1. Kato S, Maesawa S, Bagarinao E, et al. Magnetic resonance–guided focused ultrasound thalamotomy restored distinctive resting-state networks in patients with essential tremor. J Neurosurg. 2023;138(2):306-317. doi:10.3171/2022.5.JNS22411

Magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy ameliorates symptoms in patients with essential tremor (ET). How this treatment affects canonical brain networks has not been elucidated. The purpose of this study was to clarify changes of brain networks after MRgFUS thalamotomy in essential tremor patients by analyzing resting-state networks (RSNs). Fifteen patients with ET were included in this study. Left MRgFUS thalamotomy was performed in all cases, and MR images, including resting-state functional MRI (rsfMRI), were taken before and after surgery. MR images of 15 age- and sex-matched healthy controls (HCs) were also used for analysis. Using rsfMRI data, canonical RSNs were extracted by performing dual regression analysis, and the functional connectivity (FC) within respective networks was compared among pre-MRgFUS patients, post-MRgFUS patients, and healthy controls. The severity of tremor was evaluated using the Clinical Rating Scale for Tremor (CRST) score pre- and postoperatively, and its correlation with RSNs was examined. Preoperatively, essential tremor patients showed a significant decrease in functional connectivity in the sensorimotor network (SMN), primary visual network (VN), and visuospatial network (VSN) compared with HCs. The decrease in functional connectivity in the sensorimotor network correlated with the severity of tremor. After MRgFUS thalamotomy, essential tremor patients still exhibited a significant decrease in functional connectivity in a small area of the sensorimotor network, but they exhibited an increase in the cerebellar network (CN). In comparison between pre- and post- MRgFUS patients, the functional connectivity in the sensorimotor network and the visuospatial network significantly increased after treatment.

The sensorimotor network and cerebellar network, which are considered to be associated with the cerebello-thalamo-cortical loop, exhibited increased connectivity after MRgFUS thalamotomy. In addition, the FC of the visual network, which declined in essential tremor patients compared with HCs, tended to normalize postoperatively. This demonstrates the possibility of using RSN changes as biomarkers for successful treatment.

5 figures, 4 tables

2. Jamshidi AM, Soldozy S, Levi AD. Percutaneous Direct Pars Repair in Young Athletes. Neurosurgery. 2023;92(2):263-270. doi:10.1227/neu.0000000000002210

Lumbar pars defects are common in adolescent athletes and are often due to recurrent axial loading and traumatic stressors. The objective of the study was to present an updated case series of young athletes who underwent percutaneous direct pars repair after failure of conservative management.

The literature suggests that conservative management should be used for at least 6 months before surgical intervention. In this series of 21 patients, all patients failed conservative management after a mean nonoperative treatment duration of 20.5 ± 9.3 months. These cases were specifically referred from outside institutions for a minimally invasive surgical option after failure of conservative treatment.

A single-center, nonrandomized, retrospective observation study of athletes who were referred for minimally invasive direct pars repair after failure of at least 6 months of conservative management was performed. A total of 21 patients were included (mean age 17.47 years, range 14-25 years), 6 of whom were female (29%). All patients presented with bilateral pars fractures, with L5 being the most frequent level involved (n = 13). The average follow-up time was 31.52 months.

The visual analog scale score for back pain was significantly reduced from 7.62 preoperatively to 0.28 at the final postoperative examination (P < .01). Fusion was noted in 20 of the 21 patients on final follow-up (95%).

They conclude that percutaneous direct pars repair is a safe and effective means in treating young adolescents who have failed conservative management. The advantages included minimized muscle and soft tissue dissection, reduced blood loss, and early mobilization and recovery. In young athletes who desire return to high-level physical activity, this surgical technique is of particular benefit and should be considered in this patient population.

Despite conservative measures, some patients continue to experience pain. Surgical repair of the pars defect can be offered for this small minority of patients who qualify. In this cohort, despite the broad referral area and adherence to minimum conservative treatment periods combined with the 12-year recruitment period, only 21 surgical cases were selected. These facts highlight that the indication for surgery is relatively rare and that most patients respond well to conservative treatment. For those who underwent surgery, a similar return-to-play rate was seen when compared with those patients who were managed conservatively (90.3%vs 92.2%, respectively).

4 figures, 2 tables, with MR, CT, intraop fluoro

3. Schaff LR, Mellinghoff IK. Glioblastoma and Other Primary Brain Malignancies in Adults. (a review) JAMA. 2023;329(7):574. doi:10.1001/jama.2023.0023

Approximately 50% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). MRI before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation.

For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation.

