Arteriovenous malformations of the filum terminale: clinical characteristics, angioarchitecture, and management of a rare spinal vascular pathology.

OBJECTIVE: The goal of this study was to describe clinical and neuroradiological features of arteriovenous malformations of the filum terminale (FT AVMs) and to present the authors' diagnostic and therapeutic management in this rare disease. METHODS: The presented cases were retrieved from a retrospectively collected database of all spinal vascular malformations treated between June 1992 and December 2021 at the Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen. Pretreatment and follow-up clinical and neuroradiological data were analyzed for this study. RESULTS: Data in 15 patients with FT AVM with a mean age of 60 years were included, with an overall incidence of FT AVM of 19% among all spinal AVMs in our cohort. Twelve of 15 (80%) patients were men. Nonspecific but typical clinical and MR findings of thoracolumbar congestive myelopathy were found in all patients. Spinal MR angiography, performed in 10 patients, identified in all cases the arterialized FT vein as well as a lumbar/lumbosacral location of an AV shunt. Digital subtraction angiography (DSA) showed an arterial supply solely via the FT artery in 12/15 (80%) patients and via an additional feeder from the lumbosacral region in the other 3/15 (20%) patients. All patients were treated surgically. During 1-year follow-up, 2 patients presented with recurrent FT AVM due to further arterial supply from the lumbosacral region, and were treated surgically. Neurological status was improved in all patients within the 1-year follow-up, with marginal further changes during long-term follow-up. CONCLUSIONS: Congestive myelopathy is the major pathological mechanism of symptoms in these patients, with no evidence for intradural bleeding. Missing the presence of possible multiple arterial supply of FT AVM during DSA may result in misdiagnosis and/or insufficient treatment. Due to the frequently prolonged course of FT artery, resection of the FT AVM may be a favorable treatment modality in comparison with endovascular treatment. Follow-up examinations are obligatory within the first 3 years after treatment, and further MR angiography and DSA examinations are indicated if congestive myelopathy persists.

C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation.

BACKGROUNDDeciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology.METHODSWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene.RESULTSWe identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid-Schiff-positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism.CONCLUSIONSOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.

Persistence and regredience of intraspinal fluid collection determine symptom control in intracranial hypotension syndrome.

BACKGROUND AND PURPOSE: An intraspinal fluid collection (ISFC) can be observed on spinal MRI in cases of intracranial hypotension syndrome (IHS). The goal of this study was to analyze the possible persistence of ISFC after therapy and its correlation to clinical disease activity and secondary complications. MATERIALS AND METHODS: Twenty patients in our database of 57 patients, who were treated for IHS between 2009 and 2015, fulfilled the inclusion criteria of (a) diagnosed and treated IHS as well as (b) an ISFC in MRI imaging. Ten of these participated in our study. We performed follow-up visits, which included a history, a clinical examination, and a spinal MRI. RESULTS: A MRI-confirmed ISFC was seen in six patients, five of which had symptoms attributable to chronic IHS. There were two cases of superficial siderosis. One patient had a persisting ISFC and was free of symptoms. Four patients did not have an ISFC and were free of symptoms (Fisher's exact test; p < 0.048). CONCLUSION: There is statistically significant correlation between the persistence of an ISFC after IHS treatment and ongoing clinical symptoms. Resolved symptoms seem to correlate with absorbed extradural ISFC and hypothetically closed leakage site. ISFC as confirmed by MRI proofs to be a reliable follow-up marker for disease activity in chronic IHS that is possibly even superior to clinical examination.

Unique Angioarchitecture of Sacral Dural Arteriovenous Fistula.

