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Rationale and Objectives Accurate cerebrospinal fluid (CSF) pressure measurements are critical for diagnosis and treatment of pathologic processes involving the central nervous system. Measuring opening CSF pressure using an analog device takes several minutes, which can be burdensome in a busy practice. The purpose of this study was to compare accuracy of a digital pressure measurement device with analog manometry, the reference gold standard. Secondary purpose included an assessment of possible time savings. Materials and Methods This study was a retrospective, cross-sectional investigation of 71 patients who underwent image-guided lumbar puncture (LP) with opening CSF pressure measurement at a single institution from June 2019 to September 2019. Exclusion criteria were examinations without complete data for both the digital and analog measurements or without recorded needle gauge. All included LPs and CSF pressures were measured with the patient in the left lateral decubitus position, legs extended. Acquired data included (1) digital and analog CSF pressures and (2) time required to measure CSF pressure. Results A total of 56 procedures were analyzed in 55 patients. There was no significant difference in mean CSF pressures between devices: 22.5 cm H2O digitally vs 23.1 analog ( p = .7). Use of the digital manometer resulted in a time savings of 6 min (438 s analog vs 78 s digital, p < .001). Conclusion Cerebrospinal fluid pressure measurements obtained with digital manometry demonstrate comparable accuracy to the reference standard of analog manometry, with an average time savings of approximately 6 min per case.

OBJECTIVE Chiari malformation type 1 (CM-1) and spontaneous intracranial hypotension (SIH) are causes of headache in which cerebellar tonsillar ectopia (TE) may be present. An accurate method for differentiating these conditions on imaging is needed to avoid diagnostic confusion. Here, the authors sought to determine whether objective measurements of midbrain morphology could distinguish CM-1 from SIH on brain MRI. METHODS This is a retrospective case-control series comparing neuroimaging in consecutive adult subjects with CM-1 and SIH. Measurements obtained from brain MRI included previously reported measures of brain sagging: TE, slope of the third ventricular floor (3VF), pontomesencephalic angle (PMA), mamillopontine distance, lateral ventricular angle, internal cerebral vein–vein of Galen angle, and displacement of iter (DOI). Clivus length (CL), an indicator of posterior fossa size, was also measured. Measurements for the CM-1 group were compared to those for the entire SIH population (SIHall) as well as a subgroup of SIH patients with > 5 mm of TE (SIHTE subgroup). RESULTS Highly significant differences were observed between SIHall and CM-1 groups in the following measures: TE (mean ± standard deviation, 3.1 ± 5.7 vs 9.3 ± 3.5 mm), 3VF (−16.8° ± 11.2° vs −2.1° ± 4.6°), PMA (44.8° ± 13.1° vs 62.7° ± 9.8°), DOI (0.2 ± 4.1 vs 3.8 ± 1.6 mm), and CL (38.3 ± 4.5 vs 44.0 ± 3.3 mm; all p < 0.0001). Eight (16%) of 50 SIH subjects had TE > 5 mm; in this subgroup (SIHTE), a cutoff value of < −15° for 3VF and < 45° for PMA perfectly discriminated SIH from CM-1 (sensitivity and specificity = 1.0). DOI showed perfect specificity (1.0) in detecting SIH among both groups. No subjects with SIH had isolated TE without other concurrent findings of midbrain sagging. CONCLUSIONS Measures of midbrain sagging, including cutoff values for 3VF and PMA, discriminate CM-1 from SIH and may help to prevent misdiagnosis and unnecessary surgery.

CSF-venous fistulas (CVFs), first described in 2014, are an important cause of spontaneous intracranial hypotension. CVFs can be challenging to detect on conventional anatomic imaging because, unlike other types of spinal CSF leak, they do not typically result in pooling of fluid in the epidural space, and imaging signs of CVF may be subtle. Specialized myelographic techniques have been developed to help with CVF identification, but these techniques are not yet widely disseminated. This article reviews the current understanding of CVFs, emphasizing correlations between venous anatomy and imaging findings as well as potential mechanisms for pathogenesis, and describes current imaging techniques used for CVF diagnosis and localization. These techniques are broadly classified into fluoroscopy-based methods, including digital subtraction myelography and dynamic myelography, and cross-sectional methods, including decubitus CT myelography and MR myelography with intrathecal injection of gadolinium. Knowledge of these various options, including their relative advantages and disadvantages, is critical in the care of patients with spontaneous intracranial hypotension. Investigation is ongoing, and continued advances in knowledge about CVFs as well as in optimal imaging detection are anticipated.

