Brain and Spinal Cavernomas – Helsinki Experience

Juri Kivelev Academic dissertation

To be presented for public discussion in the Lecture hall 1 of Töölö Hospital on December 10th, 2010 at 12 o’clock noon.

University of Helsinki 2010 Supervisors: Professor Juha Hernesniemi, MD, PhD Department of Neurosurgery Helsinki University Central Hospital Helsinki, Finland

Associate Professor Mika Niemelä, MD, PhD Department of Neurosurgery Helsinki University Central Hospital Helsinki, Finland

Reviewers: Associate Professor Esa Kotilainen, MD, PhD Department of Neurosurgery Turku University Hospital Turku, Finland

Professor Hannu Kalimo, MD, PhD Helsinki University, Haartman Institute Department of Pathology Helsinki, Finland

To be discussed with: Murat Günel MD, Professor of Neurosurgery Professor of Neurobiology Chief, Section of Neurovascular Surgery Co-Director, Yale Program of Neurogenetics

ISBN 978-952-92-8174-9 (Paperback) ISBN 978-952-10-6665-8 (PDF) Helsinki University Print Helsinki 2010

2 To my mother

3 Juri Kivelev Department of Neurosurgery Helsinki University Central Hospital Topeliuksenkatu 5 00260 Helsinki Finland mobile: +358504270383 e-mail: [email protected]

4 Table of contents

Abstract 9

Abbreviations 12

List of original publications 13

I Introduction 14

II Literature review 15

Typical cavernomas 15 Historical aspects 15 Epidemiology 16 Pathologic features 17 Genetics and molecular biology 19 Radiology 21 Clinical aspects 24 Epileptic disorder 24 Focal neurological deficits 25 Hemorrhage 26 Headaches 28 Treatment 28 Surgical series 28 Operative techniques 31 Radiotherapy 33 Uncommon cavernomas 35

Intraventricular cavernomas 35 Patients and natural course 35 Radiology 40 Treatment and operative techniques 41 Neuroendoscopy 43 Outcome 43 Multiple cavernomas 44 Patients and natural course 44

5 Symptoms 45 Epileptic disorder 45 Hemorrhage 46 Other symptoms 47 Radiological progression 47 Surgical treatment and outcome 48 Spinal cavernomas 49 Intramedullary cavernomas 50 Patients and natural course 50 Symptoms 53 Radiology 54 Surgical treatment 55 Operative techniques 55 Monitoring 57 Outcome 58 Extramedullary cavernomas 58 Patients and symptoms 58 Radiology 60 Treatment and outcome 61 III Aims of the study 62

IV Patients and methods 63 Data collection 63 Intraventricular cavernomas 63 Multiple cavernomas 65 Spinal cavernomas 66 Temporal lobe cavernomas 67 V Results and Discussion 72

Helsinki Cavernoma Database 72 Patients 72 Symptoms 72 Radiology 74 Treatment 74 Outcome 75 Publication 1. Intraventricular cavernomas 76

6 Patients and symptoms 76 Radiology 76 Treatment 77 Outcome 79 Discussion 80 Special clinical features 80 Special radiological features 81 Treatment of the IVCs, morbidity and mortality 82 Future trends 82 Publication 2. Multiple cavernomas 83 Patients and symptoms 83 Radiology 84 Treatment 84 Outcome 86 Discussion 86 Publication 3. Spinal cavernomas 88 Patients and symptoms 88 Treatment 90 Outcome 91 Recovery from sensorimotor paresis 92 Recovery from pain 92 Recovery from bladder dysfunction 92 Discussion 93 Prognosis 94 Patients with sensorimotor deficits 94 Patients with pain 95 Patients with bladder dysfunction 95 Publication 4. Temporal lobe cavernomas 95 Patients and symptoms 95 Treatment 97 Outcome 97 Seizure outcome 97 General outcome 98 Discussion 100 Indications for surgery 100

7 General outcome 101 Predictive factors for a better outcome 102 VI Conclusions 103

Acknowledgements 104

References 105

8 Abstract Objective Cavernomas are rare neurovascular lesions, encountered in up to 10% of patients harboring vascular abnormalities of the CNS. After the advent of MRI in clinical practice, the number of patients increased markedly, allowing the main clinical features and results of surgical treatment to be determined. Due to their rareness intraventricular, multiple, and spinal cavernomas remain poorly described in the literature. We analyzed our own series and provided a literature review. In addition, temporal lobe cavernomas were analyzed to better understand the prognostic factors determining a favorable postoperative outcome.

Patients and methods Data on 383 consecutive patients with a total of 1101 brain and spinal cavernomas treated at Helsinki University Central Hospital from January 1, 1980 to December, 12 2009 were retrospectively analyzed. A catchment area of this center is 1.8 million inhabitants. Most patients were primarily examined at the neurological department of the referring hospitals and thereafter sent to our neurosurgical center for further evaluation and treatment. The collection of the series began in 2006, and the patient database was continuously supplemented by new cavernoma patients recruited to the study. Twelve patients (3.1%) had intraventricular cavernomas, 44 patients (11.5%) multiple cavernomas, 14 patients (4%) spinal cavernomas, and 53 patients (15.1%) temporal lobe cavernomas. Results of their treatment were assessed at a median of two, eight, three, and six years, respectively. The study protocol was approved by joint Ethical Committee of Helsinki University.

Results Inraventricular cavernomas (n=12) The median age of our patients on admission was 47 years (range 15 – 66 yrs). As a presenting symptom, 11 patients (92%) had an acute mild to severe headache accompanied by nausea and vomiting. Three patients (27%) with a cavernoma in the fourth ventricle had cranial nerve deficits (paresis of the III, VI, and VII nerves, separately or in various combinations). Four patients (36%) had hydrocephalus on admission, but shunting was necessary in only one patient. Eight patients (67%) experienced extralesional hemorrhage confirmed by CT and lumber puncture. The re-bleeding rate was 89% per patient-year. Six of the 12 IVCs were located in the lateral ventricle, mainly on the left side. One IVC was in the third ventricle, without radiological signs of enlarged ventricles. In five patients (45%), IVC was found in the fourth ventricle, typically in

9 the medial part of the floor. Nine patients underwent surgical excision of the IVC to prevent re- bleedings or to eliminate the mass-effect, or both. Five of the nine patients operated on were symptom-free at follow-up. Age, sex, and previous bleeding had no influence on outcome. No mortalities occurred. Patients with fourth ventricle cavernomas had a worse outcome than those with lateral-ventricle lesions.

Multiple cavernomas (n=44) In our series, mean age at diagnosis was 43.6 years (range 4-69 yrs) and 36.3 years (range 0.6-71 yrs) for men and women, respectively. Nineteen patients (43.2%) had a history of one or more symptomatic extralesional hemorrhages. Altogether, 18 patients (40.9%) had an epileptic disorder, and in six of them (33.3%) an intracerebral hemorrhage from the cavernoma was present on admission. A total of 762 cavernoma was found in these 44 patients. The median number of lesions per patient was six. The largest lesion (50mm) was a Zabramski type I frontal cavernoma that had radiologically presented as a rare cystic form. Microsurgery was performed on 30 patients (68.2%), and a total of 34 cavernomas were removed. In the majority of cases, the removed cavernoma was the largest lesion, and usually with signs of recent bleeding. No patients were lost to follow-up and no deaths occurred. Thirty-four patients (77.2%) had no disability (GOS V), nine (20.5%) had moderate disability (GOS IV), and one (2.3%) had severe disability (GOS III). During the follow-up four patients suffered from a CT-verified intracerebral hemorrhage. Bleedings occurred only in conservatively treated patients. MRI was performed during follow-up on 22 patients. Altogether, 54 de novo lesions were found 48 (89%) belonging to type IV cavernomas.

Spinal cavernomas (n=14) The median age at presentation was 45 years (range 20-57 yrs). In nine patients (63%), the cavernomas were intramedullary, while four patients (29%) had an extradural lesion and one had an intradural extramedullary cavernoma with an isolated intramedullary hemorrhage. Patients suffered from sensorimotor paresis, radicular pain, or neurogenic micturition disorders in different combinations or separately. Three patients (21%) presented with acute onset of symptoms and rapid neurological decline necessitating emergency surgical treatment. Hemorrhage occurred in seven patients (50%) before surgery. Indications for microsurgical removal of a spinal cavernoma were progressive neurological deterioration in 12 patients (86%) and prevention of bleeding and consequent neurological decline in the remaining two patients (14%). Nine patients (64%) underwent a hemilaminectomy and five (36%) a laminectomy. At discharge, ten patients (71%) experienced improvement of their neurological status, three patients (21%) had worsening of the symptoms or some new deficits, and one patient remained the same.

10 At the last follow-up, eight patients (57%) experienced further improvement of their symptoms. One patient (7%) was worse than preoperatively. An extramedullary location proved to be better and safer regarding outcome: four of these five patients (80%) demonstrated further improvement of the symptoms, whereas only four of eight (50%) with an intramedullary lesion did the same.

Temporal lobe cavernomas (n=53) The median age of patients at radiological diagnosis was 37 years (range 7-64 yrs). Epileptic seizure was the most frequent symptom occurring in 40 patients (82%). Before surgery, nine patients (18%) had a CT-confirmed hemorrhage. Altogether, 12 bleedings occurred. Forty-nine patients were operated on. Lesionectomy was performed on 38 of 40 patients (95%) presenting with seizures. All ten patients with only one seizure preoperatively, were seizure-free at follow-up. Of 16 patients who had experienced between two and five seizures preoperatively, 11(69%) were seizure-free, and of 13 patients with numerous seizures preoperatively, nine (69%) were seizure-free. Neither type, duration of seizures, nor location of the cavernoma inside the temporal lobe correlated with postoperative seizure outcome. The predictive value of preoperative EEG could be revealed. At follow-up, nine patients (18%) had a new or worsened neurological deficit. Memory disorder was present in five patients with a history of epilepsy, but four of these patients already had this problem preoperatively. None of the asymptomatic patients developed neurological deficits postoperatively.

Conclusions Microsurgical treatment of brain and spine cavernomas is safe and effective. Most operated patients with intraventricular, multiple, spinal, and temporal lobe cavernomas had significant improvement of their symptoms. Due to rareness of these lesions, a decision to operate may be difficult requiring vast experience and dexterity of the neurosurgeon. In patients with cavernomas of the fourth ventricle, surgical risks are higher than with cavernomas of other ventricles. In cases of multiple cavernomas, removal of epileptogenic cavernomas is beneficial but antiepileptic drugs are used due to the remaining lesions. Spinal intramedullary cavernomas carry higher risks of permanent neurological deficits than those in extramedullary location. In these patients, the worst prognosis was linked to bladder disorders, which occurred in 43% of patients despite surgical treatment. In cases of temporal lobe cavernoma, favorable seizure-outcome after lesionectomy is expected. Duration of epilepsy did not correlate with seizure prognosis. The most frequent disabling symptom at follow-up was memory disorder, considered to be the result of a complex interplay between chronic epilepsy and possible damage to the temporal lobe during surgery.

11 Abbreviations AED antiepileptic drugs ASO arteriosclerotic obliterans ATL anterior temporal lobe AVM arterio-venous malformation BBB blood-brain barrier CCM cavernous malformation gene CM cavernous malformation CSF cerebro-spinal fluid CT computed tomography CNS central nervous system DRE drug-resistant epilepsy DREZ dorsal root entry zone DSA digital selective angiography EC extramedullary spinal cavernomas EEG electro-encephalography GOS Glasgow Outcome Score IC intramedullary spinal cavernomas IVC intraventricular cavernomas IOM intraoperative monitoring MC multiple cavernomas MRI magnetic-resonance imaging MTL medial temporal lobe PET positron-emission tomography PTL posterior temporal lobe SR stereotactic radiotherapy SEP sensory evoked potentials TLC temporal lobe cavernomas

12 List of original publications

I. Kivelev J, Niemelä M, Kivisaari R, Hernesniemi J: Intraventricular cerebral cavernomas: a series of 12 patients and review of the literature. J Neurosurg 112(1):140-9; 2010

II. Kivelev J, Niemelä M, Kivisaari R, Dashti R, Laakso A, Hernesniemi J: Long-term outcome of patients with multiple cerebral cavernous malformations. Neurosurgery 65:450-5, 2009.

III. Kivelev J, Niemelä M, Hernesniemi J: Outcome after microsurgery in 14 patients with spinal cavernomas and literature review. J Neurosurg Spine 13(4):524-534, 2010

IV. Kivelev J, Niemelä M, Blomstedt G, Roivainen R, Lehecka M, Hernesniemi J: Microsurgical treatment of temporal lobe cavernomas. Acta Neurochir (Wien), epub Sep 26, 2010

13 I Introduction

Cavernous hemangiomas, or cavernomas, of the CNS are rare neurovascular lesions. They are usually detected between the second and fifth decade of life [57, 256, 343]. Cavernomas occur in both sporadic and familial forms. The latter are more frequent in Hispanic-Americans, accounting for up to 50% of cavernomas [254]. In contrast, among Caucasians, the familial forms are encountered in only 10-20% of patients [254, 259]. Patients with familial forms are typically affected by multiple cavernomas, whereas sporadic forms mostly present with a single lesion. In hereditary cases, cavernomas are characterized by an autosomal-dominant pattern of inheritance with incomplete penetrance. Three genes responsible for development of the cavernomas have been identified to date [60, 80, 130, 170]. When their mutations express, loss of respective proteins leads to formation of the lesion, with dilated thin-walled sinusoids or caverns covered by a single layer of endothelium that has undeveloped interstitial junctions and subendothelial interstitium [193, 334]. Blood flow inside the sinusoids is low, predisposing to intraluminal stasis and thrombosis. Due to fragility of the sinusoid wall, a cavernoma causes repetitive microhemorrhages into the surrounding neural tissue with formation of perifocal hemosiderosis and reactive gliosis. Such local homeostatic instability produced by either genetic or reactive environmental factors (inflammation, breakdown of the blood-brain barrier, gliosis) may provoke intensive neoangiogenesis and proliferation of the sinusoids. Subsequently, lesions enlarge and grow, which may coexist with clinical progression. The natural history of brain cavernomas is relatively benign and up to 21% of patients are asymptomatic [132]. The most frequent manifestations of the disease are seizures, focal neurological deficits and hemorrhage. Seizure activity occurs in up to 80% of patients with supratentorial cavernomas most probably being evoked by perilesional intraparenchymal changes [15, 71, 223, 256, 288]. Focal neurological deficits are typical for cavernomas located close to eloquent regions of the brain and for spinal lesions. Headaches are fairly common complaint in many cavernoma patients, and usually lead to further clinical and radiological work-up. However, due to their unspecific nature, headaches are not linked to the cavernoma in every patient and frequently represent some other clinical condition. An acute exacerbation of the symptoms of any clinical pattern of cavernomas is prevalently related to hemorrhage. The risk of this event, 0.1-5% per patient-year, depends on the location of the cavernoma and generally increases in deeper lesions of the brain [71, 160, 235, 256, 343]. In most patients, bleeding is not life-threatening, but, in certain cases, it can cause devastating neurological deficits. Furthermore, the risk of re-bleeding increases from 5% to 60% per patient-

14 year [90, 94, 235, 327] indicating active treatment of the lesion in early stages after the first event. Microsurgical removal of the symptomatic cavernoma is generally accepted as the most effective and safe method. Most operated patients with a lesion in a safely accessible location usually gain convincing relief of their symptoms. Nevertheless, deep or eloquent sites of the brain and intramedullary spine location increase surgical invasiveness and risks of postoperative complications. In the present work, data on all consecutive patients suffering from cavernoma and treated at the neurosurgical department of Helsinki University Central Hospital during the last 30 years have been analyzed. Due to the limited literature on intraventricular, spinal, multiple, and temporal lobe cavernomas, these entities were reviewed more extensively. The aim of this study was to integrate our knowledge on clinical features of the cavernomas located in different compartments of the CNS, and summarize results of their surgical treatment.

II Literature review Typical cavernomas

Historical aspects The first report on brain cavernoma appeared in 1854, in a publication by Luschka, who found tumor-like formation originating from vascular tissue and being located within cerebral hemispheres [162]. Luschka classified angiomas into two types: 1) those arising by sequestration of a small portion of the embryonic capillary vascular system; and 2) “true tumor” formation originating from vascular tissue. His own case belonged to the latter type and was a cavernoma according to the modern definition of this term. The term “cavernous angioma” itself has been introduced by Rokitansky before Luschka’s case – these pathological masses with cavernous structure were found and described previously elsewhere in the body [66]. The earliest report of successful surgical removal of a brain cavernoma was introduced by Bremer and Carson in 1890 [35]. The first overview of cavernous angiomas was provided by Dandy in 1928 [66]. He described five of his own cases and collected 44 previously published cases to date that delineated typical macroscopic and microscopic features of this disease. To depict clinical manifestation of the brain cavernomas, Dandy identified basic clinical signs, e.g. predisposition to bleed and to cause focal neurological deficits, with epilepsy being the most common clinical manifestation of these lesions. When describing technical nuances during cavernoma removal, he emphasized: “Although they have a good venous and arterial blood supply, neither is excessive,

15 and neither is disproportionate to the other. When opened at operation, they bleed freely and in proportion to the size of the cavernous spaces and the arterial supply.” This remark seems very important in the sense of influencing the threshold of surgeons to remove this true vascular lesion, which, however, is not prone to profuse intraoperative bleeding. Confirming this, Dandy concluded: “.... the cavernous angiomas... should be treated surgically by complete removal of the solid tumor together with a margin of contiguous brain tissue...” And still, this paradigm remains actual in vast majority of symptomatic cavernoma patients. Eight years after Dandy’s review, Bergstrandt, Olivecrona and Tönnis published their thorough experience on neurovascular pathology investigated and treated at Karolinska Institute in Stockholm [28]. This book included a literature overview of previously published cavernoma cases together with two personal cases. Applying their own pathological classification of this disease, the authors found that only 20 patients collected by Dandy in 1928 met the diagnostic criteria of a cavernoma. Curiously, even one of the reported patients with transcranial growth of the cerebellar lesion who was operated by Dandy himself was not considered by Bergstrand as a definite case of cavernoma [28]. In 1957, Krayenbuhl and Yasargil described 82 cases of cerebral cavernomas collected from the literature [162]. Nineteen years later, in 1976, Voigt and Yasargil published their comprehensive review, which included 164 cases together with one of their own patients who suffered from a temporal lobe cavernoma and was successfully operated on by Yasargil [321]. First applied to medical practice in September, 1971 at Atkinson Morley Hospital in London, computed tomography (CT) scanning has spread throughout the world as an invaluable adjunct to diagnostics of brain diseases. The apparatus was engineered by G.Hounsfeld and mathematically justified by A.Cormack. Furthermore, in 1977, a magnetic resonance imaging (MRI) was performed for the first time on humans [64]. The theoretical basis and engineering of the MRI was provided by Lauterbur, Mansfield, and Damadian. This technique revolutionized radiological diagnostics of any pathology in the CNS, particularly, - cavernomas. With the advent of CT and MRI into everyday clinical practice (the so-called “modern imaging era”) the number of cavernoma cases has increased exponentially.

Epidemiology Among the vascular malformations of the brain and spine, cavernomas constitute 5-10%. Their incidence in the general population is estimated to range between 0.34% and 0.8% [71, 104, 191, 240]. Prior to modern imaging, the diagnosis of cavernoma was rare and usually confirmed only at operative exploration or autopsy. Several classic autopsy studies have reported the incidence of cavernomas in the general population. In 1984, McCormick found 19 cavernomas in 5.734 autopsies reporting an incidence of 0.34% [191]. Just a few years later, in a consecutive series of

16 24.535 autopsies, Otten et al. reported 131 cavernoma cases, yielding an incidence of 0.53% [218]. With the advent of MRI in clinical practice reliable imaging of the cavernoma in living persons became possible, and a fairly similar incidence was noted. In 1991, Del Curling et al. analyzed 8.131 MRIs and found 32 cavernomas, the incidence thus being 0.39% [71]. In the same year, Robinson et al. published their work, where 14.035 MRIs were reviewed and 66 patients with cavernoma were uncovered, yielding an incidence of 0.47% [256]. So far, no population-based studies on the incidence of cavernomas in Finland have been performed. In the neurosurgical department of Helsinki University Central Hospital (serving 1.8 million inhabitants), 383 patients with cavernoma were treated over the last 30 years. This represents a cumulative incidence of 0.62% in this given district during last 30 years. Taking into account, that the Finnish population is epidemiologically quite homogeneous the same incidence probably exists in other parts of the country.

Pathologic features According to the pathological classification of neurovascular malformations suggested by McCormick in 1966, lesions are divided to five major groups: 1) teleangiectasias; 2) varices; 3) cavernous malformations; 4) arteriovenous malformations (AVMs); and 5) venous angiomas [192]. This classification has thereafter been modified: varices (varicose veins) have been combined with venous malformations/venous angiomas, and such lesions have been renamed to developmental venous anomaly (DVA). Although pathological criteria have been suggested for every type of malformation their structural criteria and nomenclature are somewhat ambiguous and variable. Furthermore, reports of transitional or mixed forms exist in the literature and all of the above-mentioned malformations can coexist with each other. The most frequent entity associated with cavernomas appears to be DVA [230, 237, 304]. Another common combination is a capillary teleangiectasia. Some similarities between these malformations (multiplicity, pontine involvement, familial variety) give reason to consider teleangiectasias as a precursor of cavernomas [252, 259]. From a macroscopic viewpoint, cavernomas are well-defined lesions and because of their lobulated appearance often resemble a mulberry (Figure 1). They do not invade the neural tissue. In contrast to AVMs, large feeding arteries or draining veins are not common; therefore blood flow inside the lesion is low. Their mean size is usually 1-2 cm, with a range from punctate to gigantic examples. The biggest lesion in our practice was 5 cm in diameter. There are anecdotal cases of huge lesions, with the cavernoma occupying an entire lobe or even several lobes of the brain [100, 259].

17 Figure 1 Intraoperative view of the spinal cavernoma surrounded by nerve roots In fact, in 2008, Kan et al. published an overview of 36 collected cases of giant cavernomas emphasizing the extreme rarity of such lesions [147]. Although no agreement exists regarding terminology, the authors applied the term “giant cavernoma“ to lesions exceeding 4 cm in diameter, which seems to be rational. In a typical case, the lesion’s core consists of unequal sinusoids or caverns filled with blood that are separated by fine fibrous strands. Intraluminal thrombosis with subsequent organization is typical and this area appears more solid. Calcifications and even bone formation may also exist [259]. Adjacent neural tissue is very typically discoloured due to accumulation of blood breakdown products after repetitive microhemorrhages.

Figure 2 Microscopic view of a cavernoma. The dilated vessels without intervening neural parenchyma are lined by thin endothelium and surrounded by collagenous fibrotic tissue with blue deposits of iron (hemosiderin) after hemorrhages

Microscopically, cavernomas are sinusoid structures with thin walls, which are composed of collagen lined by a single layer of endothelium [259]. Outside the lumen there are often macrophages containing iron pigment, hemosiderin, phagocytosed after microbleeds (Figure 2). Electron microscopy [305] has shown that endothelia may be fenestrated or there are gaps at intercellular junction, all these alterations indicating defective blood-brain barrier [54,305]. The basal lamina outside the endothelium may be lacking or is abnormal, and astrocytic endfeet are often absent. Some histological subtypes of cavernomas have been identified: 1) Cystic form, which is predisposed to bleeding and growth and occurs commonly in the posterior fossa [27, 241]. This form is very rare, and only 25 cases of cystic cavernoma have been reviewed to date [215]. The mechanisms of formation of large cysts are not understood; presumably, osmotic transport of the fluid into the cyst combined with microhemorrhages induces progressive enlargement of the lesion (Figure 3). This type is more frequent in females and elderly patients; 2) Dural-based form, which is usually encountered in the middle fossa close to the cavernous sinus or within it, in the cerebellopontine angle, or on the tentorium and convexities, is prone to

18 Figure 3 MRI of the frontal cavernoma with large cystic component a –T2-weighted image, axial view; b –T1-weighted image, axial view; c – T1 –weighted image with Gadolinium contrast, sagittal view.

a b c an aggressive clinical course [163, 197, 251, 319]. Middle fossa lesions may have abundant vascular supply and tend to bleed profusely when excised [319]; 3) Hemangioma calcificans is typically found in the temporal lobe and, as reflected by its name, is strongly calcified with a low risk of hemorrhage, while still being highly epileptogenic [143].

Genetics and molecular biology Primary evidence of hereditary mechanisms underlying cavernoma formation was elucidated in the early 1980s, when investigators detected several families of Hispanic origin who suffered from cavernomas [130, 189, 254, 256, 343]. These studies convincingly showed that cavernomas can present as a familial form with an autosomal dominant pattern of inheritance. Extensive laboratory research has been initiated to address the genetic substrate of this phenomenon, and genes predisposing patients for cavernomas (CCM1, CCM2 and CCM3) have been identified (Table 1). Already in 1995, Günel et al. discovered CCM1 confirming genetic mechanism of the disease [116]. All three genes are likely involved in the same molecular pathway providing interplay between the neural and glial elements (neurons and astrocytes) and the endothelium of the CNS [277]. Functions of each gene were studied and certain changes in protein interactions and consequent pathologic appearances in cytoarchitecture within the cavernoma were addressed. The CCM1 gene (alternative name KRIT 1) is located at chromosome locus 7q and stabilizes the interendothelial junctions associated with actin stress fibers [175]. Through integrin signaling, CCM1 possibly mediates bidirectional signaling between the extracellular matrix and the cellular cytoskeleton [277]. It is expressed in arterial and microvascular endothelium of the CNS [119]. More than 90 mutations of CCM1 have been reported [167].

