Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Original article
Arachnoid cysts in tuberous sclerosis complex Susana Boronat a,c, Paul Caruso b, Maria Auladell a, Agnies Van Eeghen a, Elizabeth Anne Thiele a,⇑ a Department of Neurology, Massachusetts General Hospital, Boston, USA Department of Neuroradiology, Massachusetts General Hospital, Boston, USA c Department of Pediatric Neurology, Vall d’ Hebron Hospital, Universitat Auto`noma de Barcelona, Spain b
Received 19 June 2013; received in revised form 22 August 2013; accepted 12 November 2013
Abstract Objective: Some clinical findings in tuberous sclerosis complex (TSC), such as hypomelanotic macules or angiofibromas are related to problems in development of the neural crest, which is also the origin of cranial leptomeninges. Arachnoid cysts have been reported in two TSC patients to date. The purpose of this study was to assess the prevalence and characteristics of arachnoid cysts in a large cohort of TSC. Materials and method: We performed a review of brain MRIs of 220 TSC patients searching for arachnoid cysts. Results: Arachnoid cysts were found in 12 (5.5%) (general population: 0.5%), including ten males (83.3%). Four patients (33.3%) had also autosomal dominant polycystic kidney disease (ADPKD) due to a contiguous deletion of the TSC2–PKD1 genes. Three patients (25%) had two or more arachnoid cysts, of whom two also had ADPKD. One patient with an arachnoid cyst did not have tubers, subependymal nodules or white matter migration lines. Conclusion: Our study suggests that arachnoid cysts are part of the clinical spectrum of TSC and may be also present in TSC patients without other typical TSC brain lesions. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Arachnoid cyst; Meninges; Neural crest; Tuberous sclerosis complex (TSC)
1. Introduction Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to mutations in the TSC1 or TSC2 genes. On brain MRIs, the majority of patients have tubers, subependymal nodules (SENs) and white matter migration lines, and 5–20% have subependymal giant cell tumors [1]. Less frequent lesions attributed to TSC include hemimegalencephaly or intracranial aneurysms [2]. Some clinical features of TSC, such as hypomelanotic macules or facial angiofibromas, are
likely related to dysfunction of the neural crest, which is also involved in the pathogenesis of other neurocutaneous syndromes, such as neurofibromatosis type 1 and Sturge–Weber syndrome [3]. Since the cranial leptomeninges also originate from the neural crest, arachnoid cysts may be expected in TSC. Thus far, only two cases of arachnoid cysts have been reported in TSC. The purpose of this study is to determine the prevalence and clinical characteristics of arachnoid cysts in a large cohort of TSC. 2. Materials and methods
⇑ Corresponding author. Address: Pediatric Epilepsy Program,
Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114, USA. Tel.: +1 617 726 0241; fax: +1 617 726 0230. E-mail address: [email protected] (E.A. Thiele).
We performed a retrospective review of pediatric and adult patients with TSC who underwent brain MRI imaging between January 2006 and September 2012 in our institution. Inclusion criteria for the study group
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.11.003
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
Case
Age
2
G
Mutation
Location and size in cm (SI AP TV)
B
C
V
Adjacent tubers or WMm
Other brain MRI findings
Skin findings in head and face
Left sylvian fissure (6 5.7 4) Left frontal (1.8 5.3 3.1) Left frontal (1 2.4 2.1)
Yes No
Yes Yes
Yes No
2 Tubers 1 WMm
Tubers (right: 30, left: 33) (largest on right) SENs (largest on right)
Bilateral angiofibromas
Yes
Yes
No
No
Tubers (right: 13, left: 11) (largest on left) SENs (largest on left) Tubers (right: 14, left: 16) (largest on right) SENs (largest on left) 1 right cerebellar tuber Tubers (right: 9, left: 7) (largest on left) SENs (largest on left) Tubers (right: 15, left: 18) (largest on left) SENs (largest on right) 1 right cerebellar tuber Left occipital resection (epilepsy surgery) Tubers (right: 24, left: 30) (largest on left) SENs (largest on right) 1 right cerebellar tuber Tubers (right: 13, left: 9) (largest on right) SGCT on left
Angiofibromas left > right
*
1
11 (1,5)
M
TSC2 deletion + ADPKD
2
13 (5)
M
TSC2 (NS E14)
3
35 (30)
M
Not done
Left frontal (1.8 1.8 1.2)
Yes
Yes
Yes
1 Tuber 1 WMm
4
42
F
TSC2
Left frontal (2.1 3.4 2.6)
Yes
Yes
Yes
1 Tuber 1 WMm
5
14 (4)
M
TSC2 deletion + ADPKD
Left temporal (2.4 1.2 1.4)
Yes
Yes
Yes
No
6
20 (10)
M
TSC2 (spl E29)
Right temporal (3.7 2.3 4.2)
Yes
Yes
Yes
1 Tuber
7
12 (4)
M
TSC2 c.2546-1 (spl I21)
Yes no yes
Yes Yes Yes
Yes Yes No
No 1 Tuber 1 Tuber
8
46 (38)
M
TSC1
Left temporal (2 2.9 3.4) Left frontal (0.9 1.4 1.6) Right parietal (1.6 1.4 1.6) Left temporal (1.2 1.4 2.2)
Yes
Yes
Yes
No
9
8 (6)
M
TSC2 deletion + ADPKD
Right temporal (1.8 1.8 2.1)
No
Yes
Yes
1 Tuber
10
11
F
TSC2 deletion + ADPKD
Right parietal (2.6 3.8 3.8) Right frontal anterior (1.4 1 1.2) Right frontal posterior (0.5 1.1 1.4)
Yes Yes Yes
Yes No No
Yes No Yes
No No No
Tubers (right: 2, left: 4) (largest on left) SGCT on left Tubers (right: 26 left: 23) (largest on right) SGCT on left Tubers (right: 7, left: 9) (largest on left) SGCT on left Bilateral cerebellar tubers
Right forehead plaque (1 3 cm) Left occipital collagenoma (5 4 cm) Bilateral angiofibromas Bilateral angiofibromas
Left forehead plaque Bilateral angiofibromas
Right forehead plaque Bilateral angiofibromas
Bilateral angiofibromas
Angiofibromas left > right, extending into left temporal region Right forehead plaque Angiofibromas right > left Right forehead plaque Bilateral angiofibromas
S. Boronat et al. / Brain & Development xxx (2014) xxx–xxx
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
Table 1 TSC patients with arachnoid cysts.