An expanding array of image-guided spine interventions have the potential to provide immediate and effective pain relief. Innovations in spine intervention have proceeded rapidly, with clinical adoption of new techniques at times occurring before the development of bodies of evidence to establish efficacy. Although new spine interventions have been evaluated by clinical trials, acceptance of results has been hindered by controversies regarding trial methodology. This article explores controversial aspects of four categories of image-guided interventions for painful conditions: spine interventions for postdural puncture headache resulting from prior lumbar procedures; epidural steroid injections for cervical and lumbar radiculopathy; facet and sacroiliac joint pain interventions; and vertebral augmentations for compression fractures. For each intervention, we summarize the available literature with an emphasis on persistent controversies and discuss how current areas of disagreement and challenge may shape future research and innovation. Despite the ongoing areas of debate for various aspects of these procedures, effective treatments continue to emerge and show promise for aiding relief on a range of debilitating conditions.

Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH. Eligible patients were aged 30–80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared. In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort. CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.

To identify biomarkers with potential to indicate severity of perihematomal edema and secondary tissue injury after intracerebral hemorrhage (ICH), and which could be used as surrogate markers in future clinical trials for novel ICH therapeutics.This exploratory cohort study compared trends in neuroinflammatory biomarker levels in 18 consecutively enrolled patients with acute supratentorial ICH and 16 patients treated with the investigational neuroprotective therapy CN-105 to identify a panel of 10 biomarkers. Biomarker levels over five days post-hemorrhage were then compared with edema volumes in a larger sample of patients treated with CN-105.Mean normalized edema volumes increased over time; higher CRP levels were associated with increased edema volumes (p = 0.006, r = 0.56). Higher IL8, IL10, MCP, and MMP-9 levels were associated with decreased edema volumes (p = 0.005, r =-0.57; p = 0.02, r =-0.51; p = 0.02, r =-0.52; p = .002, r =-0.63, respectively). IL1-RA, IL1-B, IL23, vWF, and IL17 levels were not significantly associated with edema volumes (p 0.05).This exploratory study provides some of the first insights into the longitudinal associations between markers of neuroinflammation and development of perihematomal edema and secondary tissue injury in human ICH. We hypothesize that these biomarkers could be used as surrogates for treatment effect in novel therapies intended to limit neuroinflammation after ICH.

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss of imaginal discs in the larva. Loss of drosha in eye clones causes small and rough eyes in adult flies. One of the identified DROSHA variants (p.Asp1219Gly) behaves as a strong loss-of-function allele in flies, while another variant (p.Arg1342Trp) is less damaging in our assays. In worms, a knock-in that mimics the p.Asp1219Gly variant at a worm equivalent residue causes loss of miRNA expression and heterochronicity, a phenotype characteristic of the loss of miRNA. Together, our data show that the DROSHA variants found in the individuals presented here are damaging based on functional studies in model organisms and likely underlie the severe phenotype involving the nervous system.

Background Spontaneous intracranial hypotension (SIH) is a debilitating disorder caused by non-iatrogenic spinal cerebrospinal fluid leaks. SIH is increasingly recognized as an important treatable cause of secondary headaches. Treatment involves either epidural blood patching or surgery, which have considerable differences in their adverse event rates, recovery times, and cost. The objective of this evidence map is to understand the breadth of studies that investigate SIH treatment efficacy and to identify knowledge gaps to inform future research. Methods This review will consider experimental, observational, and systematic review studies that assess the efficacy of epidural blood patching and surgery for the treatment of patients with SIH. Individual case studies, clinical guidelines, editorials, protocols, and studies that do not assess an intervention will not be included. English language studies will be included without limitation based on the date of publication. Databases to be searched include MEDLINE® (via Ovid), EMBASE (via Elsevier), and Web of Science™ (via Clarivate). Study selection will be performed independently by two investigators with extracted data to include study type, the number of patients included, patient descriptors, intervention characteristics, and outcome measure used. Data will be presented through a narrative summary aided by tabular and graphical formats in a manner that aligns with the objective of the evidence mapping review. Discussion The overarching goal of this evidence map is to provide an improved understanding of the breadth of studies investigating SIH treatment efficacy in the literature and to thereby identify knowledge gaps that can inform future research directions. Trial registration OSF Registry https://osf.io/nwju7.

Spinal CSF-venous fistulas (CVF) were described in 2014 and are now recognized as an important etiology of spontaneous intracranial hypotension (SIH) 1-3. Surgical ligation is highly effective for treating CVFs4. Given the relatively recent discovery of this entity, long-term follow up on treated cases has not been available, however, surgery has generally been considered definitive treatment. We report four cases of SIH in which CVFs have recurred or developed de novo at a different spinal level following complete surgical ligation of the primary lesion. In all cases, the new CVF was not present on any pre-surgical imaging.

