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Review Pediatr Neurosurg 2009;45:81–104 DOI: 10.1159/000209283

Received: April 22, 2008 Accepted after revision: December 15, 2008 Published online: March 21, 2009

Cavernous Malformations of the Central Nervous System in the Pediatric Age Group Nicola Acciarri Ercole Galassi Marco Giulioni Eugenio Pozzati Vincenzo Grasso Giorgio Palandri Filippo Badaloni Mino Zucchelli Fabio Calbucci Department of Neurosurgery, Bellaria Hospital, Bologna, Italy

Key Words Cavernoma ⴢ Cavernous malformation ⴢ Central nervous system ⴢ Childhood ⴢ Pediatric neurosurgery ⴢ Radiosurgery

Abstract Objective: The main clinico-diagnostic features, risk factors and associated diseases of cavernous malformations (CMs), also called cavernous angiomas or cavernomas, of the central nervous system (CNS) in children are described, and the most relevant differences compared to the affected adult population are pointed out, focusing on the management of pediatric patients harboring cranial and spinal CMs. Materials: This was a retrospective study of a series of 42 children symptomatic for CMs of the cranial and spinal compartments (35 supratentorial brain lesions, 5 infratentorial and 2 in the spinal region) operated on between 1975 and 2005, with a clinical follow-up ranging from 12 to 192 months. The results were compared with those found in the most recent literature dealing with pediatric CMs of the CNS. Results: Surgical treatment produced excellent or good results in 69% of our 42 children. Unchanged neurological deficits were observed in 23.8% of cases, while morbidity from surgical procedures was 7.14%. Mortality was absent in this series.

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These surgical results are comparable with those found in the literature, where morbidity and mortality rates from surgery are 8.8 and 1.13%, respectively, and are mostly associated with procedures for the excision of deep, critically located cavernomas. Conclusion: CMs represent the most common CNS vascular lesion in children, although their incidence is 4 times lower than that of the adult population. The natural history of pediatric CMs throughout the neuraxis seems to be more aggressive than in adult patients; these lesions have higher rates of growth and hemorrhage, larger dimensions and often atypical radiological pictures at diagnosis. Beside the familial form of the disease, which is more often associated with multiple lesions and an earlier age of clinical presentation, the major risk factor for CMs in children seems to be radiotherapy for CNS tumors. Furthermore, a greater number of CMs coexistent with mixed angiomatous lesions have been reported in children than in adults. Surgical results are related to the preoperative neurological status of the children; symptomatic patients who are operated on early, before they develop severe neurological deficits or long-standing seizures, may achieve the best clinical outcome. Radiosurgery does not seem to be advisable in children as an alternative treatment for deep CMs or those causing epilepsy. Copyright © 2009 S. Karger AG, Basel

Nicola Acciarri, MD Department of Neurosurgery, Bellaria Hospital Via Altura, 3 IT–40139 Bologna (Italy) Tel. +39 051 622 5511, Fax +39 051 622 5502, E-Mail [email protected]

Patients and Methods

Introduction

Cavernous malformations (CMs), also known as cavernous angiomas (hemangiomas) or cavernomas, are ‘blackberry-like’, dark-bluish lesions which pathologically belong to low-flow vascular malformations. In the neurosurgical literature, these vascular growths began to be of special interest almost 25 years ago, although historically they have been reported since the end of the 1800s [1]. Since the introduction of magnetic resonance (MR) imaging, these vascular lesions have been widely reported in the literature, and their natural history is now better defined [2–4]. CMs have been estimated to be present in about 0.4–0.8% of the population [3, 5, 6]; one fourth of CMs affect pediatric patients [2, 7–9], in whom these malformations represent 1.7–18% of all vascular growths [10]. In the pediatric age group, CMs have been reported to be one of the main causes of brain hemorrhage [11] and the most common surgically treated cerebrovascular malformation [10, 12–14]. This paper focuses on statistical and clinical data, diagnostic features and the management of pediatric patients with CMs in various compartments of the central nervous system (CNS), taking into account the pertinent literature and a series of 42 children operated on for symptomatic CNS cavernomas at our institution.

a

b

We retrospectively analyzed the clinical data of 317 patients with symptomatic, pathologically verified CMs of the CNS treated surgically at our institution from 1975 to 2005 and identified 42 pediatric cases (13.2%) with craniospinal lesions (table 1). The age of the pediatric patients ranged from 10 months to 17 years at the time of treatment, and major clinical peaks occurred under 6 years and over 12 years of age. Intracranial CMs were found in 40 children, and spinal lesions were found in another 2 children. No sex prevalence was observed among the 42 children (male to female ratio was 1); however, a prevalence of males was observed for infratentorial CMs, while the 2 spinal lesions were discovered in females (table 1). Among the children with intracranial CMs, 35 (87.5%) had supratentorial lesions, while 5 (12.5%) had infratentorial malformations, 3 in the cerebellum and 2 in the brainstem (table 1). Most of the symptomatic supratentorial CMs were located in the frontal lobes (42.8% of the treated lesions). Although we observed several deep paraventricular CMs, we did not find any purely ventricular cavernomas in these children. Among the infratentorial lesions, 2 brainstem CMs were located in the pons (fig. 1). In both the supra- and infratentorial locations, the left side was more frequent (table 1). The spinal CMs found in our pediatric patients were located in the thoracic T8–T9 epidural space in a 15-year-old girl and in the T1–T3 spinal cord in a 2.5-year-old girl (fig. 2). In the overall surgical series of spinal CMs operated on in patients of all ages between 1975 and 2005, 25% were epidural and 9% were intramedullary CMs; we treated 20 patients in all, removing 4 epidural and 11 spinal cord CMs. Multiple CMs were found at diagnosis in 5 children (almost 12% of cases), with the maximum number of CMs radiologically detectable in the same patient exceeding 10 lesions (fig. 3).

c

Fig. 1. Case No. 40 of our series. Shown are sagittal (a) and axial (b) MR images of a right pontine CM associated with a venous ectasia (c; black arrow).

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Table 1. General features of 42 pediatric patients with CNS CMs

Patient No.

Patient identity

Sex

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

C.C. S.B. M.K. M.M. B.A. P.N. P.K. G.D. V.C. S.S. C.S. L.C. G.C. L.P. P.G. A.G. P.A. R.A. B.G. P.G. M.J. R.D. D.M.D. C.V. C.P. B.S. F.A. C.F. B.P. P.S. Z.L. F.S. P.L. C.S. G.M. C.G. P.G. M.A. R.C. V.G. G.L. V.A.

F F F M F M F F F F F F M M M M M M F M F M M F M M M F F F M F M M F M F M F M M F

Age at surgery months

years

180 48 120 156 10 48 180 144 180 180 108 138 156 204 204 192 120 180 52 144 192 204 60 84 204 204 180 204 15 72 48 204 156 72 204 144 84 162 31 168 132 132

15 4 10 13 4 15 12 15 15 9 11.5 13 17 17 16 10 15 4.3 12 16 17 5 7 17 17 15 17 1.3 6 4 17 13 6 17 12 7 13.5 2.5 14 11 11

Localization of CM

Right/ left

Multiplicity (yes/no)

Familial form

Size of CM at surgery, cm

frontal frontal parieto-occipital occipital frontoparietal frontal cerebellar temporal spinal T8–T9 parieto-occipital frontal frontal cerebellar frontal temporal frontoparietal occipital frontal frontal parietal parietal frontal cerebellar frontal frontal temporal frontoparietal frontal occipital frontal parietal temporoparietal frontal pontine temporal frontal parieto-occipital temporal spinal T1–T3 pontine temporal temporal-insular

R R L L R L L L epidural R L R L L L R L R R R R L L L L L L R R L L L R R L R L R spinal cord R L R

no no no no no no no no no no no no no no no no no no no no no no yes no yes no no no no no yes no no no no yes no no no no no yes

– – – – – – – – – – – – – – – – – – – – – – – – + – – – – – – – – – – – – – – – – –

1!1 1!1.5 0.5!0.8!1 2!1 3!1!1.5 2!2 2!1.5 1.5!1 3!4!3 1.5!0.8 1.2!1.5 1!1.1 1!2 1.5!1 0.8!1 1.5!2 1!1.5 1.5!1 2!1.5 0.8!1!0.5 0.5!1 2!3!1.5 1!1.2 1.5!0.8!0.6 3!2!2.5 1.2!0.8 1!1.5 0.4!1.2 1!1 1!1.5 2!1.5 2.3!1.5 1.5!1 2!0.5 0.5!0.6 1.6!2 6!4!3.5 0.5!1!1.5 1.5!0.5!1 1!0.8 1!1.5 1!1.2, 2!1!2

F = Female; M = male; R = right; L = left; – = feature not present; + = feature present.

The familial form of the disease was ascertained in only 1 child with multiple CMs; this patient also represented the only case (about 2.4%) of familial cavernomatous disease in our pediatric series. However, we think this incidence is probably underestimated, because a systematic search for asymptomatic lesions in the relatives of the pediatric patients was not always carried out,

especially in the first decade of the series. A previous diagnosis of Klinefelter’s syndrome was reported in 1 child, but we did not observe any association of CMs with neurofibromatosis or other phacomatoses in our pediatric series (table 2). Two other children had a medical history of radiotherapy for previously operated hypothalamic dysgerminoma and fibrillar cerebellar astrocytoma 6

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Fig. 2. Case No. 39 of our series. a Sagittal T2-weighted MR image showing a large, cystic intramedullary T1–T3 CM in a 2.5year-old girl, with clinical symptoms of dorsal pain and paraparesis. b Intraoperative view after laminotomy: enlargement of the dorsal spinal cord from hemorrhagic malformation. c Postoperative MR image.

a

Fig. 3. Case No. 36 of our series. Axial MR image showing at least 10 CMs located in both cerebral hemispheres.

and 8 years, respectively, before the diagnosis of the CMs (fig. 4). Clinically, seizures were the most frequent presenting symptom in our pediatric series (table 2). Overall, seizures were present in 28 children before surgical treatment; in 25 patients, seizures were the revealing symptom, while in 15, epilepsy was the only symptom leading to diagnosis (table 3). We observed a child who developed seizures 2 months after diagnosis of a cerebral cavernoma causing headache and neurological deficits, without a previous

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b

c

history of epilepsy. One case of postsurgical epilepsy in a child who presented clinically with neurological deficits and who developed seizures only after surgery was observed. In these 29 children with epilepsy, generalized seizures were reported in 14 cases, partial motor seizures in 8, complex partial seizures in 5 and partial motor seizures, secondarily generalized, in 2 (tables 2, 3). Recurrent headache was present in 11 children in our series; in 2 cases, it was the only symptom which led to diagnostic imaging. Intracranial hypertension (ICHP) or sudden neurological deficits from radiologically evident hemorrhage were observed in all 5 children with infratentorial CMs and in 12 of the 35 children with supratentorial lesions (table 2). The duration of illness before diagnosis ranged from 1 day to 138 months in the patients with intracranial CMs. A 1-week history of rapidly progressive paraparesis was observed in a girl with a spinal epidural thoracic cavernoma. A more insidious clinical progression was observed in another girl with a thoracic intramedullary cavernoma who had a 24-month history of dorsal pain, until MR imaging carried out due to a sudden paraparesis led to the diagnosis. Neuroimaging studies performed at diagnosis in our surgical series of 42 children with CNS cavernomas are reported in table 4. These diagnostic investigations reflect our experience over a period of 30 years (1975–2005), and of course some procedures which were routinely performed on the first patients of this series, such as angiography or direct radiograms (X-rays), were then selected on the basis of diagnostic needs or were abandoned, since improved computed tomography (CT) and MR tools have progressively allowed a more detailed and specific diagnosis of CMs. MR imaging was performed in 35 of the 42 children in our series (83.3%); a typical picture of cavernoma was observed in 24 cases (68.5%), and thus other diagnostic investigations were not required.

Acciarri et al.

Table 2. Clinical manifestations and symptom duration in 42 children with CNS CMs

Patient No.

Localization of CM

Main clinical sign at diagnosis

Second clinical sign

Third clinical sign

1 2 3 4 5 6 7

frontal frontal parieto-occipital occipital frontoparietal frontal cerebellar

seizures seizures seizures seizures hemiparesis hemiparesis ICHP

headache hemiparesis

hemiparesis

8 9 10

temporal spinal T8–T9 parieto-occipital

seizures paraparesis headache

11 12 13

frontal frontal cerebellar

seizures seizures headache

14 15 16 17 18 19 20 21

frontal temporal frontoparietal occipital frontal frontal parietal parietal

seizures seizures seizures seizures seizures seizures seizures paresthesias

22

frontal

headache

48 months

23 24 25

cerebellar frontal frontal

headache seizures headache

1 day 4 months 1 day

26 27 28 29 30 31

temporal frontoparietal frontal occipital frontal parietal

seizures headache seizures seizures seizures seizures

hemiparesis motor aphasia

seizures

headache hemiparesis

ICHP

32

temporoparietal

hemiparesis

headache

33

frontal

seizures

34

pontine

ICHP

behavioral disturbances hemiplegia

35 36

temporal frontal

37 38 39

parieto-occipital temporal spinal T1–T3

seizures behavioral disturbances seizures hemiparesis dorsal pain

40 41 42

pontine temporal temporal-insular

ICHP seizures seizures

Cavernous Malformations of the CNS

cerebellar dysfunction

previous radiotherapy for cerebellar glioma

24 months 6 months 1 day

cerebellar dysfunction

8 months 24 months 3 months 4 months 6 months 4 months 12 months 3 months

hemiparesis headache ICHP seizures

hemiplegia

6 months 2 months 1 week 1 month 36 months 2 days 6 months

previous radiotherapy for dysgerminoma 2 previous hemorrhages, not surgically treated associated Klinefelter’s syndrome

late postoperative hemorrhage from new cavernoma in patient with multiple CMs seizures appearing only after surgery

48 months left VIIth cranial nerve palsy seizures

2 days 24 months 138 months 12 months 6 months 24 months

paraparesis gait impairment

Remarks

24 months 12 months 72 months 60 months 1 day 24 months 1 day 12 months 1 week 1 day

ICHP

learning dysfunction headache

Duration of illness before surgery

ataxia

2 days 60 months 1 day

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hemorrhagic recurrence 2 years after the first operation, with reintervention associated cryptic AVM

85

Fig. 4. Case No. 21 in our series. This 16year-old child developed a CM causing left paresthesias and seizures after brain irradiation for a hypothalamic tumor treated surgically 6 years before diagnosis of the cavernoma. a Axial T1-weighted MR image performed 1 year before the start of symptoms, showing no apparent cerebral malformation. b Proton density MR control image in the same patient showing a de novo right cerebral CM.

b

a

Table 3. Patients with epilepsy among the 40 children with intracranial CMs

Epileptic patient No.