BACKGROUND: Spinal dural arteriovenous fistulas (DAVFs) in the sacral region are extremely rare. The location and complex angioarchitecture of these lesions make both identification and treatment challenging, even in experienced hands. We report on a sacral DAVF with a unique angioarchitecture and discuss its specific anatomy. CASE DESCRIPTION: A 76-year-old male presented with progressive distal paraparesis and spinal ataxia. Three lumbar decompression surgeries were performed between 2016 and 2018 elsewhere on the basis of suspected degenerative lumbar syndrome. On admission to our center, the patient was wheelchair dependent due to extensive spinal ataxia associated with bilateral foot paresis and hypoesthesia. Spinal contrast-enhanced time-resolved magnetic resonance angiography and digital subtraction angiography were performed after admission to our center. Contrast-enhanced magnetic resonance angiography examinations suggested a sacral DAVF. Subsequent digital subtraction angiography demonstrated a spinal DAVF on the left side at the S2 vertebral level supplied via an arterial epidural branch from the right L4 segmental artery. The fistula was treated via surgical interruption of the proximal part of the radicular drainage vein. CONCLUSIONS: Sacral DAVFs present serious diagnostic difficulties and require a profound understanding of possible fistula-supplying arteries of the sacral region. Microsurgical interruption of the often ventrally located drainage vein presents an efficient treatment modality and could provide an immediate confirmation of fistula occlusion using indocyanine green videoangiography.

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.

BACKGROUND: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive. METHODS: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder. RESULTS: By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1. CONCLUSION: We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems. TRIAL REGISTRATION: Not applicable. FUNDING: Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.

Ectopic intracranial retinoblastoma in a 3.5-month-old infant without eye involvement and without evidence of heritability.

Heritable retinoblastoma can rarely be associated with a midline intracranial neuroblastic tumor, referred to as trilateral retinoblastoma. We present an unusual midline brain tumor in an infant that was identified as ectopic retinoblastoma by histopathology, DNA methylation analysis, and molecular genetic detection of biallelic somatic inactivation of the RB1 gene. There was no ocular involvement, and germline mutation was excluded. In this nonresectable tumor, treatment with systemic chemotherapy including high-dose therapy with autologous stem cell transplantation, but without definite local therapy, resulted in long-lasting tumor control.

Familial NEDD4L variant in periventricular nodular heterotopia and in a fetus with hypokinesia and flexion contractures.

BACKGROUND: Mutations in the HECT domain of NEDD4L have recently been identified in a cohort of eight patients with a syndromic form of bilateral periventricular nodular heterotopia (PVNH) in association with neurodevelopmental delay, cleft palate, and toe syndactyly (PVNH7). METHODS: Case report based on NGS sequencing. RESULTS: Here, we describe a girl with a novel heterozygous NEDD4L missense variant, p.Tyr679His, and characteristic clinical findings, including bilateral periventricular nodular heterotopia, cleft palate and mild toe syndactyly. Molecular testing from peripheral blood identified the healthy father to carry the NEDD4L variant in mosaic state. Notably, a previous pregnancy of the couple had been terminated due to a complex fetal developmental disorder, including hypokinesia and flexion contractures. Upon review, this affected fetus was also shown to carry the familial NEDD4L variant. CONCLUSION: Our findings may suggest a broader spectrum of NEDD4L-associated phenotypes, including severe prenatal neurodevelopmental manifestations, which might represent yet another genetic form of fetal hypokinesia with flexion contractures.

Anticoagulation Therapy After Surgical Treatment of Spinal Dural Arteriovenous Fistula. Effectiveness and Long-Term Outcome Analysis.

OBJECTIVE: Effectiveness and safety of anticoagulation therapy (AC) after treatment of spinal dural arteriovenous fistula (sdAVF) are still inadequately discussed in the literature and are addressed in this study. METHODS: We retrospectively analyzed our medical database for patients with sdAVF treated in our institution between 2006 and 2016. Neurologic status at time of admission, discharge, and last follow-up was assessed via Aminoff-Logue disability score. Patient cohorts were dichotomized as group A (postoperative therapeutic heparinization) and group B (routine thromboembolic prophylaxis with low-dose heparin). RESULTS: Fifty-three patients were included in this analysis. In group A (n = 11), no acute deterioration was reported. In group B (n = 42), 4 patients developed acute postoperative deterioration; therapeutic AC was initiated in all 4 patients resulting in complete neurologic recovery within the inpatient stay. However, the incidence of postoperative deterioration did not reach statistical significance between treatment groups (P = 0.57). Data of 40 patients were available for long-term analysis (mean, 53.4 ± 36 months). Neurologic status did not differ significantly between both groups at time of admission (P = 0.093), discharge (P = 0.723), and last follow-up (P = 0.222). CONCLUSIONS: Acute postoperative deterioration in patients with sdAVF is a clinically relevant complication and was present in 7.5% of patients in our series. Although routine therapeutic AC did not decrease the rate of acute deterioration significantly, our findings imply that therapeutic AC in cases of acute postoperative deterioration might be a safe and efficient treatment option.

