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BACKGROUND: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized. METHODS: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM. RESULTS: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified. CONCLUSIONS: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.

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Cerebral cavernous malformations (CCMs) are abnormally dilated intracranial capillaries that form cerebrovascular lesions with a high risk of hemorrhagic stroke. Recently, several somatic "activating" gain-of-function (GOF) point mutations in PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α) were discovered as a dominant mutation in the lesions of sporadic forms of cerebral cavernous malformation (sCCM), raising the possibility that CCMs, like other types of vascular malformations, fall in the PIK3CA-related overgrowth spectrum (PROS). However, this possibility has been challenged with different interpretations. In this review, we will continue our efforts to expound the phenomenon of the coexistence of gain-of-function (GOF) point mutations in the PIK3CA gene and loss-of-function (LOF) mutations in CCM genes in the CCM lesions of sCCM and try to delineate the relationship between mutagenic events with CCM lesions in a temporospatial manner. Since GOF PIK3CA point mutations have been well studied in reproductive cancers, especially breast cancer as a driver oncogene, we will perform a comparative meta-analysis for GOF PIK3CA point mutations in an attempt to demonstrate the genetic similarities shared by both cancers and vascular anomalies.

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BACKGROUND: Developmental venous anomalies (DVAs) are congenital anatomical variants of the normal deep parenchymal veins. DVAs are occasionally found incidentally on brain imaging, and most cases are asymptomatic. However, they rarely cause central nervous disorders. Herein, a case of mesencephalic DVA that caused aqueduct stenosis and hydrocephalus and discuss its diagnosis and treatment is reported. OBSERVATIONS: The patient was a 48-year-old female who presented with depression. Computed tomography and magnetic resonance imaging (MRI) of the head revealed obstructive hydrocephalus. Contrast-enhanced MRI revealed an abnormally distended linear region with enhancement on the top of the cerebral aqueduct, which was confirmed as a DVA by digital subtraction angiography. An endoscopic third ventriculostomy (ETV) was performed to improve the patient's symptoms. Intraoperative endoscopic imaging showed obstruction of the cerebral aqueduct by the DVA. LESSONS: This report describes a rare case of obstructive hydrocephalus caused by DVA. It highlights the usefulness of contrast-enhanced MRI for diagnosing cerebral aqueduct obstructions due to DVAs and the effectiveness of ETV as a treatment option.

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Cavernous malformations (CM) that arise in the central nervous system have long been considered congenital, while there are many reports of de novo non-familial-type CM adjacent to developmental venous anomalies (DVA) or after radiation. The mechanisms that cause de novo formations of sporadic cavernous malformation (CM) still remain unknown and purely speculative. We report a case of de novo cerebral CM in a child with multiple developmental venous anomalies and cutaneous vascular malformations. Histological examination and whole-exome sequencing (WES) was performed on a fresh-frozen tissue sample of the CM. WES revealed 2 missense non-synonymous variants in two genes, EPHB4 and PIK3CA. The mutant allele of EPHB4 (NM_004444.4: c.1840 T > C, p.Y614H) appeared in 248/469 WES reads (allele frequency, 52.88%), which suggested the mutation a germline one. PIK3CA (NM_006218.2) somatic mutations were found in exon 9: c.1624G > A (p.Glu542Lys) with variant frequency of 2.2% (2/89 WES reads). We did not find any non-synonymous mutations of the three CCM genes (KRIT1, CCM2, and PDCD10) in this patient. Our findings suggested that the combination of gain of function in PIK3CA and loss of function in EPHB4 may play an important role in the pathogenesis of CM, which can develop in acquired form like tumorigenesis.