ADPKD: autosomal dominant polycystic kidney disease, AP: antero-posterior, B: bone remodeling of inner table of calvarium, C: flattening of the adjacent cortex, E: exon, F: female, I: intron, M: male, NS: non-sense, SENs: subependymal nodules, SGCT: subependymal giant cell tumor, SI: superior-inferior, spl: mutation affecting splicing, TV: transverse, V: displaced vessels, WMm: white matter migration lines. * Age at latest MRI, in years. In brackets: age at time of first MRI available for review.
Poliosis in occiput No Yes Yes No Right choroidal fissure (1.5 2.6 2) (3 and 5 years of age: 1.3 2.3 1.6) No mutation identified 7 (3) 12
M
21 (13) 11
M
TSC2 c.336 + 2 T > G (spl I03)
Retro-cerebellar (3 4.1 4.4)
Yes
Yes
No
1 Tuber
Tubers (right: 11, left: 17) SENs (largest on left) Bilateral cerebellar tubers No tubers or SENs
Bilateral angiofibromas
S. Boronat et al. / Brain & Development xxx (2014) xxx–xxx
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were diagnosis of definite TSC based on the current TSC clinical diagnostic criteria [4] and brain MR images with high-quality sequences. Exclusion criteria were uncertain TSC diagnosis and incomplete or poor-quality images. Study subjects included 220 patients (95 males, 125 females, mean age: 22.7 (range: 9 months– 81 years)). Genetic testing results, including TSC1 and TSC2 sequencing and TSC2 deletion testing, were available for 177 patients: 43 had a mutation in TSC1, 103 in TSC2, including 5 who had a deletion also affecting PKD1 (which is responsible for autosomal dominant polycystic renal disease (ADPKD)), 25 had no mutation identified (NMI), and 6 patients had a variant of uncertain significance. This study was approved by the institutional review board. All MRIs were performed as part of the diagnosis or annual routine follow-up on either a 1.5 T or a 3.0 T system and standard departmental imaging protocols were used. Sequences included spin-echo T1WI, spin-echo T2WI, and FLAIR in all patients. SWI, DWI and 3D multiplanar reconstruction were reviewed when available. Scans were reviewed by 2 independent reviewers, including a pediatric neuroradiologist with 11 years experience (PC), and a pediatric neurologist (SB) with 7 years post-fellowship experience. Consensus was obtained for all criteria examined in case of difference in opinion. All patients with TSC were identified and a review of their latest MRI was performed to determine whether arachnoid cysts were present. In cases with arachnoid cysts, the patient’s first available brain MRI was also reviewed. If any changes were detected, a longitudinal evaluation of the lesion in all the MRIs of that patient was performed. Information about the following features was recorded: age at their latest MRI and age at the time of first detection of the arachnoid cysts, gender, type of mutation and distribution of TSC skin involvement at the level of face and head. Imaging characteristics of the arachnoid cysts recorded included the following: number, location, size and imaging signs suggestive of compression (inner table remodeling, flattening of the underlying cortex and vessel displacement). Size was determined by square measurements, that is, the maximum distance in each of three planes of space. Morphology of the underlying brain, noting the presence of tubers and/or white matter migration lines adjacent to the arachnoid cysts, was assessed. Information about other brain lesions recorded included: number of tubers in each hemisphere, side of the largest brain tuber and largest SEN, presence and side of subependymal giant cell tumor or cerebellar tubers. The statistical analyses were performed using SPSS version 11.5 for Windows. An alpha level of 0.05 was used for all statistical calculations. Contingency tables were analyzed using Chi-square or Fisher exact test.
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
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S. Boronat et al. / Brain & Development xxx (2014) xxx–xxx
3. Results Results are summarized in Table 1. Arachnoid cysts were present in 12 of 220 TSC patients (5.5%, CI: 3– 9.6%). Three patients had 2 or 3 arachnoid cysts, with a total of 17. Nine were on the left, 7 on the right and 1 in midline (retrocerebellar). The sex ratio was 5 (p < 0.006). None of the patients had symptoms related to the arachnoid cysts. The mutational study in the arachnoid cysts group was available in 11 of the 12 patients: one TSC1 mutation, 9 TSC2 mutations, including 4 contiguous deletion of TSC2–PKD1, and one patient with NMI. A contiguous deletion was significantly more frequent in TSC patients with arachnoid cysts (p < 0.0001). The locations of arachnoid cysts included frontal convexity (5 on the left, 2 on the right) (Fig. 1), temporal fossa (3 on the left, 2 on the right) (Fig. 2), right parietal (2) (Fig. 3), retrocerebellar (1), left sylvian fissure (1) and right choroidal fissure (1) (Fig. 4). Three patients had multiple arachnoid cysts, which were ipsilateral in two patients (both with TSC2–PKD1 deletion) and bilateral in one. Of the 10 patients with two or more MRIs, only one patient (patient 12 on Table 1) showed slight growth between 5 and 6 years of age, and was not associated to any new symptoms. Fifteen out of the total 17 (88%) arachnoid cysts showed two or three of the following: inner table remodeling, flattening of the underlying cortex or vessel displacement. Ten patients had clearly lateralized arachnoid cysts (patient 7 had arachnoid cysts in both hemispheres and in patient 11 was in midline). Six patients had clearly lateralized
Fig. 2. Coronal 3D SPGR (Spoiled Gradient Echo) image in case 6. Temporal right arachnoid cyst (arrow) and adjacent cystic tuber (curved arrow).