Localization of CM

Type of seizures

Duration of epileptic status before surgery

Frequency of seizures before surgery

Number of seizures before surgery

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

frontal frontal parieto-occipital occipital temporal frontal frontal frontal temporal frontoparietal occipital frontal frontal parietal parietal frontal temporal frontoparietal frontal occipital frontal parietal temporoparietal frontal temporal frontal parieto-occipital temporal temporal-insular

PM GM PM CP CP PM GM GM CP PM-GM CP GM GM PM PM GM GM GM GM PM PM-GM GM GM GM PM GM PM CP GM

24 months 12 months 72 months 60 months 12 months 24 months 6 months 8 months 24 months 3 months 4 months 6 months 4 months 12 months 3 months 4 months 6 months 2 months 1 week 1 month 36 months 2 days – 48 months 24 months 18 months 12 months 60 months 1 day

monthly 1 in 6 months 2 in 6 months monthly 2 in 6 months 2 in 6 months 3 in 6 months monthly 1 in 3 months 2 in 3 months 1 in 4 months 2 in 6 months 1 in 4 months 2 in 1 year 1 in 3 months 1 in 4 months 3 in 6 months 1 in 2 months 1 in 1 week 1 in 1 month 2 in 1 year 1 in 1 week daily after surgery 2 in 4 years 2 in 1 year 2 in 6 months 3 in 1 year 2 in 6 months 2 in 1 day

10 2 12 60 4 5 3 7 8 2 1 2 1 2 1 1 3 1 1 1 6 1 – 2 4 6 3 10 2

PM = Partial motor convulsions; GM = generalized convulsions; CP = complex partial convulsions.

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Seizures appearing after surgery – – – – – – – – – – – – – – – – – – – – – – 10 – – – – –

Fig. 5. The same case reported in figure 2 (patient No. 39 of our series). a Sagittal MR

images showing hemorrhagic recurrence of the intramedullary T1–T3 CM. b Postoperative result after the second surgical procedure. c Late control image; residual malformation is suspected from hemosiderinic remnants.

a

b

c

When the diagnostic picture was not completely representative of cavernoma, we also performed MR angiography and/or traditional angiography. However, MR angiography never furnished additional information compared to MR imaging and, similar to angiography, it was never directly diagnostic for CMs. Electroencephalography (EEG) was performed in 22 of our pediatric patients with seizures in order to further verify their clinical assessment; all patients exhibited focal anomalies, with spikes in 4 cases. EEG was useful in determining the most appropriate drug therapy and in estimating the effects of surgery on epilepsy at follow-up checks. All 42 children in our series were treated surgically using the approach we considered to be the most appropriate for the cavernoma location. Infratentorial CMs were approached through the posterior fossa or retrosigmoid routes. Cortical mapping was used in 2 cases of cerebral CMs located in the cortico-subcortical eloquent area, while brainstem evoked potentials were monitored during the surgical removal of 2 pontine lesions. Spinal somatosensory evoked potentials (SSEPs) were determined preoperatively in the 2 children with spinal CMs in order to better establish a prognostic evaluation; registration of SSEPs was then performed during the operation to guide surgical maneuvers and to predict spinal injuries. Removal of the intracranial CMs was complete in all children; in cases of multiple lesions, surgery was attempted on the symptomatic or hemorrhagic lesion; in 1 patient, it was possible to simultaneously remove 2 lesions. A subtotal removal of a bloody spinal epidural cavernoma, partially deriving from the vertebral bodies, was accomplished in a 15-year-old girl, which achieved clinical improvement of her paraparesis; after the pathological diagnosis, radiotherapy for the remnant of the lesion was carried out, following the adjunctive therapy protocols of that time (1986). In a 2.5-year-old girl with a spinal cord cavernoma, an apparently complete excision of the lesion was performed with a laminotomy, using a microsurgical technique (fig. 2). Clinically, the

Table 4. Preoperative diagnostic investigations performed in 42

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children with CNS CMs Diagnostic tool

Number of investigations

Spine X-ray Myelo-CT scan Skull X-ray MR angiography ANG MR imaging CT scan

1 1 2 10 20 35 41

X-rays = Plain radiograms; Myelo = myelography; ANG = traditional angiography.

patient’s paraparesis improved, and imaging follow-up for the following 2 years showed no evidence of recurrence. Then, sudden clinical deterioration led to new MR imaging, which showed a hemorrhagic cyst at the site of the previously removed cavernoma (fig. 5). The patient underwent another surgical procedure, with removal of the hematoma and presumed remnants of the cavernoma. Clinically, only her symptoms improved, while her paraparesis appeared unchanged at the last follow-up. All CMs removed in our pediatric series were pathologically verified; in 1 case, a mixed lesion, composed of cavernoma and a thrombosed small arteriovenous malformation (AVM), was found. In this series, there were no deaths, while morbidity from surgical procedures was observed in 3 children who exhibited associated neurological symptoms or deficits (tables 5, 6).

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Table 5. Epileptic outcome in 29 children with seizures operated on for intracranial CMs

Epileptic patient No.

Localization of CM

Type of seizures

Follow-up months

Epileptic outcome at 1 year

Epileptic outcome at 2 years

Epileptic outcome (last available)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

frontal frontal parieto-occipital occipital temporal frontal frontal frontal temporal frontoparietal occipital frontal frontal parietal parietal frontal temporal frontoparietal frontal occipital frontal parietal temporoparietal frontal temporal frontal parieto-occipital temporal

PM GM PM CP CP PM GM GM CP PM-GM CP GM GM PM PM GM GM GM GM PM PM-GM GM GM GM PM GM PM CP

192 48 180 36 72 60 70 36 24 15 12 48 36 52 60 48 36 60 50 120 36 60 50 72 60 24 17 40

Engel 2 Engel 1 Engel 1 Engel 2 Engel 1 Engel 2 Engel 1 Engel 3 Engel 2 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 2 Engel 1 Engel 1 Engel 1 Engel 2 Engel 2 Engel 3 Engel 2 Engel 1 Engel 3 Engel 2 Engel 1

Engel 1 Engel 1 Engel 1 Engel 2 seizure free without therapy Engel 1 seizure free without therapy Engel 2 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 seizure free without therapy Engel 1 Engel 1 Engel 1 Engel 1 seizure free without therapy seizure free without therapy Engel 2 Engel 1 Engel 1 seizure free without therapy seizure free without therapy Engel 2 Engel 2 seizure free without therapy

29

temporal-insular

GM

36

Engel 1

Engel 2 Engel 1 Engel 1 Engel 2 Engel 1 Engel 2 Engel 1 Engel 2 Engel 1 – – Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 1 Engel 2 Engel 1 Engel 2 Engel 1 Engel 1 Engel 2 – seizure free without therapy seizure free without therapy

seizure free without therapy

PM = Partial motor convulsions; GM = generalized convulsions; CP = complex partial convulsions; Engel 1 = seizure free with therapy; Engel 2 = rare (less than 3/year) seizures, with therapy; Engel 3 = 80% improvement of epileptic picture, with therapy; Engel 4 = 50% improvement of epileptic picture, with therapy.

Overall, incomplete removal of symptomatic CMs occurred in only 2 thoracic spinal cases, a vertebro-epidural lesion and an intramedullary malformation; the spinal cord cavernoma was the only lesion in our series (2.38% of cases) which exhibited a hemorrhagic recurrence requiring reintervention. Follow-up ranged from 12 to 192 months; during this period, 1 child with multiple CMs showed hemorrhage from a new, untreated cerebral cavernoma. The surgical results were considered excellent in 9 children who were completely asymptomatic for neurological deficits or signs or with no further seizures after the suspension of antiepileptic therapy (tables 5, 6). The results were considered good in another 20 children who showed near-normal life, with improvement of their presurgical neurological picture but the persistence of minor symptoms or signs and/or the need for therapy for seizure control. Fair results were obtained in 10

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children with partially improved symptoms but unchanged neurological deficits or with unstable epilepsy control with therapy. Finally, poor results were observed in 3 children, who exhibited new neurological signs and symptoms or seizures after surgery. Seizure outcome was measured using a simplified Engel score in the 29 patients with epilepsy (28 children from CMs and 1 after the surgical procedure; table 5). At the last clinical checkup, we observed the complete cure of epilepsy in 9 children who had stopped anticonvulsant therapy; another 15 patients were seizure free with therapy (Engel 1 score), while in 5 children the seizures were less well controlled (Engel 2 score) due to therapy adjustments or temporary suspension of anticonvulsants (tables 5, 6). Overall, positive (excellent and good) surgical results were obtained in 69% of our 42 pediatric patients with CMs (table 6).

Acciarri et al.

Table 6. Clinical results and follow-up in 42 children operated on for CNS CMs

Patient No.

Localization of CM

Preoperative clinical picture

Last postoperative clinical picture

Follow-up Clinical months results

1

frontal

good

frontal parieto-occipital occipital frontoparietal frontal cerebellar

improved symptoms and deficits; epilepsy control with therapy unchanged deficits; epilepsy control with therapy asymptomatic; epilepsy control with therapy hemianopsia; rare seizures with therapy improved hemiparesis unchanged hemiparesis improved symptoms and deficits

192

2 3 4 5 6 7

48 180 36 18 12 132

fair good poor good fair good

8 9 10

temporal spinal T8–T9 parieto-occipital

seizures, headache, hemiparesis seizures, hemiparesis seizures seizures hemiparesis hemiparesis ICHP, cerebellar dysfunction seizures paraparesis headache, ICHP

72 72 66

excellent good good

11 12 13

frontal frontal cerebellar

seizure free without therapy improved paraparesis improved symptoms; cerebellar impairment from previously operated tumor epilepsy control with therapy seizure free without therapy improved cerebellar dysfunction

60 70 48

good excellent good

14 15 16 17 18 19 20 21 22 23 24 25 26 27

frontal temporal frontoparietal occipital frontal frontal parietal parietal frontal cerebellar frontal frontal temporal frontoparietal

fair good fair poor good good excellent good excellent fair good good good fair

28 29 30 31 32 33

frontal occipital frontal parietal temporoparietal frontal

34

pontine

rare seizures with therapy 36 epilepsy control with therapy 24 epilepsy control with therapy; unchanged deficits 15 epilepsy control with therapy; hemianopsia 12 epilepsy control with therapy 48 epilepsy control with therapy; improved symptoms 36 seizure free without therapy 52 improved symptoms; epilepsy control with therapy 60 asymptomatic 24 moderate cerebellar dysfunction 48 epilepsy control with therapy 48 improved symptoms and signs 60 epilepsy control with therapy 36 improved symptoms but unchanged signs; epilepsy 60 control with therapy seizure free without therapy; improved deficits 50 seizure free without therapy 120 rare seizures with therapy; improved symptoms 36 epilepsy control with therapy; improved deficits 60 unchanged deficits; therapy for postsurgical seizures 50 seizure free without therapy, but continued behav72 ioral disturbances partially improved deficits 48

35 36

temporal frontal

37 38 39

parieto-occipital temporal spinal T1–T3

40

pontine

41 42

temporal temporal-insular

seizures seizures headache, cerebellar dysfunction seizures seizures seizures, hemiparesis seizures, headache seizures seizures, ICHP seizures paresthesias, seizures headache headache seizures headache, hemiplegia seizures headache, hemiparesis, seizures seizures, aphasia seizures seizures, headache, ICHP seizures, hemiparesis hemiparesis, headache seizures, behavioral disturbances ICHP, hemiplegia, left VIIth cranial nerve palsy seizures behavioral disturbances, learning dysfunction, seizures seizures, headache hemiparesis dorsal pain, paraparesis ICHP, gait impairment, ataxia seizures seizures

Cavernous Malformations of the CNS

excellent excellent fair good poor good good

seizure free without therapy school problems and behavioral disturbances; rare seizures with therapy rare seizures with therapy; improved symptoms improved deficits improvement and then worsening, due to recurrent hemorrhage improvement of clinical picture

