitation is that postoperative cerebral angiography data was not available for some patients. Future prospective longitudinal studies that evaluate postoperative changes in the ICA and extracranial carotid artery will provide important data that will help determine the optimal treatment and long-term prognosis for these patients.
C. Han et al. / Journal of Clinical Neuroscience 22 (2015) 286–290
289
Fig. 1. Radiographic progression and postsurgical collateral vessels in Patient 2, who presented with transient ischemic attacks and was subjected to conventional angiography. (A) Preoperative right internal carotid angiogram (RICA, lateral view). (B) Postoperative lateral angiography at 1 year follow-up showed progression in the terminal portion of the RICA. (C) Preoperative right external carotid angiogram (lateral view). (D) Postoperative lateral angiography at 1 year follow-up demonstrated fair revascularization via the superficial temporal artery.
5. Conclusions MMS-NF1 is a rare occurrence worldwide. The time interval from NF1 to the onset of clinical neurological symptoms indicates that the routine vascular screening of NF1 patients is necessary for the early identification of MMS and the other cerebral arteriopathies. Revascularization surgery may be the most efficient way to prevent the progression of clinical symptoms, but the long-term outcomes require close follow-up studies. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by a grant from the National Natural Science Foundation of China (81171083). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References [1] Koss M, Scott RM, Irons MB, et al. Moyamoya syndrome associated with neurofibromatosis type 1: perioperative and long-term outcome after surgical revascularization. J Neurosurg Pediatr 2013;11:417–25. [2] Yamauchi T, Tada M, Houkin K, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000;31:930–5. [3] National Institutes of Health Consensus Development Conference statement: neurofibromatosis. Bethesda, MD, July 13–15, 1987. Neurofibromatosis 1988; 1: 172–8. [4] Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis, Health Labour Sciences Research Grant for Research on Measures for Intractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (Spontaneous Occlusion of the Circle of Willis). Neurol Med Chir (Tokyo) 2012; 52: 245–66. [5] Suzuki J, Takaku A. Cerebrovascular, ‘‘moyamoya’’ disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 1969;20:288–99. [6] Matsushima T, Inoue T, Suzuki SO, et al. Surgical treatment of moyamoya disease in pediatric patients—comparison between the results of indirect and direct revascularization procedures. Neurosurgery 1992;31:401–5. [7] Rosser TL, Vezina G, Packer RJ. Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Neurology 2005;64:553–5. [8] Rea D, Brandsema JF, Armstrong D, et al. Cerebral arteriopathy in children with neurofibromatosis type 1. Pediatrics 2009;1243:e476–83. [9] Ghosh PS, Rothner AD, Emch TM, et al. Cerebral vasculopathy in children with neurofibromatosis type 1. J Child Neurol 2013;28:95–101.
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[10] Koc F, Yerdelen D, Koc Z. Neurofibromatosis type 1 association with moyamoya disease. Int J Neurosci 2008;118:1157–63. [11] Darrigo Júnior LG, Valera ET, Machado Ade A, et al. Moyamoya syndrome associated with neurofibromatosis type I in a pediatric patient. Sao Paulo Med J 2011;129:110–2. [12] Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first moyamoya disease gene. J Hum Genet 2011;56: 34–40.