Spontaneous intracranial hypotension (SIH) is a clinical syndrome that is increasingly recognized as an important and treatable secondary cause of headaches. Insight into the condition has evolved significantly over the past decade, resulting in a greater understanding of the underlying pathophysiology, development of new diagnostic imaging tools, and a broadening array of targeted treatment options. This article reviews the clinical presentation and pathogenesis of SIH, discusses the important role of imaging in diagnosis, and describes how imaging guides treatment.

BACKGROUND: Previous studies analyzed contrast agent spread during cervical interlaminar epidural steroid injections (CILESIs) by using planar fluoroscopy and reported wide variance of the rate of spread to the ventral epidural space (VES). Cross-sectional CT allows for direct viewing of contrast agent in the VES, providing improved spread assessment and thereby informing needle placement decisions when targeting pain generators. PURPOSE: To determine the extent of injectate spread at CT fluoroscopy–guided CILESI, with particular attention to the VES and bilateral neuroforamina, by using cross-sectional CT. MATERIALS AND METHODS: This study reviewed 83 consecutive CT fluoroscopy–guided CILESIs at which a postprocedural cervical spine CT was performed (June 2016 to December 2017). All procedures used the same injectate (2 mL corticosteroid, 3 mL contrast agent). Postprocedural CT scans were reviewed for the presence of contrast within the VES, dorsal epidural space, ipsilateral neuroforamen, and contralateral neuroforamen in every cervical interlaminar level. Descriptive data are presented as frequencies or means. McNemar tests or hierarchical logistic models were used to assess associations between covariates and contrast agent spread to particular locations. RESULTS: The study cohort included 73 individual patients (59% women; 43 of 73) (mean patient age, 57.6 years ± 11.5 [standard deviation]). Mean number of levels of cranial spread were 0.6 level for VES, 1.9 levels for contralateral neuroforamen, 2.1 levels for ipsilateral neuroforamen, and 3 levels for dorsal epidural space. No VES spread in any level was found with 35% (29 of 83) of injections. VES spread was more likely to occur in the level of needle placement (43%; 36 of 83) than in other interlaminar levels (19.5%; 97 of 498; P < .001). Spread was more likely to occur in the neuroforamen ipsilateral to the needle approach compared with contralateral (P < .001). CONCLUSION: Cervical interlaminar epidural steroid injections have injectate spreads with a mean of less than one level cranially in the ventral epidural space (VES) and approximately two levels in the neuroforamen. VES spread occurs more frequently at the level of needle placement and within the ipsilateral neuroforamen. © RSNA, 2019

This review discusses cerebral venous thrombosis (CVT), including diagnosis and treatment strategies, a rare class of stroke that, if unrecognized or untreated, can have devastating effects. Thrombosis of one or many cerebral veins leads to propagation of thrombosis and impaired cerebral venous drainage. Diagnosis is made using a combination of history and imaging, particularly computed tomography (CT) venogram, which demonstrates thrombosis. Currently, acute treatment consists of heparin infusion with transition to long-term oral anticoagulation. Further research, especially on prevention, endovascular therapy, and the role of newer anticoagulants (direct oral anticoagulants [DOACs]) is necessary and ongoing.

Encoding the slow skeletal muscle isoform of myosin binding protein-C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M-motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M-motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M-motif to myosin, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early-onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.

Myelopathy refers to any pathologic process that involves the spinal cord, and can be caused by a variety of different diseases. MR imaging is the primary modality for evaluating the patient presenting with myelopathy. The first step must be the exclusion of spinal cord compression. Although the MR features of many causes of myelopathy overlap, careful attention to the time course of presentation, knowledge of common and uncommon causes of myelopathy, and identification of specific imaging patterns and features can help narrow the differential diagnosis or establish a definitive diagnosis.

Spontaneous intracranial hypotension (SIH) is a condition that has become increasingly recognized, necessitating more widespread familiarity with diagnosis and management. This chapter reviews the clinical presentation, pathogenesis, approach to brain and spinal imaging, and use of image-guided intervention for treatment of SIH. Specialized imaging techniques for problem-solving difficult cases are discussed, and procedural details of how to perform epidural patching are provided.