60 24

excellent fair

17 36 36

fair good fair

14

good

seizure free without therapy seizure free without therapy

40 36

excellent excellent

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Results and Discussion

Incidence and Distribution in the Neuraxis of Pediatric CMs In the literature, CMs account for about 20% of all CNS vascular malformations [15–17], and 25% of them are reported in the pediatric age group [6, 7, 15, 18, 19]. These vascular lesions have an estimated incidence in children ranging from 0.37 to 0.53% [13]. Similarly to adults with CMs, no relevant sex differences have been documented in children [8, 10, 12, 13, 20], although some authors have reported a female predominance in very young patients and a male predominance in spinal cases [21–23]. As in the majority of pediatric series, we conventionally considered patients ranging from 0 to 18 years of age, although some authors believe it is more correct to consider as children only those patients up to 15–16 years of age [24]. CMs have been reported at every age of the pediatric period [10], including the prenatal and neonatal stages [25–28]; however, clinically they rarely appear before the first year of life [29–32]. The mean age of children at clinical presentation is 9–10 years [10]. As we observed in our series, the incidence of symptomatic children with CMs has been reported to show bimodal peaks, mainly in the age periods between 1 and 3 years and 11 and 16 years [13, 33, 34]. In particular, Fortuna et al. [24] observed a clinical incidence of CMs of 26.8% in the age group 0–2 years and 35.7% in the age group 13–16 years. CMs are located throughout the neuraxis, according to the volume of the CNS compartments [4]. From a recent review of 245 pediatric patients with CMs of the CNS [10], intracranial-supratentorial CMs accounted for 79.4% of cases, intracranial-infratentorial for 20.6% and spinal intramedullary lesions for less than 5%. In agreement with previously published pediatric series [13, 15, 23, 30], we observed that 83.3% of our 42 pediatric patients had supratentorial lesions, 11.9% infratentorial and 4.76% spinal CMs of the intra- and extradural compartments. We did not observe any cases of coexistent intracranial and spinal cavernomas, although this has been documented [35]. Among the intracranial sites, the frontal region is the most frequent location of cerebral CMs reported in pediatric series [10, 13, 20, 32, 33, 36], while basal ganglia CMs are less commonly reported in children than in adults [4, 13, 37–40]. Intraventricular CMs are not as common as parenchymal lesions, accounting for about 2.5% of intracranial cases in all age groups [8] and 4% of pediatric cases [10, 41]. A subependymal origin of ventricular CMs, with secondary growth inside the ventricle, has been postulated by Chadduck et al. [42]. 90

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Supratentorial-intraventricular CMs are more frequently recorded than infratentorial lesions [13, 15, 24, 41–48]. Other uncommon locations for pediatric intracranial CMs are the optic chiasm, hypothalamus, corpus callosum, quadrigeminal plate and pineal region [10, 13–15, 37, 49–56]. Intracranial extra-axial CMs, mainly reported in the middle fossa and parasellar region, remain exceedingly rare lesions in the pediatric age group [57–59]. Indeed, extra-axial CMs, representing about 3% of benign cavernous sinus growths [60], are lesions with a peculiar histological structure, and the issue of whether to consider them real vascular malformations [61] or different entities [62] is still being debated. Infratentorial CMs make up from 9 to 35% of all intracranial CMs [63–65], and they can represent more than 20% of intracranial lesions in children [10, 66], with a reported predominance in females [10, 29, 66, 67]. In our pediatric patients, posterior fossa CMs accounted for 7.5% of the intracranial lesions; 40% were located in the brainstem and 60% in the cerebellum. Indeed, brainstem CMs are the most frequently reported among posterior fossa lesions in children, especially in the pons, where they represent 68–77% of cases [10, 14, 29, 34, 64–66, 68– 70]. Our 2 pediatric patients with brainstem pontine CMs confirmed these data. The frequency of CMs in the spine is difficult to assess in the general population, because, for the most part, these lesions are less frequent than in the cranial sites and above all because they represent a group of heterogeneous lesions located in various places throughout the spinal region [71, 72]. From a series of 317 patients surgically treated for CNS CMs, we found a prevalence of 6.5% for spinal (intra- and extradural) lesions in adults and a rate of 4.76% in children. We treated 20 spinal CMs, of which 2 were in children; the pediatric lesions accounted for 10% of all spinal CMs found. We observed that intramedullary lesions are the most frequent among spinal CMs, which confirms the data in the literature [21, 22, 73, 74]; in our surgical series of 20 spinal CMs, including patients of all ages, 55% were intramedullary lesions, 15% intradural-extramedullary, 20% epidural and 10% vertebral. In children, intramedullary CMs account for 3.8–4.5% of CNS pediatric cavernomas [10], but only 1–1.7% of all spinal pediatric growths [22, 23]. The case of intramedullary cavernoma we reported in 1 child represented 2.3% of the CMs discovered in our pediatric series (table 1). Recently, Lena et al. [10] reported a pediatric case of thoracic spinal cord cavernoma, in addition to another 11 published cases in paAcciarri et al.

Familial Form, Multiplicity and Growth Behavior of Pediatric CMs In the neuraxis, CMs occur in 2 forms: a sporadic form and a familial form. The sporadic form is for the most part characterized by single lesions, although multiple CMs may occur in more than 30% of cases [8, 9]. The familial form of CMs is a disease with an autosomal dominant pattern of inheritance, with incomplete penetrance and variable expression [86, 87]. Up to now, linkage studies have revealed 3 pathological genetic loci [88–90]: CCM1 on chromosome 7q11–q22, CCM2 on 7p13–p15 and CCM3 on 3q25.2–q27 [86, 91–93]. Recently, an additional, 4th genetic locus involved in the genesis of CMs has also been hypothesized [94]. Genetic mutations seem to be responsible for encoding some protein factors, such as Krev interaction trapped 1 for the gene CCM1, MGC4607 or Malcavernin factor for the gene CCM2 and PDCD10 factor for the gene CCM3, which may play a pre-

dominant role in the formation of several types (e.g. type 1, type 2) of CMs [95, 96]. The incidence of the familial form of CMs has been estimated to be close to 20% of cases in all ages [13], and it is more often characterized by multiple lesions than the sporadic disease [91, 97, 98]. The most recent reviews on pediatric CMs report a rate of the familial form from 3.5 to 11.1% [10, 13], although in a previously published pediatric series, the familial form accounted for more than 26% of cases [99]. In early studies on the familial form of CMs, patients of Hispanic origin were recognized as having a greater predisposition for the development of multiple lesions [19, 98, 100], while the prevalence of multiple CMs has also recently been assessed in the Caucasian population [35, 101, 102]. The incidence of multiple CMs in the familial form of the disease may reach almost 80% [35]. The coexistence of spinal and intracranial lesions may occur in 42–47% of patients with multiple CMs [35], with an earlier age of clinical presentation [3, 103]. Multiple CMs in children are found in more than 12% of cases [10], with the number of lesions easily exceeding 10 CMs per patient [13]. The number and size of CMs are prone to vary over time, both in the familial and the nonfamilial form of the disease. The dynamic behavior of familial CMs has been well documented by Zabramski et al. [98], who reported the de novo formation of CMs with a frequency of 0.4 new lesions/patient/year. On the other hand, the de novo appearance of CMs has also been described in nonfamilial disease [104– 107]. Therefore, although external factors have been suggested to be responsible for rapid or sudden changes in the behavior of CMs [108], it is reasonable to argue that genetic alteration remains the main factor influencing the appearance and growth of CMs, both in familial and nonfamilial cases. Genetic aberrations are probably the primary causative factors which, through phenotype modifications, produce altered molecules influencing the angiogenesis network in surrounding tissues [109– 111]. Although there has been considerable research done on genetic transmission and anticipation of the familial form of CMs [91, 92, 102, 103], further investigations are still necessary to better identify the factors causing the sporadic and familial forms of CMs, and probably even more studies will be needed to determine therapeutic options. Since the risk of hemorrhage in familial CMs seems to be higher than in sporadic lesions, wide MR imaging follow-up of the asymptomatic population with CMs has been advocated [35], together with better information concerning the risk of being a carrier of asymptomatic lesions [13].

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tients under 18 years of age. The thoracic tract is the most frequently affected by spinal cord CMs in both adult and pediatric patients [10, 22, 73, 74]. However, in adults, the male to female incidence ratio is approximately 1:1, while in children, a male predominance has been reported [21, 23]. Furthermore, the functional prognosis in children treated for spinal cord CMs seems better than in adults, although the neurological picture at clinical presentation commonly appears more severe in pediatric patients [10]. Asymptomatic intracranial lesions in children with symptomatic spinal CMs have been reported by CohenGadol et al. [35], confirming a higher risk for clinical evolution in patients with multiple CMs along the neuraxis [75]. Multiple spinal cord CMs in children are estimated to account for 16.6% of the published cases [10]. Compared to intramedullary lesions, spinal intradural-extramedullary CMs seem to be exceedingly rare in children [71, 76, 77]; these lesions have been reported more frequently in men between the 3rd and the 5th decades of life, especially in the thoracolumbar tract of the spine [72, 78, 79]. Spinal CMs of the epidural space are also rare entities in the pediatric age [71, 80]; the thoracic spine is the most commonly affected [72, 79, 81–83]. Finally, vertebral CMs, frequently included in the group of vertebral hemangiomas, should be mentioned as lesions occasionally diagnosed as incidental findings on radiological examinations [71]. Vertebral hemangiomas account for approximately 2–3% of all spinal growths, with an estimated incidence of 10–12% in the overall population [84]. Among spinal CMs, symptomatic vertebral lesions found in children remain the rarest [85].

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a

b

c

d

Fig. 6. Case No. 37 of our series. This 4-year-old girl presented clinically with seizures. a, b Preoperative axial and coronal MR images of a giant, cystic CM in the left occipitoparietal lobe. c, d Postoperative MR images after removal of the malformation.

CMs are commonly characterized by dynamic clinical and radiological pictures, due to their changing size over time as a result of repetitive bleeding [99, 112]. However, the growth behavior of CMs in children seems to be more aggressive than in adults. The size of CMs reported in the literature ranges from 0.1 to 11 cm at their largest diameter, and larger dimensions are usually reported in the pediatric population (on average: 3–7 cm in children vs. 2–3 cm in adults) [13, 40, 113]. The average size is smaller with increasing age, suggesting the formation of new lesions or at least that lesions enlarge to a detectable size with age. In our pediatric series, the largest surgically excised lesion had dimensions of 6 ! 4 ! 3.5 cm (fig. 6). Compared to CMs found in adult patients, we observed larger lesions in children, both intracranially and in the spinal region. The large dimensions of pediatric CMs, 92

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which sometimes become giant in size [13, 40, 114], can probably be explained by the higher tendency of the lesions to undergo cystic changes after bleeding (2–4 times more frequently than in adults), although a clear correlation between size and risk of symptoms or long-term neurological deficits has not been reported [13]. The growth trend of CMs has been suggested to be parabolic, rather than linear [104]; an initial growth spurt which causes CMs to become symptomatic, or detectable by imaging studies, is usually followed by a more quiescent phase, where changes in size are only subtle and an involutive trend is also possible [115]. Radiological characteristics of several types of CMs along this hypothetical growing curve have been proposed in adult and pediatric patients [13, 98, 115], in order to attribute specific diagnostic pictures to CMs with different clinical behavior. However, evidence that CMs may appear in newborns and children with larger dimensions than in adults is suggestive of a different age-dependent growth predisposition in the affected population [116], probably mediated by genetic and external factors [117]. Risk Factors for Development of CMs, and Associated Diseases Among the external factors influencing the development of CMs in children, the most consistent is radiotherapy [118, 119]. Recently, cumulative cases of radiation-induced CMs in children who received cranial radiotherapy for CNS tumors have been reported in the literature [107, 112, 120–127]. The appearance of CMs after radiotherapy does not seem to be correlated to the radiation dose, and it is not clear if associated chemotherapy may possibly be involved in the genesis of malformations. The latency period between radiation and the appearance (radiological diagnosis) of CMs ranges from 1.1 to 23 years [124, 126]. In a study of 59 children with clinical and radiological follow-up for previous surgery, radiotherapy and chemotherapy performed for medulloblastoma, Lew et al. [124] observed the appearance of intracranial CMs in 18 patients (31%), with a median time between radiation treatment and lesion detection of 6.6 years. In this study group, the incidence of cavernoma formation at 3, 5 and 10 years was 5.6, 14 and 43%, respectively, with a mean follow-up period of more than 7 years. For this reason, follow-up MR imaging has been advised for as many as 15 years in patients after cerebral irradiation during childhood [121]. In our pediatric series of CMs, 2 patients (4.7%) had had previous radiotherapy for intracranial tumors 8 and 6 years, respectively, before diagnosis of the CMs (fig. 4). Acciarri et al.

It has been speculated that radiation may influence the growth of preexistent, occult CMs, inducing intrinsic hemorrhage, and therefore their clinical and radiological presentation [119, 126]. Another model proposed to explain the formation of CMs is de novo development from DNA damage to tissue cells in response to radiation [126]. Both these pathogenetic mechanisms involve a radiation effect on vascular structures, with induction of hyperplasia of the endothelium, hyalinization and fibrinoid necrosis of the vascular walls and formation of hemorrhagic telangiectasias [124, 126]. The risk of hemorrhage from radio-induced CMs in children seems to be higher than in spontaneously occurring lesions, with a bleeding rate of more than 50% of cases [121]. Another hypothetical risk factor for the development of CMs is the presence of venous anomalies [128], which are often detected as incidental findings on radiological images or at autopsy and account for about 3% of CNS vascular malformations [129]. The association of cerebral CMs with venous anomalies is well known [46, 130, 131]. A high incidence of venous anomalies has been reported in patients with brainstem CMs [65] (fig. 1). This association has also been described in the spinal region [132]. The coexistence of CMs with venous anomalies was recently reported in almost 26% of patients surgically treated for cavernomas [131], although, depending on the published series, this association may range from 2.1 to 100% of cases [65]. In children, as in adults, large venous collectors near CMs are disclosed at surgery more often than on diagnostic images [13]; in particular, on preoperative MR images, venous anomalies have been described in only 7.6% of pediatric cases [133]. McCormick et al. [128] hypothesized that blood hypertension in venous anomalies may lead to the formation of CMs through the genesis of capillary telangiectasias. Furthermore, Porter et al. [65] also suggested a role for venous drainage in the hemorrhagic recurrence of CMs. On the other hand, recent data in the literature support the hypothesis that CMs and venous malformations are 2 distinct entities, with different pathogenetic mechanisms [134]. In our pediatric series, we found CMs associated with large veins in several cases, although on preoperative angiography or MR imaging, a diagnosis of venous malformation with the classic appearance of caput medusae was not always reached. We also found a case of multiple CMs associated with a thrombosed AVM, not suspected on diagnostic investigations. The association of CMs with capillary telangiectasias, pseudoangiomatous vessels or thrombosed AVMs has been described more often in children than in adults [13], corroborating