[13] Hamilton SJ, Friedman JM. Insights into the pathogenesis of neurofibromatosis 1 vasculopathy. Clin Genet 2000;58:341–4. [14] Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med 2009;360:1226–37. [15] Garg AK, Suri A, Sharma BS. Ten-year experience of 44 patients with moyamoya disease from a single institution. J Clin Neurosci 2010;17:460–3.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Clinical characteristics and long-term outcomes of moyamoya syndrome associated with neurofibromatosis type 1 Cong Han a, Wei-Zhong Yang a, Hong-Tao Zhang b, Ting Ye a, Lian Duan a,⇑ a b
Department of Neurosurgery, 307 Hospital, PLA, 8 Dong-Da Street, Fengtai District, Beijing 100071, China Department of Radiology, 307 Hospital, PLA, Beijing, China
a r t i c l e
i n f o
Article history: Received 11 February 2014 Accepted 25 May 2014
Keywords: Clinical characteristics Moyamoya Neurofibromatosis Prognosis Treatment
a b s t r a c t Moyamoya syndrome (MMS) associated with neurofibromatosis type 1 (NF1) has rarely been reported anywhere in the world, particularly in Asia. Because of the rarity of this disorder, its natural history, clinical symptoms, management, and follow-up findings remain unclear. The objective of this study was to evaluate the clinical presentation, neurological imaging, and long-term outcomes of patients with this disease by reviewing Chinese patients with MMS associated with NF1. A retrospective review was conducted from the moyamoya disease (MMD) and MMS patient database of our hospital. Six patients who were diagnosed with MMS associated with NF1 between January 2003 and October 2013 were identified. The clinical symptoms were transient ischemic attack (TIA, three patients), headache (one patient), intracerebral hemorrhage (one patient), and cerebral infarction (one patient). The mean age of diagnosis for NF1 and MMS was 2.7 ± 2.1 years (range, 1–6 years) and 11.4 ± 8.3 years (range, 3.5–23 years), respectively. Five of six patients (nine hemispheres) underwent revascularization surgery, and their clinical symptoms were stable during a 46.3 ± 36.1 month (range, 18–108 month) follow-up. One non-surgical patient had a new infarct that resulted in visual field deficits during follow-up. Three patients had radiographic follow-up, and the postoperative angiograms showed successful revascularizations in the operated hemispheres. To conclude, the clinical and radiographic features for MMS-NF1 are similar to those of typical MMD. Routine vascular screening for NF1 patients is necessary for the early identification of MMS and other cerebral arteriopathies. Revascularization surgery may prevent the progression of clinical symptoms and reduce the risk of subsequent strokes. Ó 2014 Published by Elsevier Ltd.
1. Introduction Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis or occlusion of the intracranial internal carotid artery (ICA) that gradually progresses to the proximal branches of the anterior, middle, and posterior cerebral arteries. Due to the gradual stenosis of these arteries, a collateral network of vessels forms at the base of the brain. The etiology of MMD is unknown; therefore, the association of MMD-type angiographic findings with another systemic disease, such as neurofibromatosis type 1 (NF1), is usually called moyamoya syndrome (MMS). NF1 is a common, inherited, autosomal-dominant multisystem genetic disorder with multiple clinical manifestations, including café au lait spots, neurofibromas, freckling, optic nerve gliomas, Lisch nodules, and distinct bone lesions. ⇑ Corresponding author. Tel.: +86 10 6694 7156; fax: +86 10 6217 7976. E-mail address: [email protected] (L. Duan). http://dx.doi.org/10.1016/j.jocn.2014.05.046 0967-5868/Ó 2014 Published by Elsevier Ltd.
The occurrence of MMS associated with NF1 (MMS-NF1) is rare. Fewer than 100 patients with MMS-NF1 have been reported in the literature at the time of writing [1–2]. Although MMD occurs frequently in Asian countries, most MMS-NF1 patients have been reported in Europe and USA. In addition, there is a scarcity of reports on the treatment and long-term follow-up of these patients. The objective of this study was to report the clinical presentation, neurological imaging, management, and long-term follow-up of several Chinese MMS-NF1 patients. 2. Methods 2.1. Patient selection We reviewed the patient database of our hospital and selected the MMS patients who were also diagnosed with NF1 between July 2003 and October 2013. All of the patients included met the USA National Institutes of Health diagnostic criteria for NF1 [3]. The diagnosis of MMS was established in accordance with the criteria
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C. Han et al. / Journal of Clinical Neuroscience 22 (2015) 286–290
developed by the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis in 2012 [4]. 2.2. Clinical data and neuroimaging
of NF1 ranged from 1 to 6 years, with a median age of 2.7 ± 2.1 years. The mean age of diagnosis for MMS was 11.4 ± 8.3 years (range, 3.5–23 years). The interval from diagnosis of NF1 to MMS was 8.8 ± 7.0 years (range, 1–17 years). Indications for neurological imaging at the time of treatment included transient ischemic attack (three patients), headache (one patient), intracerebral hemorrhage (one patient), and cerebral infarction (one patient). Four patients were neurologically intact (mRS score 0), and two patients had minimal neurological deficit (mRS score 1). The NF1 clinical features in the other systems are also shown in Table 1.
