Diagnostic Utility of 3D Gradient-Echo MR Imaging Sequences through the Filum Compared with Spin-Echo T1 in Children with Concern for Tethered Cord.

BACKGROUND AND PURPOSE: Fatty intrathecal lesions are a cause of tethered cord, and detection of these on spinal MR imaging is paramount. Conventional T1 FSE sequences are the mainstay of detecting fatty elements; however, 3D gradient-echo MR images, volumetric interpolated breath-hold examination/liver acquisition with volume acceleration (VIBE/LAVA), are popular, given the increased motion resistance. We sought to evaluate the diagnostic accuracy of VIBE/LAVA compared with T1 FSE for detection of fatty intrathecal lesions. MATERIALS AND METHODS: In this retrospective, institutional review board-approved study, 479 consecutive pediatric spine MRIs obtained to evaluate cord tethering between January 2016 and April 2022 were reviewed. Inclusion criteria were patients who were 20 years of age or younger who underwent spine MRIs containing both axial T1 FSE and VIBE/LAVA sequences of the lumbar spine. The presence or absence of fatty intrathecal lesions was recorded for each sequence. If fatty intrathecal lesions were present, anterior-posterior and transverse dimensions were recorded. VIBE/LAVA and T1 FSE sequences were evaluated on 2 separate occasions (VIBE/LAVAs first followed by T1 FSE several weeks later) to minimize bias. Basic descriptive statistics compared fatty intrathecal lesion sizes on T1 FSEs and VIBE/LAVAs. Receiver operating characteristic curves were used to determine minimal fatty intrathecal lesion size detectable by VIBE/LAVA. RESULTS: Sixty-six patients were included, with 22 having fatty intrathecal lesions (mean age, 7.2 years). T1 FSE sequences revealed fatty intrathecal lesions in 21/22 cases (95%); however, fatty intrathecal lesions on VIBE/LAVA were detected in 12/22 patients (55%). Mean anterior-posterior and transverse dimensions of fatty intrathecal lesions measured larger on T1 FSE compared with VIBE/LAVA sequences (5.4 × 5.0 mm versus 1.5 × 1.6 mm, respectively; P values = .039 anterior-posterior; .027 transverse). CONCLUSIONS: While T1 3D gradient-echo MR images may have decreased the acquisition time and are more motion-resistant than conventional T1 FSE sequences, they are less sensitive and may miss small fatty intrathecal lesions.

Clinical Evaluation of Scout Accelerated Motion Estimation and Reduction Technique for 3D MR Imaging in the Inpatient and Emergency Department Settings.

BACKGROUND AND PURPOSE: A scout accelerated motion estimation and reduction (SAMER) framework has been developed for efficient retrospective motion correction. The goal of this study was to perform an initial evaluation of SAMER in a series of clinical brain MR imaging examinations. MATERIALS AND METHODS: Ninety-seven patients who underwent MR imaging in the inpatient and emergency department settings were included in the study. SAMER motion correction was retrospectively applied to an accelerated T1-weighted MPRAGE sequence that was included in brain MR imaging examinations performed with and without contrast. Two blinded neuroradiologists graded images with and without SAMER motion correction on a 5-tier motion severity scale (none = 1, minimal = 2, mild = 3, moderate = 4, severe = 5). RESULTS: The median SAMER reconstruction time was 1 minute 47 seconds. SAMER motion correction significantly improved overall motion grades across all examinations (P < .005). Motion artifacts were reduced in 28% of cases, unchanged in 64% of cases, and increased in 8% of cases. SAMER improved motion grades in 100% of moderate motion cases and 75% of severe motion cases. Sixty-nine percent of nondiagnostic motion cases (grades 4 and 5) were considered diagnostic after SAMER motion correction. For cases with minimal or no motion, SAMER had negligible impact on the overall motion grade. For cases with mild, moderate, and severe motion, SAMER improved the motion grade by an average of 0.3 (SD, 0.5), 1.1 (SD, 0.3), and 1.1 (SD, 0.8) grades, respectively. CONCLUSIONS: SAMER improved the diagnostic image quality of clinical brain MR imaging examinations with motion artifacts. The improvement was most pronounced for cases with moderate or severe motion.