Arterial Hypertension Is Associated with Symptomatic Spinal Dural Arteriovenous Fistulas.

OBJECTIVE: To determine possible systemic factors that may induce or be associated with the pathogenesis and pathologic course of spinal dural arteriovenous fistulas (SDAVFs), the most common type of arteriovenous disorder of the spinal cord and its meninges. METHODS: We assessed the role of possible systemic (vascular) risk factors (arterial hypertension, diabetes mellitus, fat metabolism disorders, and nicotine dependence) by comparing the prevalence of these risk factors in an SDAVF cohort of 59 patients with the prevalence in the general population. RESULTS: Age-corrected prevalence of arterial hypertension in the SDAVF cohort was significantly higher than in the general population (P < 0.001). Prevalence of diabetes mellitus (P = 0.150.), nicotine dependence (P = 0.561), adiposity (P = 0.217), and fat metabolism disorders (P = 0.125) did not differ from prevalence of comparable cohorts in the general population. CONCLUSIONS: Our results and data from the literature suggest that arterial hypertension may play an important role in the development of SDAVF-related symptoms or the development of SDAVFs in the presence of other predisposing factors.

Stroke as Initial Manifestation of Adenosine Deaminase 2 Deficiency.

Deficiency of adenosine deaminase 2 (ADA2) due to homozygous or compound heterozygous mutations in the cat eye syndrome chromosome region, candidate 1 (CECR1) gene causes an autoimmune phenotype with systemic vasculitis affecting the skin, inner organs, and the central nervous system. Typically, stroke has been reported to follow systemic inflammatory disease and predominantly affects posterior and central brain areas. Here, we describe one of the rare patients in whom acute mesencephalic stroke preceded systemic inflammation and presented as initial clinical symptom. Symptoms typical for ADA2 deficiency such as fever, livedo racemosa, abdominal colics, arthralgias, and Raynaud phenomenon were observed later. Moreover, angiography of cerebral arteries did not reveal typical vasculitic findings supporting the hypothesis that alternative mechanism of vascular occlusion might have caused the stroke. ADA2 deficiency should be considered in patients with childhood stroke despite the absence of systemic inflammation and cerebral vasculitis.

Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?

INTRODUCTION: Charcot-Marie-Tooth neuropathy (CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur. METHODS: We studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision. RESULTS: Patients harbored a PMP22 gene alteration (n = 28) or a mutation in MPZ (n = 11), GJB1 (n = 4), LITAF (n = 2), MFN2 (n = 2), INF2 (n = 1), NEFL (n = 1). We identified four novel mutations (3 MPZ, 1 GJB1). A total of 88% presented at least one additional feature. In MPZ patients, we detected hypertrophic nerve roots in 3/4 cases that underwent spinal MRI, and pupillary abnormalities in 27%. In our cohort, restless legs syndrome (RLS) was present in 18%. We describe for the first time RLS associated with LITAF or MFN2 and predominant upper limb involvement with LITAF. Cold-induced hand cramps occurred in 10% (PMP22,MPZ,MFN2), and autonomous nervous system involvement in 18% (PMP22,MPZ, LITAF,MFN2). RLS and respiratory insufficiency were mostly associated with severe neuropathy, and pupillary abnormalities with mild to moderate neuropathy. CONCLUSIONS: In CMT patients, additional features occur frequently. Some of them might be helpful in orienting genetic diagnosis. Our data broaden the clinical spectrum and genotype-phenotype associations with CMT.

Frequency and appearance of hemosiderin depositions after aneurysmal subarachnoid hemorrhage treated by endovascular therapy.