Clinical Picture of Pediatric CMs CMs may present with several clinical pictures, both in the adult and the pediatric age groups, without specific symptoms related to age. Some differences may be found in the numbers of several clinical profiles, since in children, hemorrhagic events from CMs are roughly 2–3 times more frequent than in adults. Almost invariably, the diagnosis of CMs in children is related to radiological investigations for neurological signs or symptoms or, sometimes, for macrocephaly in newborns and infants [29, 147]. Only 14.2% of pediatric CMs are discovered incidentally [10], since children do not usually undergo investigations for routine purposes or nonspecific symptoms. The interval between the initial symptoms and diagnosis is usually shorter in children than in adults. A median of 2 weeks from the onset of subacute symptoms to diagnosis has recently been reported [13], although the median duration of illness before diagnosis, in the case of progressive or misleading symptoms, was estimated to be as long as 20.5 months [34]. In our series, in children who had a history of illness lasting more than 1 week, we reported a mean time of 23.7 months before diagnosis (table 2); of course, the improvement in the clinical evaluation and diagnostic tools has shortened the time for diagnosis dramatically in the last decade. As in the adult age group, the most frequent clinical presentation in children with cerebral CMs are seizures. The incidence of seizures as the first presenting symptom in children with CMs ranges from 16 to 60% of cases [10, 12, 13, 20, 24, 34], while epilepsy is reported to be a revealing symptom in about 30–40% of the adult population [2, 4]. Indeed, the incidence of seizures associated with oth-

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the hypothesis that all angiographically occult malformations may be considered a pathologic continuum, rather than separate entities, since these vascular lesions often show overlapping features or may coexist in the same brain area [5, 135–138]. We found no CMs associated with neurofibromatosis, other phacomatoses or rare systemic pathological conditions [10, 13, 139–141]. We only reported 1 case of a 17-year-old boy with the familial form of CMs and a previous diagnosis of Klinefelter’s syndrome. The coexistence of CMs with several types of intracranial tumors has also been reported in the literature [142–145], but, in our opinion, these conditions remain occasional occurrences and, for the most part, are not typical of the pediatric age group. The association of brain CMs with focal cortical dysplasia, clinically evidenced by seizures, is of greater note [146].

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er clinical manifestations may range from 38 to 100% of cases in clinical series [113, 148]. Patients with CMs in cortical-subcortical brain areas, as well as those having multiple lesions, are at higher risk for epilepsy [3, 113]. Children with intraventricular CMs may also occasionally present with seizures [41]. Overall, in our pediatric series, seizures were present at diagnosis in 70% of the children with intracranial CMs, although in 37.5%, epilepsy was the only symptom leading to diagnosis, and in 32.5%, the seizures were associated with other neurological manifestations. We also observed a case of postsurgical epilepsy in a child who presented clinically with neurological deficits and developed seizures only after surgery (postsurgical epilepsy rate of 2.5%). In line with the data in the literature [2, 4], generalized seizures were the most frequent in our 29 pediatric patients with epilepsy (table 3), since they occurred in over 48% of cases. The risk rate for the onset of seizures before treatment in patients with a diagnosis of cavernoma but without previous epilepsy has been estimated to range from 1.34 to 2.4%/patient/year [3, 4], while the risk rate for new seizures in patients with a previous history of epilepsy from CMs has been established to be 5.5%/patient/year [3]. In children, although medical therapy may control epilepsy, seizures may affect school, social and sporting activities. It has been stated that patients under the age of 40 years with CMs are 5.6 times more likely to have lifelong disability from seizures than older patients [149]. Indeed, all patients with a long history of epilepsy from CMs, especially when the seizures started during childhood, are at risk of lifelong disability, because the widespread diffusion of epileptogenic foci from chronic lesions may lead to intractable epilepsy, or at least to seizures less responsive to medical therapy. On the other hand, in patients surgically treated for CMs causing recent epilepsy, suspension of anticonvulsant therapy is more easily achieved in children than in adults, in whom, due to social considerations (e.g. work, driving), antiepileptic therapy is often maintained for a longer period of time for precautionary reasons. Headache associated with other clinical features is the second most common symptom in patients with intracranial CMs and can be observed in one third of patients [14], regardless of a supra- or infratentorial location or radiological evidence of acute hemorrhage [2, 25, 98]. However, isolated headache as a revealing symptom of CMs has been reported in only 2.8% of pediatric patients [10]. More commonly, headache is included in the clinical picture of ICHP, which is observed in 20.1% of pediatric cases of CMs [10]. ICHP rarely derives from ob94

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structive hydrocephalus caused by an intra- or periventricular cavernoma [150], while in 5.4% of pediatric cases it is due to a pseudotumoral mass effect of CMs [10]. Intra-axial CMs commonly cause neurological signs and symptoms from the hemorrhagic dislocation of neural structures, while the rare extra-axial CMs are more prone to cause focal deficits from their mass effect [58, 59]. Recurrent headache was present at diagnosis in 27.5% of our children with intracranial CMs, and in 5% of cases it was the only symptom which led to cerebral imaging. Massive hemorrhage from CMs is responsible for severe clinical pictures, with headache and acute neurological deficits, in almost one fourth (22.7%) of pediatric cases [10, 36]. Seizures are sometimes the clinical expression of new, perilesional bleeding of CMs; however, minor bleeding from lesions may also cause behavioral disturbances or learning difficulties in children, potentially preceding more typical symptoms such as seizures. For prognostic purposes, the clinical distinction between cerebral overt hemorrhage and intra-perilesional bleeding has been noted [113], since radiological signs of previous bleeding are intrinsically present in all symptomatic and asymptomatic CMs. Limited destruction of tissues and perilesional blood reabsorption may explain the clinical improvement which is usually observed in patients recovering from previous bleeding of CMs. Acute overt hemorrhage from supratentorial CMs is better tolerated in children than in adults [13]. In contrast, infratentorial hemorrhage is often responsible for acute ICHP syndrome, requiring emergency surgical procedures in many cases [13]. Infratentorial CMs present clinically with acute symptoms from hemorrhage at least 10 times more frequently than supratentorial lesions, with neurological disability being 6.75 times more likely than in patients with supratentorial lesions [149]. In our series, all 5 children with brainstem and cerebellar lesions exhibited acute clinical pictures from radiologically gross hemorrhage, while macroscopic hemorrhage causing ICHP or acute neurological deficits was present in 34.2% of children with supratentorial malformations. The prospective annual risk rate of bleeding from CMs in the affected population, with no distinction made for location or age group, has been estimated to be 3.1%/patient/year [3], ranging from 0.25 to 6.4% in several clinical series [2, 68, 98, 113]. The incidence of symptomatic hemorrhage from CMs in children has been reported to be 27.3–78% [10, 13, 15, 26, 34], as compared to 8–37% for adult patients [113]. Multiple lesions, more frequent in the familial form of CMs, have a higher risk of hemorrhage [98]. Acciarri et al.

The annual risk rate of symptomatic hemorrhage from previously discovered, occasional, asymptomatic CMs has been estimated to be 1–2% [4, 98, 151, 152], although bleeding from asymptomatic CMs may be radiologically detected 2–3 times more frequently [98]. Lesions 1 cm or more in diameter have a greater tendency to cause symptoms [8]. Although previous asymptomatic bleeding may not necessarily represent a risk factor for further, subsequent symptomatic hemorrhage [3, 65], there is some evidence that once the bleeding has produced symptoms, clinical deterioration from recurrent hemorrhages is more common [152], and neurological disability is 7.78 times more likely than in cases without previous hemorrhage [149]. Among intracranial CMs, brainstem lesions present a higher risk for symptoms, especially from hemorrhage, appearing clinically with an estimated rate of 5%/patients/year [65]. The clinical picture from hemorrhage typically appears severe at onset, then improves spontaneously. However, clinically relevant rebleeding from brainstem CMs is reported in 21–60% of symptomatic patients/year [64, 65, 68, 69, 151]. In both supra- and infratentorial locations, repeated bleeding from CMs causes an increase in morbidity [13, 14]. Moriarity et al. [3] estimated an annual risk rate for clinical deterioration of 3.7% from supratentorial CMs and 17.5% from infratentorial lesions. Children with CMs in the spinal region exhibit sudden clinical onset more frequently than adult patients. The annual risk rate for hemorrhage in patients with CMs in the spinal cord has been estimated to be 1.6% of cases [23]; in children, 75% of patients present with an acute clinical picture from hemorrhage [10, 22]. Sudden myelopathy, consistent with paraparesis or paraplegia, with cervical or dorsal pain are the most common signs and symptoms in the case of intramedullary CMs in children [13, 23, 153, 154]. Progressive leg numbness, ataxia or hemiparesis, eventually with intermittent spinal pain, are also observed [21, 153, 154], although these insidious clinical pictures are more typically observed in adults, with a longer history of illness before diagnosis. Due to their particular location, spinal intramedullary CMs are more prone to cause clinically significant neurologic deficits than cerebral lesions, with an estimated duration of symptoms before diagnosis in children ranging from 1 to 12 weeks [22, 23]. Repeated microbleeds from CMs may contribute to the progressive neurological deterioration of some patients [73, 126, 153]. Rarely, in children with spinal CMs, seizures or focal neurological deficits reveal intracranial lesions clinically [35]. A more aggressive behavior of spinal lesions has been described when multi-

plicity and the familial form of the disease are present, with an earlier age of clinical onset [73]. Radicular pain [72, 78], hydrocephalus [155] or even subarachnoid hemorrhage [156, 157] have been reported to occur as the clinical presentation in patients with intradural-extramedullary CMs. Progressive spinal cord compression due to the mass effect [71] or acute myelopathy with local pain [72, 80, 82] have been reported in spinal epidural and vertebral CMs. Symptomatic vertebral CMs in children are rarely revealed by hemorrhage [85].

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Diagnostic Imaging for Pediatric CMs Among the diagnostic investigations for CMs, several procedures are not specific or are no longer advisable in children. X-rays are usually not useful in the direct diagnosis of CMs, although they may occasionally show intracranial calcifications [42] or radiological signs of chronic ICHP [13]. In the spinal region, X-rays are sometimes the first diagnostic investigation showing vertebral lesions [71, 84], while the diagnostic picture of spinal epidural CMs may not be specific [81] or notable [82] on Xrays. Before the introduction of MR technology, myelography and myelo-CT scan were the best diagnostic tools for spinal epidural masses [81, 158]; nowadays, these investigations are considered obsolete in patients with suspected spinal CMs and should be avoided, especially in children. Ultrasound investigations may be useful in the screening of intracranial masses or hemorrhage in newborns and young infants, but they are not specific for CMs. Angiography usually fails to detect CMs because they are low-flow, capillary lesions. For this reason, in the literature, CMs have been called ‘angiographically occult’ lesions, although in some instances large brain CMs may produce indirect signs of a vascular space or may exhibit late-phase venous pooling. Hypervascularity and a mass effect have been reported for intracranial extraaxial CMs, mimicking the angiographic picture of meningiomas or other cranial base tumors [61, 62, 159]. On the other hand, angiography may still play an important role in the diagnosis and therapy of vertebral CMs [71, 84]. Among the diagnostic tools, CT scan still deserves particular consideration, since it is usually the first investigation in the emergency diagnosis of children and infants, who usually require anesthesia for a longer examination by MR imaging. Undoubtedly, CT scan is less sensitive and specific than MR imaging in the diagnosis of CMs [160], but it may lead to more correct and specific investigations in the case of hemorrhagic lesions [13]. In children as in adults, the best diagnostic tool for detect95

ing CMs is MR imaging. CMs present a characteristic MR appearance which is almost invariably pathognomonic [2–4, 98, 161, 162] (fig. 1). Several years ago, Zabramski et al. [98] proposed a radiological classification of CMs consisting of 4 types, in order to better delineate the clinical evolution of patients with CMs on the basis of the MR image. More recently, Mottolese et al. [13] proposed a new radiological classification of pediatric CMs, based on the MR signal characteristics of CMs, their morphology and clinical picture. From this study, it has been observed that symptoms from CMs are not always related to their dimensions, and also that the dimensions of the halo ring surrounding brain CMs are not necessarily related to a higher risk of seizures [13]. Furthermore, in children with a radiological picture of gross brain hemorrhage, Mottolese et al. [13] tried to establish criteria for angiography. Although not very suitable in children, complementary diagnostic information from an MR functional study, axonography [70, 100] or corticospinal tract fiber tracking [163] may also aid in planning the excision of CMs in eloquent or deep brain areas. The widespread use of MR imaging has also resulted in an increased number of CMs diagnosed in the spinal region, where the majority of the lesions are detected in the spinal cord [21–23, 161]. While spinal cord CMs are quite similar to brainstem lesions, intradural-extramedullary CMs present particular MR features [164] and may therefore pose diagnostic difficulties, especially when associated with atypical clinical pictures [78, 155, 157, 165]. Spinal epidural CMs may also pose diagnostic issues, due to their MR characteristics being different from those of their intradural counterparts [82, 158]. In the case of an atypical MR picture for an extramedullary or epidural cavernoma, spinal arteriography may be justified in order to exclude the diagnosis of a high-flow vascular malformation or hemorrhagic neoplasm. Vertebral CMs are more typically diagnosed on CT scan due to their characteristic bone alterations; however, MR imaging may adequately delineate extraspinal extension or the degree of spinal cord compression [71, 84]. Therapeutic Management of Children with CMs In children, as in adults, therapeutic options for the management of CNS CMs include clinico-radiological observation, antiepileptic therapy, surgery and even radiosurgery. There is general agreement in the literature that surgery is not indicated for asymptomatic CMs, especially when they are deeply placed or located in eloquent CNS areas [2–4, 10, 64, 65, 68, 107, 113, 151, 152, 166, 167]. However, asymptomatic CMs in children re96

