1. Fox MD. Mapping Symptoms to Brain Networks with the Human Connectome. N Engl J Med. 2018;379(23):2237-2245. doi:10.1056/NEJMra1706158.

Single-lesion analysis has been the foundation of clinical neurology and the basis for localization of most neurologic symptoms and behaviors. The traditional neurologic approach to localization of brain function has been by the identification of focal areas of damage, (for example- stroke) that correspond to a symptom or sign, such as paralysis.

It has become apparent that lesion-based localization is sometimes flawed because similar symptoms can result from lesions in different brain locations. For example, most lesions that disrupt language are located outside the left frontal cortex, most lesions that disrupt memory are located outside the hippocampus, and lesions that disrupt social behavior are frequently outside the frontal cortex. Even when the locations of lesions overlap between patients with the same symptom, the site of overlap may not conform to conventional ideas about the function of that part of the brain. For example, brain-stem lesions that cause visual hallucinations overlap in the midbrain and medial thalamus, but these locations have no clear role in vision or visual imagery. The relationship between symptoms and lesion location is therefore not straightforward.

Lesion-based localization is also limited by the fact that many complex symptoms occur in patients without overt brain lesions. Common neurobehavioral and psychiatric conditions, such as delirium, amnesia, autism, and schizophrenia, occur in patients with no obvious brain lesions.

If a complex behavior requires integrated function of multiple connected brain regions, lesions in any of these regions can disrupt behavior and lead to similar symptoms. For example, complex problem solving requires coordinated function of frontal and parietal regions, and lesions in either location degrade performance. Similarly, damage to the connection between regions can cause complex “disconnection” syndromes, while the cortical regions required for the behavior remain intact. This has long been appreciated in the syndrome of alexia without agraphia, in which damage to the connection between visual and language areas disrupts the ability to read while leaving the ability to write intact, but in which there is no damage to language areas of the cortex.

Neurologic symptoms can also result from physiological changes in anatomically intact brain regions that are distant from but connected to the lesion, a phenomenon termed diaschisis. For example, lesions in the brain stem may cause visual hallucinations through remote effects on the extrastriate visual cortex.

Large-scale functional-neuroimaging efforts, such as the Human Connectome Project, have resulted in normative maps of anatomical and functional brain connectivity that surpass previously available models of brain structure and function. These maps are generated with the use of special MRI scanners, cohorts of thousands of persons, and advanced processing algorithms. The result is a detailed wiring diagram of the human brain that is referred to as the human connectome.

The human connectome can be used to determine whether lesions that are at different sites but cause similar symptoms are located within the same brain network. This is an advance over traditional lesion analysis, because the same symptom is often caused by lesions in different locations as a result of the aforementioned connectivity, disconnection, and diaschisis. The combination of lesion location and its locus in a connected network is also an advance over functional neuroimaging, because this approach requires only a static image that localizes the lesion and that can be overlaid on the connectome, rather than requiring specialized scanning in a particular patient.

4 figures

2. Jani RH, Hughes MA, Gold MS, Branstetter BF, Ligus ZE, Sekula RF. Trigeminal Nerve Compression Without Trigeminal Neuralgia: Intraoperative vs Imaging Evidence. Neurosurgery. 2019;84(1):60-65. doi:10.1093/neuros/nyx636.

Vascular compression of the trigeminal nerve has been accepted as the most common cause of classic trigeminal neuralgia (cTN) by the International Headache Society, the International Association for the Study of Pain, and the European Academy of Neurology. With advances in steady-state free precession (SSFP) magnetic resonance imaging (MRI), there is hope that this noninvasive approach could be used to guide surgical interventions for the treatment of trigeminal neuralgia.

Never the less, considerable uncertainty still exists regarding its utility. Consistent with this suggestion, results from a recent cross-sectional study of 135 patients with cTN in which 3.0 T MRI scans were evaluated blindly indicated that while neurovascular contact was prevalent (>75% of patients) on both symptomatic and asymptomatic sides, severe neurovascular contact (ie, displacement or atrophy of the trigeminal nerve) was far more prevalent on the symptomatic (53%) than the asymptomatic (13%) side.

The authors goal was to compare intraoperative and magnetic resonance imaging (MRI) findings of the prevalence and severity of vascular compression of the trigeminal nerve in patients without classical trigeminal neuralgia.