INTRODUCTION: It is still unclear how often subarachnoid hemorrhage (SAH) leads to chronic hemosiderin depositions. In this study, we aimed to determine the frequency of chronic hemosiderin depositions after aneurysmal SAH in patients who did not undergo surgery. Furthermore, we analyzed typical MRI patterns of chronic SAH and sought to obtain information on the temporal course of MRI signal changes. METHODS: We retrospectively analyzed 90 patients who had undergone endovascular treatment for acute aneurysmal SAH. In all patients, initial CT studies and at least one T2*-weighted MRI obtained 6 months or later after SAH were analyzed for the presence and anatomical distribution of SAH or chronic hemosiderin depositions. In total, 185 T2*-weighted MRI studies obtained between 2 days and 148 months after SAH were evaluated (mean follow-up 30.2 months). RESULTS: On MRI studies obtained later than 6 months after SAH, subpial hemosiderin depositions were found in 50 patients (55.5%). Most frequent localizations were the parenchyma adjacent to the frontal and parietal sulci and the insular cisterns. While the appearance of hemosiderin depositions was dynamic within the first 3 months, no changes were found during subsequent follow-up. MR signal changes were not only conclusive with subarachnoid hemosiderin depositions but in many cases also resembled those that have been associated with cortical hemosiderosis. CONCLUSIONS: T2*-weighted MRI is an effective means of diagnosing prior SAH. Our study suggests that chronic hemosiderin depositions can be found in a considerable number of patients after a single event of subarachnoid hemorrhage.

Intrathecal saline infusion: an emergency procedure in a patient with spontaneous intracranial hypotension.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is a neurologic condition with the prototypical symptom of orthostatic headache. We report a dramatic case of SIH with life-threatening bilateral hygroma and uncal herniation. METHODS: Case report. RESULTS: A 44-year-old male patient presenting with orthostatic headache and double vision was diagnosed with SIH. Diagnostic imaging showed meningeal enhancement and bilateral hygroma. A conservative treatment regime was initiated. The patient's condition rapidly deteriorated with progressive loss of consciousness. Cranial MRI showed beginning uncal herniation. As an emergency treatment measure, an intracranial pressure (ICP) probe was inserted and intrathecal lumbal saline infusion was initiated. This led to a stabilization of ICP and allowed further diagnostics and treatment. CONCLUSION: Intrathecal lumbal saline infusion in combination with ICP monitoring can be a life-saving treatment option in unstable SIH patients.

Aicardi-Goutières syndrome and systemic lupus erythematosus (SLE) in a 12-year-old boy with SAMHD1 mutations.

Aicardi-Goutières syndrome is an early-onset encephalopathy with a presumed immune pathogenesis caused by inherited defects in nucleic acid metabolism. The clinical picture resembles a congenital viral infection despite negative investigations for common viruses. In addition to leukoencephalopathy with calcifications of basal ganglia, patients show increased levels of the antiviral cytokine interferon-α in cerebrospinal fluid. We report on a 12-year-old boy with Aicardi-Goutières syndrome and systemic lupus erythematosus (SLE) due to mutations in the SAMHD1 (sterile alpha motif domain and HD domain-containing protein 1) gene, illustrating an emerging pattern of the natural history of Aicardi-Goutières syndrome characterized by neurological disease followed by symptoms of systemic autoimmunity. Thus, Aicardi-Goutières syndrome constitutes a model disease for systemic autoimmunity triggered by the activation of the innate immune system. Recognition of the etiologic link between Aicardi-Goutières syndrome and systemic lupus erythematosus has direct implications on therapeutic management and suggests that early immune modulatory intervention can improve neurological outcome.

High rate of restenosis after carotid artery stenting in patients with high-grade internal carotid artery stenosis. Medium-term follow-up.