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quire special attention, since the natural history of pediatric lesions is less predictable, and they appear to be more aggressive with regard to hemorrhage and growth than in adults [13, 14]. For symptomatic CMs, or for asymptomatic lesions exhibiting relevant radiological evolution, the ideal treatment is total removal, which can be accomplished only with surgical therapy. Criteria for the selection of CMs for surgical removal should also take into account their location in the neuraxis and their morphology. In the case of multiple CMs, surgery must be directed at the symptomatic lesion [167]. The treatment of cerebral CMs causing epilepsy in children deserves particular consideration; until 15–20 years ago, surgery for CMs was mainly indicated in patients with longstanding seizures poorly controlled by anticonvulsant therapy or no longer responsive to medication (intractable seizures), while the surgical excision of CMs was not strictly recommended in patients with good medical control of seizures [148]. Nowadays, the concept of life with seizure control in patients with CMs has changed, especially in children, and the decision regarding surgery depends mainly on the balance between the advantages and risks of the surgery. In all recent pediatric series involving patients with cerebral CMs, children with long-standing seizures were rare [168], because when lesions appear clinically, a curative and definitive therapy is usually considered. The early surgical removal of superficial or not critically located CMs causing seizures may offer real curative treatment of epilepsy, preventing psychosocial disability in patients on long-term medical therapy and avoiding the risk of neurological deficits from growth and hemorrhage of the cavernomas [169, 170]. Surgery may also improve the efficiency of anticonvulsant therapy in patients with epilepsy who are resistant to medication [171–173]. Removal of the malformation through a simple lesionectomy may obtain good results for seizure outcome when there is concordance between the site of the epileptogenic cavernoma, the clinical semeiology and the interictal EEG [13, 172–176]. Removing the hemosiderin capsule surrounding the cerebral cavernoma has also been suggested, in order to avoid possible persistent seizures from the irritative action of iron-derived substances [168, 173, 174]. However, some authors believe this is dangerous, because it is difficult to distinguish between hemosiderin-stained brain tissue and the surrounding atrophied neural tissue [12, 176], and therefore exeresis of the hemosiderinic gliosis around the cavernoma may induce vasogenic edema, with clinical neurological complications [13]. In our opinion, when CMs are placed in noncritical areas, removing the gliotic tissue Acciarri et al.

around the hemosiderin capsule may offer better clinical results for the patient, with low associated surgical risks. On the other hand, the extension of surgery may also be influenced by the widespread diffusion of the epileptic focus associated with the malformation. In this instance, accurate preoperative neurophysiological studies may help in planning the best surgical procedure, ranging from a pure lesionectomy to tailored epilepsy surgery [175, 177]. Surgery is always recommended in children with cerebral CMs causing acute neurological deficits from hemorrhage or causing a worsening of previous neurological symptoms [13, 167]. In such instances, surgery may allow immediate improvement of preoperative neurological conditions in children [10, 13, 14, 39], although surgical morbidity may be relevant when procedures are performed for CMs placed in deep or critical areas [37, 178, 179]. Surgery should also be strongly considered in children who show enlargement of low symptomatic cerebellar CMs in superficial locations on MR imaging before they cause clinical deterioration [13, 114]. In contrast, the removal of brainstem CMs should be considered only in the case of progressive clinical deterioration, with radiological evidence of mass enlargement and/or signs of rebleeding, since surgery on these CMs still remains a challenge [10, 13, 29, 64–66, 68, 70, 180]. In particular, surgery is indicated for symptomatic brainstem CMs abutting the pial or ependymal surface, since their resection can be carried out without infringing on normal neural tissue. In spinal CMs, surgical therapy is also the treatment of choice for symptomatic lesions [13, 14, 21–23]. All surgical procedures in children should be performed taking special care in the positioning of patients, avoiding the 3-pin-type head holder for cranial procedures in newborns and younger children and putting soft pads under the body and extremities for a comfortable and natural uncompressed position. In surgical procedures for infratentorial CMs, prone or Concorde positions are preferred to the sitting position when feasible due to the risk of a transvenous air embolism. In posterior fossa and retrosigmoid procedures, we suggest performing a craniotomy instead of a craniectomy, in order to avoid cerebrospinal fluid leakage from incompetent dura or dural herniation in soft, muscular tissues. In children, especially those under 10 years of age, osteoplastic bone flaps should be fixed with reabsorbable material. For the removal of spinal CMs, we suggest performing a laminotomy rather than a laminectomy in order to avoid postoperative spine deformities.

Intraoperative blood loss should be minimized, making an accurate plastic reconstruction of opened tissues. Technically, surgical excision of supratentorial brain CMs in children, as in adults, should be performed using microsurgical approaches, based on the location of the malformations and the safest route for the patient [10, 12, 13, 20, 24, 30–32, 37, 41, 42, 178, 179]. Specific routes are suitable for intraventricular CMs [44, 47, 179] or those located on the anterolateral surface of the midbrain [29, 181]. A subtemporal transtentorial approach is suitable for more laterally placed midbrain cavernomas [10, 37, 65], avoiding more invasive approaches in children, such as the transpetrosal retro- and translabyrinthine routes, when possible. For the removal of quadrigeminal plate, tegmental and pineal region CMs, the infratentorial supracerebellar approach is suitable, taking into account that when infringing on neural structures, at least one of the inferior colliculi should be spared in order to avoid deafness, and the plane of the aqueduct should be spared in order to avoid damage to the reticulate system [13, 37]. Pontine CMs may be approached via several surgical routes, depending on their position in the brainstem. Although transoral or subtemporal-transpetrosal routes, as well as the far lateral approach, have been proposed for anterolateral pontine CMs [65, 68, 100, 182], in children, when possible, we suggest considering the less invasive retromastoid route, taking care to avoid undesired stretching of the VIIth and VIIIth cranial nerves and considering as a safe entry zone for the removal of nonvisible pontine lesions the lateral space between the Vth and the VIIth cranial nerves [10, 37, 68, 70]. Pontine CMs placed posteriorly, under the floor of the 4th ventricle, may be reached with a posterior suboccipital median craniotomy, via the floor of the 4th ventricle [10, 13, 29, 37, 65, 68, 70], although surgical morbidity affecting the floor of the 4th ventricle remains relevant [68, 70, 182]. The retromastoid and median suboccipital approaches are also the surgical routes employed for the removal of cerebellar CMs. CMs located in the lower medulla oblongata may sometimes require more extreme approaches [65]. In the spinal region, as with cranial CMs, the surgical route used to reach the lesion should be the shortest one possible, but also the safest for the patient; in the majority of pediatric cases, a posterior route has been employed [14, 21–23, 74]. From a surgical standpoint, the complete removal of CMs should always be attempted in order to eliminate the risk of new bleeding from remnants, which can cause

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recurrent symptomatic bleeding in 25% of surgically treated cases/year, sometimes with regrowth of the lesions [151]. Care should be taken to spare any large venous collectors associated with CMs, in order to avoid hemorrhagic brain infarction with devastating clinical consequences [130]. Cortical and subcortical brain CMs should be removed using the smallest corticotomy possible or, when feasible, through a sulcus. Nowadays, neuronavigation has taken the place of intraoperative sonography, which was used in the past for localizing subcortical cerebral CMs; furthermore, a neuronavigation device can assist and contribute to the removal of small, deep CMs and may also help in planning the best incision point for the least invasive surgical route [166, 183]. The removal of CMs is usually easier when the bleeding is recent and perilesional hematoma has not yet organized. Since CMs in children are usually larger than in adults, sometimes reaching giant dimensions [13, 40, 114] (fig. 6), use of a Cavitron ultrasound aspirator has been suggested for the removal of huge lesions which are not amenable to en bloc or traditional piecemeal resection [12]. Cortical mapping is a useful neurophysiological tool for the removal of CMs located in eloquent cerebral areas [13, 168], as are corticospinal tract mapping, transcranial motor evoked potentials [181] or auditory evoked potential monitoring [179], and are mandatory for performing the excision of brainstem CMs more safely. Neuroendoscopy is suitable for carefully inspecting deep neural structures not adequately visible in the microscope field and for checking the lesion cavity for any remnants after the excision of the CM [37, 64, 65]. A microsurgical technique for the removal of spinal cord CMs is similar to that performed for intramedullary tumors [153, 184]. Neuronavigation and/or intraoperative ultrasound are useful in localizing lesions not abutting the spinal cord surface, while SSEPs can guide surgical maneuvers and may be predictive of gross spinal injuries. Similar to procedures for brainstem CMs, the removal of spinal cord cavernomas may be associated with surgical morbidity [79, 153, 154] or the incomplete excision of lesions, with the risk of symptomatic recurrence from remnants [14], requiring reoperation. Intradural-extramedullary CMs are usually easier to remove than intramedullary ones, while pure epidural cavernomas, although angiographically occult, may cause significant bleeding during surgery [71]. Symptomatic vertebral CMs, due to their location in the bone, may require several therapeutic options, i.e. (1) 98

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embolization, (2) surgery and (3) radiotherapy [71, 84]. Transarterial embolization followed by a laminectomy is a safe and effective procedure for the decompression of neural structures; surgical decompression alone, or percutaneous vertebroplasty, may be alternative procedures in selected cases [84]. However, after a wide laminectomy or corpectomy, spinal stabilization is needed [71]. The use of radiotherapy alone, as treatment for pain from vertebral angiomas, is no longer recommended. Irradiation was used in the past as a postoperative adjuvant treatment for incompletely removed vertebral CMs; however, the effects of radiation on these extra-axial malformations are uncertain and delayed, carrying the risk of complications [84]. It should also be noted that in children under 3 years of age, it is difficult to deliver radiation therapy for spinal lesions. Radiosurgery for CMs In this last decade, radiosurgery has been considered as an alternative therapy for deep-brain, symptomatic, surgically untreatable CMs [183, 185] and has also recently been proposed for cerebral malformations causing epilepsy [110, 186]. The rationale for its use, as by linear accelerator or by gamma knife radiation, is the presumed effect of obliteration of cavernous vascular sinusoids, avoiding clinical evolution resulting from bleeding of the CMs [187]. However, the effectiveness of stereotactic radiosurgery in the treatment of intracranial CMs has not yet been established. The fact that the optimal radiosurgical technique, dose adjustment and delineation of mass location for treatment have not been well established makes interpretation of the clinical results in the literature difficult [183, 185–193]. Indeed, due to the different structure of CMs compared to small AVMs or other angiographically occult vascular malformations, radioinduced obliteration is uncertain, and periradiation morbidity is not negligible, since transient clinical complications from edema of the perilesional neural structures have been observed in 25% of cases and severe, sometimes permanent, neurological clinical pictures are observed in 5–10% of cases [187, 192]. Therefore, indications for the radiosurgical treatment of CMs should be carefully evaluated, since the effects on clinical and radiological features are not comparable to those obtained with surgical therapy, while the risk of hemorrhage from CMs remains [119, 194]. The results reported on the bleeding rate in the first 2 years after treatment cannot be considered better than the hemorrhage rate resulting from the natural history of CMs [65, 119, 185, 189, 191, 194], while the best seizure outcome may be Acciarri et al.

comparable to that of patients with good medical epilepsy control [183, 185, 186, 190]. Furthermore, data in the literature dealing with pediatric CMs treated with radiosurgery are scarce [59, 185, 188]. We operated several times on a young woman with repeated hemorrhages from multiple CMs; this patient had previously been treated for CMs with radiosurgery when she was a child. Considering this experience and the recent data in the literature on CMs, we do not recommend radiosurgery as an alternative treatment for cavernomas, especially in children, because this technique does not seem to eliminate the risks of hemorrhage or mass effect from CMs, while peri- and postradiation complications may be significant. Surgical Results in Children with CMs Clinical results in children treated with surgical therapy for CMs of the CNS are generally excellent or good in the majority of pediatric series [7, 10, 12–15, 20, 24, 29, 31, 36, 67, 168, 173]; in a recent review of the literature, 68.2% of children treated did not have any clinical sequelae after surgery [10]. Excellent results have also been reported in newborns and children under 1 year of age [13, 27, 29, 30, 32, 46, 195]. Overall, in our pediatric series of CMs, we observed positive results in more than 69% of our 42 cases and 72.5% of our 40 intracranial cases. In particular, 20% of children with intracranial CMs were completely asymptomatic after surgery and 52.5% showed neurological improvement; furthermore, surgery allowed the complete cure of epilepsy (suspension of anticonvulsant therapy) in 31% of the children with preoperative seizures, while better medical control of seizures was seen in more than 48% of cases. In 23.8% of cases, we had fair results, since the patients’ symptoms improved, but their neurological deficits were unchanged. In the literature dealing with pediatric CMs, clinical stabilization has been reported in 19.3% of cases, while in 2.7% of patients, the clinical picture worsened after surgery [10]. In our 42 pediatric patients, there were poor results, with morbidity from surgical procedures, in 7.14% of cases, in agreement with a pediatric review of CMs by Lena et al. [10], who reported a rate of 8.8%. There were no mortalities after surgery for CMs in our series, confirming the low rate (1.13% of cases) reported in the literature [10]. Morbidity and mortality are observed mainly in the treatment of deep cerebral or infratentorial malformations [12, 13, 14, 41, 67, 196, 197] or in the case of incomplete removal of CMs, with recurrent hemorrhage [10, 13, 67], as we observed in a girl with a thoracic intramedullary cavernoma. Cavernous Malformations of the CNS

Moreover, in cases of deep, critically placed CMs, such as those in the brainstem or spinal cord, surgical complications and mortality also seem to be influenced by the natural history of the disease, rather than by the surgical procedure itself. In recent surgical series on brainstem CMs, good results were reported in 69 to more than 90% of cases [37, 64, 65, 70, 182], with a 3.8–10% rate of morbidity for surgical complications, while mortality ranged from 1.9 to 4% of cases [65, 68]. In the spinal cord, surgical results are related to the preoperative neurological status of the children; symptomatic patients who are operated on early, before they develop severe or long-standing neurological deficits, may achieve the best clinical outcome [169]. In the literature, good results and clinical stabilization have been observed in 83% of patients treated surgically for intramedullary CMs [22]; in the pediatric age group, clinical stabilization after surgery has been seen in 41.6% of cases, with about 58% of cases exhibiting clinical improvement [10]. In patients operated on for spinal intradural-extramedullary or epidural CMs, when their medical history is short and complete removal of the lesions is feasible, the results are usually better than in patients treated for intramedullary CMs. Radiotherapy has been suggested for incompletely removed or inaccessible spinal extrathecal CMs [71, 83], although the real effectiveness of this therapy on malformations is not clear, while the risks and drawbacks of radiation on neural tissues are known. Of note, in 1986, we administered postoperative radiotherapy to a 15year-old girl with an incompletely removed thoracic vertebro-epidural cavernoma, achieving clinical stabilization.