BackgroundEndogenous apoliloprotein E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apolipoprotein E-mimetic peptides can effectively penetrate the brain and down-regulate acute inflammation. CN-105 is a novel apolipoprotein E-mimetic pentapeptide with excellent preclinical evidence as an acute intracerebral hemorrhage (ICH) therapeutic. TheCN-105 in participants withAcute supraTentorial intraCerebralHemorrhage (CATCH) trial is a first-in-disease-state, multi-center, open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.MethodsEligible patients were age 30-80 years, had confirmed primary supratentorial ICH, and able to intiate CN-105 administration (1.0 mg/kg every 6 hours for 72 hours) within 12 hours of symptom onset.A prioridefined safety endpoints, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes were analyzed. For comparisons, CATCH participants were matched 1:1 with a contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on Days 0, 1, 2, and 5 and ordinal modified Rankin Score at 30 days after ICH were compared.ResultsIn 39 participants enrolled across six study sites in the United States, adverse events occurred at expected rate without increase in hematoma expansion or neurological deterioration or significant serum accumulation. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day mRS, after adjustment for ICH Score, sex, and race/ethnicity, compared to matched contemporary cohort.ConclusionCN-105 administration represents an excellent translational candidate as an actue ICH therapeutic due to its safety, dosing feasibility, favorable pharmacokinetics, and evidence of improved neurological recovery.

Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.Eligible patients were aged 30-80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared.In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort.CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.

Spinal CSF–venous fistulas are a cause of spontaneous intracranial hypotension that can be difficult to detect on imaging. We describe how the respiratory phase affects the visibility of CSF–venous fistulas during myelography.

BACKGROUND AND PURPOSE: Patient preparation for myelography and postprocedural monitoring varies widely between practices, despite published guidelines. Our aim was to examine the current practice variations in discontinuing reportedly seizure threshold–lowering medications before myelography and to assess the reported incidence of postmyelographic seizures. MATERIALS AND METHODS: An e-mail survey was sent to American Society of Neuroradiology members concerning the number of postmyelographic seizures experienced in the past 5 years, the presence of an institutional policy for discontinuing seizure threshold–lowering medications, and the type of myelographic contrast used. We compared the postmyelographic seizure frequency in the responses. RESULTS: Of 700 survey responses, 57% reported that they do not discontinue seizure threshold–lowering medications before myelography. Most (97%) indicated never having a patient experience a seizure following myelography. The number of postmyelographic seizures between those who discontinue seizure threshold–lowering medications and those who do not was not statistically significant (OR = 2.13; 95% CI, 0.91–4.98; P = .08). Most (95%) reported using nonionic hypo-osmolar agents. CONCLUSIONS: Survey results revealed widely variable practices for patient myelography preparation and postprocedural monitoring. We found no difference in reported seizures between those who discontinued seizure threshold–lowering medications and those who did not. In light of our findings, we propose that discontinuing reportedly seizure threshold–lowering medications is not warranted with the current nonionic water-soluble contrast agents and may be potentially harmful in some instances. This work supports revision of existing recommendations to withhold such medications before myelography.

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.

The objective of this study is to determine the rate of inadvertent dural puncture during CT fluoroscopy-guided cervical interlaminar epidural corticosteroid injection. In addition, in a subanalysis, we aim to assess the rate of inadvertent dural puncture superior to C5-C6 occurring during interlaminar epidural corticosteroid injection using CT fluoroscopy guidance because such injections are not performed using conventional fluoroscopy.Images obtained from consecutive CT fluoroscopy-guided cervical interlaminar epidural corticosteroid injections conducted from November 2009 to November 2015 were reviewed. The following information was recorded: the presence of inadvertent dural puncture, the level of the cervical interlaminar space, approach laterality (left or right), anteroposterior spinal canal diameter, and the presence of a trainee. Two-tailed Fisher exact tests were used for assessment of categoric variables, and t tests were used for continuous variables.A total of 974 cervical interlaminar epidural corticosteroid injections were identified in 728 patients. Inadvertent dural punctures were identified in association with 1.4% (14/974) of these injections; all punctures were recognized during the procedure. Needle placements were performed at every cervical level (C1-C2 through C7-T1). The highest rate of dural puncture (2.8%) occurred at C5-C6. No dural punctures occurred superior to C5-C6 (16.6% of cases). The complication rate was 0.4%. Only greater anteroposterior spinal canal diameter was associated with increased dural puncture rates (p = 0.049).CT fluoroscopy-guided cervical interlaminar epidural corticosteroid injections were performed at all levels throughout the cervical spine. A very low complication rate and a minimal rate of inadvertent dural puncture were noted, similar to previously reported rates for conventional fluoroscopy-guided injections limited to the lower cervical spine only.