19 The CCM2 gene (or malcavernin) located at 7p, probably determines cellular responses to osmotic stress [175]. In a study by Plummer et al, CCM2 expression in the brain was found to be primarily neuronal, but not endothelial [232]. This finding suggests that cavernomas may arise from abnormalities in surrounding neuronal and glial cells rather than in vascular endothelium [199]. The CCM3 gene is located at the chromosome locus 3q (called programmed cell death 10 or PDCD10) and is encountered in up to 40% of families with cavernomas [60]. It determines cell proliferation and transformation (cancer cell lines), together with modulating extracellular signal- regulated kinase [175].

Table 1 Genetic background of cavernomas Genes, Affected clinical chromosome Alternative name Ultrastructural profile References penetrance loci

CCM1, 7q21 KRIT1 KRIT1 protein localizes specifically to the [60, 74, 100, 60-88% (Krev-1 vascular endothelium. Expresses in foots 105, 116-120, interaction processes of astrocytes, forming BBB. 175] trapped 1) Involved in integrin signaling. Encodes a microtubule-associated protein, binds ß- catenin, integrin cytoplasmic domain associated protein-1Į (ICAP-1Į), stabilizes interendothelial junctions associated with actin stress fibers. Involved in angiogenesis.

CCM2, 7p13-15 MGC4607 Expressed in arterial and microvascular [60, 63, 100, 100% endothelium, in brain pyramidcells and in 175, 277, 310] Malcavernin; astrocytes. Mimics CCM1. Provides cellular responses to osmotic stress, binds OSM CCM1 and MEKK3 acting like scaffolding (osmosensing protein signaling through p38 after scaffold for extracellular stimulation. p38 pathway mitogen-activated involved in cell proliferation and protein kinase differentiation to apoptosis. Modulates kinase kinase 3, or mitogen-activated protein (MAP) kinase MEKK3) and Ras homolog gene family, member A (RhoA) GTPase signaling. Involved in angiogenesis.

CCM3, 3q25-27 PDCD10 Provides cell proliferation and [51, 60, 100, 63% (programmed cell transformation, involved in apoptotic 115, 296] death 10) signaling, modulates extracellular signal- related kinase (ERK). Involved in angiogenesis.

Carriers of the mutated genes have cavernomas on MRI in up to 69% of cases [74]. Thus, the presence of mutations in the above-mentioned genes is necessary but not sufficient for the development of the cavernoma [114]. Knudson’s “two-hit” mechanism, proposed to explain this phenomenon, suggests an external trigger (“second hit”) that exacerbates the disease in a given region [114, 175, 221]. Loss of one of the alleles (“first hit”) is the result of a germline mutation,

20 and loss of the second allele (“second hit”) will occur somatically within the brain [167]. Several factors have been assumed to have “second-hit” abilities. For example, a somatic mutation in the second copy of the gene or a mutation in another gene acting in the same cellular pathway is considered to be the most probable trigger of the disease [115, 175]. Clinical observations of de novo cavernomas after radiotherapy confirm that environmental factors also play a role in “second hits”. Angiogenic factors, inflammatory agents and breakdown of the blood-brain barrier may also be responsible for the development of cavernomas [54, 100, 175, 280, 291, 305].

Radiology In 1956, Crawford and Russel proposed the term ”cryptic cerebrovascular malformations”, in which cavernomas were traditionally grouped [217]. This subset of neurovascular lesions included cavernomas, thrombosed arteriovenous malformations, venous malformations, capillary teleangiectasias, and other mixed forms. The main reason why these “cryptic” or “occult” lesions got this name was based on their scarce appearance or, more commonly, invisibility in the angiographic view. Although some authors were able to find some prominent draining veins [217] or small homogeneous finely stippled areas of contrast medium, no pathognomonic angiographic features could be shown [321]. Routine use of CT scanning in patients with acute neurological events contributed considerably to preliminary diagnosis of cavernomas. However, the sensitivity of CT in cavernoma diagnostics is low, and specificity ranges from only 30% to 50% [217]. Thereby, one cannot reliably detect the lesion, especially in cases of acute intracerebral hemorrhages where the lesion is mimicked by extravascular blood. On the other hand, with an increasing frequency of CT imaging, the number of suspected cases has increased markedly. There are certain radiological features on CT that may correspond to cavernomas. They present as rounded, well-bordered lesions, hyperdense to adjacent parenchyma, and in 40-60% of cases contain calcifications [217]. Usually, no perifocal edema or pronounced enhancement exists. Due to the low blood flow inside the nidus, lesions are negative on the CT angiography (CTA), except for large ones that may even displace major vessels causing a mass-effect. A true breakthrough in cavernoma diagnostics began with the widespread use of MR imaging, which appeared to be the most sensitive tool for revealing a cavernoma throughout the cerebrospinal axis. MRI allows cavernomas to be reliably diagnosed not only after acute neurological decline but also in asymptomatic incidental cases. Thus, the number of detected cavernoma patients has increased dramatically and extensive MRI-based epidemiological studies have been performed [71, 256]. The MR appearance of a cavernoma can be quite variable depending commonly on the amount of hemorrhage. Already in 1987, Rigamonti et al. published their observations of ten cavernoma patients diagnosed with 1.5 Tesla MRI, depicting typical MR

21 features of the lesion [253].

Figure 4 MRI of a 4 year-old patient with acute somnolence and hemiparesis. a – T2-weighted image, sagittal view; b - T1 –weighted image, axial view; c – T2*-GRE image showing a pontine cavernoma with a hemorrhage

a b c Cavernoma commonly presents in the T1- and T2-weighted sequences with a reticulated “popcorn ball” appearance of mixed hyper- and hypointense blood-containing locules [217]. The lesion is surrounded by a hypointense hemosiderin rim. In FLAIR sequences, perifocal edema can be identified, especially in acute lesions. Several hemosiderin-sensitive sequences (T2* Gradient Echo, T2* Weighted Angiography - SWAN) are of value, having the highest accuracy in detecting the intraparenchymal collection of extravasated hemosiderin. The hemorrhage- resolving stage significantly affects the MR appearance of the cavernoma, as stated by Zabramski et al. [343]. The authors proposed a practical classification of MR features of cavernomas, corresponding to pathological features of the lesion and including four major types (Table 2). Type I lesions represent subacute hemorrhage, which makes them identifiable on CT as well. On T1- and T2-weighted MR images, they are hyperintense at the initial stage, while with hematoma aging and methemoglobin is converted to ferritin and hemosiderin (Figure 4). Changing of paramagnetic features starts from the margin of the hematoma, which leads to a decrease in the size of the hyperintense core and the appearance of a hypointense halo around the lesion, known as the hemosiderotic rim. In cases of major extralesional bleeding, a definitive description of the cavernoma apart from the hematoma is seldom possible, usually indicating follow-up imaging and re-evaluation of the lesion. Type II cavernomas constitute the most recognizable group, with a classical reticulated core of mixed signal that is surrounded by a hypointense ring seen in T1- and T2-weighted images (Figure 5). This appearance is considered as a pathognomonic sign of a cavernoma and reflects the existence of partial thrombosis and organization of intralesional blood within the sinusoids sometimes combined with calcification.

22 Figure 5 A type II frontal cavernoma with typical Figure 6 Sagittal view of type III frontal “pop-corn” appearance cavernoma. T1-weighted image a – preoperative view b- postoperative view

Meanwhile, on CT images type II lesions are visualized quite poorly. Type III lesions look hypointense on either T1- or T2-weighted images, representing chronic hemorrhage (Figure 6). They are not identifiable on CT, except for large lesions containing calcifications. Type IV lesions are best visualized on hemosiderin-sensitive sequences, like T2*-gradient echo, and look like punctate hyperintense lesions (Figure 7). Still no consensus exists regarding the pathological substrate of these lesions. Earlier considered as capillary teleangiectasias [252, 343], some recent evidence shows these lesions to be true cavernomas, which can even convert into other radiological types [53]. In general, type I and II lesions are more common in symptomatic patients, whereas types III and IV occur in both groups equally. Furthermore, type IV lesions more often exist in multiple forms, especially with family history [37].

Figure 7 Left frontal cavernoma of type IV. a - T2*-GRE –image, b – T2-weighted image (a lesion is not visible)

a b

23 In some disputable cases, diagnostic workup of cavernomas can be supplemented by Positron Emission Tomography (PET). PET findings demonstrate normal or decreased uptake of 11C- methionine and 11C-glucose, which is not the case in neoplasms where methionine uptake is increased [86]. Unfortunately, the practical value of this method is limited by its low accessibility in routine clinical practice.

Table 2 Grading of cavernomas according to MRI appearance as proposed by Zabramski et al.

Type MRI features Pathology features I T1: hyperintense core Subacute hemorrhage T2: hyper- or hypointense core

II T1: reticulated mixed signal core Lesions with thrombosis of varying ages T2: reticulated mixed signal core with surrounding hypointense rim

III T1: iso- or hypointense Chronic hemorrhage with hemosiderin staining T2: hypointense lesion with hypointense within and around lesion rim magnifying size of lesion

IV T1: not seen Tiny cavernoma or teleangiectasia T2: not seen GRE: punctate hypointense lesion

Clinical aspects Cavernomas can be diagnosed at any age, but are most common in individuals aged 20-50 years [104, 321], with a peak at 30 years [167]. They occur in both genders with equal frequency [132]. Most patients present with a sporadic single lesion. Supratentorial lesions comprise 70-90% of all locations [104, 218, 321]. Meanwhile, in 10-40% of cases cavernomas are familial, and thus, often multiple [240, 254]. The natural course of cavernomas seems to be relatively benign. Fatal outcome of the disease is very uncommon, occurring mostly in cases of huge lesions affecting critical brain structures that disrupt after profuse bleeding. Usually, cavernomas are characterized by three major clinical patterns – epileptic disorders, focal neurological deficits, and hemorrhage, which can present separately or in different combinations.

Epileptic disorders Seizures are the most frequent clinical presentation of supratentorial cavernomas, occurring in 41-80% of patients [14, 57, 71, 104, 167, 254, 256, 282]. The annual cumulative risk of new

24 seizures in this group is estimated to be 1.34-2.8% [71, 201]. It is not uncommon that seizures occur after a cavernoma hemorrhage. Seizure incidence in patients suffering from AVM is 20- 40%, and from gliomas 10-30% which are only half of that in cavernoma patients [15, 16]. Cavernomas do not invade parenchyma and are not intrinsically epileptogenic; thus, epileptogenicity is probably due to perifocal changes in the adjacent brain parenchyma. Typical for cavernoma perifocal collection of blood breakdown products combined with inflammatory alterations and gliotic changes seems to be an organic substrate of epileptogenicity in these patients [14]. Iron ions have a role in producing free radicals and lipid peroxides, which affect functioning of certain cell receptors [283, 333]. The subsequent cascade of changes includes a marked increase in excitatory neurotransmitter amino acids [322]. Such activation has also been discovered in electrophysiological studies, which have shown more than two times higher evoked activity values in cavernoma-neighboring neurons than in cells around glial tumors. Furthermore, there are different firing patterns in adjacent hippocampal tissue in cavernoma and glioma patients [333]. Patients with cavernomas can present with any type of seizures. For unknown reasons, cavernoma-associated seizures are more likely intractable than those related to other vascular malformations [15, 16]. The variability of the seizure disorder may be related to the location of the lesion, its size, history of hemorrhage, and patients’ age. For example, temporal lobe lesions tend to cause seizures more frequently and have an obvious propensity to intractable epilepsy [14, 15]. Less favorable seizure outcome was noted in younger persons and women [57]. Long-lasting epileptic disorders with high frequency of seizures in certain cases can lead to development of secondary epileptogenic foci located in remote brain regions [14]. Notably, the risk of recurrent seizures is 5.5% per patient-year [201]. The appearance of the epileptic syndrome in cavernoma patients is not included in the framework of the “all-or-nothing” concept, as patients with supratentorial lesions can be asymptomatic until hemorrhage or some environmental provocative factor triggers epileptic activity. Furthermore, patients with a similar location, size, or radiological appearance of the lesion may have completely different patterns of epilepsy. This variability is sharply emphasized in multiple cavernoma patients, as any of the supratentorial lesions carries a potential risk of epileptogenicity [15].

Focal neurological deficits Appearance of focal neurological deficits in cavernoma patients is not uncommon when lesions affect the motor cortex, speech areas, basal ganglia, brain stem and spinal cord. Accordingly, patients present with sensorimotor deficits, dysphasia, and cranial nerve malfunctions in 35-50% of cases [256, 282, 288]. Due to their relatively small size and slow growth, cavernomas

25 themselves rarely cause fast deterioration, even though patients complain of fluctuating appearance of symptoms with frequent spontaneous relief and subsequent deterioration. Acute decline usually occurs after a cavernoma hemorrhage into surrounding parenchyma, compressing or destroying it.

Hemorrhage Cavernomas have a well-known tendency to bleed. In some vary rare cases, hemorrhage can be fatal, but it is usually well tolerated depending on the volume, nearness to critical structures, patients’ age, and comorbidities. The term “cavernoma hemorrhage” in the literature is quite confusing and depends on the interpretation of the radiological signs of the lesion on CT and MRI when acute onset of the symptoms occurs. The presence of a thrombus may give a false impression of acute bleeding in projection of the cavernoma. Hemorrhagic events occurring in cavernoma patients are divided into two groups: intra- and extralesional bleeding [15]. An intralesional (or encapsulated) hemorrhage is limited to the border of the lesion and causes enlargement of the cavernoma. Probably, the surrounding hemosiderotic parenchyma, which is strengthened by gliosis, takes a role in preventing the hemorrhage from spreading outside into healthy parenchyma. This can lead to formation of a capsule, which behaves like a membrane of a chronic subdural hematoma, osmotically attracting fluid and leading to enlargement of the cavernoma. A weakened capsule compatible with hemodynamic stress is a possible factor predisposing to more prominent bleeding that invades nearby brain areas [22, 288]. An extralesional (or overt, gross) hemorrhage extends beyond the hemosiderotic ring and on MRI shows signs of acute or subacute bleeding (Figure 4). This “true” intracerebral bleeding can cause marked disruption of surrounding tissue and lead to permanent deficits depending on the location. Both intra- and extralesional hemorrhages usually manifest with acute onset of headaches accompanied by focal deficit or seizures. In the pre-MRI era, within the framework of cryptic vascular malformations, cavernomas were considered lesions with very high hemorrhage potential. Early series showed hemorrhage incidence in cavernoma patients to be up to 65% [325, 335]. However, most of the studies were influenced by significant patient selection bias and mixing of different pathological entities; as a rule, patients were studied after acute symptoms and hemorrhage and could have even had an AVM, which carries a higher risk of profuse hemorrhage than a cavernoma. In more recent studies based on MRI findings with recruited asymptomatic patients, the extralesional hemorrhage rate appears to be quite low, on average 1% per patient-year (range 0.25% - 2.5%) [71, 160, 169, 235, 256, 343] (Table 3). In familial cases, bleeding rates may vary depending on the cavernoma genotype. Notably, Denier et al. in 2006, found that CCM3 carriers are more prone than CCM2 and CCM1 patients to develop cerebral hemorrhages, especially at a younger

26 age [73]. Furthermore, the authors showed that in patients with multiple cavernomas CCM1 was associated with a higher number of lesions than CCM2 and CCM3. Thus, the overall risk of hemorrhage in these patients is increased due to cumulative risks from each lesion. Lesions of the infratentorial compartment and particularly the brain stem are characterized by higher bleeding rates than their supratentorial counterparts, ranging from 2.46% to 5% per patient-year [160, 166, 237]. Interestingly, larger lesion size (>1 cm), early age at presentation (<35 years), and coexistence of DVA were found to be associated with higher hemorrhage rates [166]. Nevertheless, the mechanisms of higher bleeding risk of cavernomas in infratentorial compartment remain obscure.

Table 3 Reported symptomatic hemorrhage rates of cerebral cavernomas

First author, year Annual hemorrhage rate Study design Reference (%)

Del Curling, 1991 0.1 Retrospective [71] Robinson, 1991 0.7 Prospective [256] Zabramski, 1994 1.2 Prospective [343] Kondziolka, 1995 1.3 Retrospective [160] 2.6 Prospective 0.6 For incidental lesion

Aiba, 1995 0-0.4 Prospective [2] Porter, 1999 5 Retrospective [237] Brain stem lesion

Labauge, 2000 2.5 Retrospective, familial forms [169] Kupersmith, 2001 2.46 Brain stem lesions [166] Labauge, 2001 4.3 Prospective, familial forms [168]

After initial decline, caused by extralesional bleeding, many patients recover well, but some can experience re-bleedings. The risk of having recurrent extralesional hemorrhage in this selected group varies from 5.1% to 60% per patient-year [2, 91, 94, 160, 237]. Aiba et al. found that younger women exhibited a higher incidence of re-bleeding, possibly caused by hormonal factors [2]. Furthermore, lesions of the brain stem seem to be more prone to re-bleed. In contrast to previous studies, Barker et al. proposed the concept of temporal clustering of the hemorrhages

27 after the initial event [19]. Using sophisticated statistical analysis in 141 patients, the authors discovered quantitative evidence of a spontaneous decline in the hazard of cavernoma re- hemorrhage approximately two years after the first hemorrhage. Cavernoma hemorrhage can be provoked by using anticoagulant therapy [238]. With a general trend towards population aging and ASO diseases on the rise, the number of cavernoma patients who need to be treated by anticoagulants will most likely increase. Management of such patients obviously requires special attention.

Headaches Headaches have been associated with clinical appearance of a cavernoma in 25-30% of patients [256, 282, 288]. Due to their unspecific nature, in most of the cases, headaches are actually not connected to the cavernoma, but appear as a clinical sign of some other condition such as tension neck syndrome or migraine. At the same time, headaches commonly accompany acute extralesional hemorrhages particularly when the hemorrhage extends to the subarachnoid space or ventricles. Large lesions compressing or obstructing CSF outflow pathways may cause hydrocephalus with subsequent headache.

Treatment Surgical series No unequivocal strategy of treatment exists that can be applied to all cavernoma patients. Most of these lesions do not belong to the subset of life-threatening neurovascular lesions. They rarely cause severe permanent disability and otherwise exhibit a fairly nonaggressive natural history. However, certain patients have appreciable risk of developing permanent deterioration due to hemorrhage or chronic epilepsy. Since the first report of successful surgical removal of a cerebral cavernoma, which was published in 1890 [35], several papers on the treatment of the cavernous have been published. One of the first reports that thoroughly discussed literature on the topic was introduced by Voigt and Yasargil in 1976. They reviewed 164 published cases of cerebral cavernomas adding their own case of a temporo-occipital medio-basal lesion [321]. The authors found only 21 cases (12.8%) of successfully operated cerebral cavernomas. With the advent of CT in clinical practice, the sizes of the published series have increased. One of the first reports, based on CT findings, was published by Tagle et al. and included a series of 13 patients; 12 of them underwent surgery [293]. This report elucidated the effectiveness of surgical treatment in terms of seizure outcome. The authors showed that drug resistant epilepsy in their cavernoma patients could be successfully treated by surgical removal of the lesion; six of the seven patients were seizure-free at the long-term follow-up. A larger series introduced by

28 Vaquero et al. consisted of 25 successfully operated patients [314]. In this series, 17 of 19 patients with preoperative epileptic disorders were seizure-free at follow-up, and the two remaining patients had improved significantly, having only the occasional seizures. Poor outcome was registered in those who had a cavernoma in the brain stem or spine. In a report by Yamasaki et al. on 22 of 30 patients treated surgically, the authors concluded that easily accessible lesions can be removed with favorable results, whereas incidental or asymptomatic cavernomas should only be followed [335]. With widespread use of MRI in clinical practice, the number of publications has increased. Furthermore, MRI has allowed reliable diagnosis of lesions located in the brain stem, enabling more accurate planning of the surgical approach to this critical structure. One of the first reports confirming the efficacy and safety of cavernoma removal from the brain stem and basal ganglia was published in 1991 by Bertalanffy et al [30]. The authors presented results on 26 operated patients with deep-seated cavernomas and emphasized the importance of a proper operative approach, careful dissection, and complete removal of the malformation to gain a satisfactory postoperative outcome. The authors further stressed the importance of proper selection of patients with deep-seated cavernomas located in eloquent structures that have bled or caused sustained neurological deficits, as they have the highest morbidity after surgical intervention [29]. In a meta-analysis by Fritschi et al. consisting of 139 patients with surgically treated brain stem cavernomas at the follow-up, 83.9% had no or only mild neurological deficit, 15% were moderately disabled, and none had died, whereas among the conservatively managed patients 66.6% had no or only slight neurological deficit, 6.7% were moderately disabled, 6.7% were completely dependent, and 20% had died [94]. Most of the patients who died or had severe disability suffered from gross extralesional hemorrhage and/or growth of the lesion. In 2003, Wang et al. reported their experience on 137 patients with brain stem cavernomas [327]. Surgical treatment improved the condition of 99 patients (72.3%) and none had died. To date this is the largest published series on brain stem cavernomas. The series of Oliveira et al. on cerebellum cavernomas showed that they are larger (median size 4.6 cm) on average being twice as larger as supratentorial cavernomas [70]. All patients included in the study (n=10) had good or exelent long-term postoperative outcome. The results after microsurgical removal of cavernomas in the basal ganglia and thalamus were analyzed by Gross et al. who reviewed 103 reported cases at this location [113]; 89% were completely removed, with a morbidity of 10% and a mortality of 1.9%. Accumulating data on the microsurgical treatment of deep-seated cavernomas have been summed up in several systematic reviews of extensive patient series. In 2009, Gross et al. published their meta-analysis of 78 studies on 745 brain stem cavernoma patients; 683 (92%) had the lesion completely removed [112]. At the postoperative follow-up, 85% of patients were reported to be improved or the same. The surgical mortality rate was 1.9%. Half of the patients with incomplete

29 resection experienced re-bleeding, four of them being fatal. Surgery on supratentorial cavernomas is mainly indicated when a patient has intractable epilepsy. The goal of the operative treatment in these patients is to alleviate the epilepsy and eliminate any future risks of hemorrhagic events. However, to achieve favorable seizure outcome, some patients may just be observed and treated with proper antiepileptic drugs. This approach was reported to be effective in 60% of cases in a small series of 16 patients [52]. Larger studies, by contrast, have confirmed more favorable seizure outcome after cavernoma resection. Ferroli et al. analyzed a series of 163 patients with epileptogenic cavernoma who underwent lesionectomy and reported that 132 patients (81%) attained complete seizure control [90]. Longer history of seizures was associated with worse outcome, and 17.1% of the patients remained unchanged despite surgery. Cohen et al. analyzed 51 patients with at least one preoperative seizure. All patients with a single seizure before surgery were seizure-free, as were also patients who had developed seizures within two months before surgery [57]. Only 76% of those patients who had a preoperative duration of epilepsy exceeding two months were seizure-free at follow-up. Furthermore, younger patients had low rates of favorable seizure. In a multicenter study of seizure outcome, Baumann et al. reviewed 168 consecutive patients collected from seven clinics with inclusion criteria as follows: a) epilepsy before surgery with more than three seizures; b) cavernomas surgically treated by microsurgical technique; and c) follow-up • 12 months [25]. In concordance with previous studies, the authors discovered that patients older than 30 years at operation have better chances for a favorable seizure outcome than younger persons. Conversely, duration of the epilepsy was not associated with seizure outcome. Interestingly, two years postsurgery the patients with larger lesions (>1.5 cm) had worse seizure outcome, but at three years this difference had disappeared. Patients with secondary generalized seizures preoperatively were significantly less likely to achieve a seizure-free state than those with simple partial and complex partial seizures (26% vs. 65% and 52%, respectively). A high rate of preoperative seizures was not associated with better outcome. Removal of a cavernoma in patients with intractable epilepsy should be assessed in the context of epilepsy surgery, implying indications for tailored surgery of the epileptogenic brain tissue. Failure to control epilepsy after an operation can be linked to incomplete resection and/or the persistence of a hemosiderin fringe or the development of secondary epileptogenic foci in areas remote from the primarily lesion [23]. Lesions close to limbic structures are at higher risk of forming distant loci that with time may “learn” to generate seizures independently [14]. Still, no uniform policy regarding additional resection has been suggested in the literature. Among the rare reports, Paolini et al. demonstrated successful results after tailored resection of temporal cavernomas causing intractable epilepsy in six of seven of their patients [223]. Undoubtedly, selection of patients for additional resection requires thorough preoperative evaluation with

30 performance of EEG and video-EEG, magnetoencephalography (MEG) or PET, and WADA-test with the purpose of lateralizing memory functions. Activity of the secondary foci tends to fade away after resection of the epileptogenic cavernoma and they should only be removed if resection of the cavernoma, combined with use of AED fails to attain seizure control [14, 23].