They recruited 27 patients without facial pain who were undergoing microvascular decompression for hemifacial spasm and had undergone high resolution preoperative MRI. Neurovascular contact/compression (NVC/C) by artery or vein was assessed both intraoperatively and by MRI, and was stratified into 3 types: simple contact, compression (indentation of the surface of the nerve), and deformity (deviation or distortion of the nerve).

Intraoperative evidence of NVC/C was detected in 23 patients. MRI evidence of NVC/C was detected in 18 patients, all of whom had intraoperative evidence of NVC/C. Thus, there were 5, or 28% more patients in whom NVC/C was detected intraoperatively than with MRI (Kappa = 0.52); contact was observed in 4 of these patients and compression in 1 patient.

Vascular contact of the trigeminal nerve is a frequent finding in individuals without TN. Importantly, vascular compression and, even more so, vascular deformity of the trigeminal nerve are rare findings in individuals without cTN. However, the level of agreement between high-resolution MRI and intraoperative findings is only moderate.

Commentary on this paper noted:
With a gold standard that is highly subjective (surgical assessment of contact, compression) and virtually impossible to validate in a generalizable way and an imaging assessment that has reported kappa values in the range of .5 (at best moderate agreement) the prospect of arriving at a conclusion that preoperative imaging is a good enough predictor of the presence of vascular compression that it can be used to eliminate MVD as a useful treatment for patients whose vascular compression cannot be demonstrated preoperatively is quite poor. These data do not change our assessment that patients with classic trigeminal neuralgia should not be denied microvascular decompression primarily based on preoperative imaging findings.
3 figures

3. Bevan RJ, Evans R, Griffiths L, et al. Meningeal inflammation and cortical demyelination in acute multiple sclerosis. Ann Neurol. 2018;84(6):829-842. doi:10.1002/ana.25365.

Recent findings suggest that subpial GM lesions of the neocortex, the principal lesion type of the MS cortex, are related, at least in part, to inflammatory activity in the overlying leptomeninges. It has been shown that the degree of meningeal inflammation correlates with
cortical microglial activation, neuritic and neuronal degeneration, and demyelination in primary progressive and secondary progressive MS. Inflammatory cells of the leptomeninges (T and B lymphocytes, plasma cells, and macrophages) are increased in number, can display a semi organized lymphoid-like structure, and are typically seen in the deep cerebral sulci, but are also noted in the leptomeninges of the cerebellum and spinal cord. Lymphoid-like structures (LLSs), which can resemble ectopic B-cell follicles seen in other autoimmune diseases, are observed in models of MS and in approximately 40% of secondary progressive MS cases at postmortem. Cases of progressive MS harboring elevated leptomeningeal immune cell infiltration and LLSs are associated with an early onset, shorter and more aggressive disease course, and more rapid accumulated disability than those in which LLSs could not be identified. More recently, it has also been demonstrated that a signature of immune mediators important in lymphocyte homing and lymphoid neogenesis strongly predicts those people with early MS at risk of extensive neocortical atrophy and magnetic resonance imaging (MRI)-visible cortical lesions.

In this study, tissue blocks from short disease duration MS (n = 12, median disease duration = 2 years), progressive MS (n = 21, disease duration = 25 years), non-diseased controls (n = 11), and other neurological inflammatory disease controls (n = 6) were quantitatively analyzed by immunohistochemistry, immunofluorescence, and in situ hybridization.

Cortical GM demyelination was extensive in some cases of acute MS (range = 1–48% of total cortical GM), and subpial lesions were the most common type (62%). The numbers of activated (CD68+) microglia/macrophages were increased in cases with subpial lesions, and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (p < 0.005). Significant meningeal inflammation and lymphoid-like structures were seen in 4 of 12 acute MS cases. The extent of meningeal inflammation correlated with microglial/macrophage activation (p < 0.05), but not the area of cortical demyelination, reflecting the finding that lymphoid-like structures were seen adjacent to GM lesions as well as areas of partially demyelinated/remyelinated, cortical GM.

They conclude that their findings demonstrate that cortical demyelination, neuronal loss, and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome.

4. Liman TG, Siebert E, Endres M. Posterior reversible encephalopathy syndrome. Curr Opin Neurol. 2019;32(1):25-35. doi:10.1097/WCO.0000000000000640.