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BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is one of the rare cancer predisposition syndromes. The aim of this study was to evaluate the cerebral developmental venous anomalies in children with central nervous system tumors associated with CMMRD, an area in which there is extremely little experience. METHODS: Data from children diagnosed with medulloblastoma and high grade central nervous sytem tumor were retrospectively collected. According to the European CMMRD criteria, nine patients were diagnosed as CMMRD syndrome and the others consisted of the group without CMMRD. All radiological examinations of these children were retrospectively reviewed. Whole exome sequencing was performed to index cases` germline DNA. RESULTS: Nine children from four families, six females and three males, were studied. The median age at the first tumor diagnosis was 4.5 years (range, 9 months to 14 years). All CMMRD patients had café au lait spots, but none fulfilled the diagnostic criteria for neurofibromatosis. The patients developed high-grade glial tumor (n: 7) and medulloblastoma (n: 2). The affected genes in the three families were MSH6 [c.478C > T (p.Gln160Ter)], MSH6 [c.2871dupC (p.Phe958LeufsTer5)] and MLH1 [c.236G > A(p.Arg79Lys)], respectively. Seven patients had multiple developmental venous anomalies; six patients had leptomeningeal enhancement; and five patients had cavernomas. None of these findings were present in the group without CMMRD. CONCLUSIONS: Constitutional mismatch repair deficiency should be considered when multiple developmental venous anomalies, cavernomas, and leptomeningeal enhancement are detected, especially in patients with café au lait spots.

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Developmental venous anomaly (DVA) is one of the commonest vascular malformations in the brain but rarely symptomatic. Various pathomechanisms such as mechanical compression, increased in-flow into DVA or outflow obstruction have been described as causative factors in symptomatic DVAs. We report a unique case of a pontomedullary DVA with venous outflow obstruction causing progressive neurological worsening in a young adult despite anticoagulation, who was treated with a novel approach of venous outlet stenting of the collector vein with favorable outcome. In carefully selected cases, this endovascular treatment can be an effective and safe alternative when other measures fail.

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Background: Cerebral varices are intracranial venous anomalies that are characterized as thin-walled vessels, with a single layer of endothelium lining it and a thin lamina or fibrous connective tissue surrounding it. These varices are usually associated with vascular abnormalities such as arteriovenous malformations or developmental venous anomalies, but may rarely be found as isolated lesions as well. Diagnosis of these isolated lesions on imaging is a challenge, because it is a rare entity and can mimic a space occupying lesion in the brain. The patients with isolated cerebral varix can present with neurological symptoms; however, majority are asymptomatic with the diagnosis made incidentally. Case Description: The aim of this study is to report a case of a 21-month-old boy who was diagnosed with an isolated cerebral varix and had presented with delayed milestones in addition to seizures. His MRI scans showed a solid-cum-cystic lesion with contrast enhancing walls that was excised through craniotomy. Postoperatively, he regained his milestones. Conclusion: The patients with isolated cerebral varix can present with neurological symptoms; however, majority are asymptomatic with the diagnosis made incidentally. These patients have a low risk of bleeding and are treated conservatively, with surgical intervention indicated only in symptomatic patients.

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BACKGROUND: Developmental venous anomalies are considered benign lesions; however, they can become symptomatic. A capillary stain, which is an atypical angiographical feature of developmental venous anomalies, is reported to be relevant to symptomatic developmental venous anomalies. CASE DESCRIPTION: A 20-year-old man with no pertinent medical history had an epileptic seizure. Magnetic resonance imaging showed severe focal oedema and gadolinium contrast enhancement in the right precentral gyrus and inferior frontal gyrus adjacent to the Sylvian fissure, indicating venous congestion; these presentations had not been observed on magnetic resonance imaging 8 months before. Digital subtraction angiography revealed a developmental venous anomaly with capillary stain. After conservative treatment, the brain oedema resolved spontaneously and contrast enhancement of the lesion reduced significantly. CONCLUSION: We report a rare case of a symptomatic developmental venous anomaly with unique radiological characteristics and its natural and clinical evolution. Despite the presence of a capillary stain, our patient exhibited temporary exacerbations and spontaneous regression, suggesting that the capillary stain was associated with a reversible condition. This is the first report to detail the spatiotemporal changes of a developmental venous anomaly with capillary stain through imaging, suggesting that regular follow-up imaging is warranted in the management of patients with developmental venous anomalies.