cutaneous findings including unilateral forehead plaque (3 patients), clearly asymmetric angiofibromas (2 patients) or both (patient 9). In all cases the most affected facial side was ipsilateral to the arachnoid cyst. No cases of an arachnoid cyst and an isolated contralateral skin lesion were found, although bilateral cutaneous lesions were present. Related to other brain findings: patient 12 did not have typical TSC brain lesions but had dilated perivascular spaces ipsilateral to the arachnoid cyst (Fig. 4). Eleven out of 17 arachnoid cysts were accompanied by an adjacent tuber or white matter migration line. An ipsilateral correlation was not detected between the side of the arachnoid cyst and the hemisphere with larger number of brain tubers, the largest tuber, the largest SEN or the side of cerebellar tubers. Subependymal giant cell tumors were ipsilateral to the arachnoid cysts in 2 cases and in one case was contralateral. 4. Discussion
Fig. 1. Axial FSE (Fast Spin Echo) T2 image in case 3. Left frontal arachnoid cyst (arrow) and adjacent tuber (arrowhead). Note contralateral cystic tuber (curved arrow).
Arachnoid cysts are intra-arachnoid fluid collections that are incidental findings in 0.5% (0.21–0.87%) of general population [5]. Arachnoid cysts are significantly more prevalent in our TSC cohort (5.5%, CI: 3–9.6%) (p < 0.05). So far, only two previous TSC cases with arachnoid cysts have been reported [6,7]. Arachnoid cysts in TSC frequently have inner table remodeling, flattening of the underlying cortex and/or vessel displacement, which suggests either intracyst pressure with compression of the adjacent structures or a very early formation that may disrupt the development of the surrounding structures. In a population-based study of 299 patients with arachnoid cysts, males were more frequently affected (the sex ratio was 1.64) and there was a strong predilection for the left temporal fossa [8]. In our TSC cohort, arachnoid cysts were significantly more frequent in males
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
S. Boronat et al. / Brain & Development xxx (2014) xxx–xxx
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Fig. 3. (a) This coronal FLAIR (Fluid Attenuated Inversion Recovery) image in case 10 shows a right parietal arachnoid cyst with bone remodeling (arrow) and nearby a right parietal tuber (arrowhead). (b) The sagittal T1 image in this patient shows a right high parietal convexity arachnoid cyst and a smaller right posterior frontal arachnoid cyst (arrows).
Fig. 4. In this coronal SPGR (Spoiled Gradient Echo) image of patient 12, prominent perivascular spaces in the right frontal white matter (arrowhead) lie ipsilateral to a prominent choroidal fissure cyst (arrow).
than in females (10 males, 2 females; the sex ratio was 5) (p < 0.006). Gender influences some phenotypic expressivity in TSC, and some clinical manifestations, such as lymphangioleiomyomatosis, occur almost exclusively in females [1]. Patients with multiple cysts (3/12 cases (25%)), none of them with bitemporal distribution, were more frequent in our TSC cohort than in the populationbased study group, where multiple cysts were present in 2% of cases and all were bitemporal [8]. Among the 10 patients with previous MRIs, only patient 12 showed a slight increase in the size between 5 and 6 years of age. He did not present with symptoms related to the cyst. Although the etiology of arachnoid cysts remains largely unknown and most occur sporadically, familial
[9] and syndromic cases support a genetic contribution. In autosomal dominant polycystic kidney disease (ADPKD), a prior study reported arachnoid cysts in 8% of patients, with predominance in females (3:1), location in the middle fossa, and 10% were multiple [10]. In our study arachnoid cysts were present in 4 of 5 patients (p < 0.0001) with a combined phenotype of TSC and ADPKD due to contiguous deletion of the TSC2– PKD1 genes. This raises the question if arachnoid cysts are due to ADPKD, to TSC or the combination of both disorders. Even after excluding the 4 cases with ADPKD, the prevalence of arachnoid cysts in TSC (8/ 220 (3.6%; CI: 1.7–7.3%)) is higher than in general population, suggesting that TSC is an independent risk factor for the presence of arachnoid cysts. Therefore, patients with the contiguous deletion phenotype may be at a higher risk of having arachnoid cysts and higher probability of these being multiple (2/3 patients with multiple cysts had also ADPKD). The two previous reported TSC cases with arachnoid cysts were also multiple: one male with bitemporal arachnoid cysts and one female with a left sylvian and right frontal arachnoid cysts, but no mutational information was available. Arachnoid cysts have also been reported in neurofibromatosis type 1 (11), more frequently located in the temporal fossa. Two cases with arachnoid cysts ipsilateral to a facial plexiform neurofibroma have been reported [11]. Sturge–Weber syndrome, which seems also related to neural crest dysfunction [3,12], is associated with a facial angioma that is almost always ipsilateral to the leptomeningeal angiomatosis, and a case report of Sturge–Weber syndrome showed a temporal arachnoid cyst ipsilateral to the facial nevus [13]. An ipsilateral correlation of the forehead plaque to the
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
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S. Boronat et al. / Brain & Development xxx (2014) xxx–xxx