The clinical information collected included sex, age at NF1 diagnosis, age at MMS diagnosis, clinical manifestations of vasculopathy, neurological imaging findings, treatment, and follow-up outcome. All of the patients underwent MRI of the brain with magnetic resonance angiography (MRA). Conventional digital subtraction angiography (DSA) was also conducted to confirm the diagnosis and to plan treatment. The severity of MMS was measured using Suzuki stages [5]. Brain perfusion single-photon emission computerised tomography (SPECT) was performed to evaluate the hemodynamic status. Based on the SPECT findings, the severity of the cerebral perfusion abnormality was classified as defective (with perfusion being the same as or less than that of white matter) or decreased (compared with contralateral grey matter). DSA, MRI with MRA, and SPECT were conducted during the follow-up. The preoperative and postoperative neurological imaging results were reviewed by an independent neuroradiologist.
Preoperative imaging and data were available for all patients. Most of the hemispheres (5/10) were in Suzuki stage 4, and the others were in stage 1 (two hemispheres), stage 2 (two hemispheres), or stage 6 (one hemisphere). Defective or decreased perfusion was revealed by SPECT in all six patients (Table 2). Three patients had radiographic follow-up after surgery, and all three presented radiographic progression (Fig. 1).
2.3. Treatment
3.3. Treatment and follow-up outcome
Most of the patients with cerebral vasculopathy were advised to undergo revascularization surgery on the side containing the lesion. Before the operation, a carefully designed preoperative evaluation was performed to identify indications and surgical goals. The postsurgical collateral vessels were graded according to the method described by Matsushima et al. [6], where ‘‘good’’ indicates that the postsurgical collateral vessels achieved revascularization of two-thirds of the middle cerebral artery (MCA) distribution, ‘‘fair’’ indicates that the postsurgical collateral vessels achieved revascularization of one-third to two-thirds of the MCA distribution, and ‘‘poor’’ indicates that the postsurgical collateral vessels achieved very little or no revascularization. The functional status of each patient was graded according to the modified Rankin Scale (mRS).
Five patients (nine hemispheres) underwent revascularization surgery, and eight hemispheres were subjected to encephaloduroarteriosynangiosis (EDAS), which is a standard indirect revascularization procedure. One hemisphere was subjected to a superficial temporal artery (STA)–MCA bypass, and one patient was treated with aspirin (Table 2). All six patients underwent clinical follow-up, and three underwent radiographic follow-up. The average duration of follow-up was 46.3 ± 36.1 months (range, 18–108 months). At the time of the most recent follow-up, the clinical symptoms of the five patients who underwent revascularization surgery were stable, and the degree, frequency, and durations of transient ischemic attacks and headaches were decreased. The patient who presented with hemorrhage did not suffer from rebleeding. The patient who had been treated with aspirin suffered a new infarct that resulted in new visual field deficits, and the mRS score deteriorated during follow-up (2 versus 1). During radiographic follow-up, the postoperative angiogram showed good collaterals in one hemisphere and fair collaterals in the other five hemispheres (Table 2).
2.4. Statistical analyses Descriptive statistics only were used in this study.
3.2. Neurological imaging findings
3. Results 4. Discussion 3.1. Clinical features A total of six patients, two boys and four girls, were enrolled in the study. During this period, 2008 MMD and MMS patients were managed in our hospital. As a result, the proportion of MMS-NF1 patients was 0.3% (6/2008) in this period. The clinical features of all of the patients are summarised in Table 1. The age at diagnosis
According to some recent studies, the incidence of cerebrovascular diseases in NF1 is 2.5–6% [7–9]. MMD-type changes were a significant proportion of the neurological imaging findings, at 47% (7/15 patients), in the study by Ghosh et al. [9] and 76% (13/ 17 patients) in the study by Rea et al. [8]. There are also several case reports indicating an association of MMS and NF1 [10–11].