This is a nice review (with extensive literature review) of the current knowledge base of PRES.

Posterior reversible encephalopathy syndrome (PRES) refers to a clinical and radiological disease entity that was first described by Hinchey et al. in the ‘New England Journal of Medicine’ in 1996. A reversible subcortical vasogenic brain edema defines the disorder, predominantly involving the parietooccipital region in patients along with acute neurological deficits (e.g. visual disturbances, seizures, headache, altered mental state). Acute endothelial injury with breakdown of the blood-brain barrier (BBB) and subsequent brain edema is thought to cause PRES in the setting of various diseases and conditions, such as renal failure, hypertensive crisis, sepsis, cytotoxic drugs, autoimmune disorders, and preeclampsia or eclampsia. In general, PRES is considered to be reversible (hence the name), both clinically and radiologically with a favorable prognosis if treated fast and adequately, that is by eliminating the underlying toxic condition.

Although clinical conditions and toxins that may cause PRES are numerous, a couple of theories of the pathophysiological mechanisms in PRES have been postulated. The most recognized ‘vasogenic’ theory proposes that a severe increase in blood pressure leads to impaired cerebral autoregulation followed by hyperperfusion, endothelial injury, breakdown of the BBB and secondary vasogenic edema. This theory might be particularly true for severe hypertension that exceeds the upper MAP limit of cerebral autoregulation (>140- 150 mm HG). However, in more than 50% of PRES cases no severe hypertension was found in retrospective studies. Thus, other theories have been proposed, even though the final end path of the syndrome with endothelial dysfunction, subsequent disruption of BBB, local hypoperfusion and vasogenic edema is similar. Proposed theories comprise the ‘cytotoxic’, ‘immunogenic’, and the ‘neuropeptide / cerebral vasoconstriction’ theory.

Bartynski et al. (Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR 2007; 28:1320–1327) were the first to propose the following etiologic categories: immunosuppression chemotherapy, autoimmune disorders, infections/ sepsis, preeclampsia/ eclampsia, and others (acute renal failure, other toxic substance such as cocaine or unknown). In another retrospective study including 151 patients with PRES, the authors reported the following distribution of etiologies: 21% immunosuppression, 19% chemotherapy, 18% eclampsia/ preclampsia, 19% autoimmune disorders, 9% infection / sepsis, 13% other or unknown. In addition, renal dysfunction and/or failure is present in more than 50% all patients with PRES and one of the most frequent comorbidities.

1 Table, 6 Figures.

5. Ismail M, Armoiry X, Tau N, et al. Mothership versus drip and ship for thrombectomy in patients who had an acute stroke: a systematic review and meta-analysis. J Neurointerv Surg. 2019;11(1):14-19. doi:10.1136/neurintsurg-2018-014249.

One treatment pathway is to transfer the patient initially to the nearest primary stroke center capable of initiating IV thrombolysis as early as possible (drip and ship (DS)), thereby lengthening the time to puncture and reperfusion. The second method is to transfer the patient directly to an endovascular-capable stroke center, where the bridging IV thrombolytic therapy is initiated, therefore reducing the time to puncture (mothership (MS)).

The optimal treatment pathway for these patients is not well established. Therefore, the authors aimed to conduct a systematic review and meta-analysis of the published data to determine whether the MS pathway provides better outcomes than DS in patients who have a stroke treated with MT.

Eight studies including 2068 patients were selected, including one study reporting results fully adjusted for baseline characteristics. Patients undergoing MS had better functional independence than those undergoing DS. No difference was found between the treatment pathways in successful reperfusion, symptomatic intracranial hemorrhage, and 90-day mortality.

Patients who had an acute ischemic stroke admitted directly to a comprehensive stroke center (MS patients) with endovascular capacities may have better 90-day outcomes than those receiving DS treatment. However, major limitations of current evidence (ie, retrospective studies and selection bias) suggest a need for adequately powered studies.

2 tables, 3 figures (metad-analysis graphs)

6. GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):56-87. doi:10.1016/S1474-4422(18)30415-0.

Typical GBD paper with tons on numbers. Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognized as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. The authors aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016.