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PURPOSE: Developmental venous anomalies (DVAs) have been found to be more prevalent in patients with multiple sclerosis (MS). The aim of the study was to compare the prevalence of DVAs in a large population of patients with MS compared with controls and to investigate the correlation of 3D Fluid Attenuated Inversion Recovery (FLAIR) hyperintense signal abnormalities adjacent to DVAs between MS patients and controls having DVAs, as well as DVA potential role in differential diagnosis. METHODS: Between January 2001 and December 2019, 349 patients who met the McDonald criteria for MS diagnosis (249 females, 100 males, age range 18-70 years) were retrospectively included in the study. All patients and 340 age-matched healthy controls had brain MRIs performed on a 1.5 Tesla MR system. Two radiologists reviewed all images to identify DVAs; their presence was compared between the MS and control groups. Among the subjects having DVAs, age, gender, adjacent FLAIR anomalies, and DVA location were compared between the two groups. RESULTS: Fifty (14.3%) out 349 patients presented 51 DVAs (35 supratentorial and 16 infratentorial), in comparison to 21/340 (6.2%) controls (P = 0.0005). One patient showed 2 simultaneous DVAs, while 3 patients had coexisting pontine capillary telangiectasias. FLAIR white matter changes adjacent to DVAs were found in 46.2% of patients and in 28.1% of controls (P = 0.0001). CONCLUSIONS: DVAs demonstrated a higher prevalence in the MS group in comparison to controls. We confirmed the association between DVAs and FLAIR anomalies in MS patients. However, currently there are no evidences that the presence of DVAs may be used in MS differential diagnosis.

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PURPOSE: Developmental venous anomalies (DVA) are congenital malformations of veins that drain brain parenchyma, with a prevalence up to 9.3% in normal populations and 29.5% in multiple sclerosis (MS) patients. Study purpose was to determine prevalence of DVAs in patients with clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS) and to assess whether DVAs are related to altered clinical, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) laboratory parameters. METHODS: Routine neurological and MRI examinations took place in a single center in 93 patients (39 CIS, 54 RRMS). Clinical disability (n = 93), MRI (n ≤ 90), CSF (n ≤ 82) parameters and DVA status were determined and compared statistically. RESULTS: A total of 29 DVAs were detected in 25 patients (25/93; 26.9%), 10 in 39 CIS patients and 15 in 54 RRMS patients. Most parameters were not significantly altered in patients with DVAs; no associated higher conversion rates from CIS to MS at 1-year (p = 0.411) or 2­year follow-up (p = 0.281) were registered. CONCLUSION: A higher prevalence of DVAs was detected in CIS and early MS patients than reported in non-MS populations, congruent to recent literature. The DVAs were not associated with significantly altered clinical outcomes, brain atrophy rates or disease progression, and no associated higher risk of CIS patients for converting to MS was found.

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Developmental venous anomalies (DVAs), previously also known as venous angiomas, are variations of normal trans-medullary veins draining from white and gray matter. DVAs are usually asymptomatic and mostly discovered incidentally on brain imaging. However, some studies have reported symptomatic cases associated with DVAs. In this report, we report an extremely rare case of a 14-month-old boy with obstructive hydrocephalus following aqueductal stenosis caused by developmental venous anomalies. At the age of 14 months, his head circumference exceeded + 2SD significantly. Brain magnetic resonance imaging (MRI) showed triventriculomegaly and dilated collector vein coursing through the Sylvian aqueduct, causing aqueductal stenosis. Endoscopic third ventriculostomy (ETV) was successfully performed. During the procedure, a dilated collector vein was confirmed obstructing the Sylvian aqueduct. Postoperative cine MRI showed good flow signal through the opening and improvement of hydrocephalus was noted. Obstructive hydrocephalus following aqueductal stenosis caused by DVAs is very rare; nonetheless, it can be considered as a causal differential diagnosis for hydrocephalus. Whether ETV should be chosen, as the technique for diversion of cerebrospinal fluid (CSF) flow, remains controversial. This case report showed that ETV was effective and safe.

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The association of cavernous malformations and developmental venous anomalies (DVA) is well known, but the presence of arterial fistulous connection with the main venous collector has been reported in the literature only once. We report the unusual case of a hemorrhagic cavernous angioma associated with DVA characterized by a fine arterial supply to the main venous collector. During surgery, after the excision of the cavernous angioma, few small arterial feeders were found entering the main channel of the venous developmental anomaly. The presence of an arterial fistulous connection with the main venous collector of a DVA may be a possible mechanism involved in a higher bleeding potential of cavernous angioma.