arachnoid cyst has also been noticed in 4 of our TSC patients. Although facial angiofibromas are usually bilateral in TSC, three patients had clearly asymmetric angiofibromas, with the most affected side ipsilateral to the cyst. None of the cases had predominant skin lesions contralateral to the arachnoid cysts. These findings may be related to the fact that during cranial neural crest migration, cells follow lateralized specific pathways that would explain the association of lateralized skin, vascular and meningeal findings. Arachnoid cysts can also be present without tubers, SENs and white matter migration lines, as our patient 12. This patient showed dilated perivascular spaces ipsilateral to the arachnoid cyst. Cystic white matter lesions consistent with dilated perivascular spaces have been reported in TSC [14]. Dysfunction of pericytes, which are of neural crest origin [15] and mediate capillary vasoconstriction, may account for abnormalities of perivascular spaces in TSC patients. The mechanism of arachnoid cysts formation is controversial and several mechanisms have been proposed that include agenesis of part of the brain, a defect in the development of the arachnoid or abnormalities in the cerebrospinal fluid flow, and there are some reports that favor a genetic etiology [16]. As this is the first study showing an increased prevalence of arachnoid cysts in TSC, there are not previous hypotheses regarding the pathophysiology. Aside from neural crest maldevelopment, another possible etiologic factor may be related to development of the lymphatic system. Given the fact that arachnoid granulations are formed during the last weeks of gestation [17], the absorption of the cerebrospinal fluid during development depends on extra-arachnoid pathways, mainly the lymphatic system via the olfactory nerve rootlets [18]. Some TSC patients show lymphatic system involvement in the form of lymphangioleiomyomatosis, renal angiomyolipoma or some cases of congenital lymphedema [19], so a relative malfunction of the lymphatic system during development in some TSC patients may also play a role in arachnoid cysts formation. 5. Conclusion Findings in this large cohort suggest that arachnoid cysts are part of the TSC phenotype and provides further evidence for a genetic basis in some cases of arachnoid cysts. Neural crest maldevelopment may be the main mechanism for arachnoid cysts formation in TSC, and arachnoid cysts can be present without tubers, SENs and white matter migration lines. Male gender and contiguous deletion of TSC2–PKD1 seem to be risk factors for arachnoid cysts in TSC. In the case of unilat-
eral or clearly asymmetric facial skin lesions, the side of the arachnoid cysts is usually ipsilateral to the most affected side. References [1] Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345–56. [2] DiMario Jr FJ. Brain abnormalities in tuberous sclerosis complex. J Child Neurol 2004;19:650–7. [3] Sarnat HB, Flores-Sarnat L. Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. J Child Neurol 2005;20:637–43. [4] Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13:624–8. [5] Morris Z, Whiteley WN, Longstreth Jr WT, Weber F, Lee Y-C, Tsushima Y, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2009;339:b3016. [6] Itoua B, Joubert E, Le Bras Y, Picot F, Gautier F, Wertel F, et al. What is it? Bourneville tuberous sclerosis associated with an arteriovenous malformation, a pituitary adenoma and 2 arachnoid cysts. J Radiol 1999;80:395–6. [7] Tatli M, Guzel A. Bilateral temporal arachnoid cysts associated with tuberous sclerosis complex. J Child Neurol 2007;22:775–9. [8] Helland CA, Lund-Johansen M, Wester K. Location, sidedness, and sex distribution of intracranial arachnoid cysts in a population-based sample. J Neurosurg 2010;113:934–9. [9] Pomeranz S, Constantini S, Lubetzki-Korn I, Amir N. Familial intracranial arachnoid cysts. Childs Nerv Syst 1991;7:100–2. [10] Schievink WI, Huston 3rd J, Torres VE, Marsh WR. Intracranial cysts in autosomal dominant polycystic kidney disease. J Neurosurg 1995;83:1004–7. [11] Boltshauser E, Stocker H, Sailer H, Valavanis A. Intracranial abnormalities associated with facial plexiform neurofibromas in neurofibromatosis type 1. Neurofibromatosis 1989;2:274–7. [12] Curatolo P. MRI appearance of Sturge–Weber syndrome in tuberous sclerosis complex: is the neural crest the culprit? J Child Neurol 2009;24:263–6. [13] Ergu¨n R, Okten AI, Gezercan Y, Gezici AR. Sturge-Weber syndrome accompanied with multiple congenital intracranial lesions. Acta Neurochir (Wien) 2007;149:829–30 discussion 830. [14] Van Tassel P, Cure´ JK, Holden KR. Cystlike white matter lesions in tuberous sclerosis. AJNR Am J Neuroradiol 1997;18:1367–73. [15] Etchevers HC, Vincent C, Le Douarin NM, Couly GF. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 2001;128:1059–68. [16] Gosalakkal JA. Intracranial arachnoid cysts in children: a review of pathogenesis, clinical features, and management. Pediatr Neurol 2002;26:93–8. [17] Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis 2011;128:309–16. [18] Papaiconomou C, Bozanovic-Sosic R, Zakharov A, Johnston M. Does neonatal cerebrospinal fluid absorption occur via arachnoid projections or extracranial lymphatics? Am J Physiol Regul Integr Comp Physiol 2002;283:869–76. [19] Hirsch RJ, Silverberg NB, Laude T, Weinberg JM. Tuberous sclerosis associated with congenital lymphedema. Pediatr Dermatol 1999;16:407–8.