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( NACC1 ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 −14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1 .

The objective of our study was to determine whether the presence of individual imaging signs of spontaneous intracranial hypotension (SIH) is correlated with increasing duration of headache symptoms. Of particular interest is the relationship of symptom duration to dural enhancement because it is the most commonly identified imaging sign in patients with SIH.Eighty-nine patients with SIH who underwent pretreatment brain MRI and total-spine CT myelography and whose medical record included data on the duration of clinical symptoms were included in this cross-sectional retrospective study. Brain imaging was reviewed for the presence of dural enhancement, brain sagging, and the "venous distention" sign. CT myelograms were assessed for CSF leak. If present, a leak was subcategorized as a high-flow or low-flow leak. Differences in headache duration between subjects with and those without individual imaging signs were compared.Subjects without dural enhancement on brain MRI had a longer average duration of symptoms than those with dural enhancement present (average symptom duration: 45.3 ± 59.0 [SD] vs 15.1 ± 33.0 weeks, respectively; p = 0.002). No difference in symptom duration was observed between subjects whose MRI studies showed and those whose MRI studies did not show brain sagging (p = 0.10) or the venous distention sign (p = 0.21). The presence of a CSF leak on CT myelography was not associated with symptom duration (p = 0.56) except in the subgroup of patients with low-flow leaks.Increasing symptom duration in SIH is associated with decreased prevalence of abnormal dural enhancement on brain MRI. Because dural enhancement is considered a hallmark imaging feature of this condition, its absence may exacerbate the problem of underdiagnosis in chronic cases of SIH.

Spontaneous intracranial hypotension (SIH) is a clinical syndrome that is increasingly recognized as an important and treatable secondary cause of headaches. Insight into the condition has evolved significantly over the past decade, resulting in a greater understanding of the underlying pathophysiology, development of new diagnostic imaging tools, and a broadening array of targeted treatment options. This article reviews the clinical presentation and pathogenesis of SIH, discusses the important role of imaging in diagnosis, and describes how imaging guides treatment.

Objectives Spontaneous intracranial hypotension (SIH) is a pathologic state of low CSF volume caused by a CSF to venous fistula or CSF leak. It is diagnosed based on symptoms, imaging, and CSF pressure but is often a diagnostic challenge because no single test is highly sensitive. Physician-induced changes in CSF volume may result in changes in patient symptoms, as has been shown with idiopathic intracranial hypertension (IIH). The purpose of this study is to determine the sensitivity of CSF volume provocation maneuvers in the diagnosis of SIH. Patients and Methods We reviewed consecutive patients that underwent lumbar puncture from January 2015 to January 2017. Patients were included if they met ICHD3 criteria for SIH and CSF volume provocation maneuvers were performed. Cases were considered concordant if there was improvement of symptoms with addition of CSF. Results 1084 patients underwent 2250 CT-guided lumbar punctures from January 2015 to January 2017. 92 patients with SIH were identified and 62 of these patients underwent CSF volume provocation maneuvers. 58% (36/62) had concordant lumbar puncture encounters with symptom improvement upon addition of artificial CSF. Conclusion CSF volume provocation maneuvers demonstrate 58% sensitivity for identifying patients with SIH, better than those reported for CSF opening pressure and myelography. A positive symptomatic response to CSF volume provocation maneuvers was independent of the other objective tests used for SIH and may aid in the often-challenging diagnostic workup of these patients. Future prospective case-controlled studies are needed.

Spontaneous intracranial hypotension is caused by spinal CSF leaks, but the site of the leak is not always detected on spinal imaging. We report on the additional value of decubitus positioning during CT myelography in enhancing the detection of subtle leaks.

This article reviews the role of imaging in the diagnosis, management, and treatment of spontaneous intracranial hypotension (SIH). SIH is a debilitating and often misdiagnosed condition caused by either a spinal cerebrospinal fluid (CSF) leak or a CSF to venous fistula. This pathologic condition is identified and localized via spinal imaging, including computed tomographic (CT) myelography, dynamic myelography, dynamic (ultrafast) CT myelography, MR imaging, or MR myelography with intrathecal gadolinium. Treatment of SIH involves conservative measures, surgery, or imaging-guided epidural blood patching.

Myelopathy refers to any pathologic process that involves the spinal cord, and can be caused by a variety of different diseases. MR imaging is the primary modality for evaluating the patient presenting with myelopathy. The first step must be the exclusion of spinal cord compression. Although the MR features of many causes of myelopathy overlap, careful attention to the time course of presentation, knowledge of common and uncommon causes of myelopathy, and identification of specific imaging patterns and features can help narrow the differential diagnosis or establish a definitive diagnosis.