Table 1 Clinical features of patients with moyamoya syndrome associated with neurofibromatosis type 1 Patient
Sex
Age at diagnosis of NF1, y
Age at diagnosis of MMS, y
Clinical features of NF1
Neurological symptoms
mRS
1 2 3 4 5
F F F F M
4 1 6 1 1
17 3.5 23 16 5
TIA TIA Infarction Hemorrhage Headache
0 0 1 0 1
6
M
3
4
Café au lait spots, skin-fold freckling, neurofibromas Café au lait spots, skin-fold freckling Café au lait spots, skin-fold freckling Café au lait spots, skin-fold freckling Café au lait spots, plexiform neurofibroma, skin-fold freckling, bone lesion café au lait spots, neurofibromas
TIA
0
F = female, M = male, MMS = moyamoya syndrome, mRS = modified Rankin Scale, NF1 = neurofibromatosis type 1, TIA = transient ischemic attack, y = years.
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Table 2 Neurological imaging findings and treatment outcomes of patients with moyamoya syndrome associated with neurofibromatosis type 1 Patient
1 2
3 4 5 6
Vascular findings
Right ICA occlusion, moyamoya (unilateral) Left MCA (M2) and ACA stenosis, right MCA stenosis, moyamoya (bilateral)
Right ICA occlusion Left MCA stenosis, right ICA occlusion, moyamoya (bilateral) Left ICA occlusion, right MCA stenosis, moyamoya (bilateral) Left and right ICA occlusion, moyamoya (bilateral)
Suzuki stage
SPECT
Left
Right
0
4
Defective
2
1
0 2
mRS*
Treatment
Followup, m
Matsushima scale
Progression
Left
Right
Symptom
Suzuki stage
mRS#
29
–
Unclear
Stable
Unclear
0
EDAS
19
Fair
Fair
Stable
0
– EDAS
Aspirin EDAS
32 18
– Unclear
Unclear Unclear
Infarction Stable
Left (2 ? 4) Right (1 ? 4) Unclear Unclear
STAMCA EDAS
EDAS
72
Fair
Fair
Stable
EDAS
108
Good
Fair
Stable
Left
Right
0
–
EDAS
Decreased
0
EDAS
6 4
Decreased Decreased
1 0
4
1
Decreased
1
3
4
Decreased
0
Right (1 ? 2) Left (3 ? 5) Right (4 ? 5)
1?2 0 1 0
ACA = anterior cerebral artery, EDAS = encephaloduroarteriosynangiosis, ICA = internal carotid artery, m = months, MCA = middle cerebral artery, mRS = modified Rankin Scale, SPECT = single-photon emission computerised tomography, STA-MCA = superficial temporal artery–middle cerebral artery bypass. * mRS at presentation. # mRS at last follow-up.