Operative techniques The goal of the operative treatment of a cavernoma is gross total resection. Partial removal can significantly increase the risk of bleeding with consequent complications. Total removal of the lesion requires dissection of the lesion from the surrounding brain. Thus, if the cavernoma is located within or beside critical structures of the brain (e.g. brain stem, basal ganglia, motor cortex, speech areas), any manipulation can cause mechanical or ischemic damage with concomitant dysfunctions of the affected centers. Use of the operating microscope and microsurgical instruments is essential in cavernoma removal. Preoperative planning and mapping of eloquent areas adjacent to the cavernoma are the most important part of the surgery, as any inaccuracy in direction of approach can lead to significant difficulties in finding small lesions within parenchyma. The most precise method is to combine knowledge of anatomical landmarks in the affected region and use of stereotactic navigation (frame-based or frameless). Importantly, despite seemingly correct calculations, a neurosurgeon can become lost and fail to find a lesion. The deeper the lesion sits in the white matter, the higher the risk. When analyzing MR-images preoperatively, several important anatomical landmarks should be recognized and, thereafter, used in planning of the surgical trajectory. Among these are - coronal and sagittal suture, external auditory meatus, nasion, and inion, as well as such intracranial structures as Sylvian fissure, sulcal and gyral key points (e.g. central sulcus and precentral gyrus), superior sagittal venous sinus, transversal sinus, prominent superficial veins (vein of Troland and vein of Labbe), and torcular Herophilii. The first group helps to delineate the approximate location of the lesion and extrapolate it to the surface of the skull for appropriate craniotomy. The second group facilitates orientating after dural opening. Functional MRI and diffusion tensor imaging (DTI) are invaluable in mapping the eloquent cortex and neural tracts, respectively. CT- or MRI-navigated craniotomy is a major adjunct that can aid in intraoperative localization [279]. However, intraoperative brain shift after craniotomy and CSF removal may significantly decrease the accuracy of the navigation system [78, 255]. In these cases, real-time ultrasonography, especially in conjunction with neuronavigation, is particularly useful for lesions that show no surface extensions [46, 165, 311, 323]. Due to achievements in radiological diagnostics and mapping, awake-craniotomy is not necessary. After craniotomy and dural opening, dissection of the cortex is performed through the overlying gyrus or sulcus. The transsulcal approach has been suggested to minimize cortical damage and to

31 expose the lesion in a “keyhole” fashion [69, 124]. Because the cortex is thicker over the crest of a convolution and thinner at the depth of a sulcus, the transgyral approach sacrifices a larger number of neurons than the transsulcal approach [249]. However, disruption of the arcuate U- fibers during transsulcal exposure is not proven to be less detrimental than disruption of vertical projection fibers after the transgyral approach [124, 249, 279]. Meticulous dissection of the arachnoid with sufficiently long preparation of the vessels crossing or lying within the sulcus is crucial to avoid their over-traction, stretching, or kinking, with subsequent ischemic injury to the adjacent or remote cortex. When a patient is operated on soon after overt bleeding, entry to the hematoma provides an initial route to the lesion. Otherwise, appearance of yellowish discoloration indicates an underlying cavernoma. When the lesion is approached, the gliotic plane is identified and circumferential dissection around the lesion is performed until it is free [319]. En bloc resection is recommended, although removal in piece-meal fashion is also suitable since cavernomas do not tend to cause any major intraoperative bleeding [279]. Dural-based cavernomas in the middle fossa are an exception: they may cause profuse bleeding during resection and therefore require careful handling in terms of avoiding damage to the integrity of the nidus [319]. The resection bed should be carefully inspected under high magnification for small satellite lesions [319]. Gliotic fringe discolored by blood breakdown products should be removed only when a lesion is located out of eloquent areas. The extent of resection of perifocal hemosiderotic parenchyma still remains controversial for cure or prophylaxis of epileptic disorder. Casazza et al. and Zevgaridis et al. failed to find any correlation of extended resection of the perilesional parenchyma with better seizure outcome, whereas the more recent studies by Hammen et al. and Baumann et al. confirmed its efficacy during long-term follow-up [24, 25, 44, 122, 347]. After removal of the perifocal parenchyma, precise hemostasis is performed using bipolar coagulation with minimal voltage to avoid inadvertent injury to normal vasculature. Cavernomas of the brain stem represent one of the most challenging neurosurgical pathologies requiring thorough knowledge of the functional anatomy of the region and superior dexterity of the operating surgeon. The decision to perform surgical removal in these patients is mainly based on the number of previous hemorrhages, neurological status, and precise localisation of the lesion with regard to the fourth ventricle or CSF cisterns [267]. Traversing of even a very thin fringe of healthy tissue between the lesion and brain stem surface during the approach may lead to devastating deficits. Risk of postoperative deterioration may be similar to having an overt hemorrhage from cavernoma [236]. A more favorable outcome is expected when a cavernoma extends to the pial surface and myelotomy is not necessary or only minimal [236]. Summarizing their recent experience of brain stem cavernoma surgery, Garrett and Spetzler recommended a supracerebellar infratentorial or lateral supracerebellar infratentorial approach for lesions involving the posterior or posterolateral midbrain [99]. To access lesions involving the anterior or

32 anterolateral midbrain, a full or modified orbitozygomatic craniotomy is recommended [99, 177, 342]. Lateral and anterolateral pontine lesions may be safely reached using the retrosigmoid approach. A safe entry zone, located between the fifth cranial nerve and the corticospinal tracts provides a reasonable pathway to the lesion of the anterior pons. A posterior pontine and posterior medullary cavernoma abutting the floor of the fourth ventricle is best approached via a suboccipital craniotomy, whereas lateral and anterolateral medullary lesions are reached using a far-lateral suboccipital approach [99]. Use of neurophysiologic intraoperative monitoring (IOM) during brain stem surgery is widely accepted as a remarkable adjunct to minimize surgical complications and improve outcome [112, 207, 236]. Brainstem auditory evoked potentials (BAEP), somatosensory evoked potentials, mapping of cranial nerve nuclei, free-running electromyography, and muscle motor evoked potentials are a neurosurgeon’s armamentarium to identify motor and sensory tracts and cranial nerve nuclei [83, 236, 262]. When a cavernoma is large and/or hemorrhage causes significant mass-effect with displacement of the tracts and nuclei, superficial anatomical landmarks, such as the facial colliculus or the stria medullaris, are not concordant with the presumed location of intrinsic structures [203]. In these situations, IOM is needed since it allows with a high degree of probability identification of the safest entry point to the brain stem and avoids disintegration of the tracts and nuclei. However, in rare cases, false-positive and false-negative responses are observed, and the correlation between IOM and postoperative outcome may not be totally accurate [77, 103, 262].

Radiotherapy In several reports, patients with higher surgical risks were considered for treatment with stereotactic radiosurgery (SR) [6, 47, 133, 134, 161, 179, 184]. The mechanism of response to radiosurgery is thought to be a chronic inflammatory process, including endothelial cell proliferation, vessel wall hyalinization and thickening, and eventual luminal closure with a latency interval ranging from two to three years [161]. Mainly, SR is performed on patients with cavernomas located in the brain stem, basal ganglia or highly eloquent cortex. Minimal invasiveness and short hospitalization time allow SR to be performed on patients of every age group, regardless of general condition and comorbidities. In 2010, Lunsford et al. published their pioneering experience on 103 patients who were estimated to have a high risk of resection and were treated with SR between 1988 and 2005 [184]. The authors reported a convincing reduction of hemorrhage rate from 32.5% to 1.06% in two years after SR. They emphasize the role of proper selection of patients suitable for SR of cavernomas located in high-surgical-risk areas. In analyzing the effect of SR on epileptic activity, Hsu et al. demonstrated that 13 of 14 patients (92.8%) had favorable seizure outcome after the procedure [133]. However, Shih and Pan had

33 provided both SR and microsurgery to 30 patients suffering from epilepsy and discovered a significant advantage of surgical removal in terms of epilepsy treatment; 79% of surgically treated patients were seizure-free, whereas only 25% of patients after SR showed the same outcome [281]. Pham et al. conducted an extensive literature review of SR treatment of cavernomas and found that of the 291 patients in the 16 studies, 66% had favorable seizure outcome (31% were seizure-free, and 36% had reduced of seizure rate), while 11 patients (3.8%) experienced worsening of epilepsy [231]. Sex, age, and duration of epilepsy had no prognostic value, whereas extratemporal location and history of only simple partial seizures was related to better seizure outcome. Summarizing their results, the authors noted at least a 25% response rate to SR, demonstrating a potentially true effect on epileptic activity as an alternative to surgery [231]. Despite the above-mentioned advantages, the efficacy of SR over the long term is debatable. An irradiated cavernoma still remains in the brain, and in contrast to AVMs, the effect of SR on intralumenal blood flow cannot be objectively confirmed by any reliable radiological investigation. Furthermore, morbidity rates range from 2.5% to 59% and mortality ranges from 0% to 8.3% [231]. Radiation-induced complications include edema, necrosis, increased seizure frequency, and recurrent bleeding [4, 133, 294]. Expectedly, greater dosimetry is associated with a higher risk of complications [231]. Location in the brain stem seems to be unfavorable in terms of radiation-induced complications; among 82 patients treated with SR, Hasegawa et al. described complications only for lesions located in the brain stem [127]. The overall rate of complications reported in the literature for brain stem cavernoma SR ranges from 8% to 18% [82, 178, 231]. The underlying mechanisms explaining development of adverse radiation effects (ARE) with clinical deterioration are not fully understood. Hypothetically, AREs are related to radiation dose delivered to the brain tissue immediately surrounding the cavernoma, which may be more likely to release vasoactive cytokines from an iron-impregnated gliotic brain [184]. Of note, AREs occur in cavernoma patients at a seven times higher rate than in AVM patients [148, 234]. Summarizing their experience on the SR of cavernomas, Karlsson et al. concluded that only some protection against hemorrhage after SR is not sufficient to accept the high risk for radiation- induced damage of the brain [148]. Furthermore, in 2006, Shahid et al. conducted a literature review on de novo formation of cavernomas after radiation therapy and found 76 patients – most of them children - with different pathologies of the CNS who developed de novo cavernomas [209]. The mean latency period was 8.9 years and the mean radiation dose 60.45 Gy. Although radiation dosage during SR is usually lower (mean maximal dose range 18 – 50 Gy [231]), de novo cavernomas appearance is plausible in terms of additional risks in delayed postradiation period, especially in younger patients.

34 Uncommon cavernomas Several subsets of cavernomas occur rarely, and literature on the topic is thus scarce. Many questions regarding these entities still have no answers or are under debate. To date, there is no explanation in the literature why cavernomas are commonly located supratentorially, accounting for 70% of all lesions, but affect the spine very rarely. Furthermore, what limits the size of the lesion and why gigantic lesions are extremely rare are not fully understood. The growing number of patients with incidentally found lesions tends to increase the number of patients with lesions previously considered rare. A clearer understanding of the basic pathological features and treatment results of these cases is essential when making clinical decisions and planning management adequately. Among unusual cavernomas treated at our department, we analyzed intraventricular, multiple and spinal cavernomas; we supplemented these with a literature review.

Intraventricular Cavernomas Patients and symptoms Intraventricular cavernomas constitute 2.5 - 10.8% of cerebral cavernomas [180, 282, 321]. The first report of IVC was introduced in 1905 by Finkelburg [92], and so far, altogether 77 cases have been published excluding our series (Table 4). The mean age of these patients was 35.5 years (range 2 days – 73 years). Twenty-one patients (27.3%) were younger than 18 years and only two patients (2.6%) were older than 65 years. The female : male ratio was 1.4: 1 (Table 5). In 38 patients (49%), IVC was located in the lateral ventricle, in seven patients (9%) in the fourth ventricle, and in 32 patients (42%) in the third ventricle. The histological origin of IVC still remains obscure. Chadduck et al. hypothesized that IVCs have subependymal origin and grow inside the ventricle [45]. Kumar et al. noted in their three cases of IVC that lesions were adherent to the ependyma only in some areas and connected this appearance to repeated hemorrhages, organization, and gliosis [164]. In contrast, Nieto et al. confirmed during surgery on their patients with ICV that cavernomas were independent, not attached to the ependymal layer and without prominent feeding arteries and draining veins [208]. The course of IVCs seems to be relatively benign but their natural history is different from intraparenchymal lesions. This could be explained be the fact that the surrounding CSF allows to increase in size of the cavernoma without restrictions from the parenchyma [208]. Histological profile of the IVC seems to be similar to intraparenchymal cavernomas confirming the role of environmental factors affecting natural history of the IVC.

35 Table 4 Published series on IVCs

Case Sex Age,yrs First author Year Location Treatment Outcome

1 M 2 Finkelnburg [92] 1905 fourth ventricle partial resectiol died 2 M 31 Dandy[66] 1928 fourth ventricle total removal improved 3 F 16 Merritt[198] 1940 lat.ventricle total removal comatose 4 M 2d Arnstein[12] 1951 lat.ventricle no surgery died 5 F 68 Latterman[173] 1952 third ventricle no surgery died 6 F 33 Schneider[276] 1958 lat.ventricle total removal homonymous hemianopsia 7 M 15 Jain[139] 1966 lat.ventricle total removal improved 8 F 36 Coin[58] 1977 lat. ventricle total removal hemianopia 9 M 43 Numaguchi[212] 1977 lat.ventricle total removal hemiplegia and hemianopia 10 M 27 Giombini[104] 1978 fourth ventricle partial resection died

11 F 29 Terao[300] 1979 fourth ventricle total removal improved

12 nd 56 Pau[226] 1979 lat.ventricle no surgery died 13 F 45 Namba[206] 1979 lat.ventricle partial resection improved 14 F 18 Vaquero[315] 1980 third ventricle total removal improved 15 F 31 Pozzati[241] 1981 third ventricle total removal improved 16 F 8ds Iwasa[138] 1983 lat.ventricle total removal improved 17 F 60 Kendall[152] 1983 fourth ventricle partial resection recurrence of symptoms 18 F 48 Lavyne[174] 1983 third ventricle partial resection hydrocephalus, bleeding 19 M 40 Amagasa[5] 1984 third ventricle total removal improved 20 F 44 Harbough[123] 1984 third ventricle total removal improved 21 F 21 Chadduck[45] 1985 lat.ventricle total removal hemianopia 22 F 29 Chadduck[45] 1985 lat.ventricle total removal improved 23 F 4mo Chadduck[45] 1985 lat.ventricle total removal improved 24 M 22 Simard[282] 1986 lat.ventricle not registered not registered 25 F 13 Simard[282] 1986 lat.ventricle not registered not registered

26 M 73 Yamasaki[335] 1986 lat.ventricle total removal improved 27 M 9 Yamasaki[335] 1986 third ventricle partial resection improved 28 M 36 Yamasaki[335] 1986 third ventricle total removal improved 29 M 47 Yamasaki[335] 1986 fourth ventricle total removal improved 30 M 40 Suzuki[292] 1988 lat.ventricle total removal improved 31 M 9mo Sabatier[261] 1989 lat.ventricle no surgery cerebellar dysfunction 32 F 19 Voci[320] 1989 third ventricle total removal improved 33 M 16 Ogawa[213] 1990 third ventricle total removal, shunt improved 34 M 40 Ogawa[213] 1990 third ventricle total removal transient diabetes insipidus, hemianopia 35 F 62 Andoh[8] 1990 lat.ventricle total removal homonymous quadrantanopsia

(continued)

36 Table 4 Published series on IVCs (continued)

36 M 33 Tatagiba[297] 1991 lat.ventricle total removal improved 37 M 35 Tatagiba[297] 1991 lat.ventricle total removal died

38 F 24 Tatagiba[297] 1991 lat.ventricle total removal improved 39 F 44 Itoh[137] 1991 fourth ventricle total removal improved 40 F 3 Miyagi[200] 1993 lat.ventricle total removal mild hemiparesis 41 F 39 Lynch[185] 1994 lat.ventricle partial resection improved

42 M 5 Lynch[185] 1994 lat.ventricle partial resection improved 43 F 10 Lynch[185] 1994 lat.ventricle total removal improved 44 F 9 Katayama[149] 1994 third ventricle partial resection, shunt died 45 F 50 Katayama[149] 1994 third ventricle not registered not registered 46 F 45 Katayama[149] 1994 third ventricle not registered not registered 47 M 49 Katayama[149] 1994 third ventricle not registered not registered 48 F 47 Katayama[149] 1994 third ventricle total removal transient diabetes insipidus 49 F 43 Sinson[285] 1995 third ventricle total removal died 50 F 36 Sinson[285] 1995 third ventricle total removal hemiparesis, hypothyroidism, hydrocephalus 51 F 52 Sinson[285] 1995 third ventricle total removal improved 52 F 32 Sinson[285] 1995 third ventricle total removal, shunt improved 53 M 2ds Hashimoto[129] 1997 lat.ventricle total removal, vp-shunt mild mental retardation 54 M 64 Kaim[146] 1997 third ventricle total removal not registered 55 F 44 Gaab[98] 1999 lat.ventricle total removal permanent memory loss 56 F 16 Reyns[247] 1999 lat. ventricle total removal improved 57 M 36 Reyns[247] 1999 lat.ventricle total removal right hemihypertonia 58 M 42 Reyns[247] 1999 third ventricle partial resection improved 59 F 15 Fagundes-Pereyra[87] 2000 lat.ventricle total removal improved 60 F 36 Suess[290] 2002 third ventricle total removal improved 61 M 38 Crivelli[62] 2002 third ventricle total removal improved 62 F 11 Nieto[208] 2003 lat.ventricle total removal homonymous hemianopsia 63 F 17 Tatsui[298] 2003 lat.ventricle total removal improved 64 M 52 Tatsui[298] 2003 lat.ventricle total removal improved 65 F 62 Wang[328] 2003 third ventricle total removal improved 66 F 45 Andersson[7] 2003 septum pellusidum, total removal improved lat.ventricle 67 F 47 Darwish[68] 2005 third ventricle total removal,shunt improved 68 M 56 Milenkovic[198] 2005 third ventricle total removal improved 69 F 51 Chen[50] 2006 third ventricle total removal improved 70 M 8 Kumar[164] 2006 lat.ventricle trigonum total removal improved 71 F 19 Kumar[164] 2006 lat.ventricle trigonum total removal improved, seizures 72 M 20 Kumar[164] 2006 lat.ventricle trigonum total removal improved 73 M 35 Longatti [181] 2006 third ventricle total removal improved (continued)

37 Table 4 Published series on IVCs (continued)

74 M 8 Zakaria[344] 2006 third ventricle total removal improved 75 F 47 Sato[273] 2006 third ventricle total removal improved 76 M 25 Gonzalez-Darder [108] 2007 lat. ventricle, trigone total removal improved 77 nd 56 Prat [242] 2008 third ventricle total removal improved

Katayama et al. reviewed 14 cases of IVC of the third ventricle and found that IVC at this location are prone to rapid growth [149]. Furthermore, authors noted that incomplete surgical remove can exacerbate extensive growth after long period of being stable [5, 213, 335]. Surgical or autopsy findings suggested that such growth may be attributable to repeated intralesional hemorrhages rather than to confluence of vascular channels [213]. Almost all patients with IVC had experienced intermitting headaches, which may be related to repetitive intralesional hemorrhages with consequent enlargement and rising of intracranial pressure. IVCs frequently cause symptoms due to their mass-effect, which is more prominent in the third ventricle. Hydrocephalus in these patients is not uncommon. The majority of patients with IVC who have had a third ventricle lesion developed hydrocephalus because of mechanical obstruction, and only three patients [123, 149, 320] showed no signs of raised intracranial pressure suffering only from intraventricular hemorrhage (IVH).

Table 5 Baseline data on reported cases of Characteristics No. of patients (%) IVCs

M:F ratio 1:1.4 Location Lesions of this location could cause memory lateral ventricle 38 (49) fourth ventricle 7 (9) loss, behavioral alterations such as depression, third ventricle 32 (42) Clinical presentation and endocrinological disorders such as diabetes IVH 11 (14) Mass-effect 53 (69) mellitus, sexual dysfunction, and Morgagni’s Seizures 11 (14) Incidental 2 (3) syndrome (frontal hyperostosis accompanied by Treatment modality hirsutism and obesity) [149, 173, 174, 213, Surgical removal 68 (88) Conservative 4 (5) 241], whereas seizures are very uncommon, Not defined 5 (7) Outcome occurring in only one reported case [149]. Improved 45 (58) Persistent deficit 18 (24) Clinical manifestations are related to the Died 8 (10) Not defined 6 (8) location within the third ventricle. Lesions in the suprachiasmatic region tend to cause visual field restriction or endocrine dysfunction,

38 whereas cavernomas involving the lateral wall or floor of the ventricle can affect short-term memory functions [181]. There are observations showing enlargement of cavernomas during pregnancy and shrinkage after delivery [335, 345]. Some authors believe that cavernomas in the third ventricle could be under stronger hormonal influences because of their location [149], but no data exist to confirm this. The location of a cavernoma in the lateral ventricle is also frequently associated with raised intracranial pressure. In 22 of 38 cases (58%) with lateral ventricle cavernomas reported in the literature, patients suffered from mass-effect and hydrocephalus as leading symptoms. Ten patients (13%) with this location had seizure history. The nature of the seizure activity of lateral ventricle IVCs is not described in the literature. Unlike intraparenchymal lesions, due to their location inside the ventricle IVCs do not extensively affect parenchyma with abundant hemosiderosis (Figure 8). However, Tatagiba et al. noted that subependymal origin of the IVCs seems to corroborate with epileptogenicity, as they affect parenchyma not only by mass-effect but also by their local irritating influence on parenchyma [297]. By contrast, Nieto et al. claim that IVCs in the trigonum, thus potentially irritating the hippocampus, should cause a higher incidence of seizures, which is not supported by clinical evidence [208].

Figure 8 Coronal view of a lateral ventricle cavernoma. No extensive hemosiderosis can be seen (arrow)

The least common location of IVCs was reported to be the fourth ventricle, with only seven cases published [66, 92, 104, 137, 152, 300, 335]. In six patients (85.7%), cavernomas caused mass-effect. These patients suffered from sensorimotor paresis in the extremities [66], drop attacks [104], diplopia and ataxia [152, 335], and dysartria [137]. All patients with fourth ventricle lesions experienced intermittent headaches frequently accompanied by nausea and vomiting. In total, 11 of 77 patients (14%) with IVC presented with intraventricular hemorrhage (IVH) (Table 5). In three cases (27.3%), IVH occurred from an IVC located in the third ventricle [123, 149, 320], in six patients (54.5%) from an IVC located in the lateral ventricle [200, 206, 226, 261, 297], and in two patients (18.2%) from an IVC located in the fourth ventricle [137, 300]. The annual rate of hemorrhage from IVCs is not precisely known due to limited data in small series. Typically, IVH was accompanied by severe headaches, frequently leading to

39 hospitalization. In some cases, hemorrhages recurred until the lesion was removed [300]. Usually, IVH was tolerated well and caused no disastrous consequences. However, in one case, a lesion located in the temporal horn of the lateral ventricle caused severe intraventricular bleeding and intracerebral hematoma [226]. This was the only patient who died after extralesional hemorrhage from IVC.

Radiology On CT images, IVCs present with moderate hyperintensity showing mild contrast enhancement and moderate signs of mass-effect [50]. In patients with acute onset of symptoms, CT scan is mandatory because of its high sensitivity in detecting fresh hemorrhages. In acute intraventricular bleeding, however, the radiological diagnosis of the IVC is unreliable, and MRI is more informative later after resorption of extravasated blood. The typical appearance on MRI is with a heterogeneous core, reflecting different stages of thrombus organization, but a perifocal hypointensive rim representing hemosiderosis is frequently absent. However, in lesions with subependymal origin, a hemosiderotic fringe could be detected [146]. Edema surrounding the IVC is unusual and, if present, mild [50]. Due to the rarity of the disease, a radiological misdiagnosing of IVC is not uncommon. An IVC can be interpreted as an intraventricular choroid plexus papilloma, a trigonum meningeoma, or an ependymoma (Table 6). IVCs do not increase CSF secretion per se, which may be useful in the differential diagnostics of CSF-secreting choroid plexus papillomas in a similar location [208]. Furthermore, IVCs have a reported tendency to rapid growth [149], which should be taken into account when differentiating the IVC from benign trigonum meningeomas, which are typically slow-growing tumors. Intraventricular ependymomas usually occur in children, whereas IVCs are more typical in adults [297].