Evaluation of Ultrafast Wave-Controlled Aliasing in Parallel Imaging 3D-FLAIR in the Visualization and Volumetric Estimation of Cerebral White Matter Lesions.

BACKGROUND AND PURPOSE: Our aim was to evaluate an ultrafast 3D-FLAIR sequence using Wave-controlled aliasing in parallel imaging encoding (Wave-FLAIR) compared with standard 3D-FLAIR in the visualization and volumetric estimation of cerebral white matter lesions in a clinical setting. MATERIALS AND METHODS: Forty-two consecutive patients underwent 3T brain MR imaging, including standard 3D-FLAIR (acceleration factor = 2, scan time = 7 minutes 50 seconds) and resolution-matched ultrafast Wave-FLAIR sequences (acceleration factor = 6, scan time = 2 minutes 45 seconds for the 20-channel coil; acceleration factor = 9, scan time = 1 minute 50 seconds for the 32-channel coil) as part of clinical evaluation for demyelinating disease. Automated segmentation of cerebral white matter lesions was performed using the Lesion Segmentation Tool in SPM. Student t tests, intraclass correlation coefficients, relative lesion volume difference, and Dice similarity coefficients were used to compare volumetric measurements among sequences. Two blinded neuroradiologists evaluated the visualization of white matter lesions, artifacts, and overall diagnostic quality using a predefined 5-point scale. RESULTS: Standard and Wave-FLAIR sequences showed excellent agreement of lesion volumes with an intraclass correlation coefficient of 0.99 and mean Dice similarity coefficient of 0.97 (SD, 0.05) (range, 0.84-0.99). Wave-FLAIR was noninferior to standard FLAIR for visualization of lesions and motion. The diagnostic quality for Wave-FLAIR was slightly greater than for standard FLAIR for infratentorial lesions (P < .001), and there were fewer pulsation artifacts on Wave-FLAIR compared with standard FLAIR (P < .001). CONCLUSIONS: Ultrafast Wave-FLAIR provides superior visualization of infratentorial lesions while preserving overall diagnostic quality and yields white matter lesion volumes comparable with those estimated using standard FLAIR. The availability of ultrafast Wave-FLAIR may facilitate the greater use of 3D-FLAIR sequences in the evaluation of patients with suspected demyelinating disease.

MRI Shrimp Sign in Cerebellar Progressive Multifocal Leukoencephalopathy: Description and Validation of a Novel Observation.

BACKGROUND AND PURPOSE: There are no validated imaging criteria for the diagnosis of progressive multifocal leukoencephalopathy in the cerebellum. Here we introduce the MR imaging shrimp sign, a cerebellar white matter lesion identifiable in patients with cerebellar progressive multifocal leukoencephalopathy, and we evaluate its sensitivity and specificity. MATERIALS AND METHODS: We first identified patients with progressive multifocal leukoencephalopathy seen at Massachusetts General Hospital between 1998 and 2019 whose radiology reports included the term "cerebellum." Drawing on a priori knowledge, 2 investigators developed preliminary diagnostic criteria for the shrimp sign. These criteria were revised and validated in 2 successive stages by 4 additional blinded investigators. After defining the MR imaging shrimp sign, we assessed its sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: We identified 20 patients with cerebellar progressive multifocal leukoencephalopathy: 16 with definite progressive multifocal leukoencephalopathy (mean, 46.4 [SD, 9.2] years of age; 5 women), and 4 with possible progressive multifocal leukoencephalopathy (mean, 45.8 [SD, 8.5] years of age; 1 woman). We studied 40 disease controls (mean, 43.6 [SD, 21.0] years of age; 16 women) with conditions known to affect the cerebellar white matter. We defined the MR imaging shrimp sign as a T2- and FLAIR-hyperintense, T1-hypointense, discrete cerebellar white matter lesion abutting-but-sparing the dentate nucleus. MR imaging shrimp sign sensitivity was 0.85; specificity, 1; positive predictive value, 1; and negative predictive value, 0.93. The shrimp sign was also seen in fragile X-associated tremor ataxia syndrome, but radiographic and clinical features distinguished it from progressive multifocal leukoencephalopathy. CONCLUSIONS: In the right clinical context, the MR imaging shrimp sign has excellent sensitivity and specificity for cerebellar progressive multifocal leukoencephalopathy, providing a new radiologic marker of the disease.