To the best of our knowledge, our study represents the first report of a series of Chinese MMS-NF1 patients. The presence of MMS in MMS-NF1 patients is considered to be closely correlated with NF1. The NF1 pathogenic gene is found on chromosome 17, and candidate pathogenic genes for MMD have also been identified on this chromosome [2,12]. However, the reason why the vasculopathy affects only the intracranial ICA remains unclear. Some researchers have offered a ‘‘second hit’’ hypothesis [13], which states that a ‘‘second hit’’ mutation occurs on the NF1 gene or another locus that leads to vascular changes. In addition to the ‘‘second hit’’ hypothesis, racial differences may also be relevant to the pathogenesis of MMS-NF1 because most MMSNF1 patients have been reported in Europe and America, whereas cases in Asia and Africa are extremely rare. However, none of these hypotheses have been able to resolve whether MMD and NF1 are merely co-existing or if this disease is in fact pathogenically related MMS-NF1. In this study, we report six Chinese MMS-NF1 patients. The intervals from NF1 to the onset of the clinical neurological symptoms are variable, indicating that MMS and the other complications of NF1 may not present simultaneously. NF1 patients require close follow-up for the early detection of MMS to allow targeted interventions. Clinically, all six patients exhibited obvious symptoms, including transient ischemic attacks, headaches, infarctions, and hemorrhages. In contrast to our results, a certain number of asymptomatic patients were detected in the other studies [1,7–9]. The reasons for this difference may be attributed to the selection of the samples. Our hospital provides health supervision for MMD and MMS patients; thus, the patients always came to the hospital after the onset of the clinical neurological symptoms. Not all of the MMS-NF1 patients have clinical symptoms; however, MMS appears to have a significant risk for progression compared with the other cerebrovascular abnormalities associated with NF1. In our study, a patient who did not undergo surgery manifested a new visual field defect. Rosser et al. [7] noted that eight of 316 NF1 patients had arteriopathy, and moyamoya was a risk factor for stroke. Koss et al. [1] reported 39 MMS-NF1 patients in the USA. Although only 66% were symptomatic at the time of initial diagnosis, an increase in the percentage of newly symptomatic children (from 66% to 78%) was observed during follow-up.
Based on the radiographic characteristics, our study found that the MMS-NF1 patients were in every Suzuki stage. The study by Koss et al. also showed identical findings between the NF1-related moyamoya group and the non-NF1 moyamoya group [1]. To date, revascularization has been the most successful therapy for preventing strokes in MMD patients [14–15]. There is no consensus regarding the management of cerebral arteriopathy associated with NF1. Close monitoring with MRI/MRA is necessary for asymptomatic patients. Some studies recommended medical management with an antiplatelet agent such as aspirin, as it may reduce the risk of clot formation in narrowed arteries where platelet-rich clots can easily form [8–9]. However, most researchers recommend that MMS-NF1 patients undergo a revascularization procedure to reduce the risk of stroke [1,9]. In this study, eight hemispheres of five patients were subjected to EDAS, and one hemisphere was treated with a STA–MCA bypass. The clinical symptoms of the five patients, including those who underwent direct and indirect revascularizations, remained stable during follow-up. In the three patients who underwent radiographic follow-up, a progression in the Suzuki stage was observed in five hemispheres, and successful revascularization (one good, five fair in the Matsushima scale) was observed found in all of the operated hemispheres. The stable clinical manifestations may be attributed to surgical intervention. In addition, the disease progression observed in the non-surgical patient demonstrates the need for revascularization from another perspective. Postoperative cerebral angiograms demonstrated that both the direct and indirect revascularization surgeries were effective. However, the mechanisms that initiate the vascular changes remain unclear. Furthermore, it is unknown whether the NF1associated vasculopathy can affect the extracranial carotid artery. Therefore, the long-term outcomes of MMS-NF1 patients should be closely followed. The limitations of this study include its retrospective nature and the small number of patients. Another limitation is that postoperative cerebral angiography data was not available for some patients. Future prospective longitudinal studies that evaluate postoperative changes in the ICA and extracranial carotid artery will provide important data that will help determine the optimal treatment and long-term prognosis for these patients.
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Fig. 1. Radiographic progression and postsurgical collateral vessels in Patient 2, who presented with transient ischemic attacks and was subjected to conventional angiography. (A) Preoperative right internal carotid angiogram (RICA, lateral view). (B) Postoperative lateral angiography at 1 year follow-up showed progression in the terminal portion of the RICA. (C) Preoperative right external carotid angiogram (lateral view). (D) Postoperative lateral angiography at 1 year follow-up demonstrated fair revascularization via the superficial temporal artery.
5. Conclusions MMS-NF1 is a rare occurrence worldwide. The time interval from NF1 to the onset of clinical neurological symptoms indicates that the routine vascular screening of NF1 patients is necessary for the early identification of MMS and the other cerebral arteriopathies. Revascularization surgery may be the most efficient way to prevent the progression of clinical symptoms, but the long-term outcomes require close follow-up studies. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by a grant from the National Natural Science Foundation of China (81171083). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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