Table 6 Differential diagnostics of IVCs

Third Ventricle Lateral Ventricle Fourth Ventricle

low-grade and high-grade gliomas low-grade and high-grade ependymoma gliomas subependymal giant cell astrocytoma medulloblastoma subependymal giant cell astrocytoma central neurocytoma pilocytic astrocytoma choroid plexus papilloma (carcinoma) colloid cyst choroid plexus papilloma meningeoma (carcinoma) papillary craniopharyngeoma metastases meningeoma metastases metastases

40 Treatment and operative techniques The lack of thorough prospective series and long-term follow-up studies makes decision-making in the treatment of IVCs difficult. Surgery is advocated when re-hemorrhages are frequent, and the mass-effect causes progressive neurological deficits. When estimating the operative risks, the location of IVCs is of major importance. Surgery on the IVC in the lateral and third ventricle is safer than in the fourth ventricle. In cases of acute hydrocephalus, temporary external ventricular drainage was usually applied before surgical excision of the lesion, and in five reported cases (6%) a permanent shunt was indicated [68, 128, 149, 213, 285]. In this group, the cavernoma was in the third ventricle in four patients, and one newborn had a giant lesion in the lateral ventricle. Patients with cavernomas close to the brain stem frequently present with cranial nerve deficits. Thus, surgery on this already affected region can worsen neurological status and cause new deficits, even after minimal manipulation. However, these deficits have significant recovery potential, and many of them improve after a long recovery period [267]. Removal of a cavernoma located in the lateral ventricle may be performed via several approaches, but all through the parenchyma (Table 7). D’Angelo et al. performed a thorough analysis of transcortical and interhemispheric approaches for lesions in the lateral ventricles and they found that an irreversible visual field deficit occurred after surgery in one of 14 patients after a transtemporal approach and in one of seven patients after a transparietal approach [67]. Furthermore, in anatomic investigation of the optic radiation in relation to the operative route to lesions of the trigonum, some authors recommend an interhemispheric parieto-occipital approach with a mesial entry point located anterior to the calcarine and parieto-occipital sulci and posterior and inferior to the parietal lobule [187]. By using the suggested corticotomy, the authors avoided any disruption of the optic radiation. In the series of D’Angelo et al., two of four patients operated on with an interhemispheric posterior transcallosal approach developed transient mutism. However, neuropsychological tests assessing attention, verbal memory, and disconnection showed no correlation with any of the surgical approaches. Instead, there were correlations with preoperative clinical condition and a presumably longer or chronic history of hydrocephalus [67]. Among drawbacks associated with transcortical approaches, the most common appear to be postoperative seizures and intracerebral hemorrhage. The reported risk of postoperative seizures after transcortical approaches ranges from 29% to 70%, whereas the respective figure after transcallosal approaches is only up to 10% [13, 26, 151, 172, 352]. Among IVC patients, we found no cases with postoperative seizures but two patients had developed a postoperative hydrocephalus [174, 285]. IVC in the third ventricle can be exposed via different approaches tailored to the site of the lesion inside the ventricle. Lesions located in the region of the foramen Monroe and anterior third of the

41 ventricle are exposed using an anterior interhemispheric transcallosal approach, a pterional transsylvian approach [336], or alternatively, a transchoroidal transvelum interpositum or interforniceal approach [11]. The latter two modifications carry additional risks of transient memory loss and hemiparesis due to the manipulation and possible damage to the fornix or

Table 7 Surgical approaches to IVCs

Location Approach Reference

Lateral venticle

Frontal horn and ventricle body anteroinferior or anterosuperior transcallosal [13, 26, 275] transcortical through the middle frontal gyrus

Trigonum, occipital and temporal - transcortical through superior parietal gyrus [106, 228, horn - transcortical through parieto-occipital fissure 243, 248, - interhemispheric parieto-occipital parasplenial 279, 301, - occipital interhemispheric transsplenial 336, 338] -transcortical-transtemporal through the middle and inferior temporal gyri - transoccipitotemporal approach

Third ventricle Anterior third and foramen Monroe - anterior interhemispheric transcallosal [11, 213, - pterional transsylvian 336, 340] - transchoroidal transvelum interpositum - interforniceal aproaches - interhemispheric translamina terminalis

Mid-third - subchoroidal transvelum interpositum [174, 336] - interhemispheric transcallosal - pterional transsylvian

Posterior third - median or paramedian supracerebellar suboccipital [336] - posterior parieto-occipital interhemispheric

Fourth ventricle - median inferior suboccipital craniotomy [137, 336] - through cerebello-medullary fissure (telovelar) - transvermian thalamostriate vein [11, 336]. Lavyne and Patterson accessed a lesion in the mid-third ventricle via a subchoroidal transvelum interpositum approach, but only partial resection could be accomplished and this patient experienced postoperative bleeding [174]. Yoshimoto and Suzuki excised cavernomas of the suprachiasmatic compartment via an interhemispheric trans-lamina- terminalis approach [340]. The same approach was successfully employed for removal of foramen Monroe cavernomas by Ogawa et al. [213]. A lesion located in the posterior third of the ventricle is accessed via a median or paramedian supracerebellar suboccipital approach or a

42 posterior parieto-occipital interhemispheric approach [336]. Exposure of the fourth ventricle is usually performed via median inferior suboccipital approach. After craniotomy and dural opening, the fourth ventricle is accessed using a transvermian or cerebello-medullary fissure (telovelar) approach [336]. The latter is preferable as division of the vermis can be associated with cerebellar mutism, especially in children [233]. Itoh et al. performed an incision of the posterior part of the vermis and observed ataxia in the immediate postoperative period, but after one month all symptoms resolved fully [137].

Neuroendoscopy To date, only one case of a successful removal of an intraventricular cavernoma by endoscopy has been reported [98]. The role of neuroendoscopy in treatment of IVC seems to be secondary to microsurgery, as in the literature gross total resection of the IVC using endoscopic techniques is significantly limited by ventricle wall collapse, possible bleeding, or ineffectiveness of resection in a piece-meal fashion due to the very firm consistency of the lesion and the narrowness of the device’s working channel [98, 242, 273].

Outcome In the published data, altogether 68 patients (88%) of the 77 patients with IVC were operated on, and 45 patients (58%) improved whereas 18 patients (24%) exhibited persistent neurological deficits at follow-up (Table 5). Seven patients (10%) developed visual field deficits [8, 45, 58, 208, 212, 213, 276]. Only one of these patients had a lesion in the third ventricle [213], whereas others presented with an IVC in the lateral ventricle. Four patients (6%) suffered from sensorimotor deficits after surgery [200, 212, 247, 285], three patients (4%) with a third ventricle lesion developed endocrinological disorders (in two transient diabetes mellitus and in one hypothyroidism) [149, 213, 285]. One newborn with a lateral ventricle cavernoma operated on at the age of two days developed hydrocephalus, and a ventriculoperitoneal shunt was placed [128]. At follow-up, the patient had mild mental retardation. In one case, reported by Gaab, a patient with lateral ventricle lesion had postoperative memory loss, which did not resolve during the 19- months follow-up of [98]. In total, eight patients died (10%), and, notably, five of them (7%) after surgical treatment [92, 104, 149, 285, 297]. In a case reported by Katayama et al., a cavernoma of the third ventricle demonstrated extensive re-growth after incomplete resection followed by hydrocephalus and diencephalic compression and ischemia [149]. Tatagiba et al. described a patient with a trigonal cavernoma that was removed completely, but after two weeks the patient developed intractable status epilepticus and died. The postmortem revealed diffuse brain edema, transtentorial herniation, and sinus thrombosis [297]. Another patient with a third ventricle cavernoma reported

43 by Sinson et al., became comatose eight days after surgery [285]. On CT, the ventricles were slightly enlarged, and a ventriculostomy was inserted. Despite this, the patient remained unchanged and died two months later. In Finkelburg’s case, a cavernoma was not found after surgical exploration of the posterior fossa and fourth ventricle, and the patient died from hydrocephalus [92]. Giombini et al. had a patient with a small cavernoma of the fourth ventricle, which was exposed but not actually excised [104]. This patient received irradiation to the posterior fossa, but died suddenly two months later. An autopsy confirmed a cavernoma hemorrhage.

Multiple cavernomas Patients and natural course The first report on MCs was published in 1899 by Ohlmacher, who found three brain cavernomas at an autopsy of a patient with intractable epilepsy [216]. Data on the frequency of MCs among cavernoma patients, ranging from 6% to 14.4%, have varied due to an increasing number of series including asymptomatic patients [104, 218, 321]. Russel and Rubinstein reported the proportion of MC to exceed 25% [259]. In an analyzis of a consecutive series of 8.131 craniospinal MRIs performed in a single medical center, six (18.7%) of the 32 patients with cavernomas had multiple lesions [71]. In a clinical study by Rigamonti et al., in which ten patients were investigated and imaged with MRI, 50% had familial MCs [253]. Furthermore, in 1994 Zabramski et al. performed a comprehensive study on six families afflicted by cavernomas and found that 26 of 31 patients (84%) had MCs [343]. Ten years later, in a cavernoma review, Zabramski et al. found that more than 80% of patients with three or more lesions had a history consistent with the familial form of the disease [341]. Special attention was paid to families of Hispanic origin, as they seem to have inherited cavernomas [118, 130, 341, 343]. Clinical observations were strengthened by genetic analyses, performed by Günel et al., with the discovery of the founder 7q chromosome gene mutation responsible for cavernoma formation in this ethnic group [116, 118]. Further investigations revealed two more genes (CCM2 and CCM3) involved in cavernoma formations [60, 232]. While no exact data exist on gender distribution among MC patients, some women preponderance has been noted [246]. The mean number of lesions is reported to be 5.8-7.1 per patient [150, 168, 343]. Up to 85% of these cavernomas are supratentorial. Clinical manifestations of MCs seem to be independent of the number of lesions in a particular patient [37]. Macro- and microscopic appearances of MCs are the same as in sporadic solitary cavernoma cases.

44 Symptoms The clinical picture of MCs may vary significantly depending on the location, size, and history of hemorrhage. It is not unusual that some lesions are symptomatic while others demonstrate no clinical manifestations. In the clinical picture of multiple cavernoma patients, no pathognomonic features can be noted. MCs usually cause the same symptoms as single cavernomas, but due to the multiplicity some distinguishing differences in their behavior are evident:

Epileptic disorders Mechanisms of seizure activity in patients harboring MCs are more complex than those of patients with single epileptogenic cavernomas. Any of the multiple focuses may contribute to epileptogenesis [14]. In the recent study of Rocamora et al., the authors reviewed data on 11 patients with MCs who suffered from drug resistant epilepsy (DRE) [257]. The authors noted that epileptogenicity was not dependent on the size of the lesion or the distance to limbic structures. In fact, the largest cavernoma was involved in the generation of seizures in only 54% of patients [257]. The authors emphasized that active treatment should be initiated early after diagnosing DRE. When lesions are located close to each other, the epileptogenic activity on EEG situated to this particular zone is independent of cavernomas size or hemorrhagic events. Furthermore, the coexistence of MCs and hippocampal sclerosis, known as dual pathology, should also be taken into account in the diagnostic work-up of these patients [14, 257]. In such a situation, identification of the true primary epileptogenic focus is difficult, and resection of the presumed epileptogenic cavernoma without additional temporal resection fails to control epilepsy. Identification of the epileptogenic focus in MC patients often requires extensive neurophysiologic investigations, as resection of the wrong lesion will not only be useless in controlling epilepsy but may result in devastating functional sequelae when the remaining epileptogenic lesion is located in the contralateral temporal or frontal lobe [14]. Interictal sporadic EEG is not a reliable tool to localize a focus in this group of patients. Long-term video-EEG monitoring is indicated with partial or total discontinuation of AED [257]. Functional MRI, WADA-test, and neuropsychological evaluation are valuable adjuncts to lateralize memory and speech centers when additional temporal resection is planned. Among new non-invasive technologies, magnetoencephalography (MEG) has been addressed to be useful in revealing the complexity of the case, contributing to decision-making upon further invasive diagnostic methods [287]. In controversial cases, invasive electrocorticography is warranted to precisely depict the area of epileptogenicity and to perform a tailored resection.

45 Figure 9 Acute extralesional bleeding of periventricular cavernoma in patient with MCs.

a – axial view; b – sagittal view

a b Hemorrhage Symptomatic hemorrhage in patients with MCs is not uncommon as up to 32% of patients present with hemorrhage (Figure 9) [37, 104, 254, 256]. The annual rate of bleeding ranges from 0.25%-16.5% per patient-year or, if considering the mean number of lesions in one person, 0.1%- 2.5% per lesion-year [71, 169, 256, 343]. Similar to single sporadic cavernomas, MCs within the infratentorial compartment tend to bleed at higher rates. Labauge et al. in their retrospective study measured that supratentorial cavernomas bled at a rate of 1.9% per lesion-year whereas in infratentorial cavernomas bleeding rate increased to 5% per lesion-year [169]. In this report, hemorrhage was identified in 32% of type I lesions, in 14% of type II lesions and in only 2.8% of type III lesions. Type I cavernomas carried the greatest risk to bleed, although type III lesions also presented with extralesional hemorrhage. No correlation with size of the lesion, younger age, or gender was discovered [169]. Zhao et al., in their report on MCs, stated that pathological investigations of cavernomas in a group of MCs revealed signs of frequent intralesional hemorrhages, thereby confirming aggressiveness of this disease [350]. Labauge et al., in 2001, performed a prospective analysis of asymptomatic patients with 85% having MCs and found a hemorrhage rate of 4.3% per patient-year or 0.7% per lesion-year [168]. This finding confirms that hemorrhage potential of a particular lesion in patients with MCs is the same as in single sporadic cavernomas, with overall bleeding risk accumulating according to the number of cavernomas.

46 Other symptoms Headaches are a common complaint in MC patients, occurring in up to 52% of cases [37, 343]. Due to the unspecific nature of headache, its true incidence in cavernoma patients is impossible to delineate. They frequently accompany hemorrhages, being characterized by acute exacerbation with gradual decrement. When patient with MCs has a lesion in the ventricle or close to the CSF outflow pathway, headaches may be considered in the framework of symptoms related to raised intracranial pressure. Focal neurological deficits are common manifestations of lesions located in the brain stem or eloquent cortex (Figure 10). They occur in MCs at the same rate as in single sporadic cavernomas and correspond to the affected region.

Figure 10 Posterolateral pontine cavernoma in patient with MC causing progressing hemiparesis

In some reports on MCs, the authors have noted a pronounced tendency of affected patients to present with psychocognitive alterations [150, 350]. In the report of Kattapong et al., 9 of 29 patients (31%) were afflicted by depression or some other psychiatric disorders [150]. Some authors described a case of severe dementia and parkinsonism in an MC patient [145]. Zhao et al. suggested that multiple degenerations due to repetitive microhemorrhages into the surrounding parenchyma may explain this distinguishing feature, which is very rarely observed in patients with single cavernoma [350].

Radiological progression A cavernoma is a dynamic lesion [55, 343]. In MC cases, this feature is strongly pronounced. Based on MRI screening and follow-up, investigators were able to identify obvious alterations in size and number of lesions, and a change in radiological types [55, 168, 169, 343]. Zabramski et al. showed a change in lesion size in 19% of patients, and a change in radiological signal intensity in 38% of patients [343]. The authors hypothesized that these changes are likely to be related to intralesional hemorrhages, with enlargement at the onset of the hemorrhage and shrinking after resolution of the hemorrhage. Furthermore, for the first time, they noted the appearance of de novo lesions at follow-up MRI. They identified new cavernomas in six of 21 patients (29%), yielding a rate of 0.4 lesions per patient-year. According to the authors, de novo lesions may represent the growth of a very small nidus due to capillary proliferation or a focal hemorrhage, or a combination of these two factors [239, 343].

47 In the series of 29 patients of Hispanic origin reported by Kattapong et al., a regression analysis performed to evaluate the relationship of age with number of lesions demonstrated an increase of approximately one lesion per decade [150]. By measuring the mean diameter of the lesions, the investigators noted a mean reduction in size from 15.7 mm in the first decade to 5 mm in the seventh decade, with a mean decrease of 1.7 mm per decade. Based on these data, the authors had argued for a concept of more aggressive course in Hispanic patients, which was shown in previous reports [150]. Multicenter studies in non-Hispanic patients performed in France supported this argument. In 2000, Brunereau published an analysis of MR findings in 51 families afflicted by the familial form of cavernomas where 83 patients were symptomatic and 73 were asymptomatic [37]. Among symptomatic patients, 83% had MCs, and among asymptomatic patients 78% had MCs. The authors found a significant increase in the number of lesions with increasing age in both groups, especially in type II and III cavernomas. A more rapid increase was detected after the age of 50 years [37]. One year later, Labage et al. published their remarkable work in which they prospectively followed 33 asymptomatic patients with familial cavernomas [168]. Mean follow-up time was 2.1 years (range 0.5 -4.5). In this series, 28 of 33 patients (85%) had MCs. The average number of lesions was 7.1 per patient. All but two patients had clinical and MRI examinations during the second year of follow-up. During the follow-up two patients (6%) became symptomatic. The authors found the risk of bleeding to be 4.3% per patient-year (0.7% per lesion-year), the rate of changes in size to be 4.3% per patient-year (0.8% per lesion-year), the rate of changing radiological signal intensity to be 1.4% patient-year (0.2% per lesion-year); and the rate of de novo lesions was 0.4% per lesion-year. Investigators noted that 86% of de novo lesions belonged to type IV cavernomas, which are only seen in Gradient Echo MR-sequences [168]. The nature of these lesions has been debated. No surgical specimens can be acquired, as type IV lesions are very small and asymptomatic and therefore should not be removed. Some authors speculate that they can be true cavernomas or capillary teleangiectasis [253]. In 2000, Clatterbuck et al. performed a prospective study on the issue, with a meticulous analysis of MRI data of 68 patients, 25 of whom were affected by MCs [55]. Only 23% of the lesions were stable in volume during the follow-up; 43% increased in volume and 35% decreased in volume. Symptomatic hemorrhage was not a common reason for these volumetric changes, and occurred with a rate of 3.1% per patient-year. Only two patients with MCs in this series had de novo cavernomas.

Surgical treatment and outcome Similar to single cavernoma cases, the role of surgery in MCs is to improve epilepsy outcome and

48 neurological deficits and to eliminate the risk of bleeding. This strategy is effective when a patient has a particular lesion the location and radiological characteristics of which (type I, II, or rarely III) correspond to clinical manifestations, and other cavernomas seem to be clinically silent. In contrast, when many cavernomas have signs of recent intra- or extralesional hemorrhage and symptoms may be caused by any of them, a decision as to which lesion should be removed may be arbitrary. An ideal solution is removal at the same session of all radiologically active lesions located close to each other. However, this is an uncommon situation in clinical practice. When MCs present with epilepsy, a thorough preoperative evaluation is essential to identify a cavernoma, which is responsible for the seizure activity. After localizing a zone of seizure onset, one should be aware of possible secondary epileptogenic foci that can be distant to the primary focus and maintain seizure activity even after total resection of a true epileptogenic cavernoma. In the series of Rocamora et al., evidence of interictal epileptic activity unrelated to zone of seizure onset was registered in 4 of 11 patients (36.4%) who had MCs manifesting with DRE [257]. Although this finding was not suggestive regarding secondary epileptogenic foci, it did show the complexity of epileptogenic mechanisms in MC patients. The authors registered convincing improvement of epilepsy (Engel class 1) at the one year follow-up after lesionectomy with some resection of the hemosiderotic fringe in 9 of 11 patients (81%). At the two-year follow-up, no deterioration was noted. Seizure outcome did not correlate with the number of lesions or preoperative seizure frequency. The authors emphasized the role of de novo lesions in MC patients, which may explain seizure recurrence after primarily successful epilepsy surgery [257]. A policy of AED administration in MC patients is controversial, as the risk of having a seizure seems to continue even after removal of an epileptogenic lesion due to persistence of other lesions or development of de novo cavernomas, especially in persons with a confirmed family history. Thus, close clinical and radiological follow-up is recommended to register any suggestive changes in clinical status and radiological findings [56]. Some authors even recommend to perform a yearly MRI follow-up [229].

Spinal cavernomas Spinal cavernomas are rare lesions. While the incidence is unknown they represent 5 – 12% of all spinal vascular abnormalities [59, 171] and 5-23.9% of all intraspinal lesions in adults [75, 268, 270]. The first published case of a spinal cavernoma was by Hadlich in 1903, who revealed the lesion in the spinal cord at autopsy [121]. In 1999, Zevgaridis et al. published their literature review on 117 spinal cord cavernomas [348]. In this series, only 16 patients before the modern imaging era were reported. With the advent of CT and MRI in everyday clinical practice, the number of publications on this topic has increased dramatically. We analyzed only cases

49 diagnosed and treated using modern imaging and surgical techniques and found 437 patients with spinal cavernomas with the earliest case in the series dating back to 1978 [33] (Table 8). Due to their significant differences in the clinical course and treatment, dividing spinal cavernomas into intramedullary and extramedullary groups is advocated. Published data are presented below accordingly.

Intramedullary cavernomas (IC) Patients and natural course Among the published 427 spinal cavernoma cases, 374 patients (85.6%) had ICs (Table 8). In this group, patients’ mean age was 37 years (range 12 -88 yrs) with a peak occurrence between the third and fourth decades [32]. Some authors report that ICs are two times more common in women than in men [346], whereas many others find no clear gender difference [32, 140, 270]. Histological structure was typical of CNS cavernomas in all cases. There are several studies on the natural course of ICs. Ogilvy et al. published their pioneering work on ICs, introducing the first grading system for clinical manifestations of this disease [214]. The authors analyzed their own six cases of IC, supplemented by a review of 30 previously published cases. They distinguished four major patterns of clinical course based on histopathological correlations: (1) acute episodes of stepwise neurological deterioration; (2) slow progression of neurological deterioration; (3) acute onset of neurological deterioration with rapid decline; and (4) acute onset of mild symptoms of neurological deterioration with gradual decline over weeks to months.

Table 8 Published reports on ICs

First author ʋ of Mean age, Mean Mean Long-term outcome and year patients years duration duration of of follow-up, Worse Same Improved symptoms, months months

Bicknell 1978 [33] 1 32 120 nd 1 0 0

Jellinger 1978[141] 1 62 4 nd 0 0 1

Kitahara 1982[155] 1 47 nd nd 0 0 1

Tyndel 1985[309] 1 27 nd 48 0 0 1

Cosgrove 1988[59] 5 41 47 70 1 4 0

McCormick 1988[190] 6 33 24 43 1 2 3

Vaquero 1988[313] 2 26 30 55 1 1 0

Wang 1988[326] 1 25 48 30 0 1 0

(continued)

50 Table 8 Published reports on ICs (continued)

Rutka 1988[260] 1 30 6 nd 0 0 1

Villani 1989[316] 3 38 nd nd 0 1 2

Zentner 1989[346] 2 37 90 1 1 1 0

Barnwell 1990[20] 1 37 36 0.3 0 1 0

Lopate 1990[182] 2 30 29 nd 0 0 2

Mehdorn 1991[195] 2 34 18 4 0 0 2

Nonogaki 1992[211] 1 43 24 nd 0 0 1

Fazi 1992[88] 2 37 102 nd 0 1 1

Ogilvy 1992[214] 6 43 4 6 0 0 6

Anson 1993[9] 6 35 25 48 0 3 3

Canavero 1993[40] 1 48 168 nd 1 0 0

Lunardi 1994[183] 5 42 29 nd 0 0 2

Stone 1995[289] 1 36 24 nd 0 0 1

Cantore 1995[42] 6 53 110 nd 1 3 2

Gordon 1995[109] 3 35 70 nd 0 0 3

Harrison 1995[126] 1 36 nd 18 0 1 0

Spetzger 1995[286] 9 43 150 14 0 2 7

Turjman 1995[307] 10 47 nd nd nd nd nd

Furuya 1996[91] 4 52 9 45 0 0 4

Padovani 1997[219] 4 46 nd 24 0 1 3

Visteh 1997[318] 17 40 nd 48 1 6 10

Cristante 1998[61] 12 34 20 54 2 3 7

Tu 1999[306] 7 30 nd nd 0 1 6

Zevgaridis 1999[348] 7 39 34 nd 1 1 5

Deutsch 2000[75] 16 39 nd 47 1 8 7

Nagib 2002[205] 2 12 nd 16 0 0 2

Barrena Caballo 2003[21] 12 33 30 nd 0 2 10

Sandalcioglu 2003[268] 10 35 29 11 0 6 4

Santoro 2004[270] 10 41 29 68 0 1 9

Bakir 2006[17] 1 14 nd nd 0 0 1

Kim 2006[154] 53 nd nd 45 1 9 11

Jallo 2006[140] 26 38 44 54 2 12 12

Nishikawa 2006[210] 3 48 nd nd 0 0 3

Kondziella 2006[159] 1 40 1 14 0 1 0

Fritzsche 2006[95] 1 39 6 18 0 1 0

Biluts 2006[34] 1 27 9 nd 0 0 1 (continued)

51 Table 8 Published reports on ICs (continued)

Kharkar 2007[153] 14 42 10 42 0 2 0

Cansever 2008[41] 5 46 31 27 0 0 5

Che 2008[49] 19 39 nd nd 0 0 9

Labauge 2008[171] 53 40 84 46 11 6 20

Bian 2009 [32] 16 38 34 6 0 4 12

Total 374 37 39 32 26 85 180

According to this study, in cases manifesting in frameworks of pattern 1, the punctuated neurological worsening with gradual, partial improvement between events may be a result of episodes of small either extra- or intralesional hemorrhages [214]. Pattern 2 is possibly due to the gradual enlargement of the lesion after intralesional hemorrhage and/or gradual thrombosis. Symptoms may be caused by direct compression of surrounding spinal cord tissue or by the alterations in local blood circulation. Additionally, a cavernoma can expand by capillary proliferation and recruitment of adjacent vessels [351]. The authors emphasize a hemodynamic factor having a role in such a growth. Patients presenting with pattern 3 commonly suffer from devastating symptoms at the onset of the disease. Most likely, the mechanism of this acute decline is extralesional hemorrhage with disruption of neighboring neural tissue. Clinical pattern 4 is presumably related to overt, but not massive extralesional hemorrhage or intralumenal thrombosis with enlargement of the lesion. Zevgaridis et al. subdivided clinical symptoms in IC patients into three groups: (A) multiple episodes of discrete neurological deterioration with varying degrees of recovery between the acute insults; (B) slow progression of neurological deterioration; and (C) sudden onset of symptoms with rapid decline over hours or days (C1), or gradual worsening lasting weeks to months (C2) [348]. These three patterns were noted in the study with an almost equal frequency. The duration of symptoms could last from one week to decades, but, commonly, 3-4 years passes until diagnosis is established and deduced from the pattern of presentation [348]. Bian et al. categorized IC patients’ symptoms into two subgroups: the first group is characterized by slowly progressive neurological deterioration and the second group by acute neurological decline [32]. The authors concluded that the occurrence of the first pattern is related to several minor bleedings followed by gliosis, or progressive growth and mass-effect, or repeated thrombosis within the lesion. The second group of symptoms is caused by an acute extralesional hemorrhage [32]. The same gradation was also proposed by another group of authors [268]. As can be seen from these studies, most clinical presentations are due to hemorrhagic events from

52 a cavernoma. In the vast majority of series, an annual bleeding risk is assessed retrospectively, and this therefore does not reflect the true rate of this event, as almost all patients were symptomatic at the moment of diagnosis. Sandalciouglu et al. presented a series of 10 patients with ICs and observed 17 hemorrhagic events in 375 patient-years [268]. They calculated the retrospective hemorrhage rate to be 4.5% per patient-year. Furthermore, the authors measured re- hemorrhage risk as 66% per patient-year [268]. Bian et al., who analyzed a series of 16 patient, reported the bleeding risk to be 3.1% per patient-year [32]. In a literature review by Zevgaridis et al., an average bleeding rate of 1.4% per lesion-year was found, with the assumption that patients were harboring ICs already at birth [348]. In contrast to this study, Kharkar et al. in their analysis of 14 patients found no hemorrhagic events during the mean follow-up of 6.7 years [153]. Furthermore, in eight of ten patients (80%) the neurological status remained unchanged during a long-term follow-up of 3.5 years. Therefore, the authors claimed that IC patients are a heterogeneous group with varying natural histories; some of them may be very stable, whereas others exhibit an aggressive clinical course [153].