3 figures and 2 tables, including a schematic of Integration of Histological Features and Molecular Alterations in the Revised WHO Classification of Tumors of the Central Nervous System

4. Mantovani A, Garlanda C. Humoral Innate Immunity and Acute-Phase Proteins. N Engl J Med. 2023;388(5):439-452. doi:10.1056/NEJMra2206346

Systemic manifestations of inflammation include fever, alterations in leukocyte counts, cardiovascular reactions, endocrine responses, and reorientation of metabolism in association with increased production of a diverse set of molecules referred to as acute-phase proteins. The prototypic acute-phase protein, C-reactive protein, was originally described as a molecule that was present in the circulation of patients with infections and that was capable of recognizing the C-type polysaccharides of Streptococcus pneumoniae. The appearance of increased levels of acute phase proteins in blood and other body fluids is part of a more complex response to local inflammation or to systemic inflammation (e.g., sepsis) that has been referred to as the acute-phase response, which is characterized by decreased production of albumin by hepatocytes, reorientation of iron metabolism, and hormonal changes.

Innate immunity is a first line of resistance against microbial pathogens and is involved in the activation of adaptive immune responses, as well as in tissue repair. Innate immunity is made up of a cellular arm and a humoral arm. The molecular strategies used by the cellular arm to sense microbial moieties and tissue damage involve cell-associated pattern-recognition molecules located in different cellular compartments (plasma membrane, endosomes, and cytoplasm) and belonging to different molecular families, including toll-like receptors (TLRs), nucleotide- binding oligomerization domain (NOD)–like and retinoic acid–inducible gene I (RIG-I)– like receptors.

The activation of these receptors leads to the expression of cytokines (including interferons and chemokines), adhesion molecules, and antimicrobial effectors or to the scavenging of microbes through phagocytosis. The humoral arm of the innate immune system is made up of different classes of molecules, such as pentraxins, collectins, and ficolins, which functionally act as ancestors of antibodies (anteantibodies) by initiating complement activation, opsonizing microbes and damaged cells, agglutinating or neutralizing microbes, and regulating inflammation.

4 figures, 1 table

5. Hornung AL, Barajas JN, Rudisill SS, et al. Prediction of lumbar disc herniation resorption in symptomatic patients: a prospective, multi-imaging and clinical phenotype study. Spine Journal. 2023;23(2):247-260. doi:10.1016/j.spinee.2022.10.003

Prospective study with patients recruited at a single center study which aimed to identify determinants that may predict early versus late LDH resorption. Ninety-three consecutive patients diagnosed with acute symptomatic LDH were included in this study with a mean age of 48.7 years. LDH resorption was classified as early (<3 months) or late (>3 months) (n=23 early resorption and n=67 late resorption groups). Lumbar MRIs were performed approximately every 3 months for 1 year from time of enrollment to assess disc integrity. A prediction model of pretreatment factors was constructed.

Using four pretreatment clinical factors, a prognostic model was developed to predict the likelihood of disc resorption within 3 months of conservative management consisting of gabapentin, acupuncture, and avoidance of anti-inflammatory medication. The model, which demonstrated good discrimination and excellent overall performance, identified greater L4 posterior vertebral height, greater sacral slope, and greater herniated volume at baseline to be most predictive of early resorption. In contrast, the presence of multiple herniations was associated with a low probability of early resorption. No association with disc degeneration grade, endplate changes including Modic changes, HIZ presence, or osteophytes.

3 figures, 7 tables

6. Fadda G, Flanagan EP, Cacciaguerra L, et al. Myelitis features and outcomes in CNS demyelinating disorders: Comparison between multiple sclerosis, MOGAD, and AQP4-IgG-positive NMOSD. Front Neurol. 2022;13. doi:10.3389/fneur.2022.1011579

Inflammatory myelopathies can manifest with a combination of motor, sensory and autonomic dysfunction of variable severity. Depending on the underlying etiology, the episodes of myelitis can recur, often leading to irreversible spinal cord damage and major long-term disability. Three main demyelinating disorders of the central nervous system, namely multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD), can induce spinal cord inflammation through different pathogenic mechanisms, resulting in a more or less profound disruption of spinal cord integrity. This ultimately translates into distinctive clinical-MRI features, as well as distinct patterns of disability accrual, with a step-wise worsening of neurological function in MOGAD and AQP4+NMOSD, and progressive disability accrual in MS. Early recognition of the specific etiologies of demyelinating myelitis and initiation of the appropriate treatment is crucial to improve outcome.

In this review article the authors summarize and compare the clinical and imaging features of spinal cord involvement in these three demyelinating disorders, both during the acute phase and over time, and outline the current knowledge on the expected patterns of disability accrual and outcomes.