Their estimates suggest that TBI and SCI are severely disabling injuries. The global burden of TBI increased significantly between 1990 and 2016, whereas that of SCI has not changed significantly over time in terms of age-standardized incidence and prevalence. Age-standardized incidence and prevalence of TBI and SCI were high in central Europe, eastern Europe, and central Asia; the incidence and prevalence of SCI were high in North America and western Europe. Specifically, Syria had the highest age-standardized incidence rate of TBI of any country. The incidence rates for SCI were highest in the high SDI regions high-income North America and Western Europe. However, at a country level, Syria had the highest age-standardized incidence rate of SCI, followed by Yemen, Iraq, and Afghanistan.

Addressing the global burden of these conditions requires improved efforts to decrease the causes of SCI and TBI (eg, fall-prevention strategies, reducing alcohol overuse, and improving road safety, all of which could help to prevent injuries or decrease injury severity) and improved access to, and quality of, medical and social care (which could improve survival and reduce morbidity). People with TBI or SCI can have other medical conditions that require close supervision and might benefit from rehabilitation and medical care to reduce disability. Hence, although injury prevention efforts are key, health-care systems should also anticipate a growing burden from caring for people with TBI and SCI. These conditions could necessitate special focus within health-care systems, because they can be medically complex and burdensome for patients, clinicians, and families.

7. Förster A, Al-Zghloul M, Wenz H, Böhme J, Groden C, Alonso A. Gadolinium Leakage in Ocular Structures Is Common in Lacunar Infarction. Stroke. 2019;50(1):193-195. doi:10.1161/STROKEAHA.118.023573.

In acute ischemic stroke, 2 concomitant phenomena caused by blood-brain barrier (BBB) and blood-retina barrier impairment, respectively, have been described on contrast enhanced FLAIR images: the hyperintense acute reperfusion marker (HARM) and gadolinium leakage in ocular structures (GLOS). Both findings are based on the fact that minute concentrations of gadolinium-based contrast agents result in T1 shortening and relative hyperintensity in the cerebrospinal fluid, as well as the fluid of ocular structures, on FLAIR as these share similar T1 relaxation time-constants. Although there is evidence that BBB permeability is increased in patients with lacunar infarction (LI), as well as in small vessel disease in general, the medical literature regarding the presence of HARM in LI is scarce. No reports on GLOS in LI have been published to date. Therefore, the authors sought to investigate the frequency and pattern of (1) HARM, as well as (2) GLOS and the (3) possible association of both phenomena in acute LI patients.

Overall, 24 acute lacunar infarction patients were included. On contrast-enhanced fluid-attenuated inversion recovery, GLOS was observed in 11 (45.8%) patients: in 4 (16.7%) in the anterior chamber only and in 7 (29.2%) in the anterior chamber and vitreous body. In all patients, GLOS was bilateral and symmetrical. In patients with GLOS in the anterior chamber only, the time between initial and follow-up MR was significantly shorter (7.5 hours) compared with patients with GLOS in the anterior chamber and vitreous body (28 hours). Hyperintense acute reperfusion marker could not be demonstrated in any of the patients.

The authors conclude that in acute lacunar infarction patients, unlike hyperintense acute reperfusion marker, GLOS is a frequent finding and shows a similar temporal evolution like in larger ischemic stroke.

2 MR figures, 1 table.

8. Kano H, Matsuo Y, Kubo N, Fujimi S, Nishii T. Spinal Injuries in Suicidal Jumpers. Spine (Phila Pa 1976). 2019;44(1):E13-E18. doi:10.1097/BRS.0000000000002757.

Spinal fractures and dislocations are life-changing injuries and important causes of morbidity and mortality. Spinal injuries are usually associated with high energy trauma. In most patients, the etiology of spinal injuries is an accidental fall or motor vehicle crash. Suicidal behavior, such as jumping from a height, sometimes causes spinal injury. Spinal injuries are seen in half of survivors of suicidal jumping in some series. Survivors of suicidal jumping are known to display common characteristics. They are predominantly male, middle-aged, unemployed, and single. In addition, a large proportion of suicidal jumpers have a psychiatric diagnosis. However, the etiology of spinal injuries in suicidal jumpers is not well understood. The purpose of this study was to investigate the characteristics of spinal injury caused by suicidal jumping.