Figure 11 Intramedullary cavernoma causing perifocal hemosiderosis and medullopathy

One of the largest series of ICs was published in 2008 by a French study group conducted by Labauge [171]. The authors performed a multicenter survey of 53 patients with a retrospective analysis of their clinical and radiological data collected from 11 neurosurgical centers. Acute deterioration occurred in 38% of patients, progressive deterioration in 60%, and only one patient (2%) was asymptomatic. A hemorrhage was registered in 39% of patients [171]. Notably, the authors identified triggering factors (pregnancy, trauma and, most frequently, strenuous activity) affecting the clinical course of disease in 26% of cases. This is contrary to brain cavernomas, which are less sensitive to environmental factors.

Symptoms Due to the low tolerance of the medulla to any mass lesion, patients with spinal cavernomas frequently present with progressive focal sensorimotor deficits, often combined with intensive radicular or central pain [154]. Progressive myelopathy caused by typical microhemorrhages and perifocal gliosis probably explains the neurological decline of the patients [75, 214] (Figure 11). Moreover, extralesional hemorrhage disrupts the surrounding neural tissue and may lead to

53 significant neurological decline. Distribution of symptoms is mainly dependent on the location of a lesion along the spinal cord, with involvement of respective segments. Among the wide spectrum of clinical manifestations, sensory deficits are very frequent. In some reports, they occurred in up to 45% of cases [171]. Paresthesias quite often accompany motor deficits. Their combination occurs in up to 25% of patients. In cases of larger lesions or massive hemorrhage, Brown-Sequard syndrome has been noted [75, 214]. When the cavernoma is located in the upper cervical spine, tetraparesis with respiratory muscle weakness may occur [41]. Typically, a conus medullaris lesion will lead to paraparesis and bladder dysfunction [154]. Bowel and/or bladder disorders occurred in up to 17% of the patients with IC [154]. Pain syndrome may be very common in IC patients manifesting in up to 50% [154, 190]. Acute local back pain may be the first sign of a cavernoma hemorrhage with further development of other symptoms. In the representative series of Kim et al., analyzing 53 patients with ICs, 23 patients (44%) presented with pain symptoms; radiculopathic pain in 70% and central pain in 13% [154]. In 31% of cases, pain was severe and affected daily living, and 43% of patients used either narcotic or neuropathic pain medications at the time of surgery.

Radiology MRI is the most reliable diagnostic tool to identify an IC, with the first report appearing in 1987 [309]. Before MRI, the armamentarium of diagnostic tools included myelography, CT myelography, and contrast CT imaging, but none of these could specifically distinguish ICs [93]. Myelography can only show the level of the unspecific lesion in cases of widening of the spinal cord. CT scans through the region of IC may demonstrate the intramedullary lesion by visualizing Figure 12 Intramedullary cavernoma with typical extension of the cord parenchyma. At the same time, reticulated appearance on MRI findings like hemorrhage, calcifications, or syrinx cavity can be seen [214]. On MRI, reticulated appearance with mixed signal intensity on both T1- and T2-weighted images are the most common findings [307] (Figure 12). Contrast enhancement is not typical and uniform. Notably, a rim of decreased signal intensity, most consistent with a hemosiderin deposition, is less frequent than in the brain. Homogeneous signal intensity is more common [307]. Ogilvy et al. depicted the basic MR signs of hemorrhagic events and showed that the appearance of hemorrhage on MRI depends on the age of the hemorrhage [214]. During the first days after the bleeding T1-weighted images show isointense or slightly hypointense signal

54 relative to the white matter, and hypointense signal on T2-weighted images. After a few days to two weeks, the blood appears hyperintense on T1-weighted images and remains hypointense on T2-weighted images. Over the next few weeks, as blood breaks down, the T1-and T2-weighted images show hyperintense signal in the lesion. Chronic blood products are hypointense on T2- weighted images and isointense or moderately hypointense on T1-weighted images. Gadolinium enhancement is variable [214]. Along the spinal axis, ICs are most frequently seen in the thoracic region, accounting for 77% of the cases [171]. Cervical location is less frequent, occurring in less than 23% of patients. Lumbar region ICs are very uncommon. Among all collected cases of ICs, we found only 14 of caudal cavernomas (4%) in the literature [81, 222, 309]. On a horizontal plane, centrally located lesions are the most frequent. In some series, they account for 34% of cases [171]. Posterior and lateral sites are less common, occurring in 23% and 17% of cases, respectively. The rarest location is anterior, occurring in 9% of cases [171]. There are several reports of the simultaneous occurrence of ICs and multiple brain cavernomas [75, 317, 318]. Deutsch et al. in a series of 14 IC patients reported three cases (21%) with multiple intracranial lesions. Vishteh et al. found that 47% of 17 patients with ICs harbored multiple intracranial cavernomas [317]. Four of these patients had a family history of cavernomas. Thus, it may be warranted to perform an MRI of the brain in young IC patients, as they are more likely to harbor multiple lesions. Cases of multiple spinal ICs are casuistic, with very limited data in the literature [224, 225].

Surgical treatment Due to the aggressive clinical course and frequent hemorrhagic events in IC patients, surgical treatment is considered to be beneficial [75, 140, 171, 190, 214, 348]. When planning the operative treatment, one should take into account the patient’s symptoms, age, evidence of progression, the risk of further hemorrhages, size and accessibility of the lesion, also bearing in mind the risks of surgical manipulations [154, 158, 205]. Surgery of deep and anteriorly locating lesions carries obviously higher risks due to extended dissection and manipulation within the spinal cord [102]. Longer duration of preoperative symptoms seems to be associated with less successful outcome after surgery [348].

Operative techniques A laminectomy is the most conventional dorsal approach to ICs, but may result in progressively increasing instability or deformity of the vertebral column, especially in children [32, 158, 194, 337]. In 1991, Yasargil et al. reported a series of 100 patients, who had undergone surgical removal of extra- and intramedullary tumors and AVMs via hemilaminectomy [339]. One year

55 later, Bertalanffy et al. also demonstrated that hemilaminectomy is more beneficial than laminectomy in management of extramedullary tumors [31]. The minimal invasiveness of this approach has been appreciated by many and is widely used in the management of extra- and intramedullary space-occupying lesions [18, 31, 272]. Furthermore, Koch-Wiewrodt et al. recently suggested unilateral interlaminar fenestration to expose intraspinal space-occupying lesions, showing a significant decrease in postoperative pain and duration of hospital stay [157]. Further studies are needed to confirm the effectiveness of such a limited approach. In any case, the bone resection should be large enough to provide adequate space to open the dura in a longitudinal fashion, exposing the affected area of the spinal cord. To optimize the surgical view, lateral drilling is sometimes required [32]. Purely ventral lesions can be reached via a posterolateral approach with spinal cord rotation and visualization of the anterior pial surface [188]. In rare cases of anterior IC, this approach seems to be better than the complex and very invasive anterior approaches [188]. Cavernomas demonstrating exophytic growth extending to the pial surface are the easiest lesions to remove. They are typically exposed through a myelotomy directly over the lesion, being in most cases relatively safe [140]. When neither discoloration nor bulging of the spine can be seen, choosing the safest place to enter is one of the most critical steps of the procedure. Myelotomy should be planned by taking into account such factors as remoteness of the IC from the pial surface, dorsal median sulcus, dorsal root entry zone (DREZ), findings during intraoperative sonography, and neurophysiologic response to local stimulation. All of these factors will help to avoid inadvertent damage to unaffected tracts and nuclei. The more anterior the lesion is, the more complications are to be expected due to the corticospinal tracts located in the anterolateral aspects of the cord [104, 263]. In the series of Labauge et al., only one of the four operated patients with anterior IC improved, whereas three demonstrated worsening of their neurological status [171]. Furthermore, among patients with centrally located lesions, only 64% improved, while 36% worsened. Notably, seven of eight patients (85%) with a posterior cavernoma improved after surgery [171]. The preparation of the dorsal median sulcus when approaching centrally or anteriorly located intramedullary cavernomas may be beneficial to gain direct access to the lesion and minimize the intraparenchymal dissection [36, 263]. When such exposure is planned, the bony opening should be wide enough to access the midline, and extended hemilaminectomy or conventional laminectomy should be performed. When surgery is carried out in the acute stage of bleeding and hematomyelia is massive, the dorsal midline sulcus can be displaced, which causes difficulties in its identification and proper dissection. In the extreme lateral location of the cavernoma, it can be exposed via myelotomy performed in the DREZ, although this is associated with a high risk of significant sensory deficits [1].

56 Intraoperative ultrasound is a useful adjunct to localize a cavernoma and the extent of hematoma in cases where no pathological signs can be seen on the surface. Ultrasound visualizes not only normal structures of the spine but can also provide precise assessment of the size of the lesion, thus allowing identification of an adequate site for the myelotomy [183]. When the cavernoma compromises the central medullary canal, ultrasound may show disposition of the normal structures, which is important during intraparenchymal dissection. The technique of IC removal is similar to that of any intramedullary tumor. Gentle traction and coagulation of the malformation surface allow a cleavage plane to be created [190]. Unlike with supratentorial cavernomas, the perifocal hemosiderotic rim should not be taken out. A lesion can be removed en bloc or in a piecemeal fashion, depending on its size and consistency. After excision of the cavernoma, careful inspection of the cavity is essential to exclude any remnants. A cavity can be inspected also by ultrasound to identify remnants when the size of the myelotomy is very small and visual access is limited [183].

Monitoring The majority of unsatisfactory outcomes after removal of an intramedullary lesion are primarily due to ischemic derangements of the cord secondary to its sustained traction, manipulation, rotation, and overheating produced by bipolar coagulation [72]. Intraoperative monitoring (IOM) helps the neurosurgeon to predict the degree to which the spinal cord can tolerate any surgical manipulations [72]. In part, modern neurophysiologic tools have decreased postoperative morbidity after IC removal. IOM allows a direct feedback of the functional integrity of spinal cord tracts during cavernoma surgery. The evolution of IOM during removal of intraspinal lesions had begun in the 1980s from registering sensory evoked potentials (SEP) [330, 331], which assesses possible dysfunction of sensory tracts, but not motor pathways. The limitations of this method have been shown in many studies with the appearance of false-negative and false- positive results when patients demonstrated motor deficits after awakening, although intraoperative SEP findings were not abnormal [264]. Some authors reported an incidence of false-negative results in up to 25% of patients [324]. Since the mid-1990s, transcranial electric stimulation (TES) to elicit motor evoked potentials (MEP) has been used to assess the functional integrity of motor tracts during intraspinal surgery [144, 227]. The use of multipulse transcranial electrical stimulation and recording from limb muscles is widely accepted nowadays in many neurosurgical centers as an effective monitoring method [263, 264, 324, 328]. A recent study has addressed the value of the evolvement of D-waves during a single-pulse technique with transcranial electrical stimulation and epidural recordings [262]. A D-wave is of great interest since it represents a pool of high conduction velocity fibers supporting locomotion and not impaired by typical anesthetics and myorelaxants [262]. To date, among the neurophysiologic

57 parameters, D-wave seems to have the strongest predictive value of favorable motor function/recovery after surgery on intramedullary masses [72]. A few false-positive results have been reported, but they are related to local scalp edema and do not actually argue against the value of D-wave in neurophysiologic monitoring [186].

Outcome In the published literature, follow-up data on operated patients were found in 351 cases. Patients with intramedullary lesions showed improvement in 62% of the cases. The report by Labauge et al. showed no correlation of better outcome with patients’ age, gender, and delay from onset to surgery, lesion size, cervical or thoracic location, or severity of initial neurological deterioration [171]. A statistically significant correlation with worse outcome was demonstrated in cases of anterior cavernomas. Regarding duration of preoperative symptoms, Zevargidis et al. demonstrated a correlation of shorter preoperative history with better outcome after surgery [348]. The authors noted that 76% of patients with symptoms for less than three years improved after surgery, whereas only 52% of patients with symptoms for more than three years showed equal results [348]. Persistent worsening of neurological status, registered at the long-term follow-up, occurred rarely, accounting for 9% of all cases [33, 40, 42, 59, 61, 75, 140, 171, 190, 313, 318, 346, 348]. Only 6% of the patients have had permanent disabling neurological deficits [318, 348]. Pain relief was satisfactory immediately after surgery, but during long-term follow-up pain may recur in up to 50% of patients [154]. The matter of micturition recovery is not well elucidated in the literature, but some reports indicated only partial improvement or absence of any changes in bladder functions [159, 346].

Extramedullary cavernomas (EC) Patients and symptoms The true incidence of ECs remains unknown. In the literature on spinal cavernomas, we found 63 well documented cases (14.4% of all 427 spinal cavernomas) of extramedullary lesions (Table 9). The largest series of ECs contained only seven patients [111, 269]. ECs represent 4% of all epidural tumors [269, 295, 303]. Most frequently, they are encountered between the third and fifth decade of life. In some series, a slight men preponderance was demonstrated [10]. Histological features of ECs are not different from other cavernomas. In many cases, an extramedullary lesion was encapsulated, which was uncommon in cavernomas of other locations [10, 299]. It is unclear whether extradural cavernomas have different growing patterns or hemorrhage rates from those in intramedullary lesions. Zevgaridis et al. distinguished four patterns of manifestations in published cases of ECs: 1) slow, progressive spinal cord syndrome; 2) acute

58 spinal cord syndrome; 3) local back pain; and 4) radiculopathy [349]. The authors found that in most patients with acute or chronic spinal cord syndrome, the symptoms are related to the hemorrhage, whereas in cases of local back pain and radiculopathy, symptoms are associated with growth of the lesion [125, 349]. Santoro et al. noted that acute and subacute onset is not uncommon and may be attributed to microhemorrhages or hematomas, resulting in motor or sensory deficits; this finding is supported by other authors [111, 131, 269, 299]. Naturally, symptoms are dependent on the affected level of the spine and the degree of compression of the cord or nerve roots.

Table 9 Reported cases of ECs Mean Mean Mean First author No. of age, yrs duration of f-up, Long-term outcome and year patients symptoms months Worse Same Improved preoperatively, yrs

Richardson 1979[250] 1 nd nd nd 0 0 1

Padovani 1982[220] 1 78 24 nd 0 0 1

Morioka 1986[202] 1 50 3 4 0 0 1

Ueda 1987[309] 1 28 36 nd 0 0 1

Lee 1990[176] 3 38 nd 28 0 0 3

Pagni 1990[222] 1 46 48 20 0 0 1

Enomoto 1991[85] 1 42 nd nd 0 0 1

Hillman 1991[131] 5 35 nd nd 1 1 3

Isla 1993[136] 2 25 nd nd 0 0 2

Singh 1993[284] 1 40 2 84 0 0 1

Graziani 1994[110] 7 46 nd nd 0 1 6

Bruni 1994[38] 1 28 0.1 nd 0 0 1

Harrington 1995[125] 1 37 2 nd 0 0 1

Padovani 1997[219] 5 50 nd 24 0 2 3

Rao 1997[245] 4 48 16 nd 0 1 3

Zevgaridis 1998[349] 3 43 2 21 0 0 3

Duke 1998[81] 1 49 nd 3 0 0 1

Appiah 2001[10] 1 41 12 6 0 0 1

Saringer 2001[271] 1 56 11 3 0 0 1

Goyal 2002[110] 1 55 25 5 0 0 1

D'Andrea 2003[65] 1 52 6 nd 0 0 1

Thome 2004[302] 1 47 12 12 0 0 1

Tekkök 2004[299] 1 28 24 36 0 0 1

(continued)

59 Table 9 Reported cases of ECs (continued)

Santoro 2005[269] 7 77 6 nd 0 0 4

Hatiboglu 2006[129] 1 28 12 108 0 0 1

Doyle 2008[79] 1 57 4 6 0 0 1

Iglesias 2008[135] 1 57 nd 48 0 0 1

Akiyama 2009[3] 1 40 6 nd 0 0 1

Satpathy 2009[274] 1 47 nd 76 0 0 1

Feng 2009[89] 6 42 nd nd 0 0 6

Total 63 47 13 30 1 5 54

Radiology Typically, ECs are common in the thoracic spine and only very occasional at the cervical and lumber levels [299]. Due to their rareness, diagnosis of ECs may be difficult. Conventional or CT myelography can only demonstrate a block in the flow of subarachnoid contrast medium [349]. CT imaging may show a mass in the spinal canal, but sensitivity and specificity of images are very limited. The most precise diagnostic is naturally provided by MR imaging. Zevgaridis et al. delineated the main MR features of ECs, helping to establish a correct diagnosis and avoid misinterpretations (Figure 13): T1-weighted images commonly show homogeneous signal intensity similar to that of spinal cord and muscle. Contrast enhancement is homogeneous or only slightly heterogeneous. On T2-weighted images, the signal is high, just slightly less than that of CSF [349]. Unlike IC cases, an extramedullary lesion is not characterized by a perifocal hemosiderotic hypointense fringe in both T1- and T2-weighted images. It is not uncommon that a lesion extends to intervertebral foramina [93, 96]. In contrast to some neoplasms in similar locations, ECs never cause any enlargement or bony erosion of foramina, which helps in differential diagnostics. Among pathologies to exclude are schwannomas, meningeomas, lymphomas, Ewing’s sarcomas, chordomas, ependymomas, spinal angiolipomas, osteochondromas, synovial cysts, and disc herniations [107, 299, 349]. Tekkok et al. presented a thorough overview of MR and CT findings of the vast majority of benign and malignant masses in the extradural compartment of the spine [299]. The authors stressed that the enlargement of neural foramina is typical for a schwannoma or neurofibroma, and destruction occurs typically in a lymphoma, chordoma, or Ewing’s sarcoma [299]. When a lesion is located in the lumbar spine, and especially, when it is small and occupies the intervertebral foramen, it can easily be misinterpreted as a disc herniation [349].

60 Treatment and outcome Due to the low number of patients and the lack of thorough prospective studies, the natural course of the ECs is unknown. No data exist on whether symptomatic patients experience spontaneous recovery during long-term follow-up and thus could be treated conservatively. In very rare cases, ECs have even been irradiated, but results of this treatment are doubtful [59, 176, 220]. Surgical removal of the symptomatic EC is considered by most authors the treatment of choice [10, 131, 219, 269, 349]. Similar to other cavernomas, total removal is the goal of surgery since cavernoma remnants may cause further neurological deterioration due to their growth and hemorrhage. Use of microsurgical techniques is essential to accomplish complete resection without any damage to surrounding neural structures. Depending on their size, side and relation of the lesion to the dura, hemilaminectomy or laminectomy is performed. After exposure of the epidural space, the lesion is identified. The pseudocapsule, which is common in ECs, facilitates dissection of the lesion from ligaments, dura, and nerve roots [258, 299]. If possible, integrity of the capsule should be preserved to avoid intraoperative bleeding which usually is not intensive but may obscure the surgical view and impede dissection. If a lesion is purely extradural, no further inspection of intradural space is necessary. In rare cases, an EC is located intradurally requiring a dural opening [244]. Such lesions can be adherent to the nerve roots or pial surface of the spinal cord thus necessitating meticulous preparation and dissection of the lesion. Of the 63 reported cases, 54 (90%) experienced postoperative improvement of neurological deficits, which confirms the effectiveness of surgical treatment (Table 9). In five patients (8%), no changes occurred [111, 131, 219, 245]. Only one report showed worsening of neurological status after surgery [131]. Unfavorable outcome was due to the large size of the lesion with intensive bleeding after manipulation even interrupting the excision.

Figure 13 Large extramedullary cavernoma mimicking benign tumor. a – sagittal view; b – axial view

a b

61 III Aims of the study

1. To analyze main clinical features of intraventricular cavernomas and the results of their microsurgical removal.

2. To analyze the role of surgical treatment in management of multiple cavernomas by assessing long-term seizure and general outcome.

3. To analyze a series of patients with spinal cavernomas with a special emphasis on functional recovery after lesionectomy.

4. To analyze the results of microsurgical treatment of temporal lobe cavernomas.

62 IV Patients and methods Data collection Data on 383 consecutive patients with 1101 brain or spinal cavernomas treated at Helsinki University Central Hospital (HUCH) from January 1, 1980 to December 12, 2009 were retrospectively analyzed. The catchment area of this center is 1.8 million inhabitants. In most of the cases, patients were initially examined at the neurological department of the referring hospitals and then sent to our neurosurgical center for further evaluation and treatment. The collection of the series began in 2006, and the patient database was continuously supplemented with new cavernoma patients recruited to the study. Accordingly, a total number of patients in series presented below varied. The study protocol was approved by the local Ethics Committee of HUCH.

Intraventricular cavernomas Of the 325 patients treated at our department between January 1980 and January 2008, 12 (3.7%) had an intraventricular cavernoma (Table 10). The 77 previous case reports of IVC were collected via the Pub Med database and then analyzed. All of our patients were imaged with CT and MRI prior to admittance to our department. We classified cavernomas located in the ventricles into three main groups: A) “true” intraventricular lesions which are attached to the ependyma or choroid plexus but do not extend outside the ventricle wall; B) lesions with an intraparenchymal part but no more than one half of the volume; and C) paraventricular lesions with only a minor part (less than one half of the volume) located in the ventricle; we did not include the last group in the present study. In patients with intraventricular hemorrhage, MRI was performed usually several months after the resorption of extravasated blood aiming at a more definitive preoperative diagnosis. Only one patient was imaged with CT, MRI and digital selective angiography (DSA) immediately due to a hematoma of diameter 5 cm to exclude AVM or tumor (Figure 14). Because of progressive somnolence this patient was operated on two days after the bleeding. Standard T1- and T2- weighted imaging with a T2*-weighted Gradient Echo sequence was performed. Lesions were classified according to the Zabramski classification scheme. In five patients (42%), DSA was performed to exclude AVMs. In three patients, the IVC was not removed. One patient underwent only a shunting procedure for obstructive hydrocephalus caused by a non-related aqueduct stenosis. This was followed by significant improvement of symptoms; this patient later refused removal of the cavernoma. Another two patients refused any operation.