Conclusions

Pediatric CMs represent one fourth of the lesions diagnosed in the affected population. In children, the distribution of CMs in the CNS is the same as in adults, although genetic and external factors may play a role in influencing their growth, size, multiplicity and clinical behavior. The natural history of CMs in children seems more aggressive than in adults, due to the higher hemorrhagic tendency of the lesions and their larger dimensions. The ideal therapy for CMs is their total removal. Surgery is indicated for symptomatic lesions, although removal of accessible, paucisymptomatic CMs showing a mass effect or hemorrhagic evolution on radiological follow-up should be considered, especially in children who Pediatr Neurosurg 2009;45:81–104

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have major risks of disability from the clinical evolution of the CMs compared to adults. Total excision of CMs should be attempted in order to avoid clinical, hemorrhagic recurrence from remnants. Excellent or good clinical results have been obtained in almost 70% of the cases treated, with low morbidity and mortality rates, mostly

related to surgical procedures for deep, critically placed lesions. Radiosurgery as an alternative treatment for symptomatic deep CMs or lesions causing epilepsy does not seem to have real advantages compared to conservative or medical therapy and, for the most part, is not recommended in children.

References 1 Bremer L, Carson NB: A case of brain tumor (angioma cavernosum), causing spastic paralysis and attacks of tonic spasms. Am J Med Sci 1890;100:219–242. 2 Curling OD, Kelly DL, Elster AD, Craven TE: An analysis of the natural history of cavernous angiomas. J Neurosurg 1991; 75: 702– 708. 3 Moriarity JL, Wetzel M, Clatterbuck RE, Javedan S, Sheppard JM, Hoenig-Rigamonti K, Crone NE, Breiter SN, Lee RR, Rigamonti D: The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 1999;44:1166–1173. 4 Robinson JR Jr, Awad IA, Little JR: Natural history of cavernous angioma. J Neurosurg 1991;75:709–714. 5 Johnson PC, Wascher TM, Golfinos J, Spetzler RF: Definition and pathologic features; in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, AANS Publications Committee, 1993, pp 1–11. 6 Otten P, Pizzolato GP, Rillet B, Berney J: A propos de 131 cas d’angiomes caverneux (cavernomes) du S.N.C. repérés par l’analyse rétrospective de 24535 autopsies. Neurochirurgie 1989;35:82–83. 7 Herter T, Brandt M, Szuwart U: Cavernous hemangiomas in children. Childs Nerv Syst 1988;4:123–127. 8 Hsu FPK, Rigamonti D, Huhn SL: Epidemiology of cavernous malformations; in Awad IA, Barrow DL (eds): Cavernous Malformations. AANS Publications Committee, Park Ridge, 1993, pp 13–23. 9 Robinson J, Awad IA: Clinical spectrum and natural course; in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, AANS Publications Committee, 1993, pp 25–36. 10 Lena G, Ternier J, Paz-Paredas A, Scavarda D: Central nervous system cavernomas in children (in French). Neurochirurgie 2007; 53:223–237. 11 Papadias A, Taha A, Sgouros S, Walsh AR, Hockley AD: Incidence of vascular malformations in spontaneous intracerebral haemorrhage in children. Childs Nerv Syst 2007; 23:881–886. 12 Di Rocco C, Iannelli A, Tamburini G: Cavernomas of the central nervous system in children. A report of 22 cases. Acta Neurochir (Wien) 1996;138:1267–1274.

100

13 Mottolese C, Hermier M, Stan H, Jouvet A, Saint-Pierre G, Froment JC, Bret P, Lapras C: Central nervous system cavernomas in the pediatric age group. Neurosurg Rev 2001;24: 55–71. 14 Scott RM, Barnes P, Kupsy W, Adelman LS: Cavernous angiomas of the central nervous system in children. J Neurosurg 1992;76:38– 46. 15 Mazza C, Scienza R, Beltramello A, Da Pian R: Cerebral cavernous malformations (cavernomas) in the pediatric age group. Childs Nerv Syst 1991;7:139–146. 16 McCormick WF: Pathology of vascular malformations of the brain; in Wilson CB, Stein BM (eds): Intracranial Arteriovenous Malformations. Baltimore, Williams & Wilkins, 1984, pp 44–63. 17 Sarwar M, McCormick WF: Intracerebral venous angiomas. Arch Neurol 1978;35:323– 325. 18 Houtteville JP: The surgery of cavernomas, both supra-tentorial and infra-tentorial. Adv Tech Stand Neurosurg 1995;22:185–259. 19 Rigamonti D, Hadley MN, Drayer BP, Johnson PC, Hoenig-Rigamonti K, Knight JT, Spetzler RF: Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 1988;11:343–347. 20 Giulioni M, Acciarri N, Padovani R, Frank F, Galassi E, Gaist G: Surgical management of cavernous angiomas in children. Surg Neurol 1994; 42:194–199. 21 Bakir A, Savas A, Yilmaz E, Savas B, Erden E, Caglar S, Sener O: Spinal intradural-intramedullary cavernous malformation. Case report and literature review. Pediatr Neurosurg 2006;42:35–37. 22 Deutsch H, Shrivistava R, Epstein F, Jallo GI: Pediatric intramedullary spinal cavernous malformations. Spine 2001;26:427–431. 23 Nagib MG, O’Fallon MT: Intramedullary cavernous angiomas of the spinal cord in the pediatric age group: a pediatric series. Pediatr Neurosurg 2002;36:57–63. 24 Fortuna A, Ferrante L, Mastronardi L, Acqui M, D’Adetta R: Cerebral cavernous angioma in children. Childs Nerv Syst 1989; 5: 201– 207. 25 Bergeson PS, Rekate HL, Tack ED: Cerebral cavernous angiomas in the newborn. Clin Pediatr (Phila) 1992;31:435–437.

Pediatr Neurosurg 2009;45:81–104

26 Hubert P, Choux M, Houtteville JP: Cerebral cavernomas in infants and children (in French). Neurochirurgie 1989;35:104–105. 27 Moritake K, Handa H, Nosaki E, Tohiwa K: Tentorial cavernous angioma with calcification in a neonate. Neurosurgery 1985; 16: 207–211. 28 Sabatier J, Gigaud M, Dubois G, Tremoulet M: Cavernoma in the child. Apropos of a neonatal form with recurrence in childhood (in French). Neurochirurgie 1989; 35: 109– 110. 29 Braga BP, Costa LB Jr, Lemos S, Vilela MD: Cavernous malformations of the brainstem in infants. Report of two cases and review of the literature. J Neurosurg 2006; 104(6 suppl):429–433. 30 Gangemi M, Longatti P, Maiuri F, Cinalli G, Carteri A: Cerebral cavernous angiomas in the first year of life. Neurosurgery 1989; 25: 465–468. 31 Pozzati E, Padovani R, Morrone B, Finizio F, Gaist G: Cerebral cavernous angiomas in children. J Neurosurg 1980;53:826–832. 32 Sakai N, Yamada N, Nishimura Y, Shirakami S, Futamura A, Andoh T: Intracranial cavernous angioma in the 1st year of life and a review of the literature. Childs Nerv Syst 1992;8:49–52. 33 Cavalheiro S, Braga FM: Cavernous hemangiomas; in Choux M, Di Rocco C, Hockley AD, Walker ML (eds): Pediatric Neurosurgery. London, Churchill Livingstone, 1999, pp 691–701. 34 Edwards MSB, Baumgartner JE, Wilson CB: Cavernous and cryptic vascular malformations in the pediatric age group; in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, AANS Publications Committee, 1993, pp 163–183, 185–186. 35 Cohen-Gadol AA, Jacob JT, Edwards DA, Krauss E: Coexistence of intracranial and spinal cavernous malformations: a study of prevalence and natural history. J Neurosurg 2006;104:376–381. 36 Di Rocco C, Iannelli A, Tamburrini G: Surgical management of paediatric cerebral cavernomas. J Neurosurg Sci 1995;41:343–347. 37 Bertalanffy H, Gilsbach JM, Eggert HR, Seeger W: Microsurgery of deep-seated cavernous angiomas: report of 26 cases. Acta Neurochir (Wien) 1991;108:91–99.

Acciarri et al.

38 Kawagishi J, Suzuki M, Kayama T, Yoshimoto T: Huge multilobular cavernous angioma in an infant: case report. Neurosurgery 1993; 32:1028–1030. 39 Maggi G, Aliberti F, Ruggiero C, Pittore L: Cerebral cavernous angiomas in critical areas. Reports of three cases in children. J Neurosurg Sci 1997;41:353–357. 40 Van Lindert EJ, Tan TC, Grotenhuis JA, Wesseling P: Giant cavernous hemangiomas: report of three cases. Neurosurg Rev 2007; 30:83–92. 41 Nieto J, Hinojosa J, Munoz MJ, Esparza J, Ricoy R: Intraventricular cavernoma in pediatric age. Childs Nerv Syst 2003; 19: 60– 62. 42 Chadduck WM, Binet EF, Farrell FW Jr, Araoz CA, Reding DL: Intraventricular cavernous hemangioma: report of three cases and review of the literature. Neurosurgery 1985;16:189–197. 43 Fagundes-Pereyra WJ, Marques JA, Sousa LD, Carvalho GT, Sousa AA: Cavernoma of the lateral ventricle: case report (in Portuguese). Arq Neuropsiquiatr 2000; 58: 958– 964. 44 Katayama Y, Tsubokawa T, Maeda T, Yamamoto T: Surgical management of cavernous malformations of the third ventricle. J Neurosurg 1994; 80:64–72. 45 McGuire TH, Greenwood J, Newton BL: Bilateral angioma of choroid plexus. J Neurosurg 1954;11:423–430. 46 Miyagi Y, Mannoji H, Akaboshi K, Morioka T, Fukui M: Intraventricular cavernous malformation associated with medullary venous malformation. Neurosurgery 1993; 32: 461– 464. 47 Ogawa A, Katakura R, Yoshimoto T: Third ventricle cavernous angioma: report of two cases. Surg Neurol 1990;34:414–420. 48 Reyns N, Assaker R, Louis E, Lejeune JP: Intraventricular cavernomas: three cases and review of the literature. Neurosurgery 1999; 44:648–654. 49 Houtteville JP: Rare localizations. Review of the literature (in French). Neurochirurgie 1989;35:128–131. 50 Maruoka N, Yamakawa Y, Shimauchi M: Cavernous hemangioma of the optic nerve. Case report. J Neurosurg 1988;69:292–294. 51 Muta D, Nishi T, Koga K, Yamashiro S, Fujioka S, Kuratsu J: Cavernous malformation of the optic chiasm: case report. Br J Neurosurg 2006;20:312–315. 52 Ozer E, Yucesoy K, Kalemci O: Demonstrated rapid growth of a corpus callosum cavernous angioma within a short period of time. J Neurosurg Sci 2005;49:155–158. 53 Regli L, de Tribolet N, Regli F, Bogousslavsky J: Chiasmal apoplexy: haemorrhage from a cavernous malformation in the optic chiasm. J Neurol Neurosurg Psychiatry 1989; 52: 1095–1099.

Cavernous Malformations of the CNS

54 Simard JM, Garcia-Bengochea F, Ballinger WE Jr, Mickle JP, Quisling RG: Cavernous angioma: a review of 126 collected and 12 new clinical cases. Neurosurgery 1986; 18: 162–172. 55 Sonntag VK, Waggener JD, Kaplan AM: Surgical removal of a hemangioma of the pineal region in a 4-week-old infant. Neurosurgery 1981;8:586–588. 56 Vaquero J, Carrillo R, Cabezudo J, Leunda G, Villoria F, Bravo G: Cavernous angiomas of the pineal region. Report of two cases. J Neurosurg 1980; 53:833–835. 57 Canevini P, Farneti A, Flauto U: Report of a case of cavernous hemangioma of the dura mater in a 2-day old newborn. Folia Hered Pathol (Milano) 1963; 12:163–166. 58 Hsiang JN, Ng HK, Tsang RK, Poon WS: Dural cavernous angiomas in a child. Pediatr Neurosurg 1996;25:105–108. 59 Thompson TP, Lunsford LD, Flickinger JC: Radiosurgery for hemangiomas of the cavernous sinus and orbit: technical case report. Neurosurgery 2000;47:778–783. 60 Linskey ME, Sekhar LN: Cavernous sinus hemangiomas: a series, a review, and an hypothesis. Neurosurgery 1992;30:101–108. 61 Biondi A, Clemenceau S, Dormont D, Deladoeville M, Ricciardi GK, Mokhtari K, Sichez JP, Marsault C: Intracranial extra-axial cavernous (HEM) angiomas: tumors or vascular malformations? J Neuroradiol 2002;29: 91–104. 62 Gonzalez LF, Lekovic GP, Eschbacher J, Coons S, Porter RW, Spetzler RF: Are cavernous sinus hemangiomas and cavernous malformations different entities? Neurosurg Focus 2006;21:e6. 63 De Oliveira JG, Rassi-Neto A, Ferraz FA, Braga FM: Neurosurgical management of cerebellar cavernous malformations. Neurosurg Focus 2006;21:e11. 64 Fritschi JA, Reulen HJ, Spetzler RF, Zabramski JM: Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir (Wien) 1994;130:35–46. 65 Porter RW, Detwiler PW, Spetzler RF, Lawton MT, Baskin JJ, Derksen PT, Zabramski JM: Cavernous malformations of the brainstem: experience with 100 patients. J Neurosurg 1999;90:50–58. 66 Di Rocco C, Iannelli A, Tamburrini G: Cavernous angiomas of the brain stem in children. Pediatr Neurosurg 1997;27:92–99. 67 Scott RM: Brainstem cavernous angiomas in children. Pediatr Neurosurg 1990; 16: 281– 286. 68 Ferroli P, Sinisi M, Franzini A, Giombini S, Solero CL, Broggi G: Brainstem cavernomas: long-term results of microsurgical resection in 52 patients. Neurosurgery 2005;56: 1203– 1212. 69 Wang CH, Lin SM, Chen Y, Tseng SH: Multiple deep-seated cavernomas in the third ventricle, hypothalamus and thalamus. Acta Neurochir (Wien) 2003;145:505–508.