OBJECTIVE: Carotid endarterectomy (CEA) is the gold-standard procedure for the majority of patients with high-grade symptomatic internal carotid artery stenosis and also for specified high-grade asymptomatic stenoses; however, a proportion of patients are treated with carotid endovascular therapy. We aimed to document medium-term clinical and neurosonographical outcome after carotid artery stenting (CAS). METHODS: 53 patients (mean age: 65 +/- 8 years) with high-grade (> or = 70 % by means of duplex sonography) carotid artery stenosis were enrolled into the study. Nineteen patients had asymptomatic, 34 patients had symptomatic stenoses. All patients had a pre-interventional CT, Doppler and duplex sonography, and digital subtraction angiography (DSA) or magnetic resonance angiography (MRA) prior to the procedural DSA. All patients were offered CEA as the gold-standard procedure and as an alternative to CAS. Both clinical and Duplex sonographical follow-up was obtained at day 1 and 7, month 1, month 3, month 6, month 12, and every subsequent 6 months after the procedure. Mean follow-up time was 22 +/- 1.6 months (+/- SEM). RESULTS: 2/53 patients suffered from stroke. A further 2 patients suffered from carotid artery occlusion shortly after CAS. The cumulative rate of restenosis during follow-up was 24.5 % (13/53). Four of these (7.5 %) were of high-grade and led to further interventional or surgical therapy. CONCLUSIONS: A high rate of restenosis was found during follow-up after CAS. Our analysis of non-selected patients emphasizes that CEA remains the gold-standard procedure for the treatment of symptomatic internal carotid artery stenosis. The frequently performed endovascular treatment of carotid stenosis outside the setting of a randomized controlled trial is not supported by our data.

Imaging in spinal vascular disease.

Spinal vascular diseases are rare and constitute only 1% to 2% of all vascular neurologic pathologies. In this article, the following vascular pathologies of the spine are described: spinal arterial infarcts, spinal cavernomas, and arteriovenous malformations (including perimedullary fistulae and glomerular arterivenous malformations), and spinal dural arteriovenous fistulae. This article gives an overview about their imaging features on MRI, MR angiography, and digital subtraction angiography. Clinical differential diagnoses, the neurologic symptomatology, and the potential therapeutic approaches of these diseases, which might vary depending on the underlying pathologic condition, are given.

Vertebral artery loop causing cervical radiculopathy.

We report on a 68-year-old woman with an abnormal loop of the extracranial VA enlarging the intervertebral foramen at C4-5 and compressing the C5 root causing radiculopathy. The diagnosis was confirmed on contrast enhanced CT and MR angiography after initial conservative treatment was unsuccessful. Microvascular decompression using an anterior approach was curative.

Spinal epidural arteriovenous fistula with perimedullary drainage. Case report and pathomechanical considerations.

The classic angiographically demonstrated features of spinal dural arteriovenous fistulas are shunts of radiculomeningeal branches with radicular veins draining exclusively in the direction of perimedullary veins and thereby causing venous congestion. These shunts are located at the point where the radicular vein passes the dura mater. Spinal epidural arteriovenous shunts, however, normally do not drain into the perimedullary veins and are, therefore, asymptomatic, presumably because of a postulated reflux-impeding mechanism between the dural sleeves. The authors report on a patient in whom an epidural arteriovenous shunt showed delayed retrograde drainage into perimedullary veins, leading to the classic clinical (and magnetic resonance imaging-based) findings of venous congestion. Intraoperatively the angiographically established diagnosis was confirmed. Coagulation of both the epidural shunt zone and the radicular vein resulted in complete obliteration of the fistula, as confirmed on repeated angiography. This rare type of fistula should stimulate considerations on the role of valvelike mechanisms normally impeding retrograde flow from the epidural plexus to perimedullary veins and suggest that, in certain pathological circumstances, epidural fistulas can drain retrogradely into perimedullary veins as an infrequent variant of spinal arteriovenous shunts.

Spinal dural arteriovenous fistula associated with a spinal perimedullary fistula: case report.

Among spinal cord vascular malformations, dural arteriovenous fistulas (DAVFs) must be distinguished from intradural malformations. The concurrence of both is extremely rare. The authors report the case of a 35-year-old man who suffered from progressive myelopathy and who harbored both a DAVF and an intradural perimedullary fistula. During surgery, both fistulas were identified, confirmed, and subsequently obliterated. The fistulas were located at two levels directly adjacent to each other. Although the incidence of concurrent spinal DAVFs is presumed to be approximately 2%, the combination of a dural and an intradural fistula is exceedingly rare; only two other cases have been reported in the literature. One can speculate whether the alteration in venous drainage caused by the (presumably congenital) perimedullary fistula could possibly promote the production of a second dural fistula due to elevated pressure with concomitant venous stagnation and subsequent thrombosis. The authors conclude that despite the rarity of dual pathological entities, the clinician should be aware of the possibility of the concurrence of more than one spinal fistula in the same patient.