63 Table 10 Own series of patients with IVC

Patient Sex Age,y Location Clinical presentation Re-bleeding Treatment of GOS IVC

1 male 66 lateral gait disturbances, mild no conservative V ventricle headaches, hydrocephalus (shunted because group A of nonrelated hydrocephalus) 2 female 43 fourth mild headaches, nausea no total removal V ventricle and group B vomiting

3 male 65 lateral IV-hemorrhage, severe no total removal V ventricle headaches, nausea and group A vomiting, hydrocephalus 4 female 58 fourth IV-hemorrhage, mild once, total removal IV ventricle headaches, nausea and before group B vomiting, cranial nerve surgery deficit

5 male 20 lateral IV-hemorrhage, mild twice, Stereotactic biopsy V ventricle headaches after first followed by two group B surgery partial resections

6 male 15 fourth IV-hemorrhage, cranial once, total removal IV ventricle nerve deficit before group B surgery

7 male 52 third headache, nausea and no total removal V ventricle vomiting group B 8 female 49 fourth cranial nerve deficit no total removal IV ventricle group B

9 male 35 lateral IV-hemorrhage, acute twice conservative V ventricle severe headaches, nausea group B and vomiting 10 female 49 fourth IV-hemorrhage, acute no total removal V ventricle severe headaches, group B hydrocephalus

11 male 65 lateral IV-hemorrhage, acute twice conservative V ventricle headaches, nausea and group B vomiting, hydrocephalus 12 male 53 lateral IV-hemorrhage and ICH, no total removal V ventricle headaches, hemiparesis group B

All microsurgically treated patients (9 of 12) underwent routine CT imaging in the immediate postoperative period. In one operated patient, follow-up MRI was performed after several months to exclude a cavernoma residual. Furthermore, in two of the three conservatively treated patients, MRI was performed at our department one year after the primary diagnosis. In addition to the

64 routine postoperative outpatient visit at three months, all patients were interviewed in 2008 with health questionnaires sent by post. Patients’ general outcome was assessed on the Glasgow Outcome Scale (GOS) [142].

Figure 14 Acute cavernoma hemorrhage in the vicinity of lateral ventricle causing mass-effect on basal ganglia

Multiple cavernomas Altogether 44 of 383 patients (11.5%) had multiple cavernomas, which were diagnosed between January 1980 and December 2009. A total of 762 lesions could be identified. T2*-weighted gradient-echo (GRE) sequences had been performed on 37 patients (84%). All MR images were re-reviewed by a radiologist and classified according to the Zabramski classification scheme. Furthermore, supra- and infratentorial lesions and the number of lesions were analyzed separately. The size of each cavernoma was measured, except for type IV lesions: in GRE imaging the size of these lesions was very small and strongly dependent on the equipment used, making measurement unreliable. In this study, cavernoma-related bleeding was defined as extralesional symptomatic hemorrhage seen on CT scan. A follow-up MRI was performed on 22 patients. In this group, all except one patient were treated microsurgically. CT was performed routinely on the first postoperative day in all surgically treated patients. Four patients who suffered from acute headache during follow-up were imaged with CT to exclude hemorrhage. In addition to the routine postoperative outpatient visit at three months, all patients were sent health questionnaires.

65 Table 11 Outcome assessing scales The general outcome of patients was assessed by using the Glasgow Grading Characteristics Outcome Scale (GOS) and the outcome of epileptic symptoms in Engel scale Class I Free of disabling seizures operated patients by using the Engel Class II Rare disabling seizures classification [84] (Table 11). Class III Worthwhile improvement Class IV No worthwhile improvement Spinal cavernomas Of the 376 consecutive patients with Glasgow cavernomas of the CNS treated in Outcome Scale January 1980 and June 2009, 14 GOS5 Good recovery (4%) had a spinal cavernoma (Table GOS4 Moderate disability 12). In these cases, spinal axis MRI GOS3 Severe disability GOS2 Persistent vegetative state was performed using standard T1- GOS1 Death and T2-weighted sequences. On MRI, cavernomas had a typical heterogeneous core surrounded by a hemosiderotic rim and also edema when intramedullary perifocal. Indications for microsurgical removal of a spinal cavernoma were progressive neurological deterioration in 12 patients (86%) and prevention of bleeding and consequent neurological decline in the remaining two patients (14%). To assess the patients' condition at the follow-up, the most recent data from referring departments were analyzed. The median follow-up time was three (range 1-10) years.

Table 12 Own cases of spinal cavernoma

Patient Age, Sex Location Symptoms Bleeding

1 50y, male Th12-L1, intramedullary, midline Left leg radicular pain, paraparesis yes Bladder paresis. Fast progression

2 52y, female C7-Th1, extradural, right C8 radiculopathy with motor paresis no Slow progression

3 26y, male C4-5 intramedullary, left Fast progression of tetraparesis yes Bladder paresis

4 45y, male C5-6 intradural-extramedullary, left Fast progression of Brawn-Sequard yes syndrome. Bladder paresis

5 44y, female C7-Th1, extradural, left Fast progression of tetraparesis no Diffusive pain (continued)

66 Table 12 Own cases of spinal cavernoma (continued) 6 57y, male C1-2, intramedullary, right Brawn-Sequard syndrom no Improved before surgery

7 47y,female Th-10 intramedullary,midline L5 and S1 radiculopathy no with motor paresis. No progression

8 34y, female Th4 intramedullary, left Right sensorimotor hemiparesis yes Slow progression

9 46y, male Th5-6 extradural, midline Sensorimotor paraparesis in legs no Fast progression. Bladder paresis

10 28y, female Th7 intramedullary, left Low-back pain followed by acute yes paraparalysis. Bladder paresis

11 45y, female C3-4 intramedullary, midline Left C8 radiculopathy with pain and no sensorimotor paresis. Improved before surgery.

12 54y, female Th11 intramedullary, midline Numbness in both legs, right L5 paresis yes Slow progression.

13 40y, male Th9 intravertebral, extradural, left Paraparesis in both legs no Slow progression

14 20y,male Th10, intramedullary, left Lower limb paraparesis yes Fast progression

Temporal lobe cavernomas Of the 360 consecutive patients treated from January 1980 to January 2009, 53 (15%) had a single cavernoma of the temporal lobe and 49 (92%) of them were operated on and therefore included in the study (Table 13). EEG was performed on 30 (75%) of the 40 patients with seizures, at a median of 1.2 (range 0.1- 2.1yrs) years before surgery. Three patients underwent a prolonged video EEG, including ictal registration. In adults with only a single epileptic seizure, EEG was not performed, if MR imaging verified the cavernoma soon after the event. In 11 patients (37%), EEG was within normal limits or it showed only non-epileptiform focal or diffuse slowing. No periodic lateralized epileptiform discharges were reported. Video EEG was performed in refractory epilepsy to assess the magnitude of the upcoming resection. Postoperative EEG was not performed routinely; it was carried out in only 15 patients (31%) at a median of 2.7 (range 0.1-17) years after surgery. Indications included suspected postoperative seizures, consideration of withdrawal of medication, or seizure recurrence after medication was discontinued. In 11 of these 15 patients, postoperative EEG showed epileptiform interictal activity, and AED was continued. Prior to admission to our department, each patient had an MRI performed, except for three

67 patients admitted at a time when only CT was available. MRI was performed at a median of 0.5 (range 0.1-12) years before surgery. In the vast majority of patients, the cavernoma had a typical heterogeneous core, seen on standard MR sequences, surrounded by a hemosiderin rim. The median size of the cavernoma core in the series was 10 (range 7-40) mm. In patients with acute sudden headache, a CT was performed soon after symptom onset to exclude hemorrhage. To categorize the location of the cavernomas within the temporal lobe we divided it into three compartments: I - medial (Figure 15), II - anterolateral (Figure 16), and III - posterolateral (Figure 17) (Table 14). Justification for this division was based on perceived differences in functionality and surgical risk: (I) strong tendency to be involved in epilepsy and importance in memory processing, (II) believed to be a low-risk area, and (III) increased risk due to optic radiation and the vein of Labbé. The first clinical follow-up as a routine postoperative examination was performed at a median of two months after the procedure. When needed, further follow-up was provided, mostly by neurologists at the referring hospitals. In addition to this, 45 patients were interviewed by phone, with special emphasis on their general condition. For six patients, we analyzed only the most recent neurologist’s follow-up data. One patient who came to surgery from outside Finland was lost in follow-up. Furthermore, one patient had died at the time of the study due to liver insufficiency.

Figure 15 A cavernoma in the medial part of the temporal lobe. a – axial view; b – coronal view

a b

68 Figure 16 A cavernoma in the antero-lateral part of the temporal lobe. a – axial view; b – coronal view; c – sagittal view

a b c

General outcome was assessed using the Glasgow Outcome Scale (GOS). Epilepsy outcome analysis after surgery was assessed according to the Engel classification. In cases of memory disorder, a standard Mini Mental State Examination test (MMSE) was performed at the local hospital. When needed, patients were sent to a neuropsychologist who then performed appropriate testing.

Figure 17 A cavernoma in posterior part of the temporal lobe. Associated DVA is located anterior to the cavernoma

69 Table 13 Own patients with temporal lobe cavernoma

Characteristics Seizure history of Others Total 40 patients

Sex Females 29 (73%) 6 (66%) 35 (71%)

Males 11 (27%) 3 (34%) 14 (29%)

Median age at diagnosis, years 36 (10-60) 49 (7-64) 39 (7-64) (range)

Location in temporal lobe

MTL 10 (25%) 3 (34%) 13 (27%)

ATL 13 (32%) 2 (22%) 15 (30%)

PTL 17 (43%) 4 (44%) 21 (43%) Lateralization Left 26 (65%) 5 (55%) 31 (63%)

Right 14 (35%) 4 (45%) 18 (37%)

Typeof seizure at presentation CP 7 (18%) - -

SP 5 (12%)

SGTC 28 (70%)

Median duration of 3 (0.1-23) 0.6 (0.1-1.6) 3 (0.1-23) symptoms before admission, years (range)

Hemorrhage 8 (20%)* 1 (8%)** 9 (18%)

* Seven patients with one hemorrhage and one patient with three hemorrhages preoperatively ** Patient with headaches who had two hemorrhages preoperatively, not in asymptomatic patients ATL – anterior temporal lobe, MTL – medial temporal lobe, PTL – posterior temporal lobe, SGTC – secondary generalized tonic-clonic, SP- simple partial, CP – complex partial.

Statistics Statistical analysis was carried out using SPSS 13.0 software (SPSS Inc., Chicago, IL). Clinical characteristics were presented as frequencies and percentages for categorical variables and as means +/-SD for continuous variables. Nonparametric data were analyzed using Pearson’s Chi- square test, and continuous variables were compared with Student's t-test. The level of significance was set at p<0.05. All tests were two-sided.

70 Table 14 Suggested compartmentalization of temporal lobe

Compartment Borders and structures

Medial temporal lobe Bordered by the allocortex of the temporal lobe (parahippocampal (MTL) gyrus, fusiform gyrus, uncus), hippocampal formation, amygdala

Anterolateral temporal lobe Bordered anteriorly by temporal lobe apex, medially by MTL, (ATL) posteriorly by PTL, laterally by lateral surface of temporal lobe

Posterolateral temporal lobe Bordered anteriorly by ATL (4 cm from temporal lobe apex in sagittal (PTL) direction), medially by MTL, posteriorly by posterior border of temporal lobe

71 V Results and Discussion Helsinki Cavernoma Database Patients From January 1980 to December 2009, altogether 383 patients with 1101 brain and spinal cavernomas were treated. The mean age of patients at the radiological diagnosis of a cavernoma was 42 years (range 0.6-81.6 yrs). Thirty-three patients (8.7%) were younger than 18 years, and only 21 patients (5.5%) were older than 65 years. Slight women preponderance was observed, with the women:men ratio being 1.3:1 (214 women (55.9%) and 169 men (44.1%)). The mean age of women was 43 years (range 0.6-81.6 yrs) and of men 41 years (range 3.2 – 76.8 yrs). In four women (1.9%), the cavernoma was diagnosed during pregnancy. A single cavernoma in the supratentorial compartment occurred in 247 patients (64.5%), and in the infratentorial compartment in 64 patients (16.7%) (Table 15). Multiple lesions of the brain were diagnosed in 44 patients (11.5%). One of them had exceptionally high number of lesions reaching 532 whereas remaining 43 patients had 230 lesions. The most common location among single cavernomas was the frontal lobe, occurring in 97 patients (25.3%). The rarest locations were the internal acoustic meatus (one patient) and the sellar region (two patients). Of brain lesions, 52% were located on the left side, 42% on the right side, and 6% at midline. The mean size of the cavernoma was 12 mm (range from punctate to 50mm). Associated vascular pathologies occurred in 44 patients: 33 patients (9%) had DVA, four patients (1%) had teleangiectasias, three patients (1%) had meningeoma, and three patients (1%) had cerebral aneurysm.

Symptoms Symptoms were reported by 83.6% of the patients, and a cavernoma was identified incidentally in 63 patients (16.4%) (Table 16). The most frequent symptom was epileptic disorder occurring in 141 patients (36.8%). In this group, a cavernoma was radiologically confirmed after the first seizure in 55 of 141 patients (39%). Patients exhibited secondary generalized tonic-clonic and simple and complex partial seizures without a specific correlation with radiological characteristics of the cavernoma. In 74 patients (19.3%), headaches were the only symptom. Headaches varied from slight to very severe and were frequently accompanied by nausea or vomiting. Commonly, headaches presented when a cavernoma bled. Focal neurological deficits, including cranial nerve deficits and sensorimotor paresis of the extremities were encountered in 76 patients (19.8%). Vertigo occurred presumably in patients with a cerebellar cavernoma in 13 cases (3.4%).

72 Table 15 Distribution of cavernomas in Helsinki Cavernoma Database*

Location No. of patients History of bleeding Operated on (%) (%) (%)

Supratentorial 247 (64.5) 74 (30) 200 (81) Frontal 97 (25.3) 30 (30.9) 80 (82.5) Parietal 35 (9.1) 14 (40) 26 (74.3) Temporal 58 (15.1) 11 (19) 52 (89.7) Occipital 18 (4.7) 5 (27.8) 12 (66.7) Basal ganglia 18 (4.7) 9 (50) 11 (61.1) Sylvian fissure 10 (2.6) 4 (40) 9 (90) Corpus callosum 4 (1.0) - 4 (100) Insular 5 (1.3) 1 (20) 4 (80) Parasellar 2 (0.5) - 2 (100)

Intraventricular 12 (3.1) 8 (67) 10 (83) Lateral ventricles 6 (1.6) 5 (83.3) 4 (66.7) Third ventricle 1 (0.3) - 1(100) Fourth ventricle 5 (1.3) 3 (60) 5 (100)

Multiple 44 (11.5) 19 (43.2) 30 (68.2)

Infratentorial 64 (16.7) 39 (60.9) 48 (75) Pons 26 (6.8) 22 (84.6) 21 (80.8) Cerebellum 25 (6.5) 8 (32) 14 (56) Medulla oblongata 8 (2.1) 6 (75) 8 (100) Mesencephalon 4 (1.0) 3 (75) 4 (100) Meatus acusticus internus 1 (0.3) - 1 (100)

Spinal 14 (3.7) 7 (50) 14 (100) Intramedullary 9 (2.3) 6 (66.7) 9 (100) Extramedullary 5 (1.3) 1 (20) 5 (100)

* - The database was continuously supplemented by new cases. This table represents the latest version analyzed in May 2010 including 383 patients

Visual disorders were common in patients with lesions occupying the occipital or temporo- occipital region and appeared in six cases. Memory disorder was an initial manifestation in six patients. In three patients with cavernomas affecting the hypothalamus and/or hypophysis, hormonal alterations were identified. One patient with basal ganglia cavernoma exhibited a hyperkinetic movement disorder. Acute exacerbation of symptoms was typically caused by a cavernoma hemorrhage. In total, 147

73 patients (38.4%) suffered from a radiologically confirmed symptomatic hemorrhage. Single hemorrhage before admission occurred in 118 of 147 patients (80.3%). In 18 cases (12.2%), the patients experienced two episodes of hemorrhages, in seven cases (4.8%) three hemorrhages, and in two cases four hemorrhages before admission. Neurological deterioration caused an emergency hospitalization in 57 patients (14.9%). Surgical removal of the lesion was performed within one week after bleeding in 21 of 145 patients (14.5%). In 64 cases (44.1%), a hemorrhagic cavernoma was excised within a six-month period after the bleeding.

Radiology Due to progressive neurological deterioration patients were investigated with CT and/or MRI. A CT-scan as a primary and easily available radiological method was performed on 327 patients (85.4%) with a brain cavernoma. To exclude high-flow vascular anomalies, CT angiography was performed in the same session on 88 patients (23%). Later, MRI was ultimately performed on all patients with any suspected finding on CT to verify a cavernoma. All but ten patients were finally imaged by MRI. Additionally, 38 patients (10%) underwent DSA. None of them showed obvious signs of pathological vessels or abnormal filling. On MRI, cavernomas presented with a typical heterogeneous core surrounded by a hypointense rim in most of the cases. Perifocal edema was uncommon. In cases of acute extralesional hemorrhage, MRI showed a hyperintensive blood clot and cavernoma could not be reliably diagnosed. Thus, after 6-8 weeks, when extravasated blood was resorbed, patients underwent repeated MRI to verify the source of the bleeding.

Treatment Surgical removal of a cavernoma was performed on 303 patients (79%). Operative treatment was mainly indicated when a lesion manifested with progressive neurological symptoms, and had radiological signs of bleeding. Furthermore, 31 of 63 patients (49.2%) with incidentally found asymptomatic cavernomas were operated on (Table 16). In these patients, surgery was considered as appropriate because of a superficial location of a midsize or large lesion (more than 10 mm) with MRI showing intraluminal blood at various stages of organization together with an easy access to the lesion without any risk of damaging eloquent areas. Conservative treatment, by contrast, was more rational in elderly patients who had a small, radiologically inactive lesion without signs of hemorrhage and/or growth on follow-up MRI. Spinal lesions were excised in all patients regardless of the severity of neurological deterioration due to their propensity for an aggressive clinical course. In 259 of 303 operated patients (85%), a gross total removal was provided at the first attempt. Despite using neuronavigating assistance (frame-based or frameless), in 19 patients (6.3%) a

74 cavernoma was not found, and 15 of them were re-operated on later, whereas four refused a re- operation. Twenty-one patients (7%) underwent a re-craniotomy due to incomplete resection of a cavernoma. One patient with an intraventricular lesion was shunted because of hydrocephalus, but later refused cavernoma removal. In one patient with uncertain MRI diagnosis, a biopsy was performed, which verified a cavernoma. The patient refused a re-operation and lesionectomy.

Table 16 Summary of clinical manifestations registered in the Helsinki Cavernoma Database

Symptoms No. of patients History of Operated on (%) bleeding (%) (%)

Epileptic disorder 141 (36.8) 48 (34) 128 (90.8)

Focal neurological deficit 76 (19.8) 23 (31) 67 (81.2)

Headaches 74 (19.3) 43 (57.3) 63 (85.1)

Vertigo 13 (3.4) 2 (15.4) 4 (30.8)

Visual disorder 6 (1.6) - 2 (33.3)

Memory disorder 6 (1.6) 1 (16.7) 5 (83.3)

Endocrinologic disorder 3 (0.8) - 2 (66.7)

Hyperkinetic movement disorder 1 (0.3) - 1 (100)

Incidental 63 (16.4) - 31 (49.2)

Outcome The mean follow-up time in this series was five years (range 0.2 – 36.2). Operated patients were followed on average for 5.6 years (range 0.2-36.2) and conservatively treated patients for 2.7 years (range 0.2-15.8). The vast majority of the patients showed a favorable general outcome (GOS 5 and 4) as 342 (89.3%) had no disability or only minor symptoms without significant limitation in every day activity. Eight patients (2%) had severe disability (GOS 3). Six of these patients had a symptomatic brain stem lesion, which was operated on. Furthermore, in one patient with multiple cavernomas surgical removal of a symptomatic lesion was performed at another hospital, but inadvertent injury to the median cerebral artery occurred leading to a massive infarct with subsequent hemiplegia and drug-resistant epilepsy. One patient had cardiac failure causing severe disability but notably, recovery after his frontal lobe cavernoma removal was uneventful. Four patients died during the follow-up and the overall mortality was 1%. Three of these patients died for reasons unrelated to a cavernoma, and one patient died after surgical removal of a brain stem cavernoma.

75 Intraventricular cavernomas Patients and symptoms Clinical data on the 12 patients are summarized in Table 10. Patients comprised eight men (67%) and four women (33%) showing a men preponderance of 2:1. The median age of the patients on admission was 47 years (range 15 – 66 yrs). As a presenting symptom, 11 patients (92%) had an acute mild to severe headache accompanied by nausea and vomiting. Three patients (27%) with a cavernoma in the fourth ventricle had cranial nerve deficits (paresis of III, VI, and VII nerves, separately or in various combinations). Four patients (36%) had hydrocephalus on admission but shunting was necessary in only one patient. Eight patients (67%) experienced extralesional hemorrhage confirmed by CT and lumbar puncture. In all but patient 12, bleeding was clinically and radiologically mild, and none of them required emergency surgery. Patient 12 had a large hematoma in the lateral ventricle which invaded the basal ganglia area, and presented with contralateral hemiparesis and progressive somnolence warranting emergency surgery. Re-bleeding occurred in three patients before lesionectomy and in two conservatively treated patients. One patient had two re-bleedings after partial resection of his lesion in the left lateral ventricle. A total of eight re-bleedings occurred in five patients (42%) during a median time of 0.4 years (range 0.1–5 yrs). These patients had a cumulative follow-up time of nine patient-years (from the first bleeding to surgery in operated patients, or from the first bleeding to the last follow-up in conservatively treated patients), thus yielding a re-bleeding rate of 89% per patient- year. None of the re-hemorrhages caused severe neurological deterioration, but led to a short- term hospitalization at referring hospitals. Later, patients were admitted to our department in stable condition for further evaluation and treatment.

Radiology The lesions and their location and size are presented in Table 17. In 11 patients, the intraventricular cavernomas were Zabramski type II lesions and in patient 12 type I. In comparison with the cavernomas of the group B, the typical perifocal hemosiderotic rim in group A cavernomas was thinner or absent, and the lesion core was less heterogeneous. Altogether, ten lesions belonging to group B were partially buried in the surrounding brain. In addition to an IVC, three patients had multiple type IV intraparenchymal cavernomas seen only in T2*- weighted Gradient-Echo sequences. In two patients, the lesion was initially interpreted as a choroid plexus papilloma and ependymoma, respectively, but a later histological examination confirmed it to be a cavernoma. In the other ten patients, the radiological diagnosis was initially

76 thought to be IVC. Six of the 12 IVCs were located in the lateral ventricle, mainly on the left side (Figure 18). In three cases, cavernomas were located on the lateral side of the body and atrium (trigonum) of the lateral ventricle. One patient had a lesion in the occipital horn of the lateral ventricle, attached to the choroid plexus (Figure 3a, b), and two patients had an IVC in the frontal horn, attached to the ependyma. One IVC was in the third ventricle without radiological signs of enlarged ventricles. In five patients (45%), an IVC was found in the fourth ventricle typically in the medial part of the floor (Figure 4a, b). The median size of the IVCs was 15 mm (range 10– 30 mm). IVCs of the lateral ventricles (median size 12 mm) were smaller than the ones of the fourth ventricle (median size 17 mm). The median size of the associated intraparenchymal cavernomas was 3 mm. Two patients, each with a cavernoma in the lateral ventricle, had an associated MRI-confirmed developmental venous anomaly.

Figure 18 Left lateral ventricle cavernoma. a – T2-weighted image, axial view; b - T2*-GRE image, axial view

a b

Treatment Nine patients underwent surgical excision of the IVC to prevent re-bleedings or to eliminate the mass-effect, or both. Median time from diagnosis to surgery was 1.3 years (range 2 days to 11yrs).One patient underwent emergency surgery because of a large intraventricular/intracerebral hematoma and progressive somnolence. Of the operated IVCs, three were located in the lateral, one in the third, and five in the fourth ventricle. In patients 3 and 12, a lesion of the left frontal

77 horn was exposed by paramedian craniotomy by an interhemispheric-transcallosal approach. Patient 5 with a cavernoma of the atrium of the left lateral ventricle was operated on three times. Initially, he underwent diagnostic stereotactic biopsy for an undefined lesion after intraventricular hemorrhage. Two months later he presented with intraventricular re-bleeding and was operated on via a parieto-occipital craniotomy and a transcortical approach to the ventricle. Four months after the first resection, he suffered from worsening headaches again; a CT scan showed intracerebral/intraventricular bleeding which was removed together with a cavernoma remnant. An MRI performed seven years after surgery still showed a small cavernoma remnant, but the patient refused further surgery. Patient 7 with a cavernoma in the third ventricle was operated on via a fronto-parietal paramedian craniotomy and an interhemispheric-transcallosal-transseptal approach. In this case, a strongly calcified lesion was evident in the region of the foramen of Monroe without hydrocephalus, grew upward into the septum pellucidum cavity, and had to be removed in a piecemeal manner. In five patients with fourth ventricle lesions a median suboccipital craniotomy was performed with the patient in a sitting position. The fourth ventricle was exposed via a telovelar approach by retraction of the cerebellar tonsils laterally.