BACKGROUND Cerebrospinal fluid-venous fistula (CVF) is a recently described cause of spontaneous intracranial hypotension (SIH). Surgical ligation of CVF has been reported, but clinical outcomes are not well described. OBJECTIVE To determine the clinical efficacy of surgical ligation for treatment of CVF. METHODS Outcomes metrics were collected in this prospective, single-arm, cross-sectional investigation. Inclusion criteria were as follows: diagnosis of SIH, demonstration of CVF on myelography, and surgical treatment of CVF. Pre- and postoperative headache severity was assessed with the Headache Impact Test (HIT-6), a validated headache scale ranging from 36 (asymptomatic) to 78 (most severe). Patient satisfaction with treatment was measured with Patient Global Impression of Change (PGIC). RESULTS Twenty subjects were enrolled, with mean postoperative follow-up at 16.0 ± 9.7 mo. All CVFs were located in the thoracic region (between T4 and T12). Pretreatment headache severity was high (mean HIT-6 scores 65 ± 6). Surgical treatment resulted in marked improvement in headache severity (mean HIT-6 change of -21 ± -9, mean postoperative HIT-6 of 44 ± 8). Of subjects with baseline headache scores in the most severe category, 83% showed a major improvement in severity (transition to the lowest 2 severity categories) after surgery. All subjects (100%) reported clinically significant levels of satisfaction with treatment (PGIC score 6 or 7); 90% reported the highest level of satisfaction. There were no short- or long-term complications or 30-d readmissions. CONCLUSION Surgical ligation is highly effective for the treatment of SIH due to CVF. Larger controlled trials with longer follow-up period are indicated to better assess its long-term efficacy and safety profile.

BACKGROUND AND PURPOSE: Inadvertent intrafacet injection can occur during interlaminar epidural steroid injection, resulting in a false-positive loss of resistance and nontarget injection of medication. The purpose of this investigation was to compare the observed rates of this phenomenon during lumbar interlaminar epidural steroid injection performed by using conventional fluoroscopic and CT fluoroscopic guidance. MATERIALS AND METHODS: We retrospectively reviewed 349 lumbar interlaminar epidural steroid injections performed by using conventional fluoroscopy or CT fluoroscopic guidance to determine the observed rates of inadvertent intrafacet injection with each technique. Cases of inadvertent intrafacet injection were classified as either recognized or unrecognized by the proceduralist at the time of the procedure. Multivariate logistic regression was used to determine the independent effect of imaging guidance technique, age, and sex. RESULTS: The rate of inadvertent intrafacet injection was observed to be 7.5% in the CT fluoroscopic group and 0.75% in the conventional fluoroscopy group. All 16 cases identified from CT fluoroscopic procedures were recognized during the procedure; the single case identified from conventional fluoroscopy procedures was not recognized prospectively. The type of imaging guidance showed a statistically significant effect on the detection of the phenomenon (OR for conventional fluoroscopy versus CT fluoroscopy = 0.10, P = .03) that was independent of differences in age or sex. CONCLUSIONS: Inadvertent intrafacet injection is identified during CT fluoroscopic–guided interlaminar epidural steroid injection at a rate that is 10-fold greater than the same procedure performed under conventional fluoroscopy guidance.

OBJECTIVE. The purpose of this study is to describe the procedure for CT fluoroscopy–guided lumbar medial branch blocks and facet radiofrequency ablation. CONCLUSION. CT fluoroscopic guidance allows more-precise needle tip positioning and is an alternative method for performing medial branch blocks and facet radiofrequency ablation.

BACKGROUND AND PURPOSE: Epidural blood patch treatment of spontaneous intracranial hypotension arising from ventral CSF leaks can be difficult secondary to challenges in achieving ventral spread of patching material. The purpose of this study was to determine the technical success rates and safety profile of direct needle placement into the ventral epidural space via a posterior transforaminal approach. MATERIALS AND METHODS: We retrospectively reviewed consecutive CT fluoroscopy–guided epidural blood patches from June 2013 through July 2015. Cases were included if a posterior transforaminal approach was taken to place the needle directly in the ventral epidural space. Rates of technical success (defined as contrast in the spinal canal ventral epidural space) and optimal epidurogram (defined as contrast spreading into or beyond the middle third of the spinal canal ventral epidural space) were determined. Factors influencing these rates were assessed. All complications, inadvertent intravascular injections, and intrathecal punctures were recorded. RESULTS: A total of 72 ventral epidural blood patches were identified; immediate technical success was achieved in 95.8% and an optimal epidurogram in 47.2%. Needle position within the spinal canal ventral epidural space was associated with obtaining an optimal epidurogram (P = .005). Inadvertent intravascular injection was identified in 29.3% of cases, but all were venous. There were no inadvertent intrathecal punctures or complications. CONCLUSIONS: Direct needle placement in the ventral epidural space via a transforaminal approach for treatment of ventral CSF leaks has an excellent technical success rate and safety profile. This technique can be considered as a treatment option in selected patients with ventral CSF leaks for whom traditional techniques are unsuccessful.