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
Original article
Arachnoid cysts in tuberous sclerosis complex Susana Boronat a,c, Paul Caruso b, Maria Auladell a, Agnies Van Eeghen a, Elizabeth Anne Thiele a,⇑ a Department of Neurology, Massachusetts General Hospital, Boston, USA Department of Neuroradiology, Massachusetts General Hospital, Boston, USA c Department of Pediatric Neurology, Vall d’ Hebron Hospital, Universitat Auto`noma de Barcelona, Spain b
Received 19 June 2013; received in revised form 22 August 2013; accepted 12 November 2013
Abstract Objective: Some clinical findings in tuberous sclerosis complex (TSC), such as hypomelanotic macules or angiofibromas are related to problems in development of the neural crest, which is also the origin of cranial leptomeninges. Arachnoid cysts have been reported in two TSC patients to date. The purpose of this study was to assess the prevalence and characteristics of arachnoid cysts in a large cohort of TSC. Materials and method: We performed a review of brain MRIs of 220 TSC patients searching for arachnoid cysts. Results: Arachnoid cysts were found in 12 (5.5%) (general population: 0.5%), including ten males (83.3%). Four patients (33.3%) had also autosomal dominant polycystic kidney disease (ADPKD) due to a contiguous deletion of the TSC2–PKD1 genes. Three patients (25%) had two or more arachnoid cysts, of whom two also had ADPKD. One patient with an arachnoid cyst did not have tubers, subependymal nodules or white matter migration lines. Conclusion: Our study suggests that arachnoid cysts are part of the clinical spectrum of TSC and may be also present in TSC patients without other typical TSC brain lesions. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Arachnoid cyst; Meninges; Neural crest; Tuberous sclerosis complex (TSC)
1. Introduction Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to mutations in the TSC1 or TSC2 genes. On brain MRIs, the majority of patients have tubers, subependymal nodules (SENs) and white matter migration lines, and 5–20% have subependymal giant cell tumors [1]. Less frequent lesions attributed to TSC include hemimegalencephaly or intracranial aneurysms [2]. Some clinical features of TSC, such as hypomelanotic macules or facial angiofibromas, are
likely related to dysfunction of the neural crest, which is also involved in the pathogenesis of other neurocutaneous syndromes, such as neurofibromatosis type 1 and Sturge–Weber syndrome [3]. Since the cranial leptomeninges also originate from the neural crest, arachnoid cysts may be expected in TSC. Thus far, only two cases of arachnoid cysts have been reported in TSC. The purpose of this study is to determine the prevalence and clinical characteristics of arachnoid cysts in a large cohort of TSC. 2. Materials and methods
⇑ Corresponding author. Address: Pediatric Epilepsy Program,
Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114, USA. Tel.: +1 617 726 0241; fax: +1 617 726 0230. E-mail address: [email protected] (E.A. Thiele).
We performed a retrospective review of pediatric and adult patients with TSC who underwent brain MRI imaging between January 2006 and September 2012 in our institution. Inclusion criteria for the study group
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.11.003
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
Case
Age
2
G
Mutation
Location and size in cm (SI AP TV)
B
C
V
Adjacent tubers or WMm
Other brain MRI findings
Skin findings in head and face
Left sylvian fissure (6 5.7 4) Left frontal (1.8 5.3 3.1) Left frontal (1 2.4 2.1)
Yes No
Yes Yes
Yes No
2 Tubers 1 WMm
Tubers (right: 30, left: 33) (largest on right) SENs (largest on right)
Bilateral angiofibromas
Yes
Yes
No
No
Tubers (right: 13, left: 11) (largest on left) SENs (largest on left) Tubers (right: 14, left: 16) (largest on right) SENs (largest on left) 1 right cerebellar tuber Tubers (right: 9, left: 7) (largest on left) SENs (largest on left) Tubers (right: 15, left: 18) (largest on left) SENs (largest on right) 1 right cerebellar tuber Left occipital resection (epilepsy surgery) Tubers (right: 24, left: 30) (largest on left) SENs (largest on right) 1 right cerebellar tuber Tubers (right: 13, left: 9) (largest on right) SGCT on left
Angiofibromas left > right
*
1
11 (1,5)
M
TSC2 deletion + ADPKD
2
13 (5)
M
TSC2 (NS E14)
3
35 (30)
M
Not done
Left frontal (1.8 1.8 1.2)
Yes
Yes
Yes
1 Tuber 1 WMm
4
42
F
TSC2
Left frontal (2.1 3.4 2.6)
Yes
Yes
Yes
1 Tuber 1 WMm
5
14 (4)
M
TSC2 deletion + ADPKD
Left temporal (2.4 1.2 1.4)
Yes
Yes
Yes
No
6
20 (10)
M
TSC2 (spl E29)
Right temporal (3.7 2.3 4.2)
Yes
Yes
Yes
1 Tuber
7
12 (4)
M
TSC2 c.2546-1 (spl I21)
Yes no yes
Yes Yes Yes
Yes Yes No
No 1 Tuber 1 Tuber
8
46 (38)
M
TSC1
Left temporal (2 2.9 3.4) Left frontal (0.9 1.4 1.6) Right parietal (1.6 1.4 1.6) Left temporal (1.2 1.4 2.2)
Yes
Yes
Yes
No
9
8 (6)
M
TSC2 deletion + ADPKD
Right temporal (1.8 1.8 2.1)
No
Yes
Yes
1 Tuber
10
11
F
TSC2 deletion + ADPKD
Right parietal (2.6 3.8 3.8) Right frontal anterior (1.4 1 1.2) Right frontal posterior (0.5 1.1 1.4)
Yes Yes Yes
Yes No No
Yes No Yes
No No No
Tubers (right: 2, left: 4) (largest on left) SGCT on left Tubers (right: 26 left: 23) (largest on right) SGCT on left Tubers (right: 7, left: 9) (largest on left) SGCT on left Bilateral cerebellar tubers
Right forehead plaque (1 3 cm) Left occipital collagenoma (5 4 cm) Bilateral angiofibromas Bilateral angiofibromas
Left forehead plaque Bilateral angiofibromas
Right forehead plaque Bilateral angiofibromas
Bilateral angiofibromas
Angiofibromas left > right, extending into left temporal region Right forehead plaque Angiofibromas right > left Right forehead plaque Bilateral angiofibromas
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Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
Table 1 TSC patients with arachnoid cysts.