Table 17 Radiological presentation of intraventricular cavernomas on MRI

(LV- lateral ventricle, FV- fourth ventricle, TV- third ventricle)

Patient Location Side Size (in mm) 1 LV left 10 2 FV left 18 3 LV left 10 4 FV left 10 5 LV left 20 6 FV midline 30 7 TV midline 25 8 FV midline 15 9 LV right 10 10 FV midline 10 11 LV left 12 12 LV left 10

Extremely gentle dissection of the lesion from the floor of the ventricle was performed. Tiny arterial feeders were coagulated with bipolar forceps under minimal voltage to avoid inadvertent damage to the subependymal vessels supplying the brain stem. In all of these patients, the cavernoma was partially buried in the brain stem, necessitating more invasive removal.

78 Postoperative complications are summarized in Table 18. One patient had postoperative intraventricular bleeding after partial resection.

Outcome The median follow-up of the 12 patients was two years (range 0.5 – 20 yrs) and total follow-up time was 70 person-years. No patients were lost to follow-up. Age, sex, and previous bleeding had no influence on the outcome. No mortalities occurred. Patients with fourth ventricle cavernomas had a worse outcome than did those with lateral ventricle lesions. Five of the nine patients operated on were symptom-free at follow-up (Table 18). The IVCs in the lateral ventricles and in the third ventricle were removed without any new permanent neurological deficits. A new cranial nerve deficit was seen postoperatively in patients 6 and 8 with a fourth ventricle lesion. Patients 4, 6, 8 and 12 presented with focal neurological deficits before surgery; patient 12 demonstrated complete recovery of his hemiparesis and had only mild memory disturbances at the five-year follow-up. Patient 7 had significant memory disturbances in the immediate postoperative period, but these completely resolved at the last follow-up at 1.7 years. One patient had a single epileptic seizure after partial resection of the lateral ventricle cavernoma, but after a re-operation and removal of the lesion the patient was seizure-free. Altogether, nine patients (75%) were asymptomatic or with only minor neurological problems, and three (25%) had persistent neurological deficit at the last follow-up. Two of them had deficits (VI, VII nerve paresis and memory disturbances in patient 4 and 12, respectively) before surgery. No patient had a severe disability.

Table 18 Postoperative course and complications after microsurgical treatment of nine patients with IVC

Patient On discharge Follow-up

2 Nausea, vomiting, gait disturbances no neurological deficits

3 Nausea, no new deficits no neurological deficits

4 Worsening of CN VI,VII peripheral paresis the same as preoperative CN VI, VII paresis preoperatively

5 Visual disorders and epileptic fit after first no neurological deficits resection, no deficits after the last surgery

(continued)

79 Table 18 Postoperative course and complications after microsurgical treatment of nine patients with IVC (continued)

6 new focal deficits – CN VII peripheral paresis, double vision, persistent CN VII peripheral paresis vertigo and gait disturbances

7 emotional alteration, no neurological deficits severe memory disturbances

8 new focal deficit - CN VI, VII paresis, worsening of preoperative CN VI, VII paresis double vision, vertigo and gait disturbances

10 Nausea and vomiting no neurological deficits

12 hemiparesis and memory disturbances the only minor memory disturbances, same as preoperatively, hemiparesis resolved completely

Discussion Special clinical features IVCs showed increased propensity for extralesional hemorrhage. In our consecutive series of the 12 IVC patients, eight (67%) experienced hemorrhage. Furthermore, the rate of re-hemorrhage was much higher than in other locations. In the literature, the re-bleeding risk is declared to be 5.1 - 60% per patient-year [2, 91, 94, 160, 237] being significantly lower than the 89% per patient-year demonstrated by our series. No data exists on the hemorrhage rate in IVC patients and the value of our results may be limited by the small size of the series but aggressiveness of previously bled IVCs was evident. In earlier reports, only 11 of 77 patients (14%) presented with IVH which is much less than in our series. Possibly, this is due to a more active policy of local general practitioners to send patients complaining of headaches for further evaluation. Immediate availability of CT imaging in all local district hospitals allows these patients to be imaged quickly after the disease onset, thus giving more chances to reliably diagnose fresh bleeding. A delay of even a few days decreases the sensitivity of CT to identify extravasated blood, especially when the hemorrhage is scanty. Profuse bleeding is not common in IVC patients, and in the present series, it caused no permanent neurological deficits in 11 patients. Only one patient had major bleeding that was potentially life-threatening and necessitated emergency treatment. During the short period of observation, five patients (45%) had altogether eight re-bleedings. However, in all but one neither the re-bleedings nor the primary bleedings led to any additional neurological deficits and required no emergency surgery. This is also in concordance with previous reports, where in the majority of cases, re-bleedings from IVC caused no significant permanent

80 neurological deficits. In our series, four patients (36%) had a hydrocephalus on admittance, but only one of them was shunted. In the literature, 42% of patients with IVC had a third ventricle lesion, and the majority of them developed hydrocephalus because of mechanical obstruction, whereas only three patients [123, 149, 320] presented with an intraventricular hemorrhage. At the same time, cavernomas of the lateral or fourth ventricles most frequently led to focal neurological deficits as a result of the mass-effect on the surrounding brain with acute impairment after bleeding (Figure 19). In our series, epileptic disorders occurred in one patient but only after partial resection of a lateral ventricle cavernoma, and this patient was seizure-free at the follow-up. In previous reports of patients with IVC, epileptic manifestations were more frequent, occurring in up to14% and almost exclusively in individuals with a lateral ventricle lesion. Thus, the frequency of seizures in IVC patients is significantly lower than in patients with intraparenchymal supratentorial cavernomas.

Figure 19 Fourth ventricle cavernoma in a patient with progressive paresis of the left hand and ataksia in legs

Special radiological features In patients with acute severe headaches, a CT scan is mandatory because of its high sensitivity in detecting fresh hemorrhage. However, in acute intraventricular bleeding the radiological diagnosis of the IVC is unreliable, and MRI is more informative after the resorption of

81 extravasated blood. In our series, MRI with MRA was performed immediately after bleeding only in patient 12 because of acute neurological deterioration to exclude tumor bleeding. DSA is also indicated to exclude an AVM when patient presents with a major intracerebral bleeding, which, however, is uncommon in individuals with a cavernoma. A cavernoma in the ventricle is not always limited by the ependyma and can extend to the surrounding brain and we classified cavernomas into three groups, accordingly. Although our classification is only empirically based, we suppose that in clinical practice the treatment strategy of the cavernomas of group C is quite similar to intraparenchymal ones.

Treatment of the IVC, morbidity and mortality Surgery is advocated when re-hemorrhages are frequent and the mass-effect causes progressive neurological deficits. In our series, repetitive re-hemorrhages accompanied by acute headaches with nausea and vomiting occurred often and caused discomfort. Furthermore, patients with fourth ventricle IVC developed cranial nerve deficits because of the mass-effect. A major bleeding occurred only in one of our patients; although uncommon, this still demonstrated the potential risk of severe hemorrhage from a cavernoma thus advocating operative treatment of the IVC. Four of our nine patients who were operated on had neurological deficits that persisted at follow-up, but in two of these deficits were already present before surgery (Table 18). In estimating operative risks, the location of the IVC is of major importance. Surgery on the IVC in the lateral or third ventricle is safer than in the fourth ventricle. Patients with cavernomas close to the brain stem frequently present preoperatively with cranial nerve deficits as a sign of brain-stem damage. Therefore, the increased morbidity in our series may be explained by our rather short follow-up and also by five of the eight patients operated on (63%) having the lesion in the fourth ventricle where surgical removal is known to entail higher risks.

Future trends Increasing numbers of incidentally found IVCs are to be expected with the increased number of MRI examinations. The management of these patients requires meticulous diagnostic work-up and evaluation of morbidity during the natural course of the disease weighted against the risks of surgical removal. The most dangerous manifestation of an IVC is a hemorrhage which, nevertheless, can usually be tolerated well. The development of laboratory tests or new imaging modalities allowing a lesion that is about to bleed to be recognized even in asymptomatic patients would be an invaluable aid in a neurosurgeon’s decision-making on how to manage a particular patient.

82 Multiple cavernomas Patients and symptoms In our series, a slight men preponderance was identified; of 44 patients with MCs, 25 were men (56.8%) and 19 were women (43.2%). Their mean age at diagnosis was 43.6 years (range 4-69 yrs) and 36.3 years (range 0.6-71 yrs), respectively. Five patients (11.4%) were younger than 18 years. Three patients (9%) had an MRI-confirmed family history of cavernomas in first-degree relatives. Mutation analysis as a routine diagnostic tool was not performed. Seven patients (21%) were admitted as emergencies with progressive worsening of symptoms, including epilepsy, headache, nausea, or focal neurological deficits (Table 19). Two patients had significant memory deficits, confirmed by neuropsychological testing. Three patients had incidentally revealed MCs. Nineteen patients (43.2%) had a history of one or more symptomatic extralesional hemorrhages; of these, 12 patients (63.2%) had one, four patients (21%) had two, two patients (10.5%) had three, and one patient had four bleedings. No statistically significant gender preponderance for hemorrhages was found. Altogether, 18 patients (40.9%) had an epileptic disorder, and six of them (33.3%) had an intracerebral hemorrhage from the cavernoma on admission. The mean age of the patients at epilepsy diagnosis was 42.1years (range 0.6 to 69 yrs), and there were 11 men (61.1%) and seven women (38.9%).

Table 19 Clinical presentation of patients with MCs

Symptoms All patients History of hemorrhage (%) (%)

Seizures 18 (41) 6 (33.3)

Headache 12 (27) 7 (53.8)

Focal neurological deficit 7 (16) 6 (85.7)

Memory disorder 2 (4.6) -

Visual disorder 1 (2.3) -

Vertigo 1 (2.3) -

Asymptomatic 3 (6.8) -

83 Figure 20 Patient with hundreds of type IV cavernomas. a - T2*-GRE image, axial view; b - T2-weighted image, axial view. Type IV cavernomas can not be seen whereas Type II and III lesions are evident

a b

Radiology One patient had 532 lesions, most of them belonging to Zabramski type IV (Figure 20). This patient was considered a statistical outlier and omitted from further analyses. In the remaining 43 patients, a total of 230 lesions were found. There were 112 cavernomas of type IV and 13 cavernomas of type I. The number of cavernomas of types II and III was almost equal (51 and 54, respectively). The median number of lesions per patient was six. Type I cavernomas were bigger than those of types II and III both supratentorially (average size 24 mm, 12 mm, and 7mm, respectively) and infratentorially (17 mm, 13 mm, and 8 mm, respectively). The largest lesion (50mm) was a frontal cavernoma of type I that radiologically presented as a rare cystic form. In two patients, the measurement and radiological classification of the lesions were unreliable. One had a conglomerate of cavernomas on the parietal region with growth even through the parietal bone, and the other had numerous skin and bone cavernomas in the craniofacial region and in other organs (blue rubber bleb nevus syndrome). Ten patients (22.7%) had an associated venous anomaly (Figure 21). Three had an associated meningeoma.

Treatment Fourteen patients (31.8%) were treated conservatively. Three had numerous small lesions of

84 different radiological types, making removal practically impossible. In six patients, the risks of microsurgical removal were considered too high because of eloquent location. Three patients refused any surgical procedures. None of the patients were treated with stereotactic radiotherapy. Microsurgery was performed on 30 patients (68.2%), and a total of 34 cavernomas were removed. Surgical treatment was carried out in patients with hemorrhagic and/or epileptogenic cavernomas that had led to neurological deficits or drug-resistant epilepsy and that could be safely removed. In the majority of cases, the removed cavernoma was the largest lesion and usually with signs of recent bleeding. Other cavernomas typically belonged to type III or IV and were treated conservatively. Twenty patients (45.5%) were operated on once, whereas eight patients (8.2%) underwent two procedures, and two (4.5%) had three surgeries. In most cases, surgery entailed the removal of one lesion. In some patients, two lesions were removed in one session. One of them had three consecutive bleedings from both lesions, which were located in the medulla oblongata close to each other and removable with the same approach. Another patient suffered from temporal complex partial seizures, with transformation to generalized seizures, and the frontal and temporal lesions on the right side were removed via a frontotemporal approach. Gross total removal of the symptomatic lesion was accomplished in 26 of 30 cases (86.7%). In three patients, a lesion could not be localized and removed despite use of neuronavigation, and these patients refused further procedures. One patient underwent partial resection of the lesion, which however, remained stable during follow-up. One patient had numerous lesions in the parietal convexity, with extra- and intracranial growth through the parietal bone and along the left side of the falx suggesting meningiomas, but surprisingly histology revealed a cavernoma.

Figure 21 DVA in the right basal ganglia region associated with two type IV cavernomas. a - T2*-GRE image, axial view; b - T1 –weighted image with Gadolinium contrast, axial view; c - T1 –weighted image with Gadolinium contrast, coronal view.

a b c

85 Outcome The mean follow-up was 7.7 years (range 0.3 - 43 yrs) and the total follow-up was 254 person- years. No patients were lost to follow-up and no deaths occurred. Thirty-four patients (77.2%) had no disability (GOS V), nine (20.5%) had moderate disability (GOS IV), and one (2.3%) had severe disability (GOS III). No statistically significant difference in Glasgow Outcome Score was observed between nonsurgical and surgical patients at follow-up (Pearson’s chi-square test, p>0.05). Postoperatively, one patient experienced temporary hemiparesis, and another patient developed mild expressive dysphasia that persisted over the four-year follow-up. During the follow-up four patients suffered from a CT-verified intracerebral hemorrhage. All of them presented with acute severe headache that did not lead to any permanent neurological deficits or death. Bleedings occurred only in conservatively treated patients. A patient with 532 cavernomas suffered from three symptomatic bleedings during nine years of follow-up. She recovered well from the hemorrhage-related focal neurological deficits but developed moderate disability due to progressive psychiatric disorders requiring long-term hospitalization. In other four patients with history of hemorrhage, three had no disability (GOS V) and one patient had moderate disability (GOS IV) at the follow-up. Fifteen patients suffering from seizures were operated on and three were treated conservatively. Mean follow-up time in this group was 5.8 years (range 0.3-20 yrs). Ten of the 15 patients (66.7%) became seizure-free with four of them discontinued AEDs (Engel class 1). Three (20%) had only rare seizures, and none worsened. Of the three nonsurgical patients, one was seizure- free at follow-up whereas two had occasional epileptic seizures despite anticonvulsant therapy. In patients with Engel I outcome, only minimal doses of anticonvulsants were recommended. MRI was performed during follow-up on 22 patients (Case 1 was assessed separately, although MRI follow-up was also performed). The mean time between the primary and the last MRI was 3.9 years (range 0.2 - 17 yrs). In this group, the total number of lesions of all types in the follow- up MRI was 173. At the primary MRI, these 22 patients had 144 lesions, 25 of which were removed. Altogether, 54 de novo lesions were found, 48 (89%) belonging to type IV. Follow-up MRI showed that lesions had changed from type I to II in one patient, from type II to III in one patient, and from type III to II in one patient. In seven patients (49%), the type II cavernoma had enlarged by a mean of 2 mm. We also found a decrease in size by 2 mm in two patients with type II lesions and by 12 mm in one patient with type III lesions.

Discussion In our series, almost 70% of patients with MCs were surgically treated. A decision of whether to operate or not and which lesion to remove may be difficult due to the rare possibility to excise all

86 lesions in the same session. Furthermore, lesionectomy of the “wrong” cavernoma would not alleviate symptoms, but may carry additional surgical risks. Although in our series, the biggest cavernomas were usually the most active and showed signs of recent bleeding, the remaining lesions may also bleed or cause epileptic disorder in the future. Usually, those not operated on are smaller in size, mostly of type III or IV, which seem to be inactive. However, they possess some potential for transforming to more aggressive types [53]. Still, we cannot predict which lesion carries the risk for clinical manifestations and whether prophylactic removal of radiologically inactive cavernomas is advocated. When dealing with a single cavernoma, these questions are usually not relevant, but patients with MCs naturally necessitate a different way of planning. If one decides not to operate, observation and follow-up MRI are essential to exclude progression of the disease, which can be seen either as an increased number of lesions or as an enlargement of existing cavernomas. Also, conversion to other radiological types is possible. No definitive recommendations exist on how frequently patients should be imaged for a timely diagnosis. The dynamic nature of cavernomas could be seen in up to 77% of patients, with lesions undergoing some volumetric changes [55]. Furthermore, in 50% of our patients undergoing follow-up MRI, type II lesions enlarged during the follow-up indicating progression of the disease. If patients have symptoms supported also by radiological progress, aggressive treatment of the most active lesion may be warranted, especially in younger individuals. When patients remain stable or asymptomatic but follow-up MRI shows evolution of the disease, the threshold of the surgeon to operate should be much higher. Risks of bleeding and epilepsy in MC patients are higher than in patients with single lesions increasing with the number of type I-III lesions. [168, 235, 343] No data exist about the epileptogenicity or bleeding potential of type IV cavernomas, which occur most frequently in MC patients. However, in 89% of our cases these lesions were de novo cavernomas and reflected radiological progression; similar data have been obtained by other authors [168, 169, 343]. In our series, no bleedings occurred in operated patients during the follow-up. We had no patients with bleedings from two or more lesions simultaneously. Four conservatively treated patients had a hemorrhage during the follow-up. Although we did not find a statistically significant difference in Glasgow Outcome Score between operated and nonoperated patients, we believe that surgical removal of the most aggressive “correct” lesion will diminish the overall hemorrhage and epilepsy risk, and thus, is beneficial for the patient. Epileptic seizures occurred in 41% of our patients, indicating surgery especially when epilepsy was drug-resistant. In 35% of the patients with seizures, the lesion had bled on admission, which was also an indication for surgery. Of the surgically treated patients, 67% were seizure-free at the last follow-up (Engel class I), and only minimal doses of antiepileptic drugs were

87 prophylactically used. These data are comparable with previous reports on single cavernomas [44, 57, 90], confirming the effectiveness of surgical treatment of patients with MCs. Postoperative seizure-free state has also been reported to be associated with the number of preoperative seizures and female gender [57]. However, we found no significant correlations between outcome and gender or age of surgical patients, probably because of the relatively low number of patients in our study. Microsurgical techniques used in lesionectomy performed on MC patients are similar to those of a single cavernoma removal. Minimal invasiveness and a simple and rational approach to avoid any additional damage to the vasculature or parenchyma will ensure uneventful postoperative course.

Spinal cavernomas Patients and symptoms Basic characteristics of the patients are presented in Table 12. In nine patients (63%), the cavernomas were intramedullary, while four patients (29%) had an extradural lesion (Table 20) and one patient [156] had an intradural extramedullary cavernoma with an isolated intramedullary hemorrhage (Figure 22). The median age at presentation was 45 years (range 20- 57 yrs), with an equal number of women and men. The median duration of symptoms before admission to our department was one year (range 24 hrs -14 yrs).

Table 20 Presentation of intra- and extramedullary cavernomas

Characteristics Intramedullary Extramedullary (%) (%)

Number of patients 9 (63) 5 (37)

Symptom progression fast 4 (45) 4 (80) slow 5 (55) 1 (20)

Hemorrhage yes 6 (67) 1 (20) no 3 (33) 4 (80)

Patients suffered from sensorimotor paresis, radicular pain, or neurogenic micturition disorders in different combinations or separately as follows, a) Cervical region cavernomas (six patients): two suffered from severe tetraparesis, two presented with Brown-Sequard syndrome with ipsilateral paresis and contralateral pain and temperature loss below the lesion, and two had upper extremity

88 Figure 22 Case of extramedullary intradural cavernoma (arrow) causing intramedullary hemorrhage

sensorimotor deficits accompanied by severe radicular pain. Bladder functions were impaired significantly in only one patient, b) Thoracolumbar region cavernomas (seven thoracic and one conus medullaris lesion): four patients presented with paraparesis combined with bladder dysfunction and numbness. Others suffered from drug-resistant radicular pain, numbness, and motor paresis of one of the lower extremities. Micturition disorders occurred in three patients. Three patients (21%) presented with acute onset of symptoms, with rapid neurological decline indicating emergency surgical treatment. Five patients (36%) had a gradual progression of neurological deficits over one month preceding surgery and six patients (46%) had slow progression over more than a year. In two patients (14%), the symptoms improved before admission to our hospital, but surgery was performed to prevent hemorrhage and potential neurological decline. Hemorrhage occurred in seven patients (50%) before surgery. Four of them experienced acute neurological deterioration, warranting further investigations immediately after onset. However, two patients with hemorrhage did not have acute onset of the disease, deteriorating slowly over the course of several weeks. On MRI, signs of a recent hemorrhage were found. One patient had symptomatic re-bleeding after 14 years of follow-up; he was intact after the first hemorrhage which was treated conservatively, but deteriorated acutely due to re-hemorrhage, indicating surgical removal of the lesion.

89 Treatment Indications for microsurgical removal of a spinal cavernoma were progressive neurological deterioration in 12 patients (86%) and prevention of bleeding and consequent neurological decline in the remaining two patients (14%). Three patients (21%) with a sudden onset of the disease were operated on within 24 h. Two of them with a cervical cavernoma developed severe tetraparesis and one with a lower thoracic cavernoma developed complete paraparesis. Nine patients (64%) underwent a hemilaminectomy and five (36%) a laminectomy. In cases of hemilaminectomy, the exposure was performed on the appropriate side to minimize the distance to the lesion. In patients with an epidural cavernoma, a lesion was revealed in the epidural space immediately after removal of the ligamentum flavum. Intradural cavernomas were approached by a sharp incision of the dura and arachnoid and exposure of the affected medullary segment. Myelotomy was performed at the discolored or bulging medullary surface suggesting a cavernoma or the site where the lesion had surfaced. When the location of the IC was indistinguishable on the surface, a gentle longitudinal incision of the pia and medulla was performed at the suspected site of the lesion until the pathology was exposed. Due to operating neurosurgeon preferences, no neurophysiologic monitoring was performed. In cases of a hemorrhage from a cavernoma, the hematoma was aspirated first to decompress the medulla, and thereafter, the cavernoma was removed in a piecemeal fashion to minimize distortion of the normal neural tissue. Accurate hemostasis was performed by low voltage bipolar coagulation and local hemostats. The dura was closed in a watertight manner to prevent CSF leakage. After a median of five days (range 3 -13) at our department, patients were discharged home or transferred to referring hospitals for further rehabilitation. Immediately after surgery, eight patients (57%) showed improvement of the symptoms, while two (14%) remained the same and four (28%) complained of worsening of symptoms; two of these patients experienced new neurological deficits. At discharge, altogether ten patients (71%) experienced improvement of their neurological status, three (21%) had worsening of the symptoms or some new deficits, while one patient remained the same. Four patients (28%) were re-operated on. In two of them, the cavernoma could not be found during the first operation, one had a re-growth of the removed cavernoma, and one with a giant cavernoma causing vertebral fracture underwent three posterior decompressions because of progressive growth of the lesion (laminectomy, followed by re-laminectomy and postoperative hematoma evacuation) and transpedicular fixation and biopsy of the lesion, followed by radiotherapy; ultimately with a good outcome.

90 Outcome Patients were followed for a median of three years (range 1-10 yrs). At the last follow-up, eight patients (57%) experienced further improvement of their symptoms since discharge two of them (15%) recovering fully (Table 21). Five patients (36%) had the same neurological disorders as at discharge from the hospital. One patient (7%) was worse than preoperatively. In seven patients (50%), their deficits did not affect everyday life, while seven (50%) had some mild limitations. No patient had severe disability or died.

Table 21 Available postoperative outcome data in the literature and for the present series

Patients Worsened Same Improved Total n (%) n (%) n (%) n

Intramedullary 26 (9) 85 (29) 180 (62) 291 reported

Intramedullary present series 1 (12) 4 (44) 4 (44) 9

Extramedullary 1 (2) 5 (8) 54 (90) 60 reported

Extramedullary present series 0 1 (20) 4 (80) 5

No difference in outcome was observed between cervical and thoracolumbar cavernomas (Table 22). The extramedullary location proved to be better and safer regarding outcome; four of the five patients (80%) demonstrated further improvement of symptoms, whereas only four of eight (50%) with an intramedullary lesion did the same. Five of the seven patients (71%) with a history of hemorrhage had some disability at follow-up, in contrast to only one of the seven nonhemorrhagic patients (14%). Aggressive behavior of the disease preoperatively accompanied by rapid neurological deterioration was detrimental regarding outcome; five of the seven patients with fast progression (71%) had a worse outcome, while only two patients who deteriorated slowly (33%) had a poor outcome.

91 Table 22 Follow-up data in present series

Good recovery Characteristic without Mild disabling disability deficits (%) (%)

Level Cervical 3 (50) 3 (50) Thoracolumbar 4 (50) 4 (50)

Location Extramedullary 4 (80) 1 (20) Intramedullary 4 (44) 5 (56)

Hemorrhage history yes 2 (29) 5 (71) no 6 (86) 1 (14)

Symptom progression fast 3 (38) 5 (62) slow 4 (67) 2 (33)

Total 7 (50) 7 (50)

Recovery from sensorimotor paresis All patients underwent active rehabilitation after surgery at referring hospitals. Twelve patients (86%) showed significant recovery of sensorimotor paresis at the last follow-up as compared with their preoperative state. Five of them were able to walk independently and the remaining seven with a cane or a rolling walker. Two patients experienced some new permanent sensorimotor deficits after surgery, which impaired their mobility and ability to work.