Received September 14, 2015; revised November 5, 2015; accepted November 5, 2015. From Department of Internal Medicine and Psychiatry, Duke University, Durham, NC (JF, XP); Department of Neurology, Duke University, Durham, NC (CL, GB); Department of Neuroradiology, Duke University, Durham, NC (PGK). Send correspondence and reprint requests to Jacob Feigal, M.D., Departments of Internal Medicine and Psychiatry, Duke University Hospital, 2301 Erwin Rd, Durham, NC 27707; e-mail: jacob.feigal@duke.edu & 2016TheAcademy of PsychosomaticMedicine. Published by Elsevier Inc. All rights reserved. Introduction

CT fluoroscopy-guided lumbar spine pain injections typically include a preprocedural planning CT that contributes considerably to patient dose. The purpose of this study was to quantify the degree of radiation exposure reduction achieved by modifying only the planning CT component of the examination.A retrospective review was performed of 80 CT fluoroscopy-guided lumbar spine injections. Forty patients were scanned with a standard protocol using automatic tube current modulation (method A). Another 40 patients were scanned using a new technique that fixed the tube current of the planning CT to either 50 or 100 mA on the basis of the patient's anteroposterior diameter and that reduced the z-axis coverage (method B). Dose-length products (DLPs) were compared for the two methods.The mean maximal tube current for the planning CT was 435.0 mA for method A and 67.5 mA for method B. The mean z-axis was shorter for method B at 6.5 cm than for method A at 9.6 cm (p0.0001). The mean DLP for the planning CT was 11 times lower for method B than for method A: 27.9 versus 313.1 mGy × cm, respectively (p0.0001). When method B was used, the mean DLP for the total procedure (i.e., planning CT plus CT fluoroscopy components) was reduced by 78%. There was no significant difference between methods A and B in CT fluoroscopy time (p = 0.37). All procedures were technically successful.A nearly fivefold reduction in radiation exposure can be achieved in CT fluoroscopy-guided lumbar spine pain injections through modifications to the planning CT alone.

Spontaneous intracranial hemorrhage is a commonly encountered neurologic emergency. Imaging plays important roles in both guiding the emergent stabilization of patients with ICH and in elucidating the etiology of the hemorrhage to prevent rebleeding. A thorough understanding of the factors that have an impact on immediate management, the causes of hemorrhage, and the strengths of various imaging techniques in addressing these 2 concerns is vital to crafting a patient-centered approach to this condition.

The purpose of this study was to assess the rate of inadvertent injection into the retrodural space of Okada during CT fluoroscopy-guided interlaminar epidural steroid injection in the cervical spine.Images from cases of cervical interlaminar epidural steroid injection under CT fluoroscopic guidance performed at a single institution between November 2009 and November 2015 were obtained and reviewed. For all cases, the following information was recorded: presence or absence of contrast material within the Okada space, cervical anatomic level at which the procedure was performed, laterality of approach, trainee presence, and years of proceduralist experience. Two-tailed chi-square tests were used to assess categoric variables, and t tests were performed to assess for continuous variables predictive of nontarget injection.A total of 974 CT fluoroscopy-guided cervical interlaminar epidural steroid injections were identified in 728 patients. The presence of contrast material in the retrodural space of Okada was identified in 2.9% of cases (28/974). All cases of inadvertent injection were identified and corrected intraprocedurally. The greatest rate of inadvertent injection (4.6% [18/389]) occurred at C5-6. No variables predictive of inadvertent injection into the Okada space were identified. There was a 0.4% (4/974) complication rate, and all complications were minor.We identified a 2.9% rate of unintended injection into the retrodural space of Okada during cervical interlaminar epidural steroid injection. If unrecognized, these nontarget injections can result in treatment failure in a subset of patients who undergo cervical interlaminar epidural steroid injection. Future study is warranted to assess the rate of inadvertent Okada injection under conventional fluoroscopy and to compare the rates of detection between the two imaging-guided modalities.