Clinical, Imaging, and Lab Correlates of Severe COVID-19 Leukoencephalopathy.

BACKGROUND AND PURPOSE: Patients infected with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) can develop a spectrum of neurological disorders, including a leukoencephalopathy of variable severity. Our aim was to characterize imaging, lab, and clinical correlates of severe coronavirus disease 2019 (COVID-19) leukoencephalopathy, which may provide insight into the SARS-CoV-2 pathophysiology. MATERIALS AND METHODS: Twenty-seven consecutive patients positive for SARS-CoV-2 who had brain MR imaging following intensive care unit admission were included. Seven (7/27, 26%) developed an unusual pattern of "leukoencephalopathy with reduced diffusivity" on diffusion-weighted MR imaging. The remaining patients did not exhibit this pattern. Clinical and laboratory indices, as well as neuroimaging findings, were compared between groups. RESULTS: The reduced-diffusivity group had a significantly higher body mass index (36 versus 28 kg/m2, P < .01). Patients with reduced diffusivity trended toward more frequent acute renal failure (7/7, 100% versus 9/20, 45%; P = .06) and lower estimated glomerular filtration rate values (49 versus 85 mL/min; P = .06) at the time of MRI. Patients with reduced diffusivity also showed lesser mean values of the lowest hemoglobin levels (8.1 versus 10.2 g/dL, P < .05) and higher serum sodium levels (147 versus 139 mmol/L, P = .04) within 24 hours before MR imaging. The reduced-diffusivity group showed a striking and highly reproducible distribution of confluent, predominantly symmetric, supratentorial, and middle cerebellar peduncular white matter lesions (P < .001). CONCLUSIONS: Our findings highlight notable correlations between severe COVID-19 leukoencephalopathy with reduced diffusivity and obesity, acute renal failure, mild hypernatremia, anemia, and an unusual brain MR imaging white matter lesion distribution pattern. Together, these observations may shed light on possible SARS-CoV-2 pathophysiologic mechanisms associated with leukoencephalopathy, including borderzone ischemic changes, electrolyte transport disturbances, and silent hypoxia in the setting of the known cytokine storm syndrome that accompanies severe COVID-19.

Brain MR Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary Observations.

Brain multivoxel MR spectroscopic imaging was performed in 3 consecutive patients with coronavirus disease 2019 (COVID-19). These included 1 patient with COVID-19-associated necrotizing leukoencephalopathy, another patient who had a recent pulseless electrical activity cardiac arrest with subtle white matter changes, and a patient without frank encephalopathy or a recent severe hypoxic episode. The MR spectroscopic imaging findings were compared with those of 2 patients with white matter pathology not related to Severe Acute Respiratory Syndrome coronavirus 2 infection and a healthy control subject. The NAA reduction, choline elevation, and glutamate/glutamine elevation found in the patient with COVID-19-associated necrotizing leukoencephalopathy and, to a lesser degree, the patient with COVID-19 postcardiac arrest, follow a similar pattern as seen with the patient with delayed posthypoxic leukoencephalopathy. Lactate elevation was most pronounced in the patient with COVID-19 necrotizing leukoencephalopathy.

Evaluation of Ultrafast Wave-CAIPI MPRAGE for Visual Grading and Automated Measurement of Brain Tissue Volume.