Recovery from pain Ten of the 14 patients (71%) suffered from radicular pain before surgery. During the follow-up nine of these patients showed significant pain relief and did not complain of any disturbing pain. Only one patient (10%) developed permanent painful allodynia in her hand.

Recovery from bladder dysfunction Micturition disorders were registered in six patients (43%) at follow-up, with five of these present already before surgery. No patient experienced significant improvement of micturition after surgery. Patients suffered from urinary incontinence, increased residual urine volume, and loss of

92 voluntary emptying of the bladder requiring bladder auto-catheterization daily. Frequent urinary tract infections were common, often requiring oral antibiotics. Two patients developed hyperactive bladder disorder with increased urinary frequency of up to 12 times a day accompanied by urge incontinence. In one of these patients, this disorder was not present before removal of the cavernoma. One patient was treated with anticholinergics followed by sacral epidural stimulation performed by an urologist without success.

Discussion Based on our series, spinal cavernomas can cause marked neurological deterioration due to their mass-effect or hemorrhage. In fact, 21% of our patients developed acute severe tetra- or paraparesis within a time span of only a few hours, requiring emergency surgery. In the literature, acute deterioration was reported in up to 38% of patients, and 70% of these were related to hemorrhage [75, 171]. Even without an acute onset, cavernomas affecting the spinal cord can cause neurological deterioration by chronic microhemorrhages into the surrounding tissue, with subsequent gliosis and progressive myelopathy. Although observation is reported to be an alternative to active surgical treatment [153], accumulating evidence confirms the dynamic nature of spinal cavernomas, with a tendency towards clinical deterioration often warranting operative treatment [140, 171]. Even considering that the annual bleeding rate in spinal cavernomas is relatively low, preventive removal of cavernomas before hemorrhage is more beneficial for patients than surgery after bleeding. Postoperative complications are usually mild and mostly transient. Indeed, although immediately after surgery, one-third of our patients demonstrated worsening of their neurological status with the appearance of new deficits in some, at the three-year follow-up, only one patient (7%) complained of significant surgery-related deficits while the others had improved or symptoms had completely resolved. In the literature, patients with intramedullary and extramedullary lesions showed improvement at the last follow-up in 62% and 90% of cases, respectively, in concordance with our series with corresponding rates of 44% and 80% (Table 21). Persistent worsening of the neurological state registered at long-term follow-up occurs rarely in both groups, but was more frequent in the intramedullary location both in the literature and in our series. Therefore, we suggest that the compression of rootlets by extramedullary mass seems to be better tolerated than myelopathy caused by intra-axial cavernoma affecting the gray and white matter of the spinal cord from within. Furthermore, myelopathy caused by cavernoma microhemorrhages aggravated by surgical manipulation explains the slower recovery process after intramedullary cavernoma removal. It is unclear whether ECs have different growing patterns or hemorrhage rates than intramedullary lesions. Interestingly, in our series ECs were characterized by a fast progression of

93 neurological deficits in 80% of the cases, in contrast to only 45% for ICs. However, only one of the five patients with ECs presented with a hemorrhage. Thus, one of the reasons may be a faster growing pattern of extramedullary lesions. In our patients, thoracic cavernomas were less common than reported previously, constituting 50% of cases, while cervical cavernomas occurred in 43%. None our patients had a cavernoma involving the cauda equina, which is extremely rare in the literature, with only 14 cases described to date.

Prognosis In our series, the follow-up period was a median of three years, being long enough to reliably assess the postoperative course. An extramedullary location and slower neurological deterioration in IC cases before surgery appeared to be beneficial regarding functional outcome. Most of our patients (93%) improved or remained stable in concordance with previous reports [143]. Age, sex and severity or duration of symptoms before surgery did not correlate with outcome. In contrast, some authors have reported that shorter duration of symptoms before surgery was related to a better outcome particularly in ECs [349]. Hemorrhage had a strong association with a worse outcome; five of our six patients with motor disability at follow-up had a hemorrhage before treatment, while six of seven nonhemorrhagic patients demonstrated no disability. Furthermore, patients with a rapid progression of neurological deficits had a worse postoperative outcome in 71%, while slow deterioration led to an unfavorable outcome in only 33%. In previous reports, scrupulous depiction of the persistent neurological status at the long-term follow-up was uncommon; status was most frequently assessed using gradation as follows: worse, same, or improved. In our series, we analyzed recovery from sensorimotor deficits, pain, and bladder disorders separately.

Patients with sensorimotor deficits Recovery from a sensorimotor deficit seems to be quite probable, as most (86%) of the patients experienced significant improvement in mobility and all patients were able to walk with or without aid. However, two of our patients demonstrated progressive decline of motor function after surgery. One of them was operated on three times because the lesion could not be identified at the first attempt, and the second surgery was limited to biopsy only. Finally, in the third operation the cavernoma was removed, and afterwards the patient could walk with some spasticity. The other patient with a lower cervical lesion was operated on one year after the onset of symptoms and before surgery her deficits had disappeared. After surgery, she developed tetraparesis which resolved significantly but her left hand remained weaker and her legs were atactic.

94 Patients with pain Our patients demonstrated good recovery from pain in 90% of cases. No difference existed between extra- and intramedullary cavernomas regarding pain relief. Only one patient complained of gradually worsening pain, which appeared after removal of the cavernoma with only partial alleviation after medication (allodynia). In our series, there was no pain recurrence at follow-up among those who presented with pain before surgery. This finding is opposite to the reported data, in which long-term pain resolution was shown in up to 50% of the patients, while others had recurrent pain [154].

Patients with bladder dysfunction Although bladder disorders were present in one-third of our patients, comparison with other studies can not be made since published outcome data after surgery on bladder function are nonexistent. Naturally, this defect is important clinically and socially, especially in young adults. Micturition disorders remained almost unchanged in all of our patients presenting with a bladder dysfunction preoperatively. Furthermore, one patient developed micturition disorders after surgery. Typically, at onset, patients presented with an atonic bladder with urine retention requiring catheterization preoperatively. During the postoperative period two patients developed hyperactivity and dyssynergy of the bladder, with high daytime urinary frequency and urge incontinence.

Temporal lobe cavernomas Patients and symptoms In total, 49 patients were operated on. Patient demographics are presented in Table 13. The women:men ratio was 2.5:1. The median age of the patients at radiological diagnosis was 37 years (range 7-64 yrs). Epileptic seizure was the most frequent symptom occurring in 40 patients (82%). The median duration of seizure activity before surgery was three (range 0.1-23) years. In these patients, the cavernoma was diagnosed at a median of 0.7 years (range 0.1-22 yrs) before admission to our department. Seizure had begun within one year before surgery in 16 patients (40%), between one and ten years in 14 patients (35%), and more than ten years before surgery in ten patients (25%). Of the 40 patients with seizures, 28 (70%) presented with secondary generalized tonic-clonic (SGTC) seizures, five (12%) with simple partial (SP) seizures and seven (18%) with complex partial (CP) seizures. The type of epileptic seizure preoperatively was the same as at presentation in 18 patients (45%). Notably, ten patients (25%) had not experienced any new seizures after the first one. The median age of the patients in this group was 31 (range 10-52)

95 years. In 16 patients, the number of preoperative seizures ranged from two to five, and 14 patients had numerous seizures before surgery. Four patients with epilepsy (10%) complained of mild memory disorders which did not limit everyday life and the referring clinician had not considered worthy of neuropsychological testing. The preoperative seizure type and frequency of epilepsy are presented in Table 23. Seven patients (18%) with only one seizure did not use any antiepileptic drugs (AEDs), 26 (65%) had monotherapy and seven (17%) had polytherapy. In 21 patients (53%), seizures occurred despite the use of at least two basic AEDs. Three patients without a history of seizures (6%) complained of headache and two (4%) had minor short-term memory disturbance at presentation. Three patients (6%) had an incidental cavernoma on MRI. Before surgery, nine patients (18%) had a hemorrhage confirmed by CT. Altogether, 12 bleedings occurred; seven patients had a single event, one had a re-bleeding, and one had two re- bleedings. None developed life-threatening hemorrhage. All of these patients were operated on within six months of the event.

Table 23 Data of 40 patients with a preoperative history of epilepsy

Characteristic SGTC (n=28) CP (n=7) SP (n=5)

Median duration of epilepsy preoperatively, years (range) 3 (0.1-30) 5 (1-26) 1 (0.5-18)

No. of seizures 1 7 (25%) 2 (29%) 1 (20%) preoperatively 2-5 13 (46%) 1 (14%) 2 (40%)

6-10 3 (11%) 1 (14%) -

10+ 5 (18%) 3 (43%) 2 (40%)

First EEG** Normal 7 (35%) 1 (14%) 3 (100%)

Pathological with 13 (65%) 6 (86%) - epileptiform activity

Type of Same as on debut 12 (43%) 3 (42%) 3 (60%) seizures during observation Partial only 1 (4%) - -

Both partial and secondary generalized 7 (25%) 2 (29%) 1 (20%) * Type of seizure on debut ** Performed on 30 patients

96 Treatment A decision to operate was based on our department’s policy stating that any symptomatic cavernoma should be removed when surgery can be performed without considerable neurological deficits. The goal of the surgery was not only to improve the persistent symptoms but also to prevent any deterioration due to a cavernoma hemorrhage. Lesionectomy was performed in 38 of 40 patients (95%) presenting with seizures. The two remaining patients had an epilepsy history of more than ten years and were evaluated by our epilepsy team. In both, ictal video EEG detected a temporal epileptic focus and MRI showed an abnormal hippocampus. In addition to removal of the cavernoma, one patient underwent amygdalo-hippocampectomy and the other temporal lobe resection. Cavernoma excision was performed using standard microsurgical techniques. When located in the anteromedial part of the mesial temporal region, the cavernoma was removed via a transsylvian approach, and in other locations transcortically using the shortest route to the lesion. When appropriate, intersulcal dissection was used to minimize cortical damage. Surgery was usually facilitated with a frameless neuronavigation system, and in 45 patients (85%), the cavernoma was found and removed completely at the first attempt. Removal of surrounding gliosis and hemosiderosis was included whenever considered safe. In two patients, the cavernoma was not found despite neuronavigation, and a re-operation after re-scanning became necessary. In two other patients, after a seemingly complete removal, the MRI showed a residual cavernoma, and a re-operation was performed.

Outcome Seizure outcome Follow-up data were available for 39 patients with seizures. One patient coming to Finland for surgery from abroad was lost to follow-up. Median follow-up in this group was six (range 1 – 26) years after surgery (Table 24). All ten patients who had only one seizure preoperatively were seizure-free during the follow-up. Of 16 patients who had experienced between two and five seizures preoperatively, 11(69%) were seizure-free, and of 13 patients with numerous seizures preoperatively, nine (69%) were seizure-free. Three patients (5%) had only a minor improvement of their epilepsy (Engel class III), and one had worsening of the symptoms, all four with numerous seizures before surgery. Neither type, duration of seizures, nor location of the cavernoma inside the temporal lobe correlated with postoperative seizure outcome. Only one of the ten patients who had epilepsy for more than ten years had an unfavorable outcome. The predictive value of preoperative EEG was stronger, and eight of the ten patients (80%) with normal preoperative EEG were seizure-free at

97 follow-up, whereas only 11 of the 18 patients (61%) with epileptiform abnormalities in preoperative EEG were seizure-free after surgery. Seven of the eight patients with epilepsy who had a radiologically confirmed hemorrhage from the cavernoma had a favorable seizure outcome, five being completely seizure-free. Neither the volume nor the number of bleedings correlated with seizure outcome. In 15 patients (39%), AED had been withdrawn or the dosage had been decreased during the follow-up. In some cases, an EEG abnormality had postponed the attempt to withdraw medication, but in the majority of cases the reason for postponement was fear of seizure recurrence.

Table 24 Seizure outcome data

Characteristic History of seizures (n=39)

AED after surgery Finished 10 (26%)

Dose diminished 5 (13%)

Same dose 13 (33%)

Never used 7 (18%)

Dose increased or additional AED 4 (10%)

Engel outcome at the last Class I 30 (77%) follow-up Class II 5 (13%)

Class III 1 (2%)

Class IV 3 (8%)

At follow-up, 13 patients (33%) continued with the same AED at the same dosage as before surgery, and three (8%) of them had numerous seizures after surgery. In the latter group, one patient had a concurrent psychiatric disorder with drug abuse and inadequate medication compliance. In another patient, hippocampal signal abnormality was observed on follow-up MRI. The third patient with an unfavorable outcome had undergone temporal lobectomy due to hippocampal sclerosis in addition to removal of the cavernoma.

General outcome Favorable outcome (GOS 5 and 4) was seen in 46 (96%) of the 48 patients, only one patient (2%) had a severe disability (GOS 3) because of a worsened memory deficit, and one patient (2%) died

98 (GOS 1) because of unrelated liver insufficiency. All patients were followed up for a median of six years (0.2 – 26 yrs) after surgery. Two patients had a postoperative subdural hematoma needing evacuation but recovered well. Two patients had a mild visual field deficit, one had mild dysphasia, and one had mild vertigo (Table 25).

Table 25 Postoperative course

Characteristics Before At follow- discharge up

No complications 41 36

Acute subdural hematoma 2 -

Focal neurological deficit 2 2

Meningitis 1 -

Wound infection 2 -

New/worsened memory 4 4 disturbances

Dysphasia 1 1

Coordination problems - 2

Overall morbidity 12 (24%) 9 (18%)

At follow-up, nine patients (18%) had a new or worsened neurological deficit. Two of them (4%) developed a new mild memory deficit. Of six patients with a mild memory deficit before surgery the memory function worsened (moderate and severe) in two and improved in one. Only three patients underwent testing by a neuropsychologist. One patient with a mild disorder was examined with a routine MMSE test in a local hospital. Memory disorder was present in five patients with a history of epilepsy, but four of these patients already had this problem preoperatively (Table 26). In one patient with progressive memory decline, an MRI ten years after the operation showed bilateral hippocampal atrophy (Scheltens grade III). Although the continuing seizure activity was believed to have contributed to the cognitive deficits, Alzheimer's disease was also suspected at the last follow-up visit. Median duration of preoperative seizures in patients with memory disorder was 5.2 years (range 3-28 yrs). They were followed over a median of 4.2 years (range 0.2-20 yrs) after surgery.

99 Location of the cavernoma inside the temporal lobe did not correlate with the severity of the memory problem. We found no correlation of general outcome with age, side or size of lesion, bleeding status, or type or frequency of seizures. However, patients with a cavernoma in the medial part of the temporal lobe had worse postoperative outcome compared with those patients with the lesion in the anterior or posterior part of the temporal lobe (Table 27). None of the asymptomatic patients developed deficits postoperatively, and all of them remained intact during the median follow-up of eight years (range 2-9 yrs).

Table 26 Patients with memory disturbances at the last follow-up

Discussion Characteristic No. of patients (%) Indications for surgery Gender Temporal lobe cavernomas are frequently Male 1 (14.3) associated with epileptic disorders and are often Female 6 (85.7) drug resistant. This tendency was also discovered in Type of seizure (if present) our series, since 53% of patients had seizures refractory to AED. No exact data explain the SGTC 3 (42.9) CP 1 (14.3) mechanisms of high epileptogenicity of TLCs, but SP 1 (14.3) close distance to limbic structures is likely to be a Location cause of intractable seizure activity [15]. MTL 3 (42.9) ATL 2 (28.6) Furthermore, progressive damage of the PTL 2 (28.6) mesiotemporal region, followed by subsequent Lateralization cognitive deficits and behavioral alterations with a left 6 (85.7) higher incidence of suicide attempts or accidents is right 1 (14.3) observed in patients with temporal epilepsy Course existed preop 6 (85.7) necessitating prompt treatment of epileptogenic improved postop 1 (14.3) cavernomas in the temporal region [265, 266]. In new postop 2 (28.4) worsened postop 2 (28.4) these cases, surgical removal of the epileptogenic Epilepsy outcome cavernoma is indicated to eliminate negative effects

favorable 4 (57.1) of chronic epilepsy. Results of operative treatment not favorable 1 (14.3) of TLCs reported previously and also documented General outcome in our patients confirm the effectiveness of this good recovery 4 (57.1) strategy. In our series, 90% of patients experienced moderate disability 2 (28.4) severe disability 1 (14.3) improvement in seizure frequency, with 77% becoming seizure-free after surgery. Although 25% of our patients had only one seizure before surgery, convincing improvement in close to 70% of patients with chronic epilepsy showed

100 obvious benefits of lesionectomy.

Table 27 Correlation of Glasgow Outcome Score with location of cavernoma

Glasgow Outcome Score MTL ATL PTL

GOS 5 7 (58%) 13 (86%) 20 (95%)

GOS 4 4 (34%) 1 (7%) 1 (5%)

GOS 3 - 1 (7%) -

GOS 1 1 (8%) - -

Predicting the development of epilepsy in an individual patient is still not possible. Only ten of our patients had one seizure preoperatively and some of them had no AEDs before surgery. A single seizure may not indicate major epileptogenic potential of a lesion, and it is quite possible that no further seizures would have occurred, or if so, they might have easily been controlled by medication. In our series, the average age of the patients with a single seizure was only 31 years. Considering that the cavernoma is often characterized by radiological changes and clinical progression, we felt that even one seizure warranted surgery in this particular group, thus reducing the likelihood of adverse events and decades of costly medications. Almost all of our patients underwent lesionectomy alone, with some resection of the hemosiderotic perilesional tissue in safe zones. No consensus exists regarding indications for additional mesiotemporal lobe resection. However, the likelihood of acquiring a seizure-free stage with medication in temporal lobe epilepsy with mesiotemporal sclerosis is low [278]. When an apparent MRI abnormality in addition to a cavernoma is seen, a larger resection should be considered, but confirmation of the seizure focus is required. Postoperative seizure outcome positive in patients in this series confirms the effectiveness of lesionectomy in cases without additional MRI abnormalities.

General outcome The general outcome was worse in patients with a cavernoma located in the mesiotemporal lobe, mainly manifesting as memory deterioration, and in one patient as a visual field deficit. Only two of our patients (4%) developed a new memory deficit after surgery, and two had worsening of previous symptoms. Fifteen percent of patients in our series complained of memory problems at follow-up, half of these were verified by a neuropsychologist. The other half of the patients had only a temporary short-term memory decline, without need for further examination or rehabilitation. Lesionectomy within the temporal lobe can lead to memory problems, especially

101 when the cavernoma is located in the dominant side close to the mesiotemporal region. Frequent seizures and/or long-term epilepsy may themselves cause memory problems, which was the case in 10% of our patients. Atrophy of the hippocampus with subsequent memory deterioration in chronic epilepsy is a well- described finding [39, 48]. Nevertheless, the extent of memory deficits and the effect of individual factors cannot be evaluated in our study since only a few patients underwent neuropsychological evaluation pre- or postoperatively. Memory disturbance was connected with cavernomas in all compartments of the temporal lobe, but especially with those in the mesial compartment.

Predictive factors for a better outcome In our study, we did not find any correlation between the location of cavernomas within the temporal lobe and epilepsy outcome. Patients with a lesion in the mesiobasal temporal structures, e.g. in the uncus or hippocampus, had the same chance of having a favorable seizure outcome as those with a lateral temporal cavernoma regardless of the duration or frequency of seizures. Thus, we observed a similar seizure potential of temporal cavernomas, regardless of the distance to the temporal mesiobasal region. Although this may not seem important, the data may be valuable when discussing with patients the risks and results of surgery. Seizure outcome in our series was not dependent on the duration of epilepsy before surgery. The literature on this issue is controversial [25, 43]. In our series, patients with a seizure history of more than ten years had the same chance of achieving seizure freedom as those who had had epilepsy for 0.5-2 years. This finding is not concordant with the theory of secondary epileptogenesis, which states that a prolonged preoperative history of epilepsy brings an increased risk for a worse seizure outcome as a result of developing remote epileptogenic foci [57, 204]. A high seizure frequency before surgery has been shown to worsen postoperative outcome [57]. In our series, patients with only one preoperative seizure are not relevant for comparison, but comparing patients with two to five preoperative seizures with those with more than five seizures revealed no difference in seizure outcome. Preoperative EEG was performed on 75% of our patients, and those with normal findings had better chances of being seizure-free at follow-up. This is consistent with the reported correlation between epileptiform abnormalities after the first unprovoked seizure and seizure recurrence [312]. However, 68% of our patients with preoperative epileptiform interictal EEG abnormality were also seizure-free at follow-up. Postoperative EEG findings did not correlate with seizure outcome in our study. This contradicts the literature in which interictal epileptiform activity on postoperative EEG is associated with seizure persistence and unfavorable epilepsy outcome [76]. Nevertheless, our conclusions are limited by the small series of patients.

102 VI Conclusions Due to advancements in neuroradiology, the number of cavernoma patients coming to be evaluated in neurosurgical practice is increasing. This is supplemented by the growing amount of cases earlier considered to be rare, and, thus not thoroughly investigated. In the present work, we summarized our results on the treatment of cavernomas; our findings are supported by the literature. Particular attention was paid to uncommon locations or insufficiently investigated cavernomas, including 1. Intraventricular cavernomas; 2. Multiple cavernomas; 3. Spinal cavernomas; and 4. Temporal lobe cavernomas. After analyzing the patient series with these lesions, we concluded that: 1. IVCs are characterized by a high tendency to cause repetitive hemorrhages in a short period of time after the first event. Although not life-threatening in most patients, the hemorrhage caused symptoms – mainly headache and nausea - which led to short-term hospitalization. Surgery is indicated when re-bleedings are frequent and the mass-effect causes progressive neurological deterioration. Modern microsurgical techniques allow safe removal of the IVC, but surgery on fourth ventricle cavernomas carries increased risk of postoperative cranial nerve deficits. 2. In MC cases, when the cavernoma bleeds or generates drug-resistant epilepsy, microsurgical removal of the symptomatic lesion is beneficial to patients. In our series, surgical removal of the most active cavernoma – usually the biggest lesion with signs of recent hemorrhage - was safe and prevented further bleedings. Epilepsy outcome after surgery was comparable with previous reports on single cavernomas, showing the effectiveness of active treatment of MCs. However, due to the remaining cavernomas, epileptogenic activity can persist postoperatively, frequently necessitating long-term use of antiepileptic drugs. 3. Spinal cavernomas can cause severe neurological deterioration due to low tolerance of the spinal cord to mass-effect with progressive myelopathy. When aggravated by extralesional massive hemorrhage, neurological decline is usually acute and requires immediate treatment. Microsurgical removal of a cavernoma is effective and safe, improving neurological deficits by mass removal and preventing further hemorrhage, thereby arresting progressive myelopathy. Sensorimotor deficits and pain improved postoperatively at a high rate, whereas bladder dysfunction remained essentially unchanged, causing social discomfort to patients. 4. Microsurgical removal of temporal lobe cavernomas is beneficial for patents suffering from drug-resistant epilepsy. In our series, 69% of patients with this condition became seizure-free postoperatively. Duration of epilepsy did not correlate with seizure prognosis. The most frequent disabling symptom at follow-up was memory disorder, considered to be the result of a complex interplay between chronic epilepsy and possible damage to the temporal lobe during surgery.

103 Acknowledgments I wish to express my sincere gratitude to the following persons:

Juha Hernesniemi, for giving me the possibility to enter the neurosurgical world and for being an excellent example of full commitment to the field. He inspired me to perform this work. Mika Niemelä, whose enthusiasm and patience in conducting this study was truly unlimited. Through our cooperation I’ve learned to concentrate only on the most important issues in writing scientific texts. Esa Kotilainen and Hannu Kalimo, reviewers of this thesis, for their valuable comments. Reza Dashti, who gave me some very important advices in the early days of the work. This allowed me to go to the right direction. My coworkers in publications: Riku Kivisaari, Aki Laakso, Martin Leheþka, Göran Blomstedt, Reina Roivainen who kindly shared their experience in helping to create appropriate manuscripts. Ville Kärpijoki, for image preparation. Virpi Hakala and Eveliina Salminen, for their help with matters of organization. All my neurosurgical, neuroanesthesiological and neuroradiological colleagues who had influenced me in terms of rational clinical thinking and self-organization. This allowed me to find enough time to perform this thesis. Carol Ann Pelli, for language revision. My closest friends from very early childhood: Mihail, Vladimir, Maksim, Vadim, Pavel. Your invisible but ever-present support is crucial in my changing surroundings. Eeva and Esa Mahanen. Your kind hospitality and care helped me so much to go through numerous difficulties which I experienced, being all alone in a foreign country. S.V.Rachmaninov My Nata. With years, I realise more and more how much you have done for me. My wife Antonina and sons Valentin and Daniil. Nothing is more wonderful than to see you every day. My mother. All the crucial steps that I have taken in life were somehow overseen and predetermined by you. I am the luckiest son to have such a mama.

In Helsinki, December 2010

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