70 Zausinger S, Yousry I, Brueckmann H, Schmid-Elsaesser R, Tonn JC: Cavernous malformations of the brainstem: threedimensional-constructive interference in steady-state magnetic resonance imaging for improvement of surgical approach and clinical results. Neurosurgery 2006;58:322–330. 71 Harrison MJ, Eisenberg MB, Ullman JS, Oppenheim JS, Camins MB, Post KD: Symptomatic cavernous malformations affecting the spine and spinal cord. Neurosurgery 1995;37:195–204. 72 Hillman J, Bynke O: Solitary extradural cavernous hemangiomas in the spinal canal. Report of five cases. Surg Neurol 1991; 36: 19– 24. 73 Deutsch H, Jallo GI, Faktorovich A, Epstein F: Spinal intramedullary cavernoma: clinical presentation and surgical outcome. J Neurosurg 2000;93(1 suppl):65–70. 74 Zevgaridis D, Medele RJ, Hamburger C, Steiger HJ, Reulen HJ: Cavernous haemangiomas of the spinal cord. A review of 117 cases. Acta Neurochir (Wien) 1999;141:237–245. 75 Vishteh AG, Zabramski JM, Spetzler RF: Patients with spinal cord cavernous malformations are at an increased risk for multiple neuraxis cavernous malformations. Neurosurgery 1999;45:30–32. 76 Odom GL, Woodhall B, Margolis G: Spontaneous hematomyelia and angiomas of the spinal cord. J Neurosurg 1957;14:192–202. 77 Wyburn-Mason R: The Vascular Abnormalities and Tumors of the Spinal Cord and Its Membranes. London, Henry Kimpton, 1943, pp 1–5, 49–91. 78 Nozaki K, Inomoto T, Takagi Y, Hashimoto N: Spinal intradural extramedullary cavernous angioma. Case report. J Neurosurg 2003; 99(3 suppl):316–319. 79 Padovani R, Acciarri N, Giulioni M, Pantieri R, Foschini MP: Cavernous angiomas of the spinal district: surgical treatment of 11 patients. Eur Spine J 1997;6:298–303. 80 Aoyagi N, Kojima K, Kasai H: Review of spinal epidural cavernous hemangioma. Neurol Med Chir (Tokyo) 2003;43:471–475. 81 Graziani N, Bouillot P, Figarella-Branger D, Dufour H, Peragut JC, Grisoli F: Cavernous angiomas and arteriovenous malformations of the spinal epidural space: report of 11 cases. Neurosurgery 1994;35:856–863. 82 Isla A, Alvarez F, Morales C, Garcia Blazquez M: Spinal epidural hemangiomas. J Neurosurg Sci 1993;37:39–42. 83 Santoro A, Piccirilli M, Bristot R, di Norcia V, Salvati M, Delfini R: Extradural spinal cavernous angiomas: report of seven cases. Neurosurg Rev 2005;28:313–319. 84 Acosta FL Jr, Dowd CF, Chin C, Tihan T, Ames CP, Weinstein PR: Current treatment strategies and outcomes in the management of symptomatic vertebral hemangiomas. Neurosurgery 2006;58:287–295.

Pediatr Neurosurg 2009;45:81–104

101

85 Nelson DA: Spinal cord compression due to vertebral angiomas during pregnancy. Arch Neurol 1964;11:408–413. 86 Craig HD, Gunel M, Cepeda O, Johnson EW, Ptacek L, Steinberg GK, Ogilvy CS, Berg MJ, Crawford SC, Scott RM, Steichen-Gersdorf E, Sabroe R, Kennedy CT, Mettler G, Beis MJ, Fryer A, Awad IA, Lifton RP: Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15–13 and 3q25.2–27. Hum Mol Genet 1998;7:1851–1858. 87 Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, Zerah M, Maciazek J, Tournier-Lasserve E; Société Française de Neurochirurgie: Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004;74:326–337. 88 Dupré N, Verlaan DJ, Hand CK, Laurent SB, Turecki G, Davenport WJ, Acciarri N, Dichgans J, Ohkuma A, Siegel AM, Rouleau GA: Linkage to the CCM2 locus and genetic heterogeneity in familial cerebral cavernous malformation. Can J Neurol Sci 2003; 30: 122–128. 89 Laurans MS, DiLuna ML, Shin D, Niazi F, Voorhees JR, Nelson-Williams C, Johnson EW, Siegel AM, Steinberg GK, Berg MJ, Scott RM, Tedeschi G, Enevoldson TP, Anson J, Rouleau GA, Ogilvy C, Awad IA, Lifton RP, Gunel M: Mutational analysis of 206 families with cavernous malformations. J Neurosurg 2003;99:38–43. 90 Revencu N, Vikkula M: Cerebral cavernous malformation: new molecular and clinical insights. J Med Genet 2006;43:716–721. 91 Dubovsky J, Zabramski JM, Kurth J, Spetzler RF, Rich SS, Orr HT, Weber JL: A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 1995;4:453–458. 92 Gunel M, Awad IA, Finberg K, Steinberg GK, Craig HD, Cepeda O, Nelson-Williams C, Lifton RP: Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery 1996;38:1265–1271. 93 Marchuk DA, Gallione CJ, Morrison LA, Clericuzio CL, Hart BL, Kosofsky BE, Louis DN, Gusella JF, Davis LE, Prenger VL: A locus for cerebral cavernous malformations maps to chromosome 7q in two families. Genomics 1995;28:311–314. 94 Liquori CL, Berg MJ, Squitieri F, Ottenbacher M, Sorlie M, Leedom TP, Cannella M, Maglione V, Ptacek L, Johnson EW, Marchuk DA: Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat 2006; 27: 118.

102

95 Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA: Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 2003;73:1459–1464. 96 Verlaan DJ, Davenport WJ, Stefan H, Sure U, Siegel AM, Rouleau GA: Cerebral cavernous malformations: mutations in Krit1. Neurology 2002; 58:853–857. 97 Siegel AM: Familial cavernous angioma: an unknown, known disease. Acta Neurol Scand 1998;98:369–371. 98 Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer B, Brown B, Rigamonti D, Brown G: The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 1994; 80:422–432. 99 Pozzati E, Giuliani G, Nuzzo G, Poppi M: The growth of cerebral cavernous angiomas. Neurosurgery 1989;25:92–97. 100 Kashimura H, Inoue T, Ogasawara K, Ogawa A: Pontine cavernous angioma resected using the subtemporal, anterior transpetrosal approach determined using three-dimensional anisotropy contrast imaging: technical case report. Neurosurgery 2006; 58(suppl):ONS-E175. 101 Johnson EW, Marchuk DA, Zabramski JM: The genetics of cerebral cavernous malformations; in Winn HR (ed): Youmans Neurological Surgery, ed 5. Philadelphia, Saunders, 2004, vol 2, pp 2299–2304. 102 Siegel AM, Andermann F, Badhwar A, Rouleau GA, Dam M, Hopf HC, Dichgans J, Sturzenegger M, Hopf NJ, Yasui N, Stepper F, Killer M, Vanneste JA, Acciarri N, Drigo P, Christensen J, Braun V, Konu D, Andermann E: Anticipation in familial cavernous angioma: ascertainment bias or genetic cause. Acta Neurol Scand 1998; 98: 372–376. 103 Labauge P, Laberge S, Brunereau L, Levy C, Tournier-Lasserve E: Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Société Française de Neurochirurgie. Lancet 1998; 352: 1892–1897. 104 Agazzi S, Maeder P, Villemure JG, Regli L: De novo formation and growth of a sporadic cerebral cavernous malformation: implications for management in an asymptomatic patient. Cerebrovasc Dis 2003; 16: 432–435. 105 Detwiler PW, Porter RW, Zabramski JM, Spetzler RF: De novo formation of a central nervous system cavernous malformation: implications for predicting risk of hemorrhage. Case report and review of the literature. J Neurosurg 1997;87:629–632.

Pediatr Neurosurg 2009;45:81–104

106 Labauge P, Brunereau L, Laberge S, Houtteville JP: Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations. Neurology 2001; 57:1825–1828. 107 Pozzati E, Giangaspero F, Marliani F, Acciarri N: Occult cerebrovascular malformations after irradiation. Neurosurgery 1996;39:677–682. 108 Ludemann W, Ellerkamp V, Stan AC, Hussein S: De novo development of a cavernous malformation of the brain: significance of factors with paracrine and endocrine activity. Case report. Neurosurgery 2002; 50: 646–649. 109 Clatterbuck RE, Eberhart CG, Crain BJ, Rigamonti D: Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations. J Neurol Neurosurg Psychiatry 2001; 71:188–192. 110 Lim M, Haddix T, Harsh GR, Vogel H, Steinberg GK, Guccione S: Characterization of the integrin alpha v beta3 in arteriovenous malformations and cavernous malformations. Cerebrovasc Dis 2005; 20: 23–27. 111 Seker A, Yildirim O, Kurtkaya O, Sav A, Gunel M, Pamir MN, Kilic T: Expression of integrins in cerebral arteriovenous and cavernous malformations. Neurosurgery 2006;58:159–168. 112 Pozzati E, Acciarri N, Tognetti F, Marliani F, Giangaspero F: Growth, subsequent bleeding, and de novo appearance of cerebral cavernous angiomas. Neurosurgery 1996;38:662–670. 113 Maraire JN, Awad IA: Intracranial cavernous malformations: lesion behavior and management strategies. Neurosurgery 1995;37:591–605. 114 Tamburrini G, Iannelli A, Caldarelli M, Di Rocco C: Large cerebral cavernoma mimicking a brain tumor. Pediatr Neurosurg 2002;37:105–106. 115 Clatterbuck RE, Moriarity JL, Elmaci I, Lee RR, Breiter SN, Rigamonti D: Dynamic nature of cavernous malformations: a prospective magnetic resonance imaging study with volumetric analysis. J Neurosurg 2000;93:981–986. 116 Sure U, Freman S, Bozinov O, Benes L, Siegel AM, Bertalanffy H: Biological activity of adult cavernous malformations: a study of 56 patients. J Neurosurg 2005; 102: 342– 347. 117 Tirakotai W, Fremann S, Soerensen N, Roggendorf W, Siegel AM, Mennel HD, Zhu Y, Bertalanffy H, Sure U: Biological activity of paediatric cerebral cavernomas: an immunohistochemical study of 28 patients. Childs Nerv Syst 2006;22:685–691.

Acciarri et al.

118 Allen JC, Miller DC, Budzilovich GN, Epstein FJ: Brain and spinal cord hemorrhage in long-term survivors of malignant pediatric brain tumors: a possible late effect of therapy. Neurology 1991; 41:148–150. 119 Weil SM, Tew JM Jr: Surgical management of brain stem vascular malformations. Acta Neurochir (Wien) 1990;105:14–23. 120 Baumgartner JE, Ater JL, Ha CS, Kuttesch JF, Leeds NE, Fuller GN, Wilson RJ: Pathologically proven cavernous angiomas of the brain following radiation therapy for pediatric brain tumors. Pediatr Neurosurg 2003;39:201–207. 121 Duhem R, Vinchon M, Leblond P, SotoAres G, Dhellemmes P: Cavernous malformations after cerebral irradiation during childhood: report of nine cases. Childs Nerv Syst 2005;21:922–925. 122 Heckl S, Aschoff A, Kunze S: Radiationinduced cavernous hemangiomas of the brain: a late effect predominantly in children. Cancer 2002;94:3285–3291. 123 Larson JJ, Ball WS, Bove KE, Crone KR, Tew JM Jr: Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children. J Neurosurg 1998;88:51–56. 124 Lew SM, Morgan JN, Psaty E, Lefton DR, Allen JC, Abbott R: Cumulative incidence of radiation-induced cavernomas in longterm survivors of medulloblastoma. J Neurosurg 2006; 104(2 suppl):103–107. 125 Maraire JN, Abdulrauf SI, Berger S, Knisely J, Awad IA: De novo development of a cavernous malformation of the spinal cord following spinal axis radiation. Case report. J Neurosurg 1999; 90(2 suppl):234– 238. 126 Narayan P, Barrow DL: Intramedullary spinal cavernous malformation following spinal irradiation. Case report and review of the literature. J Neurosurg 2003; 98(1 suppl):68–72. 127 Novelli PM, Reigel DH, Langham Gleason P, Yunis E: Multiple cavernous angiomas after high-dose whole-brain radiation therapy. Pediatr Neurosurg 1997;26:322–325. 128 McCormick PW, Spetzler RF, Johnson PC, Drayer BP: Cerebellar hemorrhage associated with capillary telangiectasia and venous angioma: a case report. Surg Neurol 1993;39:451–457. 129 Garner TB, Curling OD Jr, Kelly DL Jr, Laster DW: The natural history of intracranial venous angiomas. J Neurosurg 1991; 75: 715–722. 130 Rigamonti D, Spetzler RF: The association of venous and cavernous malformations. Report of four cases and discussion of the pathophysiological, diagnostic, and therapeutic implications. Acta Neurochir (Wien) 1988;92:100–105. 131 Wurm G, Schnizer M, Fellner FA: Cerebral cavernous malformations associated with venous anomalies: surgical considerations. Neurosurgery 2005;57(1 suppl):42–58.