BACKGROUND AND PURPOSE: Volumetric brain MR imaging typically has long acquisition times. We sought to evaluate an ultrafast MPRAGE sequence based on Wave-CAIPI (Wave-MPRAGE) compared with standard MPRAGE for evaluation of regional brain tissue volumes. MATERIALS AND METHODS: We performed scan-rescan experiments in 10 healthy volunteers to evaluate the intraindividual variability of the brain volumes measured using the standard and Wave-MPRAGE sequences. We then evaluated 43 consecutive patients undergoing brain MR imaging. Patients underwent 3T brain MR imaging, including a standard MPRAGE sequence (acceleration factor [R] = 2, acquisition time [TA] = 5.2 minutes) and an ultrafast Wave-MPRAGE sequence (R = 9, TA = 1.15 minutes for the 32-channel coil; R = 6, TA = 1.75 minutes for the 20-channel coil). Automated segmentation of regional brain volume was performed. Two radiologists evaluated regional brain atrophy using semiquantitative visual rating scales. RESULTS: The mean absolute symmetrized percent change in the healthy volunteers participating in the scan-rescan experiments was not statistically different in any brain region for both the standard and Wave-MPRAGE sequences. In the patients undergoing evaluation for neurodegenerative disease, the Dice coefficient of similarity between volumetric measurements obtained from standard and Wave-MPRAGE ranged from 0.86 to 0.95. Similarly, for all regions, the absolute symmetrized percent change for brain volume and cortical thickness showed <6% difference between the 2 sequences. In the semiquantitative visual comparison, the differences between the 2 radiologists' scores were not clinically or statistically significant. CONCLUSIONS: Brain volumes estimated using ultrafast Wave-MPRAGE show low intraindividual variability and are comparable with those estimated using standard MPRAGE in patients undergoing clinical evaluation for suspected neurodegenerative disease.

Validation of Highly Accelerated Wave-CAIPI SWI Compared with Conventional SWI and T2*-Weighted Gradient Recalled-Echo for Routine Clinical Brain MRI at 3T.

BACKGROUND AND PURPOSE: SWI is valuable for characterization of intracranial hemorrhage and mineralization but has long acquisition times. We compared a highly accelerated wave-controlled aliasing in parallel imaging (CAIPI) SWI sequence with 2 commonly used alternatives, standard SWI and T2*-weighted gradient recalled-echo (T2*W GRE), for routine clinical brain imaging at 3T. MATERIALS AND METHODS: A total of 246 consecutive adult patients were prospectively evaluated using a conventional SWI or T2*W GRE sequence and an optimized wave-CAIPI SWI sequence, which was 3-5 times faster than the standard sequence. Two blinded radiologists scored each sequence for the presence of hemorrhage, the number of microhemorrhages, and severity of motion artifacts. Wave-CAIPI SWI was then evaluated in head-to-head comparison with the conventional sequences for visualization of pathology, artifacts, and overall diagnostic quality. Forced-choice comparisons were used for all scores. Wave-CAIPI SWI was tested for superiority relative to T2*W GRE and for noninferiority relative to standard SWI using a 15% noninferiority margin. RESULTS: Compared with T2*W GRE, wave-CAIPI SWI detected hemorrhages in more cases (P < .001) and detected more microhemorrhages (P < .001). Wave-CAIPI SWI was superior to T2*W GRE for visualization of pathology, artifacts, and overall diagnostic quality (all P < .001). Compared with standard SWI, wave-CAIPI SWI showed no difference in the presence or number of hemorrhages identified. Wave-CAIPI SWI was noninferior to standard SWI for the visualization of pathology (P < .001), artifacts (P < .01), and overall diagnostic quality (P < .01). Motion was less severe with wave-CAIPI SWI than with standard SWI (P < .01). CONCLUSIONS: Wave-CAIPI SWI provided superior visualization of pathology and overall diagnostic quality compared with T2*W GRE and was noninferior to standard SWI with reduced scan times and reduced motion artifacts.