Decisions to limit care, including use of a do-not-resuscitate (DNR) order, are associated with increased risk of death after intracerebral hemorrhage (ICH). Given the value that patient surrogates place on the physician's perception of prognosis, understanding prognostic indicators that influence clinical judgment of outcomes is critical.The purpose of this study was to understand the patient variables and comorbid illnesses associated with DNR orders placed on patients within 72 hours after ICH.Single-center, retrospective review of medical records of 198 consecutive patients with an admission diagnosis of primary supratentorial ICH between July 2007 and December 2010.Patients who did not experience a DNR order placement during their primary admission for ICH (non-DNR group) were compared to patients who received a new DNR order in the first 72 hours of admission (DNR group).Patient characteristics obtained include demographic data, past medical history, clinical data pertaining to the admission for the ICH, and radiographic images. Demographic, medical, and ICH injury data during the first three days of admission were collected.Multiple differences in patient and hospital factors were found between patients receiving a new, early DNR order and those who did not receive a DNR order after ICH. In regression modeling, Caucasian race, direct admission, and higher ICH score were associated with placement of a new DNR order early in the course of injury.Race, transfer procedures, and injury severity may be important factors associated with placement of new, early DNR orders in patients after ICH.

Objective To discuss common myths and misperceptions about spontaneous intracranial hypotension (SIH), focusing on common issues related to diagnosis and treatment, and to review the evidence that contradicts and clarifies these myths. Background Recognition of SIH has increased in recent years. With increasing recognition, however, has come an increased demand for management by neurologists and headache specialists, some of whom have little prior experience with the condition. This dearth of practical experience, and lack of awareness of recent investigations into SIH, produces heterogeneity in diagnostic and treatment pathways, driven in part by outdated, confusing, or unsubstantiated conceptions of the condition. We sought to address this heterogeneity by identifying 10 myths and misperceptions that we frequently encounter when receiving referrals for suspected or confirmed SIH, and to review the literature addressing these topics. Methods Ten topics relevant to diagnosis and treatment SIH were generated by the authors. A search for studies addressing SIH was conducted using PubMed and EMBASE, limited to English language only, peer reviewed publications from inception to 2018. Individual case reports were excluded. The resulting studies were reviewed for relevance to the topics in question. Results The search generated 557 studies addressing SIH; 75 case reports were excluded. Fifty-four studies were considered to be of high relevance to the topics addressed, and were included in the data synthesis. The topics are presented in the form of a narrative review. Conclusions The understanding of SIH has evolved over the recent decades, leading to improvements in knowledge about the pathophysiology of the condition, diagnostic strategies, and expanded treatments. Awareness of these changes, and dispelling outdated misconceptions about SIH, is critical to providing appropriate care for patients and guiding future investigations going forward.

CSF-venous fistula is a recently reported cause of spontaneous intracranial hypotension that may occur in the absence of myelographic evidence of CSF leak. Information about this entity is currently very limited, but it is of potential importance given the large percentage of cases of spontaneous intracranial hypotension associated with negative myelography findings. We report 3 additional cases of CSF-venous fistula and describe the “hyperdense paraspinal vein” sign, which may aid in its detection.

The objective of this study is to describe the anatomic and imaging features of CSF venous fistulas, which are a recently reported cause of spontaneous intracranial hypotension (SIH).We retrospectively reviewed the records of patients with SIH caused by CSF venous fistulas who received treatment at our institution. The anatomic details of each fistula were recorded. Attenuation of the veins involved by the fistula was compared with that of adjacent control veins on CT myelography (CTM). Visibility of the CSF venous fistula on CTM and a modified conventional myelography technique we refer to as dynamic myelography was also compared.Twenty-two cases of CSF venous fistula were identified. The fistulas were located between T4 and L1. Ninety percent occurred without a concurrent epidural CSF leak. In most cases (82%), the CSF venous fistula originated from a nerve root sleeve diverticulum. On CTM, the abnormal veins associated with the CSF venous fistula were seen in a paravertebral location in 45% of cases, centrally within the epidural venous plexus in 32%, and lateral to the spine in 23%. Differences in attenuation between the fistula veins and the control veins was highly statistically significant (p0.0001), with a threshold of 70 HU perfectly discriminating fistulas from normal veins in our series. When both CTM and dynamic myelography were performed, the fistula was identified on both modalities in 88% of cases.CSF venous fistulas are an important cause of SIH that can be detected on both CTM and dynamic myelograph y and may occur without an epidural CSF leak. Familiarity with the imaging characteristics of these lesions is critical to providing appropriate treatment to patients with SIH.