Several elements differentiate the typical imaging features of AQP4+NMOSD from MS. A single, longitudinally extensive lesion (i.e., spanning over three or more vertebral segments) is observed in over 80% of cases, but lesions may appear short in 14% of cases, particularly when imaged during the phase of development or resolution. During myelitis attacks, T1-hypointensity can be observed even with conventional sequences, in contrast to the typical T1 isointensity observed in MS or MOGAD spinal cord lesions. Lesions in AQP4+NMOSD predominantly appear centrally located on axial views. Cervical lesions may sometimes extend rostrally to involve the medulla. Gadolinium enhancement is present in almost all myelitis lesions acutely, with variable patterns but typically localizing at lesion margin, with ring or elongated ring enhancement pattern observed in about 30% of cases. A characteristic imaging finding is the presence of bright spotty lesions, defined as areas of higher T2-hyperintensity within the spinal cord lesion that are comparable to the signal intensity of CSF. This finding has shown specificity for AQP4+NMOSD of 94% vs. a range of inflammatory and non-inflammatory myelopathies, and a sensitivity of 40%.

2 tables, 4 figures with MRI

7. Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Autoimmune Encephalitis Misdiagnosis in Adults. JAMA Neurol. 2023;80(1):30. doi:10.1001/jamaneurol.2022.4251

This retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), Washington University in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age 18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.

A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). MRI of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-D-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]).

When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered, and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria.

1 figure, 3 tables

8. Xu Y, Cheng L, Yuan L, Yi Q, Xiao L, Chen H. Progress on Brain and Ocular Lymphatic System. Surguchov A, ed. Biomed Res Int. 2022;2022:1-8. doi:10.1155/2022/6413553

Glymphatic system is mainly composed of three parts: para-arterial CSF influx channel, paravenous ISF efflux channel, and the water channel aquaporin-4 (AQP4) in astrocytes connecting the 2 channels. In 2012, Iliff et al., (J. J. Iliff,M. Wang, Y. Liao et al., Science Translational Medicine, vol. 4, no. 147, p. 147ra111, 2012) used in vivo imaging technology to discover for the first time the way in which CSF and ISF exchange substances and named it the glymphatic system. In brief, CSF flows into the brain through the paraarterial space and exchanges with ISF via AQP4; this type of exchange can drive metabolites and ISF into the paravenous space and then into the CSF circulation or directly through the lymphatic capillaries into the cervical lymphatics.

In 2015, Louveau et al. (Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature [Internet]. 2015; Available from: http://www.nature.com/doifinder/10.1038/nature14432 ) confirmed the existence of MLV. The team stained the entire meninges and found lymphatic vessels that drained CSF into the deep cervical lymph nodes. These vessels clear the brain of metabolites and are responsible for the migration of T cells. In the same year, Aspelund et al. not only found lymphatic vessels in mouse meninges but also studied the distribution of lymphatic vessels in detail and found that the MLV extends down to the base of the skull along the transverse sinus, sigmoid sinus, and nasal vein, as well as branches of the middle and anterior dural arteries. Since then, researchers have confirmed the existence of MLV in fish, rats, and nonprimates. Further study found that although the structure of MLV was similar to peripheral lymphatic vessels to a certain extent, the structure of MLV had a certain uniqueness, which was shown as follows: (1) lack of smooth muscle cells and valve structure, (2) diameter less than the peripheral lymphatic vessels, and (3) responsible for the migration of T-lymphoid immune cells.

4 figures (graphics)

ChatGPT recommended references!

“There have been numerous research papers published on the glymphatic system in recent years. Here are a few key references that are important for understanding the current state of knowledge:

Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., … & Nedergaard, M. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science translational medicine, 4(147), 147ra111. doi: 10.1126/scitranslmed.3003748

Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., … & Nedergaard, M. (2013). Sleep drives metabolite clearance from the adult brain. Science, 342(6156), 373-377. doi: 10.1126/science.1241224

Jessen, N. A., Munk, A. S., Lundgaard, I., & Nedergaard, M. (2015). The glymphatic system: a beginner’s guide. Neurochemical research, 40(12), 2583-2599. doi: 10.1007/s11064-015-1581-6

Kiviniemi, V., Wang, X., Korhonen, V., Keinänen, T., Tuovinen, T., Autio, J., … & LeVan, P. (2016). Ultra-fast magnetic resonance encephalography of physiological brain activity—glymphatic pulsation mechanisms? Journal of cerebral blood flow and metabolism, 36(6), 1033-1045. doi: 10.1177/0271678X15613986

Lukić, I. K., Glunčić, M., Boban, M., & Heffer, M. (2019). Glymphatic system: current concepts and relevance to neurosurgery. World neurosurgery, 126, 605-614. doi: 10.1016/j.wneu.2019.03.215

These papers cover various aspects of the glymphatic system, including its function, regulation, and potential clinical applications.”

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