The authors identified 87 survivors of suicidal jumping who sustained spinal injuries from 2007 to 2016 at Osaka General Medical Center. They compared the demographic data, radiological findings, neurological status, associated injuries, treatments, and mental health conditions between these 87 survivors and 204 nonsuicidal patients with spinal injury.

Suicidal jumpers were predominantly female (67%) and 10 years younger than non-suicidal patients. Mental health problems, mainly schizophrenia and depression, were diagnosed in 77% of suicidal jumpers. Neurological damage from spinal trauma was generally less severe in suicidal jumpers than in non-suicidal patients. Most spinal injuries in suicidal jumpers were located in the thoracic or lumbar spine region (85%). Among comorbid injuries, extremity injuries were highly associated with spine injury in suicidal jumpers. Nearly 70% of suicidal jumpers exhibited extremity injury in contrast to 33% of non-suicidal patients. Approximately, 25% of suicidal jumpers underwent surgical treatment.

They conclude that in this cohort of patients, spinal injuries in suicidal jumpers differed from spinal injuries in non-suicidal patients with regard to sex, age, mental health condition, injury location, neurologic damage, and associated injuries. Most survivors of suicidal jumping were young female patients with mental health problems. They tended to have thoracic and lumbar spine trauma rather than cervical trauma with less severe neurological deficits and a higher incidence of accompanying limb injury.

The authors note that suicide is the eighth most frequent cause of death in Japan, with more than 23,000 fatalities each year, and it is more common in younger generations. Suicide methods vary by sex. Hanging, strangulation, and suffocation are the most common in both sexes. In males, the second most common method is self-poisoning by exposure to gases and vapors, and the third most common method is jumping from a height. In females, jumping from a height is the second most common suicide method in Japan.

9. Zwartbol MHT, van der Kolk AG, Ghaznawi R, van der Graaf Y, Hendrikse J, Geerlings MI. Intracranial Vessel Wall Lesions on 7T MRI. Stroke. 2019;50(1):88-94. doi:10.1161/STROKEAHA.118.022509.

This study had 2 main objectives. First, to study the frequency, distribution, and burden of intracranial vessel wall lesions, assessed by means of intracranial vessel wall–MRI at 7T, in a population of patients with a history of vascular disease and second, to explore possible risk factors of this novel and direct marker of intracranial atherosclerosis (ICAS) and relate these to known ICAS risk factors.

Within the SMART-MR study (Second Manifestations of Arterial Disease-Magnetic Resonance), cross sectional analyses were performed in 130 patients (68±9 years) with assessable 7T intracranial vessel wall–magnetic resonance imaging data. Associations between vascular risk factors and ICAS burden, defined as the total number of vessel wall lesions, were estimated using linear regression analyses with ICAS burden as the dependent variable, adjusted for age and sex.

For MRI, a 7T whole-body system (Philips Healthcare) was used with a volume/transmit coil for transmission and a 32-channel receive head coil (Nova Medical). Intracranial vessel wall imaging was performed with a T1-weighted Magnetization- Prepared Inversion Recovery Turbo Spin Echo sequence, with the following parameters: field-of-view 250×250×190 mm3, acquired resolution 0.8×0.8×0.8 mm3 (reconstructed to 0.49×0.49×0.4 mm3), repetition time/inversion time/echo time 3952/1375/37 ms.

For image assessment, transverse multiplanar reconstructions were made from the T1-weighted Magnetization-Prepared Inversion Recovery Turbo Spin Echo sequence (slice thickness 0.8 mm; no slice gap).

In this cohort of 130 patients with a history of vascular disease, >95% of patients had at least 1 intracranial vessel wall lesion. Risk factors for these vessel wall lesions were older age, higher systolic blood pressure, diabetes mellitus, and increased hemoglobin A1c, apoB, and hs-CRP levels.

A relatively regular distribution of vessel wall lesions was found, with the highest frequency in both distal ICAs and the basilar artery, which is in concordance with previous studies. Most lesions were of the eccentric type, although in the anterior cerebral arteries and vertebral arteries, concentric lesions occurred with a similar frequency. Furthermore, increasing numbers of eccentric lesions were associated with a higher risk of concentric lesions. This finding seems to suggest that concentricity is related to the overall severity of ICAS.

4 Tables, 2 figures, one of which is 7T MR.