Diagnostic Performance of a 10-Minute Gadolinium-Enhanced Brain MRI Protocol Compared with the Standard Clinical Protocol for Detection of Intracranial Enhancing Lesions.

BACKGROUND AND PURPOSE: The development of new MR imaging scanners with stronger gradients and improvement in coil technology, allied with emerging fast imaging techniques, has allowed a substantial reduction in MR imaging scan times. Our goal was to develop a 10-minute gadolinium-enhanced brain MR imaging protocol with accelerated sequences and to evaluate its diagnostic performance compared with the standard clinical protocol. MATERIALS AND METHODS: Fifty-three patients referred for brain MR imaging with contrast were scanned with a 3T scanner. Each MR image consisted of 5 basic fast precontrast sequences plus standard and accelerated versions of the same postcontrast T1WI sequences. Two neuroradiologists assessed the image quality and the final diagnosis for each set of postcontrast sequences and compared their performances. RESULTS: The acquisition time of the combined accelerated pre- and postcontrast sequences was 10 minutes and 15 seconds; and of the fast postcontrast sequences, 3 minutes and 36 seconds, 46% of the standard sequences. The 10-minute postcontrast axial T1WI had fewer image artifacts (P < .001) and better overall diagnostic quality (P < .001). Although the 10-minute MPRAGE sequence showed a tendency to have more artifacts than the standard sequence (P = .08), the overall diagnostic quality was similar (P = .66). Moreover, there was no statistically significant difference in the diagnostic performance between the protocols. The sensitivity, specificity, and accuracy values for the 10-minute protocol were 100.0%, 88.9%, and 98.1%. CONCLUSIONS: The 10-minute brain MR imaging protocol with contrast is comparable in diagnostic performance with the standard protocol in an inpatient motion-prone population, with the additional benefits of reducing acquisition times and image artifacts.

Multiparametric Imaging Analysis: Magnetic Resonance Spectroscopy.

Magnetic resonance spectroscopy (MRS) is a magnetic resonance-based imaging modality that allows noninvasive sampling of metabolic changes in normal and abnormal brain parenchyma. MRS is particularly useful in the differentiation of developmental or non-neoplastic disorders from neoplastic processes. MRS is also useful during routine imaging follow-up after radiation treatment or during antiangiogenic treatment and for predicting outcomes and treatment response. The objective of this article is to provide a concise but thorough review of the basic physical principles, important applications of MRS in brain tumor imaging, and future directions.

Cranial CT with adaptive statistical iterative reconstruction: improved image quality with concomitant radiation dose reduction.

BACKGROUND AND PURPOSE: To safeguard patient health, there is great interest in CT radiation-dose reduction. The purpose of this study was to evaluate the impact of an iterative-reconstruction algorithm, ASIR, on image-quality measures in reduced-dose head CT scans for adult patients. MATERIALS AND METHODS: Using a 64-section scanner, we analyzed 100 reduced-dose adult head CT scans at 6 predefined levels of ASIR blended with FBP reconstruction. These scans were compared with 50 CT scans previously obtained at a higher routine dose without ASIR reconstruction. SNR and CNR were computed from Hounsfield unit measurements of normal GM and WM of brain parenchyma. A blinded qualitative analysis was performed in 10 lower-dose CT datasets compared with higher-dose ones without ASIR. Phantom data analysis was also performed. RESULTS: Lower-dose scans without ASIR had significantly lower mean GM and WM SNR (P = .003) and similar GM-WM CNR values compared with higher routine-dose scans. However, at ASIR levels of 20%-40%, there was no statistically significant difference in SNR, and at ASIR levels of ≥60%, the SNR values of the reduced-dose scans were significantly higher (P < .01). CNR values were also significantly higher at ASIR levels of ≥40% (P < .01). Blinded qualitative review demonstrated significant improvements in perceived image noise, artifacts, and GM-WM differentiation at ASIR levels ≥60% (P < .01). CONCLUSIONS: These results demonstrate that the use of ASIR in adult head CT scans reduces image noise and increases low-contrast resolution, while allowing lower radiation doses without affecting spatial resolution.