Cavernous Malformations of the CNS

132 Vishteh AG, Sankhla S, Anson JA, Zabramski JM, Spetzler RF: Surgical resection of intramedullary spinal cord cavernous malformations: delayed complications, longterm outcomes, and association with cryptic venous malformations. Neurosurgery 1997;41:1094–1100. 133 Abdulrauf SI, Kaynar MY, Awad IA: A comparison of the clinical profile of cavernous malformations with and without associated venous malformations. Neurosurgery 1999;44:41–46. 134 Guclu B, Ozturk AK, Pricola KL, Seker A, Ozek M, Gunel M: Cerebral venous malformations have distinct genetic origin from cerebral cavernous malformations. Stroke 2005;36:2479–2480. 135 Barrow DL, Awad IA: Conceptual overview and management strategies; in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, AANS Publications Committee, 1993, pp 205–213. 136 Lobato RD, Perez C, Rivas JJ, Cordobes F: Clinical, radiological, and pathological spectrum of angiographically occult intracranial vascular malformations. Analysis of 21 cases and review of the literature. J Neurosurg 1988;68:518–531. 137 Rigamonti D, Johnson PC, Spetzler RF, Hadley MN, Drayer BP: Cavernous malformations and capillary telangiectasia: a spectrum within a single pathological entity. Neurosurgery 1991;28:60–64. 138 Tomlinson FH, Houser OW, Scheithauer BW, Sundt TM Jr, Okazaki H, Parisi JE: Angiographically occult vascular malformations: a correlative study of features on magnetic resonance imaging and histological examination. Neurosurgery 1994; 34: 792–799. 139 Pichierri A, Piccirilli M, Passacantilli E, Frati A, Santoro A: Klippel-Trenaunay-Weber syndrome and intramedullary cervical cavernoma: a very rare association. Surg Neurol 2006;66:203–206. 140 Wacksman SJ, Flessa HC, Glueck HI, Will JJ: Coagulation defect and giant cavernous hemangioma. Am J Dis Child 1966;111:71– 74. 141 Wood MW, White RJ, Kernohan JW: Cavernous hemangiomatosis involving the brain, spinal cord, heart, skin and kidney: report of a case. Proc Staff Meet Mayo Clin 1957;32:249–254. 142 Acciarri N, Padovani R, Giulioni M, Roncaroli F: Cerebral astrocytoma and cavernous angioma: a case report. Br J Neurosurg 1994;8:607–610. 143 Chee CP, Johnston R, Doyle D, Macpherson P: Oligodendroglioma and cerebral cavernous angioma. Case report. J Neurosurg 1985;62:145–147. 144 Klein O, Freppel S, Auque J, Civit T: Cavernous angioma within an olfactory groove meningioma. Case report. J Neurosurg 2006;104:325–328.

145 Rao G, Jensen RL: Coexistent cerebral metastasis and cavernous malformation. J Neurol Neurosurg Psychiatry 2003;74:105. 146 Giulioni M, Zucchelli M, Riguzzi P, Marucci, Tassinari CA, Calbucci F: Co-existence of cavernoma and cortical dysplasia in temporal lobe epilepsy. J Clin Neurosci 2007;4: 1122–1124. 147 Iwasa H, Indei I, Sato F: Intraventricular cavernous hemangioma. J Neurosurg 1983; 60:1297–1299. 148 Churchyard A, Khangure M, Grainger K: Cerebral cavernous angioma: a potentially benign condition? Successful treatment in 16 cases. J Neurol Neurosurg Psychiatry 1992;55:1040–1045. 149 Robinson JR Jr, Awad IA, Magdinec M, Paranandi L: Factors predisposing to clinical disability in patients with cavernous malformations of the brain. Neurosurgery 1993;32:730–735. 150 Khosla VK, Banerjee AK, Mathurya SN, Metha S: Giant cystic cavernoma in a child. J Neurosurg 1984;60:1297–1299. 151 Aiba T, Tanaka R, Koike T, Kameyama S, Takeda N, Komata T: Natural history of intracranial cavernous malformations. J Neurosurg 1995;83:56–59. 152 Kondziolka D, Lunsford LD, Kestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 1995;83:820–824. 153 Anson JA, Spetzler RF: Surgical resection of intramedullary spinal cord cavernous malformations. J Neurosurg 1993;78:446–451. 154 Ogilvy CS, Louis DN, Ojemann RG: Intramedullary cavernous angiomas of the spinal cord: clinical presentation, pathological features, and surgical management. Neurosurgery 1992;31:219–229. 155 Ramos F Jr, de Toffol B, Aesch B, Jan M: Hydrocephalus and cavernoma of the cauda equina. Neurosurgery 1990;27:139–142. 156 Acciarri N, Padovani R, Pozzati E, Gaist G, Manetto V: Spinal cavernous angioma: a rare cause of subarachnoid hemorrhage. Surg Neurol 1992;37:453–456. 157 Mocco J, Laufer I, Mack WJ, Winfree CJ, Libien J, Connolly ES Jr: An extramedullary foramen magnum cavernous malformation presenting with acute subarachnoid hemorrhage: case report and literature review. Neurosurgery 2005;56:E410. 158 Harrington JF Jr, Khan A, Grunnet M: Spinal epidural cavernous angioma presenting as a lumbar radiculopathy with analysis of magnetic resonance imaging characteristics: case report. Neurosurgery 1995; 36: 581–584. 159 Kanaan I, Jallu A, Alwatban J, Patay Z, Hessler R: Extra-axial cavernous hemangioma: two case reports. Skull Base 2001; 11: 287– 295. 160 Perl J, Ross JS: Diagnostic imaging of cavernous malformations; in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, AANS Publications Committee, 1993, pp 37–48.

Pediatr Neurosurg 2009;45:81–104

103

161 Cosgrove GR, Bertrand G, Fontaine S, Robitaille Y, Melanson D: Cavernous angiomas of the spinal cord. J Neurosurg 1988; 68:31–36. 162 Rigamonti D, Drayer BP, Johnson PC, Hadley MN, Zabramski J, Spetzler RF: The MRI appearance of cavernous malformations (angiomas). J Neurosurg 1987;67:518–524. 163 Niizuma K, Fujimura M, Kumabe T, Higano S, Tominaga T: Surgical treatment of paraventricular cavernous angioma: fibre tracking for visualizing the corticospinal tract and determining surgical approach. J Clin Neurosci 2006;13:1028–1032. 164 Crispino M, Vecchioni S, Galli G, Olivetti L: Spinal intradural extramedullary haemangioma: MRI and neurosurgical findings. Acta Neurochir (Wien) 2005; 147: 1195–1198. 165 Acciarri N, Padovani R, Giulioni M, Gaist G, Acciarri R: Intracranial and orbital cavernous angiomas: a review of 74 surgical cases. Br J Neurosurg 1993;7:529–539. 166 Conrad M, Schonauer C, Morel Ch, Pelissou-Guyotat I, Deruty R: Computer-assisted resection of supra-tentorial cavernous malformation. Minim Invasive Neurosurg 2002;45:87–90. 167 Huhn SL, Rigamonti D, Hsu F: Indications for surgical intervention; in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, AANS Publications Committee, 1993, pp 87–99. 168 Buckingham MJ, Crone KR, Ball WS, Berger TS: Management of cerebral cavernous angiomas in children presenting with seizures. Childs Nerv Syst 1989;5:347–349. 169 Baumann CR, Acciarri N, Bertalanffy H, Devinsky O, Elger CE, Lo Russo G, Cossu M, Sure U, Singh A, Stefan H, Hammen T, Georgiadis D, Baumgartner RW, Andermann F, Siegel AM: Seizure outcome after resection of supratentorial cavernous malformations: a study of 168 patients. Epilepsia 2007;48:559–563. 170 Noto S, Fujii M, Akimura T, Imoto H, Nomura S, Kajiwara K, Kato S, Fujisawa H, Suzuki M: Management of patients with cavernous angiomas presenting epileptic seizures. Surg Neurol 2005;64:495–498. 171 Bourgeois M, Di Rocco F, Saint-Rose C: Lesionectomy in the pediatric age. Childs Nerv Syst 2006;22:931–935. 172 Ferroli P, Casazza M, Marras C, Mendola C, Franzini A, Broggi G: Cerebral cavernomas and seizures: a retrospective study on 163 patients who underwent pure lesionectomy. Neurol Sci 2006;26:390–394.

104

173 Giulioni M, Acciarri N, Padovani R, Galassi E: Results of surgery in children with cerebral cavernous angiomas causing epilepsy. Br J Neurosurg 1995;9:135–141. 174 Baumann CR, Schuknecht B, Lo Russo G, Cossu M, Citterio A, Andermann F, Siegel AM: Seizure outcome after resection of cavernous malformations is better when surrounding hemosiderin-stained brain also is removed. Epilepsia 1006;47:563–566. 175 Casazza M, Avanzini G, Ciceri E, Spreafico R, Broggi G: Lesionectomy in epileptogenic temporal lobe lesions: preoperative seizure course and postoperative outcome. Acta Neurochir Suppl 1997; 68:64–69. 176 Cohen DS, Zubay GP, Goodman RR: Seizure outcome after lesionectomy for cavernous malformations. J Neurosurg 1995; 83:237–242. 177 Siegel AM, Roberts DW, Harbaugh RE, Williamson PD: Pure lesionectomy versus tailored epilepsy surgery in treatment of cavernous malformations presenting with epilepsy. Neurosurg Rev 2000;23:80–83. 178 Pozzati E: Thalamic cavernous malformations. Surg Neurol 2000;53:30–40. 179 Steinberg GK, Chang SD, Gewirtz RJ, Lopez JR: Microsurgical resection of brainstem, thalamic, and basal ganglia angiographically occult vascular malformations. Neurosurgery 2000;46:260–270. 180 Tekkok IH, Ventureyra EC: De novo familial cavernous malformation presenting with hemorrhage 12.5 years after the initial hemorrhagic Ictus: natural history of an infantile form. Pediatr Neurosurg 1996; 25: 151–155. 181 Quinones-Hinojosa A, Lyon R, Du R, Lawton M: Intraoperative motor mapping of the cerebral peduncle during resection of a midbrain cavernous malformation: technical case report. Neurosurgery 2005; 56(2 suppl):E439. 182 Cantore G, Missori P, Santoro A: Cavernous angiomas of the brain stem. Intra-axial anatomical pitfalls and surgical strategies. Surg Neurol 1999;52:84–93. 183 Zhang N, Pan L, Wang BJ, Wang EM, Dai JZ, Cai PW: Gamma knife radiosurgery for cavernous hemangiomas. J Neurosurg 2000;93(suppl 3):74–77. 184 Spetzler RF, Detwiler PW, Riina HA, Porter RW: Modified classification of spinal cord vascular lesions. J Neurosurg 2002; 96(2 suppl):145–156. 185 Kim MS, Pyo SY, Jeong YG, Lee SI, Jung YT, Sim JH: Gamma knife surgery for intracranial cavernous hemangioma. J Neurosurg 2005;102(suppl):102–106.

Pediatr Neurosurg 2009;45:81–104

186 Hsu PW, Chang CN, Tseng CK, Wei KC, Wang CC, Chuang CC, Huang YC: Treatment of epileptogenic cavernomas: surgery versus radiosurgery. Cerebrovasc Dis 2007; 24:116–120. 187 Khalil T, Lemaire JJ, Chazal J, Verrelle P: Role of radiosurgery in the management of intracranial cavernomas. Review of the literature (in French). Neurochirurgie 2007; 53:238–242. 188 Huang YC, Tseng CK, Chang CN, Wei KC, Liao CC, Hsu PW: LINAC radiosurgery for intracranial cavernous malformation: 10year experience. Clin Neurol Neurosurg 2006;108:750–756. 189 Kim DG, Choe WJ, Paek SH, Chung HT, Kim IH, Han DH: Radiosurgery of intracranial cavernous malformations. Acta Neurochir (Wien) 2002;144:869–878. 190 Liu KD, Chung WY, Wu HM, Shiau CY, Wang LW, Guo WY, Pan DH: Gamma knife surgery for cavernous hemangiomas: an analysis of 125 patients. J Neurosurg 2005; 102(suppl):81–86. 191 Mitchell P, Hodgson TJ, Seaman S, Kemeny AA, Forster DM: Stereotactic radiosurgery and the risk of haemorrhage from cavernous malformations. Br J Neurosurg 2000; 14:96–100. 192 Pollock BE, Garces YI, Stafford SL, Foote RL, Schomberg PJ, Link MJ: Stereotactic radiosurgery for cavernous malformations. J Neurosurg 2000;93:987–991. 193 Shih YH, Pan DH: Management of supratentorial cavernous malformations: craniotomy versus gammaknife radiosurgery. Clin Neurol Neurosurg 2005;107:108–112. 194 Kondziolka D, Lunsford LD, Flickinger JC, Kestle JR: Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 1995; 83: 825– 831. 195 Yamasaki T, Handa H, Yamashita J, Paine JT, Tashiro Y, Uno A, Ishikawa M, Asato R: Intracranial and orbital cavernous angiomas. A review of 30 cases. J Neurosurg 1986;64:197–208. 196 Yamasaki T, Handa H, Yamashita J, Moritake K, Nagasawa S: Intracranial cavernous angioma angiographically mimicking venous angioma in an infant. Surg Neurol 1984;22:461–466. 197 Zimmermann RS, Spetzler RF, Lee KS, Zambramski JM, Hargraves RW: Cavernous malformations of the brain stem. J Neurosurg 1991; 75:32–39.

Acciarri et al.