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OBJECTIVE: Developmental venous anomalies (DVAs) are typically benign lesions purely venous in nature. However, a subset of DVAs are either 1) associated with brain arteriovenous malformations (AVMs) or 2) demonstrate shunting themselves. The goal of this case series and literature review is to present clinical characteristics, management strategies and outcomes of this patient population. METHODS: Consecutive patients with arteriovenous shunting DVAs or DVAs draining nidal-AVMs were retrospectively reviewed. Lesions were classified as transitional DVAs or AVM-associated DVAs. Variables studied included clinical presentation, location, size, venous drainage, and malformation architecture. Treatment outcomes were evaluated. RESULTS: We identified 8 patients with transitional or AVM-associated DVAs from our institution. Six patients had unruptured lesions and two presented with hemorrhage. We classified 5 malformations as transitional DVAs and 3 as AVMs draining into DVAs. Three patients were conservatively managed, while 5 patients underwent treatment of the shunt by means of surgery (4) or radiosurgery (1). One patient suffered a right frontal venous infarct resulting in left sided weakness post-operatively. In the literature review we found 44 additional cases (Total = 30 transitional DVAs and 22 AVM-associated DVAs). Patients with transitional DVAs were more symptomatic than patients with AVM-associated DVAs (41.4% vs 22.2%). Permanent neurologic deficit following radiosurgical or microneurosurgical treatment of transitional DVAs was 28.6% compared to 16.7% for AVMs draining into DVAs. CONCLUSIONS: Transitional DVAs and AVMs draining into DVAs are rare lesions. Treatment is associated with substantial risk of venous infarct, particularly in situations where the draining vein is occluded.

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Surgical resection of brainstem cavernous malformations (BCMs) is a high-risk procedure and can be challenging to the neurosurgeon. Lateral surgical routes are becoming increasingly used to approach ventrolaterally brainstem cavernoma. Surgical approach decision depends on the location of the cavernoma in the brainstem and a possible association with brainstem developmental venous anomalies (DVAs). DVA can affect the formation and clinical course of cavernous malformation (CM). CMs related to DVAs tend to have more aggressive behavior than isolated CM. In cases of DVAs associated with hemorrhage, CMs are most often the site of bleeding rather than DVAs themselves. In this case report, we present a 24-year-old woman with a pontomedullary CM and associated dorsally located DVA. BCM was operated through a far lateral suboccipital craniotomy. Brainstem entry point was at inferior olive with extension to the pontomedullary sulcus. This approach should be preferred as a safe surgical exposure to the central and paramedian pontomedullary cavernoma, especially in the cases with associated intraparenchymal brainstem DVA. Such surgical exposure allows preservation of the concomitant brainstem DVA.

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Venous angiomas are relatively common lesions that occur in up to 3% of the general population. It is usually asymptomatic and discovered incidentally. We present a case of developmental venous anomaly mimicking thrombosed cerebral vein on nonenhanced computed tomography scan of the brain. A 48-year-old male patient medically free referred to our center for further management of high blood pressure. Because of the concern of thrombosed cerebral vein on computed tomography, further investigation with magnetic resonance venogram revealed a small network of veins in the region of the left internal cerebral vein with a picture of venous angioma. This case highlights such findings for the junior radiologist to consider additional investigations and avoid subsequent inadvertent treatment with anticoagulation.