Accuracy of the Alberta Stroke Program Early CT Score during the first 3 hours of middle cerebral artery stroke: comparison of noncontrast CT, CT angiography source images, and CT perfusion.

BACKGROUND AND PURPOSE: The Alberta Stroke Program Early CT Score (ASPECTS) is a reliable method of delineating the extent of middle cerebral artery (MCA) stroke. Our aim was to retrospectively compare the accuracy of ASPECTS on noncontrast CT, CT angiography (CTA) source images, and CT perfusion maps of cerebral blood volume (CBV) during the first 3 hours of middle cerebral artery (MCA) stroke. MATERIALS AND METHODS: First-time patients with MCA stroke who presented <3 hours from symptom onset and were evaluated by noncontrast CT/CTA/CT perfusion, had confirmed acute nonlacunar MCA infarct on diffusion-weighted MR imaging (DWI) within 7 days, and had follow-up angiography were included. Patients were excluded for persistent MCA occlusion or stenosis. Two raters through consensus assigned an ASPECTS on the noncontrast CT, CTA source images, and the section-selective (2 x 12 mm coverage) CT perfusion CBV maps. ASPECTS on follow-up DWI served as the reference standard. For each CT technique, the detection rates of regional infarction, the mean ASPECTS, and the linear correlation to final ASPECTS were determined and compared. P values <.05 were considered significant. RESULTS: Twenty-eight patients satisfied the criteria with DWI performed at a mean of 50.3 hours (range, 22-125 hours) post-CT imaging. Of 280 ASPECTS regions, 100 were infarcted on DWI. The accuracy of noncontrast CT, CTA source images, and CT perfusion CBV for detecting regional infarct was 80.0%, 84.3%, and 96.8%, respectively (P < .0001). The mean ASPECTSs of noncontrast CT, CTA source images, CT perfusion CBV, and DWI were 8.4 +/- 1.8, 8.0 +/- 1.8, 6.8 +/- 1.9, and 6.5 +/- 1.8, respectively. The mean noncontrast CT and CTA source image ASPECTS was different from that of DWI (P < .05). Correlation of noncontrast CT, CTA source images, and CT perfusion CBV ASPECTS with final ASPECTS was r(2) = 0.34, r(2) = 0.42, and r(2) = 0.91, respectively. CONCLUSION: In a retrospective cohort of MCA infarcts imaged <3 hours from stroke onset, ASPECTS was most accurately determined on CT perfusion CBV maps.

A randomized clinical trial of valacyclovir in multiple sclerosis.

OBJECTIVE: The human Herpesvirus type-6 (HHV-6) has been implicated in multiple sclerosis (MS). Valacyclovir is an antiviral agent with an excellent safety profile. A two-year placebo-controlled, double-blind study was conducted to (1) ascertain if high-dose, prolonged treatment with valacyclovir would be safe and (2) observe if valacyclovir would delay the progression of MS clinically or by magnetic resonance imaging (MRI). DESIGN/METHODS: Fifty-eight patients were stratified as to severity and randomly assigned to receive valacyclovir (3000 mg/day) or placebo for a period of two years. Patients were followed clinically over the two-year period by means of the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI) and brain MRI scans. Patients underwent routine lab studies every three months. Patients continued on the medication for two years unless they had a sustained progression or repeated exacerbations. RESULTS: No patient discontinued the study due to side effects or toxicity. In Relative Ranking of Progression, time to first attack, attack rate, and time to withdrawal there were trends (but not statistically significant) toward drug effect over placebo in the Severe clinical category. MRI evaluation showed no significant drug effect. CONCLUSIONS: Although not statistically significant, positive trends were detected for acyclovir by clinical measures, but not by MRI.

The pathophysiology of lumbar puncture headache.