ADPKD: autosomal dominant polycystic kidney disease, AP: antero-posterior, B: bone remodeling of inner table of calvarium, C: flattening of the adjacent cortex, E: exon, F: female, I: intron, M: male, NS: non-sense, SENs: subependymal nodules, SGCT: subependymal giant cell tumor, SI: superior-inferior, spl: mutation affecting splicing, TV: transverse, V: displaced vessels, WMm: white matter migration lines. * Age at latest MRI, in years. In brackets: age at time of first MRI available for review.
Poliosis in occiput No Yes Yes No Right choroidal fissure (1.5 2.6 2) (3 and 5 years of age: 1.3 2.3 1.6) No mutation identified 7 (3) 12
M
21 (13) 11
M
TSC2 c.336 + 2 T > G (spl I03)
Retro-cerebellar (3 4.1 4.4)
Yes
Yes
No
1 Tuber
Tubers (right: 11, left: 17) SENs (largest on left) Bilateral cerebellar tubers No tubers or SENs
Bilateral angiofibromas
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were diagnosis of definite TSC based on the current TSC clinical diagnostic criteria [4] and brain MR images with high-quality sequences. Exclusion criteria were uncertain TSC diagnosis and incomplete or poor-quality images. Study subjects included 220 patients (95 males, 125 females, mean age: 22.7 (range: 9 months– 81 years)). Genetic testing results, including TSC1 and TSC2 sequencing and TSC2 deletion testing, were available for 177 patients: 43 had a mutation in TSC1, 103 in TSC2, including 5 who had a deletion also affecting PKD1 (which is responsible for autosomal dominant polycystic renal disease (ADPKD)), 25 had no mutation identified (NMI), and 6 patients had a variant of uncertain significance. This study was approved by the institutional review board. All MRIs were performed as part of the diagnosis or annual routine follow-up on either a 1.5 T or a 3.0 T system and standard departmental imaging protocols were used. Sequences included spin-echo T1WI, spin-echo T2WI, and FLAIR in all patients. SWI, DWI and 3D multiplanar reconstruction were reviewed when available. Scans were reviewed by 2 independent reviewers, including a pediatric neuroradiologist with 11 years experience (PC), and a pediatric neurologist (SB) with 7 years post-fellowship experience. Consensus was obtained for all criteria examined in case of difference in opinion. All patients with TSC were identified and a review of their latest MRI was performed to determine whether arachnoid cysts were present. In cases with arachnoid cysts, the patient’s first available brain MRI was also reviewed. If any changes were detected, a longitudinal evaluation of the lesion in all the MRIs of that patient was performed. Information about the following features was recorded: age at their latest MRI and age at the time of first detection of the arachnoid cysts, gender, type of mutation and distribution of TSC skin involvement at the level of face and head. Imaging characteristics of the arachnoid cysts recorded included the following: number, location, size and imaging signs suggestive of compression (inner table remodeling, flattening of the underlying cortex and vessel displacement). Size was determined by square measurements, that is, the maximum distance in each of three planes of space. Morphology of the underlying brain, noting the presence of tubers and/or white matter migration lines adjacent to the arachnoid cysts, was assessed. Information about other brain lesions recorded included: number of tubers in each hemisphere, side of the largest brain tuber and largest SEN, presence and side of subependymal giant cell tumor or cerebellar tubers. The statistical analyses were performed using SPSS version 11.5 for Windows. An alpha level of 0.05 was used for all statistical calculations. Contingency tables were analyzed using Chi-square or Fisher exact test.
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3. Results Results are summarized in Table 1. Arachnoid cysts were present in 12 of 220 TSC patients (5.5%, CI: 3– 9.6%). Three patients had 2 or 3 arachnoid cysts, with a total of 17. Nine were on the left, 7 on the right and 1 in midline (retrocerebellar). The sex ratio was 5 (p < 0.006). None of the patients had symptoms related to the arachnoid cysts. The mutational study in the arachnoid cysts group was available in 11 of the 12 patients: one TSC1 mutation, 9 TSC2 mutations, including 4 contiguous deletion of TSC2–PKD1, and one patient with NMI. A contiguous deletion was significantly more frequent in TSC patients with arachnoid cysts (p < 0.0001). The locations of arachnoid cysts included frontal convexity (5 on the left, 2 on the right) (Fig. 1), temporal fossa (3 on the left, 2 on the right) (Fig. 2), right parietal (2) (Fig. 3), retrocerebellar (1), left sylvian fissure (1) and right choroidal fissure (1) (Fig. 4). Three patients had multiple arachnoid cysts, which were ipsilateral in two patients (both with TSC2–PKD1 deletion) and bilateral in one. Of the 10 patients with two or more MRIs, only one patient (patient 12 on Table 1) showed slight growth between 5 and 6 years of age, and was not associated to any new symptoms. Fifteen out of the total 17 (88%) arachnoid cysts showed two or three of the following: inner table remodeling, flattening of the underlying cortex or vessel displacement. Ten patients had clearly lateralized arachnoid cysts (patient 7 had arachnoid cysts in both hemispheres and in patient 11 was in midline). Six patients had clearly lateralized
Fig. 2. Coronal 3D SPGR (Spoiled Gradient Echo) image in case 6. Temporal right arachnoid cyst (arrow) and adjacent cystic tuber (curved arrow).