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OBJECTIVE: Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. T2W-hyperintense demyelinating lesions are detected in cranial magnetic resonance imaging (MRI). Developmental venous anomalies (DVAs) have frequently been detected in enhanced cranial MRI images, and are generally accepted as normal variants of venous development. The aim of the present study was to investigate whether there was an association between demyelinating diseases and venous anomalies. METHODS: One hundred five patients who were diagnosed as having MS in accordance with the McDonald diagnostic criteria, and 105 patients who were diagnosed as having vascular headache who had no lesions similar to MS were included in the present retrospective study. RESULTS: DVAs were detected in 31 of the study group and in 14 patients in the control group. A statistically significant higher rate of DVAs and abnormal signal increase in the neighboring tissue was detected in the study group (p = 0.004) (p = 0.006). The DVA was superficially localized in the RRMS, It was deeply located in RIS. CONCLUSION: Recent studies have emphasized the association of the central vein and the lesion severity of MS with the detection of the central collecting vein in MS lesions. In our study, DVAs, which are generally regarded as innocent developmental anomalies, and neighboring signal increase were found significantly higher in the MS group compared with the control group. The role of DVAs in the etiology of demyelinating lesions must be clarified through comprehensive future studies that use more advanced techniques.

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RATIONALE AND OBJECTIVES: To determine the metabolic effects of developmental venous anomalies (DVAs) and to correlate those effects with conventional magnetic resonance imaging (MRI) findings. MATERIALS AND METHODS: We conducted a retrospective review of MRI and brain 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) examinations in subjects with DVAs. Conventional MRI was used to determine DVA number, location, size, and associated parenchymal findings such as atrophy, hemorrhage, cavernoma, capillary telangiectasia, cortical dysplasia/polymicrogyria, and white matter signal abnormality. Qualitative and quantitative measures of relative metabolism in the drainage territory of the DVA were measured on 18F-FDG-PET. RESULTS: Fifty-four subjects with 57 DVAs were included in the analysis. 38% were associated with qualitative and quantitative metabolic abnormalities on 18F-FDG-PET, with decreased metabolism in the parenchyma surrounding all but one of these DVAs. DVAs draining gray matter were significantly more likely to be hypometabolic than those draining only white matter, suggesting that the metabolic effects of DVAs may be underestimated on 18F-FDG-PET. CONCLUSION: Altered metabolism is seen in the drainage territory of a significant proportion of DVAs, suggesting that these anomalies are vascular lesions with abnormal physiologic features.

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BACKGROUND: Antiepileptic treatment strategy plays an important role in the management of intracranial vascular malformations. The intracranial vascular malformations can be divided into cavernous hemangiomas, arteriovenous malformations, developmental venous anomalies and capillary telangiectasias. Seizures and hemorrhage are among their most common clinical manifestations. OBJECTIVE: The aim of this article is to review the current literature on the antiepileptic treatment in the setting of intracranial vascular malformations and offer an updated view on when antiepileptic drug treatment should be employed for each type of vascular malformation. METHODS AND MATERIALS: Current literature has been reviewed on cavernous malformations, arteriovenous malformations, developmental venous anomalies and capillary telangiectasias. Epidemiological features, epileptogenesis, clinical presentation and antiepileptic treatment have been analyzed. RESULTS: A variety of treatment modalities exist for the management of intracranial vascular malformations, including antiepileptic treatment, microsurgery, radiosurgery and embolization. The decision-making process is different for each type of intracranial vascular malformation. Moreover, a plethora of other clinical factors needs to be taken into consideration during the decision-making process, such as the patient's age and comorbidities, the risk of hemorrhage the need for definitive treatment of the malformation, the seizure rates after the definitive treatment, the efficacy and side effects profile of antiepileptic drugs. CONCLUSION: Antiepileptic treatment strategy is a multifactorial decision that should be individualized and ideally be made by multidisciplinary teams.

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Cavernous malformations are vascular lesions that occur throughout the central nervous system, most commonly in the supratentorial location, with brainstem and cerebellar cavernous malformations occurring more rarely. Cavernous malformations are associated with developmental venous anomalies that occur sporadically or in familial form. Patients with a cavernous malformation can present with headaches, seizures, sensorimotor disturbances, or focal neurologic deficits based on the anatomic location of the lesion. Patients with infratentorial lesions present more commonly with a focal neurologic deficit. Cavernous malformations are increasingly discovered incidentally due to the increasing use of magnetic resonance imaging. Understanding the natural history of these lesions is essential to their management. Observation and surgical resection are both reasonable options in the treatment of patients with these lesions. The clinical presentation of the patient, the location of the lesion, and the surgical risk assessment all play critical roles in management decision-making.

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