The pathophysiology of lumbar puncture headache (LPH) is still unclear. There is evidence that leakage of cerebrospinal fluid (CSF) leads to CSF hypotension, which causes dilation of intracranial veins, resulting in LPH. However, CSF leaks at the skull base are not associated with orthostatic headache; there is poor correlation between recumbent CSF pressure and LPH; and there has been no satisfactory explanation of how venous dilation causes orthostatic headache. We propose the hypothesis that LPH is caused by an abnormal distribution of craniospinal elasticity. Increased compliance at the lumbar end of the spinal CSF space, resulting both from anatomic joining of the subarachnoid to the epidural space and from reduced CSF filling pressure, causes the hydrostatic indifferent point to move caudally, creating additional intracranial hypotension and venous dilation in the erect position. We are, thus, able to explain the orthostatic character of LPH, the fact that spinal but not cranial sites of leakage produce orthostatic headache and the imperfect correlations both between recumbent CSF pressure and LPH and between reduced CSF volume and LPH. The near absence of LPH in the very young and in the elderly relates to the relative stiffness of the epidural space at these ages. Epidural injections of blood or saline give immediate relief by reducing epidural distensibility.

Potential repair of rat spinal cord injuries using stimulated homologous macrophages.

The failure of the adult mammalian central nervous system (CNS) to regenerate after injury has long been viewed as a unique phenomenon resulting from the specific nature of this system. The finding that some CNS axons could be induced to regrow if provided with a permissive environment suggested that this failure is a result, at least in part, of the nature of the postinjury neuronal environment. It was further shown that the involvement of inflammatory cells, particularly macrophages, in postinjury processes in the CNS is limited. We have suggested that, to achieve recovery after injury, the adult mammalian CNS may require the assistance of the same postinjury factors as those involved in the recovery of spontaneously regenerating systems but that its accessibility to such assistance is restricted. Accordingly, we proposed that it might be possible to circumvent the restriction, allowing regeneration to occur. We showed that the implantation of autologous macrophages, which had been prestimulated by exposure to a regenerative (sciatic) nerve, into completely transected spinal cords of adult rats led to partial motor recovery. This treatment intervenes in the postinjury process by simulating in the axotomized CNS the events that occur naturally in spontaneously regenerating systems.

Restricted inflammatory reaction in the CNS: a key impediment to axonal regeneration?

Axons in the central nervous system (CNS) of adult mammals do not regenerate after injury. Mammalian CNS differs in this respect from other mammalian tissues, including the peripheral nervous system (PNS), and from the CNS of lower vertebrates. In most parts of the body, including the nervous system, injury triggers an inflammatory reaction involving macrophages. This reaction is needed for tissue healing; when it is delayed or insufficient, healing is incomplete. The CNS, although needing an efficient inflammatory reaction resembling that in the periphery for tissue healing, appears to have lost the ability to supply it. We suggest that restricted CNS recruitment and activation of macrophages are linked to regeneration failure and might reflect the immune privilege that characterizes the mammalian CNS. As macrophages play a critical role in tissue restoration, and because their recruitment and activation are among the most upstream of the events leading to tissue healing, overcoming the deficiencies in these steps might trigger a self-repair processing leading to recovery after CNS injury.

Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats.

Postinjury recovery in most tissues requires an effective dialog with macrophages; however, in the mammalian central nervous system, this dialog may be restricted (possibly due to its immune-privileged status), which probably contributes to its regeneration failure. We circumvented this by implanting macrophages, pre-exposed ex vivo to peripheral nerve segments, into transected rat spinal cord. This stimulated tissue repair and partial recovery of motor function, manifested behaviorally by movement of hind limbs, plantar placement of the paws and weight support, and electrophysiologically by cortically evoked hind-limb muscle response. We substantiated these findings immunohistochemically by demonstrating continuity of labeled nerve fibers across the transected site, and by tracing descending fibers distally to it by anterograde labeling. In recovered rats, retransection of the cord above the primary transection site led to loss of recovery, indicating the involvement of long descending spinal tracts. Injection of macrophages into the site of injury is relatively non-invasive and, as the cells are autologous, it may be developed into a clinical therapy.