cutaneous findings including unilateral forehead plaque (3 patients), clearly asymmetric angiofibromas (2 patients) or both (patient 9). In all cases the most affected facial side was ipsilateral to the arachnoid cyst. No cases of an arachnoid cyst and an isolated contralateral skin lesion were found, although bilateral cutaneous lesions were present. Related to other brain findings: patient 12 did not have typical TSC brain lesions but had dilated perivascular spaces ipsilateral to the arachnoid cyst (Fig. 4). Eleven out of 17 arachnoid cysts were accompanied by an adjacent tuber or white matter migration line. An ipsilateral correlation was not detected between the side of the arachnoid cyst and the hemisphere with larger number of brain tubers, the largest tuber, the largest SEN or the side of cerebellar tubers. Subependymal giant cell tumors were ipsilateral to the arachnoid cysts in 2 cases and in one case was contralateral. 4. Discussion
Fig. 1. Axial FSE (Fast Spin Echo) T2 image in case 3. Left frontal arachnoid cyst (arrow) and adjacent tuber (arrowhead). Note contralateral cystic tuber (curved arrow).
Arachnoid cysts are intra-arachnoid fluid collections that are incidental findings in 0.5% (0.21–0.87%) of general population [5]. Arachnoid cysts are significantly more prevalent in our TSC cohort (5.5%, CI: 3–9.6%) (p < 0.05). So far, only two previous TSC cases with arachnoid cysts have been reported [6,7]. Arachnoid cysts in TSC frequently have inner table remodeling, flattening of the underlying cortex and/or vessel displacement, which suggests either intracyst pressure with compression of the adjacent structures or a very early formation that may disrupt the development of the surrounding structures. In a population-based study of 299 patients with arachnoid cysts, males were more frequently affected (the sex ratio was 1.64) and there was a strong predilection for the left temporal fossa [8]. In our TSC cohort, arachnoid cysts were significantly more frequent in males
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
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Fig. 3. (a) This coronal FLAIR (Fluid Attenuated Inversion Recovery) image in case 10 shows a right parietal arachnoid cyst with bone remodeling (arrow) and nearby a right parietal tuber (arrowhead). (b) The sagittal T1 image in this patient shows a right high parietal convexity arachnoid cyst and a smaller right posterior frontal arachnoid cyst (arrows).
Fig. 4. In this coronal SPGR (Spoiled Gradient Echo) image of patient 12, prominent perivascular spaces in the right frontal white matter (arrowhead) lie ipsilateral to a prominent choroidal fissure cyst (arrow).
than in females (10 males, 2 females; the sex ratio was 5) (p < 0.006). Gender influences some phenotypic expressivity in TSC, and some clinical manifestations, such as lymphangioleiomyomatosis, occur almost exclusively in females [1]. Patients with multiple cysts (3/12 cases (25%)), none of them with bitemporal distribution, were more frequent in our TSC cohort than in the populationbased study group, where multiple cysts were present in 2% of cases and all were bitemporal [8]. Among the 10 patients with previous MRIs, only patient 12 showed a slight increase in the size between 5 and 6 years of age. He did not present with symptoms related to the cyst. Although the etiology of arachnoid cysts remains largely unknown and most occur sporadically, familial
[9] and syndromic cases support a genetic contribution. In autosomal dominant polycystic kidney disease (ADPKD), a prior study reported arachnoid cysts in 8% of patients, with predominance in females (3:1), location in the middle fossa, and 10% were multiple [10]. In our study arachnoid cysts were present in 4 of 5 patients (p < 0.0001) with a combined phenotype of TSC and ADPKD due to contiguous deletion of the TSC2– PKD1 genes. This raises the question if arachnoid cysts are due to ADPKD, to TSC or the combination of both disorders. Even after excluding the 4 cases with ADPKD, the prevalence of arachnoid cysts in TSC (8/ 220 (3.6%; CI: 1.7–7.3%)) is higher than in general population, suggesting that TSC is an independent risk factor for the presence of arachnoid cysts. Therefore, patients with the contiguous deletion phenotype may be at a higher risk of having arachnoid cysts and higher probability of these being multiple (2/3 patients with multiple cysts had also ADPKD). The two previous reported TSC cases with arachnoid cysts were also multiple: one male with bitemporal arachnoid cysts and one female with a left sylvian and right frontal arachnoid cysts, but no mutational information was available. Arachnoid cysts have also been reported in neurofibromatosis type 1 (11), more frequently located in the temporal fossa. Two cases with arachnoid cysts ipsilateral to a facial plexiform neurofibroma have been reported [11]. Sturge–Weber syndrome, which seems also related to neural crest dysfunction [3,12], is associated with a facial angioma that is almost always ipsilateral to the leptomeningeal angiomatosis, and a case report of Sturge–Weber syndrome showed a temporal arachnoid cyst ipsilateral to the facial nevus [13]. An ipsilateral correlation of the forehead plaque to the
Please cite this article in press as: Boronat S et al. Arachnoid cysts in tuberous sclerosis complex.. Brain Dev (2014), http://dx.doi.org/10.1016/ j.braindev.2013.11.003
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arachnoid cyst has also been noticed in 4 of our TSC patients. Although facial angiofibromas are usually bilateral in TSC, three patients had clearly asymmetric angiofibromas, with the most affected side ipsilateral to the cyst. None of the cases had predominant skin lesions contralateral to the arachnoid cysts. These findings may be related to the fact that during cranial neural crest migration, cells follow lateralized specific pathways that would explain the association of lateralized skin, vascular and meningeal findings. Arachnoid cysts can also be present without tubers, SENs and white matter migration lines, as our patient 12. This patient showed dilated perivascular spaces ipsilateral to the arachnoid cyst. Cystic white matter lesions consistent with dilated perivascular spaces have been reported in TSC [14]. Dysfunction of pericytes, which are of neural crest origin [15] and mediate capillary vasoconstriction, may account for abnormalities of perivascular spaces in TSC patients. The mechanism of arachnoid cysts formation is controversial and several mechanisms have been proposed that include agenesis of part of the brain, a defect in the development of the arachnoid or abnormalities in the cerebrospinal fluid flow, and there are some reports that favor a genetic etiology [16]. As this is the first study showing an increased prevalence of arachnoid cysts in TSC, there are not previous hypotheses regarding the pathophysiology. Aside from neural crest maldevelopment, another possible etiologic factor may be related to development of the lymphatic system. Given the fact that arachnoid granulations are formed during the last weeks of gestation [17], the absorption of the cerebrospinal fluid during development depends on extra-arachnoid pathways, mainly the lymphatic system via the olfactory nerve rootlets [18]. Some TSC patients show lymphatic system involvement in the form of lymphangioleiomyomatosis, renal angiomyolipoma or some cases of congenital lymphedema [19], so a relative malfunction of the lymphatic system during development in some TSC patients may also play a role in arachnoid cysts formation. 5. Conclusion Findings in this large cohort suggest that arachnoid cysts are part of the TSC phenotype and provides further evidence for a genetic basis in some cases of arachnoid cysts. Neural crest maldevelopment may be the main mechanism for arachnoid cysts formation in TSC, and arachnoid cysts can be present without tubers, SENs and white matter migration lines. Male gender and contiguous deletion of TSC2–PKD1 seem to be risk factors for arachnoid cysts in TSC. In the case of unilat-
eral or clearly asymmetric facial skin lesions, the side of the arachnoid cysts is usually ipsilateral to the most affected side. References [1] Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345–56. [2] DiMario Jr FJ. Brain abnormalities in tuberous sclerosis complex. J Child Neurol 2004;19:650–7. [3] Sarnat HB, Flores-Sarnat L. Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. J Child Neurol 2005;20:637–43. [4] Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13:624–8. [5] Morris Z, Whiteley WN, Longstreth Jr WT, Weber F, Lee Y-C, Tsushima Y, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2009;339:b3016. [6] Itoua B, Joubert E, Le Bras Y, Picot F, Gautier F, Wertel F, et al. What is it? Bourneville tuberous sclerosis associated with an arteriovenous malformation, a pituitary adenoma and 2 arachnoid cysts. J Radiol 1999;80:395–6. [7] Tatli M, Guzel A. Bilateral temporal arachnoid cysts associated with tuberous sclerosis complex. J Child Neurol 2007;22:775–9. [8] Helland CA, Lund-Johansen M, Wester K. Location, sidedness, and sex distribution of intracranial arachnoid cysts in a population-based sample. J Neurosurg 2010;113:934–9. [9] Pomeranz S, Constantini S, Lubetzki-Korn I, Amir N. Familial intracranial arachnoid cysts. Childs Nerv Syst 1991;7:100–2. [10] Schievink WI, Huston 3rd J, Torres VE, Marsh WR. Intracranial cysts in autosomal dominant polycystic kidney disease. J Neurosurg 1995;83:1004–7. [11] Boltshauser E, Stocker H, Sailer H, Valavanis A. Intracranial abnormalities associated with facial plexiform neurofibromas in neurofibromatosis type 1. Neurofibromatosis 1989;2:274–7. [12] Curatolo P. MRI appearance of Sturge–Weber syndrome in tuberous sclerosis complex: is the neural crest the culprit? J Child Neurol 2009;24:263–6. [13] Ergu¨n R, Okten AI, Gezercan Y, Gezici AR. Sturge-Weber syndrome accompanied with multiple congenital intracranial lesions. Acta Neurochir (Wien) 2007;149:829–30 discussion 830. [14] Van Tassel P, Cure´ JK, Holden KR. Cystlike white matter lesions in tuberous sclerosis. AJNR Am J Neuroradiol 1997;18:1367–73. [15] Etchevers HC, Vincent C, Le Douarin NM, Couly GF. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 2001;128:1059–68. [16] Gosalakkal JA. Intracranial arachnoid cysts in children: a review of pathogenesis, clinical features, and management. Pediatr Neurol 2002;26:93–8. [17] Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis 2011;128:309–16. [18] Papaiconomou C, Bozanovic-Sosic R, Zakharov A, Johnston M. Does neonatal cerebrospinal fluid absorption occur via arachnoid projections or extracranial lymphatics? Am J Physiol Regul Integr Comp Physiol 2002;283:869–76. [19] Hirsch RJ, Silverberg NB, Laude T, Weinberg JM. Tuberous sclerosis associated with congenital lymphedema. Pediatr Dermatol 1999;16:407–8.
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